Märit Jensen, MD, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Clinical Stroke and Imaging Research (CSI) group
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Thrombectomy alone fails to show non-inferiority compared with thrombectomy plus intravenous alteplase – Full results of SWIFT DIRECT and DIRECT-SAFE published in The Lancet
Over the past years there has been a controversial debate over the additional value of intravenous thrombolysis prior to mechanical thrombectomy in patients with large vessel occlusion. Doubts about the effect of intravenous thrombolysis for large thrombi and concerns about potential risks, mainly the risk of intracerebral hemorrhage, have motivated a series of clinical trials comparing thrombectomy alone to thrombectomy plus intravenous thrombolysis.
Previous studies yielded controversial results. Two trials from China (DIRECT-MT and DEVT)1, 2 found direct thrombectomy to be non-inferior to thrombectomy plus intravenous thrombolysis. However, these trials have been criticized for different reasons including wide non-inferiority margins and organizational aspects as well as rather long door-to-needle time for alteplase. In contrast, two further trials from Europe (MR CLEAN-NO IV)3 and Japan (SKIP)4 did not show non-inferiority.
In the current issue of The Lancet two further trials on this research question have been published which will likely end the debate.
SWIFT DIRECT5 randomized 423 patients with stroke due to large vessel occlusion referred to 42 endovascular centers in Europe and Canada to either thrombectomy alone or intravenous thrombolysis plus thrombectomy. Primary outcome was a score of 2 or less on the modified Rankin scale at 90 days, and a non-inferiority margin of 12% was prespecified. Overall, rates of favorable outcome were high in both groups (57% in the thrombectomy alone group and 65% in the thrombectomy plus thrombolysis group). The adjusted risk difference was -7.3% with the lower limit of one-sided 95% CI of -15.1 crossing the predefined non-inferiority margin of -12%. Thus, thrombectomy alone was not shown to be non-inferior to thrombolysis plus thrombectomy. There were no differences in the frequency of symptomatic intracranial hemorrhage between the groups (2% vs. 3%) nor for any other safety endpoints. On the other hand, successful reperfusion was less common in the thrombectomy alone group.
The study is to be commended for the high quality of treatment in all participating centers reflected by short procedural times, high recanalization rates and an overall high percentage of patients achieving good functional outcome. In SWIFT DIRECT, rigorous inclusion and exclusion criteria ensured enrollment of a population most likely to benefit from thrombectomy alone. Nevertheless, point estimates favored combined treatment of intravenous alteplase plus thrombectomy. In patients below the age of 70, thrombectomy alone was even significantly less effective with lower odds of independent outcome at 90 days as compared to thrombectomy plus alteplase. SIWFT DIRECT also yield novel findings. The rates of postinterventional reperfusion where higher with combined treatment, which provides a likely explanation for the favorable outcome shifts observed in patients treated with alteplase plus thrombectomy.
The second trial, DIRECT-SAFE6 randomized 295 patients in 24 centers in Australia, New Zealand, China and Vietnam. The primary outcome was also an mRS score of 0-2 at 90 days, with a non-inferiority margin of -0.1. As in SWIFT DIRECT the trial did not show non-inferiority. Patients treated with thrombectomy alone had numerically lower rates of functional independence (55% vs. 61%) with a risk difference of -0.051 (95% CI -0.160 to 0.059). Safety outcomes were also comparable between the groups. In contrast to SWIFT DIRECT, DIRECT-SAFE also allowed for the use of Tenecteplase (17% of patients in the combined treatment group) and for enrollment of patients with M2 or basilar artery occlusion. Of note, almost half of the patients were enrolled in Asian regions, and in a region-based subgroup analysis Asian patients with combined treatment even showed significant better outcomes than those treated with thrombectomy alone. This makes it unlikely that the previous contrary results from the Chinese trials (DIRECT-MT and DEVT) are specific for Asian patients.
The main results of SWIFT DIRECT and DIRECT-SAFE are in line with those of MR CLEAN-NO IV and SKIP. Taken together, these four trials provide a clear answer to the question whether intravenous thrombolysis can be omitted prior to thrombectomy in patient with large vessel occlusion stroke. The answer is no, thrombolysis should not be omitted in these patients unless there are contraindications against intravenous thrombolysis.
- Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med. 2020;382:1981-1993
- Zi W, Qiu Z, Li F, Sang H, Wu D, Luo W, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular treatment on functional independence in patients with acute ischemic stroke: The devt randomized clinical trial. JAMA. 2021;325:234-243
- LeCouffe NE, Kappelhof M, Treurniet KM, Rinkel LA, Bruggeman AE, Berkhemer OA, et al. A randomized trial of intravenous alteplase before endovascular treatment for stroke. N Engl J Med. 2021;385:1833-1844
- Suzuki K, Matsumaru Y, Takeuchi M, Morimoto M, Kanazawa R, Takayama Y, et al. Effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke: The skip randomized clinical trial. JAMA. 2021;325:244-253
- Fischer U, Kaesmacher J, Strbian D, Eker O, Cognard C, Plattner PS, et al. Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial. The Lancet. 2022;400:104-15
- Mitchell PJ, Yan B, Churilov L, Dowling RJ, Bush SJ, Bivard A, et al. Endovascular thrombectomy versus standard bridging thrombolytic with endovascular thrombectomy within 4·5 h of stroke onset: an open-label, blinded-endpoint, randomised non-inferiority trial. The Lancet. 2022;400:116-25