Combined Accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein IIb/IIIa Integrin Receptor Blockade With Integrilin in Acute Myocardial Infarction
Results of a Randomized, Placebo-Controlled, Dose-Ranging Trial
Background Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase.
Methods and Results We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P=.006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P=.05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively).
Conclusions The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.
Reperfusion in the infarct-related artery is a main predictor of survival after thrombolysis for acute myocardial infarction.1 Accelerated alteplase restores normal perfusion but only in ≈50% of cases,2 3 perhaps even less at the tissue level.4 Only modest success has come from pharmacological and other approaches to improving the incidence and speed of reperfusion.5
Plaque rupture, subsequent platelet adhesion and aggregation, and thrombosis are the primary causes of myocardial infarction.6 Indirect evidence of platelet activation during infarction includes increased levels of thromboxane B2,7 reflecting activation of the platelet arachidonic acid pathway. Thrombolytic agents also stimulate platelet activation through thrombin release from clotting and perhaps other mechanisms.8 Activated platelets bind fibrinogen or von Willebrand factor with the integrin receptor glycoprotein (GP) IIb/IIIa. Integrilin, a synthetic cyclic heptapeptide, competitively inhibits protein binding to this receptor.9 Integrilin has inhibited ex vivo ADP-induced platelet aggregation in normal volunteers,10 in unstable angina patients,11 and in patients undergoing angioplasty.12
We performed a placebo-controlled, dose-ranging clinical trial of Integrilin, heparin, aspirin, and accelerated alteplase in acute myocardial infarction to explore the effects of potent platelet inhibition on reperfusion, bleeding, and clinical outcomes. The study also evaluated the effects on ischemia during acute infarction as assessed by continuous ST-segment monitoring.
The study was a randomized, placebo-controlled, dose-ranging trial of Integrilin begun simultaneously with alteplase and continued for 24 hours. From July 1993 to April 1995, 13 sites enrolled 180 patients (range, 1 to 44 patients; see the “Appendix” for sites and personnel). The Institutional Review Board of each site approved the protocol, and patients gave written informed consent before entry. The study was designed and executed and the data were analyzed independent from the trial sponsor. Patients 18 to 65 years of age (18 to 75 years in group 2; see below) were eligible if they were within 6 hours of acute myocardial infarction onset, defined as >30 minutes of angina and ST-segment depression in leads V1 to V6 consistent with posterior current of injury; ST-segment elevation ≥0.1 mV (measured 20 ms after the J-point) in at least two inferior leads (II, III, or aVF), precordial leads (V1 through V6), or leads I and aVL; or primary ST-segment change in the inferior or anterior leads with left bundle-branch block.
Exclusion criteria included childbearing potential, weight >125 kg, bleeding diathesis, severe hypertension (systolic blood pressure >200 mm Hg or diastolic pressure >100 mm Hg despite antihypertensive therapy), prior stroke or central nervous system structural abnormality, current warfarin therapy or a prothrombin time >1.2 times the local control time, hematocrit <30%, gastrointestinal bleeding (gross blood or melena) or genitourinary bleeding (gross) within 6 weeks, platelet count <100 000/mm3, hemorrhagic retinopathy, serum creatinine >4.0 mg/dL, recent noncompressible vascular punctures, comorbid conditions likely to alter prognosis (eg, cancer), prolonged (≥10 minutes) cardiopulmonary resuscitation within 2 weeks, severe trauma within 6 months, known or suspected vasculitis, or participation in another study of an experimental drug within 7 days before enrollment.
Patients were enrolled in one of seven groups (Table 1⇓) through telephone contact with a randomization center (Duke University). Patients in the first six groups were randomized in a 2:1 ratio to receive Integrilin (COR Therapeutics) or placebo intravenous bolus and continuous infusion. Groups 1a through 1f were studied sequentially and in an open-label fashion; progression to each higher dose occurred after safety analyses of previous data. Group 2 was randomly assigned in a 3:1 ratio to the highest dose of Integrilin from the group 1 phase or placebo in a double-blind fashion. The 2:1 and 3:1 ratios were used to obtain more experience with adjunctive Integrilin therapy with accelerated alteplase.
The study drug was given within 10 minutes of the initiation of alteplase, up to a maximum of 30 minutes after the start of thrombolysis. All patients received aspirin 325 mg before study drug initiation and daily thereafter. Alteplase (Activase, Genentech) was given in the accelerated, weight-adjusted method of the GUSTO-I trial13 up to 100 mg. Patients received concomitant intravenous heparin (Table 1⇑); continuous heparin infusions were adjusted to maintain an activated partial thromboplastin time of 2 to 2.5 times the local control value.
Continuous 12-lead digital ECG was performed for 24 hours, beginning at study entry, to monitor signs of reperfusion. Angiography was performed 90 minutes after the start of thrombolysis and, if clinically indicated (n=69, 38%), between days 5 and 10 or before hospital discharge. Patients were continually assessed for the occurrence of bleeding.
Ex Vivo Platelet Aggregation Assessments
Samples were collected for platelet aggregation studies at entry; 2, 6, and 24 hours after the start of study drug infusion; and 4 hours after study drug termination. Samples were drawn into a tube containing 3.8% sodium citrate (blood-to-citrate ratio, 9:1) with a 19- to 21-gauge needle or from the femoral venous access sheaths (after first discarding 3 to 5 mL blood). Platelet-rich plasma was prepared by centrifuging citrated blood at 150g for 15 minutes at 25°C. The platelet-rich plasma was then poured into a clean tube. Platelet-poor plasma was prepared by microcentrifuging the remaining blood for 5 minutes at 25°C. Platelet counts were performed on platelet-rich plasma. For platelet counts >400 000/μL, the platelet-rich plasma was diluted with platelet-poor plasma until the platelet count reached 300 000/μL.
After calibration of the aggregometer (Bio/Data PAP-4, Bio/Data or Chrono-Log, Chrono-Log), 0.45 mL platelet-rich plasma was added to each of two cuvettes containing a magnetic stir bar with a stirring speed of 1000 to 1200 rpm. Once a stable baseline occurred, 0.05 mL of 200 μmol/L ADP was added to each cuvette to yield a final ADP concentration of 20 μmol/L. The change in light transmittance was determined at 5 minutes and recorded as the percentage of platelet aggregation. All assays were measured within 2 hours of sampling.
ECG Core Laboratory
All continuous ECG recordings (ST-100, Mortara Instrument) were analyzed at the core laboratory (Duke University) by an independent reviewer (Dr Krucoff) unaware of treatment. The time to steady-state ST-segment recovery (the time from start of thrombolysis to >50% recovery from the peak ST-segment deviation maintained for at least 4 hours with no further ST-segment deviation of >100 μV) was measured for each analysis with the Duke continuously updated ST-segment recovery analysis method.14 Studies were excluded if artifact or conduction defects obscured the steady-state end point by use of established criteria.15
Angiographic Core Laboratory
All angiograms were forwarded to the core laboratory (The Cleveland Clinic Foundation). An independent reviewer unaware of treatment assignment identified the infarct-related artery, determined Thrombolysis in Myocardial Infarction (TIMI) flow grade, and measured left ventricular function. Adequate 90-minute angiograms were obtained in 170 patients (94%).
The primary end point was TIMI grade 3 flow (by the angiographic core laboratory) at 90 minutes. Secondary end points included (1) time to steady-state ST-segment recovery in the lead with the greatest baseline deviation by continuous ECG monitoring; (2) a composite of death, reinfarction, stroke, percutaneous or surgical coronary revascularization, or new in-hospital heart failure or pulmonary edema; and (3) bleeding (number of transfusions, greatest change in hematocrit, number of bleeding episodes, and the Landefeld index16 ).
Bleeding complications were categorized as mild, moderate, or severe.13 Severe bleeding included intracranial hemorrhage and bleeding that resulted in hemodynamic compromise requiring intervention. Moderate bleeding was classified if transfusion was required. Bleeding that did not result in hemodynamic compromise or transfusion was considered mild. Net blood loss was calculated with a modification of the Landefeld criteria16 by adding one-third of the baseline-minus-nadir hematocrit value plus the number of units packed red blood cells transfused (ie, units transfused+Δhematocrit/3). The protocol did not include an algorithm for blood product transfusions; all transfusions were prescribed according to the local standard of care at each site.
Continuous variables were summarized as medians and interquartile ranges. The Wilcoxon rank sum test was used to compare the bleeding index between groups. Categorical variables, summarized as percentages, were analyzed with a likelihood ratio χ2 statistic. All treatment comparisons were performed under the intention-to-treat principle. Data from the double-blind phase (group 2) were combined with those of the highest unblinded regimen (group 1f) to provide more stable outcome estimates. Because the angiographic and ECG core laboratories remained blinded to treatment, we could compare all patients treated with the highest dose of Integrilin with all placebo-treated patients without the introduction of bias. Statistical significance was defined as P≤.05; 95% confidence intervals were calculated for selected outcomes. All analyses were performed with SAS software (SAS Institute).
Table 2⇓⇓ gives the patients' baseline characteristics. Four randomized patients did not receive study medication (Integrilin): 1 in group 1a, 2 in group 1b, and 1 in group 1e. The overall median (25th and 75th percentiles) duration of drug administration was 24.0 hours (22.8 and 24.1 hours) for patients allocated to Integrilin and 24.0 hours (23.8 and 24.1 hours) for placebo-treated patients.
Platelet inhibition with Integrilin was maximal after 2 and 6 hours of infusion (Fig 1⇓) and remained >70% at 24 hours at the highest Integrilin dose (group 1f). At 4 hours after infusion, aggregation in all Integrilin groups but group 1f was similar to that of placebo-treated patients.
Angiography was performed 1.5 hours (1.3 and 1.7 hours) after the start of thrombolysis in Integrilin-treated patients and at 1.6 hours (1.4 and 1.8 hours) in placebo-treated patients (Table 3⇓). Of the 170 patients with adequate 90-minute angiograms, patients allocated to the highest Integrilin dose more often had TIMI grade 3 flow (core laboratory reading, 66%) than placebo-treated patients (39%; P=.006; Fig 2⇓). The rate of TIMI grade 2 or 3 flow in these 170 patients was also higher with Integrilin (87% versus 69%; P=.01). In the 69 patients with clinically driven follow-up angiography, TIMI grade 3 flow (site reading) occurred in 79% of the Integrilin-treated and 64% of the placebo-treated patients.
Continuous ST-Segment Monitoring
The median time from starting thrombolysis to steady-state recovery of ST-segment deviation was 95 minutes (59 and 173 minutes) for all Integrilin-treated patients and 116 minutes (64 and 209 minutes) for placebo-treated patients (P=.5). For patients randomized to the highest Integrilin dose (groups 1f and 2), the duration was 65 minutes (40 and 135 minutes; 116 minutes for placebo; P=.05).
The incidence of death or reinfarction was 7.3% for placebo-treated patients, 8.0% for all patients randomized to Integrilin, and 7.8% for patients at the highest Integrilin dose (Table 4⇓⇓). The composite outcome occurred in 41.8% of placebo-treated patients, 44.8% of all Integrilin-treated patients, and 43.1% of patients at the highest Integrilin dose. Although group 2 patients assigned to Integrilin showed a trend toward increased adverse events, only the incidence of sustained hypotension was significantly different (20% versus 0%; P=.028).
Most bleeding was mild and angiographic access site-related (Table 5⇓⇓). Severe thrombocytopenia (platelet count <50 000/mm3) occurred in three patients (6%) allocated to placebo and in five patients (4%) allocated to Integrilin, none of whom were allocated to the highest Integrilin dose.
One group 2 patient suffered an intracranial hemorrhage 6.5 hours after receiving alteplase and while receiving Integrilin (0.75 μg·kg−1·min−1 infusion). This 63-year-old woman, who weighed 71 kg, had normal blood pressure at entry but had a history of hypertension for which she was receiving no medical therapy. She had posterior myocardial infarction complicated by ventricular fibrillation; no other adverse events occurred. The 6-hour activated partial thromboplastin time was 128 seconds just before intracranial hemorrhage. The baseline platelet count was 255 000/mm3 and remained normal. Computed tomography of the brain done within 2 hours of neurological deficit showed a large intraparenchymal hemorrhage with mass effect. This patient died on the second hospital day.
This trial of potent platelet inhibition with simultaneous accelerated thrombolysis for acute myocardial infarction shows that when the final pathway of platelet aggregation is inhibited by ≥70%, significantly more reperfusion in the infarct artery can result. It is also associated with a shorter duration of ischemia during infarction, as shown by the shorter time to steady-state ST-segment recovery. These findings strengthen the hypothesis that platelet activation and aggregation are key components of the failure of thrombolysis to achieve reperfusion in all cases.
Platelet-rich thrombi are more resistant to lysis with alteplase than erythrocyte-rich clots in a rabbit model of acute infarction.17 The role of platelets in modulating the response to thrombolytic therapy is supported by studies of acute thrombosis and reperfusion in dogs in which simultaneous abciximab (an antibody to the GP IIb/IIIa receptor) and alteplase treatment resulted in a shorter time to reperfusion and less reocclusion.18 A single bolus of Integrilin with alteplase has also resulted in full restoration of coronary blood flow in the canine model.19 Similar results occurred when Integrilin was combined with streptokinase.20 Thus, the present study is consistent with experimental evidence of faster and more complete reperfusion with potent inhibitors of the GP IIb/IIIa receptor.
In the TAMI-8 study, patients with acute myocardial infarction received aspirin, standard (3-hour) alteplase dosing, and heparin with various doses of abciximab.21 Despite the sequential design (alteplase given first, then abciximab), there was a trend toward less recurrent ischemia in patients who received abciximab immediately after alteplase administration.
Less potent platelet inhibitors have also been combined with thrombolytic therapy. Intracoronary prostaglandin E1 given to patients receiving intracoronary streptokinase resulted in more rapid reperfusion and less reocclusion.22 Intravenous prostacyclin with alteplase, however, did not increase 90-minute patency in the TAMI-4 study,23 and ridogrel, a thromboxane A2 synthetase inhibitor, had no effect (compared with aspirin) on speed of reperfusion or 90-minute patency.24 Nonrandomized data from the TIMI group showed a trend toward higher patency rates among patients receiving aspirin at home or in the emergency department than among patients who received no aspirin.25 Despite this very modest effect, however, mortality was reduced by 17% when aspirin was combined with intravenous streptokinase in the ISIS-2 study.26 An overview of acute myocardial infarction trials has shown less angiographic reocclusion when aspirin is used.27 Patients allocated to aspirin in ISIS-2 also had a 50% lower reinfarction rate.26 Our study shows that patients can derive an incremental beneficial effect on reperfusion with Integrilin beyond that with aspirin and heparin. Future studies must address whether this combined approach carries a clinical benefit and if it extends to other GP IIb/IIIa inhibitors.
Effects on Platelet Aggregation
The effect of Integrilin on platelet aggregation response to 20 μmol/L ADP appeared to be dose-dependent only for the lowest two doses; the response did not change when the Integrilin bolus dose increased from 135 to 180 μg/kg. This response may not be the optimal way to explore the antiaggregatory effect of GP IIb/IIIa receptor blockers. Thrombin receptor agonist peptide stimulation is more potent and provides further insight into platelet aggregatory responses to agonists such as thrombin, collagen, and epinephrine.28 The clinical instability of patients with acute ischemic syndromes may also affect the efficacy of Integrilin; patients who have acute myocardial infarction show less antiaggregatory response to ADP at a given Integrilin dose than patients with unstable angina.29 This factor requires further evaluation in various acute ischemic syndromes and different doses of Integrilin.
Administration of Integrilin, alteplase, aspirin, and heparin did not appear to be associated with excess bleeding complications, most of which were angiography related. Rates in this study were similar to those in other studies of new antithrombin agents30 and were similar in patients treated with Integrilin or placebo. One intracranial hemorrhage did occur at the highest Integrilin dose, however. As adjunctive therapies are combined with thrombolytic agents, such approaches will likely be associated with both reduced mortality and increased intracranial hemorrhage. An intracranial hemorrhage rate as high as 2.2% can result in a favorable risk profile if the therapy also provides ≥10% relative reduction in mortality.31 Several thousand patients who receive Integrilin and thrombolytic agents must be studied to provide stable estimates of the rate of intracranial hemorrhage in acute infarction. Thus, our study is too small to fully address the safety of Integrilin in this setting.
Infarct Vessel Patency and Clinical Outcomes
The small size of this study also prevents an analysis of the ability of Integrilin to reduce adverse outcomes. However, because TIMI grade 3 flow at 90-minute angiography correlates with 30-day mortality,1 it may be an optimal surrogate end point. Patients at the highest Integrilin dose had a 69% higher rate of TIMI grade 3 flow than placebo-treated patients (66% versus 39%) at 90 minutes. It would require >10 000 patients to assess whether this correlates with better outcomes.
TIMI Flow Grade Assessment by the Core Laboratory
The TIMI grade 3 flow rates in this study appear lower than those in the GUSTO-I angiographic substudy, which used a different core laboratory,2 but the 95% confidence interval (26% and 52%) approaches the point estimate from the accelerated alteplase arm of GUSTO-I (54%). Further, the core laboratory used in the present trial has also shown a link between 90-minute TIMI flow grade and in-hospital survival.32 More recently, this same laboratory showed a 47% rate of TIMI grade 3 flow with accelerated alteplase in the RAPID-2 trial.33 Thus, although the TIMI grade 3 flow rate seems low, this may reflect chance or a difference in interpretation of washout of dye, which has also been linked with survival.
Patients enrolled in the trial were relatively low risk. Elderly patients and those with cardiogenic shock were excluded, which may have resulted in some selection bias. Second, this was a small study of 180 patients, of whom only 51 received the highest Integrilin dose. Thus, interpretations should be made with caution. Not until more experience is gained with Integrilin and accelerated alteplase can clinical and hemorrhagic events be interpreted with confidence. Third, an open-label design was used for groups 1a through 1f because this was the first time a potent GP IIb/IIIa inhibitor had been given with accelerated alteplase, heparin, and aspirin. Group 2, however, was a double-blind evaluation. Because both core laboratories were blinded to treatment throughout the study, we combined the findings from group 2 with those from the highest unblinded dose group (group 1f). We could therefore gain a more complete understanding of this therapy by comparing all patients treated with the highest Integrilin dose with all placebo-treated patients.
This randomized, placebo-controlled, dose-ranging trial suggests that the incidence and speed of reperfusion can be enhanced when a potent GP IIb/IIIa inhibitor is combined with accelerated alteplase, aspirin, and intravenous heparin. Therapies targeted toward the GP IIb/IIIa receptor may open new avenues to enhance reperfusion in acute myocardial infarction.
Sites and Investigators Participating in IMPACT-AMI
Methodist Hospital, Houston, Tex: N. Kleiman, D. Rose, K. Trainor, L. Baysinger, and S. Johnston; Rochester (NY) General Hospital: G. Gacioch, V. Chiodo, and K. Karski; Lancaster (Penn) General Hospital: S. Worley, J. Tuzi, and K. Knepper; Mother Frances Hospital, Tyler, Tex: F. Navetta, R. Carney, R. LeBoeuf, and G. Murphy; University of Louisville (Ky): J. David Talley, M. Rawert, and W. Etka; University of Arkansas Medical Center, Little Rock: J.D. Talley, M. Rawert, and T. Carpenter; McClellan Veteran's Administration Hospital, Little Rock, Ark: J. David Talley, M. Rawert, and T. Carpenter; Duke University Medical Center, Durham, NC: E.M. Ohman, R. Harrington, R. Califf, E. Berrios, K. Martz, K. Brown, and K. Quintero; University of Texas, Houston: H.V. Anderson, L. Weigelt, and I. Weiser; The Cleveland (Ohio) Clinic Foundation: E. Topol (study chairman), K. Brezina, and N. Juran; St. Francis Hospital, Beech Grove, Ind: M. Cohen, D. Lee, and P. Cross; Morton Plant Hospital, Clearwater, Fla: D. Spriggs and S. Wahl; University of South Carolina Medical Center, Charleston: M. Miller and B. Owens; Christ Hospital, Cincinnati, Ohio: D. Kereiakes, N. Higby, and L. Martin; MidWest Cardiovascular Research Foundation, Columbus, Ohio: S. Yakubov, B. George, and L. Carman.
Coordinating Center, Duke University Medical Center, Durham, NC: R. Califf (director), E.M. Ohman, and D. Joseph. Angiographic Core Laboratory, The Cleveland (Ohio) Clinic Foundation: S. Ellis, D. Debowey, T. Crowe, and T. Ivanc. Continuous Electrocardiography Core Laboratory, Duke University Medical Center, Durham, NC: M. Krucoff and K. Trollinger. Electrocardiographic Core Laboratory, Duke University Medical Center, Durham, NC: G. Wagner and K. Gates. Enzymatic Core Laboratory, University of Maryland Medical System, Baltimore: R. Christenson. Biochemical Core Laboratory, University of Vermont, Colchester: R.P. Tracy and E.G. Bovill.
This study was supported by COR Therapeutics, Inc, South San Francisco, Calif. The authors gratefully acknowledge Genentech, Inc (South San Francisco, Calif) for the alteplase used in this trial and Mortara Instrument (Milwaukee, Wis) and Quinton Instrument Company (Seattle, Wash) for the ST-segment monitoring equipment. We also thank Dr Robert Swift (COR Therapeutics) for scientific advice, Diane Joseph (Duke University) for study coordination, and Pat Williams (Duke) for editorial assistance.
Guest editor for this article was J. David Bristow, MD, Oregon Health Sciences University, Portland, Oregon.
Presented in part at the 45th Annual Scientific Session of the American College of Cardiology, Orlando, Fla, March 24-27, 1996.
- Received March 19, 1996.
- Revision received October 29, 1996.
- Accepted November 18, 1996.
- Copyright © 1997 by American Heart Association
Simes RJ, Topol EJ, Holmes DR Jr, White HD, Rutsch WR, Vahanian A, Simoons ML, Morris D, Betriu A, Califf RM, Ross AM, for the GUSTO-I Investigators. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: importance of early and complete infarct artery reperfusion. Circulation. 1995;91:1923-1928.
Lincoff AM, Topol EJ. Illusion of reperfusion: does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation. 1993;88:1361-1374.
Popma JJ, Topol EJ. Adjuncts to thrombolysis for myocardial reperfusion. Ann Intern Med. 1991;115:34-44.
Scarborough RM, Naughton MA, Teng W, Rose JW, Phillips DR, Nannizzi L, Arfsten A, Campbell AM, Charo IF. Design of potent and specific integrin antagonists: peptide antagonists with high specificity for glycoprotein IIb-IIIa. J Biol Chem. 1993;268:1066-1073.
Charo IF, Scarborough RM, du Mee CP, Wolf D, Phillips DR, Swift RL. Pharmacodynamics of the GPIIb-IIIa antagonist Integrilin: phase I clinical studies in normal healthy volunteers. Circulation. 1992;86(suppl I):I-260. Abstract.
Harrington RA, Schulman SP, Kleiman NS, Lincoff AM, Goldschmidt-Clermont PJ, Joseph D, Sigmon KN, Parker J, Marchant K, Kitt MM. Profound, sustained, and reversible platelet inhibition following administration of a glycoprotein IIb/IIIa inhibitor with and without heparin in patients with unstable angina. Circulation. 1994;90(suppl I):I-232. Abstract.
Tcheng JE, Harrington RA, Kottke-Marchant K, Kleiman NS, Ellis SG, Kereiakes DJ, Mick MJ, Navetta FI, Smith JE, Worley SJ, Miller JA, Joseph DM, Sigmon KN, Kitt MM, du Mee CP, Califf RM, Topol EJ, for the IMPACT Investigators. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrilin in elective coronary intervention. Circulation. 1995;91:2151-2157.
Krucoff MW, Croll MA, Pope JE, Pieper KS, Kanani PM, Granger CB, Veldkamp RF, Wagner BL, Sawchak ST, Califf RM. Continuously updated 12-lead ST-segment recovery analysis for myocardial infarct artery patency assessment and its correlation with multiple simultaneous early angiographic observations. Am J Cardiol. 1993;71:145-151.
Langer A, Krucoff MW, Klootwijk P, Veldkamp R, Simoons ML, Granger C, Califf RM, Armstrong PW for the GUSTO-I Investigators. Noninvasive assessment of speed and stability of infarct-related artery reperfusion: results of the GUSTO ST segment monitoring study. J Am Coll Cardiol. 1995;25:1552-1557.
Jang IK, Gold HK, Ziskind AA, Fallon JT, Holt RE, Leinbach RC, May JW, Collen D. Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator: a possible explanation for resistance to coronary thrombolysis. Circulation. 1989;79:920-928.
Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation. 1988;77:670-677.
Nicolini FA, Lee P, Rios G, Kottke-Marchant K, Topol EJ. Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis. Circulation. 1994;89:1802-1809.
Song A, Scarborough RM, Phillips DR, Adelman B, Strony J. Integrilin enhances fibrinolysis and prevents acute arterial reocclusion following thrombolysis in a canine anodal current model with high-grade stenosis. Circulation. 1992;86(suppl I):I-410. Abstract.
Kleiman NS, Ohman EM, Califf RM, George BS, Kereiakes D, Aguirre FV, Weisman H, Schaible T, Topol EJ. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab following thrombolytic therapy: results of the TAMI 8 pilot study. J Am Coll Cardiol. 1993;22:381-389.
Topol EJ, Ellis SG, Califf RM, George BS, Stump DC, Bates ER, Nabel EG, Walton JA, Candela RJ, Lee KL, Kline EM, Pitt B, for the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 4 Study Group. Combined tissue-type plasminogen activator and prostacyclin therapy for acute myocardial infarction. J Am Coll Cardiol. 1989;14:877-884.
Tranchesi B, Pileggi F, Vercammen E, Van de Werf F, Verstraete M. Ridogrel does not increase the speed and rate of coronary recanalization in patients with myocardial infarction treated with alteplase and heparin. Eur Heart J. 1994;15:660-664.
Robertson TL, Forman SA, Williams DO, Dodge HT, for the TIMI Research Group. Aspirin, rt-PA, and reperfusion in AMI: a TIMI observational study. Circulation. 1988;78(suppl II):II-128. Abstract.
Kleiman NS, Raizner AE, Jordan R, Wang AL, Norton D, Mace KF, Joshi A, Coller BS, Weisman HF. Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors. J Am Coll Cardiol. 1995;26:1665-1671.
Harrington RA, Ohman EM, Sigmon KN, Kleiman NS, Schulman SP, Kottke-Marchant K, Lincoff AM, Joseph D, Parker J, Kitt MM, Tcheng JE. Intensity of inhibition of the platelet glycoprotein IIb/IIIa receptor differs among disease states. Circulation. 1995;92(suppl I):I-488. Abstract.
Cannon CP, McCabe CH, Henry TD, Schwaiger MJ, Gibson RS, Mueller HS, Becker RC, Kleiman NS, Haugland M, Anderson JL, Sharaf BL, Edwards SJ, Rogers WJ, Williams DO, Braunwald E, for the TIMI 5 Investigators. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J Am Coll Cardiol. 1994;23:993-1003.
Lincoff AM, Topol EJ, Califf RM, Sigmon KN, Lee KL, Ohman EM, Rosenschein U, Ellis SG, for Thrombolysis and Angioplasty in Myocardial Infarction Study Group. Significance of a coronary artery with thrombolysis in myocardial infarction grade 2 flow ‘patency’ (outcome in the Thrombolysis and Angioplasty in Myocardial Infarction trials). Am J Cardiol. 1995;75:871-876.
Weaver WD, Bode C, Burnett C, Kalbfleisch J, Lorch G, Sen S, Chernoff R, Smalling R, for the RAPID-2 Investigators. Reteplase Versus Alteplase Patency Investigation During Myocardial Infarction trial (RAPID 2). J Am Coll Cardiol. 1995;25:87A. Abstract.