DIRECT-MT findings aim to make case for non-inferiority of thrombectomy sans alteplase

In a randomized study of patients with acute ischemic stroke caused by large vessel occlusion, endovascular thrombectomy without prior alteplase thrombolysis achieved Rankin scale scores on a par with combination therapy (alteplase plus endovascular thrombectomy), the DIRECT-MT researchers reported in The New England Journal of Medicine.

But the mechanical approach sans alteplase “was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% versus 7.0%) and overall successful reperfusion (79.4% versus 84.5%),” wrote Pengfei Yang, MD, of Naval Medical University Changhai Hospital/Shanghai Jiaotong University Renji Hospital and colleagues.

In an editorial that accompanied the early online publication for the DIRECT-MT results, Gregory W. Albers, MD, Stanford Stroke Center, in Palo Alto, questioned the trial’s design, noting that, although noninferiority was established, “the margin that was used to declare noninferiority was generous, and the confidence intervals did not exclude a benefit of approximately 20% in the combination-therapy group. In fact, a similar Japanese trial did not establish the noninferiority of thrombectomy without alteplase pretreatment to thrombectomy alone.”

“The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8,” the authors wrote.

But they noted that, since “the lower boundary of the 95% confidence interval for the common odds ratio comparing the modified Rankin scale scores at 90 days was just above the prespecified value of 0.8 in the unadjusted and adjusted analyses, the results do not rule out a benefit of alteplase.”

They screened 1,586 patients and randomized 656 — 327 to thrombectomy alone and 329 to the combination-therapy group. The median age of patients was 69 years and 56.4% were men. Alteplase was administered at a dose of “0.9 mg per kilogram of body weight (with 10% administered as a bolus, and 90% infused over a period of 1 hour) to a maximum of 90 mg.”

“Among patients with available data, the median NIHSS score was 17 (interquartile range, 13 to 22), and the median ASPECTS value was 9 (interquartile range, 7 to 10),” they wrote. “The median time from stroke onset to randomization was 167 minutes (interquartile range, 125 to 206) in the thrombectomy-alone group and 177 minutes (interquartile range, 126 to 215) in the combination-therapy group; the median time from randomization to groin puncture was 31 minutes (interquartile range, 20 to 45) and 36 minutes (interquartile range, 22 to 50.5), respectively.”

In the combination group, 97% received alteplase: 23 completed infusion prior to groin puncture and 276 completed infusion during the endovascular procedure. Seven patients in each group required intra-arterial thrombolysis.

The 90-day mortality rate was 17.7% in the thrombectomy alone arm versus 18.8% in the combination therapy arm.

The authors noted that the trial was designed in accordance with 215 AHA-ASA guidelines, which meant that they used stent retrievers and standard dose alteplase. “Recently, newer thrombectomy devices such as aspiration catheters and thrombolytic drugs such as tenecteplase have been used to treat stroke,” they wrote.

They also acknowledged the “generous” noninferiority margin, small sample size, and wide confidence intervals as limitations. They also noted that the “prehospital triage system is more complicated in China than in many Western countries, with patients often traveling by personal transport directly to the hospital, and stroke teams are usually mobilized only on hospital admission rather than before the patients’ arrival. Furthermore, informed consent is required before the administration of alteplase in China, and counseling before treatment commonly involves many family members and is time-consuming.”

In his editorial, Albers concluded that the “mismatch between the high percentages of patients with reperfusion and the much smaller percentages of patients with clinical recovery in thrombectomy studies suggests that a substantial volume of brain tissue is already irreversibly injured in many patients by the time reperfusion occurs. To improve outcomes in future stroke trials, adjunctive therapies, such as thrombolytic or neuroprotective agents, might be started early, at the primary stroke center or in the prehospital setting. Until more data are available, it is appropriate to follow current guidelines that recommend that all eligible patients receive alteplase before thrombectomy.”

  1. In the DIRECT-MT trial, thrombectomy alone was non-inferior to alteplase plus thrombectomy, but be aware that the margin for non-inferiority was “generous.”

  2. Note that the trial design required use of older thrombectomy devices and standard dose alteplase, but currently aspiration devices are preferred for thrombectomy and tenecteplase is more commonly used to treat stroke.

Peggy Peck, Editor-in-Chief, BreakingMED™

Yang reported grants from National Natural Science Foundation of China, grants from Shanghai Municipal Health Commission, outside the submitted work.

Albers reported personal fees from Genentech, personal fees and other from IschemaView, personal fees from Medtronic, personal fees from Janssen, personal fees from Portola, personal fees from Prolong Pharma, personal fees from NuVox, personal fees from Omniox, personal fees from Johnson & Johnson, personal fees from Biogen, outside the submitted work.

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