Randomized Comparison of Coronary Thrombolysis Achieved With Double-Bolus Reteplase (Recombinant Plasminogen Activator) and Front-Loaded, Accelerated Alteplase (Recombinant Tissue Plasminogen Activator) in Patients With Acute Myocardial Infarction

Patients of each sex were considered candidates for the trial if they were >18 years old with ≥30 minutes of typical chest pain that was not relieved by nitroglycerin and ST-segment elevation of ≥0.1 mV in two of three inferior or lateral leads or ≥0.2 mV in at least two contiguous precordial leads or left bundle-branch block and presenting within ≤12 hours from onset of ischemic chest pain to the planned administration of treatment. There was no age limitation. Patients were excluded if they had had prior coronary artery bypass graft surgery, previous stroke or known intracranial structural abnormalities, previous percutaneous transluminal coronary angioplasty within 2 weeks, previous Q-wave myocardial infarction in the same anatomic region as the qualifying infarction, or severe hypertension (>180/110 mm Hg) not rapidly responding to treatment. Additional exclusion criteria consisted of concomitant use of oral anticoagulation, prolonged vigorous cardiopulmonary resuscitation (within 2 weeks), previous puncture of a noncompressible vessel (within 2 weeks) or organ biopsy, major surgery (including intracranial, intraspinal, or intraocular surgery), or active or potential internal bleeding (eg, peptic ulcers) in the previous 3 months. Women with child-bearing potential were also excluded. The protocol was approved by the institutional review board or ethics committee at each hospital or region, and written informed consent was obtained from each patient.

The RAPID II trial was conducted in 20 centers in the United States and 5 centers in Germany and overseen by international steering and safety committees. Cinefilms from all centers were evaluated in a blinded fashion at a single angiographic core laboratory (see the “Appendix”).

The RAPID II trial was a multicenter, open-label, parallel-group study in which eligible patients were randomized to receive either a double bolus of reteplase (a 10 MU bolus given over 2 to 3 minutes at the start of therapy followed by an identical 10 MU bolus 30 minutes later) or the “accelerated” alteplase regimen (Activase, Genentech, or Actilyse, Thomae): 15-mg bolus, 0.75 mg/kg over 30 minutes (maximum: 50 mg), 0.5 mg/kg over 60 minutes (maximum: 35 mg). One hundred sixty-five patients were randomized to receive reteplase, and 159 patients were randomized to receive alteplase therapy. There were 4 patients who were inadvertently randomized to receive the wrong regimen. Results are reported according to the treatment received; all results were very similar regardless of whether the analyses were done according to the treatment received or intention to treat. Adjunctive therapy, given immediately before administration of the thrombolytic agent, consisted of aspirin (160 to 350 mg/d), continued on a daily basis until discharge, and intravenous heparin, administered as a 5000 IU bolus followed by 1000 IU/h to be given for ≥24 hours. The activated partial thromboplastin time was measured, and heparin dose was adjusted to maintain a value as close as possible to 2.0 times the control value. Other medications were administered at the discretion of the treating physician. Coronary angiography was performed at 30, 60 (whenever possible), and 90 minutes (mandatory) after the initiation of thrombolytic therapy to determine patency of the infarct-related coronary artery and to treat patients with mechanical reperfusion if the infarct-related coronary artery remained occluded. The first coronary injection at each time period was used for evaluation of TIMI flow. At 30 and 60 minutes, no more than two injections into the infarct-related artery were allowed. Left ventriculography was also performed. TIMI flow was estimated by the individual investigator at 90 minutes. Mechanical or further medical interventions were left to the discretion of the investigator but were not to be performed unless there was clear evidence of ongoing ischemia or impaired flow (TIMI flow grade ≤2). Coronary angiography and left ventriculography were repeated between 5 days after hospital admission and hospital discharge for assessment of TIMI flow in the infarct-related coronary artery and global and regional left ventricular function. Blood samples for assessment of activated partial thromboplastin time, blood counts, and chemistry including cardiac enzymes were obtained during the first 3 days and before discharge. A follow-up visit was performed at 35 days after the initial admission to assess survival of the patients.

The primary end point of the RAPID II trial was coronary patency as assessed by TIMI flow grade at coronary angiography 90 minutes after initiation of thrombolytic therapy. Secondary end points were coronary patency by TIMI flow grade at 30 and 60 minutes and 5 to 14 days after initiation of therapy, reocclusion at 5 to 14 days after therapy, and global (ejection fraction) and regional (infarct zone) left ventricular function at 90 minutes and 5 to 14 days after therapy. Clinical end points, including stroke, reinfarction, heart failure, recurrent angina/ischemia, and coronary interventions (including percutaneous transluminal coronary angioplasty, atherectomy, rotablation, bypass surgery, and intracoronary thrombolysis within 35 days) were also evaluated. Bleeding episodes were monitored during the period of hospitalization. Major bleeding was defined as either intracranial bleeding or bleeding requiring transfusion or prolonging the period of hospitalization. A composite end point “unsatisfactory clinical outcome” at 35 days was defined as any of the following events: death, reinfarction, heart failure, or ejection fraction of <40% (or <35% for patients with a previous myocardial infarction) at angiography 5 to 14 days after therapy.¹⁴

The study was to be performed with 150 patients per group. This relatively small cohort limits the power with respect to relatively rare observations such as complications, death, and stroke. Assuming that the underlying 90-minute total patency and TIMI grade 3 patency rates for reteplase were 85% and 60%, respectively, this sample size provided 80% power to show a 9% difference in total patency rates between reteplase and alteplase. Differences in overall patency and TIMI flow rates and all clinical end points, except stroke and intracranial hemorrhage, were tested with Pearson's χ² statistic. Differences in stroke and intracranial hemorrhage were tested by Fisher's exact test. All tests were performed at the nominal .05 level of significance. Continuous variables are presented as mean±SD values. Patency data are presented with 95% CIs in parentheses.

A total of 324 patients were enrolled between November 11, 1993, and October 26, 1994. One hundred sixty-nine patients were treated with reteplase, and 155 patients received front-loaded “accelerated” alteplase therapy. As listed in Table 1, there were no significant differences among the two groups in baseline characteristics, including age, sex, ethnicity, weight, height, median time to treatment, infarct location, blood pressure, and cardiovascular history, with the exception that more patients in the reteplase group had a history of previous myocardial infarction (17 versus 8; P=.04). One hundred fifty-seven patients (92.9%) in the reteplase group and 146 patients (94.2%) in the alteplase group had an angiogram performed at 90 minutes. The principal demographic and baseline cardiovascular characteristics of the patients included in the analysis of 90-minute patency were not different from those of the overall group.

Patency was more rapidly and more completely achieved in reteplase-treated patients. Complete reperfusion (TIMI grade 3 flow) at 90 minutes was achieved in 59.9% (52.2% to 67.5%) in the reteplase group compared with 45.2% (37.1% to 53.3%) in the accelerated alteplase group (P=.011) (Fig 1 and Table 2); on an intention-to-treat basis, values were 60.1% versus 45.3%, respectively. Total patency (TIMI grade 2 and 3 flow) was also significantly higher in the reteplase group with 83.4% (77.6% to 89.3%)than in the alteplase group with 73.3% (66.1% to 80.5%) (P=.031); on an intention-to-treat basis, values were 83.7% versus 73.3%, respectively.

Patency was achieved more rapidly in the reteplase-treated group. At 60 minutes, the total patency was 81.8% (75.0% to 88.7%) in the reteplase group compared with 66.1% (57.4% to 74.7%) in the alteplase group (P=.032), and TIMI grade 3 flow was 51.2% (42.3% to 60.2%) versus 37.4% (28.6% to 46.2%), respectively (P=.006). Sixty-minute total patency and TIMI grade 3 flow in the reteplase group were slightly, but not significantly, higher than the corresponding 90-minute results of the alteplase group.

Follow-up angiograms were available in 75.7% (128 of 169) of patients treated with reteplase and in 72.9% (113 of 155) of the alteplase-treated patients. Late overall and TIMI grade 3 flow patencies were similar in the reteplase group (89.1% [83.7% to 95.0%] and 75.0% [67.5% to 82.5%]) and the alteplase group (90.3% [84.8% to 95.7%] and 77.0% [69.2% to 84.8%]).

Subgroup analyses of TIMI grade 3 flow and overall patency at 90 minutes by sex, weight, infarct-related artery, and time to treatment since onset of pain showed that the relative differences in the two treatment groups were comparable for all subgroups. There was a significant effect of time to treatment influencing therapeutic success. In both groups, patients who received treatment within 6 hours after the onset of symptoms had better overall patency and TIMI grade 3 flow than did patients receiving treatment between 6 and 12 hours. However, patients treated with reteplase had better patency in all time-to-treatment categories. Overall patency and TIMI grade 3 flow were 86.5% and 62.4% within 6 hours and 60.0% and 40.0% after 6 hours for reteplase. The corresponding rates for alteplase were 77.2% and 47.2% within 6 hours and 52.2% and 34.8% afterward.

During the first 6 hours after treatment, the need for additional interventions to restore normal blood flow in the infarct-related coronary artery was significantly lower in the reteplase group compared with the alteplase group (13.6% versus 26.5%; P=.004) (Fig 2).

The RAPID II trial was designed to detect differences in patency; it did not have sufficient power to detect differences in adverse events between the groups.

The incidence of reocclusion during the hospital stay did not differ between the groups, with rates of 9.0% for reteplase and 7.0% for alteplase (P=.61 [NS]) (Fig 2).

The 35-day follow-up was 99.4% complete for patients receiving reteplase and 98.7% complete for those receiving alteplase. Mortality rates were 4.1% in the reteplase and 8.4% in the alteplase group (P=.11 [NS]) (Fig 2). All patients died as a result of cardiac disease, except for one patient in the alteplase group, whose primary cause of death was intracranial hemorrhage. The importance of the primary effectiveness variable of this trial, TIMI flow grade at 90 minutes, is underscored by the significant inverse correlation between 35-day mortality rate and TIMI flow grade. Regardless of the thrombolytic agent used, 12.2% of patients with TIMI flow grade 0 and grade 1 had died at 35 days. In contrast, only 3.8% of patients with TIMI grade 2 flow and 4.2% of patients with TIMI grade 3 flow at 90 minutes experienced this fate (P<.05) (Fig 3).

The incidence of stroke was similar for the reteplase (1.8%) and alteplase (2.6%) groups; of these, 1.2% and 1.9% were hemorrhagic stroke (Fig 2). The sum of catastrophic events, death or nonfatal disabling stroke within 35 days, was 5.3% for reteplase- and 9.0% for alteplase-treated patients.

The composite end point of unsatisfactory outcome at 35 days after treatment (comprising death, reinfarction, congestive heart failure, or shock and/or an ejection fraction of <40% at predischarge evaluation) was present in 21.3% of reteplase-treated patients and 22.6% of those receiving alteplase treatment as shown in Table 4.

Of reteplase-treated patients, 12.4% required transfusions (excluding those undergoing surgery) compared with 9.7% of alteplase-treated patients (P=.43 [NS]). After exclusion of puncture site bleeds (to approximate the situation in a noninvasive setting), 5.3% and 3.2% of bleedings requiring a transfusion remained (P=.35 [NS]; see Table 5). Of all hemorrhages, 4.4% and 3.0% were rated as severe or life threatening.

There was no significant difference in global or infarct zone left ventricular function between treatment groups, either in the acute study or before discharge (Fig 4).

At both the 60- and 90-minute time points, reteplase demonstrated significantly higher rates of total (TIMI grade 2 or 3) and complete (TIMI grade 3) patencies than did front-loaded alteplase. Reteplase achieved 81.8% total patency (51.2% complete) as early as 60 minutes after the start of therapy, in contrast to 66.1% (37.4% complete) in the front-loaded alteplase group. The results suggest that reteplase achieves coronary patency 30 minutes sooner than alteplase. The reteplase patency rates reported here compare favorably with those achieved with front-loaded alteplase in the TIMI 4 trial.¹⁹ In contrast to the present trial, TIMI 4 included patients only up to 6 hours after the onset of pain and excluded patients >80 years old. Therefore, somewhat higher patency rates were to be expected.

The earliest angiographic assessment in the GUSTO trial took place at 90 minutes.⁵ In this trial, front-loaded alteplase achieved 80.8% total patency (53.8 complete), a result similar to the 60-minute outcome for reteplase in the present study. Although GUSTO did not have an age limit, recruitment stopped at 6 hours after the onset of pain. In the present study, front-loaded alteplase achieved 73.3% patency (45.2% complete), a result comparable to GUSTO, given the differences in trial design. Furthermore, for patients recruited within the first 6 hours, alteplase achieved a 90-minute patency rate of 77.2% (P=.41 versus GUSTO) and 47.2% complete patency (P=.22 versus GUSTO) in the present study. The double-bolus regimen of reteplase achieves higher patency than front-loaded alteplase at 90 minutes in direct comparison (patency 83.4%, complete 59.9%). If patients recruited beyond the 6-hour limit are excluded from the RAPID II cohort, 90 minute patency for reteplase is 86.5% with 62.4% TIMI grade 3 flow.

The results of the GUSTO angiographic substudy⁵ relative to the GUSTO mortality trial⁶ suggest that the superiority of double-bolus reteplase over front-loaded alteplase and older alteplase regimens in early achievement of infarct-related coronary patency at 60 and 90 minutes may translate into a clinical advantage of reteplase treatment. The benefit of early reperfusion, especially TIMI grade 3 flow (complete patency), has been associated with smaller infarct size,^{5 21} improved left ventricular function,^{22 23} a lower rate of reocclusion,^{24 25} and improved survival.^{5 20} In fact, regardless of the treatment regimen, patients with TIMI grade 2 or 3 flow had a significantly lower mortality in this study than did those with no reperfusion. In the present study, there was no difference in mortality for patients with either TIMI grade 2 or 3 flow. Until definitively decided in a larger study, these findings suggest that TIMI grade 2 flow may be associated with more survival benefit than previously thought or, alternatively, the core laboratory of the present study may have applied more rigid standards to TIMI grade 2 flow, approximating those of TIMI grade 3 flow in previous studies. This should be taken into account when comparing different studies. Finally, conversion of TIMI grade 2 flow at 90 minutes into TIMI grade 3 flow by rescue angioplasty may be beneficial to patients with acute myocardial infarction.

Although this relatively small trial was not of sufficient size to detect differences in mortality, double-bolus reteplase was associated with fewer deaths. Mortality was possibly further influenced by the use of rescue angioplasty, which became necessary significantly more often in front-loaded alteplase–treated patients. Given the higher efficacy in restoring TIMI grade 3 flow of the reteplase regimen and taking into account data that suggest that early percutaneous transluminal coronary angioplasty after thrombolysis confers no additional benefit to the patient when flow is adequate, the difference in acute interventions is to be expected. As illustrated in Table 3, there was no significant difference in the percentage of patients undergoing coronary artery interventions on predischarge angiography. The high overall intervention rate in the reteplase (66.3%) and alteplase groups (71.0%) suggests that the RAPID II centers were comparatively aggressive in their choice of treatment.

There was no difference in either global or infarct zone left ventricular function between the treatment groups, a result that also may have been biased by the use of rescue angioplasty. Another factor that may have contributed to the finding that the thrombolytic strategy that resulted in more open infarct-related arteries did not result in improved left ventricular function is the imbalance (alteplase group versus reteplase group: 8 versus 17 patients) with respect to patients with previous myocardial infarction between the two groups. The incidence of reocclusion was no different between the two groups—a result that also might have been different had the investigators been less aggressive in the application of mechanical revascularization procedures. Notably, there was no apparent increase in the risk of bleeding or stroke associated with the more effective double-bolus reteplase regimen.

Thrombolytic therapy with reteplase was previously shown to result in higher patency rates than conventional alteplase (100 mg/3 h).¹³ The present trial shows enhanced efficacy versus front-loaded alteplase (100 mg/90 min), the best alteplase regimen so far tested in randomized trials. An attractive feature of the double-bolus reteplase regimen is the ease of bolus administration compared with the relative complexity of infusions of varying speed of front-loaded alteplase. Taken together, these properties suggest that double-bolus reteplase may well be the regimen of choice for prehospital thrombolysis.

The observed enhanced efficacy of reteplase in achieving early patency may not be entirely due to differences in the molecular structure of reteplase and alteplase. The double-bolus reteplase regimen administers 100% of the drug within 30 minutes, whereas only 65% of alteplase has been administered at this time point. In fact, a nonrandomized, single-center, observational study reports that a double-bolus regimen of twice 50 mg alteplase administered 30 minutes apart results in higher patency rates than the front-loaded alteplase regimen used in the present trial.²⁶ Similar results have been reported for a front-loaded alteplase regimen using 100 mg over 60 minutes.²⁷ Thus, the results of this trial underscore the importance and relative safety of the concept of aggressive bolus administration of plasminogen activators in acute myocardial infarction. New plasminogen activators,^{28 29} improved schemes of administration (possibly also for reteplase), the advent of advanced antithrombotic agents like direct thrombin inhibitors,^{30 31 32} and platelet receptor antagonists^{33 34} to be combined with any of the plasminogen activators may well further improve the risk/benefit ratio for thrombolytic therapy and its relative value compared with direct percutaneous transluminal coronary angioplasty.³⁵

Reteplase was most recently shown to be at least as effective as streptokinase in reducing mortality in patients with acute myocardial infarction.³⁶ In fact, the INJECT study, which enrolled 6000 patients, had insufficient power to detect possible superiority. It did provide evidence, however, that the rate of intracranial bleeding should not exceed that reported for front-loaded alteplase. Based on these results and those of the present study, a larger mortality trial, comparing reteplase and front-loaded alteplase, appears to be warranted.

C. Bode, Universita¨t Heidelberg, Germany; R.W. Smalling, The University of Texas Medical School (Houston); W.D. Weaver, University of Washington Medical Center, Seattle.

A.D. Guerci, Roslyn, NY; K.-L. Neuhaus, Kassel, Germany.

D.J. Moliterno, T.B. Ivanc, and T. Crowe, Cleveland Clinic Foundation, Cleveland, Ohio.

Boehringer Mannheim GmbH: Erwin Bo¨hm, Adalbert Smolarz, Guenter Schirmer, Wolfgang Meyer-Sabellek. Boehringer Mannheim Pharmaceuticals Corp: Daniel J. Odenheimer.

Highline Community Hospital, Seattle, Wash: principal investigator, C. Burnett; D. Hansen, K. Kriesman, D. Gottlieb, B. Green; Valley Medical Center, Renton, Wash: principal investigator, G. Lorch; T. Block, J. Nemanich, R. Utley; Saint Francis Hospital, Tulsa, Okla: principal investigator, J.M. Kalbfleisch; R.C. Slagle, D.L. Brewer, C.W. McEntee, R.D. Okada, M.G. Spain, J.S. Waters, V. Wagner; Taylor Hospital, Ridley Park, Pa: principal investigator, R. Chernoff; R. Weiner, P. Bhark, S. Rudy, A. Meltzer; Harborview/University of Washington Medical Center (Seattle): principal investigator, W.D. Weaver; B. Titus, J. Chambers, C. Lee; Sacred Heart General Hospital, Eugene, Ore: principal investigator, L.G. Christie; J.H. Chappell; Munroe Regional Medical Center, Ocala, Fla: principal investigator, R.L. Feldman; F. Hildner, P. Urban; Memorial Medical Center, Jacksonville, Fla: principal investigator, A.A. Seals; S.B. Baker, K.E. Gilmour, R.M. Baker, R.L. Pekaar, H.A. Baker, J. Hartley; University of California (Davis): principal investigator, E.A. Amsterdam; C.T. Kappagoda; Department of Veterans Affairs, Washington, DC: principal investigator, V. Papademetriou; P. Narayan, D. Lu; University of Texas, Hermann Hospital (Houston): principal investigator, R.W. Smalling; F. Fuentes, H.V. Anderson, J. Heibig, G. Li, G. Schroth; Houston Northwest Medical Center (Tex): principal investigator, V. Aquino; H. Bhatia, G. Coleman, B. Lachterman; St Elizabeth Hospital, Boston, Mass: principal investigator, K. Ramaswamy; Baylor College of Medicine, Houston, Tex: principal investigator, G.B. Habib; D.L. Mann, M. Jeroudi, J. Mickelson, G. Villarreal-Levy; Brotman Medical Center, Culver City, Calif: principal investigator, R.P. Karlsberg; S.J. Bhatia, F.L. Murphy, S.W. Tabak; Community Hospital East, Indianapolis, Ind: principal investigator, E.A. Harlamert; W.J. Bugni, R.E. Edmands, R.A. Hahn, S. Hazlett; University of Oklahoma and VA Medical Center (Oklahoma City): principal investigator, U. Thadani; E. Schechter, D. Reynolds, A. Kugelmass; Shelby Medical Center, Alabaster, Ala: principal investigator, T.O. Paul; M. McKinney, D. Elliott, J. McBrayer, K. Unnoppet; Deaconess Medical Center, Spokane, Wash: principal investigator, P.P. Leimgruber; K. Sutherland, T. Judge, M. Hinnen, G. Goodman; Memorial Hospital Nothwest, Houston, Tex: principal investigator, R.E. Morris; P.L. Berman, A. Ali, M.B. Baig, S.E. Ahmed. University of Maryland (Baltimore): principal investigator, A. Ziskind; S.D. Friedman, C. Rajasingh, B.J. Browne, R.A. Barish. University of Texas (San Antonio): principal investigator, S.R. Bailey; R.S. Kiesz.

Klinikum der Universita¨t Heidelberg: principal investigator, C. Bode; M. Moser, K. Peter, J. Ruef, B. Kohler, T. Nordt; Klinikum der Universita¨t Homburg: principal investigator, S. Sen; G. Berg; Klinikum der Universita¨t Go¨ttingen: principal investigator, A. Buchwald; H. Kreuzer, J. Rab; Stadtkrankenhaus Worms: principal investigator, P. Limbourg; E. Roth, W. Schmalz, R. Dick; St Vincentius Krankenhaus Karlsruhe: principal investigator, G. Schuler; H. Baumann, S. Abed.