Thrombectomy Alone Noninferior to Combination Therapy in Stroke

May 07, 2020

Endovascular thrombectomy alone was noninferior to thrombectomy plus thrombolysis with alteplase in terms of functional outcome for patients with large-vessel acute ischemic stroke in a new Chinese trial.

"Because 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," the investigators, led by Pengfei Yang, MD, Naval Medical University Changhai Hospital, Shanghai, China, conclude.

Results of the DIRECT-MT trial were published online May 6 in the New England Journal of Medicine.

In an accompanying editorial, Gregory W. Albers, MD, the Stanford Stroke Center, Palo Alto, California, points out 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."

Albers concludes: "Until more data are available, it is appropriate to follow current guidelines that recommend that all eligible patients receive alteplase before thrombectomy."

The DIRECT-MT trial included 656 patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation from 41 academic tertiary care centers in China. They were randomly assigned to undergo endovascular thrombectomy alone or endovascular thrombectomy preceded by intravenous alteplase at a dose of 0.9 mg/kg, administered within 4.5 hours after symptom onset.

The primary analysis for noninferiority assessed the between-group difference in the distribution of modified Rankin scale scores at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio ≥0.8.

Results showed that this noninferiority requirement was just met. The odds ratio for endovascular thrombectomy alone was 1.07 (95% CI, 0.81 – 1.40; P = .04 for noninferiority).

Other results showed that thrombectomy alone was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs 7.0%) and overall successful reperfusion (79.4% vs 84.5%).

Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group.

Percentages of patients who experienced serious adverse events during the 90-day follow-up period were similar in the two groups (37.0% in the thrombectomy-alone group vs 36.8% in the combination-therapy group). The percentages of patients with intracranial hemorrhage (ICH) were not significantly different. Symptomatic ICH occurred in 4.3% of the thrombectomy-alone group and in 6.1% in the combination-therapy group; asymptomatic ICH occurred in 33.3% of the thrombectomy-alone group and in 36.2% of the combination-therapy group.

In his editorial, Albers notes that whether the current practice of giving thrombolysis to eligible patients before thrombectomy is beneficial is a key question.

He explains that potential advantages of giving thrombolysis first include earlier and more complete recanalization of the occluded vessel, especially in cases in which thrombectomy is delayed or in which reaching the thrombus with a mechanical device is challenging; dissolution of fragments of thrombi that are dislodged into distal vessels during the endovascular procedure; and possible recanalization of the vessel before initiation of the interventional procedure. Disadvantages include possible delayed initiation of the endovascular procedure, an increase in the risk of bleeding, and cost.

Albers says it is unclear why the higher rates of reperfusion in the combination group in the MT-DIRECT trial did not translate into clinical benefit. Noting that in this trial, alteplase was always given at the tertiary care center, he suggests that the time between the administration of alteplase and the initiation of thrombectomy may not have been long enough to allow the full thrombolysis effect to be seen.

"In clinical practice in most countries, alteplase administration is frequently initiated at primary stroke centers, often 2 or more hours before thrombectomy is performed at a comprehensive stroke center," he adds.

Albers also points out that the percentage of patients who had a favorable outcome was modest in both groups in this trial ― just 36.6% of patients had a modified Rankin scale score of 0 to 2 at 90 days despite the fact that reperfusion occurred in more than 80% of the patients. One possible explanation for this is that Chinese patients might derive less benefit from thrombectomy, owing to the fact that they have more intracranial atherosclerotic lesions than white patients.

"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," Albers suggests.

The MT-DIRCT trial was funded by the Stroke Prevention Project of the National Health Commission of the People's Republic of China and the Wu Jieping Medical Foundation. Yang has disclosed no relevant financial relationships. Albers has received personal fees from Genentech, IschemaView, Medtronic, Janssen, Portola, Prolong Pharma, NuVox, Omniox, Johnson & Johnson, and Biogen outside the submitted work.

N Eng J Med. Published online May 6, 2020. Abstract, Editorial

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