12 - Chronic Heart Failure Management - Drugs Recommended for Routine Use

Editors: Peacock, W. Frank

Title: Short Stay Management of Heart Failure, 1st Edition

Copyright ©2006 Lippincott Williams & Wilkins

> Table of Contents > 12 - Chronic Heart Failure Management: Drugs Recommended for Routine Use

12

Chronic Heart Failure Management: Drugs Recommended for Routine Use

Robert J. Stomel

Majid J. Qazi

Multiple studies have established that chronic stable heart failure patients should be on four types of medications: (a) a diuretic, (b) angiotensin-converting enzyme inhibitor (ACEI), (c) a beta-blocker, and (d) digitalis.1 Diuretics improve symptoms of heart failure patients by acutely removing fluid from the lung and by decreasing left ventricular filling pressures. Chronically, diuretics will decrease left ventricular wall stress and help slow the progression of remodeling. ACEIs result in left ventricular remodeling, which can ultimately reverse left ventricular dysfunction. Beta-blockers improve heart failure survival,2 and digoxin can cause a decrease in heart failure hospitalizations.3

Angiotensin-Converting Enzyme Inhibitors

ACEIs are the foundation of heart failure therapy. They have beneficial effects for both the symptomatic and asymptomatic patient with left ventricular dysfunction. They reduce mortality,4 decrease hospitalizations, enhance clinical status, and improve overall feeling of well-being.5,6 Their mechanism and action are multifactorial. Initially, they were used as afterload-reducing agents. It is now known that ACEIs reduce myocardial volume and improve ejection fraction by left ventricular remodeling.7,8 They also reduce norepinephrine levels9 and enhance the action of kinins.10 ACEIs should be started at a low dose and titrated upward as tolerated. Aspirin therapy may attenuate the benefit of ACEIs by blocking the effects of kinin-mediated prostaglandin synthesis.11 ACEI use is contraindicated in patients with angioedema and anuric renal failure. They must be used very cautiously in patients who are hypotensive (blood pressure <80 mm Hg), hyponatremic, or hyperkalemic or whose serum creatinine is greater than 3.0 µ/mL.12

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Beta-Adrenergic Receptor Blockers

Beta-blockers are now included as first-line therapy in all patients with mild to moderate heart failure. These patients maintain an overstimulated sympathetic nervous system, resulting in high levels of circulating serum norepinephrine. Chronic stimulation results in myocyte necrosis, peripheral vasoconstriction,13 cardiac hypertrophy, left ventricular dysfunction, and ventricular arrhythmias. These deleterious effects ultimately result in an increase in cardiac death. Beta-blockers produce a significant dose-dependent mortality and morbidity benefit. They reduce the risk of rehospitalization and lower the instance of sudden cardiac death and death from progressive heart failure.14,15

Beta-blockers should be started in low doses and titrated upward slowly. Acute decompensation can occur when starting beta-blockers, so patients should be euvolemic and already on a stable dose of ACEI. Specific target doses are as follows: metoprolol CR/XL 200 mg daily, bisoprolol 5 mg daily, and carvedilol 25 mg twice a day.16,17 Titration should be stopped if a patient's heart rate is less than 55 beats/minute or systolic blood pressure is less than 85 mm Hg. It may take up to 3 months to see a significant clinical response from beta-blocker therapy. Patients with clinically unstable heart failure are often dependent on adrenergic stimulation and can decompensate when started on beta-blockers. In patients hospitalized for decompensated heart failure, the posthospitalization goal should be to maintain or resume their previous beta-blocker dose. A withdrawal or reduction of beta-blocker therapy may result in increased mortality.

Angiotensin II Receptor Blockers

Currently, these agents are primarily used as alternatives to ACEIs in patients with heart failure who are intolerant to ACEIs. In this setting, they have been shown to be as effective as ACEIs in reducing mortality and morbidity.18 There is somewhat conflicting evidence on the addition of angiotensin receptor blockers (ARBs) to ACEI therapy. However, recent trials suggest that this combination reduces cardiovascular deaths and heart failure admissions, including those being treated with beta-blockers.19 It should be noted that the combination of ARBs and ACEIs increases the likelihood of hypotension and significant rise in serum creatinine.

Hydralazine-Isosorbide Dinitrate

Recent data indicate that the combination of hydralazine and isosorbide dinitrate may have a mortality benefit in black patients with class III or IV heart failure when added to standard heart failure therapy. Based on the results of the A-HeFT trial, the U.S. Food and Drug Administration (FDA) has approved the use of BiDil (a tablet containing 20 mg of the nitrate and

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37.5 mg of hydralazine taken three times daily) for self-identified black patients with heart failure.20 Additionally, patients unable to tolerate ACEIs or ARBs may realize a mortality reduction with the addition of the combination of hydralazine-isosorbide dinitrate.

Diuretics

The first and most important goal in the treatment of acute decompensated heart failure is to relieve the symptoms of shortness of breath, coughing, and congestion from fluid overload. Loop diuretics (furosemide, bumetanide, and torsemide) are the only medications that achieve this goal. They are important in the treatment of acute decompensated heart failure and are necessary to prevent heart failure reoccurrence. They are a requirement for the successful integration of all other medications used for the treatment of heart failure. Furosemide, the most commonly used loop diuretic, unfortunately has variable absorption when taken orally. Torsemide is more consistent and can be substituted for furosemide if the patient is no longer obtaining an appropriate diuretic response. Diuretic resistance can also occur when a patient consumes large amounts of dietary sodium or develops prerenal azotemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also block the effect of loop diuretics.21 Complications of diuretics include intravascular volume depletion, arrhythmias, and renal insufficiency. Overdiuresis can result in a decrease in stroke volume, cardiac output, and left ventricular filling pressure. This can especially occur in patients with heart failure caused by diastolic dysfunction.

Spironolactone

Patients with heart failure have increased activation of the renin-angiotensin-aldosterone system, resulting in high levels of circulating aldosterone. This potentiates heart failure through sympathetic activation and sodium retention. Aldosterone antagonists (spironolactone) should be considered for use in selected patients: those with New York Heart Association (NYHA) Class III/IV heart failure. A large multicenter study, Randomized Aldactone Evaluation Study (RALES), involving these patients demonstrated that the addition of spironolactone resulted in a 30% reduction in the risk of death (35% vs. 46%, p <.001).22 These patients should be monitored closely for hyperkalemia. The medication should not be initiated if serum potassium levels are greater than 5.0 mg/dL or creatinine is greater than 2.5 mg/dL. For those intolerant to spironolactone, eplerenone may be used. Eplerenone is a selective aldosterone inhibitor with a significantly decreased incidence of the complications of gynecomastia and impotence. Careful monitoring and surveillance of laboratory studies is required while patients are on spironolactone, and doses of potassium supplementation may need to be decreased.

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Cardiac Glycosides

Cardiac glycosides (digoxin) inhibit Na+/K+ AT ATPase, which promotes Ca2+/Na+ exchange, producing a positive inotropic action. These drugs also reduce serum levels of circulating norepinephrine and return parasympathetic tone to heart failure patients.23 In patients with mild to moderate heart failure, digoxin improves clinical symptoms and exercise tolerance and decreases hospitalizations. Unfortunately, it does not improve patient survival.24 Digoxin is not indicated as a primary therapy for patients in acute decompensated heart failure. It is not necessary to use a loading dose in patients with heart failure, and serum digoxin levels are not particularly useful as a guide for adjusting digoxin dosage.25 Most patients will respond to 0.125 mg of digoxin a day and there are no data to indicate improved effect on contractility with a larger dose. Digoxin is contraindicated in patients with sick sinus syndrome, second- and third-degree heart block, hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, hypercalcemia, and hypokalemia.

Summary

The seven golden rules of heart failure are as follows:

  • ACEIs are the cornerstone of chronic heart failure treatment. Start with a low dose and titrate to a moderate dose.

  • Aspirin and NSAIDs can block the favorable benefits of ACEIs.

  • Beta-blockers are a first-line therapy in heart failure treatment, but they should be started only after a patient is euvolemic and already on chronic ACEI therapy. Start with a low dose and titrate up slowly. Patients with stage 4 heart failure may be dependent on an adrenergic response and therefore can be intolerant to beta-blockers.

  • Overdiuresis can lead to hypotension and renal insufficiency. This may make heart failure worse, especially in patients with diastolic dysfunction.

  • Use spironolactone only in selected patients. Know which patient population was excluded in the RALES study.

  • There is no loading dose for digoxin, and serum levels are of little use.

  • Avoid antiarrhythmics, nonsteroidals, and calcium channel blockers.

References

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2. Heidenreich PA, Lee TT, Massie BM. Effective beta blockade on mortality in patients with heart failure: a meta analysis of randomized clinical trials. J Am Coll Cardiol 1997; 30:27–34.

3. Digitalis Investigation Group: the effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–533.

4. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293–302.

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5. A placebo controlled trial of captopril in refractory chronic congestive heart failure. Captopril Multi-Center Research Group. J Am Coll Cardiol 1983;2:755–763.

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7. Greenberg B, Quinones MA, Koilpillai C, et al. Effects of long term enalapril on cardiac structure and function in patients with left ventricular dysfunction. Circulation 1995;91:2573–2581.

8. Constam MA, Rousseau MF, Kronenberw M W, et al. Effects of angiotensin converting enzyme inhibitor enalapril on the long term prognosis of left ventricular function in patients with heart failure. Circulation 1992;86:431–438.

9. Benedict C, Frances GS, Shelton B, et al. Effects of long term enalapril therapy on neu-rohormones in patients with left ventricular dysfunction. Am J Cardiol 1995;75: 1151–1157.

10. Gainer JV, Morrow JD, Loveland A, et al. Effect of bradykinin-receptor blockade on the response of angiotensin converting enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998;339:1285–1292.

11. Neward L, Khadra AS, Salem DN, et al. Antiplatelet agents in survival: a cohort analysis of the studies of left ventricular dysfunction (SOLVD) Trial. J Am Cardiol 1998;31:419–425.

12. 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: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2101–2113.

13. Smith KM, MacMillin JB, McGrath JC. Investigation of alpha one adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries. Br J Pharmacol 1997;122:825–832.

14. Parker M, Bristow MR, Cohen JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349–1355.

15. Packer M, Coats AJ, Fowler MD, et al. Effects of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658.

16. Packer M, Coats AJ, Fowler MB, et al. For the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;334:1651–1658.

17. Dargie HJ. Effects of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: the CAPRICORN randomized trial. Lancet 2001;357: 1385–1390.

18. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–771.

19. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–776.

20. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049–2057.

21. Gottlieb SS, Robinson S, Krichten CM, Fisher NL. Renal response to indomethacin in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1992;70:890–893.

22. RALES Study. Randomized Aldactone Evaluation Study. Investigators: Pitt B, Zanad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–717.

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23. Krum H, Bigger JT, Goldsmith RL, Packer M. Effect of long-term digoxin therapy to autonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995; 25:289–294.

24. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–533.

25. Hoeschen RJ, Cuddy TE. Dose-response relation between therapeutic levels of serum digoxin and systolic time intervals. Am J Cardiol 1975;35:469–472.