Stroke Thrombectomy Fails Non-inferiority to Combined Therapy

October 31, 2022

Direct endovascular thrombectomy treatment for patients with acute ischemic stroke failed to achieve non-inferiority to combined thrombolysis plus endovascular therapy, in a new meta-analysis of individual patient data from six studies comparing the two approaches.

The results were presented by Yvo Roos, MD, and Urs Fischer, MD, at the World Stroke Congress in Singapore on October 27.

"Direct endovascular thrombectomy was not 'non-inferior' to bridging thrombolysis plus thrombectomy at a 5% non-inferiority margin," reported Fischer, who is chairman of the department of neurology at the University Hospital Basel in Basel, Switzerland. 

"While the combination of thrombolysis and thrombectomy appeared to show a slight benefit, this was not significant, so there is no proven benefit of thrombolysis prior to thrombectomy, and if there is a benefit it is likely to be small," Fischer noted.

Thrombolysis prior to endovascular thrombectomy was associated with a higher chance of successful reperfusion at the risk of an increase in any ICH. And the benefit of thrombolysis prior to thrombectomy appeared to be smaller with longer time from stroke onset to randomization.

However, because "non-inferiority" of the direct thrombectomy strategy was not demonstrated, thrombolysis in combination with thrombectomy will remain the standard of care, the researchers noted.

Introducing the presentation, Roos, who is professor of acute neurology at University Medical Center, Amsterdam, the Netherlands, explained that the issue of whether direct mechanical thrombectomy in acute ischemic stroke patients with anterior circulation proximal occlusions is equally effective as bridging with intravenous thrombolysis followed by mechanical thrombectomy is still a topic of worldwide debate.

Six trials have been published in last 2-3 years comparing these two approaches: DIRECT-SAFE; DIRECT-MT; DEVT, SKIP, MR CLEAN-NO IV; and SWIFT DIRECT. Still, no clear answer has been established.

"While there have been a number of study level meta-analyses performed, what is really needed is an individual patient data meta-analysis, so that is what we did," Roos said.

The investigators of the six trials formed a collaboration, known as Improving Reperfusion strategies for Ischemic Stroke (IRIS), to conduct the individual patient data meta-analysis.

The meta-analysis combined data on a total of 2313 patients, with 1153 patients having undergone direct thrombectomy and 1160 patients receiving thrombolysis followed by thrombectomy for an anterior artery occlusion, with the aim of investigating whether direct thrombectomy was "non-inferior" to the combination strategy. The primary endpoint was a shift analysis of the modified Rankin scale (mRS) score at 90 days.

The researchers chose a non-inferiority boundary of a 5% difference in the mRS 0-2 absolute risk score, based on feedback from experts in the field, which translates into a lower 95% confidence interval boundary for the adjusted common odds ratio in the mRS shift analysis of 0.82.

Presenting the results, Fischer reported that the mRS shift analysis at 90 days suggested a slightly better outcome with the combination bridging group than the direct thrombectomy group, with an adjusted common odds ratio (acOR) of 0.9 and 95% confidence interval of 0.76 to 1.04.

The lower confidence interval of 0.76 was below that of the prespecified boundary for non-inferiority of 0.82. 

"So therefore, we could not prove that direct thrombectomy was non-inferior to the bridging combination approach," Fischer said. "This is an inconclusive result."

The secondary endpoint of a good functional outcome (mRS 0-2) occurred in 49% of the direct thrombectomy cohort vs 51% in the bridging cohort — a difference of 2%, which was not significant.

However, successful reperfusion was higher in the bridging cohort (84% vs 80%), as was early recanalization (4% vs 2%).

On the other hand, rates of any intracranial hemorrhage (ICH) were also higher in the bridging cohort (35% vs 31%), but symptomatic ICH rates were not significantly different (5% in the bridging group vs 4% with direct thrombectomy).   

In terms of subgroup analysis, there was a trend that patients treated earlier might have more benefit from thrombolysis prior to endovascular thrombectomy compared with patients treated later.

Fischer noted that the data suggested a number needed to harm from dropping thrombolysis of 57. "So, if thrombolysis is not used in 57 patients receiving mechanical thrombectomy, this will lead to one fewer good functional outcome."

"Intravenous thrombolysis might have a small impact on patients with anterior circulation stroke undergoing mechanical thrombectomy, but at a 2% improvement in mRS 0-2 outcomes, this is relatively small compared to the 20% treatment effect shown with thrombectomy in the main trials," Fischer said.  

"Endovascular thrombectomy is the main treatment effect in anterior circulation large vessel occlusion stroke, and administration of thrombolysis should not delay or prohibit endovascular therapy. We have to ensure that all eligible patients receive endovascular therapy as fast as possible," he added.

"While our meta-analysis has shown direct mechanical thrombectomy has very similar outcomes to combination bridging therapy of thrombolysis followed by thrombectomy, we couldn't show non-inferiorly of the direct thrombectomy approach. So, the guidelines will continue to recommend the combination of thrombolysis plus thrombectomy for eligible patients," Fischer commented to theheart.org | Medscape Cardiology.  

"However, if a clinician is even the slightest bit worried about giving thrombolysis to a patient who is about to receive thrombectomy — maybe because of the patient's bleeding risk — then I think these data will be reassuring if they decide not to give the thrombolytic," he added.

Roos stressed though that this only applies to patients presenting at a comprehensive stroke center where they can receive immediate mechanical thrombectomy. "These results do not apply to patients presenting to primary stroke centers where they will need to be transferred to a different hospital for thrombectomy. Patients presenting to primary stroke centers should always receive thrombolysis if they are eligible," he stated.  

Commenting on the study for theheart.org | Medscape Cardiology, Stefan Kiechl, MD, Medical University of Innsbruck, Austria, who is co-chair of the World Stroke Congress scientific committee, said: "Even in this individual-data meta-analysis with more than 2000 patients, non-inferiority of direct endovascular therapy could not be proven, and findings were consistent in subgroups. Consequently, thrombolysis plus endovascular therapy remains the standard of acute therapy of stroke."

14th World Stroke Conference. Presented October 27, 2022. 

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