DEVT, SKIP Trials Add Support for Omitting IV tPA Before Stroke Thrombectomy
Accumulated trial data so far are not “absolutely convincing,” however, and the field awaits the results of additional studies.
(UPDATED) For patients with acute ischemic strokes caused by large-vessel occlusions, forgoing IV thrombolytics before mechanical thrombectomy may be a viable option, according to the results of two trials published online this week in JAMA.
In the DEVT trial, taking patients directly to the cath lab resulted in noninferior 90-day functional outcomes compared with the guideline-recommended approach of administering IV alteplase before the intervention, lead author Wenjie Zi, MD (Xinqiao Hospital and The Second Affiliated Hospital, Chongqing, China), and colleagues report.
And in the SKIP trial, which was initially presented at the International Stroke Conference last year, functional outcomes were similar with the two strategies. The trial, however, did not establish the noninferiority of skipping IV thrombolytics, a result attributed to higher-than-expected rates of recanalization and favorable outcomes.
A third trial, DIRECT-MT, published in the New England Journal of Medicine in May 2020, established the noninferiority of taking patients directly to the cath lab for thrombectomy when they present to a center equipped to do the procedure.
Commenting for TCTMD, Michael Hill, MD (Hotchkiss Brain Institute, University of Calgary, Canada), said it’s too soon to change guidelines, noting that there are additional trials underway—those include MR CLEAN-NO IV, SWIFT DIRECT, and DIRECT-SAFE. “Are we ready to make a change right away now? No, not yet because the trial data we have so far, there’s just not enough to be absolutely convincing,” he stressed.
He predicted, however, that “ultimately this will be a viable and appropriate treatment in situations where you can get patients rapidly to the cath lab and in situations where it’s likely that intravenous thrombolysis has a low probability of resulting in reperfusion.”
All of the trials in recent years that have cemented the place of endovascular therapy in the treatment of acute ischemic stroke have been done in the context of IV thrombolytic therapy administered before the procedure, and international guidelines continue to recommend the approach for eligible patients.
There are pros and cons to giving IV alteplase before thrombectomy. On the plus side, it may open up the artery without the need for additional intervention or, if thrombectomy is warranted, it may enhance reperfusion or ease the procedure. Downsides include heightened risks of intracranial bleeding, the potential for delayed thrombectomy, and higher costs.
Raul Nogueira, MD (Emory University School of Medicine, Atlanta, GA), a co-author on the DEVT paper, told TCTMD that the decision around the use of IV thrombolytics before thrombectomy should not be a black-and-white issue. Instead, he urged, “I think this is an opportunity to look more at the concept of precision medicine.”
He said that in some scenarios it makes sense to administer IV thrombolysis before the procedure—for example, when a patient presents in the middle of the night and it will take some time to mobilize the thrombectomy team. In others, however, skipping tPA might be a good option. For a patient with an M1 occlusion who presents when the thrombectomy team is immediately available, for instance, it may be reasonable to forgo thrombolytic therapy, which would potentially lower the risk of serious hemorrhage and save money, Nogueira said.
“It’s really understanding who’s the patient you have in front of you and making the best judgment based on the risk-benefit assessment rather than just saying, ‘Well, I don’t really need to give tPA to anybody or everybody should get tPA,’” he said. “I think the dogmas are the problem.”
The DEVT trial was conducted at 33 stroke centers in China and included 234 patients (mean age 68 years; 43.6% women) with a proximal intracranial occlusion in the anterior circulation. All presented within 4.5 hours of symptom onset and were eligible for IV thrombolysis.
The primary endpoint was the proportion of patients who were functionally independent—defined as a modified Rankin Scale (mRS) score of 0 to 2—at 90 days. That was achieved by 54.3% of patients who went directly to thrombectomy and 46.6% of those who were given IV alteplase first (P = 0.003 for noninferiority). None of the secondary outcomes differed between groups.
There were also no differences between groups for key safety outcomes, including the incidence of symptomatic intracerebral hemorrhage within 48 hours (6.1% vs 6.8%) and 90-day mortality (17.2% vs 17.8%).
The researchers acknowledge some limitations of the trial, including the fact that it was stopped early for efficacy at the first interim analysis and had a liberal noninferiority margin. “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,” they note. “Second, the early termination of the trial does create potential for overestimation of the effect size. However, it followed a highly conservative prespecified statistical stopping rule.”
In addition, they say, the results of this trial, as well as SKIP and DIRECT-MT, have uncertain generalizability beyond Asian patients, who have a higher incidence of intracranial atherosclerotic disease compared with Western populations and made up the entirety of the study participants.
Nogueira said it’s unlikely that additional trials performed in non-Asian populations will provide results that vary much from those obtained in DIRECT-MT, SKIP, and DEVT, pointing out that patients with intracranial atherosclerotic disease made up the minority of the study populations and that the risk of hemorrhage didn’t seem to be markedly higher in these groups compared with what would be expected. “So I think it’s very reasonable to accept this data.”
Kentaro Suzuki, MD, PhD (Nippon Medical School, Tokyo, Japan), and colleagues published the results of the SKIP trial, which included 204 patients (median age 74 years; 62.7% men) randomized at 23 stroke centers in Japan. Patients in the IV thrombolytics arm received alteplase at a dose of 0.6 mg/kg, which is the one approved in Japan but is lower than the standard 0.9-mg/kg dose used elsewhere.
The primary efficacy endpoint was the proportion of patients with a favorable outcome—defined as an mRS score of 0 to 2 at 90 days. The percentage was similar in the patients who went directly for thrombectomy and those who received IV alteplase first (59.4% and 57.3%), but criteria for noninferiority were not met (P = 0.18).
“Although this study hypothesis could not be proved, the point estimates of treatment effect for mechanical thrombectomy alone was nominally slightly better, not worse, compared with combined therapy,” the SKIP investigators write. “Accordingly, a larger trial or meta-analysis of trials is needed to conclusively assess noninferiority.”
Of 11 secondary efficacy and safety endpoints, only one significantly differed between groups—any intracerebral hemorrhage occurring 36 hours after symptom onset was less frequent in patients who did not receive IV thrombolytics (33.7% vs 50.5%; P = 0.02). Of note, there were no differences in rates of symptomatic intracerebral hemorrhage (5.9% vs 7.7%) or 90-day mortality (7.9% vs 8.7%).
Senior author Kazumi Kimura, MD, PhD (Nippon Medical School), told TCTMD in an email that there remains some question about how early administration of IV alteplase—within 90 minutes of stroke onset—would impact the results, calling for a subanalysis and additional RCTs to explore the issue.
Difficult to Apply Findings
In an accompanying editorial, Jeffrey Saver, MD (University of California, Los Angeles), and Opeolu Adeoye, MD (University of Cincinnati, OH), say DEVT and SKIP “contribute to the mounting evidence that endovascular thrombectomy alone achieves outcomes that may be noninferior to outcomes achieved with combined intravenous thrombolysis plus endovascular thrombectomy” for patients with acute strokes caused by large-vessel occlusions, and that the trials “reinforce and extend” the results of DIRECT-MT.
The results further suggest it “may be reasonable to consider for patients who present directly to thrombectomy-capable centers,” they add, noting that the ongoing trials are needed to establish whether the published trial results are applicable to non-Asian populations.
Both the editorialists and Hill point out that this issue remains in flux, since improvements in thrombolytic therapy may influence the decision around whether to take patients directly to the cath lab. Hill pointed out that in the EXTEND-IA TNK trial, use of tenecteplase versus alteplase before stroke thrombectomy doubled the proportion of patients who achieved reperfusion (22% vs 10%; P =0.002 for noninferiority and P = 0.03 for superiority).
If that’s the case, physicians are probably going to start switching from alteplase to tenecteplase, Hill said. “If one in five patients will recanalize by the time you get to cath lab, it’s absolutely worth it to think about giving thrombolysis because they’ll get faster reperfusion.”
Saver and Adeoye conclude: “While awaiting such potential advances, the current trials that have assessed IV alteplase, including [SKIP and DEVT], have enriched the current therapeutic options, even if applying these findings to individual patients will sometimes be challenging. For stroke clinicians caring for patients with acute ischemic stroke due to large-vessel occlusions, 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.”
Nogueira reiterated his message about individualization. “Let’s not look at this as an opportunity to say no to tPA but rather to say yes to tpA whenever it makes sense and no to tPA whenever it makes sense not to give the drug,” he said. “It’s an opportunity to be more thoughtful and incorporate precision medicine on intravenous thrombolytic treatment prior to thrombectomy.”
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. 2021;325:234-243.
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 trial. JAMA. 2021;325:244-253.
Saver JL, Adeoye O. Intravenous thrombolysis before endovascular thrombectomy for acute ischemic stroke. JAMA. 2021;325:229-231.
- DEVT was supported by grants from 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 funded by the Japanese Society for Neuroendovascular Therapy.
- Nogueira reports receiving consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Imperative Care, Medtronic, Phenox, Prolong Pharmaceuticals, and Stryker Neurovascular and having stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, Vesalio, Viz-AI, and Perfuze.
- Suzuki reports receiving grants from the Japanese Society for Neuroendovascular Therapy during the conduct of the study and a scholarship to study abroad from the Uehara Memorial Foundation.
- Kimura reports 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, Bayer Healthcare Co Ltd, Nippon Boehringer Ingelheim Co Ltd, and Bristol Myers Squibb Co Ltd outside the submitted work.
- Saver reports being an employee of the University of California, which has patent rights in retrieval devices for stroke and which received payments from Medtronic, Stryker, Cerenovus, BrainsGate, NONO Inc, and Boehringer Ingelheim (prevention only), and grant support from the National Institutes of Health (NIH) for Saver’s service and from Diffusion Pharma for his leadership role in the PHAST-TSC multicenter trial. Saver reports serving as an unpaid consultant to Genentech and receiving contracted hourly payments and travel reimbursement from Medtronic, Stryker, Cerenovus, BrainsGate, Boehringer Ingelheim (prevention only), NONO Inc, BrainQ, and Abbott; contracted stock options from Rapid Medical; and personal fees from Johnson & Johnson and Novo Nordisk.
- Adeoye reports being an employee of the University of Cincinnati and being a 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 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). Adeoye reports receiving hourly payments and travel reimbursement for services as a scientific consultant advising on clinical trial design and conduct to Genentech.
- Zi reports no relevant conflicts of interest.