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

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
ELITE was the evaluation of losartan in the elderly, while ELITE II evaluated losartan use in heart failure patients.
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: 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 Strength Qty Price Valsartan (Diovan®) 40mg #60 $83.98
Losartan (Cozaar®) 25mg #22 $35.93
Enalapril mg #45 $25.49
Lisinopril mg # $20.99
Prices obtained from

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
No mortality benefit seen in HF with bucindolol
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
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

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
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

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
Immediate release metoprolol used

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 and β2 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: mg BID x 2 wks, may double dose every 2 weeks, target dose = 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 Strength Qty Price
Carvedilol (Coreg®) mg #84 $155.40
Toprol XL (metoprolol) 25 mg #42 $30.80
Metoprolol mg #21 $3.85
Prices obtained from

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

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

33. 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

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)
Do not administer in patients receiving potassium supplements!

46. 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 mg #30 $112.50
Spironolactone 25mg #30 $9.00
Prices obtained from

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.

51. 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

52. Digoxin
Target serum concentration = 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

53. 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

54. Drugs to Avoid ANTIARRHYTHMICS
- Cardiodepressant and proarrhythmic effects
Exception: amiodarone

55. 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.

56. 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.

57. Questions??

58. 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):
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):
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):
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):
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):
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):
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):