COMPLEMENTARY ACTIONS AND RISK REDUCTION - THE RATIONALE FOR COMBINATION OF AN ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR WITH A NONDIHYDROPYRIDINE CALCIUM-ANTAGONIST

Requirements for drug registration Current drug registration procedure s by the United States Food and Drug Administration (FDA) require at l east two placebo-controlled factorial- and/or parallel-study designs, The statistical and graphical analysis of a factorial-design study all ows the investigator to identify the optimal dose of the combination b ut these comparisons require considerable overall patient numbers for statistical power, In contrast, parallel-design studies require about 150 matched patients in each of the four arms. Drug combinations In an effort to compare combination studies across antihypertensive drug cl asses, we examined data from studies that formed the basis of past reg istration applications to the FDA, Our review findings indicated that combined antihypertensive effects were, at best, approximately additiv e for a number of different combinations, However, this takes no accou nt of the advantages of drug combinations in allowing reduced dosages of each drug with fewer adverse effects than monotherapy. Calcium anta gonists In the case of calcium antagonists, physicians must differenti ate between rapid-onset or short-acting dihydropyridines, which raise the heart rate and plasma noradrenaline, and longer-acting newer calci um antagonists. Recent evidence indicates that the combination of a lo ng-acting calcium antagonist and an angiotensin converting enzyme inhi bitor is particularly effective in reducing cardiovascular risk. Concl usions Combining drugs with different mechanisms of action seems to be a reasonable and effective way of treating hypertension, It is essent ial, however, to establish the efficacy and safety of all new drug com binations by performing carefully designed clinical studies that fulfi l the stringent FDA requirements.