New England Journal of Medicine MAY 16, 2018

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

Götz Thomalla, Christian Simonsen, Florent Boutitie, et al.

Bottom Line

In patients with acute ischemic stroke of unknown onset time, MRI-guided intravenous alteplase therapy resulted in a significantly higher rate of favorable functional outcomes at 90 days compared with placebo, despite a numerical increase in mortality.

Key Findings

1. The primary efficacy outcome (modified Rankin Scale score 0–1 at 90 days) was achieved by 53.3% of the alteplase group compared to 41.8% of the placebo group (adjusted odds ratio, 1.61; 95% CI, 1.09 to 2.36; P=0.02).

2. Mortality at 90 days was numerically higher in the alteplase group (4.1%) compared to the placebo group (1.2%), although this difference did not reach statistical significance (adjusted odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07).

3. Symptomatic intracranial hemorrhage occurred in 2.0% of patients in the alteplase group versus 0.4% in the placebo group (P=0.21).

4. The median modified Rankin Scale score at 90 days was 1 in the alteplase group compared to 2 in the placebo group (P=0.003).

Study Design

Design

RCT

Double-Blind

Sample

503

Patients

Duration

90 days

Median

Setting

Multicenter, Europe

Population Patients aged 18-80 with acute ischemic stroke and unknown time of symptom onset who met specific MRI criteria (DWI-FLAIR mismatch).

Intervention Intravenous alteplase (0.9 mg/kg).

Comparator Placebo.

Outcome Favorable clinical outcome, defined as a score of 0 or 1 on the modified Rankin scale 90 days after randomization.

Study Limitations

• The trial was terminated early due to a cessation of funding, which limited the total sample size and potentially affected the power to detect significant differences in secondary and safety outcomes.

• The higher numerical mortality in the treatment arm remains a point of clinical concern, even if it lacked statistical significance.

• The trial results may be subject to selection bias, as a large number of screened patients were excluded primarily due to a lack of DWI-FLAIR mismatch.

• The study did not specifically address the role of thrombectomy in the modern era, as some patients with large vessel occlusions were included prior to the widespread adoption of advanced mechanical reperfusion standards.

Clinical Significance

The WAKE-UP trial provides evidence-based support for expanding the use of intravenous alteplase to patients who wake up with stroke symptoms or have an unknown time of onset, provided they demonstrate a DWI-FLAIR mismatch on MRI to identify brain tissue at risk.

Historical Context

Prior to WAKE-UP, patients with 'wake-up strokes' or unknown symptom onset were routinely excluded from thrombolytic therapy, as standard guidelines strictly limited alteplase use to a 4.5-hour window from the last known well time. This trial established MRI-based tissue imaging as a viable clinical strategy to extend this window.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the pathophysiological difference between Diffusion-Weighted Imaging (DWI) and Fluid-Attenuated Inversion Recovery (FLAIR) signals that allows for the 'DWI-FLAIR mismatch' to act as a surrogate for a 'tissue clock' in acute ischemic stroke.

Key Response

DWI detects cytotoxic edema (failure of the Na+/K+ ATPase pump) within minutes of ischemia. FLAIR detects vasogenic edema, which typically takes 4.5 to 6 hours to manifest as visible parenchymal hyperintensity. A 'mismatch' (DWI positive, FLAIR negative) suggests the stroke is likely within the 4.5-hour window for safe thrombolysis despite an unknown 'last known well' time.

Resident

A patient is brought in after being found with a right-sided hemiparesis. Their last known well was 10 hours ago, but they were found awake 30 minutes ago. If MRI shows a DWI-FLAIR mismatch and no hemorrhage, how does the WAKE-UP trial data change your management compared to traditional 'last known well' time-based protocols?

Key Response

Traditionally, intravenous alteplase is contraindicated beyond 4.5 hours from 'last known well.' The WAKE-UP trial provides evidence that MRI-guided selection (DWI-FLAIR mismatch) allows for safe and effective administration of alteplase in patients with unknown onset, significantly improving functional outcomes (mRS 0-1) at 90 days compared to placebo.

Fellow

Considering the WAKE-UP trial excluded patients for whom endovascular thrombectomy (EVT) was planned, how should a clinician prioritize imaging modalities (MRI vs. CT Perfusion) when faced with a 'wake-up' stroke patient who potentially has a large vessel occlusion (LVO)?

Key Response

This requires integrating WAKE-UP with the DAWN/DEFUSE-3 trials. While WAKE-UP supports MRI for IV tPA in unknown onset (mostly non-LVO), CTP/MRP are the gold standards for EVT selection in extended windows. If LVO is suspected (e.g., high NIHSS), perfusion imaging may be more 'high-yield' to determine eligibility for both IV tPA (via EXTEND criteria) and EVT.

Attending

The WAKE-UP trial demonstrated a significant benefit in functional independence but showed a numerical (though non-significant) increase in mortality in the alteplase group (4.1% vs 1.2%). How do you frame the risk-benefit profile to a surrogate decision-maker in a real-world scenario where the trial was stopped early?

Key Response

The early termination (due to funding) suggests the treatment effect might be slightly overestimated and safety signals underpowered. The attending must teach that while the 'odds of a favorable outcome' (mRS 0-1) are higher with tPA, there is a trade-off involving a potential, albeit small, increase in early mortality and intracranial hemorrhage risk.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The WAKE-UP trial was terminated early due to cessation of funding rather than reaching a pre-specified efficacy or safety boundary. Analyze how this 'premature' termination affects the probability of a Type I error and the potential inflation of the estimated treatment effect size.

Key Response

Truncated trials are susceptible to 'Winner’s Curse,' where the reported effect size is likely at its peak fluctuation. While the p-value was 0.02, stopping early for non-scientific reasons reduces the total person-years of safety data, potentially obscuring the true risk of mortality which showed a non-significant but concerning trend.

Journal Editor

The WAKE-UP trial utilized a primary endpoint of mRS 0-1 at 90 days. Given that many stroke trials use a 'sliding scale' or 'shift analysis' (mRS 0-6), why might the choice of a binary favorable outcome be scrutinized by a reviewer, and how does it impact the study's power?

Key Response

A binary endpoint (0-1 vs 2-6) may miss clinically meaningful improvements in patients who move from severe disability (mRS 5) to moderate disability (mRS 3). However, in a relatively mild stroke population (median NIHSS 6), the 0-1 target is more stringent and ensures the treatment is actually restoring 'normalcy,' though it requires a larger sample size to achieve power than a shift analysis.

Guideline Committee

Current AHA/ASA guidelines (2019 update) give MRI-guided alteplase for unknown onset stroke a Class IIa recommendation. In light of WAKE-UP and subsequent meta-analyses (e.g., EXTEND-IA), should this be upgraded to Class I, and what are the specific logistical barriers to implementation at non-comprehensive stroke centers?

Key Response

While the evidence is robust (Level B-R), the 'Class I' designation is often hindered by the logistical requirement for 24/7 MRI access, which is not universal. Guidelines must balance the high level of evidence for efficacy against the feasibility of recommending a protocol that requires rapid MRI turnaround, which is significantly harder to achieve than CT-based protocols.

Clinical Landscape

Noteworthy Related Trials

2008

ECASS III Trial

n = 821 · NEJM

Tested

Intravenous alteplase (tPA)

Population

Patients with acute ischemic stroke between 3 and 4.5 hours of onset

Comparator

Placebo

Endpoint

Disability at 90 days (mRS score 0-1)

Key result: Intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes.

2015

MR CLEAN Trial

n = 500 · NEJM

Tested

Intra-arterial treatment (mechanical thrombectomy) plus usual care

Population

Patients with acute ischemic stroke caused by proximal intracranial arterial occlusion

Comparator

Usual care alone (intravenous tPA if indicated)

Endpoint

Functional status at 90 days measured by mRS

Key result: Intra-arterial treatment was effective and safe in patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation.

2019

EXTEND Trial

n = 225 · NEJM

Tested

Intravenous alteplase (tPA)

Population

Patients with acute ischemic stroke 4.5 to 9 hours after onset or with wake-up stroke with salvageable brain tissue

Comparator

Placebo

Endpoint

Excellent functional outcome at 90 days (mRS score 0-1)

Key result: Thrombolysis administered up to 9 hours after stroke onset or in wake-up stroke guided by perfusion imaging resulted in better functional outcomes.

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