International, Randomized, Controlled Trial of Lamifiban (a Platelet Glycoprotein IIb/IIIa Inhibitor), Heparin, or Both in Unstable Angina
Background—Unstable angina and non–Q-wave myocardial infarction involve coronary arterial plaque rupture, platelet activation, and thrombus formation. This study tested the benefit of different doses of lamifiban (a platelet IIb/IIIa antagonist) alone and in combination with heparin in patients with these conditions to select the most promising lamifiban regimen for subsequent evaluation.
Methods and Results—At 273 hospitals in 20 countries, 2282 patients were randomly assigned to lamifiban (2×2 factorial design: low-dose [1 μg/min] with and without heparin versus high-dose [5 μg/min] with and without heparin) or to standard therapy (placebo and heparin). All patients received aspirin. The composite primary end point of death or nonfatal myocardial infarction at 30 days occurred in 11.7% of those receiving standard therapy, 10.6% receiving low-dose lamifiban, and 12.0% receiving high-dose lamifiban (P=0.668). By 6 months, this composite was lowest for those assigned to low-dose lamifiban (P=0.027) and intermediate for those assigned to high-dose lamifiban (P=0.450) compared with control (13.7%, 16.4%, and 17.9%, respectively). Compared with control, the combination of high-dose lamifiban and heparin resulted in more intermediate or major bleeding (12.1% versus 5.5%; P=0.002) and a similar rate of ischemic events. Conversely, low-dose lamifiban and heparin yielded similar bleeding rates as in the control group but fewer ischemic events at 6 months (12.6% versus 17.9%; P=0.025).
Conclusions—In unstable angina and non–Q-wave infarction, platelet IIb/IIIa antagonism with lamifiban reduces adverse ischemic events at 6 months beyond that of aspirin and heparin therapy. The role of conjunctive heparin remains uncertain but appears more favorable with low-dose IIb/IIIa antagonism. Larger-scale study is needed to more reliably estimate these effects.
Acute coronary syndromes are characterized by coronary arterial plaque rupture, platelet activation, and thrombus formation.1 2 Aspirin and heparin have been used as the therapeutic mainstay for acute coronary syndromes, acting as an antiplatelet and an antithrombin, respectively. Although the ability of aspirin to reduce recurrent ischemic events in acute coronary syndromes is consistent,3 4 5 6 7 8 9 the benefit of adding heparin to aspirin therapy remains less certain.6 7 10 More potent platelet inhibitors, the glycoprotein IIb/IIIa antagonists, have been proved effective in reducing ischemic events associated with coronary angioplasty.11 12 This benefit is beyond that provided by aspirin and has persisted while reducing concomitant heparin.12 Lamifiban is a small-molecule member of the new class of IIb/IIIa inhibitors developed for intravenous administration. In a pilot trial of 365 patients with unstable angina and non–Q-wave myocardial infarction, lamifiban at varying doses yielded encouraging results.13 Because adverse ischemic events were reduced and only a minority of patients received concomitant heparin, we designed the current trial to test two doses of lamifiban with and without heparin. Our objective was to assess the benefit and safety of IIb/IIIa inhibition and to select the best regimen for further evaluation compared with heparin to determine an optimal treatment strategy in patients with unstable angina and non–Q-wave myocardial infarction.14
Patients enrolled into study had chest discomfort within the previous 12 hours associated with transient or persistent ST-segment depression (≥0.5 mm) or T-wave inversion or transient (30 minutes) ST-segment elevation (≥0.5 mm). Patients were excluded if they were receiving oral anticoagulants and had an international normalized ratio >1.5× control, if they were receiving intravenous heparin and had an activated partial thromboplastin time (aPTT) >85 seconds (not due to recent bolus), or if they had received thrombolytic therapy within 24 hours. Patients were also excluded for active, significant bleeding; contraindication to aspirin or heparin; systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥100 mm Hg despite treatment; serum creatinine level >2.0 mg/dL (177 μmol/L); platelet count <100 000/mm3; cerebrovascular accident within the past year; any history of hemorrhagic stroke, tumor, or intracranial aneurysm; angioplasty within the previous week; or gastrointestinal bleeding, major surgery, or trauma within 1 month. Women of childbearing potential were excluded unless the pregnancy test was negative. For safety reasons, patients were discontinued from study after enrollment if the creatinine was found to be ≥2.0 mg/dL, the platelet count decreased by one third and was <100 000/mm3, or important bleeding occurred. All enrolled patients gave informed consent, and the study protocol was approved by each participating hospital’s institutional review board.
As previously described,14 the objective of this trial was to assess treatment strategies of glycoprotein IIb/IIIa inhibition, with the optimal strategy to be further tested against standard therapy. Therefore, a partial factorial design was implemented with patients randomized to low-dose versus high-dose lamifiban and to heparin or no heparin therapy. The fifth group for which randomization was possible was the control group, who received lamifiban placebo and heparin (Figure 1⇓). Thus, each patient received lamifiban, unfractionated heparin, or both in addition to aspirin. The study was double-blinded such that all patients received lamifiban or lamifiban placebo and heparin or heparin placebo. The protocol required study drug administration for a minimum of 3 days and a maximum of 5 days unless the patient underwent percutaneous coronary intervention on day 5, in which case they were to receive study drug for an additional 12 to 24 hours after the procedure. Study drug was not discontinued for coronary angiography or intervention, but heparin or heparin placebo was discontinued 4 hours in advance to protect study blinding. All patients received aspirin at enrollment (160 mg recommended) and daily thereafter (80 to 325 mg). Porcine heparin of a single lot was used, and matching heparin-placebo vials were supplied by the same manufacturer (Elkins-Sinn Inc). Patients assigned to low-dose lamifiban (Hoffman-La Roche) received a 300-μg bolus followed by an infusion of 1.0 μg/min; those assigned to high-dose lamifiban received a 750-μg bolus followed by an infusion of 5.0 μg/min. All patients assigned to standard therapy (control group) received heparin, whereas by factorial design, heparin therapy was randomized among those receiving lamifiban. For patients who weighed ≥80 kg, the heparin dose was 5000 U as bolus and 1000 U/h as initial infusion. Patients who weighed <80 kg were given a weight-adjusted heparin bolus (60 U/kg) and initial infusion (12 U · kg−1 · h−1).
Systematic blinding of heparin administration and careful control of anticoagulation was achieved by use of a bedside aPTT device that produced encrypted results. Unblinded aPTT measurements were not allowed. A Hemochron Jr microcoagulation instrument (International Technidyne Corp) automatically assayed 15 μL of fresh whole blood and generated a multidigit code corresponding to the aPTT in seconds. Multiple codes were created for each aPTT value, and all values were checksum protected (a specific mathematical formula using the encrypted numbers and producing a known integer) to ensure that transcription errors did not occur. Using the patient’s study number and the coded aPTT result, the healthcare provider telephoned a central computer system, which deciphered the patient’s aPTT and treatment assignment and then directed heparin or heparin-placebo infusion adjustments. The computer program titrated the heparin infusion according to a standardized nomogram to keep the aPTT to a laboratory equivalent of 60 to 85 seconds. Heparin-placebo infusions were adjusted according to one of several random patterns that were consistent with heparin infusion adjustments. Bedside aPTT testing was performed 6 hours after study drug initiation, then every 6 to 12 hours until the target therapeutic range was reached. Thereafter, testing was performed at least daily during study drug administration.
Invasive Cardiological Procedures
Coronary angiography and revascularization were not to be performed during the first 48 hours unless clinically necessitated by hemodynamic instability or recurrent ischemia. In patients undergoing coronary angiography or percutaneous coronary intervention, the heparin or heparin-placebo infusion was to be stopped 4 hours before the procedure. During coronary revascularization, open-label heparin was used at the direction of the attending physician. Lamifiban and lamifiban-placebo infusions were given at a constant rate throughout study and were not interrupted for coronary angiography or percutaneous intervention.
The primary end point was a composite of all-cause mortality and nonfatal myocardial infarction (or reinfarction) in the first 30 days of follow-up. Secondary end points included death, myocardial (re)infarction, disabling stroke, major bleeding, and intermediate bleeding (red blood cell transfusion or >5 g of hemoglobin drop without hemodynamic compromise) at 30 days; death and myocardial infarction at 6 months; and death at 1-year follow-up. A Clinical Events Committee, which consisted of practicing cardiologists, was blinded to treatment assignment and adjudicated all clinical primary and main secondary end point events according to published predefined criteria.15 16 On the basis of clinical outcome data from a corresponding phase II study13 and event rates from previous similar trials,13 15 16 a sample size of 2250 patients was considered adequate to select the successive regimen. A statistically significant treatment effect was not expected for a particular lamifiban dose because a 50% reduction in events would be needed for α=0.05 and β≥0.90 at 30 days.
Data Management and Statistical Analysis
Data were collected on all randomized patients, and these were included in the statistical analysis according to the intention-to-treat principle. In addition to reviewing source documents for all end-point events, 10% of all patient records were systematically reviewed, and all participating centers were visited by a study monitor. Continuous variables were descriptively summarized by use of medians with 25th and 75th percentiles. Discrete variables were summarized in terms of frequencies and percentages. Simple descriptive statistics of efficacy and safety measures were used to compare treatments to select the best regimen for further clinical trial evaluation. Comparisons among groups for the primary and secondary end points were made by use of χ2 and log-rank tests. P values were two-sided, with ≤0.05 being considered significant.
Time-to-event analyses were performed by Kaplan-Meier estimates. Among patients who had no known event by 6 months, 73 had a follow-up time <120 days. These patients were excluded from the denominator of event rates under the assumption that their event probabilities were similar to the other patients. The excluded patients accounted for 4.1% of the control group and from 1.3% to 4.8% of each of the four lamifiban groups. At 1 year, 154 patients were excluded who were lost to follow-up before 300 days. Thus, follow-up was completed on 96.8% and 93.3% of patients at 6 months and 1 year, respectively. All patients with known follow-up times were included in the time-to-event analyses.
Between August 11, 1995, and May 29, 1996, there were 2282 patients enrolled at 273 hospitals in 20 countries (see Appendix). Baseline characteristics of the entire cohort separated by treatment assignment are presented in Table 1⇓. No differences in baseline characteristics were noted among the groups. Overall, study drug was given to 98.4% of the treatment group and 99.1% of the control group. The median duration of study drug administration was 72 hours for all groups. Drug was terminated early in 13% of the control group and in 19% of the lamifiban-treated patients, most commonly for bleeding or planned surgical revascularization. Plasma lamifiban concentrations were measured in 810 patients, and the median levels for those receiving 1-μg/min and 5-μg/min infusions were 15.0 and 69.7 ng/mL, respectively (P<0.001). Study drug administration, as well as concomitant medications and in-hospital cardiac procedures, is detailed in Table 2⇓.
Principal outcome data at 30 days and 6 months are provided in Table 3⇓. No difference in the composite of death or nonfatal myocardial infarction was noted between the control group and any lamifiban group at 30 days. In contrast, at 6-month follow-up, a substantial treatment effect was present: compared with the control group, three of the four lamifiban-treated groups had a numerically lower composite event rate (Figure 2⇓). Specifically, death or nonfatal myocardial infarction at 6 months was lowered 23% by low-dose lamifiban with or without heparin (odds ratio, 0.73; 95% CI, 0.55 to 0.97) and 8% by high-dose lamifiban with or without heparin (odds ratio, 0.90; 95% CI, 0.69 to 1.18) compared with control (Figure 3⇓). The fourth group, patients receiving high-dose lamifiban with heparin, had 30-day and 6-month outcomes similar to those of the control group. In both of these groups ≈12% and 18% of patients had reached the primary end point at 30 days and 6 months, respectively. All remaining lamifiban-treated groups had continued reduction in events compared with the control group over the first 180 days (Figure 2⇓) (odds ratio, 0.75; 95% CI, 0.58 to 0.97).
The event rates for both infarction and death diverged beyond 30 days (Figures 4⇓ and 5⇓) although neither individual end point was statistically different between treatment and control. The relative increase in myocardial (re)infarction between 30 and 180 days was 35% for the control group, 15% for the low-dose lamifiban groups, and 18% for the high-dose lamifiban groups. Likewise, the relative increase in deaths during this time was 128% for the control group, 73% for the low-dose lamifiban groups, and 89% for the high-dose lamifiban groups. At 1 year, all-cause mortality was 8.7%, 7.3%, and 8.9%, respectively (P=0.320; Figure 5⇓).
The incidences of bleeding complications and stroke are presented in Table 4⇓. There were more bleeding-related events among those receiving high-dose lamifiban. The combination of major and intermediate bleeding occurred in 5.5% of control patients, 6% of low-dose lamifiban patients, and 10.7% of high-dose lamifiban patients (P=0.002). This pattern was also observed after analysis of bleeding events not related to invasive procedures. One intracranial hemorrhage occurred during study in the high-dose lamifiban group without heparin.
To assess the relative contribution of heparin to outcome, efficacy and safety parameters were compared between the corresponding lamifiban-dose groups subrandomized to heparin or heparin placebo. At 30 days, no clear distinctions in efficacy were observed (Table 3⇑). At 6 months, the combination of heparin and lamifiban produced opposing results. Specifically, the lowest rates of death and infarction were observed among patients receiving low-dose lamifiban with heparin, whereas the highest event rates were among those receiving high-dose lamifiban with heparin (Table 3⇑; Figure 2⇓). Compared with the respective group without heparin, 14% fewer ischemic events occurred in the low-dose lamifiban–with-heparin group, whereas 22% more events occurred in the high-dose lamifiban–with-heparin group, although neither difference reached statistical significance. Patients receiving heparin in combination with lamifiban had an increased incidence of intermediate bleeding. For those receiving heparin, lamifiban, or the combination, the incidence of red blood cell transfusion was 4.4%, 5.7%, and 7.5%, respectively (Table 4⇑; P=0.034).
This is the first large study to test platelet glycoprotein IIb/IIIa inhibition in patients with unstable angina and non–Q-wave myocardial infarction. At 6-month follow-up, a distinct treatment benefit was observed with lamifiban for the composite end point of death and nonfatal myocardial infarction. Compared with standard therapy, low-dose lamifiban resulted in a 23% lower event rate (P=0.027), and high-dose lamifiban resulted in a nonsignificant 8% reduction in events. Interestingly, at early (30-day) follow-up (the primary end-point assessment of the study), no treatment difference had reached statistical significance. Low-dose lamifiban combined with heparin had the greatest composite event rate reduction at both 30 days (12%) and 6 months (30%) relative to standard therapy. This group also had the greatest reduction (20%) in all-cause mortality at 1 year compared with control. The study was not adequately powered to draw clear conclusions regarding the benefit of heparin coadministration.
Comparison With Other Trials
The baseline characteristics of the current study population are similar to those of other recent unstable angina studies.16 17 Nevertheless, the 11.7% occurrence of death and nonfatal myocardial infarction at 30 days for the standard therapy group is higher than the 8.7% reported in the GUSTO IIb trial, the largest unstable angina data set available.16 The 30-day ischemic composite is more similar to the 11.9% observed in the control group of the PRISM-PLUS study,18 a trial of high-risk patients, 45% of whom had an infarction at enrollment. Thirty-six percent of patients in PARAGON had an infarction at enrollment.
In both PARAGON and GUSTO-IIb (which tested hirudin against heparin), the composite incidence of death or infarction increased roughly 50% in the interval between 30-day and 6-month follow-up. Although both trials demonstrated a modest early treatment benefit (9.4% and 8.5% respective reductions in death and infarction compared with control), patients receiving a glycoprotein IIb/IIIa antagonist derived a steadily increasing benefit over time. Late benefit has been observed among patients receiving IIb/IIIa antagonists in some angioplasty trials.11 19 A meta-analysis20 of all large, placebo-controlled trials of IIb/IIIa antagonists, including 6-month follow-up data from >12 000 patients, showed a 22% reduction in death and nonfatal infarction. Moreover, the Evaluation of c7E3 in the Prevention of Ischemic Complications (EPIC) investigators reported a 60% reduction in death at 3-year follow-up among patients with unstable angina or evolving infarction who received abciximab during angioplasty.19 Interestingly, this benefit became most evident after the first year of follow-up. Also consistent with other trials involving IIb/IIIa antagonists is the infrequent occurrence of intracranial hemorrhage. The rate of intracranial hemorrhage has been reported to be <0.2% with IIb/IIIa inhibitor use,21 which is as low as in the respective placebo groups, and only one such event occurred in the present study.
Role of Heparin With Glycoprotein IIb/IIIa Inhibitors
Oler et al10 performed a meta-analysis of six small, unstable angina studies that randomized patients to aspirin (a relatively weak antiplatelet agent) or a combination of aspirin and heparin, because no study alone showed a clear benefit with the combination. The pooled data from 1353 patients suggested a benefit from heparin addition, but this was of marginal statistical significance (relative risk, 0.67; 95% CI, 0.44 to 1.02; P=0.06). In the present study, heparin administration and adjustment was fully blinded with the use of a bedside automated system, encrypted values, and centralized computers according to a predefined nomogram. Overall, heparin provided no consistent benefit when combined with lamifiban. This may reflect the fact that the 30-day and 6-month composite ischemic event rates were numerically highest among those receiving heparin with high-dose lamifiban and lowest for those receiving heparin with low-dose lamifiban. At 6 months, the incidence of death or nonfatal infarction among patients receiving low-dose lamifiban plus heparin was 30% lower (P=0.025) than with heparin alone and 14% lower (P=0.411) than with low-dose lamifiban alone. Likewise, bleeding events were increased among those receiving heparin with high-dose lamifiban but not with low-dose lamifiban. In the current trial, as well as in previous glycoprotein IIb/IIIa angioplasty studies, bleeding and adverse events were linked to the combination of potent platelet inhibition and heparin. Compared with control, the composite of intermediate and major bleeding rates was more than doubled with high-dose lamifiban plus heparin (5.5% versus 12.1%; P=0.002). Grouping patients as receiving heparin, lamifiban, or both resulted in a composite rate of intermediate and major bleeding of 5.9%, 7.8%, and 10.5%, respectively (P=0.014).
Lack of Dose Response
Our data are consistent with those of the Canadian Lamifiban Study,13 a 365-patient dose-exploring study with parallel assignment to one of four doses of lamifiban or placebo for unstable angina or non–Q-wave infarction. In that study, the dose of lamifiban correlated well with the extent of inhibition of ex vivo platelet aggregation, although no clear dose-related correlation to clinical benefit was shown, in part due to the small sample size. The ADP-induced platelet aggregation was inhibited ≈60% by a 1-μg/min infusion, and this group of patients had the lowest 30-day ischemic event rate. The two high doses studied (4 and 5 μg/min) completely inhibited ADP-induced platelet aggregation and when combined provided a lower 30-day event rate than placebo or the combined lower doses of lamifiban (1 and 2 μg/min). In the present study, despite clearly higher plasma levels in the high-dose groups, this did not provide benefit but rather an overall neutral effect on ischemic outcome and a negative effect regarding bleeding. As displayed in Figure 3⇑, the incidence of death and infarction for the high-dose groups was consistently above that for the low-dose groups.
This observation contrasts with some previous large studies of this class of antithrombotic therapy by suggesting an upper limit of benefit or potential “toxicity.” Although the Canadian Lamifiban Study data did suggest higher doses of lamifiban were potentially superior, our findings differ, perhaps because of differences in study size, patient baseline characteristics, or study drug administration. Compared with that study, our patient population was substantially larger in number, older, and required to have electrocardiographic evidence of ischemia. Also in the current study, no downward adjustment in lamifiban infusion was made for low patient body weight. These differences may have resulted in even higher plasma levels than expected. Theoretical explanations for the apparent “toxicity” of high doses of lamifiban include intraplaque hemorrhage, paradoxical platelet activation, or an interplay between excessive bleeding and clinical outcomes.
Perhaps the most noteworthy feature of our findings is the significant reduction of late ischemic events in the low-dose lamifiban group, which was only marginally evident at 30 days. Compared with the control group, among whom the composite of death and nonfatal myocardial infarction increased 54% between 30 and 180 days, there was a 33% increase for all lamifiban-treated patients and only a 22% increase for those assigned to low-dose lamifiban with heparin. This benefit was observed in addition to the known ischemic event reduction provided by aspirin therapy. The term “passivation” has been used to describe the action of glycoprotein IIb/IIIa inhibitors in which the early and potent inhibition of platelet function renders the disrupted coronary arterial surface incapable of supporting platelet deposition. Heightened platelet activity associated with acute coronary syndromes is known to be associated with abrupt closure after angioplasty, coronary reocclusion after thrombolysis, and hyperplasia after vessel wall injury.22 23 24 Passivation may include limiting production of platelet-derived vasoconstrictors in the short term and growth factors in the long term. Importantly, by preventing platelet deposition and microaggregate formation, the arterial surface may heal more favorably, thus reducing the likelihood of (re)infarction.20 Several observational studies have shown that even small enzymatic infarctions during angioplasty are associated with a worse late survival,25 26 27 and IIb/IIIa inhibitors used during percutaneous revascularization have been shown to concomitantly reduce periprocedural creatine kinase and late mortality.20
Although this is the largest reported study to date with long-term follow-up testing the use of IIb/IIIa inhibitors in unstable angina and non–Q-wave myocardial infarction, the sample size of this study limits our ability to draw definitive conclusions. The current study was designed to identify an optimal treatment strategy of lamifiban and heparin to be further studied against standard therapy. We observed low-dose lamifiban alone to be superior to heparin alone at 6-month follow-up; however, we cannot be certain, given the current sample size, whether the addition of heparin to a low dose of lamifiban will offer further benefit.
Non–ST-segment elevation acute coronary syndromes continue to be associated with a high incidence of death and (re)infarction in the months after the index event. During this follow-up period, studies of thrombin inhibitors in these patients have shown only a modest benefit when added to aspirin.10 16 In contrast, our data suggest that potent platelet inhibition with glycoprotein IIb/IIIa antagonism can provide substantial and durable benefit. A more precise evaluation of the effect of low-dose lamifiban in conjunction with heparin will be assessed in a dedicated placebo-controlled trial.
Steering Committee: E. Topol (Study Chairman), United States; R. Califf (Director, Duke Clinical Research Institute), United States; F. Van de Werf (Director, Intermediate Coordinating Center), Belgium; R. Diaz, Argentina; E. Paolasso, Argentina; P. Aylward, Australia; J. Simes, Australia; J. Col, Belgium; L. Piegas, Brazil; P. Armstrong, Canada; A. Langer, Canada; P. Grande, Denmark; D. DeBono, England; J. Heikkilä, Finland; A. Vahanian, France; K. Neuhaus, Germany; W. Rutsch, Germany; P. Toutouzas, Greece; A. Kristinsson, Iceland; D. Tzivoni, Israel; D. Ardissino, Italy; H. White, New Zealand; R. Seabra-Gomes, Portugal; A. Betriu, Spain; A. Dalby, South Africa; H. Emanuelsson, Sweden; M. Pfisterer, Switzerland; F. Verheugt, The Netherlands; Z. Sadowski, Poland; E. Bates, United States; W. Gibler, United States; J. Gore, United States; C. Granger, United States; A. Guerci, United States; R. Harrington, United States; J. Hochman, United States; D. Holmes, United States; N. Kleiman, United States; D. Moliterno, United States; D. Morris, United States; E. Ohman, United States; W. Weaver, United States.
Coordinating Center: Duke Clinical Research Institute, Durham, NC. Clinicians: R. Califf, C. Granger, R. Harrington, K. Newby. Administrators: S. Karnash, M. Peek-Hackenson, J. Mabie, J. Melton, J. Snapp. Clinical Events Committee: D. Brown, N. Dabolt, C. Granger, C. Greene, M. McClanahan, G. Strand, B. Tardiff, M. Winchell. Coordinators and assistants: M. Peek-Hackenson, J. Bolte, R. Evans, M. Poku, S. Conder, K. Tinnin, W. Lloyd, G. Jackson. Statistics: K. Lee, M. Bhapkar, W. Sense.
Executive Center: Cleveland Clinic Cardiovascular Coordinating Center—E. Topol, D. Moliterno, D. Passmore, L. Konczos.
Canadian Coordinating Center: University of Alberta, Alberta, Canada—P. Armstrong, S. Caouette, S. Martin, W. Sutherland.
European Coordinating Center: University of Leuven, Leuven, Belgium—F. Van de Werf, A. Luyten, L. Tobback, K. Houbracken, R. Brower, L. D’Hoore.
Australian Coordinating Center: National Health and Medical Research Council Clinical Trials Center, University of Sydney, Sydney, Australia—J. Simes, A. Keech, M. Kava.
Data and Safety Monitoring Committee: R. Frye, Chairman; M. Cheitlin, D. DeMets, L. Fisher.
List of Institutions and Participants by Country (Number of Patients)
Australia (300): Woden Valley Hospital, Australian Capital Territory—Ian Jeffery, Pearl Taverner; Prince of Wales Hospital, New South Wales—Warren Walsh, Cheryl Friend; John Hunter Hospital, New South Wales—Jim Leitch, Karen Cox; Concord Repatriation General Hospital, New South Wales—Benjamin Freedman, Maureen Gaynor; St Vincent’s Hospital, New South Wales—Terry Campbell, Seval D’Arcy; Illawarra Regional Hospital, New South Wales—Dwain Owensby, Trish Davidson; St George & Community Health Service, New South Wales—David Ramsey, Trish Davidson; Bowral & District Hospital, New South Wales—William Quinn, Marose Verzosa; Canterbury Hospital, New South Wales—Ranji Wikramanayake, Geoffrey Manners; Coffs Harbour Hospital, New South Wales—Jon Waites, Pauline Cahill; Central Coast Regional Hospital, New South Wales—John Woods, Alison Kearney; The Nepean Hospital, New South Wales—Drew Fitzpatrick, Denise Schoevers; The Royal Melbourne Hospital, Victoria—David Hunt, Michele Sallaberger; Alfred Healthcare Group, Victoria—Jack Federman, Heather Briggs; The Geelong Hospital, Victoria—Alan Appelbe, Monica Miller; Western Hospital, Victoria—Robert Newman, Catherine Peeler; Box Hill Hospital, Victoria—Jeffrey Lefkovits, Louise Roberts; Dandenong Hospital, Victoria—John Counsell, Marianne Martin; Mildura Base Hospital, Victoria—Alan Soward, Jeff Breeding; Austin Hospital/Austin Campus, Victoria—Anew Tonkin, Louise Brown; Royal Brisbane Hospital, Queensland—David Cross, Loretta Fitzpatrick; Princess Alexana Hospital, Queensland—Paul Garrahy, Cindy Hall; Rockhampton Base Hospital, Queensland—Chelliah Gnanaharan, Catherine Armstrong; Redcliffe Hospital, Queensland—Pat Carroll, Maree Duroux; Cairns Base Hospital, Queensland—Chin Lim, Beverly Cooke; Nambour General Hospital, Queensland—Steve Coverdale, Lyn Joy; The Prince Charles Hospital, Queensland—JHN Bett, Donalee O’Brien; Gold Coast Hospital, Queensland—Gregory Aroney, Pam Hicks; Flinders Medical Center, South Australia—Philip Aylward, Leny Arnolder; Queen Elizabeth Hospital, South Australia—John Horowitz, Sue Lesley, Simon Stewart; Sir Charles Gairdner Hospital, Western Australia—Peter Thompson, Pam Bradshaw; Fremantle Hospital, Western Australia—Randall Henicks, Jan Garrett; Launceston General Hospital, Tasmania—Bhuwan Singh, Monica Decampo.
Poland (238): Medical Academy of Gdansk, Gdansk—G. Swiatecka; Institute of Cardiology, Krakow—W. Piwowarska; National Institute of Cardiology, Warsaw—Z. Sadowski; Silesian Medical Academy, Katowxice-Ochojel—P. Tadeusz; University School of Medicine Bydgoszcz—E. Nartowics; University Medical School, Warsaw—T. Kraska; Siaska Akademia Medyczna, Katowice—L. Giec; Emergency Medical Service, Warsaw—A. Dyduszynski; National Institute of Cardiology, Warszawa—J. Stepinska; Instytut Medycyny Morskiek, Gdynia—J. Gorski; Pomeranian Medical Academy, Szczecin—K.-J. Zdzislawa; Szpital Miejski, Gdynia—E. Czestochowska; Jagiellonian University College, Cracow—J. Kazimierz; University of Medical Sciences, Poznan—M. Wierzchowiecki; University School of Medical Science, Poznan—A. Cieslinski; Postgraduate Medical School, Warsaw—L. Ceremuzynski; Specjalistyczny Szpital Zespol, Wroclaw—K. Loboz-Grudzien; Medical University, Lodz—M. Krzeminska-Pakula; County Hospital, Wroclaw—W. Krzysztof; Silesian Medical Academy, Zabrze—J. Wodniecki.
France (213): Hopital Central, Nancy—Pr Aliot: Center Hospitalier Marechal Jo, Perpignan—Dr Bonot: Hopital Dupuytren, Limoges—Dr Cassat; Hopital de Lorient, Lorient—Dr Cazaux; C.H. Intercommunal—Dr Chestier; Hopital St. Antoine, Paris—Dr Cohen; Hopital Beaujon, Clichy—Dr Cohen Solal; Center Hospitalier Du Mans, Le Mans—Dr Fagart; Hopital Victor Dupouy, Argenteuil—Dr Fruchaud; Hopital Rene Dubos, Pontoise—F. Funck; Hopital Get R. Laennec, Nantes—Dr Godin; Hopital Arnaud de Villeneuve, Montpellier—G. Raoux; Hopital Notre Dame de Bon Secours, Metz—Dr Khalife; Hopital Civil, Strasbourg—Prof Mossard; Center Hospitalier Intercommunal, Montfermeil—Dr Nallet; Hopital Andre Mignot, Le Chesnay—Dr Normand; Center Hospitalier Schaffnes, Lens—Dr Pecheux; Hopital Gilles de Corbeil, Corbeil Essonnes—Dr Pezzano; Hopital Sud, Amiens—Dr Quiret; Hopital de Font Pre, Toulon—Dr Sans; Hopital Antoine Beclere, Clamart—Dr Michel Slama; Hopital de Feugrais, Elboeuf—Dr Toussaint; Center Hospitalier de Long Jum, Longjumeau—T. Thanh; Tenon Hospital, Paris—A. Vahanian; Center Hospitalier, Lagny—Dr Vedel; Center Hospitalier, Nevers—B. Vitoux.
Finland (184): Kuopio University Hospital, Kuopio—M. Halinen; Jorvi Hospital, Espoo—V. Naukkarinen; Pohjois-Karjala Central Hospital, Joensuu—J. Nurminen; Kymenlaakso Central Hospital, Kotka—Eero Koskela; Keski-Suomi Central Hospital, Jyväskyäl—J. Melin; Satakunta Central Hospital, Pori—H. Koskivirta; Vaasa Central Hospital, Vaasa—H. Kivelä; Kuusankoski District Hospital, Sairaalamäki—M. Rynen; Oulo University Central Hospital, Oulo—A.K. Niemi.
Belgium (171): O.L.V. Middelares, Deurne—Dr Gillebert; Kliniek St. Maria, Halle—Dr Croonenberghs; A.Z. St.-Elizabeth, Zottegem—B. Dirk; St. Norbertusziekenhuis, Duffel—Dr Van Walleghem; Ziekenhuis de Pelikaan, Temse—Dr Koentges; Kliniek Zusters Van Barmhartig, Ronse—Dr Vermeersch; Imeldaziekenhuis, Bonheiden—Dr Verstreken; Heilig Hart Ziekenhuis, Neerpelt—Dr Van Dorpe; A.Z. St. Elizabeth, Antwerpen—Dr Van Schuylenbergh; A.Z. Heilige Familie, Reet—Dr Caenepeel; A.Z. St. Jozef, Malle—Dr Claessens; Kliniek Andre Dumont, Genk—W. Van Mieghem; St. Jozefkliniek, Oostende—Dr Stroobandt; Ziekenhuis Oost Limburg, Genk—Dr Eerdekens; Hopital de Braine L Alleud, Braine L Alleud—Dr Lignian; St. Niklaaskliniek, Kortrijk—Dr Dejaegher; Hopital de Jolimont, Haine-St-Paul—Dr de Meester; St. Elizabethziekenhuis, Herentals—Dr de Scheper; Heilig Hartziekenhuis, Mol—Dr Elsschot; Algemeen Ziekenhuis St. Dimpna, Geel—Dr Schurmans; St. Elisabeth Ziekenhuis, Turnhout—Dr Thoeng; O.L.V.-Ziekenhuis, Oudenaarde—Dr Emmerechts; Stadskliniek, Sint-Niklaas—Dr Thiels; Kliniek St. Augustinus, Veurne—Dr Popeye; Universitaire Ziekenhuizen Leuven, Leuven—F. Van de Werf; Cliniques Saint-Luc, Brussels—J. Col; Sint-Janskliniek, Brussels—Dr Goethals.
Italy (152): S. Maria Delle Croci Hospital, Ravenna—F. Ottani; Galliera Hospital, Genova—C. Vecchio; Hospital Maggiore di Lodi, Maggiore di Lodi—M. Orlandi; Ospedale Civile, Piacenza—A. Capucci; S. Anna Hospital, Como—A. Politi; Hospital of Merate, Merate—F. Mauri; Ospedale Civile, Rho (Milano)—G. Rovelli; IRCCS Policlinico San Matteo, Pavia—C. Montemartini; Nicholas Green Hospital, Roma—S. Vajola; Ospedale Ca Granda Niguarda, Milano—A. Pezzano; Ospedale “Le Molinette,” Torino—A. Brusca; Ospedale Ca Granda Niguarda, Milano—C. de Vita; Ospedale Bellaria, Bologna—G. Pinelli; Policlinico S. Orsola, Bologna—A. Branzi; General Hospital, Treviso—S. Paolo; General Hospital, Brindisi—G. Ignone; Azienda Sopedaliera Careggi, Florence— G. Berni; M. Bufalini Hospital, Cesena—F. Tartagni; General Hospital, Novara—C. Cernigliaro; G.B. Morgagni Hospital, Forli—F. Rusticali; Caserta General Hospital, Caserta—G. Corsini; Ospedale “I Sacco,” Milano—A. Polese.
Canada (147): Sunnybrook Hospital, Toronto, Ontario—Christopher Morgan, Kaye Freskiw; Prince George Regional Hospital, Prince George, British Columbia—Don Macritchie, Rita Sweeney; University of Alberta Hospitals, Edmonton, Alberta—Wayne Tymchak, Cheryl Kee; Victoria Hospital, London, Ontario—Keith Finnie, Shirley McCreery; Campbell Hospital, Campbell River, British Columbia—John Heath, Mia Thompson; Northern Lights Hospital, Fort McMurray, Alberta—Michel Suave, Beth Szlachetka; Pasqua Hospital, Regina, Saskatchewan—Vernon Gebhardt, Jennifer Taylor; Lake of the Woods District Hospital, Kenora, Ontario—William Cameron, Claire Noseworthy; Ridge Meadows Hospital, Maple Ridge, British Columbia—Francis Ervin, Sue Leclair; Royal Alexandra Hospital, Edmonton, Alberta—William Hui, Linda Kvill; St. Michael’s Hospital, Toronto, Ontario—Anatoly Langer; Grace General Hospital, Winnipeg, Manitoba—J. McDowell, Ruth Ziemski; L’Hopital Maisonneuve Rosemont, Montreal, Quebec—Denis Gossard, Odette Magnon; Hopital du St-Sacrement, Montreal, Quebec—Guy Tremblay; Grey Nun’s Hospital, Edmonton, Alberta—Manohara Senaratne, Marlene Goeres; Camp Hill Medical Center, Halifax, Nova Scotia—Shauna Curley; Misericordia Hospital, Edmonton, Alberta—Paul Greenwood, Anne Prosser; Saskatoon City Hospital, Saskatoon City, Saskatchewan—J. Lopez, Patricia Kuny.
United States (134): Cardiovascular Associates, Birmingham, Ala—W. Harrison, L. Maske; Loma Linda University Medical Center Cardiology, Loma Linda, Calif—P. Ribeiro, V. Bishop; Alameda Hospital, Alameda, Calif—S. Raskin, J. Carr; Sharp Memorial Hospital, San Diego, Calif—M. Bushbinder, Diane Koester; UC Davis Medical Center, Sacramento, Calif—Gary Gershony, Beverly Atherton-Pierce; Cardio-Pulmonary Associates, Plantation, Fla—Owen Peller, Patricia Schofel; Tampa General Hospital, Tampa, Fla—James Smith, Cindi Sullivan; University Hospital, Augusta, Ga—A. Bleakley Chandler, Marcia Edwards; St. Joseph’s Hospital, Savannah, Ga—Philip Gainey, Sandra Arsenaul; Straub Cardiology, Honolulu, Hawaii—Roger White, Susan Van Ham; St. Therese Medical Center, Waukegan, Ill—Tien Cheng, Catherine Monroe; Community Hospital East, Indianapolis, Ind—Richard Hahn, David Quinn; River Cities Cardiology, Jeffersonville, Ind—Dolph Denny, Traci McCartney; Androscoggin Cardiology Associates, Auburn, Maine—Robert Weiss, Diane Thornton- Chandler; Duke University Medical Center, Durham, NC—Robert Harrington, Cathy Martz; Dartmouth-Hitchcock Medical Center, Lebanon, NH—Nathaniel Niles, Susan Kennedy; New Mexico Heart Institute, Albuquerque, NM—Jerome Goss, Susan Goebel; Albany Medical Center, Albany, NY—Robert Millar, Kay Zolezzi; Buffalo Heart Group, Buffalo, NY—Zaki Masud, Teresa Giambra; St. Francis Hospital, Roslyn, NY—Alan Guerci, Carolyn Christie-Gulotta; Bronx Lebanon Hospital, Bronx, NY—Narendra Bhalodkar, Amada Valeria; Cleveland Clinic Foundation, Cleveland, Ohio—David Moliterno, Nadine Juran; Cardiovascular Research, Cleveland, Ohio—Arvindkumar Shah, Cindy Edel; Harvey Center for Cardiovascular Research, Tulsa, Okla—Wayne Leimbach, Jolene Durham; Hershey Medical Center, Hershey, Pa—Mark Kozak, Helen Zimmerman; Westmoreland Regional Hospital, Greensburg, Pa—Peter DiBattiste, Deborah Poskus; Heart Center, Salt Lake City, Utah—Joe Perry, Wendy Schvaneveldt; Lynchburg General Hospital, Lynchburg, Va—Thomas Nygaard, Joyce White; Vermont Cardiac Investigations, Montpelier, Vt—Gregory MacDonald, Sharon Segel; Veteran’s Administration Medical Center, Seattle, Wash—Kenneth Lehmann, Mimi Platt; Waukesha Memorial Hospital, Waukesha, Wisc—Sanjay Singh, Jean Sesing; Ohio Valley Medical Center, Wheeling, WV—William Noble, Dawn Baltich Noble.
New Zealand (122): North Shore Hospital—H. Hart, H. Brannigan; Wairau Hospital—D. Durham, R. Currie; Memorial Hospital—R. Luke, D. Schmid; Napier Hospital—G. Lewis, M. Bent; Rotorua Hospital—B. Bruns, M. Liley, A. Morley; Tauranga Hospital—H. Patel, V. Watts; Wellington Hospital—P. Leslie, K. Saunders; Christchurch Hospital—H. Iikram, T. Lawson; Hutt Hospital—S. Mann, J. Dewar; Waikato Hospital—D. Friedlander, L. Low; Nelson Hospital—A. Hamer, J. Tomlinson; Timaru Hospital—D. Jardine, P. Carstensen; Dunedin Hospital—G. Wilkins, M. Blok; Ashburton Hospital—M. Audeau, A. Smart; Taranaki Base Hospital—G. Chia, S. Megee; Green Lane Hospital, Auckland—H. White, L. Bush.
The Netherlands (107): Hospital Canisius-Wilhelmina, Nijmegen—D. Hertzberger; Hospital de Honte, Terneuzen—R. Ciampricotti; Beatrix Hospital, Gorinchem—P. Van Rossum; Oosterschelde Hospital, Goes—Roeters Van Lennep; de Baronie Hospital, Breda—Strikwerda; Catharina Hospital, Eindhoven—H. Bonnier; University Hospital Nijmegen, Nijmegen—F. Verheugt; Sint Lucas Ziekenhuis, Amsterdam—B. Lutterman; Antonius Hospital, Sneek—A. Gomen; Scheper Hospital, Emmen—J. Engbers; Martini Hospital, Groningen—P. Bernink; St. Jans Gasthuis Weert, Weert—J. Chin; Ziekenhuis Gelderse Vallei, Bennekom—T. Van Loenhout; St. Anna Hospital, Geldrop; P. Polak; Diakonessenhuis, Eindhoven—L. Wely.
Argentina (103): Hospital Frances, Buenos Aires—Dr Nordaby; Hospital Leonidas Lucero, Bahia Blanca—Dr Marcos; Instituto de Cardiologia de Tucuha, S. Miguel de Tucuman—Dr Castellanos; Hospital Italiano, La Piata—O. Perrino; Sanatorio Rivadavia, San Miguel de Tucuma—E.G. Hasbani; Sanatoria Allenda, Cordoba—J.O. Bono; Hospital Luis C. Lagomaggiore, Mendoza—A.J. Gambarte; Hospital Italiano Garibaldi, Rosario—J.L. Ramos; Instituto Cardiovascular Rosario, Rosario—G. Zapata; Instituto de Cardiologia J.F Cabral, Corrientes—J. Garcia; Sanatorio Agote, Cap Federal—C. Pellegrini; Hospital Fernandez, Capital Federal—S. Simon; Sanatorio Delta, Rosario-Sta. Fe—Guillermo Covelli; Icycc-Fundacion Favaloro, Capital Federal—A. Barbagelata; Sanatorio Anchorena, Capital Federal—Dr Mele; Hospital de Clinicas “J. De San.”, Capital—E.A. Sampo.
Iceland (74): National University Hospital, Reykjavik—A. Kristinsson; Borgarspitalinn City Hospital, Reykjavik—G. Oddson; FSA-Hospital, Akureyri—J.T. Sverrisson.
Israel (68): Shaare Zedek Medical Center, Jerusalem—Prof Tzivoni; Bnei Zion Medical Center, Haifa—Dr Abinader; Nahariya Hospital, Nahariya—Prof Roguin; Barzilai Medical Center, Ashkelon—Dr Reisin; Kaplan Hospital, Rehovot—Prof Caspi; Rivka Ziv Hospital, Safed—Dr Marmor; Carmel Medical Center—S. Chen; Rabin Medical Center (Hasharon), Petach Tikka—Prof Zahavi; Beilinson Hospital, Petach-Tikra—Prof Sclarovski.
Denmark (65): Rigshospitalet, Kobenhavn—P. Grande; Gentofte Hospital, Hellerup—E. Kassis; Aarhus Amtssygehus, Aarhus—K. Thygesen; Hvidovre Hospital, Hvidovre—J.F. Hansen; Nesived Hospital, Naestvaed—H. Madsen; Oresund, Helsingor—E. Agner; R.A.S. Koge, Koge—S.L. Rasmussen; Svendborg Hospital, Svendborg—T. Pindborg; Frederiksberg Hospital, Frederiksberg—P. Hildebrandt; Horsholm Hospital, Horsholm—H.V. Nielsen.
Germany (62): Stadt Krankenhaus, Solingen—D. Kikis; Krankenhaus Post Am Rhein, Koln—V. Hossmann; Stadt Krankenhaus, Gutersloh—H. Ditter; Stadt Krankenhaus Heilbronn, Heilbronn—I. Cyron; Krankenhaus D. Landkreises, Peine—O.A. Beck; Klinikum Erfurt, Erfurt—I. Assmann; Krankenhaus Dresden-Friedrich, Dresden—K.E. Altmann; Ketteler Krankenhaus, Offenbach—H.-P. Nast; Krankenhaus Am Sud, Stralsund—G. Muller-Esch; Krankenhaus Moabit, Berlin—K.P. Schusen; Universitatsklinikum Charite, Berlin—W. Rutsch; Krankenhaus Altstadt Magdeburg, Magdeburg—W. Kettner; Universitatsklinikum, Nürnberg—Dr Bachmann; Klinikum Der Univers Giessen—H. Tillmanns; Allgemeines Krankenhaus, Viersen—F.-R. Althoff; Rheinische Friedrich-Wilhelms, Bonn—B. Luderitz; Klinikum Der Philipps-University, Marburg—B. Maisch; Drk-Krankenhaus Kopenick, Berlin—H.-F. Vohringer; Krankenhaus Zehlendorf, Berlin—C. Von Wissmann; Stadtisches Krankenhaus Am Urb, Berlin—Dr Dissmann; Fu Virchow-Klinikum, Berlin—D. Barckow; Kreiskrankenhaus, Lubben—F. Schwerffeger; Stadt Krankenhaus Neukolln, Berlin—J. Wagner; Saarbrucker Winterbergkliniken, Saarbrucken—K. Zwirner; Universitatsklinikum Karl Gust, Dresden—G.W. Daniel; Universitatsklinikum Ulm, Ulm—M. Kochs; Krankenhaus Merheim, Koln—R. Griebenow; Zentralklinikum, Augsburg—H.-D. Bolte.
South Africa (46): St. Augustine S Hospital, Durban—R.E. Matisonn; Wentworth Hospital, Durban—Prof A.S. Milha; Baragwanath Hospital, Johannesburg—A.R. Essop; Glynwood Hospital, Benoni—R.M. Jardine; J.G. Strijdom Hospital, Johannesburg—M.K. Gebka; Millpark Hospital, Johannesburg—G.A. Cassel; H.F. Verwoerd Hospital, Johannesburg—Prof D.P. Myburgh; Pretoria Heart Hospital, Pretoria—F. Snyders; Unitas Hospital, Pretoria—J.M. Bennett; Greenacres Hospital, Port Elizabeth—S. Spilkin; Panorama Clinic, Parow, Cape Town—T. Mabin.
Portugal (42): Hospital de Santa Cruz, Carnaxide—R. Seabra-Gomes; Hospital Distrital do Barreiro, Barreiro—V.C. D’Almeida; Hospital Santo Espirito de Ang, Acores—J. Coelho Gil; Hospital Distrital de Aveiro, Aveiro—N. Pinheiro; Hospitas San Francisco Xavier, Lisboa—L. Santos; Hospitais da Universidade, Coimbra Codex—L. Providencia; Hospital da Senmora Oliveira, Guimaraes—J. Almeida; Hospital Pulido Valente, Lisboa—A. Ramos; Hospital de S. Joao, Porto—J.C. dos Santos; Hospital de S. Bernardo, Setubal—L. Ines; Hospital Distrital de Santarem, Santarem—G.F. Da Silva; Hospital de Sta Marta, Lisbon—R. Ferreira; Hospital Distrital de Faro, Faro—J.G. Leiria; Hospital Garcia de Orta, Almada—M. Carrageta; Centro Hospitalar de Coimbra, Coimbra—A. Gonsalves; Hospital Sta Maria, Lisbon—C. Ribeiro.
Sweden (37): Sahlgrenska Sjukhuset, Goteborg—H. Emanuelsson; Molndalssjukhus, Molndal—M. Risenfors; Norra Alvsborgs Lanssjukhus, Trollhattan—L. Sandstedt; Centralsjukhuset, Karlstad—C. Abjorn; Regionsjukhuset, Orebro—K. Christensen.
United Kingdom (16): Oldchurch Hospital, Romford Essex—J. Stephens; Victoria Infirmary, Glasgow—R. Northcote; Derbyshire Royal Infirmary, Derby—M. Millar-Craig; Derby City Hospital, Derby—A. Mc Cance; Daunton and Somerset Hospital, Taunton Somerset—D. Maciver; Halton General Hospital, Runcorn, Cheshire—E. Rosen.
Brazil (1): Instituto Danta Pazzanese, Sao Paulo—R. Rui Fernando; Instituto Molestias Cardiovasculares, Sao I. Rio Preto-Sp—J. Nicolau; Hospital Sao Paulo, Cep Sao Paulo—D. Carvalho.
This study was supported by Hoffman La-Roche (Basel, Switzerland).
↵1 The investigators and sites participating in the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON) trial are listed in the Appendix.
- Received November 17, 1997.
- Revision received February 3, 1998.
- Accepted February 9, 1998.
- Copyright © 1998 by American Heart Association
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