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 ACE-inhibition and Beta-blockade in patients with reduced EF or recent or remote h/o MI 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 If diuretics are not needed, salt restriction should be recommended to the patient – 2-3 grams of sodium per day

ACE-Inhibitors Which 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 ELITE was the evaluation of losartan in the elderly, while ELITE II evaluated losartan use in heart failure patients. 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 Price Valsartan (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 No mortality benefit seen in HF with bucindolol JAMA, 2000

MERIT-HF Results: 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 Benefit seen across different subgroups of HF Decrease in systolic pressure was greater with placebo than with metoprolol Number needed to treat is 27 per year Only 145 out of 3991 patient were NYHA class IV

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 Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial Started in 1996 Doses selected to achieve similar heart rates Lancet, 2003

COMET Trial Results: 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 Immediate release metoprolol used

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

Activation of renin-angiotensin system 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 Loop – furosemide, bumetanide, ethacrynic acid

Diuretics Loop Thiazide K+ - Sparing Bumetanide HCTZ Spironolactone (Bumex®) Indapamide Triamterene Ethacrynic acid Metolazone Amiloride Furosemide Chlorthalidone Torsemide (Demedex®) Carbonic Anhydrase Inhib. Acetazolamide Bumetanide – shortest acting of the three loop diuretics 1mg bumetanide to 40 mg furosemide

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 Antagonists Monitoring 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) Do not administer in patients receiving potassium supplements!

Clinical Application Strength Qty Price Spironolactone should be initiated first unless the patient experiences significant side effects, then switch to eplerenone. Strength Qty Price Eplerenone 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??

References 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. 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. 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. 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. 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. 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. 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. 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. 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.