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1. JOURNAL CLUB18/6/2024 MODERATOR - Dr. G.SRINIVAS PRESENTED BY- DR.S.KRISHNA HAMSINI FIRST YEAR RESIDENT DEPARTMENT OF GENERAL MEDICINE

2. RETEPLASE VERSUS ALTEPLASE FOR ACUTE ISCHEMIC STROKE Shuya Li, M.D., Hong-Qiu Gu, Ph.D., Hao Li, M.D., Ph.D., Xuechun Wang, M.D., Aoming Jin, Ph.D., Shuming Guo, M.D., Guozhi Lu, M.D., Fengyuan Che, M.D., WeiweiWang, M.D., Yan Wei, M.D., Yilong Wang, M.D., Zixiao Li, M.D., Xia Meng, M.D., Xingquan Zhao, M.D., Liping Liu, M.D., and Yongjun Wang, M.D. Published in New England Journal of Medicine. Published on JUNE 14, 2024. DOI: 10.1056/NEJMoa2400314

3. CONTENTS INTRODUCTION TO THE STUDY METHODS - TRIAL DESIGN AND OVERSIGHT - TRIAL PATIENTS, TREATMENT, OUTCOME, STATISTICAL ANALYSIS RESULTS - TRIAL PATIENTS.PATIENT CHARACTERISTICS,EFFICACY OUTCOMES - - DISCUSSION - TRIAL STRENGTHS - TRIAL LIMITATIONS CONCLUSION

4. INTRODUCTION Reperfusion therapy is an evidence- based intervention for ischemic stroke. Intravenous alteplase is the internationally approved standard thrombolytic agent for acute ischemic stroke within 4.5 hours after symptom onset. Recent studies have shown that tenecteplase, a genetically modified form of alteplase given as a single bolus, delivers clinical benefits similar to those of alteplase. Reteplase is a recombinant plasminogen activator that is characterized by a double-bolus ap- proach (the boluses are separated by 30 minutes) with a fixed dose regimen.Reteplase was ap- proved for the treatment of acute myocardial infarction in many geographic regions.A meta- analysis that compared reteplase with alteplase in patients with acute myocardial infarction showed no significant differences between the two treatments in terms of mortality or the incidence of disabling stroke.

5. METHODS - TRIAL DESIGN AND OVERSIGHT The RAISE trial was a phase 3, multicenter, prospective, open-label, noninferiority, randomized trial with blinded end-point assessment The open-label design was implemented because of the unavailability of placebo and to avoid potential delay in the administration of thrombolytic agents. The trial was approved by the institutional review board at the Beijing Tiantan Hospital and at each participating site. Written informed consent was provided by all the patients or their representatives. An independent data and safety monitoring committee monitored the progress of the trial, with regular assessment of safety outcomes, overall trial integrity, and trial conduct.

6. TRIAL PATIENTS Patients were eligible if they were 18 to 80 years of age, could receive intravenous thrombolysis within 4.5 hours ,they had last been known to be well, had excellent functional status before the onset of their stroke Ischemic stroke is typically diagnosed by means of noncontrast computed tomography or magnetic resonance imaging in patients with symptoms of neurologic impairment. Patients were excluded from participation if they had previously undergone or were planned to undergo endovascular thrombectomy.

7. TREATMENT Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous reteplase or intravenous alteplase. The intravenous thrombolytic treatment was conducted in an open-label manner. Reteplase was given as two intravenous 18-mg bolus doses, each administered over a period of 2 minutes; the first dose was administered immediately after randomization and the second 30 minutes later. Alteplase was administered at a dose of 0.9 mg per kilogram (maximum dose, 90 mg) with 10% of the dose delivered as a bolus within 1 minute; the remaining dose was infused intravenously during the subsequent 60 minutes. All other treatments followed standard practice for the management of ischemic stroke

8. OUTCOMES The primary efficacy outcome was an excellent functional outcome, defined as a modified Rankin scale score of 0 or 1 at 90 days. The secondary efficacy outcomes included a good functional outcome (defined as a modified Rankin scale score of 0 to 2 at 90 days), the ordinal distribution of the modified Rankin scale score at 90 days, early dramatic recovery with respect to the NIHSS score (defined as a decrease of ≥4 points or a score of ≤1 at 24 hours and at 7 days), and a Barthel In- dex score of at least 95 (range, 0 to 100, with higher scores indicating better independent function) at 90 days.

9. STATISTICAL ANALYSIS a sample size of 1412 patients would provide the trial with 85% power, at a one-sided significance level of 0.025, to show the noninferiority of re- teplase to alteplase with respect to an excellent functional outcome, with the lower limit of the 95% confidence interval of the risk ratio being higher than 0.93, assuming a real efficacy risk ratio of 1.05 and a dropout rate of 3%. The non- inferiority margin of 0.93 was defined to pre- serve at least 50% of the most conservative estimate of the efficacy of alteplase as compared with placebo, which was based on a lower limit of the 95% confidence interval of the risk ratio of 1.15, as derived from two randomized clinical trials.1,2

10. The P value for noninferiority was derived from the Farrington–Manning score test Risk ratios of reteplase versus alteplase were calculated from robust Poisson regression models,25 with trial center as a random effect. The analysis of the ordinal distribution of the modified Rankin scale score was performed with the use of ordinal logistic regression, with a chi-square score test to assess the proportional-odds assumption The safety outcomes were analyzed by means of robust Poisson regression models with trial center as the random effect in the safety popula- tion, which included randomly assigned patients who received reteplase or alteplase and had at least one post-treatment safety evaluation.

11. RESULTS - TRIAL PATIENTS Between March 21, 2022, and June 22, 2023, a total of 1412 patients with acute ischemic stroke from 62sites in China underwent randomization and were included in the intention-to treat population. with 707 patients assigned to receive reteplase and 705 assigned to receive alteplase. With the exclusion of 13 patients who did not receive reteplase or alteplase , 1399 patients were included in the safety population

12. PATIENT CHARACTERISTICS The characteristics of the patients were balanced between the two trial groups . The median age of the patients was 63 years (interquartile range, 56 to 70), and 70.5% were men. The median NIHSS score was 6 (interquartile range 5 to 8), and the median time from stroke onset to the administration of reteplase or alteplase was 180 minutes (interquartile range 135 to 222). A total of 45 patients (20 in the reteplase group and 25 in the alteplase group) received rescue thrombectomy.

13. EFFICACY OUTCOMES Data with respect to an excellent functional out- come (modified Rankin scale score of 0 or 1 at 90 days) were available for 1370 of 1412 patients (97.0%). A total of 42 patients (22 in the reteplase group and 20 in the alteplase group) had the 90-day modified Rankin scale scores imputed by multiple imputation owing to missing data. An excellent functional outcome was reported in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group A good functional outcome (modified Rankin scale score of 0 to 2 at 90 days) was reported in 85.3% of the patients in the reteplase group and in 79.8% of those in the alteplase group (risk ratio, 1.07; 95%

14. ordinal analysis of the modified Rankin scale score at 90 days, the median score was 0 (interquartile range, 0 to 1) in the reteplase group and 1 (inter- quartile range, 0 to 2) in the alteplase group, which indicated better function with reteplase (common odds ratio [reteplase vs. alteplase] for a higher modified Rankin scale score,

15. SAFETY OUTCOMES symptomatic intracranial hemorrhage within 36 hours occurred in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 patients (2.0%) in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75; P = 0.64). Parenchymal hemorrhage type 2 within 36 hours occurred in 1.7% of the patients in the reteplase group and 1.4% of those in the alteplase group (risk ratio, 1.20; 95% CI, 0.36 to 4.03). Death within 90 days occurred in 30 patients (4.3%) in the reteplase group and in 24 patients (3.4%) in the alteplase group (risk ratio, 1.25; 95% CI, 0.66 to 2.35).

16. The incidence of any intracranial hemorrhage was higher in the reteplase group than in the alteplase group (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of clinically relevant nonmassive hemorrhage (5.4% vs. 2.4%; risk ratio, 2.23; 95% CI, 1.03 to 4.84) and adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20) . Other safety outcomes, including symptomatic intra- cranial hemorrhage within 7 days, major hemor- rhage within 90 days, and serious adverse events within 90 days, were similar in the two trial

17. DISCUSSION The RAISE trial showed that intravenous reteplase was noninferior to intravenous alteplase in achieving an excellent functional outcome. The percentage of patients with an excellent functional out come at 90 days was higher by 9.4 percentage points with reteplase than with alteplase. No significant between group difference was observed regarding the incidence of symptomatic intra- cranial hemorrhage, and mortality did not differ substantially between the two groups.

18. We observed a higher incidence of any intracranial hemorrhage and adverse events at 90 days in the reteplase group than in the alteplase group. In addition, the percentage of patients who had an early dramatic recovery with respect to theNIHSS score at 24 hours was higher by 10 percentage points with reteplase than with alteplase. finding suggests that the mechanism underlying the benefits of reteplase may involve a higher incidence of recanalization. There were safety concerns for reteplase in terms of any intracranial hemorrhage, clinically relevant non- massive hemorrhage, and overall adverse events.

19. Trial Strengths: The double-bolus regimen holds potential for increased flexibility in terms of selecting the dose and time interval for the second dose. Trial Limitations: This trial, which was conducted in China, excluded patients who were eligible for endovascular thrombectomy and those older than 80 years of age. Women were less represented than men in this trial. Therefore, the findings may not be generalizable to other patient populations. In this trial involving patients with acute ischemic stroke who were eligible for intravenous thrombolysis within 4.5 hours after they were last known to be well

20. CONCLUSION A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P=0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after dis- ease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events

21. Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase.

22. THANK YOU