Combination Treatment in Antihypertensive Drug TrialsGiuseppe Mancia and Guido GrassiCattedra di Medicina Interna and Centro di Fisiologica Clinicaed Ipertensione, Ospedale San Gerardo, Monza, IRCCS andUniversità di Milano, Italy

The most widely known discrepancy between the lat-est guidelines issued by the United States Joint Na-tional Committee (JNC V) and those issued by theWorld Health Organization/International Society ofHypertension (WHO/ISH) concerns the choice of thedrug to start antihypertensive treatment. While theJNC V guidelines advise starting treatment with adiuretic or a beta-blocker [1], the WHO/ISH guide-lines take a more liberal approach and indicate thefirst-choice drugs to be not only diuretics and beta-blockers, but also angiotensin-converting enzyme(ACE) inhibitors, calcium antagonists, and alpha1-blockers [2].

The restriction of the initial drug selection to diuret-ics and beta-blockers by the JNC V guidelines origi-nates from a clear-cut argument, that is, that all trialswith a controlled design that have been performed andhave shown a reduced cardiovascular morbidity in thegroup undergoing antihypertensive treatment havemade use of drugs belonging to one or the other class.Hence, no demonstration of any benefit has ever beenprovided for other agents, whose use should thus belimited to the patients in whom diuretics and beta-blockers are contraindicated, ineffective, or undesir-able for clinical considerations.

The arguments in favor of the less rigid approachsuggested by the WHO/ISH guidelines, however, are

multifold and informative. For example, treatment ofmalignant hypertension has been proved to be capableof delaying the rapid and severe cardiovascular compli-cations associated with this condition and with savingpatients’ lives before diuretics and beta-blockers werein use [3]. Furthermore, in trials on antihypertensivetreatment, the reduction of cardiovascular events ap-peared to be related to the magnitude of the decreasein diastolic and/or systolic blood pressure achieved bytreatment [4].

Finally, and most importantly, the WHO/ISH guide-lines emphasize that the initial use of diuretics or beta-blockers in the antihypertensive treatment trials wasoften complemented by drugs belonging to otherclasses, because in most instances the goal of thesetrials was to investigate not the relative benefit ofdifferent antihypertensive drugs but the benefit of ablood-pressure–lowering treatment. Indeed, it can beseen from Table 1 that most classes of antihypertensiveagents have been employed in varying proportions inantihypertensive drug trials. It can also be seen fromFigure 1 that in both the oldest and newest trials, ahigh proportion of patients were undergoing combina-tion treatment with two or more drugs rather thanmonotherapy with a diuretic and beta-blocker, whichwas intended when designing trial design to only be afirst step toward trying to achieve satisfactory bloodpressure control.

It therefore seems inappropriate to ascribe to twoclasses of drugs only a benefit that was clearly ob-tained by a therapeutic strategy that included manydifferent antihypertensive agents in many patients.This is properly phrased by the following sentence ofthe WHO/ISH guidelines: “No evidence is so far avail-able that benefits are due to any particular class ofantihypertensive agents rather than to lowering bloodpressure per se” [2].

Address for correspondence: Professor Giuseppe Mancia, Catte-dra di Medicina Interna, Università di Milano, Ospedale S. Ger-ardo dei Tintori, Via Donizetti 106 - 20052 Monza (MI), Italy.

Received 27 January 1997; receipt/review time 21 days; acceptedin revised form 18 February 1997

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Cardiovascular Drugs and Therapy 1997;11:517–518 Editorial© Kluwer Academic Publishers. Boston.

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Table 1. Antihypertensive drug classes used in controlledtrials on the treatment of hypertension (n 5 22)

No. of trials in which Classes of drugs the drug was used

Diuretics 21á Methyldopa 11

Central agents 18 Reserpine 10Clonidine 1

Beta-blockers 9Hydralazine 6Guanetidine 5Calcium-channel blockers 3Bethanidine 1Ganglion blockers 1Alpha blockers 1ACE inhibitors 1Unspecified supplementary 1 drugs

References

1. Joint National Committee on Detection, Evaluation andTreatment of High Blood Pressure. The fifth report of theJoint National Committee on Detection, Evaluation andTreatment of High Blood Pressure (JNC V). Arch InternMed 1993;153:154–183.

2. Guidelines Sub-Committee of the WHO/ISH Mild Hyper-tension Liaison Committee. 1993 Guidelines for the manage-ment of mild hypertension: Memorandum from a WHO/ISHmeeting. J Hypertens 1993;11:905–918.

3. Hansson L, Dahlof B. What are we achieving with long-termantihypertensive drug therapy? In Laragh JH, Brenner BM(eds). Hypertension: Pathophysiology, Diagnosis and Man-agement. New York: Raven Press, 1990:2131–2142.

4. Mancia G, Grassi G. Considerations on current and futuretrials in hypertension. Blood Pressure 1996;5:327–332.

Fig. 1. Percent of patients undergoing combination treatmentin various antihypertensive drug trials. MRS II = Medical Re-search Council Study II [5]; SHEP = Systolic Hypertension inthe Elderly Program [6]; STOP = Swedish Trial in Old Pa-tients [7]; COOPE = Coope and Warrender Study [8];EWPHE = European Working Party on High Blood Pressurein the Elderly [9]; IPPPSH = International Prospective Pri-mary Prevention Study in Hypertension [10]; MRC I = Medi-cal Research Council Study I [11]; MARPHY = MetoprololAtherosclerosis Prevention in Hypertension [12]; ANBPS =Australian National Blood Pressure Study [13]; VA = Veter-ans Administration [14].

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