1995: The year of the calcium antagonist controversy

The year 1995 has been an unsettling one in the history of the treatment of hypertension and ischemic heart disease. A fierce debate has sprung up about the safety of calcium antagonists, particularly the dihydropyridine nifedipine. A widely publicized case-control study showed that compared with diuretics and beta-blockers, short-acting calcium antagonists, when used in the treatment of hypertension, were associated with a higher risk of myocardial infarction, an effect which appeared to be dose related. A second study focused on clinical trials of nifedipine in patients primarily with acute myocardial ischemia syndromes. The meta-analysis showed an increased risk in the relative mortality rate of 1.16 associated with the use of short-acting nifedipine at doses of 80 mg/day or higher. The mechanisms responsible for these results were also discussed. Both publications were accompanied by editorials, and there were subsequently other commentaries published which pointed out weaknesses in the design, conduct, analysis and interpretation of the studies, and these have also been reviewed. Arising from this controversy, important questions have been raised which need to be addressed. First, are the data valid and are these drugs safe? If not, can the data be extrapolated from short-acting dihydropyridines, to the newer formulations and other sub-classes of calcium antagonists? Second, do these agents reduce cardiovascular morbidity and mortality? Finally, what are the alternatives to their use and the clinical implications? These studies have raised questions about safety, and there is little evidence to show any actual benefit on the incidence of cardiovascular events. For most patients there are clinically tested and proved therapeutic alternatives, i.e. diuretics and beta-blockers, and therefore the burden of proof must now be on those who primarily recommend the use of calcium antagonists. Recommendations and guidelines for treatment, where the primary goal is to reduce cardiovascular morbidity and mortality must be supported by adequate data.