Heart Failure Pharmacology

Christine Grenier, Pharm.D.

December 12, 2003

Objectives

• To review the medications used in heart failure.

• To summarize the 2001 ACC/AHA guidelines for the management of heart failure.

• To understand which medications are appropriate for and contraindicated in specific heart failure patient populations.

Statistics

• Heart failure affects nearly 5 million people in the U.S.

• Annually, about 500,000 people are diagnosed with heart failure in the U.S.

• Around 300,000 patients die each year of heart failure as a primary or secondary cause.

• Approximately 6-10% of people older than 65 years have heart failure.

Types of Heart Failure

Systolic dysfunction

- Decreased contractility

- Decrease in muscle mass, dilated

cardiomyopathies, or ventricular

hypertrophy

Diastolic dysfunction

- Increased ventricular stiffness, valve

stenosis, or pericardial disease

ACC/AHA Guidelines - Treatment of Symptomatic LVD

• ACE-inhibition in all patients

• Beta-blockade in all stable patients

• Diuretics for fluid retention

• Digitalis for symptomatic HF

• Moderate sodium restriction

• Influenza and pneumococcal vaccines

• Moderate exercise

J Heart Lung Transplant, 2002

ACC/AHA Guidelines - Treatment of Asymptomatic Left Ventricular Dysfunction (LVD)

• Treatment of risk factors

– HTN

– Dyslipidemia

• ACE inhibition

• Beta-blockade

J Heart Lung Transplant, 2002

Heart Failure Pharmacology

ACE-inhibitors/ARB’s

Beta-blockers

Diuretics

Aldosterone antagonists

Digoxin

ACE-Inhibitors

• Recommended in all stages of HF, benefit has been shown in all classes

• Inhibit activation of renin-angiotensin system decreases Na+ retention

• Higher doses were used in the clinical trials, but patients on multiple HF medications may become hypotensive on high dose ACE-inhibitors

ACE-InhibitorsWhich ACE-inhibitors should be used?

Lisinopril Enalapril

***Captopril is more appropriate as an inpatient medication due to its shorter half-life

When should ACE-inhibitors be avoided?- Angioedema/rash/hives, cough

- Bilateral renal artery stenosis- SCr > 3.0- Serum K+ > 5.5

ACE-Inhibitors

Monitoring Parameters:

Potassium levels (watch for hyperkalemia)

Renal function

Blood pressure

Adverse effects cough,

angioedema

Drug interactions

- NSAID’s (aspirin) effectiveness of ACE- inhibitors and increase risk of renal toxicity

Angiotensin Receptor Blockers (ARB’s)

CHARM-Preserved Trial

• Candesartan (target dose of 32mg) vs. placebo in class II-IV HF patients

• No significant difference in cardiovascular death, but significant decrease in hospital admissions with candesartan

Lancet, 2003

ARB’s

ELITE II Study

• Losartan 50mg/d vs. captopril 50mg TID in class II-IV HF patients

• No significant difference in all-cause mortality or sudden death

• Fewer # of patients in losartan group D/C’d treatment due to adverse effects

Lancet, 2000

ARB’s

Monitoring Parameters:

Potassium levels

Renal function

Blood pressure

Adverse effects cough,

angioedema

ACE-Inhibitor or ARB

ACE-inhibitor or ARB…….or BOTH?????

– ACE-inhibitor use is recommended in all classes of HF and is still considered first line therapy.

– If a patient cannot tolerate an ACE-inhibitor due to cough, then switch to an ARB.

– Will an ACE-inhibitor/ARB combo provide more complete blockade of renin-angiotensin system?

VALIANT Trial

• Valsartan 20 mg vs. captopril 6.25 mg + valsartan 20 mg vs. captopril 6.25 mg in post-acute MI patients

• Target doses = valsartan 80 mg BID, captopril 25 mg TID + valsartan 40 mg BID, and captopril 25 mg TID

VALIANT Trial

• No significant differences seen in mortality, but the combination of valsartan and captopril was associated with an increase in adverse events.

ACE-Inhibitor or ARB

What about angioedema with an ACE-inhibitor? Should the patient receive an ARB?

DO NOT switch to an ARB following angioedema with an ACE-inhibitor because there is a degree cross-reactivity. Angioedema is a serious and life threatening allergic reaction!

Instead, switch patient to hydralazine and a nitrate (VHEFT and VHEFT II).

ACE-Inhibitor/ARB

• What dose do I initiate?

Lisinopril: 2.5-5 mg/d, then may increase by up to 10 mg every 2 weeks to max of 40 mg/d

Enalapril: 2.5-5mg/d, then may increase by up to 10 mg every 2 weeks to max of 40 mg/d

Losartan: 12.5 mg/day, then may titrate to 25mg/d at 7-day intervals, target dose of 50 mg/d

Application

Strength Qty PriceValsartan (Diovan®) 40mg #60 $83.98

Losartan (Cozaar®) 25mg #22 $35.93

Enalapril 5 mg #45 $25.49

Lisinopril 2.5 mg #45 $20.99

Prices obtained from www.walgreens.com

Beta-blockers

MERIT-HF Trial

- Metoprolol CR/XL vs. placebo, target dose of 200 mg/day

- Symptomatic but clinically stable patients categorized as NYHA II-IV

- Metoprolol added onto ACE-inhibitors and diuretics

JAMA, 2000

MERIT-HFResults:• Significant decrease in mortality with

metoprolol of 38% • Significant decrease in sudden death of

41% • Significant decrease in death from

worsening HF of 49% • Number of patients needed to treat in one

year to save one life is 27

COMET Trial

• Carvedilol (25 mg BID) vs. immediate release metoprolol (50 mg BID)

• NYHA II-IV HF patients

• Carvedilol or metoprolol added onto ACE-inhibitors and diuretics

Lancet, 2003

COMET TrialResults:

• Significant decrease of 17% in all-cause mortality with carvedilol (HR=0.83)

• Absolute reduction in mortality over 5 years of 5.7% with carvedilol

• No significant differences in composite endpoint of all-cause mortality and all-cause admissions

COMET Trial

• Number of patient-years of treatment needed to save one life was 59

• Median prolongation of survival of 1.4 years with carvedilol

Carvedilol

Suggested benefits of carvedilol over metoprolol:

• β1 and β2 receptor blockade

• Inhibition of alpha-receptors

• Increased anti-ischemic effect

• Antioxidant effect (inhibition of apoptosis and free radical scavenging)

• Enhanced insulin sensitivity

Clinical Applications

• When do I start a beta-blocker?

When the patient displays mild limitation of physical activity (NYHA II).

Start low and titrate slowly in severe HF.

• Can I use beta-blockers in asthmatic and COPD patients?

Don’t withhold beta-blockers, start with low doses and titrate up slowly.

Clinical Application

• What dose do I initiate?

Carvedilol: 3.125 mg BID x 2 wks, may double dose every 2 weeks, target dose = 50 - 100 mg/d

Metoprolol: 25mg qd x 2 wks, may double dose every 2 weeks, target dose = 200 mg/d

Clinical Application

• How should a beta-blocker be removed from a patient’s therapeutic regimen?

The dose should be slowly titrated down over weeks to months before discontinuation.

Clinical Application

Strength Qty Price

Carvedilol (Coreg®) 3.125 mg #84 $155.40

Toprol XL (metoprolol) 25 mg #42 $30.80

Metoprolol 50 mg #21 $3.85

Prices obtained from www.walgreens.com

Clinical Applications

Monitoring Parameters:

Blood pressure

Heart rate

Nocturnal dyspnea

Exercise tolerance

HF and Fluid Retention

Cardiac output

Renal blood flow

Activation of renin-angiotensin system

Sodium retention

Diuretics

• Decrease pulmonary edema and cardiac filling pressures

• Loop

Thiazide

Potassium - sparing

Diuretics Loop Thiazide K+ - Sparing

Bumetanide HCTZ Spironolactone

(Bumex®) Indapamide Triamterene

Ethacrynic acid Metolazone Amiloride

Furosemide Chlorthalidone

Torsemide

(Demedex®)

Carbonic Anhydrase Inhib.

Acetazolamide

Diuretics

Which patients should get diuretics?

Patients with evidence of fluid retention

****BUT, renal insufficiency can cause decreased response to diuretics or even diuretic resistance.

Diuretics

Which diuretics should be used?

In patients with known HF, a loop diuretic is recommended.

Diuretic Issues

• Diuretic resistance• Combination diuretics• Bioavailability issues

Diuretics

Monitoring parameters:

Potassium levels

Renal function

Blood pressure

Weight

Aldosterone Antagonists

Spironolactone

Eplerenone (Inspra®)

• For use in patients with more severe HF (NYHA class III-IV)

• Can decrease Na+ retention, myocardial fibrosis, baroreceptor dysfunction, and ventricular ectopy

Aldosterone Antagonists

RALES Trial

- At doses of 25 to 50 mg/day in patients with class III or IV HF, spironolactone reduced all cause mortality by 11% and hospitalizations by 35%

(Note: effective doses are small!!)

NEJM, 1999

Aldosterone Antagonists

Eplerenone (Inspra®):

- A selective aldosterone blocker blocks mineralocorticoid receptor instead of glucocorticoid, progesterone or androgen receptors

- Decreased incidence of gynecomastia

Aldosterone Antagonists

EPHESUS Trial

• Eplerenone 25 to 50 mg/day in patients with class III-IV HF

• Added on to ACE-inhibitors/ARB’s, beta-blockers, aspirin, and lipid lowering agents

Cardiovasc Drugs Ther, 2001

Aldosterone Antagonists

EPHESUS Trial

Significant reduction in the risk of:

• Death from any cause by 8% • Sudden death from cardiac causes by

21%• Hospitalization by 15%

Aldosterone Antagonists

• What dose do I initiate?

Spironolactone: 25 mg/day, may increase or decrease based upon response

Eplerenone: 25 mg/d then may increase to 50 mg/d in 4 weeks

Aldosterone AntagonistsMonitoring Parameters:

Potassium levels (watch for hyperkalemia)

Renal function caution with

Clcr<50 ml/min

Blood pressure

Drug interactions - hepatically

metabolized CYP3A4

(amiodarone, diltiazem, erythromycin, carbamazepine, phenytoin)

Clinical Application

• Spironolactone should be initiated first unless the patient experiences significant side effects, then switch to eplerenone.

Strength Qty PriceEplerenone 25 mg #30 $112.50

Spironolactone 25mg #30 $9.00

Prices obtained from www.walgreens.com

Digoxin

• Positive inotropic action inhibits Na+/K+ ATPase which increases intracellular calcium

• Inhibits sympathetic response and increases both parasympathetic response and baroreceptor sensitivity

Digoxin

• Recommended in HF with concomitant atrial fibrillation

• Recommended in classes II-III rather than in classes I and IV

• Controversial in patients with HF and normal sinus rhythm

• NOT to be used as monotherapy in HF

Digoxin

RADIANCE Study

• Digoxin in class II-III HF patients with normal sinus rhythm

• Placebo patients had a relative risk of 5.9 of developing worsening HF of when compared to digoxin patients

NEJM, 1993

DIG Trial

• Digoxin added to ACE-inhibitors and diuretics vs. placebo in classes I-IV HF patients with normal sinus rhythm

• No significant difference in all-cause mortality from any cause, but 7.9% decrease in hospitalizations with digoxin.

DIG Trial

• Significant increase in mortality with higher doses of digoxin and small but significant increase in other cardiac deaths with digoxin (15% vs 13%, P=0.04).

J Am Coll Cardiol, 2001

Digoxin• Target serum concentration = 0.5 - 1 ng/ml in

patients with HF and normal sinus rhythm. Obtain levels 5-7 days following dosage change.

• Monitoring Parameters:

Renal function

Heart rate and rhythm

Electrolyte levels (K+, Mg+, and Ca2+)

Side effects and signs of toxicity

Drugs to Avoid

NONSTEROIDAL ANTI-INFLAMMATORIES

- Na+ retention and peripheral vasoconstriction

CALCIUM CHANNEL BLOCKERS

- Worsen heart failure due to negative chronotropic and inotropic effects

- Diltiazem and verapamil are NOT considered appropriate in HF

Drugs to Avoid

ANTIARRHYTHMICS

- Cardiodepressant and proarrhythmic effects

Exception: amiodarone

Summary

• All HF patients should be on an ACE-inhibitor, or if unable to tolerate an ACE-I, an ARB.

• Clinically stable HF patients class II-IV can benefit from a beta-blocker.

• All patients with symptomatic LVD or systolic dysfunction should be on a diuretic.

Summary

• Aldosterone antagonists provide the most benefit in more severe HF (class III-IV).

• Digoxin is not recommended for monotherapy in HF, and has neutral effects on mortality, but has been shown to decrease hospitalizations.

Questions??

References1. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic

heart failure in the adult: executive summary. J Heart Lung Transplant 2002; 21(2): 189-203.

2. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000; 283(10):1295-302.

3. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003; 362(9377): 7-13.

4. Yusef S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362(9386): 777-81.

5. 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(9215): 1582-7.

6. Pitt, B et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure: the RALES Trial. NEJM 1999; 341(10): 709-17.

7. Pitt B, Williams G, Remme W, et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 2001; 15(1): 79-87.

8. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. NEJM 1993; 329(1): 1-7.

9. Rich MW, McSherry F, Williford WO, et al. Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG Study. J Am Coll Cardiol 2001; 38(3): 806-13.