Thrombolytic Therapy and Equivalence Trials*

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494 JACC Vol. 31, No. 3 March 1, 1998:494–6 Editorial Comment to streptokinase. In this commentary, the trial design and interpretation and issues of superiority, equivalence and suffi- Thrombolytic Therapy and ciency trials are discussed. The mechanism of benefit of thrombolytic therapy is the Equivalence Trials* opening of occluded infarct-related arteries (4). Maximal benefit is obtained when reperfusion is achieved early and flow HARVEY D. WHITE, DSC, FRACP, FACC, FESC in the infarct-related artery is brisk and sustained. Is it Auckland, New Zealand appropriate to assume that this paradigm will translate into a mortality reduction if a new agent is shown to achieve greater rates of Thrombolysis in Myocardial Infarction (TIMI) grade 3 The Fibrinolytic Therapy Trialists’ (1) overview of 58,600 flow (5) or a lower corrected TIMI frame count (6) than an patients randomized to receive either fibrinolytic or control established agent, thus avoiding the need for megatrials? treatment reported a 23% mortality reduction with fibrinolytic Two recent, large megatrials evaluating mortality outcomes therapy among patients who presented with myocardial infarc- have not confirmed the promising findings of pilot patency tion with ST segment elevation and were randomized within trials. TIMI grade 3 flow with t-PA was reported to be 88% 6 h of symptom onset. These data are compelling, and it is no when given as a double bolus (7) compared with 54% when longer ethical to withhold fibrinolytic therapy from patients administered over 90 min in the GUSTO-I trial (8). However, with these demographics. The mortality rate in the Global the Continuous Infusion Versus Double-Bolus Administration Utilization of Streptokinase and TPA [tissue plasminogen of Alteplase (COBALT) trial (9) in 7,169 patients showed that activator] for Occluded Coronary Arteries (GUSTO-I) trial double-bolus t-PA was “equivalent” to t-PA in its effects on was 6.3% with aspirin, tissue-type plasminogen activator (t- mortality. In the Reteplase Angiographic Phase II Interna- PA) and intravenous heparin. The intracranial hemorrhage tional Dose-Finding (RAPID-I and RAPID-II) trials, which rate was 0.72%, and the total stroke rate was 1.55%. These were the pilot studies for the Global Use of Strategies to Open figures are too high, and would not be accepted in other areas Occluded Coronary Arteries (GUSTO-III) trial, reteplase was of medicine. More effective thrombolytic regimens are there- shown to be superior to t-PA in achieving 90-min TIMI grade fore required, and these new regimens will preferably be safer, 3 flow (reteplase 63% vs. accelerated t-PA 49%, p Ͻ 0.05) more easily administered or cheaper. It is therefore incumbent (10,11). In the GUSTO-III trial, which enrolled 15,059 pa- on cardiologists to continue to explore ways of improving tients, reteplase was judged not to be superior to t-PA (12). patient outcomes after myocardial infarction and to test these Thus, angiographic patency at 90 min is not necessarily a in appropriately designed trials—but how can this be done if it perfect surrogate for mortality benefit and clearly cannot is unethical to use placebo-controlled trials? In this issue of the predict intracranial hemorrhage rates with new thrombolytic Journal, Tebbe et al. (2) use an equivalence design to test regimens. Larger trials are required to define benefit and risk. whether saruplase was “equivalent” to streptokinase in a The COBALT and GUSTO-III trials had different aims. randomized trial of 3,081 patients. GUSTO-III used the reference standard in clinical research Saruplase is unglycosylated single-chain urokinase-type (i.e., a double-blind, placebo-controlled design) with the hy- plasminogen activator, produced by genetically transformed pothesis that reteplase was superior to t-PA, and the statistical Escherichia coli. It is converted into active two-chain testing was done to reject the null hypothesis of no treatment urokinase-type plasminogen activator by plasmin, and it also difference. The COBALT trial was designed as a positive- activates plasminogen directly, largely in the presence of fibrin. control “equivalence” trial, which aimed to demonstrate the Saruplase has been associated with high patency rates in therapeutic equivalence of double-bolus administration and angiographic studies (3) and may be cheaper than other accelerated administration of t-PA by testing the null hypoth- currently available fibrin-specific thrombolytic agents. This esis that the absolute mortality difference at 30 days would be trial is much smaller than the Gruppo Italiano per lo Studio Ͼ0.4% with double-bolus t-PA. This value is the lower 95% della Sopravvivenza nell’Infarto Miocardico (GISSI-2) trial, confidence limit of the 1% mortality difference between t-PA the Third International Study of Infarct Survival (ISIS-3) or and streptokinase shown in GUSTO-I (8). If this boundary was the GUSTO-I trial, which together randomized between not exceeded, superiority of double-bolus t-PA over streptoki- 20,000 and 40,000 patients to detect whether t-PA was superior nase would have been claimed. This design is methodologically very different from a “null-control” trial. In equivalence trials the new thrombolytic agent should be *Editorials published in Journal of the American College of Cardiology reflect proved superior to control (i.e., nonthrombolytic) treatment, the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. and these trials generally need to be larger than superiority From the Department of Coronary Care and Cardiovascular Research, trials, not smaller (13). Given the streptokinase mortality rate Green Lane Hospital, Auckland, New Zealand. of 6.7% in the current trial, it would take 10,000 patients to Address for correspondence: Dr. Harvey D. White, Department of Coronary Care and Cardiovascular Research, Green Lane Hospital, Private Bag 92 189, show a 20% superiority of saruplase with a power of 80% and Auckland 1030, New Zealand. E-mail: [email protected]. p Ͻ 0.05. The current trial has only a 32% power to show a

Abbreviations and Acronyms COBALT ϭ Continuous Infusion Versus Double-Bolus Administration of Alteplase GUSTO-I ϭ Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries GUSTO-III ϭ Global Use of Strategies to Open Occluded Coronary Arteries TIMI ϭ Thrombolysis in Myocardial Infarction Figure 2. Comparison of streptokinase versus placebo from previous t-PA ϭ tissue-type plasminogen activator randomized, controlled trials showing a 24% reduction in mortality at 30 days with streptokinase (95% confidence interval 18% to 31%) and comparison of saruplase versus streptokinase showing a 16% mortality reduction (95% confidence interval Ϫ37% to 9%). The confidence limits do not overlap, therefore showing equivalence. 20% superiority. Failure to detect a difference in a statistically underpowered superiority trial does not prove equivalence, and “lack of evidence of difference” is not the same as symptom onset showed a 24% reduction in mortality (odds “evidence of a lack of difference.” The current trial was ratio 0.76, 95% confidence interval 18% to 31%) (15–20). If designed to exclude a mortality increase of 50% with saruplase exclusion of an 18% increase in mortality with saruplase over over streptokinase and to claim equivalence if the difference in streptokinase had been chosen in the current trial (i.e., to mortality was Ͻ50%. exclude overlapping the lower boundary of the confidence The choice of a prespecified absolute difference to define interval), the statistical power would have been only 23%. equivalence has been used in other trials (9,14). This approach Figure 2 depicts the results of the current trial, which shows increases the chance of showing equivalence if a low risk a 16% mortality reduction with saruplase versus streptokinase, population is studied. For example, it would be much more with an upper 95% confidence limit of 1.09 (i.e., there could be difficult to show a 1% absolute difference between a new agent a 9% increase in mortality with saruplase) not overlapping the and t-PA if the baseline mortality were 5% than if the baseline confidence limits of the previous streptokinase versus control mortality were 10%. In the present trial, the mortality rate at trials. Saruplase has therefore been shown to be equivalent to 30 days was 6.7% in patients randomized to receive streptoki- streptokinase, but not superior. It would also have been nase, which compares with a mortality rate of 12% in previous informative to explore the consistency of this effect across streptokinase versus control trials (15–20) and a 42% higher subgroups, such as the elderly, patients with anterior infarc- mortality of 9.5% in the International Joint Efficacy Compar- tion, patients presenting before and after 6 h and those actually ison of Thrombolytic’s (INJECT) trial (14), a previous equiv- receiving the treatments. alence trial of reteplase versus streptokinase. It is very important that a population similar to that in the Rather than using absolute reductions, the preferred ap- previous streptokinase versus control trials be used if assump- proach may be to use a prespecified percentage or odds tions are to be made about superiority to control treatment. reduction for limits of the range of equivalence, as in the Age is the most important adverse prognostic factor for current trial, in which a prespecified odds ratio of 1.5 was mortality and stroke (21), and it is surprising that the first 800 chosen. According to this definition, if the 95% confidence patients enrolled in the current study excluded those Ͼ75 years limits do not overlap this boundary, the new treatment can be old. One cannot therefore confidently apply the trial results to regarded as equivalent (13) (Fig. 1). elderly patients, in whom streptokinase may be preferred Six previous trials of streptokinase versus control treatment because of its lower rate of intracranial hemorrhage. in patients randomized with ST segment elevation within6hof There were also imbalances between the patients random-

Figure 1. Equivalence testing with a range of equivalence and statistical significance. Horizontal lines ϭ 95% confidence intervals; dashed vertical lines ϭ limits of the range of equivalence. Ϫve ϭ negative; ϩve ϭ positive. Modified, with permission, from Jones et al. (13). 496 WHITE JACC Vol. 31, No. 3 EDITORIAL COMMENT March 1, 1998:494–6 ized to receive saruplase and those randomized to receive pro-urokinase against streptokinase in acute myocardial infarction. Lancet streptokinase. The two significant imbalances would count 1989;1:863–8. 4. Simes RJ, Topol EJ, Holmes DR Jr, et al. Link between the angiographic against streptokinase. Patients who received streptokinase substudy and mortality outcomes in a large randomized trial of myocardial were, on average, 1.1 years older than those who received reperfusion: importance of early and complete infarct artery reperfusion. saruplase, and 4.2% more patients in the saruplase group were Circulation 1995;91:1923–8. current smokers, who have been shown to have a lower 30-day 5. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue mortality rate than that of nonsmokers or ex-smokers (22). plasminogen activator and intravenous streptokinase: clinical findings When comparing a new thrombolytic agent with an estab- through hospital discharge. Circulation 1987;76:142–54. lished agent it is necessary to show that the new agent is 6. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative “clinically” indistinguishable from the old agent (i.e., similar method of assessing coronary artery flow. Circulation 1996;93:879–88. 7. Purvis JA, McNeill AJ, Siddiqui RA, et al. Efficacy of 100 mg of double-bolus enough to be clinically accepted as equivalent). This type of alteplase in achieving complete perfusion in the treatment of acute myocar- trial has been termed a “sufficiency trial.” Do the results of the dial infarction. J Am Coll Cardiol 1994;23:6–10. current trial enable us to declare that saruplase and streptoki- 8. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med nase are clinically similar? The investigators of the saruplase 1993;329:673–82. trial provide supportive, but not compelling, evidence that 9. The Continuous Infusion Versus Double-Bolus Administration of Alteplase saruplase is a suitable alternative to streptokinase. The intra- (COBALT) Investigators. A comparison of continuous infusion of alteplase cranial hemorrhage rates were 0.9% and 0.3% for saruplase with double-bolus administration for acute myocardial infarction. N Engl Ͻ J Med 1997;337:1124–30. and streptokinase, respectively (p 0.05). The 95% confi- 10. Smalling RW, Bode C, Kalbfleisch J, et al. More rapid, complete, and stable dence interval includes an absolute increase of 0.3% to 1.4% in coronary thrombolysis with bolus administration of reteplase compared with intracranial hemorrhage with saruplase. However, the num- alteplase infusion in acute myocardial infarction. Circulation 1995;91:2725– bers of patients with total stroke and nonfatal disabling strokes 32. 11. Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary were similar, but again the confidence intervals are wide, with thrombolysis achieved with double-bolus reteplase (recombinant plasmino- the possibility of a 0.8% reduction in stroke or a 0.9% absolute gen activator) and front-loaded, accelerated alteplase (recombinant tissue increase with saruplase. plasminogen activator) in patients with acute myocardial infarction. Circu- Conclusions. There are three approaches for improving on lation 1996;94:891–8. 12. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO the current thrombolytic regimens. The first is to attempt to III) Investigators. A comparison of reteplase with alteplase for acute improve on nature with a more effective mutant or chimeric of myocardial infarction. N Engl J Med 1997;337:1118–23. native t-PA. To date this improvement has not been achieved. 13. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the The drugs being tested in current megatrials—lanoteplase and importance of rigorous methods. BMJ 1996;313:36–9. 14. International Joint Efficacy Comparison of Thrombolytics. Randomised, TNK–t-PA—have several features with the potential to im- double-blind comparison of reteplase double-bolus administration with prove patient care. However, in small trials without the power streptokinase in acute myocardial infarction (INJECT): trial to investigate to draw definitive conclusions, the stroke rates with these equivalence [published erratum appears in Lancet 1995;346:980]. Lancet agents have been similar to those with t-PA, which was 1995;346:329–36. 15. Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington Ran- associated with a stroke rate of 1.83% in the GUSTO-III trial. domized Trial of Intracoronary Streptokinase in Acute Myocardial Infarc- A second approach is to reduce the dose of the thrombolytic tion. N Engl J Med 1983;309:1477–82. agent and add a glycoprotein IIb/IIIa receptor antagonist. A 16. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myo- third approach is to add an adjunctive therapy, such as hirulog, cardial infarction. Lancet 1986;1:397–402. to streptokinase, the aim being to improve patient outcome by 17. The ISAM Study Group. A prospective trial of intravenous streptokinase in improving infarct-related artery patency without increasing the acute myocardial infarction (ISAM): mortality, morbidity, and infarct size at stroke rate (22). All three approaches are presently being 21 days. N Engl J Med 1986;314:1465–71. 18. Collins R, Conway M, Alexopoulos D, et al., for the ISIS Pilot Study evaluated in equivalence or superiority trials that will total Investigators. 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