The Evaluation of Antihypertensive Therapy Cooperative Clinical Trial Method

doi:10.1059/0003-4819-61-5-829

The Evaluation of Antihypertensive Therapy Cooperative Clinical Trial Method

I. Double-blind Control Comparison of Chlorothiazide, Rauwolfia Serpentina, and Hydralazine

WILLIAM M. SMITH, M.D. (ASSOCIATE);
ANTHONY N. DAMATO, M.D.;
NICHOLAS J. GALLUZZI, M.D., (ASSOCIATE);
CLAUDE F. GARFIELD, M.D.;
ERNEST G. HANOWELL, M.D., F.A.C.P.;
WILLIAM H. STIMSON, M.D., F.A.C.P.;
RICHARD H. THURM, M.D., F.A.C.P.;
JOHN J. WALSH, M.D., F.A.C.P.; and
LOUIS BROMER, B.A.

Requests for reprints should be addressed to William M. Smith, M.D., U. S. Public Health Service Hospital,
15th Ave. and Lake St., San Francisco, Calif. 94118
.

Excerpt

The need for adequate clinical trial of therapeutic agents is particularly evident in the field of antihypertensive drugs. It is not possible for individual physicians to evaluate properly the plethora of agents available and recommended for use. The mounting evidence that early and effective therapy is beneficial lends urgency to the need to know which of, or in what combination, these agents are most efficacious and least toxic. Guidelines based on valid clinical trial must be established.

Many efforts have lacked validity due to insufficient numbers of cases, lack of appropriate controls, and failure to eliminate bias. The cooperative study

Acknowledgments

The contribution of Frank S. French, M.D., Chief, Office of Research and Training, Division of Hospitals, United States Public Health Service, Washington, D. C., in assisting with the administrative coordination of the program is gratefully acknowledged.

We are also grateful to E. L. Foltz, M.D., Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania, for furnishing the chlorothiazide, and for the formulation, packaging, and labeling of the identical tablets of chlorithiazide, chlorothiazide and rauwolfia, and placebos. We are likewise indebted to Harold J. Bornhold, M.D., Ciba Pharmaceutical Company, Summit, New Jersey, for providing the hydralazine and its placebo, and to The Squibb Institute for Medical Research, New Brunswick, New Jersey, for supplying and standardizing the rauwolfia serpentina (crude root).

Also acknowledged is the early encouragement and advice of Dr. Edward D. Freis and Dr. Edward Dunner of the Veterans Administration and also the continued interest and advice of Dr. Albert Sjoerdsma, Chief, Experimental Therapeutics Branch of the National Heart Institute.

Summario in Interlingua

Un evalutation a duple anonymato de plure programmas de therapia antihypertensive con le uso de chlorothiazida esseva conducite in 381 subjectos con leve o moderate hypertension. Le distribution aleatori resultava in gruppos therapeutic de composition uniforme e de potentialmente equal responsivitate al therapia. Tres centos e cinque del subjectos in le hicreportate phase del studio completava inter 3 e 18 menses de continue tractamento.

Le effecto depressive in le tension de sanguine esseva mesurate per comparar le valor medie del registrationes in domicilio del tension de sanguine durante le ultime mense del therapia con le valor medie del registrationes in domicilio del tension de sanguine durante un periodo de controlo de un mense anterior al comenciamento del therapia.

Le uso de valores domiciliari como valores de controlo esseva reguardate como preferibile in le evalutation de un therapia administrate a patientes visitante. Le effecto depressive in le tension de sanguine que es exercite per le hospitalisation mesme es tal que quando valores hospitalari es usate como valores de controlo, le effecto de un therapia applicate al patiente visitante appare minus marcate o es mesmo obscurate.

Omne le programmas therapeutic esseva plus efficace que le uso de placebos. Le combination de chlorothiazida—500 mg duo vices per die—con rauwolfia serpentina (radice crude)—100 mg duo vices per die—esseva le plus efficace del programmas studiate. Illo resultava in un reduction del tension medie per 20 mm de Hg, i.e. a un nivello de infra 140/90 mm de Hg in 68 pro cento del casos. Iste programma esseva plus efficace, per un grado statisticamente significative, que le mesme quantitate del thiazida sol o in combination con hydralazina—200 mg per die.

Le adverse effectos secundari non esseva serie e resultava in un discontinuation del tractamento in solo sex del 305 subjectos.

Esseva trovate nulle significative progresso o regresso del processo morbide in ulle del gruppos durante le periodo de observation, ben que un basse numero de casos specific de progresse esseva notate. Duo subite mortes occurreva, un in domicilio e presumitemente in consequentia de un infarcimento myocardial e le altere post un accidente cerebrovascular. Solmente cinque subjectos esseva eliminate ab le studio e tractate con cognoscite agentes a causa de deterioration cardiovascular occurrente in association con non-successo del effortio de effectuar un satisfacente regulation del tension de sanguine.

Article and Author Information

From the U. S. Public Health Service Hospital, San Francisco, Calif.
This investigation was supported in part by research grant HE-05311 from the National Institutes of Health, U. S. Public Health Service, Bethesda, Md.
- Received March 5, 1964.
- Accepted July 3, 1964.