Should calcium channel blockers be used in heart failure?

Calcium channel blockers are a distinct group of vasodilators that dilate systemic and coronary resistance arteries. In principle, these actions should enhance cardiac performance and relieve myocardial ischemia, but controlled clinical trials have failed to endorse these theoretical benefits. Calcium channel blockers neither relieve symptoms nor enhance exercise tolerance. They may also have serious adverse cardiovascular effects, producing pulmonary edema and cardiogenic shock on short-term use, and increasing the risk of worsening heart failure and death in patients with left ventricular dysfunction on longer-term therapy. These reactions have been ascribed to depression of cardiac contractility and activation of endogenous neurohumoral systems, but the contributions of such mechanisms is uncertain. Sustained-release formulations and vasoselective agents are safer, but have failed to eradicate the cardiovascular complications. Recent attention has focused on the newer calcium channel blockers (amlodipine, felodipine, mibefradil). Three large-scale trials in heart failure have been completed.

The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) randomized 1153 patients with severe ischemic or nonischemic heart failure, New York Heart Association (NYHA) class Illb to IV, to adjuvant amlodipine ^10 mg daily vs placebo for 13.8 (6-33) months. The primary end point was the combined risk of death and major cardiovascular hospitalization; survival was a secondary end point. Amlodipine had no effect on the primary end point. However, it tended to decrease all-cause mortality (P=0.07), while the number of events observed was sufficiently large to exclude an adverse effect on survival. Amlodipine lowered pump failure deaths by 45% in patients with nonischemic cardiomyopathy (P=£0.001), but this benefit was considered preliminary and in need of confirmation since observed in a subgroup. It is being addressed in the ongoing PRAISE II.

The third Vasodilator-Heart Failure Trial (V-HeFT III) randomized 450 patients with mild-to-moder-ate ischemic or nonischemic heart failure to adjuvant sustained-release felodipine 10 mg daily vs placebo for 18 (3-39) months. The primary end point was exercise tolerance; survival was an important secondary end point. Felodipine had no effect on exercise tolerance or all-cause mortality. Too few fatal events were observed to evaluate the effect on survival.

The Mortality Assessment of Congestive Heart failure (MACH-1) trial randomized 2590 patients with ischemic or nonischemic heart failure, NYHA class III or IV, to adjuvant mibefradil (target dose 100 mg daily) vs placebo for 26 (max 39) months. The primary end point was all-cause mortality. Mibefradil was associated with an 11% increase in mortality, which was statistically nonsignificant. Subgroup analyses suggested that this trend was due to interaction with other heart failure drugs. Based on these results and other reports of adverse experiences, mibefradil has been withdrawn from clinical use.

In the absence of demonstrated efficacy, calcium channel blockers should not be used to treat heart failure due to systolic dysfunction. Diltiazem and verapamil are also contraindicated in combination with P-blockers. Newer agents (felodipine, amlodipine) do not improve survival vs placebo when added to conventional therapy with angiotensin-converting enzyme inhibitors and diuretics. Felodipine and

Further reading

Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Am J Cardiol. 1999:83(2A):1 A-38A. Hager WD, Davis BR, Riba A, et al. Absence of a deleterious effect of calcium channel blockers in patients with left ventricular dysfunction after myocardial infarction: the SAVE Study Experience. SAVE Investigators, Survival and Ventricular Enlargement. Am Heart J. 1998;135:406-413.

Amlodipine may be considered as adjuvant therapy for concomitant hypertension or angina, given the long-term safety evidence of a neutral effect on survival.

O’Connor CM, Carson PE, Miller AB, et al. Effect of amlodipine on mode of death among patients with advanced heart failure in the PRAISE trial. Prospective Randomized Amlodipine Survival Evaluation. Am J Cardiol. 1998;82:881-887.

Remme WJ, Swed berg K. Guidelines for diagnosis and treatment of chronic heart failure. Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Eur Heart J. 2001; 22:1527-1560.

Kiywords

drug; calcium channel blocker; left ventricular dysfunction; mortality; contraindication; adjuvant therapy

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