Going Beyond the 4.5-Hour Window for Thrombolysis in Stroke

In the mid-1990s, initial clinical trials demonstrated the benefit of intravenous tissue plasminogen activator (t-PA) in acute ischemic stroke. Since then, treatment for patients with stroke has remained largely unchanged. With an emphasis on “time is brain,” the main therapeutic goal was to administer t-PA as early as possible — within 4.5 hours of stroke onset or since the patient was last known as well, and ideally within 3 hours — to derive the maximum benefit. 

In 2015, five landmark clinical trials in short succession showed that treatment did not need to be limited to early administration of t-PA in some patients and that intra-arterial mechanical thrombectomy within 6 hours of stroke onset further improved outcomes in patients with large artery occlusions of the proximal anterior circulation. Two years later, two other clinical trials extended the window of benefit for treatment with mechanical thrombectomy to 24 hours after stroke onset. The key was to select the right patients; those with at risk ischemic but not yet infarcted brain tissue that could be salvaged with reperfusion. In the DAWN trial, investigators made this determination based on severe neurologic deficits that were out of proportion with the infarcts seen on computed tomography or magnetic resonance imaging (MRI). In the DEFUSE 3 trial, investigators used imaging findings to identify mismatch between ischemic and infarcted tissue. For many patients who develop stroke symptoms upon awakening from sleep (“wake-up” strokes) or have an unknown time of stroke onset, there is finally another option.

Despite thrombectomy’s efficacy during an extended window, it remains applicable only to patients with the right anatomic occlusions. Whether t-PA, which doesn’t apply to specific anatomic lesions, can also provide benefit when given beyond the 4.5-hour window remains unknown. The WAKE-UP trial, published in NEJM on May 16, 2018, addresses this question. Investigators recruited patients aged 18 to 80 who presented with symptoms of acute stroke, were last known to be well more than 4.5 hours prior to stroke onset, and who had abnormal signal on diffusion-weighted imaging (DWI) — indicating ischemic tissue — and no change on fluid-attenuated inversion recovery (FLAIR) — indicating not yet infarcted tissue — in the region of the acute stroke. The authors report that this mismatch correlates with symptom onset within 4.5 hours and hypothesized that the mismatch would identify patients with unknown time of onset who might benefit from t-PA because they were presenting early. 

The investigators planned recruitment of 800 patients and randomized 503 patients to receive alteplase or placebo before the trial was stopped early because of a lack of funding. Despite early termination, the results suggested that alteplase was associated with a significant benefit in the primary outcome, defined as a score of 0 to 1 (no symptoms or no significant disability and able to carry out all usual activities) on the modified Rankin scale (53.3% vs. 41.8%; adjusted odds ratio, 1.61; 95% CI, 1.09 to 2.36). Alteplase was also associated with a lower median modified Rankin scale (1 vs. 2, respectively).

In an accompanying editorial, Dr. Tudor G. Jovin from the University of Pittsburgh Medical Center cautions against overinterpreting the results, which need to be replicated before changing clinical practice. He notes that the study was underpowered to assess safety endpoints and that there were numerically more deaths at 90 days (4.0% vs. 1.2%) and symptomatic intracranial hemorrhages (2.0% vs. 0.4%) in the alteplase group. Had the study reached the planned enrollment, these differences might have been statistically significant. Furthermore, because planned thrombectomy was an exclusion criterion, it remains uncertain how t-PA should be combined with thrombectomy in patients who present late after stroke onset and are eligible for both therapies. Nonetheless, the WAKE-UP trial is an important next step toward improving treatment of stroke by targeting the patients who are most likely to benefit.

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Mike is a 2017-2018 NEJM Editorial Fellow and a hospitalist at Beth Israel Deaconess Medical Center. He graduated from Harvard Medical School and completed his internal medicine training at BIDMC.