Calcium Blockers and Congestive Heart Failure
ABSTRACT & COMMENTARY
Synopsis: Felodipine can be used safely in patients with heart failure if used for another indication.
Source: Cohn JN, et al. Circulation 1997;96:856-863.
The efficacy and safety of calcium channel antagonists in patients with depressed left ventricular function, congestive heart failure, or both remains controversial. Initially thought to be safe, these drugs have been shown to have potentially harmful effects in patients with depression of left ventricular contractile function. However, the recent PRAISE trial (Clin Cardiol Alert 1996;15:91-92) demonstrated no benefit of amlodipine in patients with congestive heart failure, but when subjects were categorized by etiology, non-ischemic cardiomyopathy patients appeared to benefit from the calcium blocker, whereas ischemic heart disease CAD patients did not show a survival advantage. V-HeFT III, previously presented but not published, sought to determine whether felodipine, a second generation dihydropyridine (DHP) calcium antagonist, would be efficacious in congestive heart failure. Four hundred fifty patients with heart failure were enrolled (following exclusion of almost 5500 subjects) between 1991 and 1994 in this prospective study that ended in 1995. There was an average follow-up of 18 months. Patients with stable class II-III heart failure were eligible if they had a depressed ejection fraction or cardiomegaly. In addition, reduced performance on exercise testing was required (stable exercise capacity of > 2 and < 14 minutes. All individuals were treated with enalapril 20 mg daily; almost all were on diuretics; three-fourths were on digoxin; 25% were on nitrates. Mean ejection fraction was 30%, and the CT ratio on chest x-ray was 0.53.) The primary end points were the effects of felodipine on exercise tolerance, symptoms, and clinical signs of heart failure after a minimum of 12 weeks of therapy, as well as assessment of long-term safety, efficacy, and tolerability of this treatment for up to 42 months. Quality of life score, neurohormonal status, and ejection fraction were assessed; morbidity and mortality end points were calculated.
The results indicated that felodipine appeared to be safe in this population, although not particularly beneficial. Baseline variables in the two treatment groups were comparable; a little more than 50% had CAD as the cause of heart failure. Felodipine resulted in a sustained reduction in blood pressure as well as heart rate for at least one year. Exercise capacity in three months was not different between felodipine and placebo, but after more than two years, the felodipine subjects had a greater exercise time than placebo. Ejection fraction showed a trivial increase with felodipine at three months but did not persist. Quality of life was not different between the two drugs during early follow-up, but the felodipine patients had less worsening after 27 months. Neurohormonal activation was comparable, except for a depression of ANP levels at three months (but not later) with felodipine. Mean norepinephrine and ANP levels rose progressively and were not affected by the calcium blocker. Hospitalizations were not different between the two groups; of note, more than 40% of enrollees were hospitalized during the follow-up period. Mortality was similar between the two drugs, and the combined end point of hospitalization and mortality was not different.
There was a trend for improvement with felodipine in several parameters in class III patients who represented a minority of the overall cohort. Cohn and colleagues state that the reduction in blood pressure and decrease in ANP at three months suggests a benefit from felodipine, although other end points were not different from placebo, both short- and long-term. They admit that felodipine did not induce a favorable clinical response in heart failure patients on an ACE inhibitor and conclude, "nonetheless, the data suggest that felodipine can be used safely in patients with heart failure if used for another indication."
COMMENT BY JONATHAN ABRAMS, MD
V-Heft III, coupled with a recent report from England showing little important benefit from felodipine in heart failure, conclusively demonstrates that this drug does not act as a useful vasodilator in heart failure patients already on triple therapy. It is unclear why the arterial vasodilation induced by felodipine did not offer more benefit; it may be that the vasodilator concept, while valid, is part of the complex pathophysiology of heart failure, and that ACE inhibition may impart near-maximal benefits that can be achieved with vasodilator therapy. The long-term follow-up experience (> 24 months) suggests a modest benefit from the calcium channel blocker but not enough to allow a recommendation for the use of this agent for therapy. Most importantly, however, is the observation that felodipine is safe in such patients, many of whom may require a calcium channel blocker for angina or hypertension. This is a major advance over the first generation calcium channel antagonists, as well as a number of the DHP agents currently on the market. It would appear that felodipine (and amlodopine) do not have negative inotropic effects and do not induce excessive neurohormonal activation. It is important for clinicians to realize that relatively safe calcium channel antagonists are available for subjects with poor LV function. From the data available, it is unclear whether amlodipine is a safer or more efficacious agent than felodipine, although many cardiologists advocate amlodipine as being the calcium blocker of choice in patients with compromised left ventricular function. The ongoing PRAISE-2 trial will provide evidence of whether amlodipine is truly beneficial in patients with cardiomyopathy. For now, either drug can be recommended for patients with overt heart failure who need a calcium blocker for clinical reasons. Furthermore, I would recommend that for any patients with substantial depression of LV function without heart failure (e.g., LV ejection fraction < 35%), felodipine or amlodipine should be preferentially used with discontinuation of other calcium channel blockers in favor of either of these agents.