Androgen Blocking Drugs And Treating Patients With Mild Heart Failure

Background Clinical trials have shown that Ð"ÑŸ-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated.

Methods and Results We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating Ð"ÑŸ-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16Ð'±0.01 and a mean maximal oxygen consumption of 13.6Ð'±0.6 mL Ð'* kg-1 Ð'* min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n=33) or matching placebo (n=16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P=.005) and stroke volume index (P=.010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P=.003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P=.002), functional class (P=.013), and submaximal exercise tolerance (P=.006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P=.028), but carvedilol-treated patients had more dizziness and advanced heart block.

Conclusions Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

Key Words: heart failure • carvedilol • receptors, adrenergic, beta

Introduction

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Both experimental and clinical evidence suggests that activation of the sympathetic nervous system contributes importantly to the progression of left ventricular dysfunction to end-stage heart failure.1 This belief has led to the evaluation of Ð"ÑŸ-adrenergic blocking drugs in patients with heart failure in an attempt to interfere with the deleterious effects of prolonged sympathetic stimulation.2 Controlled clinical trials have shown that the long-term administration of metoprolol, bucindolol, nebivolol, bisoprolol, and carvedilol can improve ventricular function and clinical status in selected patients with an idiopathic dilated cardiomyopathy.3 4 5 6 7 8 9 In addition, long-term therapy with propranolol can reduce mortality in patients with left ventricular dysfunction after a myocardial infarction.10

Despite these encouraging results, physicians remain concerned that Ð"ÑŸ-blockers may be detrimental to patients with established heart failure. Such fears may be particularly warranted in patients with the most advanced disease, in whom the sympathetic nervous system may play a supportive (rather than deleterious) role to support cardiac contractility.11 In this regard, it is noteworthy that previous studies of Ð"ÑŸ-blockade in heart failure generally evaluated only patients with mild to moderate symptoms3 4 5 6 7 8 12 13 14 or mild to moderate hemodynamic abnormalities (ejection fraction >0.20 to 0.25 and pulmonary wedge pressure <14 to 18 mm Hg),3 4 5 6 7 8 9 10 12 13 14 and in most cases, these patients were not resistant to treatment with angiotensin-converting enzyme (ACE) inhibitors. In the few reports in which Ð"ÑŸ-blockers were given to patients with severe hemodynamic and clinical abnormalities, treated patients commonly failed to show improvement, and many tolerated the drugs poorly.15 16 These observations raised questions about the utility of Ð"ÑŸ-blockers in heart failure, since these drugs would be difficult to use if they were valuable only when patients had few symptoms but exacerbated the severity of heart failure in patients with progressive disease.

The objective of the present study was to evaluate the long-term efficacy and safety of Ð"ÑŸ-blockade in patients who had severe chronic heart failure despite the use of ACE inhibitors. The Ð"ÑŸ-blocker used in this study was carvedilol, which, in addition to having mildly selective effects on Ð"ÑŸ1-receptors, exerts peripheral vasodilator effects by blocking 1-receptors.17 18 These vasodilator properties may enhance the efficacy and safety of Ð"ÑŸ-blockade in patients with advanced disease.

Methods

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Introduction

Methods

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Patient Population

Patients with chronic heart failure who remained symptomatic despite conventional therapy were eligible for the study. Heart failure was defined as the presence of dyspnea or fatigue at rest or on exertion for >2 months in association with a left ventricular ejection fraction 0.35 as assessed by radionuclide ventriculography. All patients had one or more of the following characteristics indicative of advanced disease: (1) New York Heart Association functional class III or IV symptoms; (2) maximal oxygen consumption <14 mL Ð'* kg-1 Ð'* min-1; or (3) pulmonary wedge pressure 18 mm Hg. These clinical and physiological abnormalities were present despite 2 months of treatment with digoxin, diuretics (in sufficient doses to maintain patients free of edema), and an ACE inhibitor (except for five patients who could not tolerate captopril or enalapril). The doses of these drugs were kept constant for at least 2 weeks before entry into the study.