Calcium channel blockers in heart failure with reduced ejection fraction

INTRODUCTION — Calcium channel blockers should generally be avoided in patients with heart failure with reduced ejection fraction (HFrEF) since they provide no functional or mortality benefit and some first generation agents may worsen outcomes [1].

The clinical trials that have evaluated the use of calcium channel blockers in patients with HFrEF will be reviewed here. The use of calcium channel blockers in the treatment of HF with preserved ejection fraction is discussed separately. (See "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Secondary therapies'.)

FIRST GENERATION AGENTS — Calcium channel blockers might be expected to have beneficial effects in systolic HF by reducing peripheral vasoconstriction and thereby reducing left ventricular afterload. However, these agents also have variable degrees of negative inotropic activity, and several studies demonstrated greater clinical deterioration in patients treated with nifedipine and diltiazem compared with placebo or isosorbide dinitrate [2,3]. As a result, these drugs have generally been avoided in patients with systolic HF, even for the treatment of coexisting angina or hypertension.

Nifedipine — The effect of nifedipine in HFrEF depends, in part, upon the baseline hemodynamic status of the patient. Short-term use of the drug can cause hemodynamic deterioration when there is evidence of more severe HF, as manifested by high plasma renin activity, hyponatremia, and elevated right atrial pressure [4].

The adverse effects of long-term therapy with nifedipine were illustrated in a randomized, double-blind, crossover study of 28 patients with New York Heart Association (NYHA) class II or III HFrEF (table 1); nifedipine, with and without isosorbide dinitrate, was compared with isosorbide dinitrate alone [2]. Eight weeks of therapy with nifedipine alone or in combination with isosorbide dinitrate resulted in a significantly higher incidence of hospitalization (24 and 26 versus 0 percent with isosorbide dinitrate alone), episodes of worsening HF (9 and 21 versus 5), and premature discontinuation of therapy due to clinical deterioration or other side effects (29 and 19 versus 5 percent).

Verapamil — Verapamil does not appear to be effective in patients with HF after an acute myocardial infarction (MI), although it does not increase mortality. This was illustrated by the DAVIT II trial, which randomly assigned 1775 patients with a recent MI to verapamil (360 mg/day) or placebo; therapy was continued for a mean of 16 months [5]. In patients with HF during hospitalization, verapamil had no effect on mortality (18 percent in both groups) or the combined end point of death or reinfarction (25 percent in both groups). (See "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction", section on 'Calcium channel blockers' and "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Calcium channel blockers'.)

Diltiazem — The role of diltiazem in patients with HF has been evaluated in two randomized trials. The results are conflicting.

Multicenter Diltiazem Postinfarction trial — The Multicenter Diltiazem Postinfarction Trial (MDPIT) randomly assigned 2466 patients with an MI to therapy with diltiazem or placebo [6]. After a mean follow-up of 25 months, patients with pulmonary congestion on chest x-ray who were treated with diltiazem had a significant increase in cardiac mortality or recurrent nonfatal infarction compared with placebo (hazard ratio 1.41). In contrast, diltiazem reduced the incidence of cardiac mortality and risk of recurrent nonfatal infarction in patients without pulmonary congestion (hazard ratio 0.77).

A subsequent analysis found a similar effect of diltiazem when analyzed by left ventricular ejection fraction (LVEF) [3]. Among 623 patients with an LVEF ≤0.40, the incidence of late HF episodes was higher in those taking diltiazem (21 versus 12 percent for placebo). The incidence of late HF increased progressively with decrements in baseline LVEF. In comparison, diltiazem had no adverse effect in patients with an LVEF above 40 percent.

An increase in recurrent infarction in diltiazem-treated patients with left ventricular dysfunction was also suggested in a retrospective analysis of almost 7000 patients entered into the SOLVD trials, most of whom had a remote infarction and one-third of whom were taking a short-acting calcium channel blocker, primarily diltiazem [7]. However, such a deleterious effect of calcium channel blocker therapy was not seen in a retrospective analysis from the SAVE trial of 2231 patients who had asymptomatic left ventricular dysfunction after an acute infarction [8].

DiDi trial — The Diltiazem in Dilated Cardiomyopathy (DiDi) trial randomly assigned 186 patients with idiopathic dilated cardiomyopathy and New York Heart Association (NYHA) class II or III HF to diltiazem (60 or 90 mg TID) or placebo, added to standard therapy; however, only 153 patients completed the study [9]. The following results were noted at 24 months:

●Patients in the diltiazem group had an improved cardiac index at rest and with exercise, improved stroke volume index, and increased exercise capacity compared with those taking placebo. However, there was an equivalent improvement in mean LVEF in both groups (8 versus 6 percent for placebo).

●Subjects taking diltiazem had a subjective increase in well-being compared with the placebo group.

●There was no difference in transplant listing-free survival (85 versus 80 percent for placebo).

It is likely that the hemodynamic benefits of diltiazem in this trial were secondary to a vasodilator effect. These effects, which have also been seen with other vasodilators such as prazosin, have not translated into improvements in survival [10].

The difference in results between the MDPIT and DiDi trials likely reflects the different populations studied (eg, post-MI versus dilated cardiomyopathy), but in neither case do the results suggest a meaningful beneficial effect, and in some patients there was an adverse effect on outcomes.

SECOND GENERATION AGENTS — The second-generation calcium channel blockers amlodipine and felodipine have little or no negative inotropic activity at the usual therapeutic doses, and may be better tolerated than the other calcium channel blockers in patients with HF. As described below, studies with these drugs found neither benefit nor harm when used in patients with class II or III HF [10,11]. Thus, they appear to be safe and can be used for the treatment of hypertension or angina in patients with systolic HF [12]. However, in such patients, angiotensin converting enzyme (ACE) inhibitors and beta blockers, both of which improve patient survival, should be given first in patients with hypertension and beta blockers should be given first in patients with angina or atrial fibrillation.

Amlodipine — The effect of amlodipine, a calcium channel blocker devoid of negative inotropic effects but with vascular smooth muscle relaxing activity, was best evaluated in two major trials: PRAISE and PRAISE 2 [13,14]. Although the PRAISE trial suggested a survival benefit with amlodipine in patients with a nonischemic cardiomyopathy [13], this was not confirmed in PRAISE 2 [14].

PRAISE trial — The PRAISE trial randomly assigned 1153 patients with class III or IV HF (table 1) and a left ventricular ejection fraction (LVEF) below 30 percent to amlodipine or placebo, which were added to baseline therapy consisting of diuretics, digoxin, and an ACE inhibitor [13]. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events.

At 14 months, there was an insignificant 9 percent reduction in the primary end point with amlodipine (39 versus 42 percent for placebo) and an insignificant 16 percent reduction in all-cause mortality (figure 1). The amlodipine-treated group had a higher incidence of peripheral edema (27 versus 18 percent) and pulmonary edema (15 versus 10 percent), but they were less likely to develop uncontrolled hypertension or angina. There did not appear to be an overall excess risk of cardiovascular adverse events for patients treated with amlodipine.

Thus, the PRAISE trial established the safety profile of amlodipine for the treatment of patients with left ventricular dysfunction, especially in those with a history of angina or hypertension. In a secondary retrospective analysis, the effect of amlodipine appeared to be dependent in part upon the etiology of the HF with improvement being seen in patients with a nonischemic cardiomyopathy [15]. However, this benefit was not confirmed in PRAISE 2.

PRAISE 2 trial — The observation in the first PRAISE trial that there was a survival advantage with amlodipine in patients with nonischemic cardiomyopathy led to the PRAISE 2 trial, which evaluated the role of amlodipine in 1650 patients with a nonischemic cardiomyopathy [14]. After a follow-up of up to four years, there was no difference in mortality with amlodipine (34 versus 32 percent for placebo). When the results from PRAISE 2 were combined with those for patients with a nonischemic cardiomyopathy in PRAISE, no difference in mortality was observed. In addition, short-term data from the Amlodipine Exercise Trial found no benefit in parameters such as exercise tolerance, quality of life, or NYHA class [16].

Felodipine — Felodipine, like amlodipine, is highly selective for vascular smooth muscle and it does not have negative inotropic activity. An initial placebo-controlled trial found that 12 weeks of therapy with felodipine added to standard therapy did not improve exercise time or signs and symptoms of HF [17]. This was followed by the large V-HeFT III trial.

V-HeFT III trial — The V-HeFT III trial randomly assigned 450 men with chronic HF who were receiving enalapril and diuretics to extended release felodipine (5 mg BID) or placebo [11]. The effect of felodipine on exercise tolerance, symptoms, and clinical outcome was evaluated after 12 weeks and at an average of 18 months of therapy. The following results were observed:

●At three months, there was no improvement in exercise tolerance, quality of life, or the need for hospitalization compared with placebo, despite a significant reduction in blood pressure and serum atrial natriuretic peptide levels, and a small but significant increase in left ventricular ejection fraction (LVEF). However, the beneficial effect on LVEF and atrial natriuretic peptide did not persist during long-term follow-up.

●Felodipine prevented a worsening of exercise tolerance and quality of life at 18 months. The difference between exercise duration and quality of life between felodipine and placebo reached significance at 27 months after randomization.

●Mortality and hospitalization rates were the same in the two groups (figure 2). The only apparent side effect associated with felodipine therapy was peripheral edema.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)

SUMMARY AND RECOMMENDATIONS

●Agents to avoid in HFrEF – Calcium channel blockers (except amlodipine and felodipine) should generally be avoided in patients with heart failure with reduced ejection fraction (HFrEF) since they provide no functional or mortality benefit and some first-generation agents may worsen outcomes. (See 'First generation agents' above.)

●Agents acceptable for use in HFrEF – Amlodipine and felodipine appear to be safe and well tolerated in patients with HFrEF and can be used for the treatment of hypertension or angina. However, angiotensin converting enzyme inhibitors and beta blockers, both of which improve survival among patients with HFrEF, should be given first in patients with hypertension and beta blockers should be given first in patients with angina or atrial fibrillation. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy' and 'Second generation agents' above.)