Author + information
- Received July 15, 2002
- Revision received October 25, 2002
- Accepted November 11, 2002
- Published online April 16, 2003.
- ↵*Reprint requests and correspondence:
Dr. Robert P. Giugliano, TIMI Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston, Massachusetts 02115, USA.
- Matthew T. Roe, MD, MHS, FACC‡,
- Lynn H. Woodlief, MS‡,
- Robert A. Harrington, MD, FACC‡,
- Karen L. Hannan, BA‡ and
- Robert M. Califf, MD, FACC‡
- C.Michael Gibson, MS, MD, FACC*
- Uwe Zeymer, MD§
- Frans Van de Werf, MD, PhD∥
- Kenneth W. Baran, MD, FACC¶
- Hans-Peter Hobbach, MD#
- John Strony, MD, FACC††
- Carolyn H. McCabe, BS and
- Eugene Braunwald, MD, FACC
Objectives The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI).
Background Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established.
Methods Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 μg/kg bolus, 2 μg/kg/min infusion, and 180 μg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min.
Results In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively.
Conclusions Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.
Goals of pharmacologic reperfusion regimens in ST-elevation myocardial infarction (STEMI) include reestab-lishing rapid antegrade flow in the infarct artery, restoration of myocardial tissue level reperfusion, and maintenance of epicardial arterial patency (1). Several previous phase II angiographic studies (2–5), and most recently two larger clinical trials (6,7)have studied combinations of intravenous platelet glycoprotein IIb/IIIa inhibitor and reduced-dose fibrinolytic with the hope that the addition of a potent platelet inhibitor might overcome the failure of reperfusion that can occur with fibrinolytic monotherapy (8). Challenges to this approach to date include complex administration regimens, unclear relationship between surrogate markers of efficacy and clinical benefit, and increased risks of hemorrhage, thrombocytopenia, and transfusions.
Two previous studies of eptifibatide in combination with alteplase (5,9)demonstrated improvements in Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow compared with alteplase monotherapy. However, the doses of eptifibatide studied and the use of alteplase in these two trials may not represent the optimal combination of eptifibatide and fibrinolytic (10–12). Furthermore, alteplase is more cumbersome to administer and is associated with more non-cerebral bleeding than single-bolus tenecteplase (TNK) (13). The Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial sought to evaluate dosing combinations of double-bolus eptifibatide with reduced-dose TNK in patients with acute STEMI.
In this phase II angiographic open-label study, patients were enrolled at 67 hospitals in seven countries between May 2000 and August 2001. The trial was supported by central units and core laboratories as described in the Appendix.
1.1 Eligibility criteria
The inclusion criteria were ischemic discomfort for at least 30 min with onset ≤6 h, along with electrocardiographic criteria of STEMI (14)in patients age 18 to 75 years. All patients signed written informed consent approved by the local institutional review board/ethics committee.
Key exclusion criteria (14)were as follows: uninterpretable ST-segments, active bleeding or increased risk of bleeding; previous coronary artery bypass graft surgery (CABG); cardiogenic shock or pulmonary edema requiring intubation; blood pressure ≥180 mm Hg systolic or ≥110 mm Hg diastolic; known hypersensitivity to any study regimen component; creatinine ≥4.0 mg/dl; other serious illness; and inability to comply with the protocol.
Patients were randomized using a central, computerized, telephone randomization system (CTS Durham, Durham, North Carolina). Randomization was stratified by infarct location (anterior vs. non-anterior), and treatments were open-label. In dose-finding, all patients received the combination of eptifibatide and reduced-dose TNK, whereas in dose-confirmation patients were randomized 1:1 to either combination therapy or TNK monotherapy (Fig. 1).
1.3 Treatment regimens
All patients received aspirin (162 to 325 mg oral or 150 to 500 mg intravenous) followed by daily oral aspirin. The unfractionated heparin bolus dose was 60 U/kg (maximum 4,000 U) in all patients (15). Patients assigned to combination therapy with eptifibatide and TNK received a reduced heparin infusion of 7 U/kg/h (maximum 800 U/h), whereas patients assigned to TNK monotherapy received the heparin infusion of 12 U/kg/h (maximum 800 U/h) (15). A nomogram was used to target the activated partial thromboplastin time (aPTT) to 1.5 to 2.5 times control.
1.3.1 Eptifibatide and TNK
Patients in dose-finding all received double-bolus and an infusion of eptifibatide plus reduced-dose TNK. Because this was the first trial investigating this combination of therapies, the dose-finding phase explored varying doses of both eptifibatide and reduced-dose TNK in two sequential parts (Fig. 1A). In Part 1 of dose-finding, all patients received eptifibatide 180 μg/kg bolus, 2 μg/kg/min infusion, followed by a 90 μg/kg bolus 10 min later (180/2/90), and were randomized to either half-dose TNK (0.27 mg/kg) or three-quarter-dose TNK (0.40 mg/kg). In Part 2 of dose-finding, all patients received half-dose TNK and were randomized to one of two doses of eptifibatide, 180/2/90 or 180/2/180 (Fig. 1B). The first bolus doses of eptifibatide and TNK were administered simultaneously, followed by initiation of the eptifibatide infusion. The second bolus of eptifibatide was administered 10 min after the first. The eptifibatide infusion was reduced to 1 μg/kg/min in patients with renal dysfunction (creatinine 2 to 4 mg/dl; n = 5), and could be reduced by 33% at the investigator’s discretion in the case of mild bleeding (n = 18). The infusion continued for 18 to 24 h after coronary intervention or 40 to 48 h in patients not undergoing early percutaneous coronary intervention (PCI).
The combination of half-dose TNK (0.27 mg/kg) with eptifibatide (180/2/180) was selected for direct comparison with standard-dose (0.53 mg/kg) TNK monotherapy in the dose-confirmation phase, after review of the totality of the efficacy and safety data from the dose-finding phase (see the Results section). Patients in the TNK monotherapy group could receive adjunctive eptifibatide at the time of PCI at the physician’s discretion (but not before 60 min), although a single bolus (180/2) regimen was recommended in the first 24 h, owing to the limited safety experience available with full-dose TNK plus glycoprotein IIb/IIIa inhibitor.
1.3.2 Angiographic procedures
All patients underwent coronary angiography 60 min (window 55 to 75 min) after administration of the TNK bolus, which was considered “Time 0.” Standardized views and techniques of injection as developed by the Angiographic Core Laboratory were used by the investigators. No additional heparin was administered during diagnostic catheterization. Percutaneous coronary intervention was permitted at the investigator’s discretion after the 60-min angiogram. If PCI was performed, additional weight-adjusted heparin boluses were administered to achieve a target activated clotting time of 200 s in patients receiving combination therapy and 250 s for TNK monotherapy. Heparin use after the initial procedure was not recommended but left to the discretion of the physician, and the infusion was adjusted according to the aPTT.
1.3.3 Clinical procedures
Standard 12-lead electrocardiograms were obtained at presentation, before PCI at 60 min (55 to 75 min), at 180 min (160 to 200 min), and at discharge. Creatine kinase and creatine kinase-MB isoenzyme were obtained serially in the first 24 h, with recurrent ischemia or after routine intervention, and daily for 5 days. Complete blood and platelet counts were obtained at baseline and at least once during the first 6 to 24 h. Patients were assessed for clinical events through 30 days.
1.4 Study end points
The primary efficacy end point was the rate of TIMI grade 3 flow in the infarct-related artery at 60 min as determined by the Angiographic Core Laboratory, which was blinded to treatment assignment. All angiograms were reviewed by a single reader (C.M.G.) using previously established procedures to determine the TIMI flow grade (16), corrected Thrombolysis In Myocardial Infarction frame count (cTFC) (17), and Thrombolysis In Myocardial Infarction myocardial perfusion grade (TMPG) (18). The angiographically evaluable population consisted of patients who: 1) received some quantity of study drugs (patients randomized to combination therapy also were required to receive the first boluses of eptifibatide and TNK ≤15 min apart), and 2) had an angiogram that was within the time window (55 to 75 min post-TNK), before PCI, and of sufficient quality to permit evaluation of TIMI epicardial flow. Prespecified secondary angiographic end points included the distribution of flow grades, cTFC, and TMPG at 60 and 90 min. The degree (continuous value) of and occurrence of complete (i.e., ≥70%) ST-segment resolution on the 12-lead electrocardiogram at 60 and 180 min compared with baseline were also prespecified secondary efficacy end points. The electrocardiograms were read by the Electrocardiographic Core Laboratory, blinded to treatment assignment, using previously established techniques (19).
Clinical efficacy end points using standardized definitions (2)were analyzed for patients who received any study drug. These included death, reinfarction, and urgent target vessel revascularization (not including PCI performed immediately after the 60-min angiogram) through 48 h and 30 days, and severe pump failure through 30 days.
The primary safety end point was the rate of TIMI major hemorrhage (2)(intracranial hemorrhage [ICH] or clinically evident bleeding associated with a drop in hemoglobin ≥5 g/dl accounting for transfusion), as determined by an independent reviewer blinded to treatment assignment. Other prespecified safety end points included the rates of stroke, transfusions, and thrombocytopenia.
1.5 Statistical considerations
In dose-finding, a 40% rate of TIMI grade 3 flow at 60 min with combination therapy was selected as the lower boundary of interest given the previous experience with alteplase and bolus fibrinolytics. A sample size of 44 angiographically evaluable patients per cohort in dose-finding provided 80% power for a one-sided test of 40% versus 60% of patients with TIMI grade 3 epicardial flow at the α = 0.05 significance level.
In dose-confirmation, a sample size of 110 patients per arm provided 81% power with a two-sided test at the 0.05 significance level to detect a 20% absolute difference in the proportion of patients attaining TIMI grade 3 flow, assuming rates of 60% and 40% in the combination and monotherapy groups, respectively.
Statistical comparisons were made by chi-square analysis (Cochran Mantel-Haenszel test stratified by infarct location) for categorical variables, and a two-way analysis of variance model fit to ranked data with infarct location, treatment, and interaction effects for continuous variables, in patient cohorts according to treatment received. Comparisons between treatment groups were considered exploratory in nature and were made without adjustment for multiple comparisons. All tests were performed at the 0.05 significance level. We considered a p value of 0.05 to 0.10 a “trend,” and a p value of 0.10 to 0.20 a “weak trend.”
A total of 438 patients were randomized, 189 in the dose-finding phase and 249 in dose-confirmation. Twenty patients did not receive any study drug, and one patient in dose-finding did not receive eptifibatide; thus, 417 patients were evaluated for clinical efficacy and safety events. An additional 47 patients (angiogram outside the window: n = 33 [7.5%]; no angiogram: n = 11 [2.5%]; other: n = 3 [0.7%]) were excluded from the angiographically evaluable cohort (n = 370). Excluded patients were equally distributed between the treatment groups. Baseline characteristics are shown in Table 1. The mean duration of eptifibatide infusion was 28.5 ± 16.3 h, and the infusion was terminated early because of bleeding in 8.7% of patients. Adjunctive eptifibatide was administered in 42.9% of patients in the TNK monotherapy arm undergoing PCI after ascertainment of the primary end point.
2.1 Angiographic results
In the angiographically evaluable cohort, angiography was performed at a median of 61 min (interquartile range 58 to 63 min). The rates of TIMI grade 3 flow at 60 min in the three combinations of eptifibatide and reduced-dose TNK studied in dose-finding are shown in Figure 2A. There was no difference in the rates of TIMI grade 3 flow (64% vs. 68%, p = 0.69) or arterial patency (TIMI grade 2 or 3 flow: 77% vs. 79%, p = 0.86) in dose-finding Part 1 comparing half-dose TNK with three-quarter-dose TNK in combination with eptifibatide 180/2/90. Likewise, in Part 2 of dose-finding, no difference in TIMI grade 3 flow rates was observed when eptifibatide 180/2/90 was compared with 180/2/180 in combination with half-dose TNK (65% vs. 67%, p = 0.95). However, arterial patency was higher in the eptifibatide 180/2/180 group (84% vs. 96%, p = 0.02). There were no differences in the median cTFC or TMPG between the groups (Table 2).
In the dose-confirmation phase, there was a slightly higher rate of TIMI grade 3 flow at 60 min in patients receiving combination therapy compared with TNK monotherapy (59% vs. 49%, p = 0.15) (Fig. 2B), whereas there was no difference in the median cTFC (35.9 vs. 40.0 frames, p = 0.54). In an analysis of all the available data with half-dose TNK plus eptifibatide (180/2/180), the median frame count was faster by 6 frames on average compared with TNK monotherapy (Fig. 3). There was a weak trend towards improved arterial patency rates at 60 min (85% vs. 77%, p = 0.17), whereas the rates of TMPG grade 3 were similar (49% vs. 45%, p = 0.59).
2.2 12-lead electrocardiographic ST-segment resolution
In the dose-finding phase, there were similar rates of ST-segment resolution at 60 min (Table 2). All four groups experienced high rates of ST-segment resolution by 180 min as assessed by the median degree of ST-segment resolution (range 88% to 99%) and rate of complete (≥70%) resolution (range 83% to 100%).
Combination therapy with eptifibatide 180/2/180 and half-dose TNK exhibited a trend towards better ST-segment resolution at 60 min than TNK monotherapy (median degree of ST-segment resolution 71% vs. 61%, p = 0.08; rate of complete ST-segment resolution 51% vs. 40%, p = 0.31). At 180 min, excluding those who had preceding PCI, ST-segment resolution tended to favor combination therapy (median 89% vs. 83%, p = 0.28; complete ST-segment resolution 79% vs. 58%, p = 0.21), although the differences were not statistically significant.
2.3 Composite assessment of epicardial and myocardial reperfusion
In an exploratory analysis, combination therapy achieved nearly twice the rate of optimal reperfusion (23% vs. 13%) among patients in whom all three outcomes were assessed (Fig. 4). In the 43 patients (any treatment regimen) with all three indicators of reperfusion success at 60 min, 30-day mortality was 0% and the rate of death, reinfarction, or urgent target vessel revascularization was 2%.
2.4 Clinical efficacy
The overall rates of 30-day mortality (5.0%) and reinfarction (2.4%) were low, thus the power to detect differences was limited in this modestly sized phase II study (Table 3). In dose-confirmation, the double end point of death or reinfarction, and the triple composite of death, reinfarction, or urgent target vessel revascularization tended to be lower with combination therapy at 48 h (double end point: 1.7% vs. 4.2%, p = 0.25; triple end point: 3.4% vs. 11.0%, p = 0.02), but these differences were not present at 30 days. Combination therapy tended to shorten the time to elimination of chest pain after initiation of treatment by 36 min (p = 0.11).
The overall rate of TIMI major hemorrhage in the trial was 5.3% (occurring mostly [13/22] at the femoral access site), with a weak trend towards more bleeding with combination therapy than monotherapy in dose-confirmation (7.6% vs. 2.5%, p = 0.14) (Table 3). The only two ICHs in dose-confirmation occurred in the TNK monotherapy arm. Of the three major hemorrhages among the 118 patients receiving TNK monotherapy, two occurred early (within 2 h of randomization) among the 51 patients who received adjunctive eptifibatide during PCI.
The rate of ICH among all 299 patients in the study receiving any combination therapy was 1.0% (95% confidence interval: 0.2% to 2.9%), whereas ICH occurred in 0.57% (95% CI: 0.01% to 3.1%) of the 176 patients who received eptifibatide 180/2/180 and half-dose TNK, and in 1.7% (95% CI: 0.2% to 6.0%) of the 118 patients receiving TNK monotherapy.
In dose-confirmation, combination therapy was associated with a higher rate of red cell transfusions (13.4% vs. 4.2%, p = 0.02) and non-CABG related transfusions (10.8% vs. 2.8%, p = 0.03), consistent with the observed increase rate of major non-cerebral bleeding.
This phase II study explored a new combination of platelet glycoprotein IIb/IIIa inhibitor and reduced-dose fibrinolytic, and demonstrated modest improvements in surrogate markers of epicardial and myocardial reperfusion, similar to those noted in previous studies with combinations of abciximab and either alteplase (2)or reteplase (3,4). Specifically, in our study, the addition of double-bolus eptifibatide to half-dose TNK tended to improve absolute rates of TIMI grade 3 epicardial flow (+10%), TMPG grade 3 flow (+4%), and median ST-segment resolution (+10%) at 60 min compared with TNK monotherapy. These findings support the hypothesis that potent platelet inhibition enhances thrombolysis and permits reduced doses of fibrinolytic drug to achieve at least similar angiographic and electrocardiographic markers of efficacy compared with standard fibrinolytic monotherapy. The INTEGRITI study demonstrated that eptifibatide in combination with half-dose TNK was associated with trends towards improved epicardial and microcirculatory flow, thus extending the previously reported improvement in angiographic results with eptifibatide in combination with full-dose alteplase (9), streptokinase (20), and half-dose alteplase (5).
Two recent large randomized trials (6,7)did not demonstrate a reduction in mortality with the combination of half-dose fibrinolytic and abciximab compared with fibrinolytic monotherapy. The reasons for the lack of mortality reduction with combination therapy despite improvements in several surrogate markers remain unclear. One potential explanation is that the incremental benefit on TIMI grade 3 flow observed with combination therapy is insufficient (pooled average 6.6% across all dose-confirmation phases of phase II trials), and that clinically meaningful mortality reduction (e.g., 1% absolute) would require on the order of a 20% absolute increase in the rate of TIMI grade 3 flow (21). Also, causes of death after acute myocardial infarction (MI) are varied (e.g., shock, ICH, cardiac rupture, ventricular arrhythmias, postoperative complications), and some of these may not be favorably and/or significantly affected by more potent pharmacologic reperfusion regimens. In addition, the increasing availability of primary PCI has resulted in the enrollment of lower risk patients (e.g., fewer with anterior MI) in recent trials of combination pharmacologic therapy.
Nonetheless, reductions in ischemic complications of acute MI are a desirable goal and could improve long-term survival. The high-dose double-bolus plus infusion regimen of eptifibatide used in this trial provides the additional potential advantage that high-degree platelet inhibition is not only achieved early, but also sustained for the duration of the 18- to 48-h infusion (10); the latter is in contrast to the standard abciximab bolus plus 12-h infusion regimen which achieved <50% inhibition at 24 h (22). Such persistent high-grade platelet inhibition may be particularly relevant in patients who undergo delayed (i.e., after 12 to 24 h) PCI, and may translate into even greater prevention of periprocedural and spontaneous recurrent ischemia/infarction.
Increased rates of non-cerebral bleeding remain a challenge to combination reperfusion regimens. Of note, the 2.5% rate (95% confidence interval: 0.5% to 7.2%) of major hemorrhage with tenecteplase monotherapy in our study was unexpectedly low—less than the rates (4% to 9%) observed in other recent phase II angiographic studies with alteplase (2,23)and reteplase (3,4)monotherapy—but similar to the rate (2.4%) observed with TNK and lower-dose unfractionated heparin in a contemporaneous study (24). Hence, further work is needed on several fronts to reduce the risk of bleeding with combination therapy to improve the risk-benefit relationship. These efforts include: identification of patients at higher risk of bleeding complications; studying the utility of gastrointestinal prophylaxis in an attempt to mitigate the increased rates observed in the larger trials (6,7); exploring downward adjustment of concomitant antithrombotic therapy (e.g., 30 U/kg heparin bolus, maximum 2,000 U) (2); and considering dose reduction of the fibrinolytic, glycoprotein IIb/IIIa inhibitor, and antithrombin in patients at high risk for bleeding and especially ICH (e.g., age >75 years, low body weight, female gender). Use of low-molecular-weight heparin in combination with fibrinolytic and glycoprotein IIb/IIIa inhibitor, such as recently studied in the Enoxaparin Antithrombin Therapy for ST-Elevation (ENTIRE)-TIMI 23 trial (24), also should be investigated.
3.2 Study limitations
The optimal surrogate markers of reperfusion and their relationship to clinical outcomes in the modern era, which includes more frequent early revascularization, remain to be established. This modest-sized phase II study investigated patients at lower risk (age ≤75 years, hemodynamically stable, lower rate of anterior MI) compared with patients enrolled in fibrinolytic megatrials and large registries, resulting in low rates of clinical events. We did not adjust for multiple group comparisons, which increases the likelihood that some of the observed differences may be due to the play of chance. Lastly, 11% of patients receiving therapy had angiograms that were considered unevaluable for the primary analysis; however, inclusion of the data from all patients with angiography did not result in a meaningful change in the results.
3.3 Future directions
The data from the INTEGRITI study suggest that eptifibatide and half-dose TNK is a potentially useful combination for acute MI, and additional studies are planned. Although a total of more than 20,000 patients have been studied in the two large trials performed to date, several important issues need to be addressed before combination therapy can be recommended for widespread implementation. The efficacy and safety of various combinations of glycoprotein IIb/IIIa inhibitor, fibrinolytic, and antithrombin should not be assumed equal to one another based on presumed similar class effects—instead, each unique combination requires careful assessment. Patients at high risk for bleeding deserve particular attention, and evaluation of reduced doses of one or more of the elements of the combination regimen versus using other strategies to achieve reperfusion (e.g., primary PCI) in these patients should be undertaken. Given the proven benefit of high-grade platelet inhibition with glycoprotein IIb/IIIa inhibitors in the setting of PCI, and a recent analysis demonstrating significantly reduced mortality in patients with TIMI grade 3 flow before mechanical reperfusion (25), the role of combination therapy followed by PCI, compared with existing standards of practice (primary PCI, fibrinolytic monotherapy) also deserves further investigation. Because only 23% of patients in our trial had TIMI grade 3 flow plus TMPG grade 3 plus complete ST-segment resolution despite an extremely vigorous antiplatelet regimen, better methods of reperfusion, whether pharmacologic or mechanical or some combination of both, will need to be developed.
This randomized, controlled, open-label, phase II angiographic trial demonstrated that double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.
TIMI Study Group, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA: Principal investigator: Eugene Braunwald; Co-investigator: Robert P. Giugliano; Project directors: Carolyn H. McCabe, Kristin Schuhwerk.
Duke Clinical Research Institute, Duke University Medical School and Medical Center, Durham, NC: Principal investigator: Robert M. Califf; Co-investigators: Robert A. Harrington, Matthew T. Roe; Project director: Karen L. Hannan; Statistician: Lynn H. Woodlief.
Klinikum Kassel, Kassel, Germany: European co-investigator: Uwe Zeymer.
University Hospital Gasthuisberg, Leuven, Belgium: European co-investigator: Frans Van de Werf.
TIMI Angiographic Core Laboratory, Harvard Clinical Research Institute, Boston, MA: Principal investigator: C. Michael Gibson; Director: Susan J. Marble; Quantitative angiography technician: Nicole Kraimer; Data manager: Sabina Murphy.
Electrocardiographic Core Laboratory, TIMI Study Group, Boston, MA: 12-lead ECG ST-segment resolution. Director: David A. Morrow. Co-directors: Marc S. Sabatine, Howard A. Cooper, Graham C. Wong. Administrative assistant: Betsy Walsh.
Ischemia Monitoring Core Laboratory, Duke Clinical Research Institute, Durham, NC: Continuous 12-lead ECG ST-segment analysis. Director: Mitchell W. Krucoff. Co-Director: Cynthia L. Green. Project leader: Kathleen Trollinger.
Cardiac Marker Core Laboratory, TIMI Study Group, Boston, MA: Director: David A. Morrow. Lab director: Nadar Rifai.
Receptor Occupancy Core Laboratory, University of Tennessee-Memphis, Memphis, TN: Director: Lisa K. Jennings. Project manager: Mary V. Jacoski. Lead technologists: Shila Cholera, Rajini Krishnan.
Pharmacokinetics Core Laboratory, Phoenix International Laboratory Services, Montreal, Canada: Francis Montreuil.
Sponsors: Millennium Pharmaceuticals Inc., South San Francisco, CA: Michael M. Kitt, Sally Greenberg, Joanne Miller, Norma Lynn Fox, Nivedita Bhatt. Schering Plough Research Institute, Kenilworth, NJ: John Strony, Margaret Wernsing, Linda Sobieski, Angelina Brown.
Drug Distribution Center-North America: CTS Durham, Durham, NC: Ann Seidel, Shannon Macquarrie.
Operations Committee: Eugene Braunwald, Robert M. Califf, Norma Lynn Fox, Robert P. Giugliano, Sally Greenberg, Karen L. Hannan, Robert A. Harrington, Michael M. Kitt, Carolyn H. McCabe, Joanne Miller, Matthew T. Roe, John Strony, Frans Van de Werf, Lynn H. Woodlief, Uwe Zeymer.
Steering Committee: The members of the Steering Committee included the members of the Operations Committee and the individual principal investigators from the INTEGRITI clinical centers and the Angiographic Core Laboratory.
Clinical centers in order of number of patients enrolled (principal investigator is first individual listed)
U.S. (217 patients)
St. Paul Heart Clinic, St. Paul, MN: Principal investigator, Kenneth W. Baran; Research coordinators, Barb Bruhn-Ding, Patti Filkins, Beth Jorgenson, Cheryl Iaccarella. Baystate Medical Center, Springfield, MA: Principal investigator, Marc J. Schweiger; Research coordinator, Deborah Warwick. Lutheran Medical Center, Wheat Ridge, CO: Principal investigator, Jerry Miklin; Research coordinator, Linda McFadden. Montefiore Medical Center, Bronx, NY: Principal investigators, Mark Greenberg, Hiltrud Mueller; Research coordinator, Annemarie Logan. Robert Wood Johnson Medical School, New Brunswick, NJ: Principal investigator, Sebastian T. Palmeri; Research coordinator, Laurie Casazza. Thunderbird Samaritan Medical Center, Glendale, AZ: Principal investigator, Marvin Padnick; Research coordinator, Sue Spooner. Northridge Hospital Medical Center, Altadena, CA: Principal investigator, Ivan Rokos; Research coordinator, Kanchana Karunarantne. St. Joseph’s Hospital and Medical Center, Patterson, NJ: Principal investigator, Bruce Haik; Research coordinator, Karen Cusick. Alta Bates Medical Center, Berkeley, CA: Principal investigator, Robert M. Greene; Research coordinators, Eileen Healy, Vickie Nolan, Ben Bonnis. Ocala Regional Medical Center, Ocala, FL: Principal investigator, Rakesh Prashad; Research coordinator, Catherine McDonough. Sparks Regional Medical Center, Fort Smith, AR: Principal investigator, Ernesto Rivera; Research coordinator, Cheryl Hyde. University Hospital, Augusta, GA: Principal investigator, G. Leslie Walters; Research coordinator, Marcia Edwards. Maine Medical Center, Portland, ME: Principal investigator, Costas T. Lambrew; Research coordinator, Susan Bosworth-Farrell. Mission Hospital Regional Medical Center, Mission Viejo, CA: Principal investigator, Greg Thomas; Research coordinator, Megan Whalen. University of California Davis Medical Center, Sacramento, CA: Principal investigator, Richard Valente; Research coordinator, Beverly Atherton-Pierce. Brotman Medical Center, Culver City, CA: Principal investigator, Ronald P. Karlsberg; Research coordinators, Teri Harbour, Tracey Gerez. Metro Health Medical Center, Cleveland, OH: Principal investigator, Thomas Vrobel; Research coordinator, Linda Verrilli. Peninsula Regional Medical Center, Salisbury, MD: Principal investigator, Steven Hearne; Research coordinator, Virginia Seefried. Riverside Community Hospital, Riverside, CA: Principal investigator, Chiayu Chen; Research coordinator, Valerie Whyte. University Hospital, Augusta, GA: Principal investigator, A. Bleakley Chandler; Research coordinator, Paula Easler. Birmingham Heart Clinic, Birmingham, AL: Principal investigator, Robert Foster; Research coordinator, April Snow. High Point Regional Health System, High Point, NC: Principal investigator, Steven Rohrbeck; Research coordinator, Tami Hedrick. San Jose Medical Center, San Jose, CA: Principal investigator, K. Kam Tabari; Research coordinator, Melinda Savella. Cardiology Consultants of Napa Valley, Napa Valley, CA: Principal investigator, Andrew Wong; Research coordinator, Wendy Neustrup. Eastern Maine Medical Center, Bangor, ME: Principal investigator, Peter VerLee; Research coordinator, Cindy Whited. Gaston Memorial Hospital, Gastonia, NC: Principal investigator, Marc Silver; Research coordinator, Nancy Ratchford. North Ridge Medical Center, Fort Lauderdale, FL: Principal investigator, John Braden; Research coordinator, Mary Lou Kompa. St. Elizabeth’s Hospital, Belleville, IL: Principal investigator, Richard Hui; Research coordinator, Donna Mann. University of California at San Francisco, San Francisco, CA: Principal investigator, Thomas Ports; Research coordinator, James Madden. Central Arkansas Veterans Healthcare System, Little Rock, AR: Principal investigator, Jorge Saucedo; Research coordinator, Harisha Patel. Huntington Memorial Hospital, Pasadena, CA: Principal investigator, Allan Edmiston; Research coordinator, Donna Ujiiye. Integris Baptist Hospital, Oklahoma City, OK: Principal investigator, Jerome Anderson; Research coordinator, Ingrid Block. Overland Park Regional Medical Center, Overland Park, KS: Principal investigator, Steven Bloom; Research coordinator, Robbie Sullivan. Santa Rosa Memorial Hospital, Santa Rosa, CA: Principal investigator, Thomas Dunlap; Research coordinator, Andrea Nofi. St. Elizabeth’s Medical Center, Boston, MA: Principal investigator, Douglas W. Losordo; Research coordinator, Laura Kenney. University Hospital of Arkansas, Little Rock, AR: Principal investigator, Jorge Saucedo; Research coordinator, Harisha Patel. Los Angeles County/USC Medical Center, Los Angeles, CA: Principal investigator, Anilkumar Mehra; Research coordinator, Pooya Ataii.
Germany (111 patients)
St. Marienkrankenhaus Siegen, Siegen: Principal investigator, Peter Schuster; Research coordinator, Hans-Peter Hobbach. Klinikum Kassel, Germany: Principal investigator, Uwe Zeymer; Research coordinator, Stefan Gesing. Krankenhaus Dresden-Friedrichstadt, Dresden: Principal investigator, Ernst Altman: Research coordinators, Andreas Graf, Jochen Eberhard. Krankenhaus Neukoelln, Berlin: Principal investigator, Zdzislaw F. Forycki; Research coordinator, Lorenz Reill. Medizinische Klinik II-Klinikum Bayreuth, Bayreuth: Principal investigator, Wolfgang Maeurer; Research coordinators, Burkhard Jaeger, Stephen Korzeniowski. Marien Hospital, Wesel: Principal investigator, Klaus-Theodor Haerten; Research coordinator, Bernd Artmeyer. Klinikum der E.-M.-A.-Universitat Greifswald, Greifswald: Principal investigator, Stefan Felix; Research coordinator, Dirk Vogelgesang. Klinikum Lippe-Detmold, Detmold: Principal investigator, Ulrich Tebbe; Research coordinator, Andreas Kirchner. Vinzenzkrankenhaus, Hannover: Principal investigator, Alois Hepp; Research coordinators, Petra Wucherpfenning, Thorsten Grundmann. Med. Klinik Berlin Charite, Berlin: Principal investigator, Heinz Theres; Research coordinators, Michael Laule, Christoph Guenther. DRK Kliniken Koepenick, Berlin: Principal investigator, Hans-Friedrich Voehringer; Research coordinator, Joerg Moesenthin. DRK-Kliniken Westend, Berlin: Principal investigator, Ralf Schoeller; Research coordinator, Joachim Schroeder. Med. Klinik I-Staedt. Kliniken Offenbach, Offenbach: Principal investigator, Ernst Girth; Research coordinator, Norbert Schuh.
Netherlands (40 patients)
Stichting St. Antonius Hospital, Nieuwegein: Principal investigator, M.J. Suttorp; Research coordinator, Joke Helwig. University Hospital Maastricht, Maastricht: Principal investigator, Simon Braat; Research coordinator, Margaret Tychon. University Hospital Groningen, Groningen: Principal investigator, A.J. van Boven; Research coordinator, Peter Rasker.
France (29 patients)
Hopital Bichat, Paris: Principal investigator, Philipe Gabriel Steg; Research coordinators, Reza Farnoud, Emmanuelle Colloc. Clinique Chirurgicale Les Franciscaines, Nimes: Principal investigator, Olivier Wittenberg; Research coordinator, Christel Leperchois. Centre Hospitalier de Lorient, Lorient, Cedex: Principal investigator, Pierre Cazaux; Co-investigator, Jean-Phillipe Hacot; Research coordinator, Pierre Kattar. Clinique Pasteur, Toulouse: Principal investigator, Jean Marco; Co-investigator, Bruno Farah. CHI Le Raincy-Montermeil-Hospital, Le Raincy: Principal investigator, Simon Cattan; Co-investigator, Pierre Michaud; Research coordinator, Chakouri Boukerche. CHU Hopital La Mileterie, Poitiers Cedez: Principal investigator, Joseph Allal; Co-investigator, Damien Coisne; Research coordinator, Erwan Donal. Hopital Charles-Nicolle, Rouen Cedex: Principal investigator, Helene Eltchaninoff; Co-investigator, Stephen Chassaing; Research coordinator, Carlos Giron.
Belgium (23 patients)
Centre Hospitalier Hutois, Huy: Principal investigator, Dia El Allaf; Research coordinator, Virginie Gregoire. Onxe Lieve Vrouw Ziekenhuis, Aalst: Principal investigator, Guy Hendrickx; Research coordinators; Frank Staelens, Ann Roets. CHU Saint Pierre, Brussels: Principal investigator, J. L. van den Bossche; Research coordinator, Monica Lavens.
South Africa (15 patients)
Vergelegen Medi-Clinic, Somerset West: Principal investigators, T. Mabin, J. Roos; Research coordinator, Elzahn Lock.
Canada (3 patients)
Hamilton Health Science Corporation, Hamilton, Ontario: Principal investigator, Madhu Natarajan; Research coordinator, Gail Cappelli.
This trial was funded by research grants from Millennium Pharmaceuticals, Inc., South San Francisco, California, and Schering Plough Research Institute, Kenilworth, New Jersey.
- activated partial thromboplastin time
- coronary artery bypass graft surgery
- corrected Thrombolysis In Myocardial Infarction frame count
- intracranial hemorrhage
- Integrilin and Tenecteplase in Acute Myocardial Infarction trial
- myocardial infarction
- percutaneous coronary intervention
- ST-elevation myocardial infarction
- Thrombolysis In Myocardial Infarction
- Thrombolysis In Myocardial Infarction myocardial perfusion grade
- Received July 15, 2002.
- Revision received October 25, 2002.
- Accepted November 11, 2002.
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