Introduction
Endovascular therapy for acute ischemic stroke was investigated more than two decades ago, especially among patients with large or more proximal occlusion. Conventional intravenous thrombolysis among patients with large, proximal occlusions may not be efficacious and carries the risk of fatal intracranial hemorrhage. The PROACT trials of the late 1990s evaluated the use of intra-arterial thrombolysis with pro-urokinase in acute ischemic stroke and revealed a trend towards improved neurological outcomes (1). Subsequently, early trials of mechanical thrombectomy using retriever devices suggested effective recanalization in large-vessel occlusive disease (2,3).
The identification of penumbral tissue in the brain – areas that are ischemic, but not infarcted, has been previously investigated. Such areas carry the potential for early reperfusion and salvage, thereby improving functional outcomes (1,4). Goyal et al. performed a meta-analysis of five randomized controlled trials (RCT) between 2010–2014 that evaluated the efficacy of endovascular thrombectomy compared with standard care alone among patients with acute ischemic stroke (5). These trials included patients with occlusion of the proximal anterior artery circulation who underwent thrombectomy within 12 hours of onset of symptoms. Among 1287 patients included in the meta-analysis, 634 were assigned to thrombectomy, while 653 were in the control group. Disability at 90 days, assessed using the modified Rankin Scale, was significantly lower in the thrombectomy group. On subgroup analysis, favorable outcomes were also observed among patients who presented more than 5 hours after the onset of symptoms and those who were ineligible for intravenous thrombolysis. Another meta-analysis of the same RCTs revealed that the favorable outcomes with thrombectomy were directly related to the duration between onset of symptoms and arterial puncture. A gradual decline of favorable effects was observed with every hour of delay to reperfusion.
The efficacy of thrombectomy performed >6 hours after the time that the patient was last known to be well remained unclear. Would thrombectomy improve outcomes in patients presenting with ischemic brain tissue that had not yet undergone infarction, and hence, may be potentially salvageable? The presence of clinical deficits out of proportion to the volume of infarct on imaging may help identify patients who may have ischemic brain tissue that may be amenable to reperfusion with mechanical thrombectomy. A retrospective analysis suggested that endovascular therapy may be safely carried out beyond 8 hours from the time last seen well, when patients were selected based on MRI or CT perfusion imaging (6). Another observational study also suggested that improved outcomes following endovascular reperfusion may not be time-dependent in the presence of salvageable brain tissue, as evident on MRI (7).
The DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) investigators evaluated neurological outcomes with endovascular thrombectomy compared to standard care alone among patients with acute ischemic stroke who were last known to be well 6–24 hours earlier, and had a mismatch between infarct size and clinical deficit (8).
Population and design
The DAWN trial was a multicenter, prospective, randomized, open-label trial conducted between September 2014 through February 2017 across 26 centers in the United States, Canada, Europe, and Australia. Patients with ischemic stroke were eligible if they had occlusion of the intracranial internal carotid artery, the proximal segment of the middle cerebral artery, or both, as evident on CT angiography or magnetic resonance angiography. A disproportionately severe neurological deficit compared to the infarct volume was required for eligibility. Patients were divided into three groups based on the infarct volume – clinical deficit mismatch.
Group A: ≥80 years, infarct volume <21 ml, a score of ≥10 on the National Institutes of Health Stroke Scale (NIHSS, ranging from 0–42)
Group B: <80 years, infarct volume <31 ml, a score of ≥10 or higher on the NIHSS
Group C: <80 years, infarct volume of 31–50 ml, a score of ≥20 or higher on the NIHSS
The other inclusion criteria were a duration of 6–24 hours between the time the patient was last known to be well and randomization, a score of 0 or 1 on the modified Rankin scale at baseline, absence of intracranial hemorrhage, and involvement of less than one-third of the middle cerebral artery territory. Those who were ineligible for thrombolysis due to late presentation or had persistent vessel occlusion despite thrombolytic treatment were also eligible.
Thrombectomy group
Mechanical thrombectomy was performed in addition to standard medical therapy. The investigators employed a retrievable, self-expanding stent to remove occlusive thrombi and restore flow. Rescue interventions with reperfusion therapy or other devices were not allowed. Concurrent stenting of the cervical internal carotid artery was not permitted; however, carotid angioplasty could be performed if considered necessary to deploy the retriever device.
Control group
The control group received standard medical treatment alone, based on local guidelines.
Common management
Patients enrolled in the trial were admitted to ICUs or stroke units. Those who did not undergo thrombolysis with intravenous alteplase could be treated with antiplatelet agents within 24 hours of randomization. Aspirin was administered in a dose 81 mg; prophylaxis against deep vein thrombosis was according to local guidelines. Patients also underwent a comprehensive post-stroke rehabilitation program.
Statistical methodology
The DAWN trial was based on the hypothesis that patients with small-sized infarcts and disproportionately higher clinical deficits would most likely benefit from thrombectomy. However, the maximum core infarct size that may offer the most benefit was unclear. Hence, patients were divided into subgroups based on the infarct volume. At interim analyses, the adaptive trial design enabled reducing the largest infarct volume eligible for the trial based on the results already observed. The first primary analysis evaluated the probability that thrombectomy combined with standard care may result in less clinical disability at 90 days compared with standard care alone using a Bayesian model based on the baseline infarct volume. The adaptive design offered a flexible sample size ranging from 150–500 patients.
The trial was terminated at the first pre-specified interim analysis following the enrollment of 206 patients, as thrombectomy revealed a predictive probability of superiority of at least 95%.
Results
Baseline characteristics
A total of 206 patients were enrolled – 107 were assigned to thrombectomy, while 99 received standard medical treatment alone. Stroke severity was similar with a median NIHSS score of 17 in both groups. The median infarct volume was 7.6 ml in the thrombectomy group and 8.9 in the standard care group. The median duration between when the patient was last known to be well, and randomization was similar between groups (12.2 vs. 13.3 hours). There were more patients in the thrombectomy group with atrial fibrillation and wake-up stroke; alteplase was more commonly used in the control group. Sixty-seven of 107 patients (63%) in the thrombectomy group and 47 of 99 (47%) in the control group were wake-up strokes with an unknown time of symptom onset.
Primary endpoint
The study evaluated two co-primary endpoints. The utility-weighted modified Rankin scale ranges from 0 (death) to 10 (no disability) with higher scores indicating more favorable outcomes. The mean score on the utility-weighted modified Rankin scale was significantly higher with thrombectomy compared with standard care, suggesting improved outcomes (5.5±3.8 vs. 3.4±3.1, posterior probability of superiority >0.999).
The other co-primary endpoint was the level of functional independence, assessed using the modified Rankin scale, ranging from 0 (no disability) to 6 (death). A score of 0,1, or 2 indicates functional independence. Functional independence at 90 days was significantly greater in the thrombectomy group (49% vs. 13%, posterior probability of superiority >0.999)
Sensitivity analysis was carried out, adjusting for between-group differences at baseline. The superiority of thrombectomy persisted for both co-primary endpoints.
Secondary endpoints
Early neurological response, assessed using the NIHSS score, was greater in the thrombectomy group (48% vs. 19%). The rate of recanalization and change in the infarct volume from baseline to 24 hours was also more favorable with thrombectomy compared with standard care. In the thrombectomy group, 84% of patients achieved a mTICI score (modified Thrombolysis in Cerebral Infarction) of 2b or 3, indicating reperfusion of >50% of the affected infarct territory. The size of the core infarct reduced significantly in the thrombectomy group compared with the control group (8 versus 22 mL; P≤0.001).
Safety endpoints
The safety endpoints evaluated included stroke-related mortality at 90 days, all-cause mortality at 90 days, and symptomatic intracerebral hemorrhage. These endpoints were similar in both groups. Neurological deterioration occurred more often in the control group.
Conclusion
Among patients with stroke due to occlusion of the intracranial internal carotid or proximal middle cerebral artery, who were last known to be well 6–24 hours earlier, with a disproportionately severe deficit compared to stroke volume, functional outcomes were more favorable with thrombectomy compared with standard medical care alone. The favorable outcomes associated with thrombectomy were consistent across subgroups of patients based on age, severity of stroke, site of occlusion, and the time to treatment.
Strengths
The DAWN trial was a multicentric RCT that addressed the efficacy of a thrombectomy, a key intervention among patients who present late, up to 24 hours after stroke onset. Assessors of the primary endpoint were blinded to the allocation arm. The scores on the modified Rankin scale, one of the co-primary outcomes, were dichotomized, allowing comparison with other trials. A good clinical outcome ranged from 0–2 on the modified Rankin scale, indicating functional independence with only slight disability.
Limitations
Functionally independent outcomes in the control group were worse than expected compared with previous studies. This could have been related to the less frequent use of thrombolysis due to later presentation. Besides, patients were older, and experienced more severe stroke based on the NIHSS scale. Although randomization was stratified based on prognostic parameters that the authors considered relevant, there were baseline imbalances between groups – with more patients with atrial fibrillation and wake-up stroke in the thrombectomy group, while alteplase was more often used in the control group. However, on post-hoc sensitivity analysis adjusting for these differences, the benefit of thrombectomy persisted. The use of co-primary endpoints is unconventional; besides, the utility-weighted modification of the usual Rankin scale, one of the endpoints, may not capture individual variation in utility values and thereby reduce statistical power (9). In 21% of patients, outcome assessment was carried out through telephonic interview with the patient or caregivers – less than ideal compared with physical evaluation.
Summary
Patients in the DAWN trial presumably had large penumbral areas, considering the disproportionately severe neurological deficits in relation to the volume of the infarct. The findings of the trial reinforced the likelihood of improved outcomes with thrombectomy for up to 24 hours after symptom onset among patients who had proximal vessel occlusion with a mismatch between infarct size and neurological deficits. The most crucial facet of this strategy is the identification of penumbral zones in the brain through appropriate imaging. The DAWN trial employed CT angiography or MRI scans to establish the presence of large penumbral tissue that held the potential for reperfusion.
Overall, patients who underwent thrombectomy were twice as likely to experience an improvement in neurological status and more likely to be functionally independent at 90 days compared with the control group. Participants randomized to the active arm were 2-fold more likely to have an improvement in their neurological status (odds ratio, 2.1; 95% confidence interval, 1.20–3.12). The number needed to treat was just 2 for any lower disability at the pre-specified time. The DAWN trial heralded a new paradigm with clinical deficit to core mismatch emerging as the key criterion in the likelihood of successful thrombectomy, independent of the time of onset of symptoms.
References
1. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999 Dec 1;282(21):2003–11.
2. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008 Apr;39(4):1205–12.
3. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009 Aug;40(8):2761–8.
4. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998 Jan;29(1):4–11.
5. Goyal M, Menon BK, van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet Lond Engl. 2016 Apr 23;387(10029):1723–31.
6. Jovin TG, Liebeskind DS, Gupta R, Rymer M, Rai A, Zaidat OO, et al. Imaging-based endovascular therapy for acute ischemic stroke due to proximal intracranial anterior circulation occlusion treated beyond 8 hours from time last seen well: retrospective multicenter analysis of 237 consecutive patients. Stroke. 2011 Aug;42(8):2206–11.
7. Lansberg MG, Cereda CW, Mlynash M, Mishra NK, Inoue M, Kemp S, et al. Response to endovascular reperfusion is not time-dependent in patients with salvageable tissue. Neurology. 2015 Aug 25;85(8):708–14.
8. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11–21.
9. Dijkland SA, Voormolen DC, Venema E, Roozenbeek B, Polinder S, Haagsma JA, et al. Utility-Weighted Modified Rankin Scale as Primary Outcome in Stroke Trials. Stroke. 2018 Apr;49(4):965–71.
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