EVT Alone Demonstrates Noninferiority to Combined Intravenous Alteplase Method

Jeffrey Saver, MD

Endovascular treatment (EVT) alone, compared with intravenous alteplase, demonstrated noninferiority on the outcome of 90-day functional independence among patients with ischemic stroke in the multicenter, randomized DEVT clinical trial (Chi-CTR-IOR-17013568).¹

The trial results included 234 patients (mean age, 68 years; 102 women [43.6%]), 116 of which were randomized to the EVT alone group and 118 patients who were randomized to the combined intravenous thrombolysis (IVT) and EVT group. Researchers defined functional independence, or the primary end point, by modified Rankin Scale (mRS) scores 0–2 at 90 days.

Within the EVT alone group, 63 of 116 patients (54.3%) achieved functional independence at the 90-day follow-up compared to 55 patients (46.6%) in the combined treatment group (difference, 7.7%; 1-sided 97.5% CI, −5.1% to ∞; P for noninferiority = .003). The lower boundary of the CI of –5.1% was greater than the prespecified noninferiority margin of –10%.

Lead author Wenjie Zi, MD, department of neurology, Xinqiao Hospital, and The Second Affiliated Hospital, China, and colleagues found no significant between-group differences in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, –0.8%; 95% CI, –7.1 to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, –0.5; 95% CI, –10.3% to 9.2%).

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Post-hoc analysis showed that 15.7% of patients in the EVT alone group experienced asymptomatic intracerebral hemorrhage, compared to 25.6% in the combined group (difference, –10%; 95% CI, –20.3 to 0.3%).

Jeffrey L. Saver, MD, neurologist, University of California, commentedthe pros and cons of administration of IVT as a bridging therapy prior to EVT in a related editorial.2 Saver noted the several noted favorable effects were resolution of ischemic episode quickly, potential to change clot composition in a manner that made the thrombus more responsive to EVT removal, and the ability to dissolve thrombotic debris in downstream vessels.

Although, he noted, "giving IVT first could also exert several unfavorable effects. The time taken to initiate IVT, if not done in parallel with steps required for EVT initiation, might delay the start of the definitive endovascular procedure. IVT might partially dissolve a target thrombus, causing it to move distally and lodge in a distal vessel poorly accessible by endovascular intervention, converting a treatable into an untreatable lesion. IVT increases the risk of symptomatic brain hemorrhage. In addition, adding IVT to EVT increases care costs.”

The trial was stopped early becauseof efficacy when 234 of the expected 970 patients enrolled had undergone randomization. Patients who were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptom onset and eligible for intravenous thrombolysis were included in the study. Results from the per-protocol analysis were consistent with the primary analysis, and the post-hoc hierarchical modeling and sensitivity analyses indicated that the adverse effects were not significant.

Assessed on initial angiography, successful reperfusion before EVT was observed for 2 patients in the EVT alone group and 3 in the intravenous thrombolysis and EVT group (1.7% vs 2.6%). In total, 30.1% and 41% of patients in the EVT alone group and combined group had at least 1 procedure-associated complication, respectively, but the difference was deemed insignificant. Clot migration, distal occlusion present at procedure end, contrast extravasation, arterial perforation, and puncture access complications were among the observed procedure-associated complications.

The authors concluded that “these findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold.”

Recently, results from the SKIP randomized clinical trial (UMIN000021488) were published, which failed to demonstrate noninferiority in mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, in patients with large vessel occlusion (LVO) stroke.³

Regarding those results, Zi et al wrote, “In comparing the results of this trial with those of the SKIP and DIRECT-MT trials, the rate of intracranial hemorrhage was similarly higher among patients in the combined treatment group this trial and in the SKIP trial (34% vs 50%, P = .02), even though patients in the SKIP trial received a lower dose of alteplase (0.6 mg/km) than did the patients in this study.”

The SKIP study, led by Kentaro Suzuki, MD, PhD, department of neurology, Nippon Medical School, Japan, and colleagues observed favorable outcome in 60 of the 101 patients (59.4%) in the mechanical thrombectomy alone group compared to 59 of 103 (57.3%) in the combined group (difference, 2.1% [1-sided 97.5% CI, –11.4 to ¥]; odds ratio [OR], 1.09 [1-sided 97.5% CI, 0.63 to ¥]). Noninferiority was also proven in a separate per-protocol analysis.

"The 2 reperfusion therapies of proven benefit for acute ischemic stroke, mechanical endovascular thrombectomy and pharmacologic intravenous thrombolysis, have complementary advantages,” Saver went on to say. “EVT, which involves mechanical debulking, works well for accessible sizeable thrombi that occlude large cerebral vessels and are resistant to rapid thrombolytic dissolution. IVT, which involves chemical dissolution, works well for smaller thrombi that occlude medium and small cerebral vessels inaccessible or poorly accessible to endovascular technology.”

REFERENCES

1. Zi W, Qiu Z, Li F, 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 Neurol. Published January 19, 2021. doi: 10.1001/jama.2020.23523

2. Saver JL, Adeoye O. Intravenous thrombolysis before endovascular thrombectomy for acute ischemic stroke. JAMA. Published online January 19, 2021. doi: 10.1001/jama.2020.22388

3. Suzuki K, Matsumaru Y, Takeuchi M, 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 Neurol. published online January 19, 2021. doi: 10.1001/jama.2020.23522