Heart Failure Pharmacology

1. Heart Failure Pharmacology Christine Grenier, Pharm.D. December 12, 2003

2. 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.

3. 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.

4. 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

5. 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

6. 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

7. Heart Failure Pharmacology ACE-inhibitors/ARB’s Beta-blockers Diuretics Aldosterone antagonists Digoxin

8. 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

9. 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

10. 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

11. 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

12. 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

13. ARB’s Monitoring Parameters: Potassium levels Renal function Blood pressure Adverse effects  cough, angioedema

14. 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?

15. 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

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

17. 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).

18. 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

19. Application StrengthQtyPrice 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. Carvedilol Suggested benefits of carvedilol over metoprolol: • β1 andβ2 receptor blockade • Inhibition of alpha-receptors • Increased anti-ischemic effect • Antioxidant effect (inhibition of apoptosis and free radical scavenging) • Enhanced insulin sensitivity

26. 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.

27. 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

28. 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.

29. Clinical Application StrengthQtyPrice 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

30. Clinical Applications Monitoring Parameters: Blood pressure Heart rate Nocturnal dyspnea Exercise tolerance

31. HF and Fluid Retention  Cardiac output  Renal blood flow Activation of renin-angiotensin system Sodium retention

32. Diuretics • Decrease pulmonary edema and cardiac filling pressures • Loop Thiazide Potassium - sparing

33. Diuretics LoopThiazideK+ - Sparing Bumetanide HCTZ Spironolactone (Bumex®) Indapamide Triamterene Ethacrynic acid Metolazone Amiloride Furosemide Chlorthalidone Torsemide (Demedex®) Carbonic Anhydrase Inhib. Acetazolamide

35. 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.

36. Diuretics Which diuretics should be used? In patients with known HF, a loop diuretic is recommended.

37. Diuretic Issues • Diuretic resistance • Combination diuretics • Bioavailability issues

38. Diuretics Monitoring parameters: Potassium levels Renal function Blood pressure Weight

39. 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

40. 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

41. Aldosterone Antagonists Eplerenone (Inspra®): - A selective aldosterone blocker  blocks mineralocorticoid receptor instead of glucocorticoid, progesterone or androgen receptors - Decreased incidence of gynecomastia

42. 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

43. 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%

44. 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

45. 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)

46. Clinical Application • Spironolactone should be initiated first unless the patient experiences significant side effects, then switch to eplerenone. StrengthQtyPrice Eplerenone 25 mg #30 $112.50 Spironolactone 25mg #30 $9.00 Prices obtained from www.walgreens.com

47. Digoxin • Positive inotropic action  inhibits Na+/K+ ATPase which increases intracellular calcium • Inhibits sympathetic response and increases both parasympathetic response and baroreceptor sensitivity

48. 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

49. 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

50. 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.