Herbert L. Muncie, Jr., M.D.

Evaluation and Treatment of Hypertensive Patients

Proper technique tomeasure Blood Pressure (JNC VII)

Sitting, back supported, arm at level of heart Feet on floor, legs uncrossed Rest at least five minutes Proper cuff size (> 80% of arm with bladder) Inflate & palpate radial pulse to approximate

BP – deflate cuff Inflate 20-30 mm above palpable systolic Measure Korotkoff I (onset sounds - systolic)

and V (disappearance sounds - diastolic)

WatchBP Office

A 58 year old African American female with three separate BP readings averaging 164/92. According to JNC VII, what is her BP classification?

Question

a) Normalb) Prehypertensionc) Stage 1 hypertensiond) Stage 2 hypertension

Classification of Blood Pressure – JNC VII

Systolic Diastolic Normal < 120 And < 80 Prehypertension 120-139 Or 80-89 Hypertension Stage 1 140-159 Or 90-99 Stage 2 > 160 Or > 100

Highest value (systolic or diastolic) determines Stage

Treat Prehypertension? It is not a disease category (JNC VII) Treatment with ARB (candesartan) for

4 years Relative risk reduction of developing Stage

1 hypertension 15.6% Patients with prehypertension are not

candidates for drug therapy (JNC VII)

Lifetime Risk For men or women who are

normotensive at age 55 or 65 and Who survive to age 80 - 85 90% will develop hypertension

Tests after Initial Diagnosis Target organ damage?

ECG Urinalysis CBC BUN & creatinine

Secondary causes? Electrolytes, calcium

Other cardiovascular risk factor? Lipid profile, glucose

Whom to consider evaluating for 2o causes

Onset of hypertension before age 30 or after age 55

Initial diastolic BP is > 110 mm Patient with unexplained hypokalemia Patient with resistant or difficult to control

BP especially if initially good control Signs of Cushing’s disease Signs or symptoms of pheochromocytoma

Pheochromocytoma Measure plasma free metanephrine

(99% sensitive, 89% specific) < 61 ng/L excludes diagnosis > 236 ng/L confirms diagnosis If 62 - 235 ng/L more testing required

24 hour urine metanephrine alone highly sensitive and specific, but often incomplete collection

Renal artery stenosis Abdominal bruit suggestive often absent If high index of suspicion & normal renal function

[Hartman 2009] MRA CTA

If high index of suspicion & diminished renal function MRA Duplex Doppler ultrasonography

Primary hyperaldosteronism Screen with plasma aldosterone/renin ratio

(cutoff > 25) β-blockers & DHCCBs stop for 2 weeks Spironolactone & loop diuretics stop for 6 weeks

Plasma aldosterone should be > 20 ng/dL to make the diagnosis (Nl – 2 – 16 ng/dL – supine) Renin – nl 12 – 79 mu/dL (supine)

Cushing Syndrome

24 hr urine free cortisol useful screening (cutoff > 90 mcg/day) Sensitivity 41 – 70% Specificity – almost 100%

Overnight dexamethasone suppression test equally sensitive, less specific 1 mg dexamethasone midnight – plasma

cortisol next morning (cutoff > 100 nmol)

What if you find a 2o Cause?

Renal artery stenosis For atherosclerotic etiology

Medical therapy is cornerstone [Dworkin 2009] Stenting no better than medical but more

complications May be helpful with recurrent CHF or pulmonary

edema For fibromuscular dysplasia – balloon

angioplasty is worthwhile

White coat hypertension

White coat hypertension Elevated office BP but normal outside office

Normal would be either 24-hour BP with mean < 125/79 or home BP < 132/82

If out of office BP consistently < 130/80 & no evidence of target organ damage

24 hour monitoring or drug therapy can be avoided (JNC VII)

Increased risk of progressing to sustained hypertension [Mancia 2009]

Masked hypertension

Masked hypertension Normal office BP but elevated outside office

Suspect if patient with normal office BP has cardiovascular event

Increased risk of cardiovascular events Pharmacotherapy is indicated

Deserves “an aggressive diagnostic & therapeutic approach” [Messerli 2007]

Mrs. Jones Mrs. Jones is a 58 year old white

female treated for hypertension for the past 6 years. Her BP today in the office is 168/94.

Which number should you focus on in deciding on modifying treatment?

a) Systolic BPb) Diastolic BP

Treatment of Patients > 50 y.o.

Patients > 50 years old achieve diastolic goal when systolic goal achieved Focus on systolic control for patients > 50

years old because: Systolic BP continues to rise with age Diastolic BP levels off around age 50 & will

remain at that level or fall after age 50

Non-pharmacologic Therapy

Weight reduction alone reduces BP Regardless of weight - DASH diet

helpful in lowering BP Increase potassium (6-8 fruits or

vegetables a day) Increase fiber with whole grains

(breads, cereals) Increase calcium intake (low fat dairy) Decrease salt (DASH-low Na)

No added salt

Non-pharmacologic Therapy

Stage 1 can be treated with lifestyle only (JNC VII) For one year if no other risk factors For 6 months with other risk factors You do not have to start medication

immediately with Stage 1 (BP < 160/100)

Patients who successfully lose 3 - 9% of their body weight with lifestyle changes can expect to see their average BP decrease how many mm?

Audience Question

a) 3b) 5c) 7d) 10

Weight loss & BP - EBM

Dieting to lose weight may lower BP in overweight people but the effects are modest & dieting may not be effective alone

Cochrane Review 18 randomized trials found weight loss of 3-9% Associated with decreases of roughly 3 mmHg

systolic & diastolic http://www.chochrane.org/reviews/en/ab000484.html

Lifestyle changes

Combining intensive lifestyle counseling & physician feedback was not successful long-term (18 month) in achieving BP control [Svetkey 2009] Some early success (6 months) faded over time

Dietary choices influence control success Salt restriction is central especially in those

requiring intensive pharmacotherapy Increase fresh fruits & vegtables Maximum 1 restaurant meal/week

A 50 yo African American male with BP 155/95 (avg.) requires initiating drug therapy. What would be your initial choice of medication class for this patient?

Question

a) Thiazide diureticb) Calcium channel blocker (CCB)c) Beta blockerd) Angiotensin-converting enzyme inhibitor (ACE)e) Angiotensin receptor blocker (ARB)

Initial Therapy

JNC VII – a thiazide-type diuretic should be initial therapy unless compelling indication Most patients with Stage 1 will experience

better BP control & lower CVD risk when taking a thiazide-type diuretic

Most patients with Stage 2 disease will experience better BP control & lower CVD risk when taking a multidrug regimen that includes a thiazide-type diuretic

Initial Therapy

No treatment alters the natural progression of the disease

BP will continue to rise as the patient ages regardless of which medications are used

Therefore, every patient will eventually need for more than one medication to control their BP

Initial Therapy

Dr. Chobanian (Chair JNC VII) now suggests flexibility in choice of initial drug [Chobanian 2009] – he suggests Stage 1 – ACE, ARB, CCB or diuretic Stage 2 – two of those 4 drugs to start

With exception of β-blockers after an MI & CCBs effect on CVA risk, all drugs lowered CVD events for a given reduction in BP [Law 2009]

Initial Therapy

To increase drug persistence & compliance with therapy [Friedman 2010] Choose medications that will lower BP with few

complications & is taken less often Persistence is lower with more side effects Compliance is lower in males, lower SES

groups & in urban environments

A 50 yo African American male with BP 155/95 (avg.) requires initiating drug therapy. What would I choose?

Question

a) Thiazide diureticb) Calcium channel blocker (CCB)c) Beta blockerd) Angiotensin-converting enzyme inhibitor (ACE)e) Angiotensin receptor blocker (ARB)

STITCH Therapy Simplified Treatment Intervention to

Control Hypertension (STITCH) STITCH vs Canadian Hypertension

Education Program guideline (CHEP) CHEP is similar to JNC VII approach

STITCH Treatment Initiate therapy with ½ tablet of low dose

combination - diuretic & ACEI or ARB Increase that combination to highest dose tolerated Then add CCB & increase to highest tolerated dose Then add non-first-line agents

Alpha-blocker Beta-blocker Spironolactone

STITCH Therapy At 6 months [Feldman 2009]

64.7% controlled on STITCH 52.7% controlled on CHEP (P = 0.03)

Pharmacologic Efficacy

Average reduction in BP for major classes of drugs At standard dosage - 9.1 mm (SBP)/5.5 mm

(DBP) drop With half standard dosage -

7.1 mm (SBP)/4.4 mm (DBP) When BP > 20 (SBP) or 10 mm (DBP) above

goal (Stage 2) start two medications initially

A 52 year old African American female has not achieved BP control on diuretics. You add an ACE inhibitor to the regimen. You order electrolytes, BUN and creatinine in 1 week. Her creatinine increased from 0.9 baseline to 1.14 mg/dL, a 26.7% increase. What should you do about her ACEI?

Question

a. Discontinue the ACEI & add a different classb. Reduce the ACEI dose 50% c. Reduce the ACEI dose 25%d. Make no change in the ACEI dosage

Initiating Therapy – Change in Renal Function

After initiating treatment, common to get decline in renal function If ≤ 30% non-progressive increase in creatinine

Represents a functional response (reduced intraglomerular pressure) & no change in treatment required

This response is associated with long-term renal protection

If > 30% increase in creatinine, D/C medication & choose another class

A 52 year old African American female has not achieved BP control on diuretics. You add an ACE inhibitor to the regimen. You order electrolytes, BUN and creatinine in 1 week. Her creatinine increased from 0.9 baseline to 1.14 mg/dL, a 26.7% increase. What should you do about her ACEI?

Question

a. Discontinue the ACEI & add a different classb. Reduce the ACEI dose 50% c. Reduce the ACEI dose 25%d. Make no change in the ACEI dosage

Diuretic - Classes

Thiazide Hydrochlorothiazide (HCTZ) dosage best if

≤ 25 mg & preferably 12.5 mg Outcome benefits have not been established for

these dosages of HCTZ Increasing to 50 mg minimally lowers BP further

but significantly increases side effects Hyponatremia & hypokalemia more common in

women 12 combinations with HCTZ available

Diuretic - Classes

Thiazide Chlorthalidone 25 mg provided better 24 hr BP

control than HCTZ 50 mg Milligram for milligram twice as potent as HCTZ Outcome data available regarding reduced CV events Only 2 combinations available

Chlorthalidone/clonidine (Clorpres®) – 15/0.1,0.2, 0.3 Atenolol/chlorthalidone (Tenoretic®) – 25/50, 25/100

Diuretic - Classes

Loop If only treating hypertension - use loop

diuretics only with renal insufficiency (CrCl < 30 - 40 ml/min) Discontinue thiazides at this CrCl – not effective

Dosage frequency for BP treatment Furosemide (Lasix®) – BID

QD dosage may lead to reactive Na+ retention mediated by renin/angiotensin system

Torsemide (Demadex®) – QD

Diuretic - Classes

Potassium sparing Combined with thiazide - reduces risk

sudden death and hypokalemia Do not combine with continuous K+

supplements or give with renal insufficiency Increased risk hyperkalemia Especially with ACE or ARB combination

Should be stopped temporarily if diarrhea or vomiting occurs

Selective aldosterone receptor antagonist

Eplerenone (Inspra®) first approved in new class Primary focus in heart failure Add-on to anti-hypertensive Rx Side effects

Hyperkalemia Contraindicated with hyperkalemia, creatinine > 1.8 men,

> 2.0 women, or creatinine clearance < 50 ml Caution in use with ACE or ARB

Diuretics – diabetes & hyperlipidemia?

Diuretics can raise glucose & lipid levels short-term

However, no long-term adverse effects in diabetics

Fasting glucose increases in older adults regardless antihypertensive drug

Diuretics may be safely used in patients with diabetes or hyperlipidemia

Beta-Blockers

Available evidence does not support their use as 1st line treatment alone Weak effect in reducing CVA Absent effect on CAD [Wiysonge - Cochrane 2007] Lower heart rate with beta-blocker therapy associated

with increased risk CV events & death Compelling indications (JNC VII)

Heart failure Chronic stable angina Post MI Tachyarrhythmia

Beta-Blockers

Side effects Increased risk developing type 2 DM Decreased exercise tolerance Increased risk of Raynaud’s phenomenon Increased insomnia & risk of delirium Abrupt withdrawal can precipitate myocardial

ischemia in at risk patients

Beta-Blockers & Diabetes

In diabetics beta-blockers blunt heart rate & BP response to hypoglycemia However, no increase in severe

hypoglycemia in Type 1 or Type 2 DM Do not worsen glycemic control when used

with ACE/ARB Carvedilol (Coreg®) & nebivolol

(Bystolic®) have neutral or even favorable effect on CHO & lipid metabolism

Angiotensin-Converting Enzyme (ACE) Inhibitors

Compelling indications (JNC VII) Heart failure Post MI - systolic dysfunction Diabetics with proteinuria

Reduce cardiovascular & all-cause mortality As effectively as diuretics, β-blocker or CCB

[SOR-A] Diabetics may retain sodium

Add diuretic to enhance response

ACE Inhibitors

Side effects Cough (5-15%) - women 2x men’s risk Angioedema (0.1-0.2%) – African Americans

and Asians 3 - 4 x risk increase Hyperkalemia with renal insufficiency If patient has bilateral renal artery stenosis

Can cause renal insufficiency Measure creatinine initially & one week after

starting ACE If > 30% increase in creatinine or hyperkalemia

1st 2 months – D/C ACE

Angiotensin Receptor Blocker (ARB)

Three trials found ARBs effective in reducing CV events (LIFE, SCOPE, VALUE) But not as effectively as ACE

Reduce the risk end-stage renal disease in diabetics No evidence reduce mortality in diabetics with

renal disease Reserve for patients who cannot tolerate ACE

Angiotensin Receptor Blocker (ARB)

Low incidence of dizziness or other side effects Cough not a problem Caution with renal insufficiency or K+

supplements

Angiotensin Receptor Blocker (ARB)

Less effective if high salt intake Measure serum creatinine initially & 1 week

after starting drug Can worsen renal failure Not proven to improve survival post MI ACE & ARB should not be used in

pregnancy

Combining ACE & ARB

CHARM-Added trial found combination reduced CV events & mortality in patients with heart failure

However, in patients without heart failure Combination lowered BP without CV benefit

over ACE alone (ONTARGET) But did increase hypotension, syncope & renal

dysfunction

Ca-Channel Blockers (CCB)

More effective in African Americans than diuretic or ACE as initial therapy ALLHAT – if African American cannot take

diuretic – CCB preferred initial drug Greater risk CVA, CHD, CVD, angioedema with

ACE

Combination of benazepril/amlodipine was more effective slowing progression of renal disease than benazepril/HCTZ (ACCOMPLISH trial)

Ca-Channel Blocker Risks

CCB & diuretics are associated with best stroke prevention Could be due to less visit-to-visit variability

Caution combining non-dihydropyridine CCB (diltiazem; verapamil) with beta blocker Potential additive negative inotropic effect Can cause heart failure or complete heart

block

Direct Renin Inhibitor

Aliskiren (Tekturna®) Monotherapy or combined Modestly lowers BP High fat meals decrease absorption Older hypertensive medications should be

considered 1st (Medical Letter 2007)

Alpha Adrenergic Blockers

Peripheral sympatholytics Do not produce tachycardia & palpitations Not initial drug of choice

Associated with increased risk of MI

Alpha Adrenergic Blockers

Side effects Marked hypotension especially with first dose

Careful in elderly, volume depleted patients, or in patients taking other antihypertensive drugs

Start with lowest dose at bedtime Not recommended for patients with CHF

regardless of BP status May benefit males with BPH symptoms

JNC VII Compelling Indications

Compelling Indic. Diuretic BB ACEI ARB CCB AlDO ANT

CHF X X X X X

Post MI X X X

High CAD Risk X X X X

Diabetes Mellitus X X X X X

Chronic Kidney Disease X X

Recurrent CVA Prevention X X

Treatment Goal

For most patients goal BP is < 140/90 Does a lower target (< 135/85) reduce risk? Cochrane review found lower targets did not

change mortality, MI, CVA, CHF, major cardiovascular events or ESRD [Arguedas 2009]

In the very old (> age 80) with CAD, a suggestion of increased risk of adverse outcomes with SBP < 140 & DBP < 70 [Denardo 2010]

Treatment Goal

For diabetics or patients with CKD• ADA/AHA Goal BP is < 130/80• INVEST trial of diabetics with CAD found tight

BP control did not improve CVD outcomes over usual control

Was associated with increase in all-cause mortality Emphasis should focus on maintaining SBP

between 130 – 139 mm Hg for these patients

Your 52 y.o. African American female patient with a 6 year history of hypertension comes in for a routine office visit. No symptoms. BP 142/92. No change in therapy. When would you want to see her again for follow-up?

Question

a) Two (2) weeksb) One (1) monthc) Three (3) monthsd) Six (6) months

Monitoring Treatment

No evidence based guidelines address the frequency of monitoring treatment [Keenan 2009] Monitoring at short intervals increases

probability of false positives due to within person variability

Longer intervals (years) increase probability observed increase is real

Monitoring Treatment

Chance of detecting a true increase in BP is better if: Abnormal BP is signal for repeat readings at short

intervals Using calibrated sphygmomanometer Set times to measure BP in relation to drug therapy Taking mean of several measurements Or perhaps self-monitoring

Monitoring Treatment

What is the significance of visit-to-visit (V2V) variability, maximum SBP and episodic hypertension? V2V & maximum SBP are strong predictors of

stroke, independent of mean SBP (Rothwell 2010)

Interindividual variation is reduced with CCB & non-loop diuretics but increased with ACE, ARB and β-blockers

Does not yet prove a causal link

Telemonitoring & self-titration

Using automated BP measurement with information sent to the office, patients on 2 meds without control [McManus 2010]

Having patients request additional medicine if their BP remained uncontrolled for two consecutive months resulted in lower SBP difference of 3.7 mm (95% CI 0.8 – 6.6)

Combinations of Medications Beyond studies of 2 drug combinations, little data on

the efficacy of 3 or more drugs Advice largely empiric and/or anecdotal Triple therapy amlodipine/valsartan/HCTZ (Tribenzor®)

better BP control than dual therapy [Calhoun 2009] ASCOT study found ACE & DHPCCB better than B

blocker with diuretic In reducing CV mortality In reducing new onset DM In reducing incidence of fatal & nonfatal CVA

Combination therapy

Maximal dosage of one drug increases risk of side effects

Using ½ standard dose resulted in decrease of side effects 81% for CCBs (pedal edema) 80% for thiazides (hypokalemia) 27% for beta blockers (bradycardia/fatigue) 0 % for ACE/ARB (which are not dose related)

Combination therapy

Therefore, use lower dosages of two drugs [Wald 2009] Combining drugs from 2 classes will get 5 times

greater reduction in BP than doubling one drug If appropriate consider fixed dose combinations

May improve compliance May reduce total costs

Some Combinations Everything is combined with HCTZ Amlodipine & benazepril (Lotrel®)

Slowed nephropathy more than benazepril & HCTZ [Bakris 2010]

Amlodipine & an ARB With olmesartan (Azor®) With telmisartan (Twynsta®) With valsartan (Exforge®)

Persistence? Do patients continue to take their medication?

As many as 25% of patients stop taking their medications by 6 months

Many variables influence this rate (side effects, cost, patient’s understanding, physician’s ability to explain, etc.)

One new variable is modification of dosage or drug before the end of the 1st prescription – more persistent if adjusted [Tamblyn R 2010]

Caution in Elderly

What appears as refractory BP control may be sclerotic arteries – ‘pseudo hypertension’

If radial artery palpable when brachial artery is occluded with cuff (Osler maneuver) Measure intra-arterial pressure

Hypertension and Elderly

Criteria for diagnosis unchanged due to age Treatment reduced incidence CVA, CAD,

CHF and death from all causes Treatment initially proven beneficial up to age

80 Treatment after age 80 is now proven

beneficial

Hypertension and Elderly

Aggressiveness of treatment influenced by patient's physiologic age and life expectancy Life expectancy should be at least as long as

time required to see a clinically meaningful decrease in: Stroke - 3 years CHF - 4.5 years Heart attack - 7 years

Isolated Systolic Hypertension

Treatment recommendations: Diuretics Long-acting dihydropyridine CCBs Strong evidence treatment helpful if > 160 mm

Evidence less strong for 140 - 159 mm In oldest old males (> 85 yo) higher systolic BP

associated with lower mortality

Resistant Hypertension

BP remains above goal in spite of at least 3 medications at optimal dose Ideally one of which should be a diuretic

Patients controlled on 4 or more medications should be considered resistant to treatment

Resistant Hypertension - Treatment

Restrict salt intake Increase dose of diuretic

If CrCl is below 30-50 ml/min use loop diuretic Add aldosterone antagonist

Since up to 20% - raised aldosterone/renin ratio Consider evaluating for 2o causes Future treatment?

Radiofrequency ablation renal sympathetic nerve 23 mm drop in systolic BP in 89% patients

Incidental Hypertension

Elevated BP found incidentally during visit No consensus on how to evaluate or treat in

the acute care setting VA Cooperative Trial (1967) – 143 patients with

DBP 115 -130 No adverse outcomes vs placebo initial 3 mo

Close follow-up and perhaps treatment is all that is required

Incidental Hypertension

Prospective randomized trial of 64 asymptomatic patients with DBP 116 -139 Oral clonidine load vs placebo then

maintenance oral clonidine No clinical difference in BP at 7 days

No evidence demonstrating improved morbidity or mortality with acute treatment of BP in ED

Key Points – Lessons from clinical trials

BP is the key driver of benefit from medications Drugs that deliver less effective BP control

have never produced superior clinical outcomes

The choice of initial treatment defines the initial BP response to treatment & the longer term quality of BP control usually requiring fewer add-on drugs

Patients with treated hypertension remain at higher risk of CVD

Key Points – Lessons from clinical trials

If after formal estimate of global risk, their risk of CVD is high, offer statin & ASA therapy

Treatment of pre-hypertension with lifestyle changes might prevent development of severe hypertension, target organ damage & diminish risk of dementia

What Questions do you have?