Nifedipine. Dose-related increase in mortality in patients with coronary heart disease.
BACKGROUND
The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur.


RESULTS
We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total 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.


CONCLUSIONS
In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.
Furberg
C D
CD
Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, NC 27157-1063, USA.
Psaty
B M
BM
Meyer
J V
JV
D000787:Angina Pectoris / Q000139:chemically induced; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D016001:Confidence Intervals; D003327:Coronary Disease / Q000188:drug therapy / Q000401:mortality*; D003864:Depression, Chemical; D004095:Dihydropyridines / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000139:chemically induced; D009543:Nifedipine / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D016017:Odds Ratio; D012084:Renin-Angiotensin System / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects; D013997:Time Factors
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C038806:1,4-dihydropyridine; D009543:Nifedipine