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

Summary

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).

Methods

• Patients: NYHA class IIIB or IV congestive heart failure with an ejection fraction less than 30%. All treated with digoxin, diuretics and an ACE inhibitor.

  Exclusions: Uncorrected primary valvular disease. Recent ventricular tachycardia / fibrillation, unstable angina, MI, revascularization, stroke. Severe pulmonary, hepatic or renal disease. Hypertension (>159/89) or hypotension (<85 systolic). Treatment with beta-blockers, calcium channel blockers or class IC antiarrhythmics.

• Intervention: Patients stratified into two groups: those judged to have CHF on the basis of coronary disease (by angiographic or clinical criteria) and those felt to have nonischemic dilated cardiomyopathy. In each group, patients were randomized to amlodipine (5 mg, then 10 mg daily, if tolerated) or placebo.

• Analysis: Primary endpoint -- combined all-cause mortality and cardiovascular morbidity (hospitalization for CHF, MI, unstable angina, arrhythmia). Secondary endpoint -- all-cause mortality alone (also assessed in subgroups based on age, sex, EF, NYHA class, serum sodium, presence of angina, hypertension). Trial continued until 190 events occurred in the placebo group, with subsequent follow-up for six months.

• Patients: Trial began on March 9, 1992 and completed on December 31, 1994. 1153 patients were enrolled, 732 (63%) with ischemic heart disease, 421 (37%) with nonischemic disease. Baseline characteristics were well matched. Average ejection fraction 21%. Average daily dose of amlodipine was 8.8 mg. Median follow-up was 13.8 months.

• Effect of amlodipine overall: For the primary endpoint, combined mortality and cardiovascular morbidity, a trend favoring amlodipine did not reach statistical significance. The same was true for the secondary endpoint, all-cause mortality.

• Effect in individual strata: Among the patients with ischemic heart disease, the rates of both primary events (combined cardiovascular morbidity and all-cause mortality) and of all-cause mortality alone were practically identical, with nearly superimposable Kaplan-Meyer curves.

  Among the 37% of patients with nonischemic cardiomyopathy, there was a significant reduction in primary events and in all-cause mortality in the amlodipine group. There were 74 deaths in the placebo group and 45 in the amlodipine group (p<0.001). This is clearly demonstrated in the Kaplan-Meyer survival curves, as well.

• Effect on subgroups: The effect of amlodipine on mortality in the previously defined subgroups (age, sex, EF, NYHA class, serum sodium, presence of angina, hypertension) was not different from its overall effect, except for the subgroup without angina -- here, amlodipine had a significantly beneficial effect, as would be expected from the results in the nonischemic group.

• Adverse effects: Peripheral edema was more frequent in the amlodipine group (27% vs 18%); pulmonary edema was also more frequent in the amlodipine group (15% vs 10%). Uncontrolled hypertension was more frequent in the placebo group. The incidence of worsening heart failure (about 41%), MI (3%), ventricular arrhythmias and hypotension were similar in the two groups.

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).

Comment

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

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.

This certainly would represent a favorable NNT, if borne out by more studies. --mj

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References

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).
Details

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

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