Combination treatment in antihypertensive drug trials.

Abstract

The most widely known discrepancy between the latest guidelines issued by the United States Joint National Committee (JNC V) and those issued by the World Health Organization/International Society of Hypertension (WHO/ISH) concerns the choice of the drug to start antihypertensive treatment. While the JNC V guidelines advise starting treatment with a diuretic or a beta-blocker [1], the WHO/ISH guidelines take a more liberal approach and indicate the first-choice drugs to be not only diuretics and betablockers, but also angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, and alpha1blockers [2]. The restriction of the initial drug selection to diuretics and beta-blockers by the JNC V guidelines originates from a clear-cut argument, that is, that all trials with a controlled design that have been performed and have shown a reduced cardiovascular morbidity in the group undergoing antihypertensive treatment have made use of drugs belonging to one or the other class. Hence, no demonstration of any benefit has ever been provided for other agents, whose use should thus be limited to the patients in whom diuretics and betablockers are contraindicated, ineffective, or undesirable for clinical considerations. The arguments in favor of the less rigid approach suggested by the WHO/ISH guidelines, however, are multifold and informative. For example, treatment of malignant hypertension has been proved to be capable of delaying the rapid and severe cardiovascular complications associated with this condition and with saving patients’ lives before diuretics and beta-blockers were in use [3]. Furthermore, in trials on antihypertensive treatment, the reduction of cardiovascular events appeared to be related to the magnitude of the decrease in diastolic and/or systolic blood pressure achieved by treatment [4]. Finally, and most importantly, the WHO/ISH guidelines emphasize that the initial use of diuretics or betablockers in the antihypertensive treatment trials was often complemented by drugs belonging to other classes, because in most instances the goal of these trials was to investigate not the relative benefit of different antihypertensive drugs but the benefit of a blood-pressure–lowering treatment. Indeed, it can be seen from Table 1 that most classes of antihypertensive agents have been employed in varying proportions in antihypertensive drug trials. It can also be seen from Figure 1 that in both the oldest and newest trials, a high proportion of patients were undergoing combination treatment with two or more drugs rather than monotherapy with a diuretic and beta-blocker, which was intended when designing trial design to only be a first step toward trying to achieve satisfactory blood pressure control. It therefore seems inappropriate to ascribe to two classes of drugs only a benefit that was clearly obtained by a therapeutic strategy that included many different antihypertensive agents in many patients. This is properly phrased by the following sentence of the WHO/ISH guidelines: “No evidence is so far available that benefits are due to any particular class of antihypertensive agents rather than to lowering blood pressure per se” [2].