Effect of amlodipine on morbidity and mortality in severe chronic heart failure

Authors: Packer M, O'Connor C, Ghali J, Pressler M, Carson P, et al.
Source: New England Journal of Medicine. 335:1107-14. October 10, 1996.
Institutions: Multiple university medical centers in the U.S. and Pfizer Central Research.
Financial support: Pfizer Central Research.



Many calcium channel blockers have been noted to adversely affect patients with congestive heart failure and are generally avoided in severe CHF. It is unclear whether this problem extends to all such agents; preliminary studies have suggested that amlodipine might be safe in CHF. This double-blind, randomized trial was designed to test the safety of prolonged treatment with amlodipine in patients with severe congestive heart failure (the study acronym, PRAISE, stands for Prospective Randomized Amlodipine Survival Evaluation).



Authors' Discussion

According to the authors, their results demonstrate the safety of amlodipine in patients with severe congestive heart failure, contrary to what has been shown for several other calcium channel blockers. They note that a beneficial effect on mortality and cardiovascular morbidity was shown in the subgroup of patients with nonischemic cardiomyopathy, but that the mechanism for this is unknown. A similar beneficial effect on patients with nonischemic cardiomyopathy was noted in one trial of amiodarone and in another of a beta-blocker (bisoprolol), and they state that "[nonischemic cardiomyopathy] may be uniquely responsive to pharmacologic interventions".

They conclude that amlodipine should be safe to use for the treatment of hypertension and angina in patients with congestive heart failure and that further investigation is needed to confirm its utility in nonischemic cardiomyopathy (PRAISE-2 study in progress to look at this).


This trial appears well-designed and is certainly reassuring about the safety of amlodipine in the setting of congestive heart failure.

The differential effect of amlodipine in patients with ischemic vs. nonischemic heart failure is particularly interesting.

The authors provide data on both overall mortality and non-fatal cardiovascular endpoints (in their Table 2). There was no difference in non-fatal cardiovascular endpoints in either the ischemic or the nonischemic groups. Thus, the only statistically significant effect of amlodipine was a reduction in all-cause mortality in the nonischemic group. No data is provided about the causes of death, which might have given a clue to the reason for amlodipine's different effect in the two groups.

The authors point out that a similar effect was seen in a trial of amiodarone in CHF (1) and in a trial of the beta-blocker bisoprolol (2) and speculate that their result may be due to the same (unknown) mechanism. On the other hand, to my knowledge, no such differential effect has been noted in trials of ACE inhibitors in congestive heart failure. Also, the result in the amiodarone trial was only a trend, while a trial of another beta-blocker, carvedilol (reviewed here), showed no such differential effect.

The lack of effect in ischemic CHF and the beneficial effect in nonischemic CHF could be due to a selective beneficial effect in nonischemic cardiomyopathy, or it could be due to a global benefit in CHF which is counterbalanced by an adverse effect in the setting of coronary disease. This second hypothesis warrants consideration in light of the controversy surrounding the use of calcium channel blockers and their possible adverse effects in ischemic heart disease. The fact that adverse non-fatal ischemic events were not seen more often in the amlodipine group is very reassuring in this regard, but a clearer understanding of the reason for the lack of effect on mortality in the ischemic group would obviously be desireable.

November 13, 1996

Reader comments

Date: Fri, 22 Nov 1996
From: Kaiser@trip.com.br (Sergio Emanuel Kaiser)

The finding of a statistically significant reduction in mortality derived from the use of amlodipine only in non-ischemic cardiomyopathy was a big surprise for everyone. Since all patients were taking ACE inhibitors, there might have been some obscure beneficial interaction between amlodipine and ACEI's in the non-ischemic group, not yet understood.

The fact is that, if this turns out to be a reproducible finding in other studies, then it may well represent a cost-effective strategy for Class III/IV IDCM patients. A reduction in deaths of 29 among the 421 patients with nonischemic IDCM would mean that it would be necessary to treat with amlodipine roughly 14 similar patients for about one year in order to avoid one death, at the expense of just a slight increase in the incidence of pulmonary edema.

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1. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N. Engl. J. Med. 333: 77-82 (1995).

2. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 90: 1765-1773 (1994).

More references related to this summary from the NLM's PubMed database.

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