module 5 - pharmacotherapy for cardiovascular disorders

Geriatric Pharmacy Review

Module 5: Pharmacotherapy for Cardiovascular Disorders

Copyright 2011 American Society of Consultant Pharmacists

Accreditation Information

ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This home study web activity has been assigned 7 credit hours.

ACPE UPN: 0203-0000-11-095-H01P

Release Date: 7/11/2011

Expiration Date: 7/11/2014

To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the on-line assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.

Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.


Content Experts

Philip M. Hritcko, PharmD, CACP Clinical Pharmacy Specialist VA Connecticut Healthcare System

Michael A. Militello, PharmD, BCPS Clinical Cardiology Specialist The Cleveland Clinic Foundation

Teresa H.Seo, PharmD, BCPS Clinical Manager Cardinal Health Pharmacy Management Hospital of Saint Raphael

C. Michael White, PharmD Assistant Professor of Pharmacy Practice University of Connecticut School of Pharmacy & Co-Director Arrhythmia & Cardiovascular Pharmacology Research Hartford Hospital


Content Expert Disclosures

Faculty Disclosures:

Philip M. Hritcko, PharmD, CACP has no relevant financial relationships to disclose.

Michael A. Militello, PharmD, BCPS has no relevant financial relationships to disclose.

Teresa H.Seo, PharmD, BCPS has no relevant financial relationships to disclose.

C. Michael White, PharmD has no relevant financial relationships to disclose.


Hyperlipidemia and Atherosclerosis

Learning Objectives

By the end of this Review Concept, you should be able to:

•  Describe the epidemiology and etiology of atherosclerosis.

•  Explain the relationship between hyperlipidemia and atherosclerosis.

•  Describe the pathogenesis of atherosclerosis.

•  List medical and pharmacological causes of hyperlipoproteinemia.

•  Differentiate between primary and secondary prevention of hyperlipidemia and atherosclerosis.

•  Explain the role of diet in managing hyperlipidemia.

•  List specific agents used in the treatment of hyperlipidemia.

•  Compare and contrast mechanism, indications, contraindications, adverse reactions, drug interactions, dosing, and monitoring parameters with respect to these agents.


Epidemiology of Atherosclerosis

• Incidence and progression closely associated with age • Leading cause of death in people over age 65 years • Found in 80% of elderly patients

Atherosclerosis is a disorder of the larger arteries that underlies most coronary artery disease and peripheral artery disease of the lower extremities. It is a distinctly age-related disorder, beginning early in life and developing progressively over the life span. It is responsible for the majority of deaths in westernized societies and is by far the leading cause of death in the United States in individuals over age sixty-five. In fact, more than eighty percent of atherosclerotic cardiovascular disease patients are found in this age group.


Etiology of Atherosclerosis

Unmodifiable Risk Factors Modifiable Risk Factors

Male > 45 years Cigare/e smoking

Female > 55 years Hypertension (> 140/90 mmHg)

Family history of pre-‐mature heart disease Obesity* Hypercholesterolemia Low HDL (< 40 mg/dL) Diabetes mellitus Physical inacLvity

*Obesity can be defined based on body mass index (BMI) of 30 kg/m2 or more. Body mass index (BMI) is a mathematical formula to assess body weight relative to height (i.e. BMI = weight in kilograms divided by square of the height in meters) & correlates highly with body fat.

Atherosclerosis appears to be a multifactorial disease. Risk factors for atherosclerosis include heredity, cigarette smoking, dyslipidemia, diabetes mellitus, obesity, physical inactivity, and hypertension. Risk factors are often interrelated.

For example, obesity is associated with hypertension, hypercholesterolemia, and hypertriglyceridemia. Additionally, heredity factors may predispose an individual to hypertension, hyperlipidemia, or diabetes.


Relationship of Hyperlipidemia and Coronary Artery Disease

Low levels of low—density-lipoprotein cholesterol or L-D-L cholesterol appear to be protective against atherosclerosis, while elevated levels may lead to the development of coronary artery disease or coronary heart disease.

Suggestion from epidemiological data and clinical trials is that there is a log-linear relationship between L-D-L-cholesterol and relative risk for coronary artery disease. So for every 30 milligram per deciliter change in L-D-L-cholesterol, the relative risk for coronary heart disease is changed by about 30%.

Because cholesterol and triglyceride levels increase with age, hyperlipidemia is especially important as a risk factor for atherosclerosis in the elderly. Genes associated with inherited hyperlipidemia may accelerate atherosclerotic changes seen with age, leading to premature development of the disease.


Response-to-Injury Theory of Atherogenesis

• Chemical or immunological injury to endothelial cells • Exposure of subendothelial tissue to plasma constituents • Monocyte and platelet adherence - Migration of monocytes into arterial wall to become macrophages - Platelet aggregation and formation of microthrombi • Release of platelet and macrophage secretory products (mitogenic factors, cytokines) • Migration of smooth muscle cells into the intima and subsequent proliferation • Deposition of connective tissue matrix and accumulation of lipid


Response-to-Injury Theory of Atherogenesis

Inflammation is believed to play a major role in the atherosclerotic process. Although various theories have been proposed to explain atherogenesis, one theory that is commonly discussed is the “reaction-to-injury” theory. This theory is based on the premise that the endothelial cells lining the intima are exposed to repeated or continuing chemical and immunological assaults, leading to the progressive loss of this cellular barrier. With subsequent exposure of subendothelial cells to increased concentrations of plasma constituents, a series of events is set into motion: monocyte and platelet adherence, the conversion of monocytes into macrophages, and the formation of microthrombi. Eventually, the secretions of these additional platelets and macrophages, along with other plasma constituents, stimulate the migration of smooth muscle cells into the intima, where they deposit connective tissue.

The connective tissue matrix deposited on the arterial wall accumulates lipid, a process exacerbated by hyperlipidemia. As the lesion slowly progresses, the intima becomes thicker, altering blood flow over the site of injury and putting the endothelial cells at even greater risk. This vicious cycle eventually culminates in a more complicated lesion, which upon rupturing, can result in myocardial infarction or peripheral vascular disorders. Endothelial dysfunction may also contribute this process.


Other Age-Related Factors Implicated in Atherogenesis

• Mitogenic or mutagenic proliferation of smooth muscle cells • Decline of mitotic inhibitors due to failure of smooth muscle control cells • Loss of endothelial cell replication • Altered function of lysosomes to lipid accumulation

Other theories have been proposed to explain the role of aging in atherogenesis. Atherosclerotic lesions may develop from the multiplication of smooth muscle cells, as do benign tumors. Failure of feedback control cells may contribute to this cellular proliferation. Loss of endothelial cell replication could lead to loss of integrity of the endothelial lining of the arterial wall. Altered function of lysosomes, possibly due to lipid overloading, may also be a factor in atherogenesis.


The Role of Hyperlipidemia in Atherogenesis

Hyperlipidemia Atherosclerosis Risk of death from MI

Studies show that the development of atherosclerosis accelerates in direct relation to the degree of hyperlipidemia. Epidemiologic studies have shown a strong correlation with hyperlipidemia and the development of atherosclerosis up to the age of 82 years old. Because most of the coronary heart disease (or C-H-D) events occur in the elderly, and the death rates are highest in the elderly, aggressive risk factor modification is prudent.

The link between elevated cholesterol levels and the development of atherosclerosis is derived from information about genetic disorders in which there is marked elevation of serum L-D-L-cholesterol with development of atherosclerosis in the absence of other C-H-D risk factors.


Patterns of Lipoprotein Elevations in Plasma

Frederick-‐Levy Classifica:on

Category Plasma Lipoprotein

Type I Chylomicrons

Type IIa LDL

Type IIb LDL & VLDL

Type III Chylomicron remnants & LDL

Type IV VLDL

Type V VLDL & Chylomicron

The Frederick-Levy system has been used to classify hyperlipidemic patients in terms of plasma lipoprotein levels. Almost all patients present as Type II-A, II-B or Type IV. Types I, III and V are more characteristic of rare genetic deficiencies. Descriptive terms may also be commonly used to classify lipoprotein disorders. Examples include terms such as Primary Hypercholesterolemia (heterozygous familial and non-familial), Homozygous Familial Hypercholesterolemia, and Hypertriglyceridemia.


Medical Causes of Secondary Hyperlipoproteinemia

Hypothyroidism Diabetes Obstructive liver disease Nephrotic syndrome Chronic renal failure Medications

In addition to excessive dietary intake of cholesterol-rich foods, several medical conditions can produce high serum lipoprotein levels. Endocrine disorders such as hypothyroidism and diabetes mellitus can cause secondary hypolipoproteinemia. Obstructive liver disease and nephrotic syndrome have also been implicated.


Pharmacological Causes of Secondary Hyperlipoproteinemia

05.01.09 Pharmacological Causes of Secondary Hyperlipoproteinemia

Medica:on Poten:al Effect on Lipids

Thiazide diureLcs May Total and LDL cholesterol

Beta blockers May Triglycerides May HDL cholesterol

ProgesLns May Chylomicrons, VLDL cholesterol

Glucocor:coids May Total, VLDL, and LDL cholesterol

Anabolic steroids May Total cholesterol May HDL cholesterol

Cyclosporine May Total and LDL cholesterol

IsotreLnoin May Total cholesterol May HDL cholesterol

Various medications can also have an effect on serum lipoprotein levels. Thiazide diuretics, for example, can increase total and low-density lipoproteins by as much as ten percent. Beta-blockers and anabolic steroids may raise the level of serum low-density lipoproteins and may reduce the level of protective high-density lipoproteins. However, selection of medications must be based on “benefit-to-risk” profile since many cardiac patients may benefit greatly from beta-blocker therapy while many hypertensive patients may benefit from thiazide diuretics.


Coronary Heart Disease (CHD) and CHD Equivalents

• Coronary Heart Disease (CHD) • History of myocardial infarction (MI) • History of unstable angina or stable angina • History of coronary artery procedures (angioplasty or bypass) • Evidence of clinically significant myocardial ischemia

• CHD Equivalents • Peripheral arterial disease • Abdominal aortic aneurysm • Carotid arterial disease (TIA, stroke of carotid origin, or > 50% obstruction of carotid artery) • Diabetes mellitus • 2+ risk factors with 10-year risk for hard CHD > 20%

People with coronary artery disease are at high risk of having subsequent events and require aggressive risk factor modifications, including lipid management. This is true for all patient age groups, especially the elderly. Elderly patients have the highest risk for new and recurrent events.

The National Cholesterol Education Program or NCEP guidelines use a risk assessment strategy for management. A first step is identification of patients who are at high risk, that is, those with C-H-D or C-H-D equivalents. These C-H-D equivalents include comorbid conditions with high rates of cardiovascular events such as noncoronary forms of atherosclerotic disease, including peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease. Diabetes mellitus is considered a C-H-D equivalent, so diabetic patients would also be in this high-risk category.

The presence of multiple risk factors, such as smoking, hypertension, or family history is important in determining a patient’s estimated 10-year risk of myocardial infarction and CHD death.


Risk Factors

Risk factors for CHD*

• Cigarette smoking

• Hypertension (BP 140/90 mmHg or higher or on antihypertensive medication)

• Low HDL cholesterol (< 40 mg/dL)

• Family history of premature CHD (CHD in male first-degree relative < 55 years; CHD in female first-degree relative < 65 years)

• Age (men 45 years or older; women 55 year or older)

*Electronic 10-year risk calculators are available at www.nhlbi.nih.gov/guidelines/cholesterol. (Of note, almost all people with 0 – 1 risk factors have 10 year risk < 10%, so a 10-year risk assessment in these individuals is not necessary).


Risk Factors

Electronic 10-year risk calculators are available from the National Heart, Lung, and Blood Institute and examples are displayed on the screen.

These assessment tools were developed based on epidemiologic data derived from the Framingham heart study. The 10-year risk helps to determine the goal L-D-L cholesterol and when to begin drug therapy in patients with hyperlipidemia.


NCEP ATP III Update Treatment Goals

Adapted from Circulation 2004; 110: 236


NCEP ATP III Update Treatment Goals

Because of the role of lipoproteins in plaque formation, primary prevention of atherosclerosis in individuals without coronary artery disease is directed at the clinical management of hyperlipoproteinemia. All patients 20 years and older should have their total cholesterol checked at least every 5 years. Patients who have already been diagnosed with coronary artery disease would fall into the category of secondary prevention, to help reduce the risk of a future cardiac event.

Several large clinical trials have been published since the 2001 National Cholesterol Education Program Adult Treatment Panel III guidelines (or the NCEP A-T-P III). In 2004, an update to the NCEP A-T-P III guidelines was released in order to incorporate these new study findings with discussion of implications to patient management. Specific lipid-lowering goals are listed in the accompanying table from this document. Therapeutic lifestyle changes (TLC) continue to remain essential in management, and more emphasis was placed on reaching L-D-L cholesterol goals (versus achieving a percentage lowering of L-D-L cholesterol).

Patients are classified into one of 4 categories: High Risk, Moderately High Risk, Moderate Risk, and Lower Risk. Of note, an optional goal of lowering L-D-L cholesterol below 70 milligrams per deciliter is listed for High Risk patients, and recent literature has focused on studying how low the targets should be for optimal outcomes, especially in patients with existing coronary heart disease.


Other Considerations in Managing Hyperlipidemia

Other Considerations in Addition to Lifestyle and LDL Cholesterol Modification:

• Elevated Triglyceride (e.g. > 150 mg/dL) • Low HDL Cholesterol (e.g. < 40 mg/dL)

Highly Sensitive C-reactive Protein (hs-CRP):

• Routine screening is NOT recommended for all patients • Consider measurement in intermediate to high-risk patients

Homocysteine:

• Routine screening is NOT recommended for all patients • Consider measurement in high-risk patients

NCEP ATP III guidelines focus on L-D-L cholesterol reduction, but elevated serum triglycerides (e.g. > 150 mg/dl) and low high-density cholesterol or H-D-L-cholesterol (i.e. < 40 mg/dl) can also play a role in the development of atherosclerosis.

Elevated triglyceride and low H-D-L cholesterol can be linked to diabetes, obesity, and physical inactivity. Lifestyle changes are the best initial steps, with considerations for drug therapy handled on an individual basis. More information is needed on impact of altering these components alone and impact on cardiovascular outcomes.

Of note, patients with an elevated high-density-lipoprotein (or H-D-L) cholesterol, of 60 mg/dL or higher, may have some protection against some of the negative risk factors for cardiovascular risk – the 10-year risk calculator allows subtraction of a point of risk for patients with elevated H-D-L levels. Further study is ongoing to explore potential medications to target H-D-L cholesterol.


Other Considerations in Managing Hyperlipidemia

Some other measurements that may be discussed with patients are C-reactive protein or C-R-P and homocysteine.

CRP is a marker of inflammation that has been shown to predict cardiovascular risk. Highly sensitive assays for C-R-P can detect levels of less than 1, 1 to 3, and greater than 3 milligrams per liter, corresponding to low-, moderate- and high-risk groups for future cardiovascular risk. Addition of C-R-P to standard cholesterol evaluation may provide additional information on risk; however, major infections, trauma, or acute hospitalizations can cause large elevations in C-R-P. Routine screening for C-R-P is NOT recommended for all patients. Measurement may be considered for patients judged to be at intermediate risk by global assessment (10 – 20% risk of C-H-D per 10 years), at the discretion of the patients’ physicians. It is unclear whether directly impacting upon C-R-P will necessarily reduce cardiovascular risk, and future study is warranted.

While NOT entirely conclusive, high levels of homocysteine may be related to an increase risk of cardiovascular disease. Several vitamins serve as cofactors and substrates in homocysteine metabolism, and there may be an inverse relation between levels of such vitamins as folic acid, vitamin B6 and vitamin B12 and homocysteine. It is uncertain whether reducing the level of homocysteine will reduce the risk of cardiovascular diseases.

At this time, routine screening is NOT recommended. High-risk patients may benefit from screening for homocysteine levels, such as those with family history of premature cardiovascular disease or those with malnutrition or malabsorption syndromes. The American Heart Association recommends patients meet the minimum dietary daily requirements for folic acid (400 mcg), vitamin B6 (1.7 mg) and vitamin B12 (2.4 mcg). These nutrients can be obtained by eating vegetables, fruits, legumes, meats, fish and fortified grains and cereals or by supplementation.


Prevention of Atherosclerosis


Prevention of Atherosclerosis

Therapies used in the primary prevention of hyperlipidemia and atherosclerosis have been investigated. The first method of modifying risk for C-H-D is therapeutic life style modification including: change in diet, increase in physical activity, smoking cessation, weight-loss for overweight individuals, and control of high blood pressure.

Dietary modifications in the elderly can be challenging. It is important to decrease intake of fats and cholesterol; however, many elderly patients have diets which are deficient in protein, minerals and vitamins and can be vulnerable to further restrictions in their oral intake. It is essential that dietary modifications are introduced with assistance from health care professionals who understand the complexities of low-fat diets.

The results of some of the drug investigations are shown on your screen. Note that the reduction in the risk of coronary heart disease is approximately twice the reduction in cholesterol level. Studies investigating the secondary prevention of hyperlipidemia have revealed significant reductions in cardiac disease and deaths using statin drug therapy.


Prevention of Atherosclerosis: Dietary Management

For any type of hyperlipidemia, therapeutic lifestyle modifications, especially dietary management, should be considered a first line of defense. National Cholesterol Education Program guidelines for dietary modifications are shown on your screen. Diet therapy must be sustained over a three to six month period before its success can be evaluated. Patients with C-H-D or C-H-D equivalents are NOT required to maintain this diet PRIOR to starting lipid lowering therapy, rather both diet and drug therapy should be initiated together.


Initiating TLC and Drug Therapy

Decisions regarding the treatment of patients with hyperlipoproteinemia are based on the levels of L-D-L cholesterol. This table shows how L-D-L cholesterol levels influence such decisions with respect to patients with and without coronary heart disease and with respect to the 10-year risk assessment. In fasting patients with triglyceride levels below 400, low-density lipoprotein levels may be calculated by subtracting high-density and very low-density lipoprotein levels from total cholesterol. L-D-L cholesterol may be measured directly as well.



Secondary prevention of atherosclerosis in individuals with evidence of coronary artery disease is also directed at the clinical management of hyperlipoproteinemia. Risks versus benefit should be reviewed with patients prior to initiating drug therapy. The usual agents of choice are HMG-CoA reductase inhibitors, also known as “statins.” The choice of statin is dependent on the healthcare professional’s experience and oftentimes on how payment will be made for the medication (e.g. insurance, out of pocket, etc.)

There is much data for simvastatin and pravastatin on secondary prevention benefits, with over 25,000 people studied on simvastatin and 13,173 people studied on pravastatin. In large trials of simvastatin such as the Scandinavian Simvastatin Survival Study (4S) and the Heart Protection Study (HPS) and for pravastatin such as the Cholesterol and Recurrent Events (CARE) and the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID), there were significant reduction in both morbidity and mortality. Atorvastatin and fluvastatin have been investigated in a similar fashion.

Most recently, clinical trials have focused on evaluating intensive lipid lowering, aiming for lower L-D-L cholesterol levelss, to evaluate outcomes in both stable coronary disease patients and in acute cardiac patients.


Specific Agents Used in the Treatment of Hyperlipidemia

Drugs for Lipids • HMG Co-A reductase inhibitors or “statins” • Bile acid sequestrants • Nicotinic acid (niacin) • Fibric acid derivatives • Cholesterol absorption inhibitors

If drug therapy is initiated, the LDL-cholesterol level should be measured at baseline, at 4 - 6 weeks, and then again at 3 months to individualize drug therapy.

Classes of drugs used in the treatment of dyslipidemia include “statins” or HMG CoA reductase inhibitors, bile acid sequestrants, niacin, fibric acid derivatives, and cholesterol absorption inhibitors.

Hormone replacement therapy is NO longer recommended for the treatment of dyslipidemia in women based on the Women’s Health Initiative study findings of increased risk of heart disease, stroke, M-I and breast cancer in those treated with estrogens. The Food and Drug Administration has mandated a black box warning for oral estrogen products to caution against these risks.


Treatment of Hyperlipidemia with HMG Co-A Reductase Inhibitors

Mechanism of Action: Competitive inhibitor of hydroxymethyl glutaryl (HMG) Co-A reductase, thereby affecting the rate-limiting step in cholesterol synthesis

Effect: Decreases cholesterol levels & increases LDL cholesterol catabolism

Indications: Familial hypercholesterolemia, Type IIa and IIb hyperlipidemia, diabetic dyslipidemia, nephrotic dyslipidemia, hypoalphalipoproteinemia

Contraindications: Active hepatic disease

Adverse Effects: Gastrointestinal disturbances, headache, myalgia and myopathy, rash, increased hepatic enzymes (e.g. transaminases). Risk of rhabdomyolysis is increased when combined with certain drugs (e.g. erythromycin, cyclosporine, fibric acid derivatives, azole antifungals)

Drug Interactions: Cyclosporine, niacin, gemfibrozil, erythromycin, warfarin(See package labeling for specific drug-drug interactions)

Monitoring: Fasting lipid profile, transaminases, . Creatine phosphokinase (CK) may be considered if myalgia/myopathy occurs



HMG Co-A reductase inhibitors are generally the best tolerated lipid-lowering drugs, and they are very effective for reducing L-D-L cholesterol levels. Although prospective trials have documented their safety and efficacy, an increased risk of myalgias and muscle weakness has been observed when HMG Co-A reductase inhibitors or “statins” are combined with drugs such as fibrates or cyclosporine. Many of the statins are eliminated by the cytochrome P450 enzyme system, so special care should be taken to minimize these drug interactions and adjust the doses of statins accordingly.

For example, for patients concomitantly on amiodarone or verapamil, the maximum simvastatin dose is 20 mg/day and for patients concomitantly on gemfibrozil, cyclosporine, or danazol, the maximum simvastatin dose is 10 mg/day. It is recommended to AVOID simvastatin if on itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, or nefazodone. See product information for specific drug interaction recommendations.



Baseline lipid profile and transaminase tests should be obtained when starting statin therapy. An increase in tranaminase liver function tests to more than 3 times the upper limit of normal may occur in about 1 to 2% of patients taking higher doses of statins, but development of symptomatic hepatitis is rare. Current recommendations for testing vary (refer to package labeling for specific product recommendations).

Myalgia and muscle weakness may occur, with or without increase in creatinine phosphokinase (or CK). If symptoms of myalgia and muscle weakness occur, then patients should discontinue the statin (and any concomitant fibrate or niacin product) and see their primary care provider. A creatinine kinase (CK) may be measured to compare against a baseline value, if available, although it may NOT always be elevated. If the CK is greater than 5 to 10 times normal, it is recommended to NOT restart therapy. Rarely, rhabdomyolysis and myoglobinemia with renal failure can occur. Patients may notice dark red or “cola”-colored urine that results from excretion of myoglobin in urine. Additionally, a thyroid function test may be performed in patients with complaints of myopathy since hypothyroidism is a risk factor for myopathy.

The elderly may be at risk for myopathy for multiple reasons: advanced age, multiple medications (with potential for drug-drug interactions), lower body weight in some, and multiple disease processes. Other rare side effects have been reported such as memory loss, sleep disturbances, impotence, and gynecomastia. Close monitoring may be necessary when initiating and titrating medications in combination with statins in the elderly.

Additionally, emphasis should be placed on medication adherence. After a year of treatment, up to forty to fifty percent of patients may stop their statin therapy.


Examples of HMG Co-A Reductase Inhibitors

Generic (Brand) Name Dose Range Approximate Dose to Produce 30 – 40% LDL-‐C Reduc:on

AtorvastaLn (Lipitor®) 10 – 80 mg/day 10 mg

FluvastaLn (Lescol®) 20 – 80 mg/day, taken in evening 40 – 80 mg

LovastaLn (Mevacor®) 10– 80 mg/day, taken with evening meal 40 mg

PravastaLn (Pravachol®) 10 – 80 mg/day 40 mg

RosuvastaLn (Crestor®) 5 – 40 mg/day 5 – 10 mg

SimvastaLn (Zocor®) 10 – 80 mg/day, taken in evening 20 – 40 mg

Adapted from Table 1; Circulation 2004; 110; 233.

For new initiation of therapy, consider starting on a statin dose to produce about a 30 – 40% LDL-C reduction (UNLESS lower starting dose may be advised due to situations/conditions that can increase risk of myopathy (e.g. renal impairment, certain drug-drug interactions such as cyclosporine or gemfibrozil, etc). See package insert for additional product information, including monitoring considerations.


Examples of HMG Co-A Reductase Inhibitors

The commercially available HMG Co-A reductase inhibitors are atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, and rosuvastatin. Rosuvastatin and atorvastatin produce the most dramatic reductions in L-D-L cholesterol. Dosages are started and generally adjusted at four-week intervals.


Treatment of Hyperlipidemia with Bile Acid Sequestrants

Mechanism of Action: Bind bile acids, increase conversion of liver cholesterol to bile acids and up-regulate LDL receptors in liver

Effect: Decrease LDL cholesterol (about 20 - 25%) & total cholesterol (about 12 - 25%); Increase triglyceride synthesis (about 10 - 25%) and increase HDL cholesterol

Indications: Type IIa hyperlipidemia

Contraindications: Chronic constipation, hemorrhoids, hiatal hernia, multiple GI complaints

Adverse Effects: Constipation, flatulence, abdominal pain, nausea and vomiting, heartburn, elevation in triglyceride levels

Drug Interactions: Decreased absorption of warfarin, digoxin, thiazide diuretics, ß-blockers, (e.g. propranolol), thyroid hormone. General recommendation is to take all other medications either 2 hours before or 4 hours after to avoid any potential for absorption interactions.


Treatment of Hyperlipidemia with Bile Acid Sequestrants

Bile acid sequestrants provide a non-systemic therapeutic option for patients with complicated hyperlipidemia. These agents bind bile acids, increasing the conversion of liver cholesterol to bile acids and up-regulating L-D-L receptors in the liver.

If the patient can tolerate the common side effects of constipation, bloating, and dyspepsia, bile acid sequestrants can be very effective. However, care must be taken to avoid interactions with medications such as thyroid hormones, warfarin, and digoxin. These agents are NOT ideal for patients with elevated triglyceride levels secondary to their ability to raise serum triglycerides.


Examples of Bile Acid Sequestrants

Cholestyramine Resin (Questran®, Questran Light®*) • Initial dose: 4 gm resin once to twice daily within 1 hour of meals • Maintenance dose: 8 gm resin TID (24 gm/day) • Maximum dose: 24 gm resin/day • Caution in phenylketonuria – Questran Light® contains aspartame

Colestipol (Colestid®) • Initial dose: 5 gm granules once to twice daily within 1 hour of meals • Maintenance dose: 10 gm granules /day • Maximum dose: 30 gm granules/day • Tablet (1 gm) formulation available: initially dosed as 2 gm once to twice daily; usual 2 – 16 gm/day

Colesevelam (WelChol®) • Dose: 3 tablets (625 mg/tab) two times daily or 6 tablets once daily with a meal • Maximum dose: 7 tablets daily (4.375 gm)

Examples of bile acid sequestrants include cholestyramine, colestipol and colesevelam. Dosing with cholestyramine can be confusing. Although a nine-milligram scoop of normal cholestyramine contains four grams of resin, cholestyramine “light” uses a five-milligram scoop that also contains four milligrams of resin. The powder should be mixed with water, highly fluid soups, or pulpy fruit. It is unusual for patients to tolerate more than two scoops in the morning and another two scoops in the evening. Both colestipol and colesevelam are available as tablets, thus improving compliance. Colesevelam is the most recent bile acid sequestrant on the market. It appears to have less adverse G-I effects when compared to the other bile acid sequestrants.


Treatment of Hyperlipidemia with Nicotinic Acid (Niacin)

Mechanism of Action: reduces LDL and VLDL synthesis, HDL catabolism

Effect: Decreases LDL (about 15 - 20%), VLDL, TG (about 20 - 60%), and total cholesterol (about 15 - 30%); Increases HDL (about 10 – 15%)

Indications: Type II, III, IV; familial combined hyperlipoproteinemia

Adverse Effects: Cutaneous flushing, pruritus, rash, abdominal pain, nausea and vomiting, increased liver function tests, uric acid, and fasting glucose, abnormal glucose tolerance test.

Drug Interactions: Decreased effects of hypoglycemic drugs (e.g. insulin, sulfonylureas)

Dosing for Immediate Release Niacin: • Initial: 100 mg TID of immediate release niacin (can double dose at 3 to 7 day intervals to achieve maximally

tolerated maintenance dose), • Usual Target Dose: 1.5 – 6 gm/day in divided doses

• Take with meals; avoid hot drinks around time of niacin dose; Consider using aspirin pre-treatment to reduce flushing

Dosing for Extended Release Niacin (Niaspan®): • Initial: 500 mg at bedtime for 4 weeks, then 1 gm at bedtime for 4 weeks • Maintenance: Adjust dose based on response and tolerance. Increase to maximum of 2 gm/day, but only at

500 mg/day at 4-week intervals • Monitoring: lipoprotein levels, liver function tests, fasting glucose, serum uric acid, compliance


Treatment of Hyperlipidemia with Nicotinic Acid (Niacin)

Nicotinic acid reduces L-D-L cholesterol, V-L-D-Lcholesterol, and elevates H-D-L cholesterol levels. However, its usefulness is limited due to side effects such as flushing and gastrointestinal upset. Pre-treating nicotinic acid with aspirin may decrease the vasodilation or flushing reaction that occurs when starting or increasing the dose. Although the flushing will decrease with time, the symptom will return if the patient is noncompliant with the medication. Longer acting preparations such as Niaspan® are reported to have lower incidence of flushing. Niacin can increase uric acid levels and may worsen glycemic control.


Treatment of Hyperlipidemia with Fibric Acid Derivatives

Mechanism of Action: Increased lipoprotein lipase activity through interactions with peroxisome proliferator-responsive receptor alpha.

Effect: Increases VLDL, LDL catabolism; Decreased cholesterol synthesis and triglycerides

Indications: Treatment of hypertriglyceridemia, Adjunctive therapy for reducing elevated LDL cholesterol, total cholesterol, triglycerides and increase HDL cholesterol.

Contraindications: Hepatic or severe renal insufficiency, gallbladder disease.

Drug Interactions: Increased effects of warfarin, statins, cyclosporine, and bile acid resins binders

Monitoring: Fasting lipid profile, liver function tests. Periodic blood counts recommended during first 12 months of fenofibrate therapy.


Treatment of Hyperlipidemia with Fibric Acid Derivatives

Fibric acid derivatives are very effective in lowering triglyceride levels and moderately effective in raising H-D-L cholesterol levels. The primary benefit of these drugs is to reduce dramatically elevated triglyceride levels in order to decrease the risk of pancreatitis. Recent data suggests that patients with relatively normal L-D-L cholesterol levels and low H-D-L cholesterol levels will benefit from gemfibrozil by reducing mortality.

These agents are used in combination with statins however; cautious monitoring for myopathy and rhabdomyolysis and liver dysfunction is warranted. Use with lower doses of statins to minimize this risk. Gastrointestinal side effects are the most common complaint, especially with gemfibrozil.

Fibric acid agents may increase cholesterol excretion into the bile, leading to cholelithiasis or formation of gallstones - if this is suspected, gallbladder studies should be performed.

Rare hematologic abnormalities may occur (e.g. decrease hematocrit, hemoglobin, white blood cell count, or platelet count); and periodic monitoring of complete blood count is recommended during the first 12 months of therapy.


Examples of Fibric Acid Derivatives

Gemfibrozil (Lopid®):

Initial dose: 600 mg BID (300 mg for patients with renal/hepatic insufficiency) Maximum dose: 600 mg twice daily Administration: 30 minutes before morning and evening meal Adverse Effects: Abdominal pain, diarrhea, nausea and vomiting, rash, myalgia, headache

Fenofibrate (Tricor®):

Initial Dose: 48 to 145 mg per day (available in 48 mg & 145 mg strengths) Maximum Dose: Dose adjusted to patient response, with maximum dose of 145 mg/day Administration: May be taken without regards to meals Adverse Effects: Nausea, constipation, diarrhea, rash, myopathy, gallstones

Examples of fibric acid derivatives are gemfibrozil and fenofibrate. In clinical trials, gemfibrozil has reduced triglycerides by as much as forty percent. Fenofibrate, a newer drug in this class, can be dosed once daily and has a more pronounced effect on lowering serum triglycerides (up to 50%).

Both gemfibrozil and fenofibrate can raise H-D-L cholesterol, ranging from about 10 – 20%.


Treatment of Dyslipidemia with Ezetimibe, A Cholesterol Absorption Inhibitor

Mechanism of Action: Inhibits gastrointestinal absorption of cholesterol, bile acid and phytosterols.

Effect: Lowers serum cholesterol and LDL-cholesterol. LDL-cholesterol is lowered by 20% when used alone, and ezetimibe adds about a 15% reduction when added to an HMG-CoA reductase inhibitor.

Indication: Ezetimibe is indicated for use alone or in combination with HMG-CoA reductase inhibitors as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia, in combination with statins for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid lowering therapies (e.g., LDL apheresis) or if such treatments are not available and as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

Contraindications: Use of ezetimibe in conjunction with an HMG-CoA reductase inhibitor is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases and in patients with moderate to severe hepatic dysfunction or persistently elevated aminotransferases.

The newest lipid-lowering therapy is ezetimibe. It has a unique mechanism of action and is generally well tolerated. Ezetimibe inhibits the absorption of dietary cholesterol and bile acids within the gastrointestinal tract. The mechanism of action is different than that of bile acid resins.

Ezetimibe is indicated for the treatment of high L-D-L and total cholesterol. Used as monotherapy, ezetimibe can lower L-D-L cholesterol by about 20% and when added to a statin, further reductions of L-D-Lcholesterol by about 15% are expected.

Currently, ezetimibe is generally reserved for use in combination with with statins when goal cannot be reached with statin alone. It is also used as a single agent or in place of a statin when a statin cannot be tolerated or significant adverse effects have occurred. Finally, there may be a role in using ezetimibe with low dose statins in patients who cannot tolerate higher doses of statins.



Drug Interactions: Close monitoring required when given with cyclosporine (cyclosporine may increase the absorption of ezetimibe) – clinical significance is unknown. Unknown if concomitant statin threrapy increases risk of rhabdomyolysis. Safety and efficacy is unknown with concomitant fibrate therapy.

Monitoring: Fasting lipid profile

Dose: Take 10 mg once daily without regards to meals. No dosing changes necessary in the elderly patients.

Adverse Effects: GI (flatulence, diarrhea, abdominal pain) most common. Cases of myopathy and rhabdomyolysis have been reported regardless of causality.

Ezetimibe is a compound of the 2-azetidinone class that inhibits absorption of dietary and biliary cholesterol and related phytosterols. It is believed to act at the brush border of the small intestine and result in reduction in hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. The molecular mechanism of ezetimibe remains to be elucidated. Ezetimibe is metabolized to a glucuronide metabolite, which is more potent than ezetimibe in inhibiting cholesterol absorption, but it is not presently known whether ezetimibe, its glucuronide, or both are responsible for the activity.



Ezetimibe does not appear to have effect on plasma concentrations of fat-soluble vitamins. There are few known drug interactions with ezetimibe. Patients being treated with cyclosporine had an increase in the ezetimibe concentration when these drugs were given together, and close monitoring should be employed. In post-marketing experience, cases of myopathy and rhabdomyolysis have been reported with both ezetimibe in combination with statins and as ezetimibe monotherapy – causality is unknown.

Safety and efficacy with concomitant fibrate therapy is unknown – fibrates may increase cholesterol excretion into bile, leading to cholelithiasis, and it is not known whether ezetimibe concomitant therapy increases cholesterol in the gallbladder bile. In pharmacokinetic studies, fenofibrate and gemfibrozil both caused increase in ezetimibe concentrations, but about 1.5-fold and 1.7-fold, respectively, when given concomitantly with ezetimibe.

Most common adverse effects include gastrointestinal side effects such as diarrhea and abdominal pain. Other adverse effects may or may not be related to ezetimibe. The only dose approved is 10 mg daily. There is no dose titration and it can be taken without regards to meals.


Conclusion

• Atherosclerosis is a multifactorial disease, and risk factor identification as well as modification can play an important role in management.

• NCEP ATP III guidelines provide specific recommendations for risk assessment and treatment strategies for hyperlipidemia.

• Therapeutic lifestyle modifications are essential for all hyperlipidemia patients.

• Drug therapy options include statins, bile acid sequestrants, niacin, fibric acid derivatives, and cholesterol absorption inhibitors.

• Careful monitoring, titration of medications, and follow-up is required.

Atherosclerosis is a multifactorial disease, and risk factor identification and risk modification can play an important role. Hyperlipidemia management is important, especially in elderly patients, to reduce risk for cardiovascular events. The NCEP ATP III guidelines provide specific recommendations for risk assessment and treatment strategies. Therapeutic lifestyle modifications such as smoking cessation, dietary modification, and exercise, are essential for all hyperlipidemia patients.

Drug therapy options include statins, bile acid sequestrants, niacin, fibric acid derivatives, and cholesterol absorption inhibitors. Careful monitoring and titration of agents is required. Pharmacists can help patients and other healthcare providers in providing education about the medications, drug-drug interactions, as well as dosing and monitoring considerations.


Resources

For additional information, see:

Abramowicz M, Zuccotti G (eds). Treatment Guidelines from the Medical Letter: Drugs for Lipids. March 2005; 3(31); 15 – 22.

American Heart Association. Heart Disease and Stroke Statistics – 2004 Update. Dallas, Tex.: American Heart Association; 2003. ©2003, American Heart Association.

De Lemos JA, Blazing MA, Wiviott SD, et al. for the A to Z Investigators. Early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292: 1307-1316.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Panel (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497.

Gamble, C. L. (1994). Lipid disorders: Tailoring diet and drug therapy for individual needs. Geriatrics; 49:52-58.


Resources

Grundy SM, Cleeman JI, Merz NB, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227-239.

Kendrach MG, Kelly-Freeman M. Approximate equivalent rosuvastatin doses for temporary statin interchange programs. Ann Pharmacother 2004; 38: 1286 – 1292.

Knopp RH. Drug treatment of lipid disorders. N Eng J Med 1999; 341: 498 – 511.

Ito MK. Should hyperlipidemia in the elderly be treated? AJHP 1996; 53: 2867-72.

Lopez L.Hyperlipidemia. Preparatory Program for the Certification Exam in Geriatric Pharmacy. 1997. Alexandria, VA: American Society of Consultant Pharmacists.

Malinow MR, Bostom AG, Krauss RM. Homocysteine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Ciruclation 1999; 99: 178-182.

National Cholesterol Education Panel (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Panel (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143-3421.


Resources

Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499 – 511.

Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107: 363-369.

Product Information: Crestor® (rosuvastatin) Package Insert. AstraZeneca Pharmaceuticals LP. August 2003. Lescol®/Lescol XL® (fluvastatin/fluvastatin XL) Package Insert; Novartis Pharmaceuticals Corporation. May 2003. Lipitor® (atorvastatin) Package Insert. Pfizer Pharmaceutical. July 2004. Mevacor® (lovastatin) Package Insert. Merck & Company, Inc. November 2004. Pravachol® (pravastatin) Package Insert. Bristol-Myers Squibb. November 2003. Zetia® (ezetimibe) Package Insert. Merck-Schering Plough. March 2005. Zocor® (simvastatin) Package Insert. Merck & Company, Inc. November 2004.

Websites:

Heart Information Network. Drugs Used for the Treatment of Hyperlipidemia. http://www.heartinfo.com/chol_drg.html

Pharmacist’s Letter 2003; Vol. 19; No. 8: (Detail Document #190801, Characteristics of the various statins, Updated 3/2004). Therapeutic Research Center, Stockton, CA. www.pharmacistsletter.com.

The Pathology Guy – Heart Disease http://www.pathguy.com/lectures/heart.htm


Ischemic Heart Disease in the Elderly

Learning Objectives

• By the end of this Review Concept you should be able to:

• Discuss the epidemiology of ischemic heart disease.

• Explain the pathophysiology of ischemic heart disease as it relates to oxygen supply and demand.

• Describe cardiovascular changes that typically occur as a person ages.

• List major risk factors for ischemic heart disease.

• Describe process for diagnosing ischemic heart disease.

• List pharmacotherapeutic options for treating stable ischemic heart disease (focusing on treatment of chronic stable angina).

• Outline the mechanism of action and administration guidelines for the treatment of stable ischemic heart disease with nitrates, beta-blockers and calcium channel blockers.

• Identify other considerations for management of common co-morbidities in patients with ischemic heart disease.


Epidemiology of Ischemic Heart Disease (IHD)

• Ischemic heart disease or coronary heart disease (CHD) is a leading cause of death in the United States • Prevalence increases with age • An estimated 700,000 Americans will have a new coronary attack in a year • About 500,000 Americans will have a recurrent attack in a year

• Lifetime risk of developing CHD after age 40: about 49% in men & about 39% in women

• Chronic stable angina afflicts millions of Americans, with associated annual costs in the tens of billions of dollars


Epidemiology of Ischemic Heart Disease (IHD)

Ischemia can be defined as a lack of oxygen and decreased-to-no blood flow to the heart muscle. Ischemic heart disease, also known as coronary heart disease (CHD), is the leading cause of death in the United States. Ischemic heart disease encompasses a wide-spectrum of conditions, ranging from acute coronary syndromes (i.e. unstable angina or myocardial infarction) to exertion-induced angina and ischemia without clinical symptoms (or “silent” ischemia). About half of patients present initially with chronic stable angina.

It is estimated that 700,000 Americans will have a new coronary attack this year and that about 500,000 will have a recurrent attack. The average age of a person having a first heart attack is about 65.8 years in men and about 70.4 years in women. The lifetime risk of developing CHD after age 40 is about 49% in men and about 39% in women. The incidence of CHD in women lags behind men by about 10 years for total CHD and by about 20 years for more serious clinical events such as MI and sudden death. In women, coronary heart disease rates post-menopause are about 2 –3 fold greater than those of women the same age before menopause.

Treatment strategies are aimed at reducing risk of CHD and its associated morbidity and mortality. The focus of this Module’s pharmacotherapy will be on chronic stable angina. Please refer also to the Acute Coronary Syndromes Module for information on pharmacotherapy for unstable angina and myocardial infarction.


Pathophysiology of Ischemic Heart Disease

Myocardial O2 Supply O2 carrying capability Coronary blood flow

Myocardial O2 Demand Heart Rate Contractility Wall tension

O2 Supply

O2 Demand

The most common presentation of ischemic heart disease is angina pectoris - this term literally means “strangling in the chest.” Angina is a condition that arises when there is an imbalance between supply and demand of oxygen (or O2) to the heart. In a normal heart, there is a continuous match between oxygen requirements of heart and supply by the coronary arteries – so with increased exertion and increased metabolic needs, the body increases delivery of oxygen to heart to meet these demands. Many factors affect this balance between supply and demand, and one of main reason for an imbalance is due to reduced oxygen supply secondary to atherosclerotic narrowings in one or more coronary arteries.

The supply of oxygen to the heart depends on oxygen carrying capacity of the blood (determined by hemoglobin content of blood and systemic oxygenation) and the rate of coronary blood flow. In the absence of anemia or lung disease, the oxygen carrying capacity remains relatively constant. The heart cannot increase its extraction of oxygen on demand (since it is already removing nearly all of the oxygen it can from the blood supply). Changes in coronary blood flow responsible to allow the body to alter oxygen supply to meet increased metabolic demands. The coronary blood flow is proportional to the perfusion pressure of the blood vessels and inversely related to the resistance of the coronary vasculature. Unlike other arterial systems in the body in which the greatest blood flow occurs during systole (or contraction of the heart), the coronary vessels have maximal flow during diastole (or relaxation of the heart).


Pathophysiology of Ischemic Heart Disease

There are three major components to myocardial oxygen demand: ventricular wall stress, heart rate, and contractility. Ventricular wall stress is the force acting on heart muscle fibers, tending to pull them apart & energy is used to oppose this force.

Wall stress is related to intraventricular pressure, radius of the ventricle, and ventricular wall thickness. Compensatory changes can occur to help reduce wall stress such as hypertrophy in conditions of chronic pressure overload. Antihypertensive therapy can reduce ventricular pressure and reduce myocardial oxygen consumption. Heart rate is another major determinant of demand – if heart rate increases, number of contractions & energy expended increases, causing increase in oxygen demand. Slowing heart rate can reduce demand. The last major determinant is heart contractility – a measure of force of the contraction.

In a normal heart, autoregulatory mechanisms exist to adjust myocardial oxygen supply to meet demand. Pathologic changes can occur, such as narrowing due to atherosclerotic plaques or abnormal vascular tone, which can result in mismatch and resultant ischemia.


Cardiovascular Changes with Aging

• Increased vascular stiffness • Decreased heart rate (HR) • Decreased responsiveness to catecholamines • Increased systolic blood pressure • Left ventricular hypertrophy (LVH)

As a person ages, disease processes and biological changes associated with aging itself begin to take their toll on the cardiovascular system. An increase in vascular stiffness is accompanied by an intrinsic slowing of heart rate. The system’s responsiveness to catecholamines begins to decline. Additionally, there is a trend toward increased systolic blood pressure with a concurrent enlargement (or hypertrophy) of the left ventricle over time.


Risk Factors for Ischemic Heart Disease

Unmodifiable Risk Factors Modifiable Risk Factors

Male > 45 years Cigare/e smoking

Female > 55 years Hypertension (> 140/90 mmHg)

Family history of pre-‐mature heart disease • Obesity* • Hypercholesterolemia • Low HDL (< 40 mg/dL) • Diabetes mellitus • Physical inacLvity

*Obesity can be defined based on body mass index (BMI) of 30 kg/m2 or more. Body mass index (BMI) is a mathematical formula to assess body weight relative to height (i.e. BMI = weight in kilograms divided by square of the height in meters) & correlates highly with body fat.

With advances in medicine to prolong survival of patients with coronary heart disease, more elderly Americans are eligible for secondary prevention measures. Individuals without coronary heart disease can also benefit greatly from primary prevention measures to reduce risk of a first cardiac event. Cardiovascular risk factors for ischemic heart disease are highly prevalent in the elderly. Major risk factors for C-H-D include hypertension, cigarette smoking, diabetes, and hypercholesterolemia. Other risk factors are male gender, obesity, family history, age, sedentary lifestyle, and stress.


Diagnosis: History, Physical Examination, Risk Assessment

• Obtain a detailed symptom history • Perform a focused physical exam • Assess patient’s risk factors

Classification of Chest Pain Symptom Complex



Alternative Diagnoses to Angina for Patients with Chest Pain

Adapted from: Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 Guideline update for the management of patients with chronic stable angina – a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002.



While preventive measures are gaining increased attention through practice guidelines and educational initiatives, cardiovascular disease remains the number one killer of Americans. The most common presentation of ischemic heart disease is angina in a majority of patients. Angina can be described as a discomfort in the chest, jaw, shoulder, back or arm. Typically the pain is brought on by physical exertion or emotional stress and is relieved with rest and/or nitroglycerin. A patient’s history may help to ascertain whether the pain might be cardiac or non-cardiac in nature. Some examples of noncardiac chest pain are included above.

In general, diagnosis is begun with a detailed symptom history, focused physical exam, and assessment of risk factors. Most elderly patients will describe typical angina symptoms as above. An increased number of the elderly (compared to younger patients) may present with an atypical manifestation of myocardial ischemia, such as shortness of breath or worsening heart failure during times of myocardial ischemia. These atypical symptoms may be the result of a stiff (or a non-compliant) left ventricle due to left ventricular hypertrophy.

Risk assessment should be performed. Presence of hyperlipidemia, diabetes, hypertension, smoking, and family history of premature CHD indicate major risks for CHD. A past history of cerebrovascular disease or peripheral vascular disease may also be associated with an increased likelihood of CHD.


Diagnosis: Noninvasive and Invasive Testing

• Laboratory tests • Noninvasive testing • Invasive testing

After the history, physical examination, and risk assessment, selected testing is performed to help further with risk assessment and determining probability and severity of cardiac disease. Certain laboratory tests will complement the history in terms of assessing risk factors for CHD such as diabetes.

All patients with symptoms suggestive of heart disease should have a resting 12-lead electrocardiogram (or ECG). Based on a patient’s ECG results, further study may be indicated such as noninvasive exercise testing, either with nuclear imaging, and with or without echocardiography.

Invasive testing, namely cardiac catheterization, is NOT for all patients without prior history of CHD, but rather it is reserved for a very select group.


Laboratory Testing

• Hemoglobin • Fasting glucose • Fasting lipid panel (including total cholesterol, HDL cholesterol, triglycerides and calculated LDL cholesterol)

Initial laboratory tests include hemoglobin, fasting blood glucose and a cholesterol panel. These tests help to rule out anemia as a cause for chest pain, determine if the patient has diabetes (which is a known risk factor for cardiovascular disease), and diagnose hyperlipidemia.

The results of these laboratory tests will help to individualize both pharmacologic and non-pharmacologic treatment.


Cardiovascular Testing: Non-Invasive and Invasive

• Non-Invasive Testing

• Resting ECG • Chest X-Ray • Exercise Treadmill Test (ETT)

• Interpretation without thallium is difficult with bundle branch block (BBB) or LVH. • Patients with respiratory or musculoskeletal disease may have difficulty in reaching target HR. • Addition of adenosine or persantine allows imaging of the cardiovascular system as under circumstances of exercise.

• Dobutamine Stress Echo • Provides a dynamic image of coronary function as it would appear under circumstances of exercise.

Invasive Testing

Cardiac Catheterization with Coronary Angiography • Elderly have only a slightly higher risk of complications than younger patients

There are a number of noninvasive tests that can be performed on patients with known or unknown ischemic heart disease. The most basic of all tests is the 12-lead ECG. All patients with symptoms of ischemic heart disease should have an ECG performed; however, it is important to recognize that the ECG is diagnostic about 50% of the time. Additionally, a chest x-ray should be obtained in patients with symptoms of congestive heart failure to assess for cardiomegaly (enlargement of the heart).


Cardiovascular Testing: Non-Invasive and Invasive

There are several other diagnostic tests for ischemic heart disease. In general, these tests work well for both young and elderly patients, but some limitations exist. Patients with respiratory or musculoskeletal disease may have difficulty reaching the target heart rate required in performing these studies. Patients unable to undergo exercise stress testing may be candidates for perfusion imaging using adenosine or dipyridamole or dobutamine echocardiography.

Cardiac catheterization allows direct visualization of the coronary arteries to determine the precise location of stenosis (or blockage of the arteries). The process involves the use of contrast dye injected into the coronary arteries under fluoroscopy. If a stenotic lesion is located, the physician can determine whether stent placement to open the lesion or medical management is appropriate. Elderly patients who undergo cardiac catheterization with coronary angiography have a slightly higher risk of complications than younger patients, and therefore elderly can benefit as well from catheterization..


Treatment Guidelines

Aspirin and anti-anginals

Beta blockers and blood pressure

Cholesterol and cigarettes

Diet and diabetes

Education and exercise

The American College of Cardiology, American Heart Association, American College of Physicians and the American Society of Internal Medicine have developed guidelines for the treatment of chronic stable angina. The guidelines include an ABCDE pneumonic of the 10 most important treatment elements: aspirin and anti-antianginals, beta-blocker and blood pressure, cholesterol and cigarettes, diet and diabetes, and education and exercise. The following screens will review most of these treatment efforts.

Treatment should be focused on the risk factor modification and therapies to improve ischemia and associated morbidity and mortality.


Pharmacotherapeutic Options for Ischemic Heart Disease

Ischemic Heart Disease: Drug Therapy

Drug Class O2 Supply O2 Demand

Heart Rate Contrac:lity Wall Tension

Nitrates 0

Beta-‐blockers 0 / *

Non-‐DHP CCBs

DHP CCBs 0 / 0 /

Non-DHP CCBs = non-dihydropyridine calcium channel blockers; DHP CCBs = Dihydropyridine calcium channel blockers = increase; = decrease; 0 = no change; *uncertain wall tension change but overall reduction in O2 demand


Pharmacotherapeutic Options for Ischemic Heart Disease

The primary pharmacotherapeutic options used to treat ischemic heart disease are the same for the elderly as for the younger population. Each option has its own advantages and limitations.

Nitrates may help to increase oxygen supply (through coronary vasodilation), but also increase heart rate (reflex tachycardia) and decrease arterial wall tension. Beta-blockers reduce heart rate and contractility, and therefore decrease myocardial oxygen demand overall; however, they may decrease oxygen supply (if there is unopposed alpha-receptor stimulation and hence, vasoconstriction). Nondihydropyridine calcium channel blockers verapamil and dilitiazem may increase oxygen supply (by coronary vasodilation), while reducing heart rate, contractility and wall tension. Dihydropyridine calcium channel blockers may increase both oxygen supply (by coronary vasodilation) and heart rate, while reducing wall tension.

Of note: only long-acting calcium channel blockers are recommended for treatment of chronic angina (due to reports of short-acting calcium channel blockers being associated with increased incidence of myocardial infarction and mortality, possibly due to rapid hemodynamic and blood pressure changes).


Treatment of Stable Ischemic Heart Disease

Nitrates

Mechanism of Action • Biotransformation to nitric oxide (aka endothelium-derived relaxing factor or EDRF). • Nitric oxide increases cGMP, which produces dilation of coronary (improving coronary blood flow) and venous

vessels (decreasing preload). • Nitrates reduce platelet adhesion and aggregation.

Agents and Dose Nitroglycerin

• IV: 5 to 100 mcg/min • SL: 0.4 to 0.6 mg • Transmucosal: 1 to 3 mg every 3-5 hrs • Oral SR: 6.5 to 9 mg TID • Topical: 0.5 to 2 inches QID (to maintain a 10 to 12-hour nitrate free interval)

Isosorbide dinitrate (Isordil®) • SL: 2.5 to 10 mg q 2-4 hrs • Chewable: 5 to 10 mg q 2-4 hrs • Oral: 5 to 60 mg TID (scheduled to maintain a 10 to 12-hour nitrate free interval) • Oral SR: 40 to 80 mg TID (scheduled to maintain a 10 to 12-hour nitrate free interval)

Isosorbide mononitrate • Oral: 5 to 20 mg BID for ISMO®, Monoket® • Oral SR: 30 to 240 mg once daily for Imdur®



Precautions

• Use 10 to 12-hour nitrate free interval for long-acting agents. • Hypotension rarely occurs; however, dehydration may increase risk for hypotension. • Avoid concomitant use of phosphodiesterase inhibitor for erectile dysfunction (e.g. sildenafil, vardenafil, or tadalafil).

Nitrates help increase oxygen supply in ischemic patients by dilating coronary and venous vessels. Biotransformation by denitration liberates nitric oxide, leading to an increase in cyclic guanosine monophosphate or cGMP, which causes vasodilation. Nitroglycerin is typically used for the treatment of acute attacks using quick-onset preparations such as sublingual spray or tablets.

Longer acting products help to decrease the number of chest pain episodes. The most current guidelines recommend the use of these agents as initial therapy with or without a calcium channel blocker when beta-blockers are contraindicated. They are also considered adjunctive therapy when beta-blocker therapy has NOT been successful or if there have been unacceptable side effects to beta-blockers.

To avoid tolerance, therapy with long-acting agents should be interrupted periodically to provide a nitrate-free interval (typically 10 – 12 hours). The extended release or longer acting formulations such as isosorbide mononitrate have specific recommendations to provide a nitrate free interval. Elderly patients using nitrates should also be monitored for hypotension. Concomitant use of phosphodiesterase inhibitor for erectile dysfunction should be avoided.



Beta-Blockers

Mechanism of Action: Reduces heart rate (HR), contractility, and blood pressure leading to a decrease in myocardial O2 demand.

Therapeutic Objective: Target heart rate of 50 to 60 beats/minute, maintaining normotensive blood pressure without angina symptoms, and avoiding/minimizing side effects.

Example Agents and Usual Doses:

• Atenolol (Tenormin®): 25 to 100 mg/day • Metoprolol (Lopressor®, Toprol XL®): 50 to 200 mg/day • Nadolol (Corgard®): 40 to 320 mg/day • Propranolol (Inderal®): 40 to 480 mg/day

• Maximum doses are relative; agents should be dosed to maximum response with little or no adverse effects. Note: routes of elimination when choosing a beta-blocker (i.e. atenolol and nadolol have significant renal elimination).

Precautions

• Use selective agents and monitor patients with PVD, reactive airway disease, or diabetes (NOTE: Loss of B1 or cardio-selectivity occurs with use of higher-doses of beta-selective agents).

• Monitor patients with other interacting concomitant disease states (i.e. heart block, hypotension, symptomatic heart failure).

• AVOID agents with intrinsic sympathomimetic activity (e.g., acebutolol, carteolol, labetolol, penbutolol, pindolol). • AVOID abrupt withdrawal of chronic beta-blocker therapy - these agents may cause a rebound hypertension,

increased heart rate and induce myocardial ischemia.



Beta-blockers help relieve ischemia by reducing heart rate, blood pressure, and ultimately, oxygen demand. Therapeutic objectives include targeting a heart rate of 50 to 60 beats per minute, or the lowest heart rate the patient can tolerate.

Patients with peripheral vascular disease, reactive airway disease (asthma or reactive component with chronic obstructive pulmonary disease), and diabetes should be closely monitored while initiating therapy. Even though beta-blockers may adversely affect lipid profile, they are considered first-line therapy in patients with ischemic heart disease. Agents with intrinsic sympathomimetic activity such as acebutolol and pindolol should be AVOIDED. Additionally, if a patient must discontinue beta-blockers, it is recommended to AVOID abrupt withdrawal of the drug, if possible,so as to prevent rebound tachycardia and hypertension, which could lead to worsening ischemia.



Calcium Channel Blockers (CCBs):

Mechanism of Action • Non-dihydropyridine CCBs (verapamil and dilitiazem) decrease HR, contractility and wall tension. • Dihydropyridine CCBs decrease wall tension. • All CCBs improve oxygen supply and reduce vasospasm.

Precautions • AVOID verapamil and dilitiazem in patients with heart failure, bradycardia, or heart block. • Use dihydropyridines with caution in patients with hypotension, syncope, or peripheral edema. • AVOID short-acting dihydropyridine agents, like nifedipine, in patients with heart disease as it may induce

ischemia, myocardial infarction and stroke.

Calcium channel blockers are used in the treatment of ischemic heart disease because they promote coronary dilation, increase oxygen supply, and prevent vasospasm. These agents are generally considered second-line therapy in patients who have contraindications to beta-blocker therapy, cannot tolerate beta-blocker therapy due to unacceptable side effects, or as add-on therapy in patients not controlled with beta-blockers alone.

Verapamil and dilitiazem decrease heart rate, contractility and arterial wall tension, reducing afterload. These agents are contraindicated in patients with congestive heart failure, bradycardia, or heart block. Dihydropyridine agents primarily decrease wall tension. Dihydropyridines must be used with caution in patients with hypotension, syncope, or peripheral edema.

The immediate release dihydropyridine calcium channel blocker nifedipine should be AVOIDED in patients with active chest pain due to reflex tachycardia and the potential to induce myocardial and cerebral ischemia.



In Patients with Systolic HF: • AVOID verapamil or diltiazem • Consider use of amlodipine or felodipine • Beta-blockers are a good choice in patients stabilized on chronic standard heart failure medications

Patients with Postural Hypotension: • AVOID dihydropyridines • Consider beta-blockers, verapamil or diltiazem (if a nitrate & calcium channel blocker required).

Patients with AV block or Symptomatic Bradycardia: • AVOID verapamil or diltiazem • Consider a dihydropyridine CCB

Combination drug therapy may be necessary for management of ischemic heart disease. Certain combinations are contraindicated when other disease states are involved. For example, in patients with a history of congestive heart failure, calcium channel blockers such as verapamil and diltiazem should be AVOIDED. These agents are negative inotropes and could worsen systolic dysfunction. If a calcium channel blocker is required, amlodipine or felodipine may be used safely as they have not been shown to increase mortality in heart failure. Beta-blockers should be considered, depending on the stage of the disease, since beta-blockers have shown benefits in morbidity and mortality in heart failure. If the patient is hypotensive and requires a nitrate plus calcium channel blocker, consider using verapamil or diltiazem instead of dihydropyridines. If the patient has an atrioventricular block or symptomatic bradycardia, dihydropyridines are preferred.


Anti-Platelet Therapy in Stable Ischemic Heart Disease

Antiplatelet Therapy

Aspirin considered first-line therapy for ischemic heart disease Clopidogrel is option for those unable to take aspirin

Choice of antihrombotic medication in patients with ischemic heart disease depends on the patient’s history (e.g. angina and myocardial infarction, tolerance to medication). Aspirin has been successfully used to treat patients with stable and unstable angina and is considered first-line therapy in ischemic heart disease. Aspirin reduces risk of cardiovascular events by about 33% and may also help prevent recurrent myocardial infarction. Clopidogrel is often substituted in cases where aspirin is contraindicated.

Post-myocardial infarction patients with high embolic risk may receive warfarin in lieu of aspirin. The use of low-intensity warfarin WITH aspirin may be an option in a small set of patients, but this combination is NOT routinely recommended for all ischemic heart disease patients.


Lipid-lowering in Stable Ischemic Heart Disease

• Lipid-lowering therapy should be started or continued in elderly patients.

• Lipid-lowering therapy benefits patients > 65 years of age as well as younger patients.

• Goals of therapy are the same for the elderly as younger patients. • Consider starting with lower doses and titrating to goal. • Monitor patient for complications from medications (e.g. side effects or drug interactions).

The most recent National Cholesterol Education Program guidelines for the detection, evaluation and treatment of high cholesterol recommend that all adult patients at risk for cardiovascular disease should have aggressive cholesterol lowering and risk factor modification. Even though no large clinical trial has included just elderly patients, there are a number of trials that have sufficient data to make the recommendation that patients > 65 years will benefit as well as younger patients.

In the Scandinavian Simvastatin Survival Study (4S), a post hoc analysis showed that patients < 65 years old had a 42% reduction in coronary heart disease mortality. For patients > 65 years, the reduction in mortality was also similar at about 43%.

There is very limited data in patients 75 years or older with respect to the use of statin therapy. Current data from major clinical trials indicate that there does not seem to be a diminishing effect with age. The current National Cholesterol Education Program Adult Treatment Panel III guidelines are recommended for all patients. .


Angiotensin Converting Enzyme Inhibitors in Stable Ischemic Heart Disease

• Ramipril 10 mg daily is indicated to reduce cardiovascular disease associated morbidity and mortality

Recent data from the Heart Outcomes Prevention Evaluation (HOPE) trial suggest that ramipril at 10 mg daily reduces the risk of cardiovascular death, myocardial infarction, and stroke. Additionally, there were fewer complications from diabetes and fewer newly diagnosed diabetics in the 4-year study follow-up period.

Ongoing trials with other ACE-Inhibitors will help to confirm these results. Until then, the current recommendation is that all patients with coronary artery disease who also have diabetes and/or left ventricular systolic dysfunction should be on an ACE-Inhibitor.


Other Considerations: Comorbid Conditions

• Hypertension • Smoking cessation • Diabetes • Obesity • Exercise

A major treatment modality for patients with ischemic heart disease is risk factor modification and control of comorbid conditions. It is important in secondary prevention to include specific strategies to control blood pressure, diabetes, and weight. Emphasis should be placed on increasing physical activity, when possible, as part of the lifestyle modifications to manage ischemic heart disease.


Hypertension

• About half of patients over the age of 60 years have hypertension • Two-thirds of patients are inadequately controlled

• More than one medication is generally needed to manage hypertension • Drug selection is usually based on concomitant disease states • Initial therapy usually includes a beta-blocker and/or thiazide diuretic

Hypertension is common in the elderly population and is a major risk factor for ischemic heart disease, stroke, and peripheral vascular disease. More than 50% of people over the age of 60 years have hypertension, and nearly two-thirds of patients over the age of 75 years have inadequately controlled hypertension.

Management should be the same as for younger people, and this includes lifestyle modifications such as weight reduction in overweight individuals, increased physical activity, decreased sodium intake, and limiting alcohol intake. Drug selection depends on other disease states and generally should include a beta-blockers and thiazide diuretic. Please refer to review the Hypertension Module for more information.


Smoking Cessation

Smoking cessation reduces risk of overall mortality by about 25 - 50% in patients with previous MI

While there is limited data on the impact of smoking cessation in the elderly, information obtained from the Coronary Artery Surgery Study indicates that patients over the age of 70 years who have stopped smoking and have had a bypass surgery had a lower mortality rate. Smoking cessation overall seems to reduce the risk of mortality by about 25 to 50% in patients with a previous myocardial infarction, with most of the benefit occurring within the first year.


Diabetes

• Treatment goals for diabetes are based on American Diabetes Association recommendations

• Target HbA1c < 7%

• ACE-I are recommended (for hypertension and possible renal protection)

Diabetes is a powerful predictor for the occurrence of secondary coronary events in elderly. Oftentimes, patients in this age group also have hypertension, obesity, and other risk factors for ischemic heart disease. Management should include surveillance for the development of diabetes, and treatment goals should be the same as that for younger patients (specifically euglycemia and a target hemoglobin A-1-C of less than 7%). Treatment should include weight reduction, anti-hyperglycemic agents, and exercise. The American Diabetes Association provides specific recommendations and treatment strategies.


Obesity

• Reasonable diet • Regular exercise/activity • Surgical interventions possible (e.g. gastric bypass surgery)

There is little data on the cardiovascular benefit of weight reduction in the elderly population. However, for older men and women, there is a higher degree of coronary artery disease. This is due to the fact that obesity can contribute and may be interrelated to the development of diabetes, hypertension and dyslipidemia. This patient population is also at risk secondary to lower levels of physical activity.

A prudent diet with an increase in physical activity is recommended, even in the elderly.


Exercise

• Monitored/supervised

• Aerobic and anaerobic

Exercise should be tailored to the individual, taking into consideration any comorbid disease states that may limit certain activities, such as arthritis or Parkinson’s disease. Overall, patients should be encouraged to maintain physical activity, including physical conditioning, aerobic activity, and strength training.

It is recommended that these activities be supervised in Cardiac Rehabilitation Centers. Patients should also be reminded of the benefits of walking, and encouraged to walk as frequently as tolerated.


Summary

ABCDEs of Management

Aspirin and anti-anginals Beta blockers and blood pressure Cholesterol and cigarettes Diet and diabetes Education and exercise

Ischemic heart disease involves an imbalance between oxygen supply and demand, and it represents a wide-spectrum of disorders. Diagnosis involves careful history, physical examination, risk assessment, and testing. Most patients will receive aspirin and beta-blockers as first-line therapies in addition to other risk factor modification for chronic stable angina. General treatment strategies for chronic stable angina can be remembered using the ABCDE pneumonic.


Resources


Fein SA, Breisblatt W, Doyle JT, and Singh A. Approach to ischemic heart disease, coronary care, and severe heart failure (including cardiogenic shock). Clin Geriatr Med 1994; 10(1): 145-60.

Frishman WH. Treatment of myocardial ischemia and myocardial infarction in the elderly. South Med J 1993; 86(10): 2S29-37.

Ganz L, Andrews TC, Barry J, and Raby KE. Silent ischemia preceding sudden cardiac death in a patient after vascular surgery. Am Heart J 1994; 127(6): 1652-4.

Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 Guideline update for the management of patients with chronic stable angina – a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002. Available at www.acc.org/clinical/guidelines/stable/stable.pdf.

Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 Guideline update for the management of patients with chronic stable angina – summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). Circulation 2003; 107: 149 – 158.

Keller NM and Feit F. Coronary artery disease in the geriatric population. Progress Cardio Dis 1996; 38(5): 407-18.


Resources

McCully JD, Levitsky S. Myocardial protection in the elderly. biology of the senescent heart. Ann New York Acad Science 1996; 793: 305-18.

Williams MA, Fleg JL, Ades FE, et al. Secondary prevention of coronary heart disease in the elderly (with Emphasis on Patients > 75 Years of Age). Circulation 2002;105:1735-1743.

Sabatine MS, O’Gara PT, Lilly LS. Ischemic Heart Disease. In Lilly LS, ed.: Pathophysiology of heart disease. Baltimore: Williams & Wilkins, 1998.

Talbert RL. Ischemic Heart Disease. In Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. eds.: Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2002, 219-250.

Théroux P, Fuster V. Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation 1998; 97: 1195-1206.

Verdouw PD, Duncker DJ, and Gho BC. Ischaemic preconditioning: is it clinically relevant. Euro Heart J 1995; 16(9): 1169-76.

Websites

http://www.americanheart.org/presenter.jhtml?identifier=2158 for scientific statements and guidelines.


Acute Coronary Syndromes

Learning Objectives

By the end of this Review Concept you should be able to:

• Discuss epidemiology of coronary heart disease.

• Define acute coronary syndromes.

• Describe the underlying pathophysiology of acute coronary syndromes.

• List differences between unstable angina, non-ST elevation myocardial infarction, and ST elevation myocardial infarction.

• Discuss treatment strategies for unstable angina and non-ST-segment elevation myocardial infarction.

• Describe treatment strategies for acute ST-elevation myocardial infarction (MI).Discuss approach to the long-term management of the post-MI patient.


Epidemiology

• Ischemic heart disease or coronary heart disease (CHD) is a leading cause of death in the United States

• Prevalence increases with age • An estimated 700,000 Americans will have a new coronary attack in a year • About 500,000 Americans will have a recurrent attack in a year

• Lifetime risk of developing CHD after age 40: about 49% in men & about 39% in women

• About every 26 seconds, an American will suffer a coronary event & about every minute, an American will die from a coronary event

• Over 83% of people who die of CHD are > 65 years.


Epidemiology

Ischemia can be defined as a lack of oxygen and decreased-to-no blood flow to the heart muscle. Ischemic heart disease, also known as coronary heart disease (CHD), is the leading cause of death in the United States. Ischemic heart disease encompasses a wide-spectrum of conditions, ranging from acute coronary syndromes (i.e. unstable angina or myocardial infarction) to exertion-induced angina and ischemia without clinical symptoms (or “silent” ischemia).

CHD remains the leading cause of deaths in the United States. About every 26 seconds, an American will suffer a coronary event & about every minute, one will die from a coronary event. Lifetime risk of developing CHD after age 40 is about 49% in men & about 39% in women. The elderly are especially affected as over 83% of people who die of CHD are 65 years or older.

Treatment strategies are aimed at reducing risk of CHD and its associated morbidity and mortality. The focus of this Module’s pharmacotherapy will be on unstable angina, non-ST elevation myocardial infarction and ST-elevation myocardial infarction. Please refer also to the Ischemic Heart Disease Module for information on chronic stable angina.


Acute Coronary Syndromes (ACS)

Source: 2002 ACC/AHA guidelines on ACS



Acute Coronary Syndromes (ACS) refers to

• Unstable angina • Non-ST segment elevation myocardial infarction (NSTEMI) • ST segment elevation myocardial infarction (STEMI)

Presentation:

Symptoms are felt to be consistent with acute cardiac ischemia within 24 hours of hospital presentation, with at least one of the following:

ECG changes

• Transient ST segment elevation > 1 mm • ST segment depression > 1 mm • New T wave inversion > 1 mm • Pseudo-normalization of previously inverted T waves • New Q-waves (1/3 the height of the R wave or > 0.04 seconds) • New R wave > S wave in lead V1 (posterior MI) • New left bundle branch block



Documentation of Coronary Artery Disease

• History of myocardial infarction (MI), angina, heart failure felt to be due to ischemia or resuscitated sudden cardiac death

• History of/or new, positive stress test with imaging • Prior, or new, cardiac catheterization documenting coronary artery disease

The term acute coronary syndromes or ACS is often used to refer to unstable angina, non-ST elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). ACS would be suspected in patients with symptoms consistent with acute cardiac ischemia within 24 hours of hospital presentation and with characteristic electrocardiogram (or ECG) changes and/or documentation of coronary artery disease.

For ease of discussion, treatment of unstable angina (UA) and non-ST elevation MI (NSTEMI) will be grouped together and ST-elevation MI (STEMI) will be handled separately as reperfusion therapy is a consideration in STEMI. Prinzmetal’s angina, a rare presentation of ACS, will also be briefly discussed.


Pathophysiology of Acute Coronary Syndromes


Pathophysiology of Acute Coronary Syndromes

In acute coronary syndromes or ACS, the pathophysiology involves atherosclerotic plaque rupture with exposure of platelet pro-aggregatory substances such as collagen, thromboxane A2, and adenosine diphosphate. The plaque rupture initially results in vasoconstriction and platelet adhesion, and is followed by platelet aggregation and then finally thrombus formation. Acute coronary ischemia is considered a continuum where patients presenting initially with unstable angina may progress to acute myocardial infarction. In this setting there is irreversible necrosis or cell death of heart muscle as a result of prolonged ischemia.

Unstable angina and NSTEMI are considered closely related with similar pathogenesis and clinical presentations but different severity – i.e. whether ischemia is severe enough to cause sufficient damage to cardiac muscle to release detectable amounts of biomarkers. In unstable angina (UA), there is a transient occlusion of the vessel following acute plaque rupture without any myocardial necrosis. This is distinguished from myocardial infarction (or MI), in which prolonged ischemia results in myocardial necrosis. The prolonged ischemia is often the result of an acute thrombus or occlusion in the coronary artery.

Myocardial necrosis is detected by elevation of cardiac enzymes or biomarkers on laboratory testing, most commonly troponin and creatine kinase. Myocardial infarction (or MI) is classified based on changes on electrocardiogram (ECG): non-ST-elevation MI (NSTEMI) is the term used for MI in the absence of an ST-segment elevation on ECG while in ST-elevation MI (STEMI), MI occurs with ST-segment elevation.

Patients with NSTEMI will typically receive potent antiplatelet mediations. Patients with STEMI may receive immediate reperfusion therapy, either by administration of thrombolytic medications or by percutaneous intervention (PCI). A less common variant of angina, called Prinzmetal’s angina, occurs when coronary vasospasm decreases cardiac oxygen supply. Most vasospasm will occur near an atherosclerotic plaque.


Unstable Angina and NSTEMI

Presentation of Unstable Angina and NSTEMI

Definition:

• Chest pain at rest • New onset (< 2 months of presentation) • Previously stable but increasing frequency or intensity • Within 3 months of MI

Signs & Symptoms:

• Chest pain, pressure, tightness, or heaviness • Pain radiating to neck, jaw, shoulders, back or one or both arms • Indigestion or “heartburn,” nausea and/or vomiting associated with chest discomfort

Persistent shortness of breath, weakness, dizziness, lightheadedness, loss of consciousness

Diagnosis: • History & Physical Exam • ECG • Serum biomarkers • Angiography



Angina can be described as a deep, poorly localized chest or arm discomfort that is reproducibly associated with physical exertion or emotional stress and is relieved promptly (i.e. less than 5 minutes) with rest and/or the use of sublingual nitroglycerin. Unstable angina has all the qualities of typical angina as in chronic stable angina patients EXCEPT that episodes are more severe and prolonged, may occur at rest, or may be precipitated by less exertion than before.

In taking a history of patients with suspected ACS, chief complaint may be: 1.) central/substernal compression or crushing chest pain; 2.) pressure, tightness, heaviness, cramping, burning, aching sensation; 3.) unexplained indigestion, belching, epigastric pain; or 4.) radiation of pain in neck, jaw, shoulders, back, or one or both arms. Often patients have associated shortness of breath, nausea and/or vomiting, and diaphoresis (or sweating).

As mentioned above, in ACS, angina may classically present as prolonged (usually > 20 minutes) and occurring at rest; as new-onset angina with marked limitations of ordinary physical activities or anginal symptoms of rest; or as previously diagnosed angina that is more frequent, longer in duration, or lower in threshold. Symptoms may appear gradually or more abruptly. Diabetics, women, and elderly patients may present in an atypical fashion, making diagnosis more challenging. For example, older patients may present with isolated unexplained new-onset or worsened exertional dyspnea, generalized weakness, or change in metal status.

Early recognition is important, and ideally an electrocardiogram (or ECG) should be obtained and interpreted quickly (i.e. within 10 minutes). Typical ECG changes in NSTEMI are ST-segment depression and T-wave inversion, without Q-wave formation. These ECG changes may or may not occur in unstable angina.



Cardiac enzymes or serum biomarkers such as troponin are a sensitive marker for myocardial damage and are routinely obtained to rule in or rule out myocardial infarction. One limitation to troponin levels is that they can be elevated in patients with renal dysfunction. In this subset of patients, the change in level over time is more important than the elevation above normal values. Other standard biomarkers obtained include creatine kinase and the MB fraction of creatine kinase, which is more specific for heart muscle. Biomarkers are negative in unstable angina and are positive in NSTEMI.

Coronary angiography may be recommended in certain patients, such as patients with UA/NSTEMI who have recurrent symptoms of ischemia despite adequate medical therapy or those are at high risk categorized by clinical findings (e.g. congestive heart failure, malignant ventricular arrhythmias) or noninvasive test findings (e.g. significant left ventricular dysfunction, ejection fraction < 35%, large anterior or multiple perfusion defects). Patients with UA who have had previous percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery would be candidates for angiography, unless prior results indicate that further revascularization would not be of benefit.

Information about the patient, such as demographics, other comorbid conditions like heart failure, and vital signs are important in determining the overall prognosis. Elderly patients have increased risks of both underlying coronary artery disease and multivessel coronary artery disease, and older patients are at higher risk of adverse outcome than younger (especially those above 70 years of age).


Prinzmetal’s (Variant) Angina

Definition: Coronary vasospasm decreasing cardiac oxygen supply and causing angina

Signs & Symptoms: Chest pain at rest, often without atherosclerosis

Diagnosis: Ergonovine provocation test

Therapy: Prevention of coronary artery vasospasm using coronary vasodilators, calcium channel blockers, and nitrates

Patients with Prinzmetal’s or variant angina present with chest pain at rest and often show minimal signs of atherosclerosis –sometimes there is no coronary atherosclerosis. Patients rarely progress to myocardial infarction. Therapy consists of increasing oxygen supply with coronary vasodilators and administering calcium channel blockers or nitrates. Beta-blockers should be avoided as the unopposed alpha-receptor stimulation may cause vasospasm.

Diagnostic cardiac catheterization is helpful in patients with suspected variant angina. Ergonovine is an ergot alkaloid with vasoconstrictive properties; when it is given, it will induce vasospasm. The presence of vasospasms after ergonovine administration is indicative of Prinzmetal’s angina; however, false positive readings can also occur.


Treatment of UA/NSTEMI

• Antiplatelet Medications • Anticoagulation • Anti-ischemic Medications • Adjunctive therapy

The drug treatment of unstable angina and NSTEMI is generally the same since the underlying pathophysiology are similar. Potent antiplatelet and anticoagulant therapies are used to help prevent thrombus formation. Antiischemic medications such as beta-blockers, nitrates, and calcium-channel blockers may be used, with adjunctive therapies as needed.


Antiplatelet Therapy for UA/NSTEMI

Aspirin • Dose: 162 to 325 mg on presentation, then give 81 to 162 mg daily

Clopidogrel (Plavix®) Dose: 300 mg upon presentation then give 75 mg daily, for up to 9 months

Glycoprotein IIb/IIIa inhibitors

Tirofiban (Aggrastat®) • Dose: Initial loading dose is 0.4 mcg/kg/min for 30 minutes then 0.1 mcg/kg/min for 48 hours or 24 hours after

coronary intervention (angioplasty with or without stent placement).

• In renal insufficiency: Reduce both loading and maintenance dose by ½ in patients with a creatinine clearance < 30 ml/min.

Eptifibatide (Integrilin®)

• Dose in ACS: IV bolus 180 mcg/kg then start IV infusion at 2 mcg/kg/min for 48 – 72 hours or 18 – 24 hours after coronary intervention (angioplasty with or without stent placement). For patients with serum creatinine between 2 and 4 mg/dl, use ½ of the maintenance infusion. Contraindicated when serum creatinine is > 4 mg/dl.

• Dose in percutaneous coronary intervention (PCI): IV bolus of 180 mcg/kg administered immediately before PCI followed by a continuous infusion of 2 mcg/kg/min AND a second 180 mcg/kg bolus 10 minutes after the first bolus. Infusion should be continued for up to 18 to 24 hours or until hospital discharge, whichever comes first. Infusion should be continued for a minimum of 12 hours.



• In renal insufficiency: reduce infusion dose to 1 mcg/kg/min in patients with renal insufficiency (i.e. estimated creatinine clearance (CrCl) < 50 ml/min or if estimated CrCl is not available, serum creatinine > 2 mg/dl). No change in bolus dose.

Abciximab (ReoPro®): Avoid use in acute coronary syndromes unless use is in the cardiac catheterization lab during coronary intervention. Patients with unstable angina NOT responding to conventional medical therapy and who are planned to undergo PCI within 24 hours may be treated with abciximab 0.25 mg/kg IV bolus followed by an 18 to 24 hours IV infusion of 10 mcg/min, concluding 1 hour after the PCI.

Antiplatelet therapy should be given as soon as possible - Aspirin, chewed immediately upon appearance of symptoms, has been found to reduce mortality in patients with acute myocardial infarction. In UA/NSTEMI, aspirin at dose of 162 to 325 mg should be given initially and then continued at a dose of at least 81 mg daily. Using lower doses decreases bleeding risks. Aspirin therapy should be considered life-long in post-myocardial infarction patients.

The antiplatelet agent clopidogrel has been evaluated in acute coronary syndromes. A trial entitled “CAPRIE” or “Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events” evaluated approximately 12,500 patients within 24 hours of symptom onset. All patients received aspirin and half of the patients received clopidogrel, using a 300 mg loading dose and then 75 mg daily as a maintenance dose. There were fewer cardiovascular events in the clopidogrel-treated patients; however, there were also more episodes of major and minor bleeding in the clopidogrel-treated group.



Of note, only 23% of patients in the study underwent early invasive procedures, which is less than what is typically seen in the United States. Patients who had coronary artery bypass grafting surgery (or CABG) within 5 days had an increased risk of bleeding. Recommendations developed from this study are to use clopidogrel in patients who will be conservatively managed, and in patients who may have CABG surgery, it is reasonable to postpone clopidogrel therapy until therapeutic plans are finalized.

Ticlopidine is another antiplatelet in the same class as clopidogrel, but its use has declined due to adverse effects such as neutropenia (in about 2.4% of patients), requiring additional monitoring.

Glycoprotein IIb/IIIa inhibitors are potent antiplatelet drugs, which may be used in patients presenting with unstable angina or NSTEMI. The most recent recommendations from the American College of Cardiology and the American Heart Association are that glycoprotein IIb/IIIa inhibitors should be considered in addition to aspirin and heparin/low molecular weight heparin (LMWH) in patients for whom catheterization and percutaneous coronary intervention (PCI) are planned. Glycoprotein IIb/IIIa inhibitors should be considered in patients on aspirin or heparin/low-molecular weight heparin with continuing ischemia, an elevated troponin, or with other high risk features in whom an invasive management strategy is not planned.

Abciximab should not be used as an agent for conservative medical management of UA or NSTEMI (i.e. if percutaneuous intervention is not planned) as mortality rates were higher in this patient population. Abciximab is indicated as an adjunct to percutaneous coronary intervention (PCI) for the prevention of cardiac ischemic complications 1.) in patients undergoing PCI and 2.) in patients with unstable angina not responding to conventional medical therapy when PCI is planned within 24 hours.

Tirofiban, in combination with heparin, is indicated for the treatment of acute coronary syndrome (ACS) in patients who are to be managed medically (and those undergoing percutaneous transluminal coronary angioplasty (PTCA) or atherectomy).


Anticoagulation Therapy for UA/NSTEMI

Heparin IV:

• Initial dose 60 – 70 units/kg bolus (maximum initial bolus 5000 units), then initial infusion 12 – 15 units/kg/hr (maximum initial rate 1000 units/hr)

• Titrate dose to therapeutic aPTT and continue until pain is relieved, usual duration 2 to 5 days. • Contraindications: Active internal bleeding, high bleeding risk, or heparin-induced thrombocytopenia.

Enoxaparin:

• Dose 1 mg/kg SQ every 12 hours, in combination with aspirin (first dose may be preceded by a 30 mg IV bolus); Continued until clinically stable, for at least 2 days (usual duration 2 to 8 days).

• Do not need to monitor for therapeutic levels. Monitor for adverse drug reaction • Contraindications: Active bleeding, history of heparin induced thrombocytopenia; Caution in renal insufficiency.

Dalteparin:

• 120 international units/kg every 12 hours for 5 to 8 days (Maximum 10,000 international units twice daily). • Do not need to monitor for therapeutic levels. Monitor for adverse drug reaction. • Contraindications: Active bleeding, heparin-induced thrombocytopenia; Caution in renal insufficiency.


Anticoagulation Therapy for UA/NSTEMI

Intravenous heparin is helpful in patients without active internal bleeding or high risk of bleeding. Weight-adjusted dosing is important to achieve optimal levels of anticoagulation while minimizing the risk of bleeding, and activated partial thromboplastin time (or APTT) is monitored for effect.

Target or therapeutic APTT is generally determined in each laboratory, and this corresponds to heparin levels of 0.3 to 0.7 units per milliliter by anti-factor Xa studies. While on heparin, APTT is usually measured every 6 hours and used to adjust dose; once 2 consecutive APTT values are therapeutic, measurements of APTT may be reduced to every 24 hours. Platelet count is measured at baseline and usually every three days while on heparin, and patients are monitored for signs and symptoms of bleeding. Heparin therapy is typically continued for 2 to 5 days. In patients who are taken immediately to the cardiac catheterization lab after presentation and receive a coronary stent with a glycoprotein IIb/IIIa inhibitor, heparin therapy is discontinued (so these patients would receive a shortened course of antithrombotic therapy).

Recent data suggests that low molecular weight heparins (LMWHs) such as enoxaparin are advantageous in unstable angina and NSTEMI. In the ESSENCE trial, enoxaparin was found to be more effective than heparin in decreasing mortality, MI, and recurrent angina at 14 days, 30 days, and 1 year after therapy.

However, overall bleeding risk was higher in the patients receiving enoxaparin.

Advantages of LMWHs include better bioavailability, more predictable anticoagulant response and ease of administration. Enoxaparin, like heparin, is contraindicated in patients with active bleeding or with heparin-induced thrombocytopenia. However, unlike heparin it is not necessary to measure activated partial thromboplastin time (or aPTT) to monitor therapy. Enoxaparin is primarily eliminated by the kidneys, so caution should be used in patients with renal insufficiency. LMWHs are not interchangeable, and at this time, enoxaparin and dalteparin are the only two LMWHs indicated for NSTEMI and Unstable Angina.

Warfarin is not recommended for long-term anticoagulation in patients with UA/NSTEMI in absence of other indications for warfarin such as atrial fibrillation or mechanical prosthetic heart valves.


Anti-Ischemic Therapy for UA/NSTEMI

Beta-blockers: • Example: Metoprolol 5 mg IV every5 min x 3; then in 1 to 2 hrs, 25 to 50 mg po every 6 hours;dose to response. Higher doses may be required.

• Target Heart Rate (HR) 50 to60 bpm.

• Contraindications: Acutely decompensated congestive heart failure, severe reactive airway disease, shock, hypotension (e.g. systolic blood pressure < 90 mmHg), and HR < 50 bpm. Avoid in patients with right ventricular infarction and bradycardia or heart block greater than 1st degree

Nitroglycerin (NTG): • Sublingual (SL) Tablet or Spray: 0.4 mg dose every 5 minutes x 3

• IV NTG 10 mcg/min, titrated until pain is relieved (usual maximum 200 mcg/min)

• Maintain mean arterial pressure 70 to 75.

• Avoid in patients with right ventricular infarction (because they are dependent of preload to maintain adequate cardiac output and blood pressure).


Anti-ischemic Therapy for UA/NSTEMI

Calcium Channel Blockers: Second-line agents when beta-blockers cannot be used, or if variant angina is suspected.

Other:

Morphine Sulfate: 2 to 5 mg IV; may repeat every 5 to 30 min (Consider when symptoms are not immediately relieved by NTG or when acute pulmonary congestion and/or severe agitation present).

Supplemental Oxygen: for patients with cyanosis or respiratory distress.

Beta-blockers such as metoprolol may be effective in treating angina, and help primarily through reducing cardiac workload and myocardial oxygen demand. Beta-blockers should be avoided in patients with contraindications to use, such as those with acutely decompensated congestive heart failure, severe reactive airway disease, or shock.

Initial choice of agent is based on patient specific factors, pharmacokinetics, and prescriber preference. Agents with intrinsic sympathomimetic activity should be avoided. A commonly used beta-blocker is metoprolol, and an example of dosing is provided on your screen. After an initial IV load, patients may be switched to oral therapy, with target heart rate of 50 – 60 beats per minute (unless rate-limiting side effect occurs).

Nitroglycerin may be administered as sublingual sustained release tablets or spray, usually in a 0.4 mg dose. Intravenous (IV) nitroglycerin may be beneficial in non-hypotensive high-risk patients and in those who do not experience relief after 3 sublingual doses while also receiving beta-blocker. Tolerance may occur after 24 hours of continuous therapy with any nitroglycerin formulation – patients who need continuous IV nitroglycerin beyond 24 hours may require periodic increases in infusion rate to keep effect.


Anti-ischemic Therapy for UA/NSTEMI

Once patients have been pain-free and absent of other signs or symptoms of ischemia for 12 – 24 hours, attempts can be made to switch to oral or topical formulation. A major drug interaction of nitroglycerin is with phosphodiesterase type 5 inhibitors such as sildenafil (Viagra®) – use of the two drugs within 24 hours has been associated with profound hypotension, myocardial infarction, and death. Nitrates should be avoided in patients for 24 hours since last dose of sildenafil and for 48 hours since last dose of tadalafil.

If nitroglycerin is ineffective or if symptoms continue despite adequate anti-ischemic therapy, morphine sulfate may be prescribed. Morphine can provide benefit through analgesic and anxiolytic effects, and it can also reduce myocardial oxygen demand (through venodilation and modest reduction in heart rate) and blood pressure.

Supplemental oxygen is recommended for patients with cyanosis or respiratory distress. Calcium channel blockers are generally considered second-line agents for use when beta-blockers are ineffective or contraindicated or as add-on therapy for patients who are already receiving adequate doses of nitrates and beta-blockers. Immediate-release short acting dihydropyridine agents, such as nifedipine, must be avoided in absence of concurrent beta-blockade as trials have suggested increased adverse outcomes.

Thrombolytic therapy has been evaluated in the setting of unstable angina and NSTEMI, but it has found to be potentially harmful. Patients receiving this therapy have had worsened outcomes as compared to those that have not received thrombolytics. One possible explanation is that in UA/NSTEMI, there is an incomplete occlusion of the vessel –or- only a transient occlusion, so giving a thrombolytic may induce a localized hypercoagulable state (through liberating clot-bound thrombin), causing a complete coronary artery occlusion and worsened outcomes.


Acute ST-segment elevation Myocardial Infarction

Signs & Symptoms:

• Chest pain • Dyspnea • Left arm pain or numbness • Jaw or back pain • Confusion • Syncope • Stroke • Vertigo • Weakness • Abdominal pain • Persistent vomiting • Cough • Feeling of impending doom

Diagnosis (patients must meet 2 - 3 criteria)

• Chest pain > 30 minutes (difficult diagnosis in elderly) • ST-segment elevation on ECG • Positive cardiac enzymes (i.e. Creatine kinase, troponin T or I)

Acute myocardial infarction occurs in about ten percent of patients with unstable angina. Remote myocardial infarctions are common in the elderly, occurring in about ten percent of men and five percent of women age sixty-five years and older. The annual incidence of acute myocardial infarction in adults age sixty-five years and older is 15 to 20 per 1000 individuals.

Elderly patients with acute MI may present with classic symptoms such as prolonged crushing chest pain, and dyspnea, or other symptoms such as left arm pain or numbness, syncope, dyspnea, abdominal pain, and mental changes. Patients with symptoms of STEMI should be transported by ambulance immediately to the hospital.


Acute ST-segment elevation Myocardial Infarction

In patients who have been prescribed sublingual nitroglycerin previously, recommendations are now to instruct patients to take one (1) dose in response to chest discomfort/pain and if there is no improvement or if there is worsening, to immediately call 911 to access EMS. Diagnosis of STEMI is based on clinical signs and symptoms (obtained during history & physical exam) as well as electrocardiogram and cardiac enzyme changes.

Acute myocardial infarction is typically divided into NSTEMI and STEMI. Diagnostic features of STEMI are the same as those for NSTEMI except that the ST-segment is elevated on the ECG in the former. Patients with STEMI are candidates for thrombolytic therapy (whereas those with NSTEMI are candidates for glycoprotein IIb/IIIa inhibitors and clopidogrel). Focus of the next few screens will be on management of STEMI.


Treatment of Acute Myocardial Infarction

• Aspirin • Nitroglycerin • Oxygen • Beta-blockers • Morphine sulfate • ACE inhibitors • Antithrombotic agents (e.g., heparin, warfarin) • Thrombolytic agents (e.g. streptokinase,

alteplase/t-PA, reteplase, tenecteplase)

Because the risk of further cardiovascular complications increases with age, pharmacologic management of elderly patients with acute myocardial infarction must be prompt and aggressive. The American College of Cardiology and American Heart Association recently updated guidelines on the management of ST-elevation myocardial infarction in 2004. Standard therapies include aspirin, beta-blocker, thrombolytics plus heparin, and angiotensin converting enzyme inhibitors post-MI.

Aspirin (at least 162 mg initially then at least 81 mg daily) should be taken as soon as possible, and EMS dispatchers may advise patients to chew aspirin while awaiting arrival of EMS personnel). Patients who have been prescribed sublingual nitroglycerin previously may take one (1) dose to see if improvement in chest discomfort/pain – if no relief, they should contact 911 – patients may receive an additional 2 more doses spaced 5 minutes apart, after which, assessment can be made about need for IV nitroglycerin.

Patients may receive oxygen and/or morphine, and beta-blockers if no contraindications exist. Thrombolytic agents such as streptokinase and tissue plasminogen activator may be used in combination with anti-thrombotic agents such as heparin and LMWH. Beta-blockers help to reduce the size of the infarction and should be used in all patients who can tolerate them. Recently, carvedilol has been shown to decrease mortality and reinfarction in post-myocardial infarction, left ventricular dysfunction patients. Eventually angiotensin-converting enzyme inhibitors may be added to therapy post-MI.


Treatment of Acute MI with Thrombolytic Agents

Administration: Thrombolytic agents should be given as soon as possible following MI (most effective when initiated within 90 minutes of MI).

Agents/Dosing:

IV streptokinase (Streptase®, Kabikinase®) 1.5 million units over 1 hour

IV reteplase (Retavase®) 10 unit bolus - then in 30 mins, repeat 10 units bolus with heparin.

IV tenecteplase (TNKase®) 30 to 50 mg (weight-based) bolus, given with heparin.

IV t-PA, alteplase (Activase®) 15 mg bolus, then 0.75 mg/kg (up to 50 mg) over 30 min, then 0.5 mg/kg (up to 35 mg) over 60 min, given with heparin

Age > 75 years, Female Sex, Black Race, Prior stroke, BP > 160 mmHg, Excessive anticoagulation, and Lower body weight (women weighing less than 65 kg, men weighing less than 80 kg) have been associated with increased risk of intracranial hemorrhage.



Source: Executive summary of STEMI guidelines from Circulation 2004.

Thrombolytic agents for the treatment of STEMI provides benefits for both younger patients and the elderly. Thrombolytic agents are more effective when they are given within 90 minutes of MI, and should be initiated as soon as possible. Most elderly patients however present with NSTEMI and are often not candidates for thrombolytic therapy.

It is well known that the elderly are at higher risk for intracranial hemorrhage. A retrospective analysis of fibrinolytic therapy in > 31,000 patients over the age of 65 years found a 1.43% incidence of intracranial bleeding. Other independent risk factors for intracranial bleeding include: age over 75 years, female sex, black race, prior stroke, blood pressure over 160 mmHg, use of alteplase (versus other thrombolytic agents), excessive anticoagulation (INR = 4), and lower body weight (< 65 kg for women and < 80 kg for men).

The ASSENT-3 Plus trial (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) also demonstrated that patients > 70 years old who have received tenecteplase and enoxaparin had a 2.1% incidence of intracranial bleed. Many physicians prefer, if possible, to send elderly patients to have a primary percutaneous coronary intervention rather than use thrombolytic therapy.



Absolute contraindications for thrombolytic therapy include: active internal bleeding or bleeding diatheses, pericarditis, aortic dissection, prior cerebral hemorrhage, and severe hypertension. The table on your screen lists other absolute and relative contraindications for thrombolytic therapy.

Primary percutaneous coronary intervention (PCI) may be used alternatively instead of thrombolytics, especially if the patient has contraindications to fibrinolysis (including increased risk of bleeding and intracranial hemorrhage), is in an institution that has a skilled PCI lab available with surgical back-up, patient has high risk from STEMI such as cardiogenic shock, and late presentation (symptom onset was over 3 hours ago). The glycoprotein IIb/IIIa inhibitor abciximab may be used with primary PCI for patients with STEMI.


Other Agents Used in the Immediate Treatment of Acute MI

Oxygen: 2 to 4 L/min for at least the first few hours.

ASA: 160 to 325 mg

Clopidogrel: 300 mg loading dose, then 75 mg daily in patients allergic to aspirin

NTG: Sublingual 0.4mg or IV 10 mcg/min – titrated to effect (usual maximum 200 mcg/min)

Morphine: 2 to 3 mg every 5 to 15 mins as needed for pain

Emergency medical treatment of acute myocardial infarction may also include the immediate administration of oxygen; 2 to 4 liters per minute should be administered in the first few hours. Studies have shown that aspirin administered at the onset of acute MI can reduce the risk of death by about 23%. With long-term aspirin use, reinfarction is reduced by about 33%.

Clopidogrel is an alternative for patients with aspirin allergy. Usual dosing is 300 mg loading dose then 75 mg daily. Some recent trials have looked at using a 600 mg load of clopidogrel prior to percutaneous coronary intervention to reduce time to allow maximal platelet inhibition within 2 hours versus 6 hours or more; amount of platelet inhibition does not differ among the two loading doses.

Prior to the use of thrombolytic agents, it was believed that the immediate administration of nitroglycerin reduced post-infarction mortality; however, more recent data from GISSI-3 indicate otherwise. Nitroglycerin is used in MI for more symptomatic benefit. Immediate administration of morphine sulfate has been found to reduce myocardial oxygen demand and provide analgesic and anxiolytic benefit; however; it is not considered a first-line therapeutic agent.


Treatment of MI with Antithrombotic Agents

Heparin:

• IV 60 units/kg bolus (maximum initial bolus 4000 units) then 12 units/kg/hr initially (maximum initial rate 1000 units/hr); Then titrate dose to therapeutic APTT range

• Duration may be for about 48 hrs

• Used in combination with alteplase, reteplase or tenecteplase or in patients who are at high risk for embolism and/or cannot tolerate a thrombolytic. If streptokinase is given, wait 6 hours or until aPTT < 2x control, then begin heparin without a bolus

Warfarin (INR 2.5 to 3.5):

3 months in high risk for thromboembolism (e.g. heart failure, previous emboli, mural thrombus).

Antithrombotic agents such as heparin play an important role in the treatment of acute MI. Heparin should be started at the same time with alteplase, reteplase and tenecteplase. The thrombolytics will lyse or break-up the clot whereas heparin will help keep the artery patent. Dosing recommendations are as follows: initiate heparin therapy with a 60 unit/kg bolus (4000 unit maximum with concomitant thrombolytics) then initiate an infusion at 12 units/kg/hour (maximum 1000 units/hour) – adjust dose to maintain therapeutic APTT range. Heparin is usually given for about 48 hours.


Treatment of MI with Antithrombotic Agents

Streptokinase produces a systemic fibrinolysis as compared to the other more selective thrombolytic agents, and therefore, there is a greater systemic depletion of fibrinogen and an increase in fibrin degredation products, causing more effect on systemic hemostasis. Because of this, patients receiving streptokinase should NOT receive heparin until after 6 hours of ending streptokinase infusion or until APTT has declined.

Patients NOT receiving thrombolytic therapy should receive full-dose heparin if they are at risk for systemic emboli (i.e. large or anterior wall MI, atrial fibrillation, previous embolus or known left ventricular thrombus).


Treatment of MI with Beta-Blockers

Administration: Within 12 hrs

Agents/Dosing: • IV atenolol 5 mg to start, then another 5 mg IV in 10 min; Follow with 50 mg orally. in 10 min, then 50 mg PO BID

• IV metoprolol 5 mg every 5 min for 3 doses, then 100 mg PO BID

• Carvedilol 6.25 mg PO BID; Titrate to 25 mg PO BID over the next 4 – 6 weeks; NOTE: Patients were NOT initiated on therapy until 3 – 21 days after their event and had to be on ACE-I for at least 48 hours (on a stable dose for at least 24 hours).

Effectiveness: • Mortality reduced ∼15% acutely (ISIS-1) • Mortality reduced ∼13% with metoprolol acutely (GISSI-3) • Reinfarction reduced ∼23% with long-term use

Precautions: Avoid beta-blockers with intrinsic sympathomimetic activity (ISA)


Treatment of MI with Beta-Blockers

Beta-blockers are also effective in reducing mortality due to myocardial infarction. When administered within twelve hours of the event, agents such as metoprolol reduced the risk of reinfarction by as much as 23% and the risk of mortality as much as 15%. Intravenous atenolol is dosed at five milligrams to start, then another five milligrams within ten minutes; this is followed by 50 milligrams of oral atenolol.

If intravenous metoprolol is used, three 5-milligram doses administered at five minute intervals are recommended, followed by 100 milligrams of the oral form twice daily. Typically, the beta-blocker dose is dependent on response, and absolute doses should be taken in context with the clinical picture. Beta-blockers with intrinsic sympathomimetic activity should be avoided.

Beta-blockers were studied in an era before reperfusion therapy was widely used, so little is known about what additional benefit they add to current standards of acute treatment of MI. The most recent data on beta-blockers is for carvedilol in post-myocardial infarction patients with left ventricular dysfunction (EF < 40%). Carvedilol-treated patients had fewer cardiovascular events even though there was no difference in the primary endpoint.


Treatment of MI with ACE Inhibitors

Administration: within 24 h

Agents/Dosing†

• Captopril (Capoten®): 6.25 mg, titrating up to target dose of 50 mg TID; Avoid hypotension > 72 hours post- MI.

• Lisinopril (Prinivil®, Zestril®): 5 mg; increase up to 10 mg once daily.

†These are examples; other ACE inhibitors may also be used.

Effectiveness: • Mortality reduced 25% after 42 mos. of treatment (SAVE trial). • Morbidity & mortality reduced 21% in patients over 70 (GISSI-3).

Contraindications: Hypotension

Precautions: Due to its hypotensive effects (worsening ischemia), mortality was increased with use of enalaprilat IV (Vasotec IV®) in the Consensus II Study.


Treatment of MI with ACE Inhibitors

The use of angiotensin-converting enzyme inhibitors (ACE-I) has been shown to reduce mortality and improve cardiac function in elderly MI patients. ACE inhibitors appear to prevent myocardial remodeling. Starting doses of 6.25 milligrams of captopril or 5 milligrams of lisinopril are recommended. Because captopril is short-acting, patients are usually started on captopril to see if they will tolerate an ACE inhibitor and then are switched to a longer acting agent to help with compliance. The effects of ACE-I post myocardial infarction seem to be valid with the entire class of drugs. Use of these agents is contraindicated in patients who are hypotensive.

All patients post myocardial infarction are candidates for ACE-I therapy even in the absence of left ventricular dysfunction. Recent data from the Heart Outcomes Prevention Evaluation (HOPE) trial suggest that ramipril at 10 mg daily reduces the risk of cardiovascular death, myocardial infarction, and stroke in patients with coronary artery disease and without left ventricular dysfunction.


Other Medications Used in MI

• Eplerenone (Inspra®): a selective aldosterone-receptor blocker, which may be considered in patients with left ventricular dysfunction following a myocardial infarction

• Calcium channel blockers have not been shown to reduce mortality with acute MI and are typically avoided, especially short-acting dyhydropyridines.

• Magnesium not recommended as routine MI therapy.

• Routine prophylactic lidocaine post-MI no longer supported.

A selective aldosterone-receptor blocker, eplerenone (Inspra®), may be considered in patients with left ventricular dysfunction following a myocardial infarction. Recommended dose is 25 mg once daily, titrated to 50 mg daily within 4 weeks. Other agents with more questionable clinical value have been used to treat patients with myocardial infarction. Magnesium has been studied, and its use is no longer supported by current research. Although calcium channel blockers continue to be used, they have not been shown to reduce mortality due to acute MI. And because of its toxicity, routine use of prophylactic lidocaine to prevent arrhythmias post-MI is no longer recommended.


Secondary Prevention of Recurrent MI

Management of Lipids: Low cholesterol, heart-healthy diet continued indefinitely (goal is to keep LDL < 100 mg/dL; optional goal LDL < 70 mg/dL)

Aspirin: Continue indefinitely.

Beta-blockers: Continue indefinitely in all except low-risk patients.

Warfarin: • ≥ 3 months if left ventricular mural thrombus or large akinetic region of the left ventricle • Post-MI in patients with persistent atrial fibrillation. • Secondary prevention of MI in post-MI patients unable to take daily aspirin

ACE-inhibitors: Consider indefinite therapy in all patients

Modify Risk Factors, examples: • Cholesterol • Diabetes • Smoking Cessation • Hypertension


Secondary Prevention of Recurrent MI

Secondary prevention of recurrent myocardial infarction involves management of hyperlipidemia. In elderly patients, this includes a low-cholesterol, heart-healthy diet and adjunctive drug therapy if low-density lipoprotein (or LDL) cholesterol is > 100 mg/dl – in high risk patients, optional goal for LDL cholesterol is less than 70 mg/dl.

Aspirin should be taken indefinitely, and beta-blockers continued in all patients. In patients who cannot tolerate aspirin, clopidogrel should be used indefinitely. Warfarin should be continued indefinitely in patients with atrial fibrillation unless contraindicated (e.g. patients at risk of significant bleeding or falls).

Angiotensin-converting enzyme inhibitors may be continued indefinitely in patients with an ejection fraction of less than forty percent or those who have been diagnosed with heart failure. All patients with coronary artery disease are candidates for long term ACE-I therapy as well, based on the HOPE trial.

Aggressive management of comorbid conditions is essential to minimize the risk of secondary events. Therapies should be focused on weight loss, exercise (i.e. cardiac rehabilitation), lipid management, diabetes control, and blood pressure reduction. Smoking cessation is also important for all cardiac patients.


Nonpharmacological Therapy for MI

Percutaneous Coronary Intervention (PCI):

Angioplasty with coronary stent placement Early invasive strategy vs. conservative strategy in unstable angina/NSTEMI Drug-eluting stents (e.g. sirolimus, paclitaxel)

Coronary Artery Bypass Grafting (CABG):

Age is not a contraindication (mortality rate is 2 to 3 times higher than younger populations, but is still only 5 - 6%)

Comorbidities such as heart failure, unstable angina and valvular heart disease are stronger predictors of poor outcome than age alone.

The most recent guidelines from the American College of Cardiology and American Heart Association recommend use of early invasive strategy for patients with UA/NSTEMI without serious comorbidity and who have high risk indicators such as positive troponin, heart failure, or low ejection fractions. Invasive procedures such as percutaneous coronary interventions (or PCI) may incorporate use of drug-eluting stents, which contain small amounts of anti-proliferative drugs like sirolimus and paclitaxel. Drug eluting stents have been shown to reduce coronary stent restenosis rates greater than traditional bare metal stents.

Physicians generally prefer to take elderly patients with acute STEMI directly to the cardiac catherization laboratory for initial treatment, if possible, rather than using thrombolytics. This limits the possibility of intracranial hemorrhage and provides potentially better outcomes in the elderly population.


Resources


Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients with Acute Myocardial Infarction). Circulation 2004; 110: e82-e293.

Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients with Acute Myocardial Infarction). Circulation 2004; 110: 588-636.

Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). 2002. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.

Heart Information Network http://www.heartinfo.org/

Stringer KA, Lopez LM. Uncomplicated Myocardial Infarction. In Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. eds.: Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2002, 251 - 271.

Théroux P, Fuster V. Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation 1998; 97: 1195-1206.


Heart Failure

Learning Objectives:


• Describe the epidemiology of heart failure.

• Identify clinical presentation (i.e. signs/symptoms) of heart failure.

• Identify NYHA functional classification and ACC/AHA staging of heart failure.

• List common etiologies of heart failure.

• Describe compensatory mechanisms in heart failure.

• Discuss general recommendations for heart failure management (including non-pharmacologic measures).

• Discuss medications used in treatment of heart failure, including mechanism of action, common side effects, and major drug interactions.

• Describe management strategies for patients with diastolic dysfunction.


Heart Failure Statistics in the United States

Prevalence - About 5 million Americans Incidence - 550,000 new cases each year Mortality - An estimated 80% of men & 70% of women < 65 years with heart failure will die within 8 years Cost - $ ~ 25.8 billion

About FIVE million Americans have heart failure, and approximately 550,000 new cases are diagnosed each year in the United States. An estimated SIX to TEN percent of people older than 65 years of age have heart failure, and heart failure is the most common reason for hospitalization in elderly patients. Despite advances in the management of heart failure, associated morbidity and mortality remain high. Hospital discharges for heart failure rose from 377,000 in 1979 to 995,000 in 2001 (an increase of about 164%).

Estimates are that EIGHTY-PERCENT of men and SEVENTY-PERCENT of women less than 65 years of age who have heart failure will die within 8 years. Additionally, sudden cardiac death in heart failure patients occurs at 6 to 9 times the rate of the general population. The healthcare costs associated with heart failure are significant and are estimated at TWENTY_FIVE-POINT-EIGHT billion dollars in 2004, which includes direct costs (such as cost of hospitalization or nursing care) and indirect costs (such as lost productivity from morbidity and mortality).


Definitions

Heart Failure – the inability of the heart to pump blood forward at a sufficient rate to meet the metabolic demands of the body and/or the ability to do so only if the cardiac filling pressures are elevated.

Systolic dysfunction – diminished left ventricular contractility (usually ejection fraction* of less than 40%).

*Ejection fraction (EF) – the fraction of end-diastolic volume ejected from the ventricle during each systolic contraction, expressed as a percentage(normal range EF = 55 – 75%).

Diastolic dysfunction – diminished left ventricular relaxation (i.e. decreased lusitropy), either alone or in combination with systolic dysfunction.

Heart failure results from the inability of the heart to pump enough blood to meet the body’s metabolic requirements, or, to be able to do so only in the context of elevated filling pressures. In the past, it was referred to as CONGESTIVE HEART FAILURE; HOWEVER, the preferred term is HEART FAILURE, since a patient can have the clinical syndrome of heart failure without actually having signs or symptoms of congestion.

The normal heart cycle is composed of ventricular diastole and systole. Filling of the ventricles occur during diastole, and ventricular contraction and ejection of blood occur during systole.

While reduced heart muscle contractility or systolic dysfunction is responsible for heart failure in many patients, it is also known that disturbances in relaxation of the heart or diastolic dysfunction - account for symptoms of heart failure in about ONE-THIRD of patients. The remaining TWO-THIRDS of patients have systolic dysfunction WITH or WITHOUT diastolic dysfunction.

Of note, patients with diastolic dysfunction are treated with many of the same agents as patients with predominant systolic dysfunction, although the rationale for use is generally different, and this will be discussed during the latter part of this “review concept.”


Heart Failure Presentation

Symptoms:

• Abdominal pain • Anorexia • Ascites • Bloating • Constipation • Cough • Exertional dyspnea (i.e. shortness of breath with exertion) • Exercise intolerance • Fatigue • Hemoptysis • Nausea • Nocturia • Paroxysmal nocturnal dyspnea • Tachypnea • Weakness • Central nervous system symptoms (e.g. confusion, mental

status changes) • Orthopnea – shortness of breath in recumbent position,

relieved by elevating head with pillows

Signs:

• Bibasilar rales

• Cardiomegaly

• Cheyne-Stokes respiration

• Cyanosis of digits

• Jugular venous distension

• Hepatojugular reflux

• Hepatomegaly

• Pallor

• Peripheral edema

• Pleural effusion

• Pulmonary edema

• S3 gallop (pathologic third heart sound)

• Tachycardia


Heart Failure Presentation

Heart failure is a complex clinical syndrome characterized by specific signs and symptoms. Diagnosis is largely clinical, based on careful history and physical examination findings. Additional testing or imaging is generally required to identify the nature of structural abnormality leading to heart failure. An example is echocardiography to allow measurement of left ventricular ejection fraction and visualization of anatomy as patients may have more than one cardiovascular abnormality. An ejection fraction of less than FORTY PERCENT is generally considered systolic dysfunction.

There is preliminary information that measurement of B-type natriuretic peptide (BNP) may be a valuable laboratory tool to help practitioners distinguish acute heart failure from noncardiac dyspnea in urgent care settings such as an emergency department. Plasma BNP is released from cardiac ventricles in response to increased wall stretch and volume overload. Evidence suggests good negative predictive value for excluding heart failure (i.e. when the level is normal, patient does not have heart failure). Various clinical conditions may affect BNP level, including renal insufficiency, so if the BNP level is elevated (e.g. > 100 pg/ml), it does not necessarily mean heart failure is present. Some have suggested considered BNP threshold of 400 pg/ml for heart failure, but this may increase the false negative rate. Whether there is a role of BNP testing for chronic heart failure or screening is unclear, and the exact role of BNP measurements remains to be fully defined.

The hallmark presentation of heart failure is shortness-of-breath and fatigue, which can limit a patient’s exercise tolerance, as well as fluid retention, which can lead to lung congestion or peripheral edema.

Sometimes signs and symptoms are referred to as relating to left or right-sided heart failure, although many patients present with findings of both. Left ventricular dysfunction typically causes signs and symptoms of pulmonary congestion (such as dyspnea on exertion, orthopnea, and bibasilar rales) while right ventricular failure causes signs and symptoms of systemic congestion (such as peripheral edema, ascites, and hepatomegaly). Nonspecific findings of heart failure can include fatigue, weakness, pallor, and CENTRAL NERVOUS SYSTEM symptoms such as confusion or mental status changes.


Heart Failure

New York Heart Association (NYHA) Functional Classification of Heart Failure:

• NYHA Class I – No symptoms with usual activity. • NHYA Class II – Symptoms with moderate activity. • NYHA Class III – Symptoms with minimal activity. • NYHA Class IV – Symptoms at rest.

American College of Cardiology/American Heart Association (ACC/AHA) Stages of Heart Failure:

• Stage A – patient at high risk for developing heart failure but has no structural heart disorder

• Stage B – patient with structural heart disorder but who has never developed symptoms of heart failure

• Stage C – patient with past or current symptoms of heart failure associated with underlying structural heart disease

• Stage D – patient with end-stage disease who requires specialized treatment strategies such as mechanical circulatory support, continuous inotropic infusions, cardiac transplantation, or hospice care.


Heart Failure

The New York Heart Association functional classification is commonly used in practice to grade severity of heart failure based on a patient’s symptoms and limitations of activity. Patients in class I have no heart failure symptoms with moderate activity; patients in class II and III have symptoms with activity; AND patients in class IV have symptoms even at rest. An example of moderate activity would be walking a block. An example of minimal activity would be getting dressed. Mortality rates are generally highest in patients in class IV.

In 2001, the American College of Cardiology and American Heart Association developed a classification system of FOUR stages of heart failure to emphasize preventive strategies. This staging is intended to complement but not replace the New York Heart Association functional classification.

• Stage A refers to patients at high risk of developing heart failure because of the presence of conditions that are strongly associated with the development of heart failure

• Stage B refers to patients who have developed structural heart disease that is strongly associated with the development of heart failure but who have never shown signs or symptoms of heart failure.

• Stage C refers to patients who have current or prior symptoms of heart failure associated with underlying structural heart disease.

• And stage D refers to patients with advanced structural heart disease and marked symptoms of heart failure at rest despite maximal medical therapy and who require specialized interventions.

Only stage C and D qualify for the traditional clinical diagnosis of heart failure, but this classification scheme was developed in recognition of: established risk factors, structural prerequisites for development of heart failure, and demonstrated reduction of morbidity and mortality of heart failure through therapeutic interventions performed even before appearance of left ventricular dysfunction or symptoms.


Etiologies of Heart Failure

Systolic dysfunction (i.e. impaired “pump” function)

• Muscle mass reduction (e.g. myocardial infarction) • Dilated cardiomyopathies (e.g. viral, alcoholic, idiopathic) • Ventricular hypertrophy • Volume overload (e.g. valvular regurgitation, shunts, high-output states) Pressure overload (e.g. hypertension, aortic valve stenosis, pulmonic valve stenosis)

Diastolic dysfunction (i.e. impaired ventricular filling)

• Increased ventricular stiffness • Ventricular hypertrophy (e.g. hypertrophic cardiomyopathy, hypertension) • Myocardial ischemia and infarction • Mitral or tricuspid valve stenosis • Pericardial disease (e.g. pericarditis, pericardial tamponade) • Infiltrative myocardial diseases (e.g. amyloidosis, sarcoidosis, endomyocardial fibrosis)

*Adapted from Johnson JA, Parker RB, Patterson JH. Heart failure. In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathyophysiologic Approach. New York, McGraw-Hill, 2002; 185 – 218.


Etiologies of Heart Failure

Heart failure is a complex clinical syndrome, and it can result from many cardiac diseases or disorders.

In the United States, the most common causes of heart failure are coronary artery disease, hypertension, and dilated cardiomyopathy.

Systolic dysfunction may occur from:

• Reduced heart muscle mass (such as that resulting from myocardial ischemia or infarction) • From dilated cardiomyopathy, or • Ventricular hypertrophy due to pressure or volume overload (such as mitral or aortic valve stenosis or regurgitation, respectively.).

Diastolic dysfunction may occur due to:

• Increased ventricular stiffness (such as with ventricular hypertrophy, infiltrative myocardial disease, or ischemia or infarction), • Mitral or tricuspid valve stenosis, or • Pericardial disease.


Factors That Can Precipitate Heart Failure Decompensation

Factors that can Precipitate Heart Failure Decompensation:

• Inadequate or inappropriate therapy • Noncompliance with drugs • Noncompliance with diet (i.e. excessive dietary sodium or fluid intake) • Cardiac ischemia • Arrhythmias

Examples of Drugs that May Precipitate or Exacerbate Heart Failure: • Negative inotropic agents

• Antiarrhythmic agents disopyramide and flecainide • Non-dihydropyridine calcium channel blockers (i.e. diltiazem, verapamil) • Beta-blockers*

• Cardiotoxic • Anthracyclines doxorubicin and daunorubicin • Trastuzumab • Cyclophosphamide

• Sodium and Water retention • Nonsteroidal antiinflammatory drugs (NSAIDS) • Cyclooxygenase 2 (COX-2) inhibitors • Steroids • Drugs with high sodium-content (e.g. ticarcillin)



*Beta-blockers carvedilol and metoprolol XL are approved for heart failure management; however, these agents may need to be decreased or stopped in acutely decompensated heart failure patients, to be reinitiated when the patients are stable.

While there are many factors that can precipitate heart failure decompensation, noncompliance with medications and diet accounts for nearly FIFTY-percent of the episodes.

Additionally, certain medications can precipitate or exacerbate congestive heart failure such as negative inotropic agents, cardiotoxins such as anthracyclines, and medications that promote sodium and fluid retention. These are best avoided, if possible.



Irrespective of the etiology of heart failure, the body develops compensatory mechanisms to help maintain cardiac output. While these adaptations initially help maintain cardiac output, over the long term, they lead to worsened heart function.

Adaptations include neurohormonal changes, such as:

• increased activity of the renin-angiotensin-aldosterone or R-A-A-S system, manifested as sodium and water retention and vasoconstriction

• increased activity of the sympathetic nervous system, manifested as tachycardia and increased contractility, AND

• increased circulating or tissue levels of norepinephrine, angiotensin II, aldosterone, endothelin, vasopressin, and cytokines

• increased levels of atrial and brain natriuretic peptide, producing vasodilation of both veins and arteries and producing a mild diuretic effect

• as well as ventricular hypertrophy and remodeling of the heart muscle

Neurohormonal systems have become targets of drug therapy in heart failure. Examples include the angiotensin converting enzyme inhibitors (or ACE inhibitors) and aldosterone receptor blockers to act on the R-A-A-S system and the beta-blockers to act on the sympathetic nervous system.


Goals of Therapy

Goals of Therapy:

• Prevention • Improve symptoms • Improve quality of life • Prolong survival

General Management Strategies:

• Decrease risk of new cardiac injury • Quit smoking • Weight reduction in obese patients • Control of hypertension, hyperlipidemia, and diabetes • Avoid excessive alcohol • Avoid cocaine and other illicit drugs • Maintain fluid balance in heart failure patients • Limit sodium intake (3 gm or less daily) • Check daily weights • Improve physical conditioning • For patients with mild-to-moderate symptoms, aerobic exercise may improve function • Consider influenza and pneumococcal immunizations


Goals of Therapy

Treatment goals of heart failure include prevention, improvement in symptoms and quality of life, and increased survival.

Coronary artery disease and hypertension are two of the most common causes of leading to heart failure in the United States, and treatment can reduce risk of heart failure.

For patients who are diagnosed with heart failure, management depends on:

• type of dysfunction (for example, whether heart failure is predominantly systolic vs. diastolic), • underlying etiology • clinical presentation. • Treatment should be directed at the underlying etiology, if possible.

Non-pharmacologic approaches are important in overall management as well. Patients should be counseled to check daily weights (to check for fluid retention), adhere to treatment regimens, and keep all appointments. Patients should minimize intake of sodium to THREE grams or less daily. Aerobic activity may help improve symptoms and exercise capacity in patients with mild-to-moderate symptoms. Additionally, heart failure patients may benefit from influenza and pneumococcal immunizations to reduce risk of respiratory infection.

Patients should also be cautioned against the health dangers associated with obesity, smoking, excessive alcohol, and use of cocaine or other illicit drugs.


Medications Commonly used for Chronic Heart Failure

Medications Commonly used for Chronic Heart Failure:

• Diuretics • Angiotensin converting enzyme (ACE) inhibitors • Beta blockers • Digoxin

Additional Medications for Consideration:

• Aldosterone antagonists (e.g. spironolactone) • Angiotensin receptor blockers (ARBs) • Hydralazine and isosorbide dinitrate

Pharmacologic management of heart failure typically involves several medications such as loop diuretics, angiotensin converting enzyme inhibitors, and beta-blockers, plus or minus digoxin. Additional medications for consideration include: aldosterone receptor antagonists such as spironolactone, angiotensin receptor blockers (or A-R-Bs), and the combination of hydralazine plus isosorbide dinitrate.


Loop Diuretics

Loop Diuretics

Common Examples

• Furosemide (Lasix®) • 20 to 40 mg daily – BID, titrate to achieve dry weight (up to 400 mg/day)

• Bumetanide (Bumex®) • 0.5 to 1 mg daily – BID, titrate to achieve dry weight (up to 10 mg/day)

• Torsemide (Demadex®) • 10 to 20 mg daily – BID, titrate to achieve dry weight (up to 200 mg/day)

Side Effects

• Hypokalemia • Hypomagnesemia • Dehydration • Dizziness/Light-headedness • Hypocalcemia (with loop diuretics); Hypercalcemia (with thiazide diuretics) • Increased uric acid levels • Prerenal azotemia


Loop Diuretics

Diuretics block sodium and fluid retention by inhibiting reabsorption of sodium chloride in the renal tubules. Loop diuretics, such as furosemide, act in the Loop of Henle and maintain their efficacy unless renal function is severely compromised, such as in end stage renal disease. Thiazide diuretics, such as hydrochlorothiazide, which act in the distal tubules, tend to lose their effectiveness in patients with moderate impairment of renal function with Creatinine Clearances of less than 30 milliliters per minute. AS A CONSEQUENCE, loop diuretics have been adopted as the preferred diuretics in heart failure.

Diuretics are recommended in heart failure with symptoms or evidence of predisposition to fluid retention. Effects of diuretics on mortality are unknown, so diuretics cannot be recommended as MONOTHERAPY in heart failure. Rather, diuretics are recommended for use in conjunction with an angiotensin converting enzyme inhibitor and beta-blocker, which have both demonstrated reductions in morbidity and mortality in clinical trials of heart failure patients.

Dose of diuretic is dependent upon a patient’s renal function and clinical effect. Electrolytes and renal function should be monitored during diuresis, as hypokalemia and hypomagnesemia can often occur. If hypotension or azotemia develop, diuresis may be slowed, although likely continued until fluid retention is eliminated, and then a maintenance dose would be determined.

Mechanistically, there is little difference between the loop diuretics, and intravenously they are equipotent at comparable doses. However, in patients with heart failure and gut edema, furosemide has a dramatically diminished bioavalability. Both bumetanide and torsemide have minimal bioavailability differences in patients with gut edema and may be useful in certain patients.


Loop Diuretics

Resistance to diuretic effects due to impaired renal perfusion or impaired absorption secondary to gut edema from heart failure can be managed by generally by:

• Increasing the diuretic dose; • Using a combination of diuretic PLUS thiazide or thiazide-like diuretic; • Using intravenous diuretic instead of oral OR • Using a continuous intravenous infusion of loop diuretic in a hospital setting.


Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)


Common Examples

Captopril (Capoten®) Usual dose – initiate with 6.25 mg TID, then titrate up to 50 mg TID, as tolerated

Enalapril (Vasotec®) Usual dose – initiate with 2.5 mg BID, then titrate up to 10 to 20 mg BID, as tolerated

Lisinopril (Prinivil®; Zestril®) Usual dose – initiate with 2.5 to 5 mg daily, then titrate up to 20 to 40 mg daily

Ramipril (Altace®) Usual dose – initiate with 1.25 to 2.5 mg daily, then titrate up to 10 mg/day (5 mg BID or 10 mg daily)



Side Effects

• Hypotension • Dizziness/Light-headedness • Hyperkalemia • Cough, nonproductive • Worsening renal function • Angioedema • Dysgeusia (i.e. altered taste sensation) • Neutropenia • Rash

Angiotensin converting enzyme inhibitors or ACE inhibitors significantly reduce morbidity and mortality of heart failure and should be used in all patients with left ventricular dysfunction unless patients are intolerant to or have a contraindication to this class of drugs. Contraindications to ACE inhibitors include: bilateral renal artery stenosis and pregnancy.

Patients with an acute myocardial infarction benefit from ACE inhibitors, beta-blockers, or both, to reduce risk of reinfarction or death, especially in patients whose course is complicated by heart failure. Thus ACE inhibitors are recommended for use in patients with recent or remote history of myocardial infarction, regardless or ejection fraction.



There are about TEN commercially available ACE inhibitors in the U.S.ACE inhibitors prevent the formation of the potent vasoconstrictor angiotensin-TWO from angiotensin-ONE by inhibiting the angiotensin converting enzyme. Treatment should be titrated to target doses, as tolerated, for maximal benefit.

For example, therapy may be initiated with the short-acting captopril at 6.25 milligrams THREE TIMES DAILY, intermediate-acting enalapril 2.5 milligrams TWICE daily or 2.5 to 5 milligrams lisinopril ONCE daily, and titrated upward to target doses of captopril 50 milligrams THREE times daily, enalapril 10 to 20 milligrams TWICE daily, or lisinopril 20 to 40 milligrams ONCE daily. Preference might be to start with shorter-acting captopril if patients are hypotensive, post-myocardial infarction, or ACE inhibitor naive, to allow for quick down- or up-titration as needed.

Renal function and serum potassium should be assessed at baseline, within ONE to TWO weeks after initiation, and periodically thereafter.

Of note, the Heart Outcomes Prevention Evaluation or “HOPE study” demonstrated patients at high risk for cardiovascular events but without heart failure had significant reduction in risk of stroke, myocardial infarction, and cardiovascular death from treatment with ramipril. Ramipril recently received FDA-approval for this indication in patients FIFTY-FIVE years of age or greater


Beta-blockers

Beta-blockers

Common Examples

Carvedilol (Coreg®) • Usual dose – initiate with 3.125 mg BID titrated up to 25 mg BID (or 50 mg BID if > 85 kg) or as tolerated

Metoprolol succinate extended release (Toprol-XL®) • Usual dose – initiate with 12.5 mg or 25 mg daily titrated up to 200 mg daily or as tolerated

Side Effects

• Hypotension • Bradycardia • Heart block • Fatigue • Dizziness, lightheadeness • Worsening or exacerbation of heart failure • May mask signs/symptoms of hypoglycemia in patients with diabetes


Beta-blockers

Clinical trials have demonstrated a reduction in morbidity and mortality in heart failure patients receiving beta-blockers in addition to standard therapy of ACE inhibitor, diuretics, plus or minus digoxin. Beta-blockers are now considered standard of care for patients with left ventricular systolic dysfunction.

Contraindications to beta-blocker therapy include: decompensated New York Heart Association class IV, cardiogenic shock, severe bradycardia, second or third degree AV block, sick sinus syndrome unless patient has permanent pacemaker in place; or bronchial asthma or related bronchospastic conditions that are exacerbated by beta-blockade.

The TWO beta-blockers currently approved for the indication of heart failure are an extended-release formulation of metoprolol, which is a beta-ONE selective beta-blocker, and carvedilol, which is a non-specific beta-blocker and alpha-blocker with antioxidant properties.

Patients should be advised they may not see symptomatic improvement for TWO to THREE months after starting beta-blocker therapy, AND, even if symptoms do not improve, long-term therapy should be maintained to reduce risk of major clinical events.

Titration to target doses is usually gradual. For example, carvedilol is generally initiated in stable heart failure patients at a dose of 3.125 milligrams TWICE daily for 2 weeks and then dose is doubled, as tolerated, every TWO to FOUR weeks until target dose is reached.

Patients should be monitored closely for side effects or worsening of heart failure during titration period, and titration may be slowed to allow stabilization of heart failure before advancing to next dose level. Acutely ill patients may require decreased dose or discontinuation of their beta-blockers, especially if they are hospitalized and in an intensive care unit with need for inotropic support.


Digitalis Glycosides


Digoxin (Lanoxin®, Lanoxicaps®)

• Therapeutic range 0.7 – 2 ng/ml • Usual dose 0.125 to 0.25 mg daily (tablets) or 0.1 to 0.2 mg daily (capsules)* [*Note: difference in bioavailability of tablets vs. capsules]

Side Effects/Toxicity*

• Gastrointestinal symptoms (e.g. anorexia, nausea, vomiting) • Visual (e.g. greenish-yellow halos) • Cardiovascular (e.g. arrhythmias, heart block, bradycardia) • Central nervous system (e.g. fatigue, weakness, confusion, nightmares, hallucinations, ataxia) • May see potassium shifted extracellularly in digitalis toxicity, causing hyperkalemia

*Toxicity may be enhanced in hypokalemia, hypomagnesemia, or hypercalcemia.



Digitalis glycosides inhibit sodium – potassium adenosine triphosphatase enzyme in cardiac and noncardiac cells. This results in an increase in the contractile states of the heart and attenuation of activation of neurohormonal systems, the latter of which has been proposed to be more responsible for beneficial effects in heart failure.

The only available glycoside in the United States is digoxin. Digoxin therapy has been demonstrated to provide symptomatic relief and reduced risk of hospitalization, but it does not decrease mortality in heart failure patients. Digoxin may be also beneficial in patients with heart failure who have atrial fibrillation, although beta-blockers may be more effective for controlling ventricular rate during exercise.

Therapy is commonly initiated at a dose of 0.125 or 0.25 milligrams once daily, depending on the patient’s lean body weight and renal function. Lower dose may be appropriate in elderly patients or in patients with impaired renal function, since approximately SEVENTY to EIGHTY percent of drug is eliminated renally, and doses of 0.0625 milligrams once daily may be necessary. Therapeutic levels generally range from ZERO-POINT-SEVEN to TWO nanograms per milliter. Digoxin toxicity is more commonly seen with digoxin levels greater than TWO nanograms per milliliter, but it may occur with lower levels, and toxicity may be enhanced in patients with low serum potassium or magnesium levels or elevated calcium levels.

Recent data suggests that female patients and those with serum digoxin concentrations greater than TWO nanograms per milliliter are at greater risk of dying than those NOT receiving digoxin. Many experts suggest that digoxin should be reserved for patients with heart failure and atrial fibrillation and in patients with multiple episodes of re-hospitalization.



Some significant drug interactions that can increase digoxin levels include: verapamil, and the antiarrhythmic drugs amiodarone and quinidine. Low serum potassium or magnesium levels can potential digoxin toxicity and elevated serum calcium levels can potentiate digoxin toxicity. Toxicity may be manifested as;

• G-I side effects, such as nausea, vomiting or anorexia • visualization of greenish-yellow halos • fatigue/weakness, hallucinations, ataxia – or unsteady gait • serious cardiovascular toxicities of arrhythmias, heart block or bradycardia

For life-threatening digitalis intoxication with or without associated arrhythmias, digoxin immune fab is available as an antidote to bind to and inactivate free serum digoxin.


Aldosterone Receptor Blockers


Spironolactone (Aldactone®) • Usual dose 25 mg daily

Eplerenone (Inspra®) • Usual starting dose is 25 mg daily, titrated to target dose of 50 mg daily* (indicated for left ventricular dysfunction post-myocardial infarction)

Side Effects

• Hyperkalemia • Gynecomastia (about 8% incidence) • Dehydration • Dizziness • Menstrual irregularities • Rash

Aldosterone appears to cause adverse effects on the heart independent of effects on blood pressure and in addition to the harmful effects of angiotensin-TWO, so aldosterone blockade has been investigated in clinical trials.

The Randomized Aldactone Evaluation Study or “RALES –study” demonstrated that spironolactone TWENTY-FIVE milligrams once daily added to conventional heart failure therapy reduced mortality and morbidity in patients with severe heart failure. Therefore, low dose spironolactone is recommended in patients with severe heart failure, in combination with conventional therapy of ACE inhibitor, beta-blocker, diuretic, plus or minus digoxin. However, the role of spironolactone in patients with mild to moderate heart failure is unclear.



Side effects associated with spironolactone are hyperkalemia and about an EIGHT-percent incidence of gynecomastia. Recommendations are to reduce or stop potassium supplements in patients in whom spironolactone therapy is to be initiated. Serum potassium and creatinine levels should be assessed at baseline before initiation of therapy and periodically thereafter. This is critically important to minimize the risk of hyperkalemia.

Eplerenone, like spironolactone, is a competitive antagonist of the aldosterone receptors. The “EPHESUS study” or the “Eplerenone Post-acute myocardial infarction Heart Failure Efficacy and Survival study” showed that the addition of eplerenone to conventional medical therapy in patients with left ventricular dysfunction following myocardial infarction reduced morbidity and mortality.

Eplerenone was initiated at dose of TWENTY-FIVE milligrams daily, titrated to maximum of FIFTY milligrams per day. Most common side effect with eplerenone is hyperkalemia. Eplerenone has a lower affinity for progesterone and aldosterone receptors than spironolactone;gynecomastia has been reported but less commonly than with spironolactone. Eplerenone, is known by trade name

Inspra®, and carries an FDA-approved indication of left ventricular dysfunction post myocardial infarction. Eplerenone is contraindicated in patients with serum potassium greater than 5.5 mEq/L at initiation, creatinine clearance less than or equal to 30 ml/min, or on concomitant therapy with potent CYP3A$ inhibitors: ketoconazole, itraconazole, nefazodone, clarithromycin, ritonavir, and nelfinavir.


Angiotensin Receptor Blockers (ARBs)


Common Examples • Valsartan (Diovan®) • 40 mg BID, titrate to 80 to 160 mg BID as tolerated (maximum 320 mg/day) • Losartan (Cozaar®) • 50 mg/day

Side Effects • Hypotension • Hyperkalemia • Cough • Angioedema • Dizziness, lightheadedness • Fatigue • Worsening renal function • Rash

Another approach to effecting the Renin-Angiotensin-Aldosterone system is via angiotensin II receptor blockade. Agents were developed in attempts to produce benefits of angiotensin II inhibition without risk of adverse reactions associated with ACE inhibitors such as cough and angioedema as well as investigate possibility of more complete blockade of angiotensin-TWO at the receptor level.



While ARBs are associated with less cough, there have been case reports of angioedema with A-R-Bs. A-R-Bs can be used in patients who have developed cough due to ACE inhibitors, but A-R-Bs should be AVOIDED in patients who have developed angioedema with ACE inhibitors. Serum potassium and creatinine levels should be assessed at baseline before initiation of therapy and periodically thereafter. Contraindications to A-R-Bs include: bilateral renal artery stenosis and pregnancy.

Losartan was the first agent in this class to be evaluated in heart failure management via the Evaluation of Losartan in the Elderly studies – also known as ELITE I and ELITE II. Primary endpoint in ELITE I was increase in serum creatinine, and ELITE II was developed as a follow-up study. While not designed as a mortality trial, ELITE II demonstrated reduction in morbidity and mortality in patients receiving losartan.

The Valsartan Heart Failure Trial (or Val-HeFT study) demonstrated valsartan significantly reduced hospitalizations for heart failure in patients not taking an ACE inhibitor. Valsartan recently received FDA-approval for the indication of heart failure.

At this time, A-R-Bs are considered an alternative or second-line agent to ACE inhibitors in patients who are intolerant to ACE inhibitors. More studies are needed to determine potential for combination of A-R-Bs with ACE inhibitors and further define role of A-R-Bs in management of heart failure as compared to ACE inhibitors.


Combination Hydralazine / Isosorbide Dinitrate

Combination Hydralazine/Isosorbide Dinitrate

Hydralazine (Apresoline®) • 10 to 25 mg TID – QID, titrate up to 75 mg QID (i.e. 300 mg/day)

Isosorbide Dinitrate (ISDN, Isordil®) • 10 mg TID, titrate up to 40 mg QID (i.e. 160 mg/day)

Hydralazine Side Effects • Hypotension • Lightheadedness, dizziness • Drug induced lupus-like syndrome (increased risk with larger doses and longer duration therapy) • Tachycardia • Nausea

Isosorbide Dinitrate Side Effects • Headache, most commonly • Hypotension, infrequent • Lightheadedness, dizziness, infrequent • Flushing • Rash


Combination Hydralazine / Isosorbide Dinitrate

Nitrates are venous vasodilators, which can reduce ventricular volume and pressures by dilating capacitance vessels, but they may also have activity to attenuate the process of ventricular remodeling.

Hydralazine acts as an arterial vasodilator, which can reduce systemic vascular resistance and enhance ventricular ejection, but it may also have some antioxidant effects.

The combination of isosorbide dinitrate and hydralazine has been evaluated in two large studies of heart failure patients. The VHeFT I or “Vasodilator Heart Failure Trial I” demonstrated the combination therapy reduced mortality but did not affect hospitalization rates. The VHeFT II study compared the effects of combination hydralazine and isosorbide dinitrate versus enalapril in heart failure patients. The enalapril-treated group had significantly less mortality, but the combination therapy group did experience favorable effects on ejection fraction and exercise tolerance.

The combination of hydralazine and isosorbide dinitrate is recommended as an alternative to patients who are INTOLERANT of ACE inhibitors, especially those who cannot take ACE inhibitors due to renal insufficiency or angioedema from ACE inhibitors.

This combination should NOT be used in heart failure patients with NO prior history of ACE inhibitors, and it should NOT be substituted for ACE inhibitors in patients who are tolerating ACE inhibitors without difficulty. There is little evidence to support use of nitrates alone or hydralazine alone in heart failure.

More frequent dosing is required for this combination therapy than with ACE inhibitors, which can be inconvenient for patients. As with ACE inhibitors, this combination therapy can produce additive blood-pressure lowering effects in patients already on medications that can lower blood pressure. Nitrates should NOT be used in patients who are taking sildenafil (or Viagra®), vardenafil (Levitra®), or tadalafil (Cialis®) because this drug interaction can precipitate severe hypotension, myocardial infarction, or death.


Additional Considerations

• Avoid calcium channel blockers in patients with systolic dysfunction. Possible exceptions are amlodipine and felodipine.

• Class I antiarrhythmics should be avoided in heart failure patients.

• No clear guidelines exist regarding anticoagulation use in heart failure.

• Acutely decompensated heart failure patients may require intensive care unit admission with management using intravenous medications and/or mechanical circulatory assistance.

Short-term treatment with many calcium channel blockers has produced worsening heart failure and mortality in patients with left ventricular dysfunction. Exceptions are amlodipine and felodipine, which may be safe to use in this patient population. Amlodipine was found to NOT produce an increase in mortality, and it may provide beneficial effect on survival in nonischemic cardiomyopathy. In general though, calcium channel blockers should be avoided in patients with systolic dysfunction.

Class ONE antiarrhythmics should NOT be used in heat failure patients, with the exception of treatment of immediately life-threatening ventricular arrhythmias that are refractory to other therapies. Some class THREE antiarrhythmics, such as amiodarone, do NOT appear to increase risk of death in chronic heart failure patients.



There are NO clear recommendations regarding anticoagulant use in heart failure. Some physicians may prescribe warfarin to a patient with significantly impaired left ventricular function and dilated heart. Other physicians may prescribe warfarin for heart failure patients with a known cardiac thrombus. Most justification is likely available for warfarin use in heart failure patients who have atrial fibrillation or who have had a previous embolic event.

For heart failure patients who become acutely decompensated, hospitalization and intensive care unit management may be required. Therapy may include use of:

• Intravenous inotropic agents, such as milrinone or dobutamine, • Vasodilators, such as nitroglycerin, nitroprusside, or nesiritide, • AND/OR mechanical circulatory assistance such as with an intra-aortic balloon pump or IABP.

Of note, nesiritide is a recombinant form of BNP or brain natriuretic peptideI It decreases preload and afterload through vasodilation, and produces a mild diuretic effect. Studies are ongoing to determine role of BNP levels and further define role of nesiritide in management of heart failure. It is currently FDA-approved for management of acutely decompensated heart failure severe enough to require hospitalization and intravenous therapy, and it is marketed under the tradename Natrecor®.



There is preliminary information available regarding outpatient management of heart failure via some published cases/case series and one randomized, pilot study entitled “Feasibility of Using Serial Infusions of Nesiritide” or FUSION I.

Preliminary findings of the FUSION I pilot study indicate intermittent infusions of nesiritide (e.g. twice weekly to every other week) in an outpatient setting for patients with advanced heart failure were safe and well tolerated. As a follow-up study, FUSION II is a randomized, double-blind, placebo-controlled, multicenter trial study that is ongoing to evaluate serial infusions of nesiritide on morbidity and mortality in advanced heart failure patients. This study aims to enroll 900 high-risk patients with advanced heart failure, including patients with renal insufficiency.

Patients will be randomized to receive nesiritide or placebo infusions once or twice weekly for 12 weeks in addition to standard care. Nesiritide will be administered as a bolus of 2 mcg/kg followed by an IV infusion of 0.01 mcg/kg/min for 4 – 6 hrs. Further information will become available regarding role of nesiritide in the outpatient heart failure management setting.


Management of Diastolic Dysfunction

Management of Diastolic Dysfunction • Control blood pressure • Control heart rate – reduce tachycardia • Decrease volume overload • Reduce myocardial ischemia

Approximately ONE-THIRD of patients with heart failure have preserved systolic function or normal left ventricular ejection fraction. In these patients, although the heart contracts normally, there is abnormal relaxation or diastole AND cardiac output is impaired, especially during exercise, DUE to the impaired filling.

Patients develop symptoms of pulmonary congestion, dyspnea and edema. Prognosis is uncertain - compared to systolic dysfunction - but long-term mortality may be similar, especially in the elderly population. Rates of hospitalization may be similar for predominant systolic versus diastolic dysfunction.

Diastolic dysfunction is less studied than systolic dysfunction in clinical trials, so there is less information regarding treatment guidelines.

General management involves: • Controlling blood pressure • Controlling heart rate – to reduce tachycardia • Decreasing volume overload, • AND relieving myocardial ischemia


Management of Diastolic Dysfunction

Hypertension causes detrimental effects on diastolic function – causing both structural and functional changes to the heart over time. Increases in blood pressure can slow myocardial relaxation and lead to hypertrophy of cardiac muscle and result in increased heart chamber stiffness. Blood pressure should be managed according to published guidelines such as the JNC or Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

A reduction in cardiovascular complications in hypertensive individuals is achieved by reaching target systolic blood pressure (SBP) and diastolic blood pressure (DBP) of less than 140 OVER 90 millimeters of mercury. For patients with hypertension and diabetes or renal disease, the target goal blood pressure is less than 130 OVER 80 millimeters of mercury.

Angiotensin-TWO also has negative effects on heart muscle relaxation, so ACE inhibitors are commonly used in treatment of diastolic dysfunction.

Diuretics are useful to reduce volume overload and provide symptomatic relief.

Since the hallmark of diastolic dysfunction is impaired left ventricular filling, then allowing more time for filling to occur can help reduce symptoms. So use of rate-slowing agents such as beta-blockers and non-dihydropyridine calcium channel blockers such as diltiazem and verapamil are beneficial. Digoxin may be used, although it is not clear whether it might be detrimental by increasing intracellular calcium and contractility and thereby further impairing ventricular relaxation.

Coronary revascularization should be considered in patients with coronary artery disease in whom symptoms or demonstrable myocardial ischemia is believed to be causing a negative effect on diastolic function.


Summary

Heart failure is a complex clinical syndrome that can result from diastolic dysfunction (i.e. impaired ventricular filling) and/or systolic dysfunction (i.e. reduced contractility).

Compensatory mechanisms initially may help maintain cardiac output, but long-term consequences are deleterious and lead to worsening and progression of heart failure.

Drug therapy for heart failure includes: • ACE inhibitors (or hydralazine/isosorbide dinitrate or ARBs as alternatives) • Beta-blockers • Diuretics • Plus or minus digoxin

Spironolactone should be considered for patients with severe heart failure to help reduce mortality.

Pharmacists can play an important role in optimizing heart failure therapy through: • Titrating drug therapy to target doses • Educating patients about adherence to heart failure regimens • Screening for drugs that can exacerbate or worsen heart failure • Screening for drug-drug interactions • And monitoring for adverse effects


Summary

Heart failure is a complex clinical syndrome caused by inability of the heart to pump sufficient blood to meet the metabolic demands of the body, or, to be able to do so only in the context of elevated filling pressures.

Heart failure can result from reduced ventricular filling (which is also referred to as diastolic dysfunction) and/or from reduced contractility (also known as systolic dysfunction).

In heart failure, compensatory mechanisms are activated, such as stimulation of the Renin-Angiotensin-Aldosterone system or sympathetic nervous system, in order to help maintain cardiac output. While these adaptations may initially help, long-term consequences are heart failure worsening and disease progression.

All patients with systolic heart failure should receive an ACE inhibitor, unless contraindicated or not tolerated. The combination of hydralazine and isosorbide dinitrate or an angiotensin receptor blocker may be used if patients cannot receive an ACE inhibitor.

Beta-blockers are recommended for all patients with systolic dysfunction. Initial doses are usually low with slow titration, as tolerated, up to target doses.

Diuretics are frequently used in heart failure treatment to provide symptomatic relief from fluid retention. Most clinical studies of other drug therapy in heart failure have included diuretics as part of treatment.

Digoxin may provide symptomatic relief and reduce risk of hospitalizations for heart failure but does not provide survival benefits.


Summary

Pharmacists can play an important role in a multidisciplinary team to help improve the care of heart failure patients through activities such as titrating drug therapy to target or optimal doses, educating patients about adherence with heart failure regimens (including non-pharmacologic and pharmacologic treatments), screening for drugs that can exacerbate or worsen heart failure and for drug-drug interactions and monitoring for adverse effects.


Resources


Advisory Council To Improve Outcomes Nationwide in Heart Failure (ACTION HF). Am J Cardiol 1999; 83: 1A – 38A.


Angela BG, Grossman W. Evaluation and Management of Diastolic Heart Failure. Circulation 2003; 107: 659 – 663.

Brown NJ. Eplerenone: Cardiovascular Protection. Circulation 2003; 107: 2512 – 2518.

Burnier M, Brunner HR. Angiotensin II Receptor Antagonists. Lancet 2000; 355: 637 – 645.

Cohn JN, Archibald DG, Ziesche S, et al. Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure: Results of the Veterans Administration Cooperative Study. N Engl J Med 1986; 316: 1547 – 1552.

Cohn JN, Johnson G, Ziesche S, et al. A Comparison of Enalapril with Hydralazine-Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure. N Engl J Med 1991; 325: 303 – 310.

The DIG study investigators. The Effects of Digoxin on Mortality and Morbidity in Patients with Heart Failure: The Digitalis Investigation Group. N Engl J Med 1997; : 525 – 533.


Resources

Foody JM, Farrell MH, Krumholz HM. Beta-blocker Therapy in Heart Failure: Scientific Review. JAMA 2002; 287: 883 – 889.

Heart Failure Society of America (HFSA). HFSA Guidelines for Management of Patients with Heart Failure caused by Left Ventricular Systolic Dysfunction – Pharmacologic Approaches. J Card Fail 1999; 5: 357 - 382.

Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001. American College of Cardiology Web site. Available at: http://www.acc.org/clinical /guidelines/failure/hf_index.htm Jessup M, Brozena S. Heart Failure. N Engl J Med 2003; 348: 2007 – 2018.

Johnson JA, Parker RB, Patterson JH. Heart failure. In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach 336.New York, McGraw-Hill, 2002; 185 – 218.

Manohar P, Piña IL. Therapeutic Role of Angiotensin II Receptor Blockers in the Treatment of Heart Failure. Mayo Clin Proc 2003; 78: 334 – 338. Natrecor® (Nesiritide) Product Information. Data on File. Scios, 2005.

Packer M. Should B-type Natriuretic Peptide Be Measured Routinely to Guide the Diagnosis and Management of Chronic Heart Failure? Circulation 2003; 108: 2950-2953.

Pitt B, Remme W, Zannad F, et al. Eplerenone, A Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction. N Engl J Med 2003; 348: 1309 – 1321.

Pitt B, Poole-Wilson PA, Segal R, et al. Effect of Losartan Compared with Captopril on Mortality in Patients with Symptomatic Heart Failure: Randomised Trial – the Losartan Heart Failure Survival Study, ELITE II. Lancet 2000; 355: 1582 – 1587.


Resources

Pitt B, Segal R, Martinez FA, et al. Randomized Trial of Losartan versus Captopril in Patients over 65 Years with Heart Failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997; 349: 747 – 752.

Pitt B, Zannad F, Remme WJ, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709 – 717.

Shapiro BP, Chen HH, Burnett J, Redfield MM. Use of Plasma Brain Natriuretic Peptide Concentration to Aid in the Diagnosis of Heart Failure. Mayo Clin Proc 2003; 78: 481-486.

Vasan RS, Benjamin EJ, Levy D. Congestive Heart Failure with Normal Left Ventricular Systolic Function: Clinical Approaches to the Diagnosis and Treatment of Diastolic Heart Failure. Arch Intern Med 1996; 156: 146 – 157.

Yancy CW, Saltzberg MT, Berkowitz RL, et al. Safety and Feasibility of Using Serial Infusions of Nesiritide for Heart Failure in an Outpatient Setting (from the FUSION I Trial). Am J Cardiol 2004; 94: 595-601.


Cardiac Arrhythmias



• Describe the epidemiology of cardiac arrhythmias in the elderly. • Differentiate between supraventricular and ventricular arrhythmias • Differentiate between Premature Ventricular Contractions (PVC), nonsustained and sustained ventricular tachycardia in terms of seriousness and need for drug therapy. • Understand caveats about beta-blockers, sotalol, and amiodarone for the treatment of ventricular arrhythmias.Describe why encainide, flecainide, moricizine, and propafenone should not be used in structural heart disease. • Define atrial fibrillation and differentiate between acute and chronic AF.Cite medical and pharmacological factors that can cause atrial fibrillation. • List signs and symptoms that characterize atrial fibrillation. • Describe treatment goals and management protocols for patients with atrial fibrillation. • Describe advantage and disadvantages of electric cardioversion for treating patients with acute, symptomatic AF. • Describe the use of electrical and pharmacological treatment options for patients with acute, asymptomatic AF, including dosing, administration, side effects and drug interactions. • Describe treatment options for patients with chronic AF. • Understand and describe Torsade de Pointes, the risk factors, co-factors, and treatments.


Epidemiology of Cardiac Arrhythmias

• Common among elderly • Frequent/complex arrhythmias occur in 20-75% of patients with heart disease • 2/3 of arrhythmias are ventricular; 1/3 supraventricular • Atrial Fibrillation is the most common arrhythmia requiring drug therapy

In a normal heart, the SA node generates a beat which is then spread as a wave of depolarization through the atria and to the AV node. The impulse is held by the AV node momentarily before it is released into the ventricles through the Bundle of His, down the bundle branches, and up the Purkinje fibers. Shortly after the impulse wave spreads through the atria or ventricles, contraction of muscle occurs. You can see that the blood would first be ejected from the atria into the ventricles and then after ventricular depolarization, the ventricles would eject blood either to the lungs or to the brain and rest of the body.

Arrhythmias reflect an alteration in this normal rhythm or an abnormal alteration in heart rate. Arrhythmias are common occurrences in elderly patients. Ventricular arrhythmias account for 2/3 of cases while arrhythmias occurring above the Bundle of His called supraventricular arrhythmias account for the remaining third. However, atrial fibrillation is the most common single arrhythmia.


Risk of Ventricular Arrhythmias


• Increased if ventricular scar tissue, hypoxia, necrosis, or serum hypokalemia/magnesemia

Clinical Presentation of Ventricular Arrhythmias

• Premature Ventricular Contractions (PVCs) • Ventricular tachycardia (VT) – At least three ectopic ventricular beats in a row • Sustained VT – at least 30 seconds of consecutive ectopic ventricular beats • Pulseless VT/ventricular fibrillation – rhythms that can cause loss of pulse and cardiac arrest



A ventricular arrhythmia can be caused when several cells (called an ectopic focus) in one area of the ventricles begin to pace the ventricles rather than an impulse initiated in the SA node and propagated to the ventricles. Connective tissue or scar tissue that partially walls off a group of cells in the ventricles can help set up for ventricular arrhythmias. This can happen in the post-MI patient or the patient with heart failure. In addition, hypoxia of the myocardium from angina or an acute myocardial infarction and electrolyte abnormalities can increase the risk of ventricular arrhythmia as well. Idiopathic ventricular arrhythmias can also occur in people with no discernable risk factors.

If an ectopic ventricular beat only happens once or twice in a row with normal beats in between, they are called Premature Ventricular Complexes (also known as PVCs). PVCs may be benign. However, when a patient develops three PVCs in a row the criteria of ventricular tachycardia are met. If a string of ventricular complexes last for more than 30 seconds, this is sustained ventricular tachycardia. Longer stretches of ventricular tachycardia can cause syncope, hypotension, and in the worst case scenario, cardiac arrest. Ventricular tachycardia can also degenerate into ventricular fibrillation which always causes cardiac arrest. Lack of pulse and severe reduction or elimination of cardiac output without cardiopulmonary resuscitation characterizes cardiac arrest.


Ventricular Tachycardia


Therapy for Preventing Nonsustained Ventricular Tachycardia Recurrence:

• Normal heart function (ejection fraction >40%) + patient without symptoms = no therapy unless post-MI or CHF • Normal heart function + patient with symptoms = beta-blockers • Beta-blockers for post-MI or CHF regardless of symptoms

• Proven reduction of overall mortality • Slow dosing titration if CHF

• Left ventricular dysfunction (ejection fraction <40%) = Beta-blockers unless contraindications • Amiodarone if beta-blockers contraindicated • Fewer arrhythmias but no mortality benefit

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9078198&dopt=Abstract

Cairns JA, for the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT). Randomized trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarizations. Lancet 1997;349:675-82.




Julian DG, for the European Myocardial Infarction Amiodarone Trial (EMIAT). Randomised trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction. Lancet 1997;349:667-74.


Echt DS, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. N Engl J Med 1991;324:781.


The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992;327:227.



Here we can see five PVCs in a row. They look markedly different than the regular rhythm seen in the rest of the strip. Notice the very wide and taller than usual QRS complex. This meets the criteria of nonsustained ventricular tachycardia. Since each ectopic ventricular complex looks the same this is called monomorphic ventricular tachycardia. Monomorphic means “one shape”. Drug therapy depends on the left ventricular ejection fraction, presence of symptoms like palpitations and lightheadedness, and presence of an underlying identifiable cause of the arrhythmia.

In contrast, polymorphic ventricular tachycardia is a ventricular arrhythmia with ectopic QRS complexes of different amplitudes. Torsade de Pointes is an example of a polymorphic ventricular tachyarrhythmia.

A patient without left ventricular dysfunction, characterized by an ejection fraction of over 40%, and no symptoms would not need therapy specifically for nonsustained monomorphic ventricular tachycardia. If the patient had a normal ejection fraction but did have symptoms associated with the nonsustained monomorphic ventricular tachycardia, beta-blockers would be first line therapy.



Patients with left ventricular dysfunction (ejection fraction <40%) who are post-MI or have heart failure should be on beta-blockers as first line therapy. These therapies have proven mortality benefits in these patients with a portion of the benefits being derived from decreasing the incidence of life threatening ventricular arrhythmias. Remember that dosing of beta-blockers in heart failure patients is a slow process and over aggressive use of the agents can worsen heart failure symptoms.

The target dose of metoprolol in post-MI patients and heart failure patients is 200mg per day, or a dose sufficient to achieve a targeted heart rate of 50 – 60 beats per minute. Amiodarone may have a role if beta-blockers are contraindicated or inadequate. This drug has been shown in two trials (CAMIAT and EMIAT) to reduce arrhythmic deaths but did not show reductions in overall mortality.

The one class of drug therapy you would never use in a patient with an MI or heart failure are the class 1c agents encainide, flecainide, moricizine and propafenone. Encainide, flecainide and moricizine were associated with increased mortality when used to suppress PVCs in the CAST trial and thus propafenone is implicated as being risky by association.


Therapies to Prevent Sustained VT Recurrence

Therapies to Prevent Sustained VT Recurrence:

Focus on Sotalol:

• Sotalol – Better efficacy and safety than class I antiarrhythmics in sustained VT

• Has beta-blocking properties • Can increase risk of Torsade de Pointes • Needs dosage adjustment in renal disease


Mason JW, for the ESVEM Investigators. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. N Engl J Med 1993;329:452-8

If a patient had sustained ventricular tachycardia, a drug will probably be given to the patient to suppress future episodes. Sotalol is a first line therapy in this disorder based on results from the ESVEM study, which showed better suppression of arrhythmia recurrence and lower death from any cause versus several class 1 antiarrhythmics. Sotalol possesses beta-blocking properties and thus has all of the beta-blocker precautions and contraindications. It is also a class 3 antiarrhythmic agent and as such can increase the risk of Torsade de Pointes, a polymorphic.



Sotalol is partially renally eliminated and needs dosage adjustment in renal dysfunction. Periodic reevaluation of the patients renal function can reduce the chances for drug accumulation and the development of Torsade de Pointes. Senior Care Pharmacists should alert health-practitioners and patients that syncope could be a sign of loss of efficacy or the development of Torsade de Pointes. Either way the patient needs to be followed-up if this occurred. This includes having a stat 12-lead ECG taken to check the corrected QT interval. If the corrected QT is over 500ms then the therapy needs to be held and the dose should be subsequently reduced or therapy should be switched.



Therapies to Prevent Sustained VT Recurrence:

Focus on Amiodarone: Class III antiarrhythmic

• Amiodarone – solid second line therapy but several long-term adverse effects and drug interactions can occur • Safe in asthmatics • Lower risk of Torsade de Pointes than other class III antiarrhythmics including sotalol

• Adverse Reactions • Pulmonary Fibrosis • Liver toxicity • Corneal Microdeposits • Blue-gray skin discolorations (nose/ear) • Hypo/Hyperthyroidism

• Inhibits CYP 2C9, 1A2, 3A4, and p-glycoprotein therefore watch for interactions with • Warfarin (increased anticoagulation) • Simvastatin & lovastatin • Digoxin (increased digoxin levels)



If a patient fails sotalol due to arrhythmia recurrence or cannot take the drug due to contraindications or side effects; amiodarone is an efficacious alternative. Amiodarone has antiadrenergic properties but is not a beta-blocker. Hence, it can be used in patients with reversible airway disease such as asthma.

Amiodarone is a class 3 antiarrhythmic agent but has a lower risk of Torsade de Pointes as compared to the other agents in the class. These advantages are levied against several potentially serious adverse events such as pulmonary fibrosis, liver toxicity, corneal microdeposits, blue-gray skin discoloration of the nose or ear, hypothyroidism and hyperthyroidism.

The pharmacist needs to assure that patients started on amiodarone have baseline chest x-ray and pulmonary function testing. If dyspnea or nonproductive cough is noted, follow-up pulmonary testing should be done. Liver function testing also needs to occur at baseline and every 6 months with levels three times the upper limit of normal requiring action. Thyroid function testing should occur if the patient develops signs and symptoms of hypothyroidism or hyperthyroidism. Remember that lack of energy with reduced affect can be a sign of amiodarone induced hypothyroidism and not an underlying psychiatric disorder.

Finally, amiodarone can block the CYP 2C9 and 1A2 metabolism of warfarin, 3A4 metabolism of simvastatin and lovastatin, and can block P-glycoprotein removal of digoxin. Closer monitoring of these agents and dosage reduction is usually needed. Patients failing amiodarone therapy due to toxicity or lack of efficacy usually require device therapy as described in the next screen.



Focus on Device Therapy:

• Implantable Defibrillators

• Effective but expensive • Can cause ICD psychosis, reducing number of times it needs to go off by combining with antiarrhythmic therapy is valuable


The Antiarrhythmics vs. Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from near fatal ventricular arrhythmias. N Engl J Med 1997;337:1576-82.


Moss AJ, for the Multicenter Automatic Implantable Defibrillator Trial Investigators. Improved survival with an implantable defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J med 1996;335:1933-7

Pacifico A, Hohnloser SH, Williams JH, et al for the d, l-Sotalol Implantable Cardioverter-Defibrillator (SICD) Study Group. Prevention of implantable-defibrillator shocks by treatment with sotalol. N Engl J Med 1999;340:1855-62.



The implantable defibrillator is a valuable machine for treating arrhythmias. Unlike antiarrhythmics, implantable defibrillators do not prevent arrhythmias from occurring but rather shock the heart back to a normal rhythm when an arrhythmia occurs. They have been shown to have superior efficacy over several antiarrhythmic drugs but are very expensive. In addition, patients who receive frequent shocks from the machines have an increased risk of developing ICD psychosis.

In ICD psychosis, the patients develop an intense anxiety over when the machine will go off next and fears that pain associated with the electrical discharge necessary for efficacy. Although counseling is helpful, the best therapy is to reduce the number of times the machine discharges per unit time by adding an antiarrhythmic agent to the regimen. Beta-blockers are usually the first drugs of choice for this indication given their safety and efficacy.

Sotalol plus an ICD halves the number of shocks needed per year and is an effective adjunctive strategy and can be used if beta-blockers are inadequate for this indication.


Third Line Antiarrhythmics for VT

Third Line Antiarrhythmics for VT:

• Quinidine – Risk of Torsades, diarrhea, inferior to sotalol in ESVEM

• Procainamide – Increased risk of Torsade, drug induced systemic lupus erythematosus, inferior to sotalol in ESVEM

• Disopyramide – Increased risk of Torsade, anticholinergic effects increases risk for urinary retention and blurred vision

There are third line drug therapies for ventricular arrhythmias after sotalol, amiodarone, and device therapy options have been exhausted. These drugs include quinidine, procainamide, and disopyramide. These class Ia antiarrhythmics can induce Torsade de Pointes just like the class III agents discussed previously and also have other adverse effects of note.

Quinidine can cause nausea and diarrhea, procainamide can induce drug induced systemic lupus erythematosus, and disopyramide can induce urinary retention and blurred vision given its anticholinergic side effects. Pharmacists should be very careful when using quinidine and procainamide in renal dysfunction as adverse event risks are accentuated upon accumulation of the drugs.

When treating a patient with heart failure, these drugs should be used with caution as well. Heart failure reduces quinidine absorption and volume of distribution but also reduces the clearance of quinidine which leads to higher quinidine plasma concentrations. Disopyramide in a negative inotropic agent and as such can worsen heart failure symptoms in at risk patients.


Introduction to Atrial Fibrillation


Defining Characteristics:

Supraventricular arrhythmia Extremely fast (400-600 BPM) and disorganized atrial rate

Mechanism of Action:

Multiple re-entrant loops formed within atrial conducting tissue

Types:

First Detected – First time AF ever occurred Paroxysmal – When AF occurs, it will go away without shocks or antiarrhythmics; considered acute AF Persistent –When AF occurs, it will persist until shocks/antiarrhythmics given; considered acute AF Permanent – Person in AF all the time regardless of shocks/antiarrhythmic drugs; considered chronic (12 months of continuous AF)



Atrial fibrillation is a supraventricular arrhythmia characterized by an extremely fast and disorganized activity of atrial conducting tissue. It is thought to be caused by multiple re-entrant loops formed within atrial conducting tissue and/or the pulmonary veins. The clinical significance of atrial fibrillation varies from trivial to life threatening, and proper management depends on accurate diagnosis of the rhythm disturbance and knowledge of the clinical circumstances.

Atrial fibrillation that comes and goes on its own is called paroxysmal while atrial fibrillation which continues unless electrical or chemical cardioversion occurs is called persistent. If AF cannot be shocked or converted with drugs back to a normal rhythm, it is called permanent. It is likely that anyone with persistent AF who remains in AF for more than one year will develop permanent AF.


Etiology of Atrial Fibrillation

Etiology of Atrial Fibrillation

Primarily triggered by agents that increase metabolic demand, disorders that stretch out the atrial tissue, or local atrial inflammation.

• Ischemic heart disease • Hypertension • Heart Failure • Alcohol withdrawal • Excessive exertion • “Lone” AF • Valvular heart disease • Acute pulmonary emboli • Thyrotoxicosis • Sepsis • Electrolyte disturbances • Drugs (e.g., albuterol, dopamine, theophylline)

Atrial fibrillation may be caused by a number of medical conditions, including ischemic heart disease, hypertension, and acute pulmonary emboli. In addition to alcohol withdrawal and electrolyte disturbances, chemically-induced atrial fibrillation may be caused by albuterol, dopamine, and theophylline.


Risk of Atrial Fibrillation in Heart Failure

NYHA % AF Study

I 4 SOLVD PrevenLon

II-‐III 10-‐26 SOLVD Treatment, Diamond, CHF-‐STAT, MERIT-‐HF

III-‐IV 20-‐29 GESICA, Middlekauf, Stevenson

IV 50 CONSENSUS

AHA/ACC AF Guidelines. JACC 2001;38:1266.

Two-thirds of people with AF have structural heart disease (left ventricular hypertrophy, post-myocardial infarction, heart failure). In people with mild heart failure the incidence is 4% but as the heart failure severity worsens, the incidence can rise to 50%. As such, drug therapies which slow the progression of heart failure can reduce the incidence of atrial fibrillation.


Impact of ACE Inhibitor on Development of Atrial Fibrillation

This slide shows the impact of ACE Inhibitor therapy on the incidence of atrial fibrillation after a severe myocardial infarction. In this large clinical trial, patients given trandolapril had a 45% reduction in the risk for developing atrial fibrillation as compared to those given placebo. This is in addition to all the other benefits associated with ACE inhibitors in post-MI patients. Other studies have shown the same types of benefits for other ACE inhibitors and angiotensin receptor blockers.


Signs and Symptoms of Atrial Fibrillation

Signs and Symptoms of Atrial Fibrillation

• Hypotension • Pulmonary congestion • Syncope • Heart failure • Angina

In some cases only palpitations are the only signs or symptoms noted. Some patients with atrial fibrillation are also at risk of developing atrial thrombus formation and arterial embolization.

Patients with atrial fibrillation may be symptomatic or asymptomatic. Common symptoms include hypotension, pulmonary congestion and syncope. Angina and heart failure are also associated with the condition. The elderly are especially prone to having myocardial ischemia or symptoms of heart failure during atrial fibrillation. For one reason, fast ventricular rates can reduce ventricular filling time and can compromise stroke volume. Fast heart rates also increase myocardial oxygen requirements making ischemia more likely. Rate control can alleviate the symptoms if it is due to this mechanism.

Loss of atrial contraction can reduce cardiac output in some individuals as well. The elderly sometimes need the contraction of the atria to optimize ventricular filling. Without it, there is a reduction in stroke volume due to the Frank-Starling mechanism. In other people, the loss of evenly spaced ventricular contractions reduces cardiac output probably via the same mechanism. In this last case, simply achieving ventricular rate control can alleviate the patient’s symptoms.

Finally, the loss of contraction in patients over 60 years of age increases the risk of clot formation in the left atria. This clot could break off and embolize to the brain or to other organs such as the kidneys.


Diagnosis of Atrial Fibrillation

Electrocardiograms of patients with atrial fibrillation show an irregularly irregular pattern. The lack of P-waves and the unevenly spaced QRS complexes are both irregular. Such patients should be further evaluated with echocardiography to see if the atria are dilated or if valvular problems like mitral regurgitation are responsible for the arrhythmia. A good history for drug and alcohol abuse should be taken, and thyroid function tests should be determined if hyperthyroidism is a possible cause.


Treatment Goals for Atrial Fibrillation

Treatment Goals for Atrial Fibrillation

• Relieve symptoms of angina, CHF or hypotension that can be directly attributed to rapid HR • Decrease the risk of embolic stroke • Improve overall cardiac function • Improve exercise tolerance in patients with chronic AF

The first treatment goal for patients suffering from atrial fibrillation is relief from symptoms that can be directly attributed to rapid heart rate. Additional goals include risk reduction for embolic stroke and improvement of overall cardiac function. In patients with chronic atrial fibrillation, improvement of exercise tolerance is a priority.


Algorithm for Treating Atrial Fibrillation

The treatment choices and their sequence reflect the goals previously described: Classify the severity of the condition, treat the most acute risks first, improve cardiac performance, and decrease long term risks of embolic stroke to the greatest degree possible.


Electrical vs. Chemical Cardioversion


• If the patient is hemodynamically unstable – electrically cardiovert right away • If the patient is hemodynamically stable gain ventricular rate control first, assess need for anticoagulation (providing it

if needed) and then decide between chemical or electrical cardioversion • If chemical used first and fails, electrical cardioversion is an option

Electrical Cardioversion Advantages:

• Initial rate of return to sinus rhythm > 90% at 360 Joules • Quick onset of effect • No Torsade de Pointes risk like with chemical cardioversion (Class Ia and III agents only)

Electrical Cardioversion Disadvantages:

• Light anesthesia or sedation required • Patient fear about the procedure • Risk of ventricular arrhythmias if used in digoxin toxicity or hypokalemia • Significant bradycardia after cardioversion

• Unmasking sinus node dysfunction • Recurrent AF after conversion




American College of Cardiology/American Heart Association Task Force of Practice Guidelines & European Society of Cardiology Committee for Practice Guidelines. ACC/AHA Guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001;38:1266-1357

If a patient experiences hemodynamic instability (such as severe symptomatic hypotension), develops severe myocardial ischemia or necrosis, or if the patient experiences a marked worsening of their heart failure associated with AF, electrical cardioversion is needed as soon as possible. The risk of thromboembolism in this strategy is increased but the risk of morbidity and mortality is reduced to a greater extent.

Patients who remain hemodynamically stable while in AF should undergo ventricular rate control and be assessed for anticoagulation and provided anticoagulation before deciding on cardioversion. Either chemical or electrical cardioversion can ultimately be used in this case, each with advantages and disadvantages.

Do not attempt electrical cardioversion in patients who have digoxin toxicity because it can increase the risk of ventricular arrhythmias. Instead wait until the toxicity resolves or use Digibind. If the patient has hypokalemia, correct the electrolyte abnormality before attempting cardioversion.

Patients with very longstanding AF before cardioversion may have sinus node dysfunction after the procedure so be aware of the patients pulse rate afterwards and be prepared to intervene.

Just because a patient cardioverted does not mean that he or she will remain in sinus rhythm. In one study of patients successfully cardioverting, only 23% remained in sinus rhythm at one year without post-cardioversion antiarrhythmic drug therapy.


Treatment of Acute, Hemodynamically Stable AF with Digoxin


MOA: effects mediated through vagotonic properties

Dosing: PO or IV load= 0.5mg initially followed by a supplemental dose of 0.25mg 6 hours later and a final supplemental dose of 0.25mg 6 hours after that

Therapeutic serum concentration: 0.5-2 ng/ml

Half-life:1.6 days, renally eliminated

Contraindications: Patients with known accessory pathway

Drug Interactions: Verapamil, quinidine, propafenone, and amiodarone are P-glycoprotein inhibitors and can increase the digoxin concentration



Negative dromotropic agents block the AV node of the heart and include digoxin, non-dihydropyridine CCBs and Beta-blockers. These agents are used to reduce the number of atrial impulses that reach the ventricles. These agents can lessen symptoms of atrial fibrillation by decreasing the ventricular rate but will not eliminate the underlying arrhythmia.

Digoxin is one agent used to treat patients with acute, asymptomatic atrial fibrillation. Digoxin decreases ventricular rate through its vagotonic properties, although it works slower than other rate control agents like non-dihydropyridine calcium channel blockers or beta-blockers.

Digoxin is a poor choice for most patients needing rate control because it does not control the ventricular response well in higher sympathetic states. This means that it may give you a beneficial resting ventricular heart rate of 80 beats per minute but during exercise it may not control the rate and this could lead to symptoms. However, digoxin is a positive inotropic agent unlike beta-blockers and non-dihydropyridine calcium channel blockers and as such is useful in patients with concurrent heart failure. Please note the important pharmacokinetic drug interactions noted with digoxin.

Digoxin is a drug of choice to combine with either beta-blockers or non-dihydropyridine calcium channel blocker as an adjunctive drug. Only one of the drugs in this picture is a non-dihydropyridine, can you guess which one? If you guessed the diltiazem you are correct. Only verapamil and diltiazem are non-dihydropyridines and provide beneficial myocardial effects in atrial fibrillation.


Treatment of Acute, Asymptomatic AF with Non-dihydropyridine Calcium Channel Blockers


MOA: blocks slow Ca-dependent channel (prolonging AV nodal conduction)

Dosing:

Verapamil: IV load 5-10 mg over 2-5 min.; after 30 min., 10 mg IV if needed; PO maintenance - 80-160 mg every 6-8 h

Diltiazem: IV load 0.25 mg/kg over 2 min.; repeat with 0.35 mg/kg over 2 min. prn.; IV maintenance - 5-15 mg/h (PO 180-360 mg daily)

Contraindications: left ventricular dysfunction, hypotension, SSS, AF with accessory pathways

Drug Interactions: Verapamil is a p-glycoprotein inhibitor and can increase the concentrations of digoxin. Verapamil and diltiazem are CYP 3A4 inhibitors and can increase concentrations of lovastatin, atorvastatin, and simvastatin.

Note: When using IV verapamil/diltiazem, concurrent IV calcium can reduce the vasorelaxant effects and help preserve blood pressure. Calcium does not attenuate the negative dromotropic effects of the drugs so they will still work in patients with atrial fibrillation.



Non-dihydropyridine calcium channel blockers also decrease ventricular rate. Verapamil and diltiazem usually provide rate control in minutes rather than the hours it takes for digoxin to work. Diltiazem may produce fewer problems with blood pressure drops when compared to intravenous verapamil.

Be aware of the drug interactions listed for these agents. Also, do not use verapamil or diltiazem in patients with a diagnosis of Wolfe-Parkinson-White syndrome to control the ventricular response in atrial fibrillation. Using any negative dromotropic agent in Wolfe-Parkinson-White syndrome with atrial fibrillation can increase the risk for ventricular fibrillation. Finally remember that IV calcium given with verapamil or diltiazem can attenuate the effects of these drugs on systemic vascular resistance which can shore up a patient with borderline low blood pressure in need of these agents.


Treatment of Acute, Asymptomatic AF with b-Blockers

Treatment of Acute, Asymptomatic AF with b-Blockers

MOA: in nodal tissues, b-blockers interfere with Ca++ entry by altering catecholamine-dependent channel integrity

Dosing: Propranolol

Loading: IV load 1-3 mg, at rate < 1 mg/min. Maintenance: PO 10-160 mg q 6 h

Contraindications: heart failure, asthma, Sick Sinus Syndrome

Beta-blockers decreases ventricular rate by altering catecholamine-dependent channel integrity, which interferes with calcium entry. These agents may be more effective at rate control than digoxin in a patient who is exercising.


Treatment of Acute, Asymptomatic AF with Warfarin

Treatment of Acute, Asymptomatic AF with Warfarin

Indications: • AF > 48 h

Dosing: • Optimal INR – 2.0-3.0 control

Administration: • Start 1-3 weeks prior to cardioversion and continue for 2-4 weeks after •  Do not load – protein C inhibition

Precautions: • Increased risk of bleeding

Drug Interactions: • Sulfinpyrazone, sulfamethoxazole, amiodarone, disulfiram, metronidazole

Anticoagulation therapy is usually required if atrial fibrillation lasts more than forty-eight hours. Warfarin should be started one to three weeks before cardioversion and continued for two to four weeks after cardioversion. Even though the atria successfully converts and normal P-wave show up on the ECG, there is electromechanical dissociation and no atrial contraction occurs for the next week to two weeks. So it is imperative that warfarin be continued after successful conversion for three weeks. Certain drugs can have important interaction with warfarin by blocking the CYP 2C9 enzyme system. Please refer to section 5.08 for a more detailed discussion on anticoagulation.


Treatment of Acute, Asymptomatic AF with Chemical Cardioversion

Treatment of Acute, Asymptomatic AF with Chemical Cardioversion:

• Quinidine sulfate (Quinidex®): Class Ia Agent:

• Dose: 200-500 mg PO four times daily

• Therapeutic serum concentration: 1-5mcg/ml

• ADRs: Proarrhythmic (Torsade de Pointes), diarrhea. Use cautiously with renal or liver dysfunction

• Drug interactions: digoxin and warfarin

Dofetilide (Tikosyn®): Class III Agent:

• Dose: individualized PO dosing based on algorithm taking into account QTc and Clcr; IV doses using in conversion to sinus rhythm range from 2.5 to 4 mg/kg

• ADRs: Headache, dizziness, chest pain, proarrhythmic (Torsade de Pointes)

• Alter dose in renal dysfunction • Drug Interactions: Dofetilide contraindicated if used with verapamil (mechanism unknown) or the following

cation tubular secretion inhibitors (trimethoprim, ketoconazole, prochlorperazine, megestrol, cimetidine)


Treatment of Acute, Asymptomatic AF with Chemical Cardioversion

Ibutilide (Corvert®): Class III Agent:

Dose: IV use only: 1mg over 10 minutes, if no conversion in 10 minutes repeat 1mg over 10 minutes. ADRs: Proarrhythmia (Torsade de Pointes).

Elective cardioversion is another treatment option for the patient with acute, symptomatic atrial fibrillation. In addition to electric cardioversion, the clinician can use chemical cardioversion. Traditionally, the class IA agent quinidine was used in this indication but due to the risk of diarrhea, tricky pharmacokinetics, and proarrhythmia it is not commonly used anymore. Ibutilide and dofetilide are potassium channel blocking agents that can be used for acute chemical conversion.

Like quinidine, they all increase the risk of Torsade de Pointes and as such, hypokalemia should be corrected before using these drugs. In addition, if the baseline corrected QT interval is greater than 440ms, these agents should not be used. This is because they could increase the corrected QT intervals above 500ms which increases the risk of Torsade de Pointes even more. Dofetilide is contraindicated when it is being used with cation tubular secretion inhibitors (trimethoprim, ketoconazole, prochlorperazine, megestrol, cimetidine) as these drug increase the dofetilide concentrations and risk of Torsade de Pointes.


Treatment of Chronic Atrial Fibrillation


Reduction of Ventricular Rate:

• Digoxin • Verapamil • Diltiazem • Beta-Blockers

Anticoagulation:

• Warfarin – Preferred • Aspirin – If warfarin contraindicated

Chronic Antiarrhythmic Therapy:

Sotalol – Risk of Torsade de Pointes

Dofetilide - Risk of Torsade de Pointes

Amiodarone – Liver toxicity, pulmonary toxicity, hypothyroidism, hyperthyroidism

Quinidine - Risk of Torsade de Pointes

Flecainide – Not in MI, CHF pts

Propafenone – Not in MI, CHF patients

Note: Never use a class Ib antiarrhythmic agents (like lidocaine and mexiletine) to treat an atrial arrhythmia. These agents do not act in atrial tissue and would be completely ineffective.




Some patients will not remain in sinus rhythm after electrical or chemical cardioversion. In these patients the practitioner has to choose to leave a patient in atrial fibrillation with rate control and possibly anticoagulation or to use chronic antiarrhythmic therapy to hold the patient in sinus rhythm.

All patients over the age of 60 years need to have anticoagulation as long as they remain in atrial fibrillation and do not have contraindications. Aspirin can be used in those with warfarin contraindications but works poorly. Patient survival is not helped by trying to keep the patient in sinus rhythm with antiarrhythmic therapy long term. Although the risk of thromboembolism is reduced in sinus rhythm, the risk of Torsade de Pointes with class 1a or class 3 antiarrhythmic agents negates the benefit.

However, some patients may opt for antiarrhythmic therapy including, those who cannot take anticoagulation with warfarin and patients with symptomatic atrial fibrillation that reduce their quality of life. These patients can take class 1a agents like quinidine or Class 3 agents like sotalol but these agents can increase the risk of Torsade de Pointes.

Amiodarone, a class 3 agent with a very low risk of Torsade de Pointes can cause several toxicities. Class 1c agents such as flecainide or propafenone should never be used in patients with structural heart disease like a myocardial infarction or congestive heart failure. A majority of patients can be left on rate control and anticoagulation without using antiarrhythmic agents.


Torsade de Pointes:

Understanding Torsades de Pointes:

This is an ECG showing a Polymorphic Ventricular Tachycardia. If the QTc interval immediately before or after cardioversion is prolonged, then it would be termed Torsade de Pointes, if it isn’t prolonged, then it would just be called polymorphic VT. It is polymorphic because there are several different shapes of the tachycardia wave. Compare this to the monomorphic VT you saw previously. In order to prevent Torsade de Pointes in your patients, Pharmacists need to be aware of QTc Prolongation, the levels of risk, and which drugs can cause it.


QTc Intervals

How do you interpret the QTc Interval?

Normal QTc in healthy subjects without drugs is 403ms

• 397ms in those 20-40 years • 401 in those 41-60 years • 412ms in those over 70

• Women have higher QTc intervals than men (13ms higher) • In coronary disease or heart failure QTc intervals are 420-430ms • Hypokalemia & hypomagnesaemia can raise the QTc interval

In normal people over the age of 70 without co-morbidities, the average QTc interval is 412ms. When co-morbid conditions such as coronary artery disease or heart failure are added, the average baseline QTc intervals can reach into the 230-240mg range. Low serum potassium and magnesium can raise the QTc interval so caution and more prudent monitoring of the ECG is needed when these electrolyte abnormalities arise.


Measuring the QTc Interval

Computer calculated QTc intervals on the ECG may overestimate risk in some people but otherwise provide a good estimate of QTc intervals.

Manual calculations:

•  QTc = QT interval/(RR)1/2 •  All measured intervals in ms

The QTc interval is calculated by measuring from the beginning of the QRS complex to the end of the Twave. When you measure, each mm in length is equal to 40ms. Then measure from the peak of one QRS complex to the peak of an adjacent one. Again convert to milliseconds. Take the square route of the RR interval. Divide the QT by the square root of the RR interval to derive the QTc interval. In general, using the computer reading of QTc on the top of a 12-lead is a reasonable screening test for most patients. Be sure to have the ECG looked at by a physician if it is prolonged.


QTc Intervals that Cause Concern

• A QTc interval >500ms or increases from baseline of >60ms be concerned, take action!

• A QTc interval increase from baseline of 30-60ms is aware but not concerned.

• Avoid Class Ia/III antiarrhythmics in those with baseline QTc intervals >440ms

If a patient’s QTc interval exceeds 500ms or is raised 60ms above baseline, the pharmacist should act to get the physician to reduce the dose, discontinue the drug either temporarily or permanently, and monitor the patient more closely until the QTc interval begins to fall. Since class Ia and III antiarrhythmics can boost the QTc interval about 30-50ms on average, they should not be given to people with baseline QTc intervals above 440ms.


Nonantiarrhythmic Drugs and the QTc Interval

Four main classes of concern:

Macrolides - Erythromycin

Antipsychotics – All typical and atypical

Fluoroquinolones – moxifloxacin

Sympathomimetics – Beta-2 agonists (albuterol, salmeterol, ephedra, epinephrine)

There are four main classes of nonantiarrhythmic drugs which can cause QTc interval prolongation or Torsade de Pointes. The average QTc interval prolongation is modest at 6-20ms and does not pose a risk to most subjects. However, certain patients may be more at risk including those on concurrent therapy with antiarrhythmic drugs, therapy with these drugs plus their specific enzyme inhibitors, patients overdosing on these drugs, and patients prone to hypokalemia or hypomagnesemia.

Antipsychotics are less likely to cause dramatic increases in QTc intervals (above 30ms) as a result of overdose and drug interactions as a ceiling effect seems to occur. As a general rule, be concerned when using these drugs in someone with a baseline QTc interval or above 480ms.


Treatments for Torsade de Pointes.

If patient is hemodynamically unstable: electrical shock immediately

If stable – Magnesium 2g bolus then 1g/hour for 18 to 24 hours infusion (re-bolus in 5-15 minutes if needed)

• Check stat potassium and correct hypokalemia if present • Lidocaine can be used to convert Torsade de Pointes • Cardiac pacing can also be effective

Narrative: If a patient develops Torsade de Pointes, several therapies can be employed. If the person is hemodynamically unstable or becomes unstable due to the arrhythmia at any time, shock the patient immediately. If the patient is stable, magnesium is usually used first and is effective even if serum magnesium is normal. Correcting hypokalemia can be important in treating the arrhythmia and preventing recurrence. Lidocaine and cardiac pacing can be used if magnesium is not effective in an individual patient. If drugs are involved, discontinue the drug right away.


Resources

For additional information:

White CM, Song J, Chow MSS. Cardiac Arrhythmias (Chapter 20). In: Koda-Kimble MA, Young LY (Eds). Applied Therapeutics: The Clinical Use of Drugs. 8th Edition. Lippincott Williams & Wilkins, NY, NY 2004;Pg 20.1-20.33.

American College of Cardiology/American Heart Association Task Force of Practice Guidelines & European Society of Cardiology Committee for Practice Guidelines. ACC/AHA Guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001;38:1266-1357.

Cheng JW, Frank L, Garrett SD, Lu Y, Sanoski CA, White CM. Key articles and guidelines in pharmaceutical management of arrhythmia. Pharmacotherapy 2004;24:248-79.

Caron M, Kluger J, White CM. Amiodarone in the New AHA Guidelines for Ventricular Tachyarrhythmias. Annals of Pharmacotherapy 2001;35:1248-54.

White CM. Prevention of Sub-Optimal Beta-Blocker Treatment in Patients with Myocardial Infarctions. Annals of Pharmacotherapy 1999;33:1063-72.

Mason JW for the ESVEM Investigators. A comparison of electrophysiologic testing with holter monitoring to predict antiarrhythmic drug efficacy for ventricular arrhythmias. N Engl J Med 1993;329:329-445.

The Antiarrhythmics vs. Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from near fatal ventricular arrhythmias. N Engl J Med 1997;337:1576-82.


Resources

Cairns JA, for the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT). Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarizations. Lancet 1997;349:675-82.

Julian DG, for the European Myocardial Infarction Amiodarone Trial (EMIAT). Randomised trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction. Lancet 1997;349:667-74.

Aronow WS. Management of the older person with atrial fibrillation. JAGS 47(6):740-8, 1999

Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation--Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000 Nov 25; 356(9244):1789-94.

Pederson OD on behalf of the TRACE Study Group. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999;100:376-80.

Tran H, White CM, Chow MSS, Kluger J. An evaluation of the impact of gender and age on QT dispersion in healthy subjects. Ann Noninv Electrocardiol 2001;6:129-33.

White CM, Song J, Chow MSS. Cardiac Arrhythmias (Chapter 20). In: Koda-Kimble MA, Young LY (Eds). Applied Therapeutics: The Clinical Use of Drugs. 8th Edition. Lippincott Williams & Wilkins, NY, NY 2004;Pg 20.1-20.33.


Resources

ECG Tutorial

http://www.xs4all.nl/~gallardo/ecgtutorial/ecgframes.htm

ACC/AHA Guidelines for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Executive Summary

http://www.americanheart.org/Scientific/statements/1998/049802.html

Brandeis University Life Sciences, Human Physiology Lecture, Cardiovascular System

http://www.bio.brandeis.edu/pages/classes/biol42a/presentations/lecture8/sld003.htm

PharmInfo Net – Cardiovascular Information Center

http://www.pharminfo.com/disease/cardio_db.html

American Heart Association

http://207.211.141.25/

Heart Information Network

http://www.heartinfo.org/


Peripheral Arterial Disease

Learning Objectives


• Describe incidence, progression, and mortality associated with peripheral arterial disease (PAD).

• Describe the pathogenesis and clinical presentation of peripheral arterial disorders

• .List risk factors for peripheral arterial disease.

• Describe the clinical manifestations of PAD.Explain diagnostic procedures for peripheral arterial diseases.

• Compare and contrast treatment goals and therapeutic options for symptomatic and asymptomatic PAD.

• Explain why direct vasodilators are generally contraindicated in patients with PAD.

• Describe the therapeutic value of antiplatelet agents and pentoxifylline in treating patients with PAD.

• Describe nonpharmacological options for treating PAD.


Types of Peripheral Arterial Disorders

Obstructive • Atherosclerotic Obliterans • Fibromuscular Dysplasia • Thromboangitis Obliterans • Vasculitis • Acute Arterial Occlusion • Atheroembolism

Vasospastic • Raynaud’s disease

The majority of peripheral arterial disorders can be classified as “obstructive.” Arteriosclerosis obliterans is the most common form of arterial disease in patients over 40 years of age.

Fibromuscular dysplasia is another type of PAD. It is a nonatherosclerotic, noninflammatory disease of unknown cause and is characterized by segmental irregularity of small and medium-sized muscular arteries.

Thromboangitis obliterans (aka Buerger’s Disease) is an episodic and segmental inflammatory and thrombotic process of the peripheral arteries and veins; underlying cause is unknown. Patients affected by this disease most commonly are men under age of 40 years who smoke, especially those of Eastern European or Asian background. This disease is characterized by occlusion of distal arteries, producing claudication, rest pain, and tissue necrosis.


Types of Peripheral Arterial Disorders

Vasculitis describes a diverse group of inflammatory disorders characterized by multi-organ system vascular involvement, systemic markers of disease (e.g. fever, weight loss, elevated sedimentation rate), and suspected immunologic origin. Causes of vasculitis often include drugs, chronic inflammatory diseases, and cancer.

Acute arterial thrombosis is most commonly a complication of chronic atherosclerotic occlusive disease, but it can also occur as a consequence of trauma, low-flow states such as hypovolemic or cardiogenic shock, or an inflammatory arteritis.

Atheroembolism arise from the heart in 80 to 90% of all cases. Atrial fibrillation is a common finding of patients, and the formation of thrombus commonly occurs in the left atrial appendage. Noncardiac emboli from arterial ulcerations are usually small, giving rise to peripheral ulceration and digital ischemia or occasionally to a systemic illness resembling vasculitis.

Raynaud’s syndrome is an episodic vasospastic disorder characterized by color change of fingers and toes (white-blue-red) with exposure to cold environment or emotional stress. If idiopathic, it is called Raynaud’s disease. If it is associated with a possible precipitating systemic or regional disorder, it is called Raynaud’s phenomenon. The distinction between disease and phenomenon is meant to reflect a difference in prognosis. While Raynaud’s disease is benign and reversible, Raynaud’s phenomenon may progress to atrophy of the terminal fat pads and development of fingertip gangrene.


Epidemiology of Peripheral Arterial Disease

Incidence • Age dependent, increases with age

Progression • Lower limb amputation • Impaired wound healing • Ulceration of limbs or gangrene may develop

Patients with PAD may present with lower limb symptoms such as claudication, pain at rest, or gangrene or may be completely asymptomatic. Signs or symptoms of disease progression may be impaired wound healing, ulceration of limbs, or need for lower limb amputation.

An ankle-brachial index (or ABI) can be used in outpatient offices or clinics to diagnose patients with peripheral arterial disease. To perform an ABI, an appropriately sized blood pressure cuff is placed over the ankle of a patient in supine position – then with use of a hand-held Doppler, systolic blood pressures are measured in the posterior tibial and dorsalis pedis arteries. The ABI is calculated for each extremity by dividing the lower extremity pressure by the higher of the systolic brachial pressure. A normal value is greater than 1, and values less than 0.9 are consistent with claudication in those with characteristic symptoms. Values less than 0.5 are considered severe obstructive disease. Older patients and patients with diabetes may have stiff-noncompressible vessles, and an ABI of greater than 1.3 may elicit suspicion of PAD.


Epidemiology of Peripheral Arterial Disease

PAD is relatively uncommon in those less than 40 years old. However, the incidence of intermittent claudication increases dramatically as we age, and about 2.5% of those between the ages of 55 – 64 years and 8.8% of patients 65 – 74 years have the diagnosis. Many patients (16 – 20%) with PAD can have an ABI of less than 1but be completely asymptomatic. It is important to know that PAD patients without symptoms are still at increased risk for cardiovascular events such as myocardial infarction.

Patients with claudication typically have a slow progressive course. About 25% of patients develop worsening symptoms and about 5% have amputations within five years, leading to decreased ambulation and quality of life.


Pathogenesis of Peripheral Arterial Disorders

Atherosclerosis

• Endothelial Dysfunction • Response-to-injury • LDL cholesterol oxidation to modified LDL (mLDL) • Formation of fatty streaks

• Plaque disruption • Platelet adhesion or thrombus formation

• Possible exertional leg ischemia from vessel occlusion

• Intermittent Claudication • Blood flow has decreased resistance at rest • Exertion increases blood flow and a subsequent drop in pressure

• Produces symptoms of claudication

Development of pathologic atherosclerotic lesions in the extremities can be likened to the development of coronary atherosclerosis, with atherosclerosis arising from endothelial dysfunction. Endothelial dysfunction is thought to occur as a “response-to-injury.” Low density lipoprotein (or LDL) cholesterol transport into the intima occurs secondary to increased endothelial permeability. Trapped subendothelial LDL then undergoes oxidation by localized oxygen free radicals to form modified LDL (mLDL).

The modified LDL acts as a chemo-attractant and can be ingested by circulating macrophage, changing the macrophages into foam cells and forming fatty streaks. Eventually, these fatty steaks develop fibrotic caps that can be either stable or unstable, depending on the cap thickness. Disruption of these plaques leads to exposure of collagen, tissue factor and other pro-aggregatory substances, which can then lead to platelet adhesion and thrombus formation.


Pathogenesis of Peripheral Arterial Disorders

Stable atherosclerotic plaques may lead to exertional leg ischemia. Typically, stenotic plaques do not give rise to symptoms until the lesion occludes over 80% of the vessel. Blood flow distal to a stenotic lesion is derived from the sum of flow through the stenosis and from collateral blood flow; however, flow is inversely related to peripheral resistance.

During rest, blood flow through an area of stenosis is maintained by decreased resistance. On the contrary, as blood flow rates increase during exercise, there is a dramatic drop of pressure across the stenotic lesion, causing symptoms of claudication. As in the coronary vasculature when there is an acute plaque rupture, platelets adhere, become activated and aggregate, leading to a thrombus formation, with resultant occlusion of blood flow and symtoms (i.e. acute leg ischemia).


Risk Factors for Peripheral Arterial Disease

• Smoking • Hypercholesterolemia • Hypertension • Diabetes mellitus • Hyperhomocysteinemia • Age • Family history of PVD

Risk factors for PAD are the same as for coronary artery disease. Smoking robs the body of oxygen and causes vasoconstriction. Cessation of smoking may provide improvements in symptoms in some patients. Benefits of tobacco cessation may also include slowing the rate of arterial occlusive disease progression and reducing cardiovascular mortality.

Lipid-lowering medication and blood pressure control have been shown to produce an approximate 40% risk reduction for new-onset claudication or worsening of claudication. In general, optimal glycemic control is beneficial in preventing microvascular complications of diabetes, however it has not been shown to alter macrovascular complications in clinical trials. In the United Kingdom Prospective Diabetes Study (UKPDS) aggressive glycemic control had no effect on death or amputations secondary to PAD. Therefore, while optimal glycemic control is essential in decreasing microvascular complications it may have no effect on reducing the onset or progression of peripheral arterial disease.

Recent data suggests that elevated homocysteine levels may be an independent risk factor for peripheral arterial disease. Homocysteine converts low-density lipoprotein cholesterol (or LDL) to modified LDL secondary to oxidation. As with diabetes, treatment of elevated homocysteine levels has not been shown to reduce the risk of peripheral arterial disease. Family history of peripheral vascular disease and increasing age are also risk factors for PAD.


Clinical Presentation of PAD (Lower Extremities)

Typical Manifestations of PAD

• Exertional symptoms • Unilateral or bilateral leg pain • Muscle ache in legs • Muscle cramping in legs • Numbness in legs • Muscle fatigue in legs

• Symptoms of severe arterial occlusion • Above symptoms at rest • Pain in feet and/or toes • Coldness in feet and/or toes • Numbness in feet and/or toes

Peripheral arterial disease most commonly affects the lower extremities. While lower extremity symptoms are relatively non-specific in PAD, the occurrence of these symptoms on exertion is a characteristic finding in PAD. The most common feature associated with peripheral vascular disease is intermittent claudication, which typically involves unilateral leg cramping and pain, especially when stressed by exercise. Exertional symptoms rarely involve the feet and/or toes but can be used to distinguish for presence of severe arterial occlusive disease.


Screening and Diagnosis of Peripheral Arterial Disease

Patient History: • Risk factor assessment (including presence of comorbid conditions) • Walking impairment • Location and characteristics of pain • Duration of symptoms • Distance and time patient can walk before symptoms • Speed and grade elevations that elicit symptoms • Description of how pain is typically relieved

Physical Examination: • Blood pressure measurements in both arms • Bilateral palpation (of carotid, temporal, axillary, brachial, radial, ulnar arteries, femoral, popliteal, posterior tibial

and dorsalis pedis pulses) • Ausculation for bruits (in carotid, subclavian, cervical, femoral, abdominal aortic, and epigastric regions) • Inspection of lower limbs (for color, skin health, temperature, atrophy, nail thickening, gangrene, and tinea pedis)

Other Diagnostic Procedures: • Ankle-Brachial Index (ABI) • Doppler ultrasound • Plethysmography • Percutaneous oxygen electrode measurement


Screening and Diagnosis of Peripheral Arterial Disease

History, history, and history is perhaps the single most important factor in diagnosing and determining treatment strategy for PAD, especially in the elderly. Minute details of patients’ symptoms and how these have impacted on their activities of daily living are imperative in deciding upon a regimen that will work best for the patient and provider alike.

Physical exam should include the Ankle-Brachial Index or ABI, as depicted in the picture. Use of this technique enables the provider to further determine if the symptoms are truly unilateral or bilateral. Remember, patients may be symptom free, but by definition of the ABI, could present with moderate to severe peripheral arterial disease.

Impedance plethysmography relies on changes in electrical impedance to determine the presence of thrombus. Accuracy is comparable, though not quite as high, as ultrasonography. Both ultrasonography and impedance plethysmography are useful in the serial examination of patients with high clinical suspicion of venous thromboembolism but with negative leg studies. Magnetic resonance imaging may be indicated in certain patients for evaluation prior to surgery (in lieu of angiography).


Treatment of Peripheral Arterial Disease

Risk Factor Modification

• Smoking cessation • Blood pressure control • TGlycemic control • Management of hyperlipidemia • Exercise

Pharmacologic Therapies

• Antiplatelet drug therapy • Aspirin • Clopidogrel • Ticlopidine • Cilostazol • Pentoxifylline

• Antihypertensive agents • Medications for glycemic control • Lipid-lowering drugs

Non-pharmacologic Therapies

• Percutaneous repair • Surgical repair

Treatment goals for peripheral arterial disease include: improving functional status of the patient, preserving limb function, slowing progression of PAD, and reducing cardiovascular morbidity and mortality.

First-line treatment methods should involve smoking cessation, control of blood pressure, glucose, and lipids. Institution of a regulated and monitored exercise plan can help patients with activities of daily living and quality of life.


Treatment of Peripheral Arterial Disease

Intermittent claudication is caused by inadequate blood supply to muscle stressed by exercise, and certain medications may exacerbate symptoms. By reducing systemic blood pressure, beta-blockers may reduce blood flow through stenotic arteries or collateral vessels. Non-selective beta-blocker may attenuate epinephrine-induced vasodilation during exercise by blocking beta-2 receptors in peripheral tissues and worsen the signs and symptoms of peripheral vascular disease.

Direct vasodilating agents such as papaverine may induce a “steal” effect and shunt blood away from diseased vessels, leading to ischemia and worsening of symptoms. Individual risk vs. benefit must be assessed in managing a patient’s overall medication profile – for example, many PAD patients do have existing coronary artery disease and may benefit from beta-blocker therapy.

Pharmacologic therapies for PAD are primarily antiplatelet agents, with severe PAD possibly necessitating more involved medical or surgical intervention.


Other Treatment Considerations for PAD

Angiotensin-converting enzyme inhibitors

• Unsure if beneficial • Do not withhold treatment

Direct-acting vasodilators not generally recommended

There is not direct evidence that pure vasodilators such as papaverine have any benefit in the chronic treatment of PAD. Agents such as papaverine or isoxsuprine may induce a “steal” effect and shunt blood away from diseased vessels, leading to ischemia and worsening of symptoms.

Angiotensin-converting enzyme inhibitors (or ACE inhibitors) may be of benefit based on findings from the Heart Outcomes Prevention Evaluation (HOPE) study. In more than 9000 patients enrolled into the trial, 4000 of whom had PAD, there was a reduction in the rates of death, myocardial infarction, and stroke (with a relative risk reduction of 0.78) in patients treated with ramipril.

Based on the current evidence, use of ACE inhibitors is appropriate in this patient population while use of direct acting vasodilators may not be warranted.


Treatment of PAD with Antiplatelet Medications

Aspirin

• Mechanism of Action: Inhibits prostaglandin synthesis and blocks prostaglandin synthetase action which prevents formation of the platelet-aggregating substance thromboxane A2

• Dose: 81 – 325 mg daily

• Adverse Effects: Stomach upset, gastrointestinal bleeding, intracranial hemorrhage (rare), others

• Cautions: Concurrent use of aspirin/NSAIDs and ACE-I may worsen adverse reactions and lead to other complications (renal insufficiency)

The American College of Chest Physicians recommends the use of 81 – 325 mg of aspirin daily in patients with PAD. However, there is little data suggesting this therapy will reduce cardiovascular events in patients with PAD. Because of the high prevalence of coronary artery disease in patients with PAD, aspirin therapy is recommended.



Thienopyridine Derivatives

Clopidogrel (Plavix®)

• Mechanism of Action: Blocks the ADP receptors, which prevent fibrinogen binding at that site and thereby reduce the possibility of platelet adhesion and aggregation

• Dose: 75 mg daily • Adverse Effects: Stomach upset, gastrointestinal bleeding (less incidence than with aspirin), risk of bleeding

(increased by other meds with similar effects)

Ticlopidine (Ticlid®)

Mechanism of Action: Not completely understood; inhibits platelet function Dose: 250 mg twice daily with food Adverse Effects: Diarrhea (can become chronic), neutropenia (less than 3% of reported adverse effects; requires

specific monitoring early in therapy), increases in serum creatinine (although extensively metabolized by liver)

Thienopyridine antiplatelet medications do not appear to relieve symptoms of PAD; however, they may decrease cardiovascular events in patients with PAD. In the large secondary prevention trial entitled “Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (or CAPRIE)” trial, more than 19,000 patients were randomized to receive either clopidogrel or aspirin.



This study demonstrated that patients who received clopidogrel experience fewer cardiovascular endpoints than did the aspirin-treated group, and the subgroup that seemed to benefit the most were those who had PAD. Based on this trial, clopidogrel received labeling for the indication of secondary prevention of atherosclerotic events in patients with atherosclerosis, including patients with PAD.

There is limited data for the efficacy of ticlopidine and neutropenic side effects, necessitating blood tests every 2 weeks for the first 3 months of treatment, make this agent of limited value in PAD.



Cilostazol (Pletal®)

Mechanism of Action: Cilostazol and its metabolites inhibit phosphodiesterase III, increasing cyclic AMP, leading to inhibition of platelet aggregation and vasodilation.

Dose: 100 mg BID, 30 minutes prior to or 2 hours after breakfast and dinner. Dose should be reduced to 50 mg twice daily during concurrent therapy with CYP3A4 and CYP2C19 inhibitors

Adverse Effects: Palpitations, peripheral edema, dizziness, headache, diarrhea, abnormal stools, gastrointestinal upset

Contraindications: Congestive heart failure of any severity

Drug Interactions: Cilostazol is metabolized by CYP450; Adverse reactions with cilostazol may be increased with concurrent therapy of CYP inhibitors such as diltiazem, erythromycin, itraconazole, ketoconazole, and grape fruit juice (all 3A4 inhibitors), and omeprazole (2C19 inhibitor. The manufacturer recommends reducing dose to 50 mg BID if using these drugs concurrently.

Cilostazol is the newest drug FDA-approved to treat intermittent claudication. In a controlled trial, cilostazol was proven to be superior to pentoxifylline.

Cilostazol works by inhibiting phosphodiesterases to ultimately cause an inhibition in platelet aggregation induced by adenosine diphosphate (ADP), collagen, and arachadonic acid. Other effects of phosphodiesterase III inhibition include increased cardiac contractility, accelerated atrioventricular (AV) nodal conduction, and increased ventricular automaticity, heart rate, and coronary blood flow.



The dose of cilostazol is 100 mg twice a day. However, if patients are on any interacting medications, the dose should be reduced to 50 mg twice a day.

Side effects of the medication include palpitations, peripheral edema, headache, dizziness, diarrhea and abnormal stools.

Cilostazol is contraindicated in patients with congestive heart failure of any severity. This contraindication is based on previous heart failure trials demonstrating increased mortality in patients treated with phosphodiesterase inhibitors. Avoid concurrent ingestion of grapefruit juice due to the potential to inhibit cytochrome P450 enzyme 3A4. Avoid administration with meals as high-fat meals increase the concentration (AUC – area under curve -by 25%) of cilostazol, and peak concentration may be increased by 90%. It is best to take cilostazol at least 30 minutes before or 2 hours after meals.


Other Treatment Options for PAD

Pentoxifylline (Trental®)

Mechanism of Action: Decreases blood viscosity and increases blood flow due to alterations in red blood cell rheology

Dose: 400 mg TID with meals; reduce to BID if side effects occur

Adverse Effects: Dizziness, headache, flushing, stomach upset, and palpitations

Contraindications: Patients with low tolerance for methylxanthine derivatives; patients with recent cerebral and/or retinal hemorrhage

Pentoxifylline, an FDA-approved hemorrheologic agent, improves microcirculation in ischemic limbs by increasing oxygen supply to skeletal muscles during exertion. The drug increases blood cell flexibility, inhibits platelet aggregation, reduces fibrinogen production, and reduces neutrophil elastase proteinase inhibitor complex levels. This results in decreased blood viscosity and improved blood flow to ischemic tissue. Pentoxifylline is absorbed rapidly and completely, and it is extensively metabolized during its first pass through the liver.

Pentoxifylline is commercially available in 400 milligram sustained release tablets. The usual dose is one tablet three times daily with meals for eight weeks. Results are normally seen in the second or third weeks.

Pentoxifylline is a methylxanthine derivative and is contraindicated in patients who do not tolerate other methylxanthine derivatives such as theophylline or caffeine.

The benefits of pentoxifylline may be very modest - a recent meta-analysis determined the net benefit in terms of walking distance increase was about 44 meters. At this time, there is insufficient data to recommend routine use of pentoxyfylline.


Nonpharmacological Treatment of Peripheral Arterial Disease

• Surgical bypass grafts • Percutaneous transluminal angioplasty

Surgical or percutaneous revascularization is indicated in patients with acute limb threatening ischemia or in patients with disabling claudication. Newer devices such as regular stents or drug-coated stents may be indicated with severe symptomatic disease.

Percutaneous or open operation may be considered for favorable candidates, patients with short-distance (less than two blocks) claudication that impairs their ability to work or perform activities of daily living. The addition of clopidogrel and aspirin is necessary after percutaneous intervention.


Conclusion

Symptoms (may or may not be present) • Claudication • Rest pain • Gangrene

Ankle-Brachial Index • Normal ratio is 1. • Less than 0.9 considered claudication

Treatment • Exercise • Smoking cessation • Pharmacologic therapy (e.g. cilostazol, pentoxifylline, aspirin, clopidogrel) • Control of blood pressure, lipids, glucose


Conclusion

Patients with lower extremity occlusive disease can present with a variety of symptoms such as claudication, rest pain, and gangrene, or be asymptomatic. The history and physical examination can help predict location and severity of disease.

An ankle-brachial index is useful in determining the degree or severity of arterial insufficiency. A normal ratio of ankle to brachial systolic pressures is; less than 0.9 is consistent with claudication and lower numbers indicate increasing severity of obstruction. However, elderly patients may have stiff, noncompressible vessels, with elevated ABI values. Exercise can lower the ABI and sometimes aid in detection of occlusion disease.

Tobacco cessation, adequate control of blood pressure, lipids, and glucose, and initiation of an exercise program are important in the overall management of PAD. Pentoxifylline and cilostazol are the only drugs that have Food and Drug Administration indications for treatment of intermittent claudication; however, other agents have been used as well.

Pentoxifylline, which works by causing deformation of red blood cells, has been used with variable therapeutic success. Cilostazol, a phosphodiesterase inhibitor that impairs platelet aggregation, has been shown to increase walking distance by about 34% more than placebo. Cilostazol is contraindicated in patients with heart failure and has side effects of headache, dizziness, and diarrhea.

Aspirin and/or clopidogrel are almost always prescribed (in absence of contraindication or intolerance) in order to decrease thrombotic complications, and use of these drugs may slow disease progression/associated complications.


Resources


Burns P, Gough S, Bradbury AW. Management of Peripheral Arterial Disease in Primary Care. BMJ 2003; 326; 584-585.

Federman DG, Bravata DM, Kirsner RS. Peripheral Arterial Disease: A Systemic Disease Extending Beyond the Affected Extremity. Geriatrics 2004; 59; 26-34.

Frost L, et al. Incident thromboembolism in the aorta and the renal, mesenteric, pelvic, and extremity arteries after discharge from the hospital with a diagnosis of atrial fibrillation. Arch Intern Med 2001;161:272.

Hiatt WR Medical Treatment of Peripheral Arterial Disease and Claudication. N Engl J Med 2001; 344:1608-1621.

Hirsch AT, Criqui, MH, Treat-Jacobson D, et al. Peripheral Arterial Disease Detection, Awareness, and Treatment in Primary Care. JAMA 2001;286:1317-1324.

Olin JW. Management of Patients with intermittent Claudication. Int J Clin Pract 2002;56(9):687-693. Ouriel K. Peripheral arterial disease. Lancet 2001;358:1257-64.

Websites: Heart Information Network http://www.heartinfo.org/

http://www.medscape.com/viewarticle/438150


Hypertension in the Elderly

Learning Objectives


• Discuss the epidemiology of hypertension.

• Describe types of end-organ damage that can be caused by hypertension.

• Describe the pathophysiology and hemodynamic complications that can result from isolated systolic hypertension.

• Explain the classification system most commonly used to stage blood pressure disorders.

• List risk factors for hypertension.

• List medications that can cause or exacerbate hypertension.

• Outline goals and therapeutic interventions appropriate for elderly patients with hypertension.

• Describe the benefits of pharmacological treatment of hypertension and classes of agents most commonly used.

• Describe indications, contraindications, dosing guidelines and side effects of common antihypertensive drugs.


Definition and Epidemiology of Hypertension

Hypertension Definition:

• Systolic blood pressure (SBP) > 140 mmHg or diastolic blood pressure (DBP) > 90 mmHg • (Based on average of > 2 blood pressure (BP) measurements on each of > 2 office visits)

• Being told at least twice by a physician or other health care provider that you have high blood pressure • Taking antihypertensive medication

Incidence:

• Hypertension (HTN) affects ∼50 million Americans • Nearly 1 in 3 adults has high blood pressure

• Individuals at age 55 will have an approximately 90% lifetime risk for developing HTN. • Individuals between 40 – 70 years old have a doubling of CVD risk with each 20 mmHg systolic and 10 mmHg diastolic increase in blood pressure • In elderly age 65 – 74 years, ∼30% have increased SBP, 63% have increased SBP, increased DBP or both

Mortality: For each 1 mmHg increase in SBP, there is ∼1% increase in mortality over an 8 yr period.

Costs: In 2005, the estimated direct and indirect costs of high blood pressure is $59.7 billion.


Definition and Epidemiology of Hypertension

Approximately 50 million Americans have high blood pressure or hypertension (HTN), defined as a systolic blood pressure (SBP) of 140 millimeters of mercury or higher or diastolic blood pressure (DBP) of ninety millimeters of mercury or higher. Worldwide estimates are as high as 1 billion people affected by hypertension.

There is a relationship between increased blood pressure and cardiovascular disease (CVD) risk. With each increase of 20 mmHg in systolic BP or 10 mmHg in diastolic BP, patients between ages of 40 – 70 years will have an approximate doubling of risk for cardiovascular disease.

Estimates are for each millimeter of mercury increase in systolic blood pressure, the risk of mortality increases one percent over an eight-year period. About 63% of individuals between the ages of 65 and 74 years are hypertensive, about half with isolated systolic hypertension.

While antihypertensive therapy has been associated with reductions in cardiovascular events and stroke, current control rates are still below the community program Healthy People 2010 goal of 50%, and 30% individuals are unaware they are hypertensive.


End Organ Damage Caused by Hypertension

Organ Disorders Caused by Hypertensive Damage

Heart Coronary artery disease (angina pectoris, myocardial infarction) Heart failure (systolic, diastolic, left ventricular hypertrophy)

Eyes Papilledema Retinopathy (arterial narrowing, arterial nicking)

Kidneys Chronic renal insufficiency End-stage renal failure

Brain Stroke Transient ischemic attack

Vasculature

Abdominal aortic aneurysm Aortic dissection Peripheral arterial disease (legs, neck)

Hypertension is a complex disorder that affects not only blood pressure, but metabolic and structural integrity as well. Examples of disorders caused by hypertension-induced end-organ damage include congestive heart failure, retinopathy, and chronic renal insufficiency. Complications can be reduced through early identification, treatment, and monitoring.


Blood Pressure Classification

BP Classification SBP (mmHg) DBP (mmHg)

Normal < 120 and < 80

Prehypertension 120-139 or 80-89

Stage 1 Hypertension 140-159 or 90-99

Stage 2 Hypertension > 160 or > 100

BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure

The Seventh Report of the Joint National Committee of Detection, Evaluation, and Treatment of High Blood Pressure (or JNC 7) was recently released in 2003. The major changes since the last update in 1997 include the addition of the category of “prehypertension” and the merging of stages 2 and 3 hypertension.

Goal blood pressure is < 140/90 mmHg or < 130/80 mmHg for patients with diabetes or chronic kidney disease. Individuals in the prehypertension stage, if identified and started on these lifestyle modifications, can be helped by reducing blood pressure, decreasing progression to hypertension, and possibly preventing hypertension.


Risks Associated with Isolated Systolic Hypertension (ISH)

∼2-5 times greater risk of:

• Coronary artery disease • Cerebrovascular disease • Mortality in general

In patients older than 50 years, systolic blood pressure over 140 mmHg is a more important risk factor for cardiovascular disease risk than elevated diastolic blood pressure. When compared with isolated diastolic hypertension, isolated systolic hypertension is more likely to cause complications such as cardiovascular and cerebrovascular events. In fact, isolated systolic hypertension increases the risk of coronary artery disease, cerebrovascular disease, and mortality in general by about 2 to 5 times.

Since elevated systolic blood pressure is also a leading risk factor for stroke and other complications of hypertension in the elderly, early identification and management can help reduce associated morbidity and mortality.


Age-related Hemodynamic/Vascular Changes

Age-related Hemodynamic/Vascular Changes

• Lower cardiac output • Lower renin production • Unchanged stroke volume • Increased peripheral vascular resistance • Increased incidence of isolated systolic hypertension

The pathologic effects of isolated systolic hypertension are better understood through comparison of hemodynamic changes associated with aging. Elderly adults have a lower cardiac output and renin production than their younger counterparts. While stroke volume remains unchanged, progressive arterial stiffness increases peripheral vascular resistance. Isolated systolic hypertension occurs more frequently in the elderly secondary to decreased compliance of the large arteries, which become less able to absorb pressure in systole and less able to recoil during diastole. The increased pulse pressure increases risk for cardiovascular disease.


Risk Factors for Hypertension

Risk Factors for Hypertension

• Family history • Race (increased risk in African Americans) • Sex (increased risk in males) • Age (increased risk in elderly) • Sodium sensitivity • Obesity • Cigarette smoking • Alcohol abuse • Inactivity • Recreational drugs (e.g., cocaine) • Diet pills • Amphetamines

Risk factors for hypertension are similar to those for ischemic heart disease. Non-modifiable factors include heredity, race, gender and age. Factors that can be modified include sodium intake, alcohol consumption and activity levels.


Secondary Causes of Hypertension

Secondary Causes of Hypertension

• Sleep apnea • Drug-induced or relates causes • Chronic kidney disease • Primary aldosteronism • Renovascular disease • Chronic steroid therapy • Cushing’s syndrome • Pheochromocytoma • Coarctation of the aorta • Thyroid or parathyroid disease

The majority of patients have primary or essential hypertension, in which there is no underlying, fixable cause identified. However, patients need to be evaluated to rule out secondary causes of hypertension. In patients with an identified secondary cause, modifying or treating this underlying cause for hypertension may obviate the need for long-term hypertension treatment.


Medications that Cause or Exacerbate Hypertension

Medications that Cause or Exacerbate Hypertension

• Antidepressants (e.g., venlafaxine, MAO inhibitors with tyramine-containing foods) • Caffeine • Corticosteroids and mineralocorticoids • Cyclosporine and tacrolimus • Ethanol • Ergot alkaloids • Erythropoietin • Estrogens and oral contraceptives (with high estrogenic activity) • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Sympathomimetic agents (e.g., ephedra, pseudoephedrine, phenylephrine, CNS stimulants such as methylphenidate,

amphetamine) • Thyroid hormone excess

Several classes of therapeutic drugs are known to cause or exacerbate hypertension. They include antidepressants, oral decongestants such as phenylpropanolamine and analogues, corticosteroids, and nonsteroidal anti-inflammatory drugs. Avoiding these medications and using alternatives may help to reduce risk for hypertension or exacerbation of hypertension; however, some of these agents may not have viable alternatives, so careful monitoring may be needed.


Laboratory Tests/Diagnostic Procedures Before Initiating Treatment

Laboratory Tests/Diagnostic Procedures Before Initiating Treatment

• Electrocardiogram • Urinalysis • Blood glucose • Hematocrit • Serum potassium • Serum creatinine • Calcium • Lipid profile • Optional tests

• Urinary albumin excretion • Albumin/creatinine ratio

After history and physical examination, baseline laboratory and diagnostic measurements are recommended to determine the extent of left ventricular hypertrophy, proteinuria, renal dysfunction, and assess cardiovascular risk factors.


Management of Patients with Hypertension

Goals:

• Control BP with a minimum impact on quality of life • Prevent and reduce morbidity and mortality associated with HTN

Nonpharmacological Measures:

• Weight loss in overweight or obese individuals • Regular aerobic exercise (e.g. brisk walking) at least 30 minutes daily for most days of week • Cessation of smoking • Dietary modification

• Reduction of alcohol consumption • Reduction of sodium intake • Reduction of dietary saturated fat and cholesterol • Maintenance of adequate dietary potassium and calcium



Pharmacological Measures:

• Diuretics • Beta-blockers • ACE inhibitors • Calcium channel blockers • Angiotensin II receptor antagonists • Alpha-1 blockers • Combination drug therapy –

• Most patients will require 2 or more antihypertensives to achieve goal • If BP > 20/10 mmHg above goal, consider starting therapy with 2 drugs, one of which usually is a thiazide diuretic

The goals of antihypertensive therapy are to control blood pressure with a minimum impact on quality of life, and to prevent morbidity and mortality associated with hypertension. Both pharmacological and nonpharmacological measures play a role in achieving these therapeutic goals.

Lifestyle modifications recommended for lowering blood pressure and reducing cardiovascular risk include weight loss, regular exercise, and reduction of alcohol and sodium intake, following a DASH plan (or Dietary Approaches to Stop Hypertension). Implementing lifestyle modifications can reduce blood pressure and should be continued, even if drug therapy is needed.



Since most patients with hypertension, especially those over age of 50 years, will reach diastolic blood pressure goal when systolic blood pressure is at goal, primary focus is on achieving the systolic blood pressure goal. Goal blood pressure is < 140/90 mmHg in most patients, but in patients with diabetes or renal disease, blood pressure target should be < 130/80 mmHg.

Pharmacological measures include the use of diuretics, beta-blockers, angiotensin converting enzyme inhibitors and calcium channel blockers. The recommendations from the JNC 7 state that the treatment of HTN in the elderly should be similar to younger patients, with initial therapy to include a thiazide or thiazide-like diuretic.

Benefits of pharmacologic treatment can include: decrease in all-cause mortality, strokes, and coronary events.


Treatment Algorithm for Hypertension


Treatment Algorithm for Hypertension

Lifestyle modifications are always the first-line of treatment in patients with hypertension. Examples of lifestyle modification include weight loss in those who are overweight or obese, regular exercise, and adoption of a diet low in sodium.

Patients not at goal with lifestyle modifications should begin drug therapy. The goal for most patients is a systolic blood pressure less than 140 mmHg and a diastolic pressure of < 90 mmHg. For patients with diabetes or chronic kidney disease, target or goal blood pressure is < 130/80 mmHg.

Patients with stage 1 HTN should be started on thiazide-type diuretics; however, ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, or a combination may be considered.

Those with stage 2 HTN should consider combination therapy including a thiazide –type diuretic and an ACEI or ARB, beta-blockers, or calcium channel blockers. For patients with comorbid disease states, choice of medications will be determined based these factors or compelling indications.


Drug Therapy Considerations

Compelling Indications

• Diabetes mellitus*: Consider ACEI, diuretic, beta-blocker, ARB, or CCB

• Heart failure: Consider ACEI, diuretic, beta-blocker, ARB, aldosterone antagonist

• High coronary disease risk: Consider diuretic, beta-blocker, ACEI, CCB

• Myocardial infarction: Consider beta-blocker (non-ISA), ACEI, aldosterone antagonist (if post-MI LV dysfunction)

• Chronic kidney disease*: Consider ACEI, ARB

• Recurrent stroke prevention: Consider diuretic, ACEI



Drugs Which May Have Favorable Effects on Comorbidities

Atrial tachycardia and fibrillation: Consider beta-blockers, Calcium channel blockers (non-DHP)

Benign Prostatic Hyperplasia/hypertrophy (BPH): Consider alpha-blockers (unless the patient is African American and has heart failure).

Essential tremor: Consider beta-blockers

Migraine: Consider beta-blockers

Osteoporosis: Consider thiazides

Peri-operative hypertension: Consider beta-blockers

Drugs Which May Have Unfavorable Effects on Comorbid Conditions

Asthma or reactive airway disease: Avoid beta-blockers

Second or third degree heart block: Avoid beta-blockers

Peripheral vascular disease (PVD): Caution beta-blockers

Renal insufficiency: Caution potassium-sparing diuretics



ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker, CCB = calcium channel blocker; ISA = intrinsic sympathomimetic activity

* Goal blood pressure in diabetes or chronic kidney disease is < 130/80 mmHg; for most other patients, goal blood pressure is < 140/90 mmHg

Some antihypertensives can have beneficial effects on other disease states. Therefore, choosing one drug for treatment of multiple disease states can be very cost-effective – these considerations are often discussed as “compelling indications.”

On the other hand, some antihypertensives can exacerbate or worsen comorbid diseases and should be avoided or used with caution in these patients. As recommended by the JNC 7 algorithm for management of hypertension, always review the patient’s comorbid disease states when making decisions on best drug choices for the individual.


Treatment of Isolated Systolic Hypertension (ISH)

• Thiazide/thiazide-like diuretics • Long-acting dihydropyridine calcium channel blockers • Beta-blockers • ACE inhibitors

The treatment of isolated systolic hypertension has been studied in a number of clinical trials. Thiazide-like diuretics (chlorthalidone) and long-acting calcium channel blockers like amlodipine are considered initial therapy for this type of hypertension. In patients not at goal, recommendations from the JNC 7 state that elderly patients should be treated like other patients with hypertension following treatment algorithms.


Treatment of Hypertension with Diuretics

Compelling Indications:

• Thiazide and thiazide-like diuretics should be considered first-line in most patients. • Patients with concomitant heart failure and edema may require switching to a loop diuretic for diuresis • Patients with impaired left ventricular dysfunction and class III or IV heart failure may require addition of an aldosterone antagonist.

Advantages: Inexpensive, easy to administer (one dose per day), well-tolerated

Agents:

• Thiazides (e.g., hydrochlorthiazide, chlorthalidone) – Creatinine clearance > 30 mL/minute is required for efficacy • Thiazide-like agents (e.g., indapamide, metolazone) – Creatinine clearance > 20 mL/minute is required for efficacy • Loop diuretics (e.g., furosemide, torsemide, bumetanide) - Dosed daily in normal renal function; close monitoring is

required to prevent fluid loss and dehydration and electrolyte abnormalities. • Aldosterone antagonists – Potassium sparing, consider discontinuing additional potassium supplements when starting these agents.


Treatment of Hypertension with Diuretics

Adverse Reactions:

• ∼5 - 7% short-term increase in total cholesterol with thiazide/ thiazide-like and loop diuretics • Increase in insulin resistance and glucose levels • Electrolyte wasting (K+, Mg++, Na+) with loop and thiazide/thiazide-like diuretics • Hypercalcemia with thiazide/thiazide-like diuretics (decreased calcium may occur with loop diuretics) • Hyperuricemia (may exacerbate gout) • Azotemia

Diuretics are considered a first line of treatment hypertension. They are particularly effective in patients with concomitant congestive heart failure and edema. Thiazides are also useful in increasing arterial compliance. In general, diuretics have several advantages over other classes of drugs in that they are inexpensive, easy to administer, and are well-tolerated by most patients.

The disadvantages of diuretics are mainly related to their potential side effects. For example, patients on diuretic therapy may experience a five to seven percent increase in total cholesterol. This condition is usually temporary, and may not be evident after one year and is not a contraindication to use. Diabetic patients may experience an increase in insulin resistance and glucose levels.

Other side effects of diuretics include electrolyte wasting, hyperuricemia (which may exacerbate gout), and azotemia, which is more common in elderly patients. These side effects tend to increase in frequency and severity as the dosage is increased.


Treatment of Hypertension with Beta-Blockers

Compelling Indications: • Coronary artery disease (CAD), post-myocardial infarction, diabetes, heart failure, migraines, tachyarrhythmias

Contraindications: • Asthma, diabetes in patients with frequent hypoglycemic episodes, bradyarrhythmias

Agents: • Avoid agents with ISA or intrinsic sympathomimetic activity (e.g., acebutolol, penbutolol, pindolol) • Beta-1 selective agents should be first-line (e.g., atenolol, betaxolol, bisoprolol, metoprolol, pindolol) • Atenolol and nadolol are renally eliminated and should be avoided in patients with renal insufficiency • Use cautiously in patients with peripheral arterial disease

Adverse Drug Reactions: • May increase triglycerides and decreased HDL cholesterol • May mask symptoms of hypoglycemia • CNS effects (e.g., depression, sleep disturbances) • Bronchoconstriction • Fatigue • Bradycardia • Impotence • Leg cramps


Treatment of Hypertension with Beta-Blockers

While not as effective as diuretics in reducing the risk of cardiovascular events, beta-blockers have been somewhat helpful in reducing overall morbidity and mortality associated with coronary artery disease (or CAD) in patients with isolated systolic hypertension. They are often prescribed for patients with migraines, arrhythmias, and angina.

Beta-blockers can be classified based on various properties. For example, atenolol is a water-soluble beta-blocker with beta-1 selectivity. Agents that are beta-1 selective are more cardioselective, in effect, than non-beta-selective agents, and these may be preferred in certain patients (such as those with airway disease who do not require regular doses of beta-agonist inhalers). However, at higher doses, beta-selectivity is reduced. Other beta-blockers with beta-1 selectivity include betaxolol, bisoprolol, metoprolol, and pindolol. Another property of some beta-blockers is ISA or intrinsic sympathomimetic activity. Beta-blockers like acebutolol that have intrinsic sympathomimetic activity do not allow for a low resting heart rate and therefore may precipitate angina and thus should be avoided in these patients.

Although they reduce the risk of recurrent infarctions and mortality, beta-blockers, as with any drug class, do have associated side effects. In addition to decreasing levels of high-density lipoprotein and increasing triglycerides, beta-blockers may mask symptoms of hypoglycemia. Other side effects attributed to this class of drugs include depression, sleep disturbances, fatigue and bradycardia.


Treatment of Hypertension with Calcium Channel Blockers

Compelling Indications: CAD, diabetes

Contraindications: Bradyarrhythmias (non-dihydropyridines only) Dihydropyridines: nifedipine (Procardia®), amlodipine (Norvasc®), felodipine (Plendil®), nisoldipine (Sular®):

• Effective at increasing arterial compliance and decreasing BP • 

• Indicated for patients with low rennin states (e.g., elderly, African-Americans) • 

• May worsen cardiovascular events • 

• Side effects: Leg edema, flushing, reflex tachycardia, headache, lightheadedness

Non-dihydropyridines: diltiazem (Cardizem®) and verapamil (Isoptin®):

Useful in treating patients with angina, atrial fibrillation, diastolic heart failure

Negative inotropic effects may worsen systolic heart failure

Side effects: Constipation, abdominal discomfort, atrioventricular (AV) block


Treatment of Hypertension with Calcium Channel Blockers

Calcium channel blockers, especially dihydropyridines, have been found to be very effective at lowering blood pressure and are particularly useful in the elderly. Unfortunately, they may increase the risk of cardiovascular events by promoting reflexive tachycardia. Diltiazem and verapamil are more useful in treating patients with angina, atrial fibrillation, and diastolic heart failure although they do not have a significant effect on overall mortality. The negative inotropic effects of these two drugs may exacerbate systolic congestive heart failure symptoms.


Treatment of Hypertension with ACE Inhibitors

Compelling Indications: Heart failure, renal insufficiency, diabetes, post myocardial infarction, coronary artery disease, recurrent stroke prevention

Contraindications: Bilateral renal artery stenosis, pregnancy, and patients who have experienced angioedema from ACE inhibitors or ARBs, Caution use in renal failure, renovascular hypertension, volume depletion.

Agents

• Non-prodrugs • e.g., captopril, lisinopril

• Dual-route elimination • (hepatic + renal elimination) e.g., fosinopril

• Post-HF • FDA-approved labeling: captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril • Not FDA-approved labeling: moexipril, trandolapril, benazepril


Treatment of Hypertension with ACE Inhibitors

Adverse Reactions:

• Acute renal failure (use with caution in patients with serum Creatinine > 2.5 mg/dL)

• Dry, hacking cough (∼3-15% of pts.)

• Hyperkalemia - Consider discontinuing additional potassium supplements when starting these agents.

• Angioedema (rare)

Monitoring: BP at end of each dosing interval; monitor for hyperkalemia and changes in renal function.

Angiotensin-converting enzyme inhibitors or ACE inhibitors prevent or at least slow the progression of systolic congestive heart failure. They also help to prevent recurrent myocardial infarction, reducing morbidity and mortality in patient’s post-myocardial infarction with or without impaired left ventricular function.

They have been used to treat diabetics with nephropathy and hypertension and may be beneficial in preventing recurrent stroke. Side effects of angiotensin-converting enzyme inhibitors include acute renal failure, hyperkalemia, angioedema (rare), and a dry, hacking cough, which is believed to result from the accumulation of bradykinin.

It is important to evaluate the 24-hour control of ACE inhibitor therapy by monitoring blood pressure at the end of a dosing interval. It is generally recommended to also stop any additional potassium supplements when starting an ACE inhibitor.


Treatment of Hypertension with Angiotensin-II Receptor Antagonists (ARBs

Compelling Indications: Systolic HF in patients intolerant to ACEI, Diabetes, chronic kidney disease.

Contraindications: Bilateral renal artery stenosis, pregnancy, and patients with hypersensitivity reactions to drug and patients with angioedema (especially if related to ACEI or other ARB).

Agents • Losartan (Cozaar®) • Valsartan (Diovan®) • Irbesartan (Avapro®) • Candesartan (Atacord®) • Eprosartan (Teveten®) • Telmisartan (Micardis®) • Olmesartan (Benicar®)

Advantages/Disadvantages: Reduced bradykinin production reduces incidence of dry cough produced by ACE inhibitors. Potassium sparing, consider discontinuing additional potassium supplements when starting these agents.

Adverse Reactions: Hyperkalemia, renal dysfunction, and hyperkalemia and angioedema (rare)


Treatment of Hypertension with Angiotensin-II Receptor Antagonists (ARBs

Angiotensin II receptor antagonists or ARBs directly block angiotensin II at the receptors (and are not believed to cause an increase in bradykinin levels the way ACE inhibitors do). ARBs have a reduced incidence of dry cough as compared to ACE inhibitors, which is believed to be related to the difference in mechanism of action.

ARBs may be useful in treating patients with systolic congestive heart failure. Drugs in this class include losartan, valsartan, irbesartan and candesartan. Losartan may be dosed once or twice daily, especially at higher doses. The other drugs are usually dosed once daily. The side effect profile of these drugs is similar to ACEI with exception of lower incidence of cough.

While rare, angioedema has been reported with ARBs and use is contraindicated in patients who have developed angioedema from an ACE inhibitor. When starting an ARB, it is usually best to stop any additional potassium supplements due to hyperkalemia that is associated with these agents.


Treatment of Hypertension with Alpha-1 Blockers

Compelling Indication: Benign prostatic hyperplasia/hypertrophy (BPH)

Contraindications: Postural hypotension, heart failure

Agents: Prazosin (Minipress®), terazosin (Hytrin®), doxazosin (Cardura®)

Advantages/Disadvantages: Drugs of choice for benign prostatic hyperplasia; Caution orthostatic hypotension, may increase risk of heart failure compared to thiazides.

Alpha-1 blockers antagonize alpha-1 receptors in the periphery to reduce total peripheral resistance through direct vasodilatory effects. Although they are the drug of choice for patients with benign prostatic hyperplasia / hypertrophy (or BPH) and hypertension, they are generally reserved for refractory patients because they produce more adverse effects than some other commonly used antihypertensive agents.

The recent “ALLHAT” or “Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial” demonstrated use of doxazosin to treat hypertension put patients at an increased risk for developing heart failure as compared to chlorthalidone, a thiazide diuretic. Alpha-1 blockers can cause orthostatic hypertension, and doses are usually given at bedtime, with caution to patients to arise from either supine or sitting positions carefully and slowly.


Treatment of Hypertension with Combination Drugs

Compelling Indication: Patients requiring multiple drug therapy

Contraindications: Same as for each individual drug

Agents: • Beta-blockers and diuretics • ACE inhibitors and diuretics • Angiotensin II receptor antagonists and diuretics • Calcium channel blockers and ACE inhibitors • Potassium-sparing diuretics and hydrochlorothiazide (HCTZ)

Advantages: • Potassium-sparing diuretics or ACE inhibitors and HCTZ combinations may decrease hypokalemia • Combination pills may be more convenient for patients on multiple drug therapy

Most patients will require 2 or more drugs to achieve goal BP. Combination therapy can be a good choice for patients who are already on multiple drug therapies to treat their hypertension or other comorbidities. Combining two drugs into one pill has the advantage of being more convenient for the patient. Combination products are in fixed doses, so titration may be accomplished first using individual drug components.


Summary: Managing the Hypertensive Elderly Patient

Treatment of HTN and ISH in elderly can help reduce morbidity/mortality

Diuretics, dihydropyridine CCBs, or ACE inhibitors can reduce arterial stiffness in elderly patients and reduce BP

Drugs of choice in elderly (depending on comorbid disease states): • Consider diuretics, calcium channel blockers • Also useful: ACE inhibitors, ARBs • ARBs

General Recommendations: • Individualize • Start low and go slow & sometimes say no (for contraindications) • Monitor for adverse effects

In summary, there appears to be ample clinical evidence that pharmacotherapeutic treatment of hypertension, including isolated systolic hypertension, can reduce morbidity and mortality in elderly patients. Diuretics, dihydropyridines, and angiotensin converting enzyme inhibitors are all helpful in reducing the arterial stiffness in large arteries. While diuretics and calcium channel blockers are the drugs of choice for treating hypertension in the elderly, ACE inhibitors and angiotensin-II receptor antagonists also have therapeutic value. Compelling indications should be considered based on individual patient comorbidities.

Whichever drugs are selected, therapy must be individualized, starting with low doses and increasing slowly. Patients should be closely monitored for efficacy and adverse effects. Follow-up with adjustment of medications is usually recommended at about once monthly intervals until goal is achieved. More frequent visits may be needed for stage 2 hypertension or individuals with multiple comorbidities. Once goal blood pressure is achieved, follow-up may be reduced to 3- to 6-month intervals. Lifestyle modification should be initiated and reinforced with all patients, with emphasis on compliance.


Resources



Chobanian AV, Bakris GL, Black HR, et al. and the National High Blood Pressure Education Program Coordinating Committee. JNC 7 Express: The Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. December 2003. NIH Publication No. 03-5233 (also published in JAMA 2003; 289;2560-2572).

Chobanian AV, Bakris GL, Black HR, et al. and the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42; 1206 – 1252.

Psaty, B. M., Heckbert, S. R., Koepsell, T. D., et al. The risk of myocardial infarction associated with antihypertensive therapies. JAMA 1995; 274: 620-5.

SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 266: 3255-64.

Websites: American Heart Association http://www.americanheart.org Heart Information Network http://www.heartinfo.org/


Warfarin Therapy



• Understand processes contributing to thromboembolism.

• Explain the mechanism of action of the anticoagulant warfarinList indications for warfarin therapyIdentify. contraindications to warfarin therapy.

• Describe pharmacokinetic and pharmacodynamic properties of warfarin.

• Recognize clinically significant drug interactions with warfarin, including food-drug interactionsIdentify adverse effects and complications associated with warfarin therapy.

• Understand general principles for warfarin dosing.

• Identify monitoring parameters for efficacy and safety when using warfarin therapy.

• Describe strategies for managing overanticoagulation secondary to warfarin therapy.

• Understand implications of generic substitution of warfarin products.


Understand Processes Contributing to Thromboembolism

Objective 1 – Understand processes contributing to thromboembolism.

Virchow’s Triad refers to three major factors which contribute to thromboembolism: venous stasis, vascular injury, and hypercoagulability. Venous stasis may result from prolonged bed rest, congestive heart failure, and other conditions, which can lead to concentration of activated clotting factors locally. Vascular injury, secondary to injury or trauma to vessel walls (e.g. venipuncture, bone fracture, surgery) or chemical irritation from medications or other agents, can trigger thromboembolic formation.

Injury to tissue may stimulate the coagulation cascade as well as platelet adhesion, platelet activation (secondary to release of adenosine diphosphate, thrombin, epinephrine, or other substances), and platelet aggregation. When coagulation cascade activity exceeds the body’s natural fibrinolytic system to prevent thrombus formation, hypercoagulable states can develop.


Explain the Mechanism of Action of the Anticoagulant Warfarin

Objective 2 – Explain the mechanism of action of the anticoagulant warfarin



Warfarin was developed as a medication to prevent or treat thromboembolic diseases, and its mechanism of action is best understood through its relationship with vitamin K. Vitamin K is a cofactor for carboxylation of vitamin K-dependent proteins, such as coagulation factors II, VII, IX, and X. These vitamin K-dependent factors require carboxylation for activation (for biologic activity).

By interfering with the cyclic interconversion of vitamin K and its 2,3-epoxide (vitamin K epoxide), warfarin inhibits formation of the vitamin K-dependent clotting factors. In addition to an anticoagulant effect, warfarin also inhibits carboxylation of the regulatory anticoagulants, proteins C and S.



Objective 2 – Explain the mechanism of action of the anticoagulant warfarin

Adapted from CHEST 2004; 126; 205S.



The carboxylation reaction requires the reduced form of vitamin K (vitamin K H2) and is linked to the oxidation of this reduced form to vitamin K epoxide. Vitamin K epoxide is then recycled to the reduced form of Vitamin K through two steps.

The first step is sensitive to vitamin K antagonists, like warfarin, while the second step is relatively insensitive to vitamin K antagonists. Treatment with warfarin leads to depletion of the reduced form of vitamin K and therefore limits the carboxylation of vitamin K-dependent coagulant proteins.

The effect of warfarin can be counteracted by giving vitamin K1 (ingested in food or administered therapeutically), and patients treated with large doses of vitamin K1 can become warfarin resistant up to a week.


List Indications for Warfarin Therapy

Warfarin is effective for numerous indications as listed on Table 1. Although effectiveness has not been established by randomized trial, warfarin is also indicated for prevention of systemic embolism in high-risk patients with mitral stenosis. For most indications, an INR range of 2 to 3 is appropriate.



Primary Prophylaxis

Low-risk General Surgery Patients (i.e. minor procedure, < 40 years old, and no additional risk factors) No prophylaxis aside from early ambulation.

Moderate-risk General Surgery Patients (i.e. undergoing nonmajor procedure and age 40 – 60 years or have additional risk factors; or those undergoing major operations and are < 40 years with no additional risk factors) Low-dose heparin (e.g. 5000 units twice daily) or low molecular weight heparin (LMWH).*

High-risk General Surgery Patients (i.e. those undergoing nonmajor surgery and are > 60 years or have additional risk factors; or those undergoing major surgery who are > 40 years or have additional risk factors.)

* For patients at high risk of bleeding or as an adjunct to anticoagulant-based prophylaxis, mechanical methods of prophylaxis are recommended such as graduated compression stockings (GCS) or intermittent pneumatic compression (IPC). GCS should be used with caution in patients with arterial insufficiency.



Other Categories:

Gynecologic and Urologic - Thromboprophylaxis is recommended for all patients undergoing major gynecologic surgery or major, open urologic procedures using low-dose heparin two or three times daily.

Orthopedic Surgery - For patients undergoing elective total hip or knee arthoplasty, any of the following are recommended: LMWH, fondaparinux, or adjusted-dose warfarin (INR range 2 – 3). For patients undergoing hip fracture surgery, any of the following are recommended: low-dose heparin, LMWH, fondaparinux, or adjusted-dose warfarin (INR range 2 – 3). For hip or knee arthoplasty or for hip fracture surgery, thromboprophylaxis is recommended for at least 10 days.

Trauma - All trauma patients with at least one risk factor for venous thromboembolism should receive thromboprophylaxis.

Medical - Acutely ill medical patients admitted to the hospital for congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors should receive prophylaxis with low-dose heparin or LMWH.

Critical Care - All patients admitted to an intensive care unit should be assessed for their risk of venous thromboembolism, with most patients receiving thromboprophylaxis.



Most hospitalized patients have one or more risk factors for venous thromboembolism or VTE, and the risk factors are generally cumulative. For example, a patient undergoing hip fracture surgery may also have additional risk due to advanced age, presence of injury at the site needing repair, and immobility following surgery. The recommended approach for prophylaxis against thromboembolism (i.e. thromboprophylaxis) depends upon the patients’ risk factors and risk associated with their illness or procedure.

No prophylaxis aside from early ambulation is required for low-risk general surgery patients with no added risk factors. In moderate-risk surgical patients, low-dose heparin or low-molecular weight heparin is recommended. In higher-risk surgery patients, generally low-dose heparin or low molecular weight heparins (LMWH) are recommended. For patients at high risk of bleeding or as an adjunct to anticoagulant-based prophylaxis (such as with high-risk surgery patients with multiple risk factors), mechanical methods of prophylaxis are recommended such as graduated compression stockings (GCS) or intermittent pneumatic compression (IPC).

Thromboprophylaxis is recommended for all patients undergoing major gynecologic surgery or major, open urologic procedures using low-dose heparin two or three times daily. For patients undergoing elective total hip or knee arthoplasty, any of the following are recommended: LMWH, fondaparinux, or adjusted-dose warfarin (INR range 2 – 3). For patients undergoing hip fracture surgery, any of the following are recommended: low-dose heparin, LMWH, fondaparinux, or adjusted-dose warfarin (INR range 2 – 3).

For hip or knee arthoplasty or for hip fracture surgery, thromboprophylaxis is recommended for at least 10 days, and for total hip replacement or hip fracture surgery, extended prophylaxis may be for up to 28 to 35 days after surgery. All trauma patients with at least one risk factor for venous thromboembolism should receive thromboprophylaxis. Acutely ill medical patients admitted to the hospital for congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors should receive prophylaxis with low-dose heparin or LMWH. All patients admitted to an intensive care unit should be assessed for their risk of venous thromboembolism, with most patients receiving thromboprophylaxis.

Please refer to the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy for additional recommendations regarding prevention of venous thromboembolism and specific product information for additional dosing considerations.




Treatment of Venous Thrombosis*

Usual duration of oral anticoagulant therapy:

• At least 3 months in patients with first-episode of DVT due to transient (reversible) cause.

• At least 6 – 12 months for idiopathic DVT (i.e. DVT occurring in absence of a known identifiable risk factor). Consideration may be given for indefinite anticoagulant therapy for first-episode idiopathic DVT.

• At least 6 – 12 months for patients with first-episode of DVT who have documented deficiency of antithrombin, deficiency of protein C or protein S, or the factor V Leiden or prothrombin 20210 gene mutation, homocysteinemia, or high factor VIII levels. Consideration may be given for indefinite therapy as for patients with idiopathic DVT.

• 12 months for patients with first-episode of DVT who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions (e.g. combined factor V Leiden and prothrombin 20210 gene mutations). Consideration may be given to indefinite anticoagulant therapy for these patients.



Indefinite therapy is indicated for patients with:

• 2 episodes objectively documented DVT

• Thrombosis complicating malignancy

• Idiopathic venous thrombosis, antiphospholipid antibodies, or thrombophilic conditions (e.g. protein C or protein S deficiency, prothrombin 20210 gene mutation, etc.) as described above.

*Note: lower intensity warfarin therapy (INR of 1.5 – 2) following full-dose anticoagulation has been studied for prevention of recurrent venous thromboembolism, and it has been demonstrated to be more effective than placebo but less effective than standard-intensity therapy (INR 2 – 3).

General recommendations are for goal INR 2 – 3 for treatment of venous thrombosis, with avoidance of high-intensity and lower intensity therapy. Risks vs. benefits of anticoagulant therapy must be taken into account for each patient.



For treatment of venous thrombosis, optimal duration of treatment is influenced by whether the thrombosis is: idiopathic, associated with ongoing risk factors, such as malignancy, or secondary to a reversal cause. In acute deep vein thrombosis or DVT, recommendation is for initial treatment with heparin or LMWH for at least 5 days.

(In patients with severe renal failure, heparin is recommended over LMWH). Warfarin is recommended to be started together with heparin/LMWH on the first treatment day and heparin/LMWH discontinued when INR is stable and greater than 2. Usual duration of anticoagulant therapy with warfarin is illustrated on the slide.

Longer duration of therapy is given for idiopathic thrombosis and when there is an ongoing risk factor. Treatment is generally longer for patients with proximal vein thrombosis than distal thrombosis and for patients with recurrent thrombosis vs. those with a single episode. Lab evidence of thrombophilia (i.e. tendency to the occurrence of thrombosis) may also necessitate longer duration of therapy.



Treatment of Pulmonary Embolism (PE)

Usual duration of oral anticoagulant therapy:

• At least 3 months in patients with acute PE secondary to a transient (reversible) risk factor • At least 6 – 12 months in patients with first-episode of idiopathic PE, with consideration of indefinite therapy. • At least 6 – 12 months for patients with first-episode of PE who have documented deficiency of antithrombin,

deficiency of protein C or protein S, or the factor V Leiden or prothrombin 20210 gene mutation, homocysteinemia, or high factor VIII levels. Consideration may be given for indefinite therapy as for patients with idiopathic PE.

• 12 months for patients with first-episode of PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions (e.g. combined factor V Leiden and prothrombin 20210 gene mutations). Consideration may be given to indefinite anticoagulant therapy for these patients.

• Longer duration treatment may be indicated for patients with recurrent thrombosis • Indefinite therapy is indicated for patients with > 2 episodes of PE

Treatment regimens for pulmonary embolism (or PE) are similar to that of DVT, with goal INR of 2 to 3. In treatment of pulmonary embolism, short-term heparin or LMWH are recommended with overlap of warfarin as with DVT. At least 5 days of heparin or LMWH are recommended, with heparin preferred in patients with severe renal insufficiency.

A longer duration of warfarin therapy is considered for idiopathic thrombosis and when there is an ongoing risk factor. Treatment should also be longer for patients with recurrent thrombosis vs. those with a single episode. For indefinite anticoagulant therapy, reassessment of risk vs. benefit should be performed periodically.



Table 2 – An:thrombo:c Therapy in Valvular Heart Disease

Valve Disorder Recommenda:ons

Rheuma:c mitral valve disease (mitral stenosis and/or mitral regurgita:on)

History of systemic embolism or paroxysmal or chronic AF

Long-‐term warfarin (INR target range 2 – 3)

NSR & LA diameter > 5.5 cm Consider long-‐term warfarin (INR target range 2 – 3) based on risk factors for thromboembolism, esp. paLent’s age, LA size, and hemodynamic severity of lesion.

Recurrent systemic embolism despite adequate warfarin therapy

Add aspirin (75 – 100 mg/day) to long-‐term warfarin.

If unable to take aspirin, add dipyridamole (400 mg/day) or clopidogrel

Mitral valve prolapse (MVP)

No systemic embolism, unexplained TIA or AF Avoid long-‐term anLthromboLc therapy

Documented, unexplained TIA Long-‐term, low-‐dose aspirin therapy (50 – 162 mg/day)

Documented systemic embolism or recurrent TIAs, despite aspirin therapy

Long-‐term warfarin therapy (INR target range 2 – 3)



Table 2 – An:thrombo:c Therapy in Valvular Heart Disease

Valve Disorder Recommenda:ons

Mitral annular calcifica:on (MAC)

Systemic embolism, not documented to be calcific embolism

Long-‐term warfarin therapy (INR target range 2 – 3)

Aor:c valve and aor:c arch disorders

Mobile aorLc atheroma and aorLc plaque > 4 mm, measured by TEE

Warfarin therapy

No other indicaLon for anLcoagulaLon Long-‐term warfarin therapy is not recommended

Infec:ve endocardi:s

Mechanical prostheLc valve ConLnue warfarin long-‐term therapy, unless specific contraindicaLons exist (When making the therapeuLc decision, consider the presence of comorbid factors and the success of anLbioLc therapy).

Nonbacterial thrombo:c endocardi:s (NBTE)

Systemic embolism or PE OR Disseminated cancer, or debilitaLng disease, with asepLc vegetaLons seen on echocardiography

Heparin therapy

AF = atrial fibrillation; NSR = normal sinus rhythm; LA = left atrium; TIA = transient ischemic attack; TEE = transesophageal echocardiography



Antithrombotic therapy is administered for prevention of systemic embolism in patients with valvular heart disease, as shown in Table 2.Please note I-N-R data has been included when specified. Please refer to the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy for additional recommendations regarding antithrombotic therapy in valvular heart disease.



Table 4a – Recommenda:ons for Mechanical Prosthe:c Heart Valves

Pa:ent Characteris:cs Recommenda:ons*

St. Jude Medical bileaflet valve in aorLc posiLon, normal size LA, NSR OR Carbomedics bileaflet aorLc valve, normal size LA, NSR OR Medtronic-‐Hall LlLng disk mechanical aorLc valve, normal size LA, NSR

Goal INR range 2 – 3

TilLng disk valves or bileaflet valves in the mitral posiLon

Goal INR range 2.5 – 3.5

Caged ball or caged disk valves OR Mechanical valves and addiLonal risk factors (e.g. AF, myocardial infarcLon, lel atrial enlargement, endocardial damage, low ejecLon fracLon) OR Systemic embolism despite adequate therapy with oral anLcoagulants

Goal INR range 2.5 – 3.5 AND aspirin 75 to 100 mg/day

LA = left atrium; NSR = normal sinus rhythm; AF= atrial fibrillation) *Unfractionated heparin or LMWH should be used until INR is at a therapeutic level for 2 consecutive days



Table 4b – Recommenda:ons for Bioprosthe:c Heart Valves

Concomitant Condi:on Recommenda:ons

Valve in the mitral posiLon Oral anLcoagulants for the first 3 months aler valve inserLon (goal INR range 2 – 3)*

Valve in aorLc posiLon Oral anLcoagulants for the first 3 months aler valve inserLon (goal INR range 2 – 3)* or aspirin 80 – 100 mg/day

Valve and history of systemic embolism Oral anLcoagulants for 3 – 12 months (goal INR range 2 – 3)

Valve and evidence of lel atrial thrombus at surgery

Long-‐term oral anLcoagulant therapy (goal INR range 2 – 3); OpLmal duraLon of therapy is uncertain

Valve with atrial fibrillaLon Long-‐term oral anLcoagulant therapy (goal INR range 2 – 3)

Valve and NSR Long-‐term aspirin therapy (75 – 100 mg/day)

NSR = normal sinus rhythm *Heparin (unfractionated or LMWH) until INR at therapeutic levels for 2 consecutive days

Recommendations are that all patients with mechanical heart valves receive oral anticoagulants (See Table 4a). The American College of Chest Physicians recommends an INR goal of 2.5 to 3.5 for most patients with mechanical prosthetic valves and an INR goal of 2 to 3 for low-risk patients with bileaflet mechanical valves (e.g. St. Jude) in the aortic position. For patients with bioprosthetic heart valves (as listed in Table 4b), an INR goal of 2 to 3 is suggested.



AF = atrial fibrillation *High Risk Factors for Stroke: Prior ischemic stroke/TIA or systemic embolus, Age > 75 years, Poor left ventricular systolic function and/or congestive heart failure, History of hypertension or diabetes mellitus.

Table 3 – Risk Stra:fica:on and Recommended Therapy for Atrial Fibrilla:on

Risk Factor Long-‐term Therapy

Persistent and Paroxysmal AF Plus Any high-‐risk factor*

Warfarin (INR target range 2 – 3)

Persistent or Paroxysmal AF PLUS Age 65 – 75 years without any other risk factors

Aspirin 325 mg/day OR Warfarin (INR target range 2 – 3)

Persistent or Paroxysmal AF PLUS < 65 years and with no other risk factors

Aspirin 325 mg/day

AF PLUS Mitral stenosis

Warfarin (INR target range 2 – 3)

AF PLUS ProstheLc heart valve

Warfarin therapy, with target INR +/-‐ aspirin, depending on valve type and posiLon and paLent risk factors



Duration of therapy is usually indefinite for patients with atrial fibrillation or A-Fib. In patients with very infrequent and brief episodes of A-Fib, benefits of warfarin therapy may be offset by inconvenience and bleeding risk. Warfarin therapy should be strongly considered in patients with frequent or prolonged paroxysms of A-Fib, particularly those with stroke risk factors.



Anticoagulation for Elective Cardioversion:

• Treat potential precipitants of atrial fibrillation (i.e. thyrotoxicosis, pneumonia, congestive heart failure) prior to attempting elective DC cardioversion.

• Warfarin therapy for 3 weeks before and at least 4 weeks after elective DC cardioversion of atrial fibrillation patients (Target INR range 2 – 3).

Anticoagulation recommendations for elective cardioversion are warfarin therapy (I-N-R target range 2 to 3) for 3 weeks before and at least 4 weeks after elective DC cardioversion of atrial fibrillation patients. Alternatively, atrial fibrillation patients can undergo anticoagulation then undergo transesophageal echocardiography (TEE) and have cardioversion performed without delay if no thrombi are seen.

For these patients, adjusted-dose warfarin should still be continued until normal sinus rhythm has been maintained for at least 4 weeks. Although data are limited, risk of embolism following cardioversion in patients who have been in atrial fibrillation for < 48 hrs appears to be low. However, recommendations are to use anticoagulation during the pericardioversion period.



Prevention Against Coronary Artery Disease

For primary prevention in patients with at least one moderate risk for a coronary event (based on age and cardiac risk factor profile with a 10-year risk of cardiac event of > 10%), aspirin (75 – 162 mg/day) is recommended over either no antithrombotic therapy or warfarin. For patients at high risk of events in whom INR can be monitored without difficulty, low dose warfarin can be considered (with target INR of about 1.5).

For patients with chronic coronary artery disease without prior myocardial infarction, long-term warfarin is not recommended.

For patients after myocardial infarction, after acute coronary syndrome, and with stable coronary artery disease, aspirin is recommended (75 – 325 mg/day initially and in doses of 75 – 162 mg indefinitely). For patients with contraindications to aspirin, long-term clopidogrel is recommended.

Anticoagulation after Acute Myocardial Infarction (MI)

Class I Recommendations

• Warfarin may be given to aspirin-allergic, post-ST elevation MI (STEMI) patients without stent implanted (INR 2.5 – 3.5) or with stent implanted and clopidogrel 75 mg/day administered concurrently (INR 2 – 3)

• Warfarin (INR 2.5 – 3.5) is alternative to clopidogrel in aspirin-allergic patients after STEMI who do not have a stent implanted.

• Warfarin (INR 2 – 3) should be prescribed for post-STEMI patients with persistent or paroxysmal atrial fibrillation. • In post-STEMI patients with left ventricular (LV) thrombus noted on an imaging study, warfarin should be prescribed at

least 3 months and considered for indefinite duration in patients without an increased risk of bleeding.



Class IIa Recommendations

• For post-STEMI patietns < 75 years without specific indications for anticoagulation who can have their INR reliably monitored, consider warfarin alone (INR 2.5 – 3.5) or warfarin (INR 2 – 3) in combination with aspirin (75 – 162 mg/day) for secondary prevention.

• Consider warfarin for post-STEMI patients with LV dysfunction and extensive regional wall motion abnormalities.

Class IIb Recommendations

Warfarin may be considered in post-STEMI patients with severe LV systolic dysfunction with or without CHF

KEY:

Class I – Benefit >>> Risk. Procedure should be performed/administered.

Class II – Benefit >> Risk. Additional studies with focused objectives needed. It is reasonable to perform procedure/administer treatment.

Class IIa – Recommendation in favor of treatment or procedure being useful/effective. Some conflicting evidence from multiple randomized trials or meta-analyses

Class IIb – Recommendation in favor of treatment or procedure being useful/effective. Some conflicting evidence from single randomized trial or nonrandomized studies.



For primary prevention against coronary artery disease (CAD), American College of Chest Physicians recommends aspirin or for those who are aspirin-intolerant, clopidogrel is recommended.

Low-dose warfarin may be considered an alternative for patients at high risk of events in whom INR can be monitored without difficulty. Class I, IIa, and IIb recommendations for long-term anticoagulation after acute myocardial infarction from the American College of Cardiology/American Heart Association are listed on the screen.


Identify Contraindications to Warfarin Therapy

Contraindications to Warfarin Therapy

• Hypersensitivity to warfarin or any component • Pregnancy • Hemorrhagic disorders or blood dyscrasias • Active bleeding • Recent or contemplated surgery or anesthesia • Malignant hypertension • Warfarin-induced skin necrosis • Inadequate laboratory facilities • Noncompliant or unreliable patients • Fall history

Numerous medical conditions contraindicate or caution against use of warfarin. Active bleeding is usually considered a contraindication to oral anticoagulants. Severity and site of bleeding must be evaluated for each individual. Oral anticoagulants generally should be withheld for:

1.) active ulcers or overt bleeding of the gastrointestinal, respiratory or genitourinary tract; 2.) cerebrovascular hemorrhage; 3.) cerebral or dissecting aorta aneurysms; 4.) pericarditis or pericardial effusions; 5.) bacterial endocarditis (due to increased risk of hemorrhage except for patients who are at high risk for embolism, i.e. mechanical prosthetic valves, recurrent thromboembolic disease).

Evaluate patients at increased risk of falls or history of falls. Factors to consider include physical factors (e.g. neurological, visual musculoskeletal, gait), mobility, environmental issues (e.g. loose carpet, slippery bathtubs) and concurrent medications. “Benefits” must be weighed against “risks” of therapy for each individual.


Describe Pharmacokinetic and Pharmacodynamic Properties of Warfarin

Properties of Warfarin

Absorption: rapid from GI tract; nearly 100% bioavailability

Distribution: >98% protein bound, primarily to albumin

Metabolism: liver to inactive metabolites; S-isomer metabolized by CYP450 2C9 (and to lesser extent by CYP450 3A4) with R-isomer by CYP450 1A2 (and to lesser extent by CYP450 3A4)

Elimination: t½ = 36 to 42 hours; steady state in about 5 to 9 days

Patient Response: variable, due to differences in absorption, clearance, individual response to drug concentration and adherence to prescribed regimen

Warfarin is available commercially as a racemic mixture of R- and S-isomers. When administered orally, warfarin is absorbed rapidly from the gastrointestinal tract, with nearly 100% bioavailability. Warfarin circulates highly bound to plasma proteins, primarily albumin, and warfarin is metabolized in the liver to inactive metabolites. The S-isomer is approximately 2 to 5 times more potent than the R-isomer and is metabolized through different cytochrome P450 enzyme pathways.

Elimination half-life of warfarin is approximately 36 to 42 hours, and steady state is generally achieved in about 5 to 9 days. Patient response to warfarin is variable, due to differences in absorption, clearance, and inherent variation in individual response to drug concentration as well as adherence to prescribed regimen.


Recognize clinically significant drug interactions with warfarin, including food-drug interactions

Table 6 – Drugs that May INCREASE An:coagulant Effect*

Alcohol (e.g. binge drinking; acute ingesLon)

Amiodarone (Cordarone®, Pacerone®)

CimeLdine (Tagamet®)

Ciprofloxacin (Cipro®)

Clarithromycin (Biaxin®)

Cotrimoxazole (Septra®, Bactrim®)

Erythromycin

Fluconazole (Diflucan®)

Itraconazole (Sporanox®)

Ketoconazole (Nizoral®)

LovastaLn (Mevacor®)

Metronidazole (Flagyl®)

*Not a complete listing of medications that can alter the effect of warfarin



Table 7 – Drugs that May DECREASE An:coagulant Effect*

Alcohol (e.g. chronic ingesLon)

Carbamazepine (Tegretol®)

Cholestyramine (Questran®, Questran Light®)

Phenobarbital (Luminal®)

Phenytoin** (DilanLn®)

Rifampin

Sucralfate (Carafate®)

Vitamin K

*Not a complete listing of medications that can alter the effect of warfarin

**There may be a transient increase in anticoagulant effect by phenytoin (since both warfarin and phenytoin are highly protein bound drugs)



Some medications may increase or decrease the anticoagulation effect of warfarin and risk for associated adverse effects. Interactions can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions refer to interactions that alter the amount or concentration of warfarin delivered to its site of action.

Examples include reduced absorption of warfarin with concomitant cholestyramine administration; inhibition of warfarin metabolism by metronidazole; and induction of warfarin metabolism by rifampin. Pharmacodynamic interactions refer to interactions that alter the actions of warfarin without affecting its drug concentration. An example is coadministration of antiplatelet agents such as aspirin or ibuprofen and increased risk of bleeding of patients on warfarin.



Table 8 – Examples of Foods High in Vitamin K*

Food Por:on Size

Beverages

Green Tea 1 cup

Fats

Mayonnaise 7 tbsp

Oils (soybean, canola, salad) 7 tbsp

Vegetables

Broccoli, raw and cooked ½ cup

Brussels sprouts 5 sprouts

Cabbage, raw 1 ½ cups, shredded

Collard greens ½ cup, chopped

Cucumber with peel 1 cup

Endive, raw 2 cups, chopped

Green scallion, raw 2/3 cup, chopped



Vitamin K-containing nutritional supplements and foods rich in vitamin K, such as green leafy vegetables, can interact with warfarin to reduce its anticoagulant effect. This occurs because ingestion of vitamin K bypasses the reductase step in recycling of vitamin K, which is normally blocked by warfarin. However, these foods should be consumed in moderation rather than avoided, most importantly to maintain a balanced, healthy diet

Table 8 – Examples of Foods High in Vitamin K*

Food Por:on Size

Vegetables

Kale, raw leaf ¾ cup

Le/uce, raw 1 ¾ cups, shredded

Mustard greens, raw 1 ½ cups, chopped

Parsley, raw and cooked 1 ½ cups, chopped

Spinach, raw leaf 1 ½ cups

Turnip greens, raw 1 ½ cups, chopped

Watercress, raw 3 cups



Drug interactions can occur between warfarin and alternative therapies such as herbal products or dietary supplements. These interactions can be more difficult to characterize and predict because of differences in manufacturing standards and regulations with alternative therapies. However, these interactions can produce significant changes in level of anticoagulation and must be managed carefully.



Patients should be instructed not to stop or start any medications, including over-the-counter medications, herbal products, natural remedies, or nutritional supplements without first talking to a health care provider about potential drug interactions. Also, patients should inform the pharmacist, physician, or nurse managing his or her warfarin therapy of any changes in his or her medication regimen and diet.


Identify adverse effects and complications associated with warfarin therapy

Factors that May Affect Bleeding Risk

• Intensity of anticoagulation therapy • Patient characteristics • Concomitant medications • Length of anticoagulant therapy • Age > 65 years • Prior history of stroke or gastrointestinal bleeding

The most common adverse effect of warfarin is bleeding. The risk of bleeding is influenced by: intensity of anticoagulation therapy, patient characteristics, concomitant medications, and length of therapy. Patients older than 65 years or those with previous history of stroke or gastrointestinal bleeding may also be at increased risk for bleeding on warfarin therapy. Benefits of therapy, i.e. reduction in thromboembolism, must be weighed against risk of adverse events for each patient.


Identify adverse effects and complications associated with warfarin therapy

Non-hemorrhagic Adverse Effects

Rash

• Maculopapular rash (i.e. both discolored and elevated areas on the skin) and purpuric skin eruptions (i.e. small hemorrhagic lesions) have been reported.

Skin Necrosis

• Not common; Reported Incidence rates of 1:1000, 1:5000, and 1:10000 • Usually observed on 3rd to 8th day of therapy • Pathogenesis is unknown • Skin necrosis may be secondary to extensive thrombosis of venules and capillaries within the subcutaneous fat • If patients develop this complication, discontinue warfarin and initiate heparin. Warfarin is considered contraindicated, but there have been reports of successful retreatment of patients requiring long-tern anticoagulation.

Purple Toe Syndrome

• Characterized by a dark cutaneous lesion with blue discoloration of the feet and lower leg • Purple toe syndrome may be related to cholesterol microembolization, with crystals being released from atherosclerotic plaques. It may also be related to toxic effect of warfarin on the capillaries. • Symptoms resolve with discontinuation of warfarin.

Nonhemorrhagic adverse reactions of warfarin are rare but important to identify and can include: rash, skin necrosis, purple toe syndrome, and other uncommon adverse effects such as drug-induced hepatitis, alopecia, tracheobronchial calcification, and priapism.


Understand general principles for warfarin dosing

Anticoagulant activity, as measured by increase in INR, first becomes detectable about 1 – 2 days following start of warfarin therapy and is due primarily to factor VII depletion. Recent evidence suggests that reduction of factor II is more important for the therapeutic anticoagulant effect of warfarin than reduction of the relatively shorter t½ factors such as factor VII.

Therefore, the initial reduction of factor VII induced by warfarin therapy does not represent adequate anticoagulation despite an increase in INR. This concept is important clinically, and this is the basis for overlapping heparin with warfarin during treatment of patients with thrombosis, until prothrombin time (PT)/international normalized ratio (INR) tests have been prolonged into the therapeutic range for at least 4 days.



Warfarin Dosing Considerations

• Typical adult starting dose is 5 mg • Starting doses < 5 mg may be appropriate in the following patients:

• Elderly • Liver disease • Congestive heart failure • Impaired nutrition • Low weight • High risk for bleeding (including drug interactions) • Elevated baseline PT/INR values

Use of a loading dose is unnecessary in most patients, and starting therapy with an average daily maintenance warfarin dose of 5 mg usually results in an INR of 2 in around 4 to 5 days. If treatment is not urgent (e.g. chronic stable atrial fibrillation), treatment can be begun out-of-hospital with an anticipated maintenance dose of 4 to 5 mg daily, which usually achieves therapeutic anticoagulant effect in about 5 days, although it may take longer to achieve a stable INR. The reduction of PT/INR is similar with either a 5 mg or 10 mg dose.”

In contrast, the anticoagulant protein C is reduced more rapidly with the 10 mg dose. Also more patients have excessive anticoagulation (INR > 3) with the 10 mg loading dose. However, there is room for flexibility in selecting a starting dose of warfarin; some clinicians prefer to use a larger starting dose (e.g. 7.5 mg to 10 mg) if there is urgency in obtaining a therapeutic INR or in patients who are very obese. Starting doses of less than 5 mg may be appropriate for elderly patients or those with liver disease, impaired nutrition, low weight, or high risk for bleeding (incl. drug interactions).

Lower initial doses may be considered also for patients with elevated baseline PT/INR values.



Warfarin Dosing Considerations

• If rapid anticoagulant effect required (e.g. treatment of thrombosis), administer heparin with warfarin for at least 4 days until therapeutic INR

• Adjust warfarin dosage by no more than 5 – 20% at one time (modification is usually based as a percentage of weekly total dose)

• Perform repeat INR checks for assessment.

• Evaluate patient adherence and understanding of therapy

When a rapid anticoagulant effect is required when initiating warfarin therapy, heparin should be given concurrently with warfarin for at least 4 days. For example, during treatment of patients with thrombosis, recommendations are to provide overlapping heparin with warfarin until PT/INR tests have been prolonged into the therapeutic range for at least 4 days.

In general, warfarin dosage should be adjusted by no more than 5 – 20% at one time, with repeat INR checks to assess effectiveness of the dose adjustments. Individualized therapy and close monitoring are necessary due to warfarin’s narrow therapeutic index and multiple factors affecting response.

Patient adherence and understanding of therapy is crucial. Information about therapy (e.g. indication, drug interactions, diet, missing doses, lab tests and monitoring, complications, when to contact health care practitioner, etc.) should be provided to the patient and reinforced frequently.



Table 11 – Managing Oral An:coagula:on During Invasive Procedures

Clinical Situa:on Guidelines

Low risk for thromboembolism* • DisconLnue warfarin therapy ∼ 4 days before surgery and allow INR to return to near-‐normal levels

• If intervenLon increases a risk for thrombosis, begin short-‐term low-‐dose heparin (UFH) therapy (5000 units SC) or a prophylacLc dose of LMWH and resume warfarin therapy

• AlternaLvely, a low dose of UFH or prophylacLc dose of LMWH can also be used preoperaLvely

Intermediate risk for thromboembolism • Stop warfarin therapy ∼ 4 days before surgery & allow INR to fall

• About 2 days preoperaLvely, give either low-‐dose heparin (5000 units SQ) or a prophylacLc dose of LMWH

• PostoperaLvely, give low-‐dose heparin (or LMWH) and warfarin





High risk for thromboembolism** •  DisconLnue warfarin therapy ∼ 4 days before surgery, and allow INR to return to normal range

•  About 2 days preoperaLvely, as the INR falls, give full-‐dose heparin or full-‐dose LMWH

•  Heparin can be given SC on an outpaLent basis, and presurgically, aler hospital admission, as a conLnuous IV infusion, and disconLnued 5 hrs before surgery; AlternaLvely, conLnue SC heparin or LMWH therapy unLl 12 to 24 hrs before surgery

Low risk for bleeding •  Lower the warfarin dose 4 or 5 days before surgery to reach an INR of 1.3 to 1.5 at Lme of surgery

•  Resume warfarin therapy postoperaLvely, supplement if necessary, with low-‐dose heparin or a prophylacLc dose of LMWH



*e.g. No venous thromboembolism (VTE) for > 3 mo; Atrial fibrillation, without history of stroke; Bileaflet mechanical cardiac valve in the aortic position

**e.g. VTE in < 3 mo; History of VTE, mechanical cardiac valve in mitral position; Old-model cardiac valve (ball/cage)

Management of oral anticoagulants during invasive procedures is based on clinical situation. Recommendations are listed on the screen.



Dental procedures •  PaLents at high risk for bleeding: disconLnue warfarin therapy

•  PaLents not at high risk for bleeding: warfarin therapy should not be disconLnued

Dental procedures, with need to control local bleeding

•  Administer a tranexamic acid or epsilon amino caproic acid mouthwash, without interrupLng anLcoagulant therapy


Identify monitoring parameters for efficacy and safety when using warfarin

INR = (Patient’s PT)ISI / (Mean of Normal PT)



Monitoring for efficacy of warfarin therapy is performed via PT or prothrombin time tests and are generally reported as INR values or international normalized ratio values. The PT responds to reduction of 3 of the 4 vitamin K-dependent clotting factors (II, VII, and X). During the first few days of warfarin therapy, prolongation of PT in seconds reflects mainly a reduction of factor VII, while later on in therapy it also reflects a reduction of factors X and II.

Efforts to standardize reporting of PT values resulted in development and adoption of the international normalized ratio (INR). The INR can be viewed as the PT ratio that would have been obtained if the World Health Organization (WHO) international reference preparation (IRP) for thromboplastin reagent had been used to perform the PT test on the same sample with the manual PT technique. INR is based on patient’s PT value and the ISI for the thromboplastin being utilized and is a calculated value (with no units).

Although it is not perfect and its accuracy has been questioned in patients with liver disease, the reliability of the INR exceeds alternatives such as the PT ratio or the PT itself and is valid in this situation as well.



Recommendations for Frequency of PT/INR Monitoring • Daily until therapeutic range achieved and maintained for at least 2 consecutive days • Followed by PT/INR 2 – 3 times weekly x 1 – 2 weeks • Then PT/INR less often, depending on stability of test results

Monitoring of PT/INR is usually performed daily until therapeutic range has been achieved and maintained for at least 2 consecutive days, then it is monitored 2 – 3 times weekly for 1 to 2 weeks, then less often, depending on stability of test results. If PT/INR response remains stable, frequency may be reduced to as long as every 4 weeks, although some evidence suggests that more frequent testing will lead to greater time in therapeutic range. If adjustments to dose are required, then the cycle of more frequent monitoring is repeated until a stable dose response is achieved again.



Monitoring for Adverse Effects • Baseline Hgb/Hct and periodically thereafter • Daily observation for signs or symptoms of bleeding • Daily observation for development of any other adverse events • If on heparin therapy, monitor platelet counts at baseline and periodically thereafter

Monitoring should be performed for complications to warfarin therapy, primarily hemorrhagic adverse effects. A baseline hemoglobin (Hgb) and hematocrit (Hct) should be obtained and followed periodically during therapy initiation. Patients should be evaluated for signs and symptoms of bleeding (e.g. easy bruising, blood in urine or stool, etc.) or development of any adverse effects. If on heparin therapy, activated partial thromboplastin time (aPTT) should be monitored for therapeutic effect as well as monitoring of platelet counts (baseline and periodically) in addition to signs and symptoms of bleeding.


Describe strategies for managing overanticoagulation secondary to warfarin therapy

Degree of INR Elevation:

• Usually patients with INR > 9 receive vitamin K to minimize time over-anticoagulated; 5 mg is the recommended oral dose, with repeat INR test within 24 hrs.

• For patients with INR values between 5 and 9, either of the following is suggested: • Withhold 1 – 3 doses of warfarin, monitor INR more frequently, and when INR falls within therapeutic range, restart warfarin at a lower dose, if indicated.

• Withhold 1 – 2 doses of warfarin and give 2.5 mg oral vitamin K; recheck INR within 24 hrs, and restart warfarin therapy when indicated

Risk for Bleeding or Thromboembolic Complications: It is preferable to administer vitamin K to patients at high risk for bleeding; patients with high underlying risk for thromboembolic complications with INR between 5 and 9 should probably not receive vitamin K, if possible.

Laboratory Availability for Repeat INR Testing: Ideally, patients receiving vitamin K should have a repeat INR performed within 24 hrs to allow prompt restart of warfarin therapy should over-correction occur.

For situations where the patient will not have access to a laboratory in this time frame (e.g. weekends or holidays), temporary interruption of warfarin therapy may be preferable to allow for more flexibility with scheduling of repeat INR tests (with INR declining over 2 – 3 days vs. 24 hrs).



Even with close monitoring, patients on warfarin often present with elevated INR. Management involves clinical judgment and includes holding warfarin, administering vitamin K (phytonadione), fresh frozen plasma (FFP) or prothrombin complex concentrates. Published recommendations stratify risk based on bleeding and INR value. Optimal management depends on several factors including: degree of INR elevation, risk for bleeding or thromboembolic complications, and laboratory availability for repeat INR testing.



TABLE 13 – 2004 Guidelines for Management of Pa:ents with High INR Values with or without Bleeding

INR Symptoms Treatment

3.5 < INR < 5 NO bleeding and rapid reversal NOT indicated for reasons of surgical intervenLon

Dose can be lowered or next dose omi/ed and resumed at lower dose.

If INR only minimally elevated, dose may NOT need to be adjusted.

5 < INR < 9 NO bleeding and rapid reversal NOT indicated for reasons of surgical intervenLon

1)  Omit next one or two doses of warfarin and monitor INR, then resume at lower dose once INR is in therapeuLc range.

2) Omit next dose of warfarin and give vitamin K PO 1 – 2.5 mg* (Round dose to 2.5 mg or ½ of 5 mg tablet).

Use second approach if paLent a high risk for bleeding.





5 < INR < 9 NO bleeding BUT rapid reversal required for urgent surgical intervenLon or dental extracLon

Administer vitamin K PO 2 – 4 mg* (Round to 2.5 – 5 mg); expect a reducLon in INR in 24 hrs.

If INR sLll elevated at 24 hrs, give addiLonal vitamin K PO 1 -‐ 2 mg dose (Round to 2.5 mg).

> 9 NO bleeding Hold warfarin therapy and administer vitamin K PO 5-‐10 mg*and expect INR to be reduced in 24 – 48 hrs.

May repeat vitamin K dose if necessary.

-‐-‐-‐ Very rapid reversal is indicated because of : Serious bleeding Or Major warfarin overdose (INR > 20)

Hold warfarin therapy and administer vitamin K (10mg by slow IV infusion) +

FFP or prothrombin complex depending on urgency of situaLon.

May need to repeat vitamin K dose every 12 hrs.





-‐-‐-‐ Life-‐threatening bleed Or Serious warfarin overdose

Hold warfarin therapy and administer prothrombin complex concentrate or recombinant factor VIIa supplemented with vitamin K (10mg by slow IV infusion).

Repeat the procedure if necessary, depending on INR.

*Oral vitamin K available commercially only as 5 mg tablet strength.

Adapted from guidelines published in CHEST 2004; 126:204S-233S



Vitamin K

• Available as oral 5 mg tablets and injection for IV or SC administration • Dilute IV for infusion and rate not to exceed 1 mg/min • IM administration is contraindicated • Caution: Patients treated with large doses of vitamin K can become warfarin resistant for up to a week. • Reversal of overanticoagulation with IV vitamin K typically occurs within a day; adequate response may be seen as early as 8 hrs

Vitamin K is available in oral 5 mg tablets and parenteral injection for intravenous or subcutaneous administration. IM administration is contraindicated (due to possibility of inducing hemorrhage or hematoma at the injection site). Subcutaneous administration should be reserved for patients unable to take oral medications and in whom venous access is unavailable. IV administration is indicated when other routes are not feasible, and it is useful when oral absorption of vitamin K may be impaired, patients are unable to take oral drugs, or situations requiring prompt reversal due to active bleeding or very high INR values.



Fresh Frozen Plasma (FFP)

• Indicated for immediate reversal of anticoagulation • Dose depends on situation, typical starting dose ~10 – 15 ml/kg (rounded to nearest unit of FFP); • Adverse reactions potential similar to other blood products • Monitor for effect by repeat INR testing and ability to control bleeding

Fresh frozen plasma or FFP is indicated for use when immediate reversal of anticoagulation is needed (e.g. overanticoagulation with severe or life-threatening bleed or emergency pre-operative reversal of anticoagulation). FFP is prepared by centrifugation of anticoagulated whole blood and freezing of the separated plasma within 6 hrs of collection.

Before use, FFP must be thawed and used within 2 hrs to avoid a significant loss in coagulant activity. Average volume of thawed unit of FFP ~ 250 ml; a typical unit contains all of the coagulation proteins. Dose depends upon situation and ~10 – 15 ml/kg is a typical starting dose (rounded to nearest unit of FFP). Monitor for effect by repeat INR testing and ability to control bleeding.

Adverse reaction potential with FFP transfusion is similar to other blood products and can include: allergic reactions, infectious complications, hemolysis, fluid overload, and a rare syndrome called transfusion-related acute lung injury (due to leukocyte aggregation in pulmonary vessels)



Prothrombin Complex Concentrates (PCCs)

• Reserved for life-threatening bleeding due to excessive anticoagulation • Starting dose typically 30 international units/kg but may be up to 50 international units/kg • Repeated INR checks are necessary to ensure appropriate effect • At a minimum, INR should be checked before giving PCCs and 30 – 60 mins after transfusion of the PCCs.

Prothrombin complex concentrates or PCCs are reserved for life-threatening bleeding due to excessive anticoagulation. PCCs are impure mixtures of vitamin K-dependent proteins. They may be produced as “three-factor” or “four-factor” concentrates, which contain factors II, IX, X, and VII. PCCs also typically contain the inhibitor proteins C and S. Preference is for “four-factor” concentrates also containing protein C and S. Potency of the various commercially available products is expressed as international units (IU), referring to factor IX activity. Starting dose is typically 30 IU/kg.

In life-threatening bleed, the dose can be increased up to 50 IU/kg for fast response. Rapid infusion (exceeding 25 IU/min) should be reserved for life-threatening bleeds and to the first 500 – 1000 IU of the total dose; the rate of infusion for the remaining dose should not to exceed 25 IU/min. Overdosage of PCCs may activate the hemostatic system and increase risk of thrombosis or lead to disseminated intravascular coagulation.

Repeated INR checks are necessary to ensure appropriate effect; at a minimum, INR should be checked before giving PCCs and 30 – 60 mins after transfusion of the PCCs. PCCs generally contain small amounts of heparin to reduce thrombogenicity. Adverse reactions may occur such as: allergic reactions, transmission of blood-borne viruses (although this is reported to be low risk due to pretreatment of products with virus inactivation procedures), heparin-induced thrombocytopenia due to heparin contained in the preparations, and thromboembolic complications (including disseminated intravascular coagulation).


Understand implications of generic substitution of warfarin products

There are several AB-rated brands of warfarin available. If a change in brand of warfarin occurs, more frequent PT/INR monitoring is required to assess changes in intensity of anticoagulation and the possibility of dosing adjustments should be considered. Patients should be educated to inform health care providers of any change in color and shape of their warfarin tablets as this can indicate a change in strength and manufacturer or brand of drug.


Resources


Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. CHEST 2004; 126: 240S – 233S.

Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing Oral Anticoagulation Therapy: Clinical and Operational Guidelines. Gaithersburg, MD: Aspen Publishers, Inc. 2001.

Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand H, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornator JP, Pearle DL, Sloan MA, Smith SC Jr. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to revise the 1999 Guidelines on the Management of Patients with Acute Myocardial Infarction). Circulation 2004: 110: 588 – 636.

Buckley NA, Dawson AH. Drug Interactions with Warfarin. The Medical Journal of Australia 1992; 157: 479 – 483. Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic Therapy for Venous Thromboembolic Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. CHEST 2004; 126: 401S – 428S.

Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of Venous Thromboembolic Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. CHEST 2004; 126: 338S – 400S. Klasco RK (Ed): DRUGDEX® System. Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires 3/2005).


Resources

Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S. Hemorrhagic Complications of Anticoagulant Treatment: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. CHEST 2004; 126: 287S – 310S.

Halbmayer WM. Rational, High Quality Laboratory Monitoring Before, During, and After Infusion of Prothrombin Complex Concentrates. Thrombosis Research 1999; 95 (4 suppl 1): S25 – S30.

Hellstern P. Production and Composition of Prothrombin Complex Concentrates: Correlation Between Composition and Therapeutic Efficiency. Thrombosis Research 1999; 95 (4 suppl 1): S7 – S12.

Pindur G, Morsdorf S. The Use Prothrombin Complex Concentrates in the Treatment of Hemorrhages Induced by Oral Anticoagulation. Thrombosis Research 1999; 95 (4 suppl 1): S57 – S61.

Salem DN, Stein PD, Al-Ahmad A, Bussey HI, Horstkotte D, Miller N, Pauker SG. Antithrombotic Therapy in Valvular Heart Disease – Native and Prosthetic: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. CHEST 2004; 126: 457S – 482S.

Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic Therapy in Atrial Fibrillation: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. CHEST 2004; 126: 429S – 456S.

module 5 - pharmacotherapy for cardiovascular disorders

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