Randomized, Double-Blind, Placebo-Controlled, International Trial of the Oral IIb/IIIa Antagonist Lotrafiban in Coronary and Cerebrovascular Disease
Background— This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.
Methods and Results— Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.
Conclusions— Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.
Received May 20, 2003; revision received June 10, 2003; accepted June 10, 2003.
Blockade of platelet glycoprotein IIb/IIIa receptors via intravenous agents has been effective in reducing death or nonfatal myocardial infarction in the settings of percutaneous coronary intervention and in acute coronary syndromes.1 On the other hand, use of oral platelet IIb/IIIa antagonists has been associated with an unexpected 37% increase in mortality in 4 previous large-scale, randomized trials with more than 33 000 patients.2–6 The explanation for the higher rate of fatality is unclear, but the possibilities of improper dosing regimens or suboptimal clinical indications have been raised.
After completing an extensive phase II study of lotrafiban,7 an orally administered IIb/IIIa antagonist, in patients with atherosclerotic coronary or cerebrovascular disease, we undertook a large-scale clinical trial. The results of the previous trials in this class of agents were not available at initiation of the BRAVO (Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion) trial. The trial was unique in targeting a diverse patient population with vascular disease and using a dose titration to take into account age and anticipated creatinine clearance. However, it was stopped prematurely because of an excess in mortality in the lotrafiban group. This report presents the primary findings of the trial, highlighting the timing and cause of death along with the scope and magnitude of bleeding complications encountered with lotrafiban.
The details of the design of the trial have been published previously.8 To summarize, patients aged 18 years or older were eligible if they had (1) prior myocardial infarction or unstable angina within 14 days of baseline evaluation, (2) ischemic stroke no sooner than 5 days and no later than 30 days after the acute event, (3) a transient ischemic attack within 30 days, or (4) “double bed” vascular disease, defined as documented peripheral vascular disease combined with either coronary or cerebrovascular disease. Patients were excluded if they had predisposition to bleeding, suboptimal blood pressure control, intolerance or allergy to aspirin, recent use of an intravenous IIb/IIIa antagonist, or need for therapy with warfarin or a thienopyridine drug. All patients gave informed consent, and the protocol was approved by the institutional review board at each participating center.
Patients were randomly assigned to lotrafiban or matching placebo. The dose of lotrafiban was either 30 mg or 50 mg BID depending on the age and creatinine clearance. For patients aged ≥65 years or with creatinine clearance ≤60 mL/min, the dose was 30 mg. The dose was decreased from 50 to 30 mg if there was a reduction in creatinine clearance or evidence of bleeding and from 30 to 20 mg for the same reasons. Concomitantly, patients received aspirin at 75 to 325 mg/d, the exact dose being at the discretion of the physician-investigator. The study drug was to be administered for a maximum of 2 years after randomization.
The primary end point was the composite of death, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Prespecified subgroups were defined to be gender, age (<65 or ≥65 years), and enrollment criteria (cardiovascular or cerebrovascular). All events were reviewed by an independent clinical events committee blinded to treatment assignment. A sample size of 9200 patients provided 90% power to detect a 20% treatment effect, with a minimum of 1345 clinical events, assuming a 2% loss of follow-up, a 16.7% event rate in the placebo group, and intention-to-treat analysis.
A multivariate mortality model was developed to determine the factors associated with an increased mortality. A total of 19 candidate variables were included in the model: age, gender, body mass index, race, heart rate at baseline, diastolic and systolic blood pressure, diabetes, baseline aspirin dose, lotrafiban treatment assignment, history of hypertension, heart failure, PTCA, angina, myocardial infarction, prior CABG, peripheral vascular disease, stroke, or transient ischemic attack. Linearity of the log hazard ratio for each of the continuous predictors was verified. A stepwise variable selection was performed for proportional hazards regression of the time to death, and proportional hazards assumption was evaluated for all variables.
A Data and Safety Monitoring Board reviewed the data on 5 occasions as follows: (1) October 17, 1999, on 2386 patients followed up an average of 1.7 months; (2) January 15, 2000, on 4665 patients followed up an average of 3.6 months; (3) May 20, 2000, on 8112 patients followed up an average of 5.1 months; (4) August 14, 2000, on 9190 patients followed up an average of 7.0 months; and (5) December 9, 2000, on 9190 patients followed up an average of 11.1 months. At the last review, the Data and Safety Monitoring Board recommended premature termination of the trial because of an excess of mortality in the lotrafiban group, and this was unanimously adopted by the Steering Committee.
The trial enrollment began April 23, 1999, and was completed on June 26, 2000, in 23 countries in 690 hospitals (Appendix). Premature termination of the trial occurred on December 12, 2000, because of an excess of mortality that was statistically significant.
The baseline characteristics of the patients are summarized in Table 1. Their ages ranged from 20 to 96 years, and the 2 treatment groups were balanced with respect to all demographic features. The primary enrollment criteria are provided in Table 2. Approximately 40% of the patients enrolled had cerebrovascular disease.
The dose at the time of randomization was 30 mg BID in 46.5% of patients and 50 mg BID in 53.5%. A dose reduction was required in 4.6% of the placebo group and 8.1% of the lotrafiban group (P<0.0001). Study drug was discontinued prematurely in 22.9% of placebo-assigned patients and 29.3% of the lotrafiban patients (P<0.0001). The reasons for premature discontinuation of study drug were major bleeding (1.6% with placebo compared with 9.9% with lotrafiban; P<0.0001) or important minor bleeding (2.6% versus 8.1%, respectively; P<0.0001). The length of follow-up was a median of 366 days in both groups (25th and 75th percentiles, respectively, were 279 and 463 days for the placebo group and 278 and 460 days for the lotrafiban group).
The primary end point and individual components of the composite are presented in Table 3. There were 139 deaths in the lotrafiban group compared with 104 in the placebo group. This excess of 35 deaths was primarily accounted for by more vascular deaths (107 in the lotrafiban group versus 78 in the placebo group). There was a numerical excess of sudden deaths (29 versus 17) and unwitnessed deaths (16 versus 5, respectively) in the lotrafiban group. The Kaplan-Meier event curves for the primary composite end point and all-cause mortality are provided in Figures 1 and 2⇓. There was a significant reduction in urgent rehospitalization in the lotrafiban group (Table 3).
Of the stroke events, cerebral infarction occurred in 98 patients in the placebo group and 78 in the lotrafiban group, and hemorrhagic stroke occurred in 6 and 3 patients, respectively. Infarction with hemorrhagic conversion was the cause in 3 and 4 patients, respectively. Uncertain cause of stroke was classified in 2 and 10 patients, respectively.
Bleeding complications are presented in Table 4, with the source of bleeding summarized in Table 5. Subgroup analysis for efficacy in patients by age (partitioning at 65 years), gender, and enrollment criterion did not show evidence of heterogeneity (Figure 3) with respect to risk of increased mortality or lack of effect of lotrafiban on the composite end point of death, myocardial infarction, or stroke.
The data for aspirin dose at the time of randomization for patients receiving placebo study drug are summarized in Table 6. A similar proportionate increase in bleeding complications was observed among patients who received lotrafiban with higher-dose aspirin (>162 mg/d) than with lotrafiban and aspirin 75 to 162 mg/d. The incidence of serious bleeding was 9.0% compared with 7.1%, respectively (P<0.001), and the incidence of any transfusion was 5.9% compared with 3.4% (P<0.001).
The multivariate model for mortality identified 10 covariates independently associated with an increased or decreased risk of death (Figure 4). Of note, lotrafiban was independently associated with higher mortality (hazard ratio 1.36, 95% CI 1.05 to 1.76; χ2=5.53, P=0.018). Furthermore, higher-dose aspirin was associated with a decreased mortality (hazard ratio 0.74, 95% CI 0.56 to 0.97; χ2=4.71, P=0.03).
The present trial is noteworthy for 3 major findings. First, it confirms the increased risk of fatality and serious bleeding for oral platelet glycoprotein IIb/IIIa inhibition, with a similar magnitude (33%) as exhibited in the previous 4 trials.2–6 Second, it demonstrates for the first time that the increased risk of fatality is also extended to patients with cerebrovascular disease, because the BRAVO trial was the only one that incorporated this group as an entry criterion, and >40% of patients qualified on the basis of having cerebrovascular disease. Third, although the dose of aspirin was not randomized and was left to the discretion of the physician-investigator, doses higher than 162 mg/d were associated with an increased risk of the primary composite end point, an increased risk of serious bleeding and transfusion, but also a decreased risk of mortality.
The increased risk of fatality with oral IIb/IIIa blockade has been noted in all 4 prior large-scale trials that tested orbofiban, xemilofiban, and sibrafiban.2–6 The magnitude of risk of 37% excess in fatality rate observed in the prior trials is in keeping with the present report with lotrafiban. This higher risk of fatality appeared to be increasing over the duration of drug exposure (Figure 2) and was largely attributable to an excess in vascular deaths. Although attempts were made in the present trial to titrate the dose of lotrafiban according to the patient’s age and calculated creatinine clearance, this did not achieve any reduction of risk.
Unlike parenteral short-term IIb/IIIa inhibition, dosing of the oral IIb/IIIa blockers has been challenging because high levels of inhibition (>80% receptor blockade at steady state) are not tolerated owing to excessive bleeding complications. Although the precise mechanism is not known for the increased risk of death due to oral platelet glycoprotein IIb/III inhibition, recent studies have indicated that a subthreshold inhibition (<80%) of the IIb/IIIa receptor promotes shedding of platelet CD40 ligand, which has both a principal prothrombotic and proinflammatory role.9–12 Along with P-selectin expression that can be potentiated by oral platelet glycoprotein inhibition,9 platelet-derived constituents may indeed be responsible for inducing more fatal vascular events than were observed in trials of these agents.
The extension of the hazard of death among patients with cerebrovascular disease is important because one may have expected the absence of coronary disease as an enrolling criterion might have made these patients less likely to incur the risk. The risk of serious bleeding complications across both coronary and cerebrovascular disease patients is not surprising in light of similar data from the previous trials6 but might have been considered a potentially acceptable tradeoff had there been a striking reduction in major vascular events. The benefit in terms of less urgent revascularization or hospitalization is modest, in keeping with previous reports,2–6 and not meaningful compared with the higher risks of fatality and bleeding.
The findings on the dose of aspirin are important. Although the data are based on nonrandomized selection of dose by physician-investigators, there was a very large population with a considerable number of events during extended follow-up. The narrow dose range of 75 to 325 mg, which was necessary to accommodate international practice, afforded the opportunity to study lower versus higher dosing, which has not been assessed adequately by any previous large randomized trial in patients with coronary or cerebrovascular disease. The Dutch Transient Ischemic Attack trial randomly assigned aspirin at a dose of 30 or 283 mg/d in 3131 patients with cerebrovascular disease and showed more bleeding at the higher dose.13 In BRAVO, most of the dosing between 75 and 162 mg/d used a 100-mg tablet, which is commonly used outside the United States, whereas in the United States, 81 or 162 mg/d was primarily used. Although the assessment of aspirin dosing will require further intensive analysis from the BRAVO database, accounting for international differences and other potentially confounding variables through modeling and propensity analyses, there was strong evidence for heightened risk of serious bleeding (approximate doubling); no benefit of the composite end point of death, myocardial infarction, or stroke; but a lower risk of mortality when this end point was assessed independently through logistic regression. Such a finding certainly underscores the need for more dedicated clinical research to determine the optimum dose of aspirin. One of the limitations of the present trial is a failure to collect information concerning aspirin dose during extended follow-up, because only the dose used at study entry was available.
Finally, the trial raises potential ethical issues as to whether such a large-scale effort was appropriate given data from previous trials that showed an increased risk of mortality for patients treated with other agents in the class of oral IIb/IIIa inhibitors. The present trial was initiated before the results of SYMPHONY I and II4,5 and the meta-analysis of previous trials6 were available. Previous assessment of risk in the orbofiban trial had suggested that titrating the dose for renal impairment would reduce the risk of adverse events,2 and this was a major strategy incorporated in the lotrafiban project. Careful surveillance of risk was monitored during the trial by an experienced Data and Safety Monitoring Board, and the first time there was a significant demonstration of hazard, the trial was stopped. Consideration was given to stopping the trial before this point on the basis of the results of other trials, but the lack of evidence of hazard, the unique population under study, and the specific dose and drug strategy led to continuation with close monitoring.
On the basis of the trial, it can be recommended that oral platelet glycoprotein IIb/IIIa blockade carries undue hazard with respect to mortality and serious bleeding complications, and the present trial extends this theme to a fourth agent in the class and an even more diverse patient population. It appears that doses of aspirin ≤162 mg/d may be prudent to avoid bleeding complications for the time being, unless patients are at particularly high risk, in which case, consideration of a dose of 325 mg/d may be appropriate but will be associated with increased bleeding complications. Without question, further assessment of aspirin dosing through large-scale, randomized trial investigations would be helpful to clarify optimal antiplatelet therapy for patients with atherosclerotic vascular disease.
Eric. J. Topol, MD (USA); Donald Easton, MD (USA); Robert Harrington, MD (USA); Pierre Amarenco, MD (France); Robert M. Califf, MD (USA); Carmen Graffagnino, MD (USA); Stephen Davis, MD (Australia); Lloyd Fisher (USA); Hans Christophe Diener, MD (Germany); James Ferguson, MD (USA); Desmond Fitzgerald, MD (Ireland); Ashfaq Shuaib, MD (Canada); Peter J. Koudstaal, MD (the Netherlands); Pierre Theroux, MD (Canada); Frans Van de Werf, MD (Belgium); James T. Willerson, MD (USA).
Data Safety and Monitoring Board
Mark Verstraete, MD (Belgium); Marie Germaine-Bousser (France); Philip A. Wolf, MD (USA); John R. Hampton, MD (United Kingdom); James Tcheng, MD (USA). Statistician: David Jones (United Kingdom); Leroy Walters, MD (USA).
Clinical Event Committee
Chairman: Kenneth Mahaffey, MD. Coordinator: Freda Wood, Duke Clinical Research Institute, USA.
William Glenn Friesen, MD, Bart G. Denys, MD, Susan P. Graham, MD, Ronald A. Ford, MD, Kenneth Ng, MD, Douglas L. Roberts, MD, Glenn Hamroff, MD, David J. Ende, MD, Salah El Hafi, MD, Martin R. Berk, MD, John M. Burks, MD, Benjamin Williams, MD, PhD, Raymond Englander, MD, Carlos B. Saenz, MD, Dorothy H. Banish, MD, Alan K. Jacobson, MD, William B. Smith, MD, FACC, Richard G. Friedman, MD, Roy S. Small, MD, Marc Raphaelson, MD, Joseph Connolly III, DO, Steven Promisloff, MD, Louis J. Cioci, MD, Janet L. Wilterdink, MD, Solomon Fishman, MD, C. David Hassel, MD, David Meyer, MD, John B. Bedotto, MD, FACC, Archie G. Davis, MD, William R. Logan, MD, James R. McDowell, MD, David H. Schoening, MD, Timothy Dewhurst, MD, Mark Vincent Hart, MD, Keith A. Kadel, MD, Patrick J. Bergin, MD, Daniel P. Stein, MD, Michael A. Nocero, Jr, MD, Ray V. Matthews, MD, Randolph B. Shey, MD, Cornelius Flowers, MD, Bruce J. Iteld, MD, FACP, FACC, Gary Shiffrin, MD, Christopher S. Boylan, MD, A. Alan Chu, MD, Marc D. Tischler, MD, Robert L. Feldman, MD, Jeffrey A. Leavy, MD, FACC, Jeffrey H. Kramer, MD, FACC, Mark D. Gelernt, MD, FACC, Melvin J. Tonkon, MD, Wayne Pharo, MD, Patricia H. Davis, MD, Scott E. Kasner, MD, Michael D. Hoffstetter, MD, Kenneth A. Levin, MD, Andrew J. Keller, MD, Martin J. Frey, MD, Alan L. Niederman, MD, FACC, Daniel J. O’Dea, MD, FACC, Jay Jonas Rubin, MD, Harish Chandra, MD, Bruce A. McLellan, MD, Imran K. Niazi, MD, Wendall Helveston, MD, Eric W. Enger, MD, Henry Christmas Waterer III, MD, George K. Wong, MD, Craig Narins, MD, Laryenth Lancaster, MD, Ralph Vicari, MD, Arthur L. Riba, MD, W. Herbert Haught, MD, Michael J. Martinelli, MD, Arthur Schiff, MD, Bruce T. Bowling, MD, Sheldon B. Staunton, MD, Thomas S. Parker, MD, Terrence C. Hack, MD, Kyra J. Becker, MD, Robert Brockie, MD, Victor Echenique, MD, L. Matthew Frank, MD, Charles L. Brown III, MD, Jeffrey L. Gross, MD, Harvey Resnick, MD, James C. Grotta, MD, Daniel R. Wynn, MD, ABSM, George H. Dooneief, MD, Raye L. Bellinger, MD, Taher Husainy, MD, John Winterton, MD, John Jayne, MD, Raymond M. Stephens, MD, Paul McDowell, MD, Jonathan Gilbert, MD, Richard W. Asinger, MD, Bernard Schrager, MD, Thomas Chippendale, MD, William F. Penny, MD, Chung Y. Hsu, MD, PhD, Lawrence G. Yellen, MD, Robert L. Jesse, MD, Michael A. Douglas, MD, Mark Pirwitz, MD, Michael J. Koren, MD, Richard Heuser, MD, Kenneth A. Fath, MD, FACC, William Ferrell, MD, F. Martin Lester, MD, James M. Burke, MD, Robert J. Weiss, MD, FACC, FAC, Thomas A. Kelly, MD, FACC, John Sobolski, MD, Marcus L. Williams, MD, David M. Hill, MD, Michael Z. Chesser, MD, Wayne N. Leimbach, MD, FACC, FCCP, David B. Ross, MD, Carl H. Sadowsky, MD, John S. Golden, MD, Dean Tippett, MD, James J. Ferguson, MD, Francis Kiernan, MD, Joshua DeLeon, MD, Jonathan Harris, MD, Dean J. Kereiakes, MD, Mitchell S. Elkind, MD, John Bennett Kelly, MD, Cathy M. Helgason, MD, Wayne Clark, MD, Barry D. Bertolet, MD, William J. Rogers, MD, Ronald E. Rediker, MD, Allan L. Bernstein, MD, Norman Gordon, MD, T. Erik Borresen, MD, Frank Fleming, MD, William T. Maddox, MD, Alan Einstein, DO, J. Douglas Pappas, MD, JD, H. Vernon Anderson, MD, Samuel Markind, MD, Randy K. Bottner, MD, Robert J. Wityk, MD, A.R. Zaki Masud, MD, Jeffrey S. Garrett, MD, Anthony J. Furlan, MD, Bruce B. Cleeremans, MD, Walter D. Truax, MD, Richard Chernick, MD, Gregory Pennock, MD, FACP, FACC, David Sease, MD, FACC, William H. Bentley, MD, Joseph A. Puma, DO, FACC, Robert Martin Pinner, MD, William David Honeycutt, MD, James M. Hagar, MD, William Lewis, MD, Guy N. Piegari, Jr, MD, Steven Sparr, MD, Alejandro A. Caballero, MD, Sarkis Nazarian, MD, M. El Shahawy, MD, MS, FACC, Alan N. Tenaglia, MD, Kevin Konzen, MD, George W. Carr, MD, Laura Lennihan, MD, Karen Furie, MD, MPH, V. Daniel Kassicieh, DO, Paul Martin Popper, MD, FACC, Robert Lehman, MD, Martin S. Topiel, MD, Jerry Becker, MD, Mark I. Harris, MD, Taher Husainy, MD, Chelsea Kidwell, MD, Stanley Rockson, MD, Allen Stahl, MD, Labros A. Karagounis, MD, Venkatesh K. Nadar, MD, Steven E. Hearne, MD, Athol Morgan, MD, Richard Gray, MD, Martin S. Weiss, DO, Donald K. Stott, MD, M. Gabriela Pugliese, MD, Robert Payne, MD, Ofsman E. Quintana, MD, Robert Berkowitz, MD, Carol M. Meils, MD, Douglas J. Spriggs, MD, David S. Grubbs, MD, Zaheer Baber, MD, Frank A. McGrew, MD, Conrad C. Simpfendorfer, MD, Kirk Roberts, MD, Nabil F. Jarmukli, MD, Souvik Sen, MD, Rodney D. Bell, MD, Khalid Hasan Sheikh, MD, FACC, FACP, Bosh G. Zakhary, MD, FACC, PC, Thomas Tift Mann III, MD, Gregg Schuyler, MD, PhD, Glenn Albin, MD, Randall Thompson, MD, Arthur Bleakley Chandler, Jr, MD, FACC, Shilpesh S. Patel, MD, Edgardo A. Crisostomo, MD, Kenneth P. Madden, MD, PhD, Rick R. McClure, MD, Diana Pollock, MD, Franklin Fleischhauer, MD, Vasco Rudolph Geer, MD, Hal Tobias, MD, Rajinder K. Bhalla, MD, PA, Sally Zachariah, MD, John P. Parker, MD, David W. Hayes, MD, Mark H. Fletcher, MD, Jalal K. Ghali, MD, Charles F. Dahl, MD, Joseph Sacco, MD, Christopher D’Haem, MD, Robert A. Ringel, MD, Robert Don Campagna, MD, John Tadson Funai, MD, Michael C. Dillon, MD, Robert Barry Schlesinger, MD, Carmelo Graffagnino, MD, FRCP(C), Ismail S. Ahmed, MD, Massoud Ansari-Leesar, MD, James R. Morgan, MD, Douglas B. Gersh, MD, Dale Daly, MD, Dennis Dietrich, MD, Wayne D. Old, MD, John H. Wertheimer, MD, Dwayne A. Schmidt, MD, Steven Goldman, MD, Joseph M. Kmonicek, MD, FACC, Richard Gray, MD, Umesh A. Patel, MD, FACC, Kathleen Quealy, MD, Jonathan Zaroff, MD, Seth L. Krauss, MD, E. Clarke Haley, Jr, MD, Gary E. Sander, MD, PhD, FACC, Robert G. Zoble, MD, PhD, Alan Schob, MD, Joseph Emory B. Burchenal, MD, Peter H. Stone, MD, Douglas Losordo, MD, Mario J. Lopez, MD, FACC, John E. Ervin, MD, Sanjeev Puri, MD, Robert M. Siegel, MD, Nalin Srivastava, MD, Eduardo DeMarchena, MD, Stanley N. Cohen, MD, Robert A. Harrington, MD, Paul A. Gurbel, MD, James F. Butler, DO, Fen-Lei Chang, PhD, MD, Charles H. Tegeler, MD, Steven Borzak, MD, John R. Belden, MD, Patrick Capone, MD, Walter C. Brogan III, MD, PhD, David Vorchheimer, MD, Udho Thadani, MD, Gerald McIntosh, MD, Peter Goodfield, MD, Daniel Rodriguez, MD, Ferdando Lopez, MD, Warren L. Felton III, MD, G. Leslie Walters, MD, Adeyemi Johnson, MD, FACC, Mitchell S. Finkel, MD, Marvin Padnick, MD, FACP, FACC, Jonathan Liss, MD, Patricia Cole, MD, FACC, Louis A Cannon, MD, FACC, FACP, Kim A. Klancke, MD, James Frederick McNeer, MD, Stephen A. Stowers, MD, Marshall Nash, MD, Jorge Saucedo, MD, FACC.
Brian A. Anderson, MD, FRCPC, Rudolph Arts, MD, Edward Auersperg, MD, Neville Bayer, MD, Michel G. Beaudry, MD, Leo Berger, MD, Jorge Bonet, MD, C. Buller, MD, D. Cameron, MD, Sharon Cohen, MD, FRCPC, Christian Constance, MD, Robert Cote, MD, T. Curran, MD, Andre Douen, MD, John Ducas, MD, Robert Jackson Duke, MD, L.J. Charles, MD, Marek J. Gawel, MD, John Heath, MD, K. Ho, MD, Andrew Kertesz, MD, FRCPC, Gary M. Klein, MD, Simon Kouz, MD, Louise-Helene Lebrun, MD, Sheldon Lewis, MD, John Axler, MD, Patrick T.S. Ma, MD, Jeffrey Minuk, MD, Garry Moddel, MD, Letitia Muresan, MD, Shah Nawaz, MD, John Norris, MD, David J. Novak, MD, Nawal K. Sharma, MD, Stephen Phillips, MD, G. Calvin MacCallum, MD, D. Selchen, MD, Manohara Piyasiri Jayatilaka Senaratne, FRCPC, FACC, PhD, Michael J. Winger, MD, Ashfaq Shuaib, MD, Denis Simard, MD, Gerald Simkus, MD, Paul Smylie, MD, J. David Spence, MD, Philip A. Teal, MD, Jeanne Teitelbaum, MD, Pierre Theroux, MD, Christopher Thompson, MD, A.G.G. Turpie, MD, Wayne Tymchak, MD, Felix Veloso, MD, Toni R. Winder, MD, Martin del Campo, MD, A. Penn, MD, S. Bose, MD, Monique Ruel, MD, R. Bhargava, MD, William Pryse-Phillips, MD.
Maria del Socorro Gonzalez Sanchez, MD, Hector Gonzalez Zambrano, MD, Ernesto Cardona, MD, Eduardo Chuquiure Valenzuela, MD, Norberto Garcia Hernandez, MD, Cantos Cantu Brito, MD.
Prof Stefka Yancheva, Assoc Prof Penko Shotekov, Stefka Veleva, MD, Eugenia Kirilova Pavlova, MD, Assoc Prof Ivan Hristov Manchev, Anastassia Aleksandrova Maliakova, MD, Prof Choudomir Natchev, Prof Anna Todorova Elenkova, Assoc Prof Temenouga Ivanova Donova, Assoc Prof Dimitar Christov Raev, Prof Nikolai Iordanov Penkov, Maria Lumomirova Tzekova, MD.
Ladislav Groch, MD, Martin Herold, MD, Jirí Kettner, MD, Josef Stásek, MD, Rostislav Stríbrny, MD, Tomás Janota, MD, Karel Urbánek, MD, Jolana Marková, MD, Prof Ivan Rektor, Otakar Keller, MD, Dagmar Krajícková, MD, Edvard Ehler, MD.
Prof Laszló Csiba, Zoltán Nagy, MD, Péter Harcos, MD, Samuel Komoly, MD, Ilona Sági, MD, Prof Pál Kárpáti, László Rudas, MD, György Csókor, MD, Sándor Timár, MD, Karoly Zámolyi, MD.
Ovidiu Alexandru Bájènaru, MD, Prof Alexandru Serbanescu, Prof Constantin Popa, Assoc Prof Cornelia Zaharia, Prof Leonida Gherasim, Dina-Maria Cupsa, MD, Tiberiu Nanea, MD, Assoc Prof Carmen Doina Ginghiná, Prof Maria Dorobantu.
Dmitry A. Zateyshchikov, MD, Prof Yuri S. Titkov, Alexander Anatolievich Petrov, MD, Prof Valery G. Radchenko, Prof Victor A. Sorokoumov, Mikhail P. Maltchougine, MD, Michael V. Alexandrov, MD, Prof Gregory Pavel Aroutiounov, Maria Glezer, MD, Oxana M. Drapkina, MD, Alexander M. Vein, MD, Aleksei Nikonov, MD, Zinaida A. Suslina, MD, Vladimir A. Karlov, MD, Prof Veronika I. Skvortsova.
Geoffrey Kingston Lane, MD, Roger Ralph Taylor, MD, Graeme John Hankey, MD, Julie Ann Bradley, MD, Prof John D. Horowitz, Christopher C. Rowe, MD, Prof Geoffrey Alan Donnan, Prof Stephen Misha Davis, Judith Helen Frayne, MD, Christopher Levi, MD, David Martin Colquhoun, MD, Jeff Karrasch, MD, Christopher C. Rowe, MD, Prof Stephen Misha Davis.
Douglas S. Scott, MD.
Prof Peter Paul De Deyn, Prof Paul J. Delwaide, Philip Bourgeois, MD, Patrick Uytdenhoef, MD, Serge Anicet Charles Blecic, MD, Cécile Delwaide, MD, Prof Patrick Cras, Prof Frans Van De Werf, Prof Wim Robberecht, André Peeters, MD, Geert T.O. Vanhooren, MD, Professor J. De Reuck, Guy Robert Heyndrickx, MD, Jean-Claude Wautrecht, MD, Gérard Boxho, MD, Jacques Lalmand, MD, Prof Patrice Laloux, Filip De Man, MD, Prof Raymond Verhaeghe, Herman Nachtergaele, MD, Michel Vandormael, MD, Jan De Letter, MD, Dirk Bladt, MD, Philippe Desfontaines, MD, Prof W. Van Mieghem, Jan Stillaert, MD.
Koos Keizer, MD, Jan A.L Vanneste, MD, Egbert A.C.M Sanders, MD, Elias Siebenga, MD, Adrie J.A.M. Withagen, MD, Herman Rudolf Michels, MD, Willem G. de Voogt, MD, Johannes Christiaan Kelder, MD, Johannes M. Hartog, MD, Leo van Bogerijen, MD, W.G. de Voogt, MD, Peter-Paul Henri Marie Delnoy, MD, René Dijkgraaf, MD.
Prof Menachem Sadeh, Prof Eldad Melamed, Hillel Halkin, MD, Gad Keren, MD, Amos D. Korczyn, MD, Prof Yonathan Hasin.
Pierre Dumoulin, MD, Nicolas Christophe Gabriel Delarche, MD, Fabrice Leroy, MD, Jean Marc Boulenc, MD, Emmanuel Gras, MD, Eric Tison, MD, Joël Sainsous, MD, Cyril Charlin, MD, Renaud Fouché, MD, Marc Lang, MD, André Marquand, MD, Prof Philippe Piquet, François Viallet, MD, Antoine Medvedowsky, MD, Alain Huyghe-Mahenge, MD, Paul Cotronis, MD, Jean-Marc Diamand, MD, Yves Mocquard, MD, Jean-Pierre Binon, MD, Robert Anselme-Martin, MD, Jean-Pierre Caussanel, MD, Bertrand Petit, MD, Pierre Roelens, MD, Prof Pierre Amarenco, Prof Jacques A. Bonnet, François Petit, MD, Prof Hervé Decousus, Marie-Hélène Mahagne, MD, Thierry Moulin, MD, Gerard Rancurel, MD, Jean François Pinel, MD, Guy Mialet, MD, Prof François Chollet, Vincent Larrue, MD, Jacques Vedel, MD, Prof Gilles Montalescot, Christine Magne, MD, Philippe D’ Bonnet, MD, Prof Marc Hommel, Jacques Boulliat, MD, François Chedru, MD, Jean-Marc Bouvier, MD, Jean-Louis Mas, MD, Cyrille Blum, MD, Frederic Fossati, MD, Francis Bezot, MD, Didier Leys, MD, Prof Michel Pagès, Jean-François Rousseau, MD, Jean-Baptiste Cesari, MD, Pierre Weiss, MD, Prof Jean-Marc Orgogozo, Pascal Cornec, MD, Thomas De Broucker, MD, Prof Etienne Roullet, Claude Grellet, MD, Jean-Claude Kahn, MD, Christophe Bretelle, MD, Emile Ferrari, MD, Jean-Yves Brunet, MD, Ali Chibatte, MD, Danielle Matina, MD, André Hita, MD, François Funck, MD, Prof Jean-Marc Davy, Thierry Jullien, MD, Luc Ardouin, MD, Dominique Desbrosses, MD, Eric Olivier Tricoire, MD, Sandrine Bonnay Canaple, MD, Prof Michel Weber, Bruno Mihout, MD.
Michael Adelmann, MD, Prof Otto Busse, Prof Günther Deuschl, Prof Hans-Christoph Diener, Prof Henning Henningsen, Frank Joachim Erbguth, MD, Prof Johannes Dichgans, Prof Heinz Reichmann, Prof Claus-W Wallesch, Hans W. Greiling, MD, Martin Andreas Grond, MD, Prof Roman Ludwig Haberl, Prof Werner Hacke, Gerhard F. Hamann, MD, Prof Karl M. Einhäupl, Prof Alexander Hartmann, Prof Christof Kessler, Prof Peter Marx, Volkmar Maennl, MD, Udo Müller, MD, Konrad Scheglmann, MD, Prof Dictmar Schneider, Günter Seidel, MD, Ulrich Sliwka, MD, Prof Manfred Kaps, Prof Andreas Thie, Prof Walter Mathias Paulus, Gerd Baack, MD, Prof Martin Sigmund, Prof Andreas Mügge, Prof Johannes Brachmann, Prof Joachim Cyran, Harald Darius, MD, Prof Wolfram Delius, Prof Hans Reiner Figulla, Peter Jakob Gaudron, MD, Prof Reinhard Griebenow, Prof Dechend, Prof Franz-Job Harenberg, Karl Eugen Hauptmann, MD, Prof Dieter Hey, Thomas Horacek, MD, Michael Keck, MD, Prof Dietrich Pfeiffer, Prof Gulba, Prof Wolfgang Lengfelder, Johann Wolfgang Scheinpflug, MD, Veselin Mitrovic, MD, Prof Helmut Ulrich Klein, Andreas Reinheimer, MD, Prof Claus Spieker, Prof Reinhard Voss, Jürgen Wilhelm, MD, Peter Wirtz, MD, Wolfgang Müllges, MD, Angela Genov, MD, Prof Eckart Fleck, Prof Cornelia Spamer, Prof Gerd J. Meyer, Prof Christoph Nienaber, Berthold Pollock, MD, Prof Hansjörg Schütz, Georg V. Sabin, MD, Brigitta Krosse, MD, Prof Günter Ochs, Prof Abderrahman Machraoui, Peter Boekstegers, MD, Prof Hanns-Gerd Dammann.
Professor Franz Thaddäus Aichner.
Prof Philip Michael William Bath, Simon Jonathan Ellis, MD, Clifford Adrian Bucknall, MD, Kevin Stephen Channer, MD, Prof John A. Dormandy, Michael John Gough, MD, Peter Ronald David Humphrey, MD, Philip S. Lewis, MD, Prof Gordon Douglas Ogilvie Lowe, Peter Frederick Ludman, MD, John Christopher Mucklow, MD, Robin John Northcote, MD, David Oakley, MD, Maurice P. Pye, MD, Graham S. Venables, MD, Peter Marshall Schofield, MD, Kennedy Richardson Lees, MD.
Prof Desmond J. Fitzgerald, Brendan J. Foley, MD, Peter J. Quigley, MD, Thomas Matthew, MD, David Andrew Mulcahy, MD.
Alberto Conti, MD, Prof Luigi Murri, Nicola Palestini, MD, Luigi Curatola, MD, Domenico Sabatini, MD, Prof Francesco Colace, Prof Tommaso Sacquegna, Prof Nicola Alberti, Prof Francesco Paolo Alo’, Prof Giuseppe Maria Andreozzi, Natalino Bedin, MD, Gabriele Bittolo Bon, MD, Massimo Bocca, MD, Prof Piergiorgio Cao, Prof Sergio Coccheri, Marcello Farinelli, MD, Maria Luisa Davoli, MD, Prof Virgilio Gallai, Carlo Giansante, MD, Maria Luisa Cattabiani, MD, Angelo Ghirarduzzi, MD, Giuseppe Lombardi, MD, Prof Elmo Mannarino, Donata Guidetti, MD, Giulio Mazzilli, MD, Prof Claudio Novali, Adriana Visonà, MD, Eugenio Palese, MD, Mauro Paolicelli, MD, Amerigo Gori, MD, Prof Carlo Pratesi, Prof Franco Michele Puca, Prof Arturo Reggio, Gaetano Scondotto, MD, Prof Carlo Setacci, Prof Carlo Spartera, Prof Giuseppe Spinella, Giuseppe Micieli, MD, Prof Bruno Trimarco, Massimo Franceschi, MD, Vito Zambelli, MD, Marco Rossi, MD, Paola Merlo, MD, Giorgio Giovanni Bono, MD, Michele Morra, MD.
Oyvind Rosjo, MD, Helge Riisoeen, MD, Stein Roalso, MD, Torstein Gundersen, MD.
Per Hildebrandt, MD, Tage Lysbo Svendsen, MD, Karsten Overgaard, MD, Prof Gudrun Boysen, Tonny Nielsen, MD.
Prof Markku Kaste, Prof Juhani Sivenius.
Assoc Prof Biruté Petrauskiené, Assoc Prof Rima Steponènienè, Prof Petras Zabiela, Nerija Vaiciene, MD, Sture Sjögren, MD, Per Katzman, MD, Assoc Prof Ingrid Mattiasson, Barbro Kjellgren-Leijd, MD, Tom Wickstroem, MD, Rebecca Undén-Göransson, MD, Kurt-Ove Borén, MD, Ulf Hurtig, MD.
Jeffrey Granett, MD, Medical Group Director, North America; Robert E. Samuels, MS, Scientific Director, North America; Tony Chen, PhD, Principal Statistician, North America; Robert Chan, MD, Medical Director, Europe; Shiona Laing, PhD, Scientific Assistant Director, Europe.
This study was sponsored by Glaxo Smith Kline, Collegeville, Pa.
Guest editor for this article was Paul W. Armstrong, MD, University of Alberta, Alberta, Canada.
This article originally appeared Online on July 21, 2003 (Circulation. 2003;108:r16–r23).
↵*An expanded appendix, including a full list of investigators and the study network, is available in the online-only Data Supplement at http://www.circulationaha.org.
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