Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: a critical analysis based on 100 studies.

Recently, serious concerns have been expressed about the long-term safety of the calcium channel blockers (CCBs) as a group. Safety and efficacy are, however, ultimately linked to each other; therefore both must be evaluated especially in the therapy of angina and hypertension, the main clinical indications for CCBs. The structural, functional, and pharmacokinetic heterogeneity of CCBs means that the efficacy and dangers of one subclass, such as the short-acting dihydropyridines (DHPs), in one situation, such as unstable angina, do not necessarily apply in other clinical situations. One hundred studies are reviewed according to their methods of data collection: case series, case control, cohort, randomized controlled trials (RCTs), and meta-analyses. Large, well-designed RCTs and the meta-analyses based on these trials remain the gold standard. Observational studies, though potentially less reliable sources of information because of selection bias, may nevertheless produce hypotheses that must then be tested in RCTs. Regarding safety, both observational studies and RCTs suggest that adverse effects of CCBs may be linked to short-acting agents, specifically short-acting nifedipine. Two good studies favor the safety of verapamil, even in short-acting form. Incomplete but increasing overall evidence favors the safety of longer-acting DHPs. Heart failure remains a class contraindication to the use of all CCBs, with some exceptions. Regarding efficacy, there are positive results of RCTs with CCBs in 2 specific clinical situations, namely, verapamil in postinfarct protection in the absence of pre-existing heart failure, and 2 outcome studies on hypertension with longer acting DHPs. These results cannot automatically be applied to other clinical situations and to other CCBs. For example, there is no evidence for the safety or efficacy of DHPs used without beta blockers in postinfarct patients. In diabetic hypertensives, 2 relatively large RCTs show that the blood pressure can be reduced by DHP-based therapy in diabetics, with a reduction in hard end points. To achieve current blood pressure goals, combination therapy is almost always necessary, and in diabetics there is strong evidence that 1 essential component should be an angiotensin converting enzyme inhibitor. The future aim with CCBs must be to obtain a large database gathered from RCTs, which will give the same certainty about efficacy and safety that already holds for use of the diuretics in hypertension, beta-blockers in postmyocardial infarction patients, and the angiotensin converting enzyme inhibitors in heart failure.