Calcium channel blockers for hypertension: dissecting the evidence for adverse effects

Safety in the drug treatment of hypertension can only be seen in relation to efficacy, which has now come to mean not just blood pressure (BP) reduction but improvements in hard end points including mortality. Information on safety can come from a variety of sources, in an ascending hierarchy, which is as follows: case-control studies, cohort studies, randomized control trials (RCTs), and metaanalyses based on good RCTs. Only in the case of metaanalyses are definite criteria for acceptability established, but evaluation of case-control and cohort studies remains subjective. Despite these reserves about the data sources, it is proposed that the case-control study pointing to the risk of acute myocardial infarction during therapy with short-acting calcium channel blockers (CCBs) can be balanced out by another better more recent study, and by a large cohort study from Israel. In a very elderly population, a well-designed cohort study strongly suggests that short-acting nifedipine can be linked to increased mortality and that the specific links may be with a high dose and when the initial BP is less than 160/90 mm Hg. However, initial BP was only available in an unspecified number of patients. The risk of using short-acting verapamil was no more than that of beta-blockade. These differences can be attributed at least in part to the low catecholamine profile of verapamil and the marked rapid adrenergic activation with short-acting nifedipine, which could also explain the adverse effects found when this agent is given to patients with acute coronary syndromes. During the chronic use of long-acting dihydropyridine (DHP) CCBs, most evidence suggests that there is little or no catecholamine activation, or in the case of amlodipine, even a decrease in plasma catecholamine levels. These differences may explain why the expected regression of left ventricular hypertrophy is obtained with long- but not short-acting DHPs. At present the results of several large randomized controlled trials with long-acting CCBs are awaited. In the meantime, when the decision has been made to use a CCB, the preferential choice is for the use of a non-DHP for hypertension with clinical ischemia or for postinfarct hypertension, for a long-acting CCB for the control of left ventricular hypertrophy, and for the DHP amlodipine when there is associated depression of myocardial function.