Parneet Grewal, MD
ESO-WSO 2020 Large Clinical Trials Webinar
Presenter: Dr. Jianmin Liu (China)
Article: Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, et al, for the DIRECT-MT Investigators. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. NEJM. 2020.
The goal of current therapeutic strategies for acute ischemic stroke with large vessel occlusion (LVO) is recanalization of the occlusion before irreversible damage has occurred. In this large multicenter, prospective, randomized, open-label trial with blinded outcome assessment, Dr. Jianmin Liu and his team aimed to answer the question of whether mechanical thrombectomy (MT) alone (thrombectomy alone group) would be non-inferior to combined treatment of IV-tPA and MT (combined group) in patients with LVO.
This trial included patients ³ 18 years of age who presented to 41 pre-selected academic medical centers in China within 4.5 hours of symptom onset, had National Institutes of Health Stroke Scale (NIHSS) ³ 2 with imaging showing an LVO (intracranial segment of ICA, M1 or proximal M2 only). Any patients who did not meet American Heart Association/American Stroke Association guidelines for alteplase or MT were not included in the trial. The standard dose of tPA at 0.9 mg/kg was used, and the first-line strategy for MT was stent-retriever. Statistically, the trial was designed to provide 80% power (at a two-sided alpha level of 0.05) to determine a non-inferiority margin of 0.8. 656 patients were randomized in 1:1 fashion by a web-based system with 327 patients in the thrombectomy alone group and 329 patients in the combined group. The patient enrollment period was 17 months (February 23, 2018, to July 2, 2019). The baseline characteristics of patients were similar in both the groups with a median age of 69 years, median NIHSS score of 17, and median ASPECTS value of 9. The median duration from stroke onset to randomization was 167 minutes in the thrombectomy alone group and 177 minutes in combined group with time from randomization to groin puncture being 31 minutes and 36 minutes, respectively.
Endovascular thrombectomy alone was found to be noninferior to IV-tPA with endovascular thrombectomy in the univariable ordinal regression analysis that used a margin of 0.8 (common odds ratio, 1.09; 95% CI, 0.84 to 1.43), as well as after adjustment for age, the NIHSS score at baseline, the time from stroke onset to randomization, the mRS before stroke onset, and the cerebral collateral blood-flow status in an analysis with multivariable ordinal regression that used a margin of 0.8 (adjusted common odds ratio, 1.07; 95% CI, 0.81 to 1.40) (Table 2). On analysis of secondary outcomes, it was found that mortality at 90 days was 17.7% in the thrombectomy alone group and 18.8% in the combination therapy group, and successful reperfusion before MT on angiography was observed in 8% and 23% patients, respectively (adjusted common odds ratio, 1.33; 95% CI, 0.14 to 0.74). The safety outcomes of death, symptomatic intracranial hemorrhage, and procedural complications were not statistically different in both groups.
This was one of the key trials of the ESO-WSO Large Clinical Trials Webinar and could potentially have far-reaching implications on our management of acute ischemic stroke. There have been several meta-analysis and observational studies, but this trial was the first randomized trial that specifically attempted to address the role of IV-tPA in patients with LVO who are candidates for MT. However, the trial had several limitations, which were also discussed during the webinar by other clinicians. Two of the main limitations were design in accordance with 2015 AHA/ASA guidelines with stent retriever being the first-line strategy for MT and generous prespecified non-inferiority margin with small sample size and wide confidence intervals. Newer devices and thrombolytic agents were excluded. Another issue that was pointed out was the inclusion of only the mothership model of stroke triage and transport, which would make the trial results not applicable to the widely practiced drip and ship model. Also, since the trial was conducted in China on the Asian population, the results may not be generalizable due to different pre-hospital triage systems and differences in cause of stroke between Asian and non-Asian populations.
In conclusion, I think this trial is an important landmark in the debate “to tPA or not to tPA” in patients with LVO, but confirmation from other larger trials in different patient populations will be needed before we can safely consider aborting tPA before MT in patients with LVO.