What have we learned from the calcium channel blocker controversy?

Hundreds of thousands of patients around the world have been treated with drugs that antagonize the function of calcium channels. The development of these drugs was based on the remarkable scientific discovery of calcium channels, the identification of methods to antagonize their effects, and the development of compounds to block them.1 2 As concepts of the pathophysiology and treatment of hypertension and atherosclerosis evolved in parallel with the science of calcium channels, an approach to determining whether these therapies have clinical benefit was developed. In the treatment of hypertension, the strategy for therapeutic evaluation has been based on the simple concept that lowering blood pressure will result in a decrease in the incidence of stroke, myocardial infarction, renal failure, and death.2 In the treatment of angina, a more complex set of concepts has prevailed. Three factors have formed the framework for evaluating therapies for angina: (1) the role of coronary vasospasm in the production of myocardial ischemia,3 (2) the belief that reduction in myocardial ischemia over a specified time interval or improvement in exercise time on a treadmill provided strong evidence of an overall health benefit,4 and (3) more difficult extrapolations related to preservation of cellular function during myocardial ischemia.5 The synthesis of these factors has led to the acceptance of a reduction in frequency of angina or an improvement in exercise time as adequate evidence of a desirable clinical benefit of a therapy for angina. On the basis of these constructs, a variety of compounds were developed that had disparate properties but the common action of antagonizing calcium channels. Regulatory authorities in the United States and other countries approved these agents for clinical use on the basis of their pathophysiological constructs, relying on evidence that they lowered blood pressure or improved exercise time. Hundreds …