Two trials add to the discussion about whether IVT can be skipped

Two randomized clinical trials added to the discussion about whether endovascular treatment (EVT) alone can achieve non-inferior outcomes compared to when intravenous thrombolysis (IVT) and EVT are used together in patients with large vessel occlusion acute ischemic stroke.

In the DEVT trial of patients with acute ischemic stroke due to large vessel occlusion who were eligible for thrombolysis, EVT alone, compared with IVT plus EVT, met the pre-specified statistical threshold for noninferiority in 90-day functional independence, reported Qingwu Yang, MD, PhD, of Third Military Medical University in Chongqing, China, and co-authors, in JAMA.

Findings from the SKIP trial, also published in JAMA, did not demonstrate non-inferiority of mechanical thrombectomy alone versus combined IVT and EVT for favorable functional outcome in acute large vessel occlusive ischemic stroke, according to Kazumi Kimura, MD, PhD, of Nippon Medical School in Tokyo and co-authors. “However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority,” they wrote.

Recent studies assessing IV alteplase “including the two clinical trials in this issue of JAMA, have enriched the current therapeutic options, even if applying these findings to individual patients will sometimes be challenging,” said Jeffrey Saver, MD, of University of California Los Angeles, and Opeolu Adeoye, MD, MS, of University of Cincinnati, in an accompanying editorial.

DEVT and SKIP, along with the recent DIRECT-MT trial, “suggest that the simpler EVT alone strategy is broadly noninferior to combined EVT and IVT and accordingly may be reasonable to consider for patients who present directly to thrombectomy-capable centers,” the editorialists noted. “Additional trials are needed to determine whether these findings generalize to non-Asian patients and are underway.”

The DEVT trial randomized 234 adults in China within 4.5 hours of anterior ischemic stroke onset to EVT alone (n=116) or combined EVT plus IVT (IV alteplase, 0.9 mg/kg of body weight; n=118). Ninety-day modified Rankin scale (mRS) scores of 0-2 (0 indicating no residual symptoms; 2 slight disability) were seen in 54.3% with EVT alone and 46.6% for the combined group (difference 7.7%, 1-sided 97.5% CI −5.1% to infinity, P for noninferiority =0.003).

Neither 90-day mortality (17.2% vs 17.8%) nor symptomatic intracerebral hemorrhage (6.1% vs 6.8%) differed significantly between groups in the DEVT trial.

“Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence,” Yang and co-authors wrote. “These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold.”

The SKIP study randomized patients in Japan to EVT alone (n=101) or with IVT (n=103) but used a lower dose of IV alteplase for IVT (0.6 mg/kg). A 90-day mRS of 0-2 was seen in 59.4% for EVT alone and 57.3% with combined treatment, with no significant difference seen between groups (difference 2.1%, 1-sided 97.5% CI −11.4% to infinity, P for noninferiority=0.18).

Neither 90-day mortality (7.9% vs 8.7%, difference –0.8%, P > 0.99) nor symptomatic intracerebral hemorrhage was significantly different between groups (5.9% vs 7.7%, difference –1.8%, P = 0.78), although any intracerebral hemorrhage was observed less frequently in the EVT only group (33.7% vs 50.5%, difference –16.8%, 95% CI –32.1% to –1.6%, P = 0.02).

Lower IVT doses in Asian patients, as in the SKIP trial, are based on concerns that Asian patients may have higher risk of cerebral hemorrhage after IVT. Patients in both trials were adults with large vessel occlusion ischemic stroke eligible for both EVT and IVT. In DEVT, patients were enrolled from May 2018 to May 2020; about 44% were women and participants had an average age of 68. SKIP patients were enrolled from January 2017 to July 2019; about 37% were women and median age was 74. In DEVT, roughly 40 minutes occurred between lytic drug start and EVT procedure start; in SKIP, the interval was 8 minutes.

The DEVT group based their noninferiority margin of −10.0% as the clinically relevant limit for the outside bound of the CI. “The lower boundary of the CI of −5.1% was greater than the prespecified noninferiority margin of −10%,” Yang and co-authors wrote. “The noninferior margin of 10% is broad, reaching no consensus in the clinical community, which may lead to concerns about the robustness of study results.”

SKIP investigators set the noninferiority margin as an odds ratio of 0.74 using the fixed-margin approach based on a previous meta-analysis of combined versus medical-only treatment.

“For stroke clinicians caring for patients with acute ischemic stroke with large vessel occlusion, it now will sometimes be reasonable to avoid using two therapeutic approaches, pharmacologic and mechanical, and instead proceed with a single strategy of rapid direct endovascular thrombectomy,” observed Saver and Adeoye.

For stroke patients with small to medium vessel occlusions — for whom EVT is not an option — IVT should be used as a stand- alone therapy, they said. Among patients with large vessel occlusions, “thrombolytics prior to EVT should be withheld only when clinicians are confident EVT will be delivered quickly and reliably,” the editorialists wrote. “Patients with acute ischemic stroke large vessel occlusions who present to a nonthrombectomy-capable hospital, among whom EVT start will be delayed until after interfacility transfer, should receive IVT at the first hospital site so that reperfusion therapy could be started before the stroke has progressed to near completion.”

Initial IVT also should be administered to patients who harbor conditions that slow endovascular access to intracranial vessel occlusions, including excessive aortocervical arterial tortuosity and chronic cervical occlusions, and certain other subgroups, they added.

Limitations of the trials include their Asian-only populations. The studies provide information only about alteplase as the IV thrombolytic strategy, Saver and Adeoye added.

  1. Two randomized clinical trials added to the discussion about whether endovascular treatment (EVT) alone can achieve non-inferior outcomes compared to when intravenous thrombolysis (IVT) and EVT are used together in patients with large vessel occlusion acute ischemic stroke.

  2. In the DEVT trial, patients with EVT alone — compared with IVT plus EVT — met the pre-specified statistical threshold for noninferiority in 90-day functional independence. In the SKIP trial, findings did not demonstrate noninferiority of mechanical thrombectomy alone versus combined IVT and EVT for favorable functional outcome, but wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority.

Paul Smyth, MD, Contributing Writer, BreakingMED™

DEVT was supported by the National Natural Science Foundation of China, the Chongqing Major Disease Prevention and Control Technology Research Project, the Clinical Medical Research Talent Training Program of Army Medical University, and the Major Clinical Innovation Technology Project of the Second Affiliated Hospital of Army Medical University.

SKIP was supported by the Japanese Society for Neuroendovascular Therapy.

Yang reported no disclosures.

Kimura reported receiving grants from 38th Mihara Cerebrovascular Disorder Research Promotion Fund Ltd during the conduct of the study and grants from Teijin Pharma Ltd, Medtronic Co Ltd, Pfizer Japan Inc, Daiichi Sankyo Co, and Nippon Boehringer Ingelheim Co Ltd, personal fees from Daiichi Sankyo Co, personal fees from Bayer Healthcare Co Ltd and personal fees from Nippon Boehringer Ingelheim Co Ltd and Bristol-Myers Squibb Co Ltd outside the submitted work.

Saver reported being an employee of the University of California, which has patent rights in retrieval devices for stroke. The University of California received payments on the basis of clinical trial contracts for the number of participants enrolled in multicenter clinical trials sponsored by Medtronic, Stryker, Cerenovus, BrainsGate, NONO Inc, and Boehringer Ingelheim (prevention only). The University of California receives grant support from the National Institutes of Health (NIH) for Dr Saver’s service in leadership roles in the National Institute of Neurological Disorders and Stroke StrokeNet national clinical trial network and from Diffusion Pharma for Dr Saver’s leadership role in the PHAST-TSC multicenter trial. Dr Saver reported serving as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr Saver received any payments for this voluntary service. Dr Saver paid for his own travel. Dr Saver reported receiving contracted hourly payments and travel reimbursement for services as a scientific consultant advising on rigorous trial design and conduct to Medtronic, Stryker, Cerenovus, BrainsGate, Boehringer Ingelheim (prevention only), NONO Inc, BrainQ, and Abbott; contracted stock options for services as a scientific consultant advising on rigorous trial design and conduct to Rapid Medical; and personal fees from Johnson & Johnson and Novo Nordisk.

Adeoye reported being an employee of the University of Cincinnati. He is cofounder and equity holder for Sense Diagnostics Inc, which is developing a brain monitoring device for which the University of Cincinnati holds the patent. The University of Cincinnati receives grant support from the NIH for Dr Adeoye’s leadership role in the Multi-arm Optimization of Stroke Thrombolysis (MOST) trial and the Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN). Dr Adeoye reported receiving hourly payments and travel reimbursement for services as a scientific consultant advising on clinical trial design and conduct to Genentech.

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