Trial of Abciximab With and Without Low-Dose Reteplase for Acute Myocardial Infarction
Background—Low-dose alteplase with standard-dose abciximab enhances reperfusion 90 minutes after acute myocardial infarction (MI). We combined standard-dose abciximab with low-dose reteplase for acute MI in 2 phases. Two heparin doses were also explored.
Methods and Results—Phase A patients were randomized 4:1 to receive an abciximab bolus with infusion alone (n=63) or with 5 U, 7.5 U, 10 U, 5 U+2.5 U, or 5 U+5 U of reteplase (total n=241). Phase B tested the best phase A strategy (abciximab plus 5 U+5 U reteplase, expressed as abciximab-reteplase 5+5 U; n=115) against 10 U+10 U reteplase alone (n=109). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 60 to 90 minutes. In phase A, 62% of the abciximab-reteplase 5+5 U group had TIMI grade 3 flow versus 27% of the abciximab-only patients (P=0.001). In phase B, 54% of the abciximab-reteplase 5+5 U group had grade 3 flow versus 47% of the reteplase-only patients (P=0.32). Grade 3 flow rates were 61% for a 60 U/kg heparin bolus and abciximab-reteplase 5+5 U, 51% for a 40 U/kg heparin bolus and abciximab-reteplase 5+5 U (P=0.22), and 47% for reteplase alone (P=0.05 versus the 60 U/kg heparin group). Major bleeding rates in phase A were 3.3% for abciximab alone and 5.3% for abciximab-reteplase 5+5 U; rates in phase B were 9.8% for abciximab-reteplase 5+5 U and 3.7% for reteplase alone. Major bleeding was similar with standard- or low-dose heparin (6.3% versus 10.5%, P=0.30).
Conclusions—In this phase II trial, adding reteplase to abciximab treatment of acute MI versus reteplase alone enhanced the incidence of early complete reperfusion after the initiation of therapy in the emergency department.
Inhibition of the platelet glycoprotein IIb/IIIa receptor can lead to modest rates of reperfusion after acute myocardial infarction (MI) even without exogenous fibrinolytic therapy,1 but the combination of glycoprotein IIb/IIIa receptor blockers and fibrinolytics enhances the incidence and speed of reperfusion in preclinical studies2 and in patients with MI (combination therapy compared with fibrinolytics alone).3 However, effects differ among fibrinolytic agents. In the Thrombolysis In Myocardial Infarction (TIMI)-14 trial, greater reperfusion occurred when combining standard-dose abciximab with a low-dose fibrin-specific tissue plasminogen activator (alteplase),4 but only modest effects occurred with reduced doses of streptokinase and abciximab. The reason for the different effects among fibrinolytic agents is unknown.
Reteplase, a modified fibrin-specific plasminogen activator, has undergone extensive clinical study.5 Although mortality and intracranial hemorrhage rates have been similar for reteplase and alteplase, reteplase has shown a higher reperfusion rate.6 Other pharmacological effects also differ, including greater fibrinogen depletion after standard-dose reteplase versus alteplase treatment (but less depletion than after streptokinase treatment).7 We performed a 2-phase trial of low-dose reteplase with standard-dose abciximab, aspirin, and heparin in acute MI and explored the effects on reperfusion, bleeding, and clinical outcomes. Phase A compared reduced doses of reteplase plus abciximab versus abciximab alone; phase B compared the best combination strategy from phase A with reteplase alone (dose confirmation).
The Strategies for Patency Enhancement in the Emergency Department (SPEED, Global Use of Strategies To Open occluded coronary arteries [GUSTO-IV] Pilot) trial was a randomized, multicenter, angiographic study of abciximab with and without various doses of reteplase and of abciximab plus reteplase versus reteplase alone in patients with acute MI. The abciximab-alone (control) group in phase A was selected to evaluate the safety of adding various doses of reteplase. Phase B tested the safety and preliminary efficacy of the best phase A strategy versus standard-dose reteplase alone. Patients provided written informed consent before randomization, and the ethics board of each site approved the protocol before patients were enrolled.
The inclusion/exclusion criteria were those of the TIMI-14 trial,4 but there was no upper age limit in SPEED, and patients could arrive ≤12 hours after chest-pain onset. We also excluded patients with atrioventricular block, need for temporary transvenous pacemaker for conduction disturbance, severe sinus bradycardia, puncture of a noncompressible vessel in the past 24 hours, cardiac catheterization in the past 3 days, prolonged cardiopulmonary resuscitation, known or suspected vasculitis, prior heparin-induced thrombocytopenia, participation in studies of any experimental therapy in the past week, conditions that could prove hazardous if enrolled, other serious illness (eg, cancer or severe liver disease), weight >120 kg, and <100 000/μL platelets at randomization.
In phase A, patients were randomized in a 4:1 ratio to receive a bolus dose of abciximab (0.25 mg/kg) and a 12-hour infusion (0.125 μg · kg−1 · min−1) with either a bolus dose(s) of reteplase (5 U, 7.5 U, 10 U, 5 U+2.5 U, or 5 U+5 U) or no reteplase. The decision to proceed to higher reteplase doses was made after the Operations Committee reviewed the safety and efficacy data. In phase B, the best abciximab-reteplase regimen from phase A (abciximab plus 5 U+5 U reteplase, expressed as abciximab-reteplase 5+5U; similar expressions are used to indicate other treatments) was compared directly with reteplase alone (reteplase 10+10 U).
The abciximab bolus was given as soon as possible after randomization, followed by abciximab infusion. The reteplase bolus was given within 5 minutes after the abciximab bolus. If patients were randomized to a second reteplase bolus, it was given 30 minutes after the first. Patients began treatment in emergency departments and were transferred immediately to catheterization laboratories for angiography.
All patients received aspirin (150 to 325 mg PO or 250 to 500 mg IV) on diagnosis of MI and then oral aspirin at 80 to 325 mg daily for ≥30 days. Other medications were given at the investigator’s discretion. Low molecular weight heparins, dextran, and other platelet glycoprotein IIb/IIIa inhibitors were not given with study drugs.
For phase A, intravenous heparin (60 U/kg) was given shortly after a bolus dose(s) of the study drug. Additional weight-adjusted bolus doses or a continuous infusion of heparin was given during angiography (and intervention) to maintain an activated clotting time ≥200 seconds. It was recommended that heparin be stopped at the end of the procedure to permit early sheath removal, but if continued (at the investigator’s discretion), the dose was titrated to maintain an activated partial thromboplastin time of 50 to 70 seconds. When the results of the TIMI-14 trial became known, the initial bolus dose of heparin in the phase B abciximab-reteplase 5+5 U group was reduced from 60 to 40 U/kg (maximum 4000 U). All patients in the reteplase-only group received a 70 U/kg bolus (maximum 5000 U).
Angiography and Intervention
Angiography of the infarct-related artery (IRA) was performed within 60 to 90 minutes after the initiation of reperfusion therapy. Two orthogonal views were obtained, and then intervention was performed at the investigator’s discretion. The time window for the angiogram designated “60 to 90 minutes” was ≥55 minutes and ≤110 minutes after reperfusion therapy began. All approved interventional techniques and devices, including stents, were permitted.
Angiographic Core Laboratory
Films were reviewed independently by blinded core laboratory personnel. Variables collected from all films included location of stenosis, TIMI flow grade,8 and percent diameter stenosis. The corrected TIMI frame count in the IRA was also obtained from all available films.9 A score of 100 was imputed for occluded vessels (TIMI grade 0 to 1 flow). Procedural success was defined as residual stenosis <50% and TIMI grade 3 flow.
End Points and Definitions
The primary end point was TIMI flow grade8 in the IRA, by core laboratory assessment, 60 to 90 minutes after treatment began. Secondary end points included the following: corrected TIMI frame count at 60 to 90 minutes; the composite of death, reinfarction, or urgent (ischemia-driven) repeat revascularization at 30 days; the composite of death or reinfarction at 30 days; stroke (any type) at 30 days; other bleeding complications until discharge or at 14 days (whichever occurred first), including severity (see below) and the modified Landefeld index10 ; and thrombocytopenia (<100 000 platelets/μL and ≥25% decrease from baseline) until discharge or at 14 days.
Clinical end points of reinfarction, ischemia-driven revascularization, pump failure, and stroke were defined as described previously.11 12 13 14 Major bleeding was (1) intracranial, retroperitoneal, or intraocular or (2) clinically overt with a hemoglobin decrease >5 g/dL (or a hematocrit decrease ≥15%). Minor bleeding was other clinically overt bleeding not meeting the criteria for major bleeding.
Categorical variables are summarized as percentages; continuous variables, as medians (with 25th and 75th percentiles). There were 3 patient cohorts: the intention-to-treat cohort, the safety-evaluable cohort, and the angiography-evaluable cohort. The intention-to-treat analyses included all randomized patients except 2, who withdrew consent to participate; the safety-evaluable cohort included all randomized patients given the study drug; and the angiography-evaluable cohort included patients from the safety-evaluable cohort who also, if randomized to combination therapy, received both drugs within 15 minutes.
The χ2 test was used to compare discrete variables, and the Wilcoxon rank sum test was used for continuous variables. Cumulative data for abciximab-only treatment and for abciximab-reteplase treatment are shown for phase A; results for each dose group did not change markedly over time.
Phase A enrolled 304 patients at 61 hospitals from October 1997 to July 1998. Phase B enrolled 224 patients from July 1998 to December 1998. Baseline characteristics for the dose groups (individual, combined, and by phase) did not differ significantly (Table 1⇓). The overall cohort had low baseline risk, with a median age of 59 years and infrequent heart failure. Patients randomized to abciximab plus reteplase in phase A had a longer time from symptom onset to treatment than those receiving abciximab only (P=0.04).
The time from first study-drug bolus to 60- to 90-minute angiography was 62 (60, 70 [25th and 75th percentiles, respectively]) minutes and did not differ among groups (Table 2⇓). Most patients (88%) underwent angiography at 55 to 80 minutes, with no significant differences between groups; only 12% underwent angiography at 80 to 110 minutes. The IRA, distributed similarly among groups, was most often the right coronary artery. Most patients underwent intervention at initial angiography; of these, 77% received a stent. Intervention was successful in 87% of the patients in all dose groups, with no significant differences. Patients undergoing intervention received 42.9 (28.4, 67.1) U/kg heparin during the procedure.
Core laboratory data were available for 437 of the 444 patients undergoing angiography at 55 to 110 minutes (98.4%). The incidence of TIMI grade 3 flow was lowest in the abciximab-only group (27%, Figure⇓ and Table 3⇓) and highest in the abciximab-reteplase 5+5 U group (62%, P=0.001). The median corrected TIMI frame count was lowest among patients given reteplase 5+5 U and highest in the abciximab-only group (P<0.001, Table 3⇓). No dose response was seen with individual bolus doses of 5 U versus 10 U reteplase, but the incidence of TIMI grade 3 flow increased from 46% to 62% when 10 U was given as two 5 U bolus doses (30 minutes apart) instead of 1 bolus (P=0.13). TIMI frame counts tended to be lower among the split-dose reteplase groups than among the single-bolus groups (P=0.35 and P=0.17 versus the 7.5 U and 10 U single-bolus groups, respectively). More patients in the reteplase 5+2.5 U group (38%) and the reteplase 5+5 U group (36%) had a “normal” (<30) TIMI frame count versus the abciximab-only group (16%, P=0.02).
In phase B, 54% of the patients given abciximab-reteplase 5+5 U had TIMI grade 3 flow versus 47% of those given reteplase alone (P=0.39). Patients from both phases given abciximab-reteplase 5+5 U and standard-dose heparin (n=90) showed a trend toward greater reperfusion versus patients given abciximab-reteplase 5+5 U and low-dose heparin (n=70) (61% versus 51%, Figure⇑), which was not statistically significant. Of the phase B patients given reteplase alone, 47% had TIMI grade 3 flow (P=0.05 versus the standard-dose heparin group).
Overall, 11.4% of patients underwent transfusion by day 14 or discharge (Table 4⇓); major bleeding occurred in 3.3% of the abciximab-only group and in 9.2% of the abciximab-reteplase groups combined. Adding reteplase to abciximab was associated with a trend toward increased major bleeding (P=0.11), but it did not significantly increase the rate of transfusions (P=0.67) or minor bleeding (P=0.95). Patients given reteplase with abciximab had higher bleeding index values in phase A (median 2.7 versus 2.3 for abciximab alone, P=0.03) but not phase B (median 2.7 versus 2.6 for reteplase alone, P=0.67). Major bleeding was similar between patients in both phases given abciximab-reteplase 5+5 U with standard-dose versus low-dose heparin (6.3% versus 10.5%, P=0.30). Thrombocytopenia occurred slightly more often among patients given abciximab-reteplase versus those given abciximab alone (P=0.12), but the rate of platelet transfusion was similar among groups (Table 4⇓). Only 5 patients developed severe thrombocytopenia (<50 000/μL); all had severe bleeding, and 3 received blood and/or platelet transfusions.
Overall, clinical event rates were low, with an overall mortality rate of 3.8%. Rates of ischemic complications (reinfarction and ischemia-driven revascularization) did not differ between the groups (Table 5⇓). The composite outcomes of death or reinfarction and death, reinfarction, or ischemia-driven revascularization also did not differ substantially among groups.
Three had intracranial hemorrhage; of these, 2 died. One 62-year-old woman had no neurological deficit, but computed tomography showed a small intracranial hemorrhage 4 days after receiving abciximab-reteplase 5 U. She was discharged without sequelae. One 66-year-old woman given abciximab-reteplase 5+5 U developed left-sided hemiparesis 4 hours after successful PTCA. Computed tomography showed intracranial hemorrhage and recent cerebral infarction; she died 24 hours later. The third patient was a 65-year-old man given reteplase 10+10 U. Computed tomography showed left-sided intraparenchymal hemorrhage with brain stem compression, which was fatal. The overall rate of intracranial hemorrhage in patients given abciximab-reteplase 5+5 U with 60 U/kg heparin was 1.1% (1 of 90 patients).
Adding low-dose reteplase to abciximab treatment of acute MI provided results slightly superior to those with standard-dose reteplase alone, when a 60 U/kg bolus of heparin was used. Furthermore, a small dose of reteplase substantially enhanced the thrombolytic ability of abciximab, particularly with sustained reteplase dosing (2 boluses given 30 minutes apart). Continuous plasminogen activation may be needed to achieve more complete reperfusion by sustained red-clot lysis.15 Coronary thrombosis involves simultaneous deposition and lysis of red (fibrin-rich) and white (platelet-rich) clot components, causing intermittent vessel occlusion.16 17 Our data indicate that potent platelet inhibition by abciximab with reduced-dose fibrinolytic therapy appears to enhance fibrin and platelet lysis, resulting in rapid complete reperfusion in a high proportion of patients with MI.
Our findings extend the TIMI-14 trial observations in several ways. We found the highest TIMI grade 3 rates at 60 minutes with half-dose reteplase (5+5 U) and standard-dose abciximab. Similarly, in TIMI-14, the 60-minute TIMI grade 3 rate with half-dose alteplase (50 mg) and standard-dose abciximab was 72% versus 43% with alteplase alone.4 The importance of sustaining the fibrinolytic effect was apparent in both trials. When 10 U of reteplase was split into 2 bolus doses, TIMI grade 3 flow rates improved from 46% to 62% in phase A of our trial. In the TIMI-14 trial, when alteplase was given as a bolus and infused for 1 hour instead of given as 1 bolus, the TIMI grade 3 flow rate at 1 hour increased from 45% to 63%. Thus, reteplase combined with abciximab may behave more like alteplase than like streptokinase in improving reperfusion rates.
In the TIMI-14 trial, reduced-dose heparin (30 U/kg bolus) was associated with slightly less TIMI grade 3 flow at 90 minutes (69% versus 77%).4 Similarly, in our trial, the use of 40 U/kg heparin was associated with slightly less TIMI grade 3 flow at 1 hour (51% versus 61%). In neither trial did this small difference achieve statistical significance. This finding is not unique to studies of abciximab. Such a pattern (reduced efficacy of a fibrinolytic with lower-dose heparin) also occurred with eptifibatide/alteplase in a randomized trial.3 Clearly, heparin dosing is particularly important when low-dose recombinant plasminogen activators are used with abciximab. Thus, the GUSTO-IV acute MI trial, which will randomize 16 600 patients to reteplase with or without abciximab, will use standard heparin dosing (60 U/kg).
This trial used angiography at a median 62 minutes to assess the effectiveness of reperfusion therapies. A 60-minute angiogram may provide data qualitatively as important as that from a 90-minute angiogram,2 but TIMI grade 3 flow rates are ≈8% to 9% higher at 90 minutes. The present guidelines mandate that primary PTCA should begin within 1 hour of arrival to be the preferred reperfusion strategy; waiting 90 minutes to perform angiography may be inappropriate. In the GUSTO-IIb substudy of primary PTCA for acute MI, the incidence of TIMI grade 3 flow after PTCA (median time to balloon inflation, 1.3 hours after randomization) was 73%, with analysis by the same core laboratory.18 Thus, the target for reperfusion therapies should be to achieve early TIMI grade 3 flow rates comparable to those achieved with primary PTCA (78% to 95%).19 The present study also confirms the TIMI grade 3 flow rate of 51% at 60 minutes for reteplase from the Reteplase vs Alteplase Patency Investigation During myocardial infarction (RAPID II) trial.6
Bleeding complications in this trial were similar to those seen in other angiographic trials of reperfusion therapy.3 4 19 Combined plasminogen activation and platelet glycoprotein IIb/IIIa inhibition had only a minor effect on overall bleeding as judged by a bleeding index. The true rate of intracranial hemorrhage with abciximab and reteplase combined remains unknown. This also will be assessed in the GUSTO-IV acute MI trial.
Adding reteplase to abciximab treatment of acute MI can increase the incidence of complete reperfusion as early as 1 hour after therapy begins. Reperfusion rates with this combination appear sensitive to the amount of heparin given concomitantly. The combination of full-dose abciximab, reteplase 5+5 U bolus doses, and 60 U/kg heparin provides a 61% incidence of TIMI grade 3 flow at 60 minutes, which is superior to standard reteplase alone (47%) and historical controls. This therapy offers an opportunity to improve the outcome after acute MI by providing earlier more complete reperfusion.
SPEED Trial Organization
Coprincipal Investigators: E.J. Topol and E.M. Ohman.
Operations Committee: E. Barnathan, R.M. Califf, K.L. Lee, A.M. Lincoff, E.M. Ohman, J. Scherer, R. Scott, M.H. Sketch Jr, E.J. Topol, and H.F. Weisman.
Clinical and Data Coordinating Center: Duke Clinical Research Institute: W. Cantor, B. Evans, J. Harris, J. Kirby, J. Miller, D. Minshall, R.M. Oliverio, A.L. Stebbins, L. Webb, and J. Wittlief.
Executive Coordinating Center: Cleveland Clinic Foundation: E.J. Topol and A.M. Lincoff.
Angiographic Core Laboratory: Cleveland Clinic Foundation: D.J. Moliterno and T. Ivanc.
Sponsor: Lilly-Centocor: E. Barnathan, L. Damaraju, K. Hadley, L. Kukulewicz, J. Scherer, R. Scott, R. Schwarz, M. Waller, and H. Weisman.
US Sites: Cleveland Clinic Foundation: A.M. Lincoff; Pinnacle Health Hospital: W.B. Bachinsky; Erlanger Medical Center: C. Bell; Lee Memorial Hospital: J.F. Butler; Providence Hospital: S.W. David; Mease Hospital Dunedin: K. Gibbs; Good Samaritan Hospital and Health Center: M. Sakhaii; North Memorial Medical Center: G. Hanovich; University of Pennsylvania Health System: H. Herrmann; Vanderbilt University Medical Center: W. Hillegass; Christ Hospital, Jewish Hospital Kenwood, and University Hospital: D.J. Kereiakes; Fairfax Hospital: J. Kiernan; Baptist Memorial Hospital: F.A. McGrew; Lutheran Medical Center: J.S. Miklin; Alexandria Hospital: L. Miller; Duke University Medical Center: M.H. Sketch Jr; Oakwood Hospital and Medical Center: A. Riba; St. John Hospital and Medical Center: T.L. Schreiber; Hermann Hospital: R.W. Smalling; John L. McClellan Memorial Veterans Hospital: J.D. Talley; Lancaster General Hospital and St. Joseph Hospital: S. Worley; University of Michigan Medical Center: E.R. Bates; Peninsula Regional Medical Center: S. Hearne; Emory University Hospital and Crawford Long Hospital: D.C. Morris; St. Luke’s and St. Alphonsus Regional Medical Centers: M.F. Priest; St. John’s Hospital and Health Center: P. Pelikan; Memorial Hospital: A.A. Seals; St. Vincent Hospital: J.E. Smith; Easton Hospital: D. Mascarenhas; St. Louis University Hospital: R.G. Bach; Good Samaritan Regional Medical Center: N. Laufer; Scripps Mercy Hospital: P.S. Phillips; Central Baptist Hospital: R. McClure; Mother Frances Hospital: F.I. Navetta; and MeritCare Medical Center: V. Bhoopalam.
International Sites: Flinders Medical Centre: P.E. Aylward; Policlinico San Matteo: D. Ardissino; Hospital Clinic I: A. Betriu; Ospedale S. Maria della Misericordi: G. Morocutti; St. Vincent Hospital: D.W.M. Muller; Hospital Italiano de Buenos Aires: L. Grinfeld, A. Cagide; Universiteit Heidelberg: C. Bode; Krankenhaus Neukoelln: F. Forycki; Royal Melbourne Hospital: J. Lefkovits; Hopital Bichat: G. Steg; Hospital Universitario San Carlos: C. Macaya; Universiteit-Klinikum Benjamin Franklin: H.P. Schultheiss; and Inselspital: F. Eberli.
This study was funded by Eli Lilly and Co, Indianapolis, Ind, and Centocor, Inc, Malvern, Pa. The authors thank Betty Summers for secretarial assistance and Pat French for editorial assistance.
Reprint requests to E. Magnus Ohman, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.
↵1 Participants in SPEED are listed in the Appendix. On behalf of the Operations Committee, Dr Ohman assumes overall responsibility for this article.
- Received August 18, 1999.
- Revision received January 3, 2000.
- Accepted January 25, 2000.
- Copyright © 2000 by American Heart Association
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