OVERVIEW ON ACC/AHA GUIDELINE ON TREATMENT OF BLOOD CHOLESTEROL

Done by: Abdalrhman Alanizi, PharmD Intern

OBJECTIVES:▪ Review the 2013 ACC/AHA Recommendations on Treatment of Blood Cholesterol

by Statin Therapy▪ Brief review the 2016 ACC Guidelines for Non-statin Therapies

OUTLINE: ▪ Introduction▪ Classification of Recommendations and strength of Evidence, 2013 ACC/AHA & NHLBI ▪ Classification of four statin benefit groups▪ Recommendations on primary & secondary prevention of ASCVD (management of blood

cholesterol)▪ Classification of statins (based on intensity)▪ Recommendations for monitoring statin therapy▪ Safety recommendation on statin therapy ▪ Insufficient response to statin therapy▪ Brief review of 2016 ACC recommendations on non-statin therapy for lowering blood

cholesterol▪ Summery

INTRODUCTION: ▪ “The goals of the American College of Cardiology (ACC) and the American Heart Association (AHA) are to prevent cardiovascular diseases; improve the management of people who have these diseases through professional education and research; and develop guidelines, standards, and policies that promote optimal patient care and cardiovascular health. Toward these objectives, the ACC and AHA have collaborated with the National Heart, Lung, and Blood Institute (NHLBI) and stakeholder and professional organizations to develop clinical practice guidelines for assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk, management of blood cholesterol in adults, and management of overweight and obesity in adults.”

INTRODUCTION: ▪ In November 2013 the ACC/AHA published guidelines on Blood Cholesterol Treatment. ▪ The previous guidelines (2004 Adult Treatment Panel III) focused on titrating the dose of

anti-hyperlipidemic agent based on level of LDL-C, until achieving the goal of LDL-C level

▪ The current 2013 ACC/AHA guidelines changed the focus to put the primary and secondary prevention of Atherosclerotic Cardiovascular Diseases (ASCVD) the first priority by ASCVD risk reduction in four statins-benefit groups, but not by achieving a specific LDL-C level

▪ After the publication of 2013 ACC/AHA guidelines, an issue has raised about the role of non-statin therapy

▪ In 2016, the ACC published an “Expert Consensus Decision Pathway on the Role of Non-Statin Therapies or LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk”

This guideline is “based on using data from randomized controlled trials (RCTs) and systematic reviews and meta-analyses of RCTs to update the clinical practice recommendations for the treatment of blood cholesterol levels to reduce ASCVD risk.”

CLASSIFICATION OF RECOMMENDATIONS AND LEVEL OF EVIDENCE, 2013 ACC/AHA

CLASSIFICATION OF FOUR STATIN BENEFIT GROUPS

▪The ACC/AHA classified the patients into four groups, these groups are called “four statin benefit groups”▪These groups were identified, based on large and consistent body of evidence, for whom the likelihood of reducing the risk of ASCVD event or death outweighs the risk of developing serious statin adverse event

CLASSIFICATION OF FOUR STATIN BENEFIT GROUPS

▪ These groups are:1. Patient with Clinical ASCVD2. Patient, without Clinical ASCVD, age > 21 year, who has primary

elevation in LDL-C level defined as LDL-C > 190 mg/dl3. Patient, without Clinical ASCVD, whose age between 40-75 years,

LDL-C level between 70-189 mg/dl, and diabetic4. Patient, without Clinical ASCVD, whose age between 40-75 years,

LDL-C level between 70-189 mg/dl, without diabetes, and with an estimated 10-years ASCVD risk > 7.5 %

2013 ACC/AHA RECOMMENDATIONS ON PRIMARY & SECONDARY PREVENTION OF ASCVD▪ There was no data from large RCTs have evaluated the outcomes of titrating statin dose to achieve a specific LDL-C level▪ Based on large RCTs, this guideline focuses on reducing the risk of ASCVD by a fixed dose of statin (specific intensity of statin) in the 4 statin benefit groups▪ In each group, a specific intensity of statin therapy should be initiated unless there is a barrier (e.g. contraindication, intolerability, ….)▪After initiating of statin therapy, LDL-C level is monitored to evaluate patient’s adherence to statin therapy.

2013 ACC/AHA RECOMMENDATIONS ON SECONDARY PREVENTION OF ASCVD▪ 1- Patient with Clinical ASCVD:▪ASCVD is defined, by ACC/AHA, by having one or more of the following:

Acute coronary syndromes, a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin

2013 ACC/AHA RECOMMENDATIONS ON SECONDARY PREVENTION OF ASCVD▪ 1- Patient with Clinical ASCVD:

▪Men or women, Age ≤75 y and no safety concerns* initiate or continue High-intensity statin (Class 1, Evidence A)- A (strong)▪Men or women, Age >75 y or safety concerns* initiate or continue Moderate-intensity statin (Class 1, Evidence A)

* Safety recommendation section

2013 ACC/AHA RECOMMENDATIONS ON PRIMARY PREVENTION OF ASCVD

▪ 2- Patient, without Clinical ASCVD, who has primary elevation in LDL-C level defined as LDL-C > 190 mg/dl:▪Rule out secondary causes of hyperlipidemia (table1) (Class1, Evidence B)- B(moderate)▪Age ≥21 years old initiate High-intensity statin, if no safety concern (Class1, Evidence B)- B(moderate)▪ LDL-C lowering non-statin therapy may be considered to further reduce LDL-C if not reaching 50% reduction from baseline(Class IIb, Evidence C)- E (Expert Opinion)

TABLE 1

2013 ACC/AHA RECOMMENDATIONS ON PRIMARY PREVENTION OF ASCVD▪ 3- Patient, without Clinical ASCVD, whose age between 40-75 years, LDL-C level between 70-189 mg/dl, and diabetic:

▪ Initiate or continue moderate-intensity statin (Class 1, Evidence A)- A (strong) ▪Consider high-intensity statin, if no safety concern, when ≥7.5% 10-years ASCVD risk by using the Pooled Cohort Equation (Class IIa, Evidence B)- E (Expert Opinion)

2013 ACC/AHA RECOMMENDATIONS ON PRIMARY PREVENTION OF ASCVD▪ 4- Patient, without Clinical ASCVD, whose age between 40-75 years, LDL-C

level between 70-189 mg/dl, without diabetes, and with an estimated 10-years ASCVD risk > 7.5 % :

▪ Estimate 10-y ASCVD risk using the Risk Calculator based on the Pooled Cohort Equations* (Class 1, Evidence B)- E (Expert Opinion)▪ If ≥7.5% 10-y ASCVD risk initiate or continue a moderate or high-intensity

statin (Class 1, Evidence A)- A (strong)▪ It is reasonable to offer treatment with a moderate-intensity statin if

estimated 10-years ASCVD risk of 5% to <7.5% (Class IIa, Evidence B)- C (weak)

* http://tools.acc.org/ASCVD-Risk-Estimator/

CLASSIFICATION OF STATINS (BASED ON INTENSITY)

▪The maximum tolerated intensity of statin should be used in individuals for whom a high- or

moderate-intensity statin is recommended but not tolerated

(Class I, Evidence B)- B(moderate)

RECOMMENDATIONS FOR MONITORING STATIN THERAPY ▪ Adherence to medication and lifestyle, therapeutic response to statin therapy, and

safety should be regularly assessed, these done by: ▪ Perform baseline fasting lipid panel and then 4–12 weeks after initiation or dose

adjustment, and every 3–12 months thereafter (Class I, Evidence B)- A(strong)▪ Screen and treat type 2 diabetes according to current practice guidelines (Class I,

Evidence B)▪ Other safety measurements should be measured as clinically indicated (Class I,

Evidence B)- A(strong)▪ Other safety measurements include:▪ CK▪ ALT

RECOMMENDATIONS FOR MONITORING STATIN THERAPY▪ CK should not be routinely measured in individuals receiving statin therapy (Class

III: no benefit, Evidence A)- A (strong)▪ Baseline measurement of CK is reasonable for individuals believed to be at

increased risk for adverse muscle events because of a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk of myopathy (Class IIa, Evidence C)- E (expert)

▪ During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue (Class IIa, Evidence C)- E (expert)

RECOMMENDATIONS FOR MONITORING STATIN THERAPY▪ Baseline measurement of hepatic transaminase levels (ALT) should be performed

before initiation of statin therapy (Class I, Evidence B)- B(moderate)▪ During statin therapy, it is reasonable to measure hepatic function if symptoms

suggesting hepatotoxicity arise (e.g. unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera) (Class IIa, Evidence C)- E (expert openion)

SAFETY RECOMMENDATIONS ON STATIN THERAPY▪Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present (Class 1, Evidence B) – A (Strong)

▪ Characteristics predisposing individuals to statin adverse effects include but are not limited to:

▪ Multiple or serious comorbidities, including impaired renal or hepatic function▪ History of previous statin intolerance or muscle disorders▪ Unexplained ALT elevations ≥3 times ULN▪ Patient characteristics or concomitant use of drugs affecting statin metabolism. ▪ Age >75 years

SAFETY RECOMMENDATIONS ON STATIN THERAPY▪ Decreasing the statin dose may be considered when 2 consecutive values of LDL-C

levels are <40 mg/dL (Class IIb, Evidence C)- C (weak)▪ It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of

simvastatin to 80 mg daily (Class III: Harm, Evidence A)- B(moderate)

SAFETY RECOMMENDATIONS ON STATIN THERAPY (NEW ONSET DIABETES)▪ Those who develop diabetes during statin therapy should be encouraged to

adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, treat type 2 diabetes according to current practice guidelines, and continue statin therapy to reduce their risk of ASCVD events (Class I, Evidence B)- B (moderate)

SAFETY RECOMMENDATIONS ON STATIN THERAPY (MYOPATHY)▪ It is reasonable to evaluate and treat muscle symptoms, including pain,

tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm:

▪ To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiation of statin therapy

▪ If unexplained severe muscle symptoms or fatigue develop during statin therapy, promptly discontinue the statin and address the possibility of rhabdomyolysis

(Class IIa, Evidence B)- E (Expert Opinion)

SAFETY RECOMMENDATIONS ON STATIN THERAPY (MYOPATHY)▪ If mild to moderate muscle symptoms develop during statin therapy: ▪ Discontinue the statin until the symptoms can be evaluated▪ Evaluate the patient for other conditions that might increase the risk for muscle symptoms (eg,

hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases)

▪ If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy

▪ If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin. Once a low dose of a statin is tolerated, gradually increase the dose as tolerated

▪ If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above

▪ If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose

(Class IIa, Evidence B)- E (Expert Opinion)

During statin therapy, unexplained muscle symptoms or fatigue

Mild to moderate muscle symptoms or fatigue

D/C statinEvaluate if other causes of muscle

symptoms present

If symptoms not resolved after 2 months

Find other causeResume statin therapy at original dose

If symptoms resolved

Establish a casual

relationship*

If casual relationship

not exists

If casual relationship

exists

Wait until symptoms disappear, then start with low dose of a different statin then titrate up as

tolerated

Sever muscle symptoms or fatigue

D/C statinAddress the possibility of

rhabdomyolysis

* A casual relationship between statin and muscle symptoms can be established by giving the original dose of statin or lower

dose of the original statin, if no contraindication and the symptoms

disappeared, and watch the symptoms

INSUFFICIENT RESPONSE TO STATIN THERAPY ▪ It is reasonable to use the following as indicators of anticipated therapeutic

response to the recommended intensity of statin therapy (focus is on the intensity of the statin therapy):

▪ High-intensity statin therapy generally results in an average LDL-C reduction of ≥50% from the untreated baseline

▪ Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline LDL-C levels

▪ Percent reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards

(Class IIa, Evidence B)- E (expert opinion)

INSUFFICIENT RESPONSE TO STATIN THERAPY ▪ In individuals who have a less than anticipated therapeutic response or are

intolerant of the recommended intensity of statin therapy, the following should be performed:

▪ Reinforce medication adherence▪ Reinforce adherence to intensive lifestyle changes▪ Exclude secondary causes of hyperlipidemia

(Class I, Evidence A)- A(strong)

INSUFFICIENT RESPONSE TO STATIN THERAPY ▪ In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less than anticipated therapeutic response, addition of non-statin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for adverse effects (Class IIb, Evidence C)- E (expert opinion)

▪If non-statin therapies are to be added, which agents should be considered and in what order ?

2016 ACC RECOMMENDATIONS ON NON-STATIN THERAPY FOR LOWERING BLOOD CHOLESTEROL▪ “It should be noted that this process of did not involve formal systematic reviews, grading of evidence, or synthesis of evidence. The goal was to provide practical guidance for clinicians and patients in situations not covered by the 2013 ACC/AHA guideline until such time as the next round of guidelines has the opportunity to formally review recent scientific evidence and cardiovascular outcomes trials are completed”

SUMMERY

▪ 2013 ACC/AHA guidelines focus on the intensity of statin therapy rather than titrating statin’s dose to target a specific level of LDL-C to reduce the risk of ASCVD in four statin-benefit groups

▪ Baseline LDL-C level and ALT should be measured before statin therapy ▪ Assessment of adherence, therapeutic response, and symptoms of myopathy at

each visit is preferred▪ Ezetemibe is preferred to be the first non-statin to be added in patient who is

insufficiently treated by statin

“We are in the era of Evidence-Based Medicine”

Thank you…

Abdalrhman Alanizi, PharmD Intern

REFERENCES

▪ Stone, N. J., Robinson, J. G., Lichtenstein, A. H., Merz, C. N. B., Blum, C. B., Eckel, R. H., ... & McBride, P. (2014). 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 63(25_PA), 2889-2934.

▪ AACC, C. (2016). 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk.