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Clin. Cardiol. Vol. 24 (Suppl. V), (2001)

The INternational VErapamil SR/trandolapril STudy (INVEST) - The First Randomized Clinical Trial Evaluating Aggressive Blood Pressure Management (JNC VI) in Patients with CAD

Carl J. Pepine, M.D., MACC, FESC
Guest Editor

Proceedings from an international symposium held in Istanbul, Turkey on May 12, 2001 among investigators of the INternational VErapamil SR/trandolapril STudy (INVEST). This publication is supported by an unrestricted educational grant from Abbott Laboratories, on behalf of the study sponsors Knoll AG, and the University of Florida.


Introduction: The European INVESTigators Meeting

Original Contributions

V-1 The Vascular Biology of Hypertension and Atherosclerosis and Intervention with Calcium Antagonists and Angiotensin-Converting Enzyme Inhibitors

C. Pepine, M.D., MACC, FESC, and E. M. Handberg, Ph.D.

Recent advances in the understanding of vascular disease genesis suggest that atherosclerosis and hypertension, primary targets of therapy in the INternational VErapamil SR/trandolapril STudy (INVEST), are closely related. A unified model for the development of cardiovascular disease (CVD) is emerging from recent advances related to atherosclerosis and hypertension. The process of vascular disease appears to begin early in life, when signs of endothelial dysfunction first appear. Information derived from INVEST will help to identify treatment strategies, such as those containing a calcium antagonist and an ACE inhibitor, that are targeted directly at the vascular disorder responsible for hypertension and atherosclerosis.

V-6 Characteristics of Patients with Coronary Artery Disease and Hypertension: A Report From INVEST

S. Erdine, M.D., E. M. Handberg, Ph.D., B. Kolb, R.N.

In all, 22,599 patients with coexisting hypertension and coronary artery disease (CAD) from around the world are enrolled in the INternational VErapamil SR/trandolapril STudy (INVEST). As a result, much will be learned regarding the use of treatment strategies using verapamil SR and atenolol with and without trandolapril and/or hydrocholorthiazide in patients with hypertension and CAD, all of whom are at high risk for adverse cardiovascular outcomes. This trial will provide meaningful data for each risk group, especially among patients who are elderly, have diabetes, left ventricular hypertrophy, or who are dyslipidemic.

V-9 INVEST Substudies: Design and Patient Characteristics

M. Keltai, M.D., Ph.D., J. A. Johnson, Pharm.D., P. R. Kowey, M.D., L. D. Ried, Ph.D., M. Tueth, M.D.

Proposed substudies for analysis in the INternational VErapamil SR/trandolapril STudy (INVEST) include ambulatory blood pressure monitoring (ABPM), depression, genotyping, atrial fibrillation, electrocardiogram (ECG), echocardiography, renal dysfunction, diabetes, and cardiac care cost. Ambulatory blood pressure monitoring is an especially useful technology because of the role of nocturnal hypertension and circadian blood pressure irregularities in the development of hypertensive disease. The depression substudy, which enrolled 2,393 patients in the United States, will report quality-of-life (QOL) data, including information regarding energy and fatigue. The biomarker genotyping substudy will provide genomic DNA samples from approximately 15,000 patients in the United States, including Puerto Rico.

V-12 INVEST: Results of Combined Strategies to Control Blood Pressure

R. Kolloch, M.D.

The treatment of hypertension continues to be challenging due to the lack of understanding regarding underlying modulators of blood pressure as well as co-existing conditions such as atherosclerosis and diabetes. Based on a review of preliminary data, it appears that the treatment regimen used in the INternational VErapamil SR/trandolapril STudy (INVEST) has been more successful than other studies at controlling systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. These preliminary data from INVEST suggest that a high proportion of CAD patients with hypertension should receive combination therapy to achieve contemporary blood pressure targets.

V-14 Electronic Prescribing via the Internet for a Coronary Artery Disease and Hypertension Megatrial

R. M. Cooper-DeHoff, Pharm.D., E. M. Handberg, Ph.D., C. Heissenberg, R.N., K. Johnson, R.N.

A unique feature of the International Verapamil SR/Trandolapril Study (INVEST) is the Internet-based, electronic data capture system developed at the University of Florida for this trial. This system allows for direct collection of patient enrollment data, randomization, study drug prescribing, and real-time monitoring of patient data online. Electronic prescribing eliminates errors associated with illegible handwriting, inappropriate dosing, and inappropriate medication choice. The INVEST protocol allows flexibility of medication choice and dosage range within randomly assigned treatment strategies based on patient tolerance and blood pressure response, physician investigators may use individual practice patterns and preferences.

V-17 Enhancing Clinical Trials on the Internet: Lessons From INVEST

R. Marks, Ph.D., H. Bristol, M.S., M. Conlon, Ph.D., C. Pepine, M.D., MACC, FESC

The INternational VErapamil SR/trandolapril STudy (INVEST) is the first long-term, large-scale, randomized, multicenter clinical trial to be conducted using primarily Web-based technology. The World Wide Web is a powerful tool for clinical trials management because of its ability to centralize study information and coordinate multiple trial processes in real time, with immediate oversight and improved coordination of all parties involved. In Web-based clinical trials, investigators only need a personal computer with Internet access. Researchers focus primarily on medicine and science, rather than trial administration, and the process is cheaper, quicker, safer, and more efficient than traditional clinical trials.

V-24 How Will INVEST and Other Hypertension Trials Change Clinical Practice?

C. Richard Conti, M.D., MACC, and R. M. Cooper-DeHoff, Pharm.D.

Three large, international clinical trials, which enrolled a combined total of 81,649 patients over a 7-year period, will greatly improve our understanding of hypertension. Of all the patients enrolled in the three trials, 38% were smokers, 25% had a history of myocardial infarction (MI) or stroke, and 52% had a history of dyslipidemia. In the INternational VErapamil SR/trandolapril STudy (INVEST), 100% of enrolled patients had documented CAD and 27% had diabetes. Of patients treated for 12 months in INVEST, an SBP <140 mmHg was achieved by 70% of nondiabetics, and 66% of patients with diabetes achieved that level.

V-30 Questions and Answers Related to the INternational VErapamil SR/trandolapril STudy (INVEST)


The opinions expressed in this presentation are those of the panelists and are not attributable to the sponsor or the publisher, editor, or editorial board of Clinical Cardiology. Clinical judgment must guide each physician in weighing the benefits of treatment against the risk of toxicity. References made in the articles may indicate uses of drugs at dosages, for periods of time, and in combinations not included in the current prescribing information.