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Evidence summaries

The Use of Diltiazem, Verapamil and Short-Acting Nifedipine in Heart Failure

The use of calcium channel blockers acting mainly on heart (diltiazem, verapamil) and short-acting nifedipine increases the risk of worsening of heart failure. Level of evidence: "B"

Goldstein and coworkers examined the effects of diltiazem on late-onset congestive heart failure in post-infarction patients with early reduction in ejection fraction 1. The Multicenter Diltiazem Postinfarction Trial (MDPIT) was a randomized, double-blind, placebo controlled trial of diltiazem in 2,466 postinfarction patients followed up for 12-52 (mean 25) months. Patients from 38 collaborating hospitals were enrolled and assigned to start diltiazem (240 mg/day) or placebo 3-15 days after a documented acute myocardial infarction, while still hospitalized. The primary end points for MDPIT were first recurrent cardiac event and cardiac mortality.

Development of congestive heart failure (CHF) was particularly frequent in the patients who were randomized to diltiazem and had pulmonary congestion, anterolateral Q wave infarction, or reduced ejection fraction (EF) at baseline. Among those with a baseline EF <40%, late CHF appeared in 12% (39/326) receiving placebo and 21% (61/297) receiving diltiazem (p=0.004); NNH 11. Life table analysis in patients with an EF <40% confirmed more frequent late CHF in those taking diltiazem (p=0.0017). In addition, the diltiazem-associated rise in the frequency of late CHF was progressively greater with increasingly severe decrements in baseline EF. This diltiazem effect was absent in patients with pulmonary congestion at baseline but an EF 40%, suggesting a unique association between diltiazem-related late CHF and systolic left ventricular dysfunction. Diltiazem-associated enhancement of CHF was evident both in the presence and absence of concomitant beta-blockers use. The authors conclude that postinfarction patients with reduced EF are at particular risk for subsequent CHF when treated with diltiazem.

  • Study quality: High
  • Applicability: Good

Furberg and coworkers 2 assessed in their meta-analysis the effect of the dose of nifedipine, a dihydro-pyridine calcium antagonist, on the risk of mortality in randomized secondary-prevention trials of coronary heart disease and reviewed the mechanisms by which this adverse effect might occur.

The dose-response analysis of nifedipine included the results of the 16 randomized secondary-prevention clinical trials for which mortality data were available. Twelve trials randomized patients with myocardial infarction, three trials included patients with unstable angina, and one trial evaluated patients with stable angina, one third of whom had a history of prior infarction. About 8350 patients were studied, and the doses of nifedipine ranged from 30 to 120 mg/d.

Overall, the use of nifedipine was associated with a significantly increased risk for mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects.The authors concluded that in patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality.

  • Study quality: High
  • Applicability: Moderate

References

  • Goldstein RE, Boccuzzi SJ, Cruess D ym. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation 1991;83:52-60 [PubMed]
  • Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-31[PubMed]

Primary/Secondary Keywords