CLINICAL STUDIES
Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension
Carl J. Pepine, MD, FACC*,
Eileen Handberg-Thurmond, PhD*,
Ronald G. Marks, PhD ,
Michael Conlon, PhD,
Rhonda Cooper-Dehoff, PharmD ,
Peter Volkers, PhD,
Peter Zellig, MD** for The INVEST Investigators1
* Division of Cardiovascular Medicine, University of Florida, College of Medicine, Gainesville, Florida, USA
Department of Biostatistics, University of Florida, College of Medicine, Gainesville, Florida, USA
Research Pharmacy Division of Shands Hospital, University of Florida, College of Medicine, Gainesville, Florida, USA
** Knoll AG BASF Pharma, Ludwigshafen, Germany
Manuscript received August 5, 1998;
accepted August 7, 1998.
Address for correspondence: Dr. Carl J. Pepine, University of Florida College of Medicine, Division of Cardiovascular Medicine, PO Box 100277, Gainesville, Florida 32610-0277
pepincj{at}medicine.ufl.edu
Objectives. The primary objective of the International Verapamil SR/Trandolapril Study (INVEST) is to compare the risk for adverse outcomes (all-cause mortality, nonfatal myocardial infarction [MI] or nonfatal stroke) in hypertensive patients with coronary artery disease (CAD) treated with either a calcium antagonist-based or a noncalcium antagonist-based strategy.
Background. Treatment recommendations for hypertension include initial therapy with a diuretic or beta-adrenergic blocking agent, for which reductions in morbidity and mortality are documented from randomized trials but are less than expected from epidemiologic data. For this reason, recent attention has focused on calcium antagonists or angiotensin-converting enzyme inhibitors. While these agents reduce blood pressure, outcome data from large randomized trials are lacking, but some case-control data, dominated by short-acting dihydropyridines, suggest an increased risk of cardiovascular events. These studies had methodologic limitations and did not differentiate among calcium antagonist types and formulations. Several studies differentiating among calcium antagonist types and an overview of published randomized trials show no increased risk with verapamil and suggestion for benefit in CAD patients.
Methods. A total of 27,000 CAD patients with hypertension will be randomized at 1,500 primary care sites to receive either a calcium antagonist-based (verapamil) or beta-blocker/diuretic-based (atenolol/hydrochlorothiazide) antihypertensive care strategy. The study uses a novel, electronic "paper-less" system for direct on-screen data entry, randomization and drug distribution from a mail pharmacy linked to the coordination center via the Internet.
Results. Contract negotiations with the United States and international sites are ongoing. Patients being enrolled are predominantly elderly (72% aged 60 years or older) men (54%), with either an abnormal coronary angiogram or prior MI (71%). In addition to hypertension, CAD and elderly age, most patients (89%) have one or more associated conditions (diabetes, dyslipidemia, smoking, cerebral or peripheral vascular disease, etc.) contributing to increased risk for adverse outcome. While 26% have diabetes, most of these are noninsulin dependent. Using the protocol strategies, target blood pressures (according to JNC VI) have been reached in 58% at the fourth visit, and as expected most (89%) are requiring multiple antihypertensive drugs.
Conclusion. The design and baseline characteristics of the initial patients recruited for a prospective, randomized, international, multicenter study comparing two therapeutic strategies to control hypertension in CAD patients are described.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | CAD | = coronary artery disease | | INVEST | = International Verapamil SR/Trandolapril Study | | JNCVI | = The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure | | MI | = myocardial infarction | | SR | = slow release |
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