Recently updated clinical guidelines reflect major changes in our understanding of and approach to heart failure.1,2 In my previous article (CONSULTANT, July 2007), I reviewed the latest developments in diagnosis and disease staging. Here I discuss key shifts in focus in the management of heart failure. These include:
•The need for prompt titration of lifesaving neurohormonal antagonists.
•The benefits of treating underlying and comorbid diseases.
•Strategies for monitoring patients over time.
•The evolving role of device-based therapy.
Back in the 1980s, randomized clinical trials showed the potential benefits of hydralazine and isosorbide dinitrate in the treatment of chronic heart failure. In the 1990s, several pivotal trials demonstrated the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and b-blockers in patients with chronic heart failure. Today, ACE inhibitors and b-blockers are recommended for all patients with stage C or stage D heart failure (and for select patients with stage A or B) unless clearly contraindicated (Table). These drugs can be initiated after optimization of volume status (even while the patient is still in the hospital). However, do not start them in patients who have recently undergone aggressive diuresis with relative intravascular volume depletion (azotemia or hypotension might be triggered) or in the presence of other factors that could hinder drug titration.
The rationale for starting ACE inhibitors first is largely historical. Recent clinical data show that ACE inhibitors and b-blockers are equally effective as initial therapy.3 The goal is to have patients take both drugs at their target (or maximally tolerated) dosages. This usually takes 1 to 3 months to achieve, although the duration and intensity of follow-up visits needed to attain optimal dosages of both agents vary widely, depending on the self-care ability and adherence of the patient.
It is customary to up-titrate a single drug at each visit (unless blood pressure is poorly controlled) to allow better assessment of drug intolerance. The effectiveness of a systematic "start low, go slow" approach to up-titration has been clearly demonstrated. Still, the pace of this titration is largely tailored to the individual patient's tolerance and need. For example, a patient with significant hypertension might receive maximal drug doses within a few weeks, whereas a patient with marginally elevated blood pressure might take months to adapt to a relatively modest drug dose.
NEWER APPROVED AGENTS
Other therapeutic options for heart failure have emerged in recent years. However, the guidelines indicate that these agents should be considered primarily in patients with underlying left ventricular systolic dysfunction who have persistent or progressively worsening symptoms despite optimal therapy.
Aldosterone receptor antagonists. These drugs significantly reduced mortality in patients with advanced chronic heart failure in the RALES trial4 (the acronyms of all trials mentioned in this article are expanded in Box I) and in those with post-infarction heart failure in the EPHESUS trial.5 However, broad use of these otherwise beneficial agents has led to a high rate of hyperkalemia and renal insufficiency in real- world settings. Thus, vigilance is mandatory when using these drugs.
In general, when aldosterone receptor antagonists are initiated, patients should have estimated glomerular filtration rates of greater than 30 mL/min, serum potassium levels below 5.0 mEq/L, and no diarrhea or history of serious hyperkalemia. In addition, advise patients to discontinue potassium supplements and NSAIDs.
Except in cases of persistent fluid retention, spironolactone is rarely up-titrated beyond 25 mg/d, whereas the dosage of eplerenone is usually between 25 and 50 mg/d. The recommended monitoring protocol, which helps guard against hyperkalemia and renal insufficiency (especially important in elderly patients), includes checking potassium levels and renal function at 2 to 3 days and 1 week following drug initiation, and afterwards at least monthly for the first 3 months.
Angiotensin receptor blockers (ARBs). Several mega-trials have illustrated the relative equivalence of ARBs (such as valsartan and candesartan) and ACE inhibitors when an ARB is substituted for a drug in the latter class. However, the potential cardiovascular benefits of add-on therapy with ARBs were recently demonstrated with candesartan in the CHARM-Added trial.6 Still, risks of hyperkalemia and hypotension are important limitations to the use of ARBs—especially when these are used in addition to an ACE inhibitor—and potassium levels and blood pressure should be carefully monitored. The safety of using an ARB in addition to both an ACE inhibitor and an aldosterone receptor antagonist is supported only by limited data.
Fixed-dose combination of hydralazine and isosorbide dinitrate. This combination pill is recommended as add-on therapy to be used along with an ACE inhibitor or ARB.It is used primarily in African American patients with symptomatic systolic heart failure, after reduced mortality was observed in this population in the A-HeFT study.7 As with ARBs, associated hypotension and other adverse effects can limit the use of this therapy.
VASODILATORS AND DIURETICS
Optimal systemic and right-sided pressures (achieved with vasodilators and diuretics) remain important treatment goals, especially in the advanced stages of heart failure. Many cardiologists add vasodilators to the regimen to optimize afterload reduction and improve perfusion. Diuretics may still be needed even in patients who are no longer "congested"—especially those who have reached target dosages of neurohormonal antagonists.
Although most experts interpreted the results of the recent ESCAPE study as showing no benefit from hemodynamic assessment with a pulmonary artery catheter in "equipoise" patients admitted for acute decompensated heart failure,8 select patients (particularly those with end-organ compromise or symptoms refractory to existing medical regimens) may still benefit from hemodynamic assessment and tailored medical therapy in experienced heart failure centers.
TREATMENT OF UNDERLYING AND COMORBID DISEASE
As we continue to delay the progression of heart failure with drugs, patients are presenting with a greater number of comorbidities. Earlier recognition and prompt treatment of these comorbidities may lead to improved survival. However, clinical studies are still needed to demonstrate that targeting comorbid conditions has a direct impact on long-term clinical event rates in patients with heart failure.
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2. Heart Failure Society of America. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006;12:10-38. Available at: www.heartfailureguidelines.org.
3. Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation. 2005;112:2426-2435.
4. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709-717.
5. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
6. 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:
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7. 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.
8. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005;294:1625-1633.
9. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006;47: 1987-1996.
10. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004; 350:647-654.
11. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol. 2007;49:1733-1739.
12.Packer M, Abraham WT, Mehra MR, et al. Utility of impedance cardiography for the identification of short-term risk of clinical decompensation in stable patients with chronic heart failure. J Am Coll Cardiol. 2006;47:2245-2252.
13.Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883.
14.Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225-237.
15. Stevenson LW, Desai AS. Selecting patients for discussion of the ICD as primary prevention for sudden death in heart failure. J Card Fail. 2006;12: 407-412.
16. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352: 1539-1549.
17. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140-2150.
18. Starling RC, McCarthy PM, Buda T, et al. Results of partial left ventriculectomy for dilated cardiomyopathy: hemodynamic, clinical and echocardiographic observations. J Am Coll Cardiol. 2000;36: 2098-2103.
19. Wu AH, Aaronson KD, Bolling SF, et al. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction. J Am Coll Cardiol. 2005;45: 381-387.
20. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 2001;345:1435-1443.
Therapeutic Agents in This Article
Hydralazine and isosorbide dinitrate (BiDil)
*Available in generic formulation.