Author + information
- Received August 5, 1998
- Accepted August 7, 1998
- Published online November 1, 1998.
- 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 Investigators Appendix 11
- ↵*Address for correspondence: Dr. Carl J. Pepine, University of Florida College of Medicine, Division of Cardiovascular Medicine, PO Box 100277, Gainesville, Florida 32610-0277
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.
Hypertension and coronary artery disease (CAD) frequently coexist as an important management problem, and the prevalence of this problem is likely to increase as our population ages (1,2). Among over 5,000 contemporary outpatients with angina pectoris cared for by primary care physicians, we found that 58% also had hypertension and 65% required multiple medicines (2). Diuretics and beta-adrenergic blocking agents have been recommended as standard therapy for hypertension because of reductions in stroke, heart failure, coronary heart disease events and cardiovascular mortality (1,3–8). Yet reductions in coronary events have been consistently less than predicted from epidemiologic studies based on blood pressure reduction, and these reductions have plateaued in recent years (1). So newer antihypertensive agents such as calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors have seen increasing use. While they have potential benefits in patients with concomitant CAD (9–23), concern has arisen over their safety because of lack of outcome data from randomized trials. Some nonrandomized evaluations suggest an increased risk of ischemic events with calcium antagonists (11–15)while others (including several randomized studies) have not (16–20). Study methodology (e.g., case control, retrospective analyses, meta-analyses) and type of calcium antagonist (e.g., rapid release, short-acting dihydropyridines vs. slow release [SR], long-acting or heart rate-controlling agents) likely contribute to some of the risk differences reported (21–29). The consensus is that until large randomized trials demonstrate safety, caution should be used (at least with rapid-release, short-acting, dihydropyridines) for patients with hypertension and CAD (21,23,24,26,30–32).
However, verapamil has been shown effective and safe alone or in combination in patients with hypertension and/or CAD (19,33–43). Indeed, a recent overview of all published randomized verapamil trials by one of us (C.J.P.) concluded that in patients with CAD there was no evidence for harm and considerable evidence to suggest benefit in those with recent acute coronary syndromes (44). Yet it was acknowledged that data were limited in patients with CAD and hypertension (44–47). Randomized studies have also demonstrated that ACE inhibitors reduce mortality in patients with left ventricular dysfunction (48–52), acute myocardial infarction (MI) (53)or heart failure (49), but randomized trial data on outcomes are lacking in hypertension. A pilot study of combined treatment with verapamil and trandolapril in patients with stable angina and left ventricular dysfunction suggested improved ventricular function and exercise capacity with reduction in angina (54). In post-MI patients, rates of reinfarction, unstable angina and readmission for heart failure were lower with the verapamil–trandolapril combination compared with trandolapril alone (54). However, neither of these studies (54,55)was of sufficient size and duration to be definitive.
To address uncertainty regarding clinical outcomes with antihypertensive treatment that includes a calcium antagonist, large-scale randomized trials are necessary. Because data for many of the reports of adverse outcomes with calcium antagonist therapy were based on outpatients treated by primary care physicians, these trials should focus on a similar patient population. As the diagnosis of CAD is often difficult to exclude with certainty in hypertensive outpatients and the adverse outcomes of interest are related to CAD, it would seem reasonable to focus on the hypertension population with evidence for coronary disease. Finally, because there is evidence for safety with verapamil in patients with CAD, this agent seems to be a rational choice.
The purpose of this article is to provide the design and baseline characteristics of the patients being recruited for the International Verapamil SR/Trandolapril Study (INVEST).
The primary objective of INVEST is to examine the hypothesis that risk for adverse outcomes in hypertensive CAD patients is at least equivalent during treatment of hypertension initiated with a calcium antagonist-based strategy compared with a beta-blocker/diuretic-based strategy. Adverse outcomes are defined as all cause mortality, nonfatal MI or nonfatal stroke. The calcium antagonist-based strategy initiates treatment with either verapamil SR or the combination of verapamil SR and trandolapril for special populations according to JNC VI (1). The noncalcium antagonist strategy initiates treatment with either atenolol or hydrochlorothiazide or the combination of one of these with trandolapril for special populations. Special populations for INVEST are those with poor renal functioning, diabetics and those with heart failure due to systolic left ventricular dysfunction defined by an ejection fraction <40%. These strategies are representative of two widely used strategies to treat patients with hypertension and CAD in the primary care setting and are based on current guidelines (1). Secondary objectives are to determine that these strategies are at least equivalent in the control of blood pressure, symptoms of myocardial ischemia and important adverse experiences. Other objectives include assessing trends for cancer, Parkinson’s disease, Alzheimer’s disease, autoimmune disease and gastrointestinal bleeding, as well as determining cost of cardiac care, quality of life and compliance.
Study design and patient selection
An international, multicenter, randomized clinical trial, INVEST uses a parallel prospective design with two treatment arms. Patient eligibility criteria include age 50 years or older, essential hypertension as defined by the JNC VI (1)requiring drug therapy and documented CAD. Documented CAD is defined as any one of the following: remote confirmed MI, abnormal coronary angiogram (>50% narrowing of at least one major coronary artery), abnormalities on two different types of stress tests or diagnosis of classical angina pectoris. All patients must be willing and able to grant informed consent and the study must be approved by appropriate review committees for the protection of human subjects.
Exclusion criteria include unstable angina, angioplasty, coronary bypass or stroke within the previous month; beta-blocker use within the previous 2 weeks or previous year for post-MI patients; sinus bradycardia, sick sinus syndrome or atrioventricular block of more than first degree in the absence of an implanted pacemaker; severe (New York Heart Association class IV) heart failure; severe renal (creatine ≥4.0) or hepatic failure; or contraindication to verapamil.
Ambulatory hypertensive patients with CAD, who qualify, are randomized to receive therapy with either the calcium antagonist-based or a noncalcium antagonist-based treatment strategy (Fig. 1). Those randomized to the calcium antagonist strategy begin with verapamil SR (Isoptin SR; Knoll AG, Germany) 240 mg/daily, and those randomized to the noncalcium antagonist strategy begin with atenolol 50 mg/daily. These doses can be adjusted downward by the physician if needed. Additional drugs (trandolapril [Mavik, Knoll AG, Ludwigshafen, Germany] and hydrochlorothiazide) are added in either strategy when needed either for special populations or to reach the target blood pressure. When trandolapril is needed in the calcium antagonist strategy, it is supplied as the verapamil SR/trandolapril combination (Tarka, Knoll AG, Ludwigshafen, Germany). The target blood pressure is defined as a mean of two sitting cuff blood pressure measurements <140/<90 mm Hg or <135/85 mm Hg for special populations. Nonprotocol antihypertensive drugs may be added if needed to reach target pressures provided that the calcium antagonist is retained in the calcium antagonist strategy and a calcium antagonist is not added in the noncalcium antagonist strategy.
In addition, the general care in both treatment strategies will be in accordance with the nonpharmaceutical guidelines provided in JNC VI (1). These are available to the patient as printed instructions from the INVEST on-line system and include nurse counseling in tobacco, caffeinated beverages and alcohol. Instructions for secondary prevention of atherosclerosis complications are also standardized according to the National Cholesterol Education Program (NCEP-2).
Patients are to return for follow-up visits 6, 12, 18, 24, 52, 78 and 104 weeks after their randomization visit and at the close of the study. At each visit, response to treatment, occurrence of symptoms (e.g., angina frequency or those related to a potential adverse outcome), a brief physical exam including blood pressure and heart rate, and compliance are assessed. Changes in medication or dosage as per the protocol (Fig. 2)are made as necessary during follow-up to reach target blood pressure or minimize unacceptable adverse experiences should they occur. Serious outcomes such as death, nonfatal MI and nonfatal stroke are to be reported within 24 h to the INVEST Administrative Coordinating Center. These events and pertinent patient documents are reviewed by an Event Committee masked to treatment assignment (Appendix 1). Treatment and follow-up are expected to last 2 to 3 years, with final visits for the last enrolled patients occurring at the end of the year 2000.
Prior to enrollment of any patients, a prepilot stage was conducted using mock patients to test the study electronic system and recruit pilot sites. The active treatment stage then consisted of a pilot phase and a full-scale phase. The purpose of the pilot phase was to observe the electronic system under actual study conditions, which included ordering and dispensing study medications to enrolled patients. This plan provided time to interrupt enrollment to make any system changes that might be deemed necessary before the full complement of study sites were on line. During the pilot phase, 160 patients from 30 sites in various geographic regions throughout the United States were randomized.
Novel organization features
This study has many novel organizational features. For example, in contrast to the usual organization of a clinical trial in which a limited number of investigators enroll many patients, the 27,000 patients in INVEST will be drawn from approximately 1,500 primary care site physicians with each physician enrolling about 15 to 20 patients. These physicians (site investigators) report to 156 local specialists who serve as specialist investigators for their geographic area. Worldwide, these local specialist investigators in turn report to opinion leaders in various geographic regions who serve as regional directors and members of the International Steering Committee for INVEST. Overseeing the study is the Principal Investigator and Executive Committee. An independent Data and Safety Monitoring Committee (Appendix 1)serves in an advisory capacity to the Steering Committee.
Also, INVEST is the first international randomized trial completely designed for and conducted via the Internet. The operational structure for data collection and handling allows rapid enrollment of the numerous investigators and patients necessary to complete the study. In particular, INVEST utilizes the Internet for patient enrollment, randomization, drug prescription and tracking of patient data (Fig. 3). All sites are supplied with a personal computer configured with local Internet access. Use of computer technology allows site physicians to not only enroll patients very quickly, but also receive immediate notification electronically of the assigned randomized treatment strategy for the patient during the initial visit. The system allows the site physician to customize the patient prescription, in terms of dosing and additional drugs, with a special section for computerized prescribing (Fig. 2). When the completed prescription is verified by the physician, an electronic signal is sent to the pharmacy coordinating center and study medications are dispensed from a central mail order pharmacy that receives the prescription and patient information electronically at the time of the visit. Patients receive their medication within 7 days and return a bar-coded postcard or call a toll-free phone number to confirm receipt of the medication. On follow-up visits, patient information is entered into the computer at the time of the visit and transmitted electronically to the data coordinating center as well as the pharmacy center for medications.
All facets of study operation, including study management, randomization, titration and dispensing of study medications, patient data access, and study monitoring are, therefore, part of the INVEST Internet-based electronic system. Among the advantages of this system are rapid data collection and management procedures, simplified data handling, reduction in data errors, immediate responses to requests and more timely generation of data summaries and study results. Advantages of computerized prescribing and dispensing of study medications for research purposes include the fact that prescription information is legible and does not have to be transcribed by the pharmacy, prescriptions are actually filled and prescriptions are processed, filled immediately and shipped directly to the patient. All of these actions are secured by unique password protection for the physicians and high-level encryption. The INVEST System Description is summarized in Appendix 2.
Sample size considerations
The hypothesis to be tested is that the two initial antihypertensive treatment strategies are equivalent. With 13,500 patients in each treatment strategy arm, the confidence interval for risk is ±15%. The sample size of 27,000 patients is adequate to detect a 20% difference in event rates, if one exists, with power ranges and alpha outlined below. From the literature only sparse data are available on the event rates to be expected in the patient population targeted by INVEST. In the APSIS trial, hypertensive patients with stable angina had a combined rate for death and nonfatal MI of 3.4% per year (46). In the Quinapril Ischemic Event Trial (QUIET), the yearly rate for nonfatal MI in patients with CAD and hypertension was 1.8% to 2.1% depending on the treatment group, whereas the yearly death rate in both groups was only 0.7% (C. Pepine, personal communication, 1997). In patients with hypertension and CAD, the Framingham study revealed age- and gender-dependent 2-year mortality rates ranging from 0% (<50 years old) to 26% (C. Pepine, personal communication, 1997).
As the inclusion criteria of INVEST exclude very high-risk patients, a yearly event rate for death, MI or stroke of 1.7% to 2.0% is expected. This is believed to be a conservative estimate. Assuming a total of 27,000 patients (13,500/treatment strategy), 10-month accrual period, a fraction of 10% of patients to be censored and a (two-tailed) significance level of 5%, the power will range from 91.2% (yearly event rate = 2.0%) to 86.4% (yearly event rate = 1.7%).
Full-scale site recruitment and patient enrollment began in January 1998. A total of 701 sites are under contract as of August 1998. In addition to the United States, sites are on line in Australia, New Zealand and Germany, with Canada, Mexico, Italy, France, Spain, Israel and South Africa scheduled shortly. Baseline data on patient characteristics of age, gender, race, concomitant disease and self-report quality of life are summarized for the first 1,500 patients enrolled (Table 1).
The patients being enrolled are predominantly elderly (72% aged 60 years or older) males (54%), with either an abnormal coronary angiogram or prior MI (71%). The majority had a history of smoking (54%). In addition to hypertension, CAD and elderly age, most patients (89%) had one or more associated conditions (diabetes, dyslipidemia, smoking, cerebral or peripheral vascular disease, etc.) that contribute to increased risk for adverse outcome. A total of 27% have diabetes and most of these are noninsulin dependent. Interestingly, 26% reported their health quality at entry as only fair or poor.
Target blood pressures within guidelines using study drug therapy have been achieved by 58% of those reaching their fourth visit. As expected, most (89%) are requiring multiple antihypertensive drugs.
The treatment of patients who have both hypertension and CAD is a major concern for physicians worldwide, particularly because safety data for calcium antagonists from randomized controlled trials are lacking. Clearly more data are needed on the effects on these agents on adverse outcomes. This study will make a major contribution toward resolving the issue. In its stepped-care strategy approach to the management of hypertension, INVEST will compare the adverse outcomes observed with treatment initiated using the calcium antagonist, verapamil, with that observed using treatment initiated with the beta-blocker, atenolol in patients with CAD. To date, INVEST, with 13,500 patients in the calcium antagonist strategy, will represent the largest calcium antagonist exposure yet undertaken to determine the safety and efficacy of this form of treatment. (Table 2).
The organizational structure and conduct of INVEST is unique. The study is a “paper-less” international multicenter study using a novel electronic system for direct on-screen data entry, randomization and drug distribution from a central mail order pharmacy, all linked via the Internet. The on-line electronic data system simplifies patient entry and data handling and should reduce errors and increase the speed with which data can be produced. The integrated central drug distribution system controls drug dispensing. The integration of central drug assignment and distribution should prevent unauthorized access to drugs, eliminate assignment errors and generally simplify the process of titration dispensing, and monitoring of patient compliance. Thus, in addition to its sites and international scope, the INVEST design mimics standard clinical practice and is believed to be a forerunner of clinical trial research for the future.
Data on adverse outcomes during calcium antagonist treatment of hypertension are lacking. Studies with verapamil have shown beneficial effects on ischemic events and mortality in patients with CAD. To resolve uncertainty related to the effects of calcium antagonists on adverse outcomes in patients with hypertension and associated conditions, large-scale trials are necessary. The International Verapamil SR/Trandolapril Study is an ongoing randomized controlled trial of 27,000 CAD patients with hypertension designed to provide data to help address this uncertainty.
Administrative Center: C. Pepine (Project Director and Principal Investigator), E. Handberg-Thurmond (Project Coordinator), R. Cooper-DeHoff (Pharmacy Coordination), R. Kolb, J. Mitchell (Administration and Technical Support), P. Zilles (Consultant); Data Coordinating Center: R. Marks (Project Biostatistician), M. Conlon (Biostatistician and System Coordination), P. Volkers (Consultant Biostatistician); Steering Committee: G. Bakris, A. Benetos, A. Chobanian, A. Coca, J. Cohen, R. Davies, V. DeQuattro, E. Frohlich, W. Klinke, R. Kolloch, P. Kowey, G. Mancia, F. Messerli, W. Parmley, C. Pepine (Chair) P. Sareli, J. Viskoper; Event Committee: E. Handberg-Thurmond, K. Jayaram, P. Kowey (Chair); Data and Safety Monitoring Committee: C. Conti (Chair), E. Davis, N. Kaplan, T. Ryan, P. Sleight, L. Hansson.
Site Investigators: M. Abel, K. Adams, S. Adkins, M. Ahmed, O. Ahmed, S. Akgun, A. Alaziz, J. Alexander, A. Ali, Y. Ali, A. Alperovich, L. Alton, V. Alugubelli, E. Alvarez, K. Amin, M. Amin, D. Anders, E. Anderson, J. Anderson, F. Angella, M. Ansari, M. Anwar, J. Aranda, A. Arevalos, G. Aristimuno, S. Arora, S. Array, M. Ascano, R. Ashley, S. Ashley, D. Austin, J. Austin, B. Aycock, B. Babcock, V. Babu, M. Bach, J. Backman, D. Bailey, S. Bakali, L. Barai, S. Barclay, M. Barney, C. Bashir, L. Basset-Sheltoe, J. Beall, R. Beasely, L. Beauregard, G. Becker, R. Bedinger, R. Bellam, C. Bengs, M. Bergal, P. Berman, R. Bernauer, B. Bernstein, B. Bertolet, B. Bethancourt, D. Bhamber, B. Bhambi, G. Bhaskar, G. Bhatt, L. Bickford, J. Birge, J. Bishop, N. Bittar, L. Blacher, A. Blanchard, J. Boak, J. Boerner, M. Boland, L. Bonavita, R. Bond, J. Bonnano, J. Borkovec, K. Boyer, P. Bradley, A. Brandau, T. Brill, H. Brodsky, D. Browder, N. Brown, S. Brown, R. Browning, E. Bryce, M. Buchbinde, A. Buhr, W. Bullock, J. Butler, D. Byler, C. Bynum, JF. Cadet, G. Caine, W. Calhoun, A. Campoy-D, J. Capo, D. Capper, U. Caraballo, E. Cardona, J. Carter, R. Carter, S. Carter III, S. Cassidy, R. Cater, M. Caveness, B. Chacko, M. Chamberl, M. Chance, M. Charlat, F. Charles, A. Charmatz, J. Chavez, J. Checton, T. Cheng, A. Cherkasky, S. Choi, J. Ciocon, M. Clarke, R. Co, A. Cohen, B. Cohen, J. Cohen, D. Colan, K. Colleran, P. Colon, W. Conrad, M. Cook, S. Corse, M. Cotto, S. Courtnage, J. Cox, D. Crocker, R. Curry, A. Cykiert, J. Daniel, J. Daniels, S. Daniels, M. Danoff, R. Davis, G. De La Pen, T. Deering, J. DeLuca, A. Delwadia, C. Demas, G. Dennish, V. DeQuattro, K. Desai, M. Deterding, C. Diaz De L B. Dickerson, J. Dimen, D. Ding, D. Dizmang, V. Doan, A. Domeier, T. Don Micha, A. Droba, J. Drury, H. Dulamal, M. Duren, A. Durfey, G. Dy, L. Egbujiobi, M. El Shahaw, H. Ellison, L. Eng, B. Erb, J. Esparrago, A. Estrada, P. Eupierre, H. Evans, R. Evans, S. Evans, J. Farjat, J. Farrell, J. Faulkner, J. Feeman, D. Felker, D. Feller, T. Ferguson, J. Fidelholtz, L. Fischer, P. Flamion, M. Flores, L. Florescu, C. Flowers, F. Forquigno, J. Foster, D. Fouchi, G. Fox, E. Frutos, J. Galeski, M. Galler, S. Ganti, R. Garrett, D. Gaskin, S. Gavin, E. Gaxiola, T. Geffen, M. Gheorghia, K. Gilbert, I. Glass, S. Glasser, F. Gloth, G. Goforth, J. Gonce, D. Gonzalez, D. Goodman, D. Goodman, J. Gordon, R. Gordon, A. Gorovets, K. Gosai, M. Gozun, D. Grant, J. Greene, J. Greiff, J. Griffin, R. Grogan, G. Groth, R. Guest, A. Gupta, A. Gupta, J. Gupta, D. Habell, E. Habig, R. Habig, L. Haglund, A. Halkos, J. Hall, J. Hall, K. Hall, V. Hall, S. Halpern, C. Hamburg, R. Hanlon, S. Hanna, G. Harman, A. Harrow, G. Hayes, M. Headley, R. Heckey, C. Heinsen, G. Held, T. Hemmapl, J. Heneisen, M. Henriquez, E. Heurich, D. Heyerdahl, C. Hill, D. Hill, J. Hill, R. Hill, D. Hilliard, M. Hogenson, M. Holland, I. Holman, L. Hong, J. Hood, S. Horowitz, M. Horseman, R. Hughston, Y. Imamura, D. Irwin, P. Isbell, T. Ishimori, P. Jacobson, G. Jagan, K. Jahn, J. Jaikishen, G. Jarrard, M. Jenkins, M. Jones, M. Jones, W. Jones, J. Joshi, J. Kagan, B. Kaminski, S. Kanner, M. Kantzler, J. Karas, P. Karim, R. Karl, A. Karns, R. Karns, R. Karody, J. Karrasch, R. Kasmikha, D. Katz, S. Katzman, S. Kaveh, A. Kejriwal, R. Keller, H. Kempe, R. Kerensky, N. Kerin, W. Kerr, S. Kestin, A. Khan, M. Khan, R. Khan, R. Khant, K. Khooblall, I. Khurana, J. Kinahan, L. King, G. Kini, R. Kirstein, C. Koeppl, R. Kohn, D. Kondos, L. Korman, G. Koshkaria, G. Kotlewski, M. Kozinn, W. Kracht, A. Krepostm, D. Kresnicka, M. Kumar, K. Kundlas, M. Kuttappan, E. La Kier, A. Lachman, N. Lamarche, R. Landefeld, E. Lanear, J. Lang, L. Larson, N. Laufer, R. Lee, R. Lee-Pack, B. Lemke, R. Lepiane, G. Lessmann, D. Leszkowit, R. Leverence, J. Levine, R. Levine, C. Li, G. Limandri, B. Lipschutz, A. Liu, Jr., D. Loew, J. Lousteau, R. Lucke, B. Lumicao, J. Lynch, J. Maddi, M. Mahjoub, P. Malen, R. Malhotra, J. Mallett, D. Mangum, R. Mann, S. Mareburg, S. Margolis, V. Marino, T. Marshall, W. Martin, F. Martinez, M. Martinez, W. Mashman, A. Masood, M. Masroor, S. Mathan, M. Mathur, C. Mattina, A. Mauskar, T. May III, T. Mayer, B. McCarroll, L. McCauley, J. McCoy, P. McCulloug, T. McKnight, A. McLaren, B. McLean, J. Medina, R. Mehra, J. Mehta, J. Mehta, A. Meier, R. Mella, M. Mendizabal, R. Merrill, F. Messerli, B. Messinger, D. Meyer, R. Michal, R. Michels, S. Mihyu, R. Miles, J. Millan, J. Miller, P. Miller, T. Mills, J. Minnich, J. Mitchell, R. Mitchell, C. Mock, K. Modi, R. Mohr, T. Monitz, S. Monroe, M. Montrichar, A. Moosvi, R. Moran, M. Moreno, R. Morgan, L. Morris, M. Moses, G. Mosquera, J. Mourad, M. Mrzyglocki, A. Munis, J. Myers, R. Myers, S. Myers, J. Nadeau, M. Nadeemul, L. Nadgir, R. Nair, S. Najar, D. Najman, P. Nalos, V. Namiredd, R. Nasr, A. Naumovic, A. Nautiyal, D. Nemetz, S. Newaz, N. Nguyen, T. Nguyen, R. Noel, B. Norton, G. Novak, J. Nunnelee, O. Nwabara, W. Nyitray, J. Nystrom, M. Oefelein, R. Oglesby, G. Okonski, S. Ong, V. Orendain, T. Ostrowski, R. Palmer, P. Parikh, S. Park, B. Patel, H. Patel, P. Patel, S. Patel, S. Patel, T. Patel, R. Pathapati, H. Patton, K. Paulus, H. Payne, W. Pearce, M. Pearson, S. Pennal, N. Perlman, D. Perry, J. Perry, F. Petersen, T. Petry, C. Pettus, S. Philip, A. Phillips, O. Pickus, N. Pierson, G. Pimentel, P. Pitroda, P. Platzer, L. Pluta, D. Pocock, S. Podnos, T. Poe, M. Pond, P. Popper, M. Poss, P. Potu, J. Prasad, S. Prasada, N. Premsingh, D. Pritchard, H. Punzi, W. Qazi, V. Rajput, JC. Ramirez, A. Rao, T. Rashid, M. Rattinger, S. Raubort, W. Rawlings, M. Ray, T. Raymond, A. Rayner, T. Razdan, M. Reddy, M. Reddy, V. Reddy, E. Reh, R. Remler, T. Retta, L. Reyes, L. Reznick, W. Rhodes, L. Rink, F. Rivers, M. Rivera, T. Rizzo, A. Robb, J. Roberts, R. Rodriguez, M. Romeo, H. Rose, M. Rosenbloo, L. Rosenfield, P. Rosman, D. Ross, E. Ross, D. Rothman, J. Routh, JA. Roye, M. Rubin, P. Rubin, L. Rupp, H. Sabbota, H. Sacks, M. Saklayen, J. Salberg, A. Samadani, M. Samalik, W. Sampson, S. Samy, S. Sanchez, S. Sanchez, B. Sandoval, B. Sangani, J. Saponaro, C. Saraiya, R. Sarma, D. Sauers, S. Savran, P. Sawrey, S. Schabelm, A. Schachter, N. Scharff, C. Schearer, D. Scheer, R. Schellenb, A. Schimmel, S. Schmidt, J. Schmitz, R. Schofield, A. Schonber, M. Schor, B. Schrager, M. Schwarta, F. Schwartz, L. Schwartzb, M. Schwarze, J. Schyberg, C. Scott, M. Scott, E. Searcy, RM. Sears, G. Sehapaya, P. Seigel, H. Semler, F. Sessoms, S. Sexter, A. Shah, A. Shah, D. Shah, G. Shah, H. Shah, S. Shah, S. Shahab, M. Shaker, O. Sharma, K. Sheikh, M. Sherman, M. Shoop, A. Simpson, L. Sinatra, W. Sine, G. Singh, J. Singh, S. Singh, S. Singh, V. Singh, G. Sinha, M. Sinha, D. Slater, R. Smith, T. Smith, G. Snyder, A. Somers, C. Sparks-Ar, R. Sparling, D. Spigner, S. Spivey-Mil, J. Spruill, J. Sraow, R. Starritt, R. Steinberg, J. Stern, M. Stiles, J. Stokes, R. Stoltz, J. Stone, D. Stout, E. Struik, B. Stryjewsk, D. Subich, L. Sukienik, W. Sullivan, R. Sweeney, M. Tachman, J. Tanner, R. Tate, M. Taylor, A. Teklinski, H. Tettamanti, H. Tjoa, R. Toban, S. Toloyan, B. Tome, B. Tran, T. Tran, N. Trehan, P. Trentham, H. Trivedi, N. Tucker, S. Turner, M. Tyler, C. Ulrich, J. Valdez-Gu, S. Varela, S. Varma, G. Vasquez, G. Vellanikar, A. Villacastin, J. Voelz, W. von Ohlen, C. Voss, D. Vyas, A. Wagner, E. Wahley, D. Walker, L. Walker, T. Wallace, W. Wallizada, L. Walter, S. Wan, D. Watenber, J. Wassenaa, M. Wasserm, L. Weaver, D. Webber, R. Weiderhol, R. Weiss, R. Weiss, S. Wesonga, F. Westmeye, D. White, R. Whitman, B. Williams, D. Williams, J. Williams, M. Williams, J. Wilson, J. Wilson, Jr., J. Winegar, E. Witt-Bockl, L. Wojonowi, W. Woody, J. Wortman, E. Wozniak, J. Wright, R. Wyndham, S. Yaddanap, G. Yearwood, P. Yee, K. Yehyawi, T. Yetil, D. Yorro, S. Young, K. Zaveri, S. Zellner, J. Zizzi, B. Zuberi, F. Zugibe, L. Zukerman, N. Zukkoor, J. Zuniga-Se, D. Zwicke.
↵1 A complete list of the investigators and centers participating in the INVEST study appears in .
☆ This study is supported by a grant from Knoll AG BASF Pharma, Germany.
- angiotensin-converting enzyme
- coronary artery disease
- International Verapamil SR/Trandolapril Study
- The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure
- myocardial infarction
- slow release
- Received August 5, 1998.
- Accepted August 7, 1998.
- American College of Cardiology
- Pepine CJ, Abrams J, Marks RG, Morris JJ, ScheidtSS, Handberg E, for the TIDES Investigators
- MRC Working Party
- Hansson L.
- Hansson L.
- Furberg C.D.,
- Psaty B.M.,
- Meyer J.V.
- Fox K.M.,
- Mulcahy D.,
- Findlay I.,
- et al.
- Dargie HJ, Ford I, Fox KM, for the TIBET Study Group
- Rehnqvist N.,
- Hjemdahl P.,
- Billing E.,
- et al.
- Leitch J.W.,
- McElduff P.,
- Dobson A.,
- Heller R.
- Messerli F.H.
- Pepine C.J.
- Pepine C.J.
- Ryden L.,
- Malmberg K.
- Kloner R.A.
- Opie L.H.,
- Messerli F.H.
- Parmley W.W.
- Holzgreve H, Distler A, Michaelis J, Phiipp T, Wellek S, for the Verapamil versus Diuretic (VERDI) Trial Research Group
- Holzgreve H.
- The Danish Study Group on Verapamil in Myocardial Infarction
- ACE Inhibitor Myocardial Infarction Collaborative Group