Complementary actions and risk reduction: the rationale for combination of an angiotensin converting enzyme inhibitor with a non-dihydropyridine calcium antagonist.
REQUIREMENTS FOR DRUG REGISTRATION: Current drug registration procedures by the United States Food and Drug Administration (FDA) require at least two placebo-controlled factorial- and/or parallel-study designs. The statistical and graphical analysis of a factorial-design study allows the investigator to identify the optimal dose of the combination but 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.
In an effect to compare combination studies across antihypertensive drug classes, we examined data from studies that formed the basic of past registration applications to the FDA. Our review findings indicated that combined antihypertensive effects were, at best, approximately additive for a number of different combinations. However, this takes no account of the advantages of drug combinations in allowing reduced dosages of each drug with fewer adverse effects than monotherapy.
In the case of calcium antagonists, physicians must differentiate between rapid-onset or short-acting dihydropyridines, which raise the heart rate and plasma noradrenaline, and longer-acting newer calcium antagonists. Recent evidence indicates that the combination of a long-acting calcium antagonist and an angiotensin converting enzyme inhibitor is particularly effective in reducing cardiovascular risk.


CONCLUSIONS
Combining drugs with different mechanisms of action seems to be a reasonable and effective way of treating hypertension. It is essential, however, to establish the efficacy and safety of all new drug combinations by performing carefully designed clinical studies that fulfill the stringent FDA requirements.
Messerli
F H
FH
Alton Oschner Medical Foundation, New Orleans, Louisiana 70121, USA.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004095:Dihydropyridines; D004359:Drug Therapy, Combination; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C038806:1,4-dihydropyridine