DAWN: Thrombectomy 6 to 24 Hours after Stroke (2018)

“Among patients with a clinical deficit that is disproportionately severe relative to the infarct volume, an extended time window for treatment with thrombectomy is beneficial.”

  • The DAWN Trial Investigators

1. Publication Details

  • Trial Title: Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct
  • Citation: Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018;378(1):11-21. DOI: 10.1056/NEJMoa1706442
  • Published: January 4, 2018, in The New England Journal of Medicine
  • Author: Raul G. Nogueira, M.D.
  • Funding: Stryker Neurovascular.

2. Keywords

  • Ischemic Stroke, Mechanical Thrombectomy, Extended Time Window, Neuroimaging, Mismatch, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute ischemic stroke from a large-vessel occlusion who present 6 to 24 hours after they were last known to be well and who have a clinical-core mismatch (Population), does mechanical thrombectomy plus standard care (Intervention) compared to standard care alone (Comparison) improve functional outcomes at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Mechanical thrombectomy was a proven, highly effective therapy for acute ischemic stroke, but its benefit had only been established when performed within 6 hours of symptom onset. This left a large population of patients who woke up with stroke symptoms or presented late without a proven treatment option.
  • Knowledge Gap: It was unknown if a select group of patients with favorable imaging (a small “core” of dead brain tissue but a large “penumbra” of salvageable tissue) could still benefit from thrombectomy in an extended time window (6 to 24 hours).
  • Proposed Hypothesis: The authors hypothesized that in patients selected based on a mismatch between the severity of their clinical deficit and the size of their infarct on imaging, mechanical thrombectomy would be superior to standard medical care in improving functional outcomes at 90 days.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 26 centers in the United States, Canada, Europe, and Australia.
  • Trial Period: Enrollment ran from November 2014 to February 2017.
  • Population:
    • Inclusion Criteria: Adult patients with an ischemic stroke from an occlusion of the internal carotid artery or proximal middle cerebral artery who were last known to be well 6 to 24 hours earlier and who had a “clinical-core mismatch” (a severe clinical deficit that was disproportionately large compared to the small volume of the established infarct on imaging).
    • Exclusion Criteria: Included a large infarct core or evidence of intracranial hemorrhage.
  • Intervention: Patients received mechanical thrombectomy with the Trevo device plus standard medical care.
  • Control: Patients received standard medical care alone.
  • Management Common to Both Groups: All patients received standard medical management for acute ischemic stroke, including blood pressure control and antiplatelet therapy as appropriate.
  • Power and Sample Size: The authors planned to enroll a maximum of 500 patients, which would provide high power to detect a difference in the primary outcome.
  • Outcomes:
    • Primary Outcome: A utility-weighted score on the modified Rankin Scale (mRS) for disability at 90 days, which reflects patient-centered functional outcomes.
    • Secondary Outcomes: Included the rate of functional independence (mRS score of 0-2) at 90 days.

6. Key Results

  • Enrollment and Baseline: 206 patients were randomized (107 to thrombectomy and 99 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board after the first planned interim analysis because of a clear and overwhelming benefit in the thrombectomy group.
  • Primary Outcome: The mean utility-weighted mRS score at 90 days was significantly higher (indicating a better outcome) in the thrombectomy group: 5.5 in the thrombectomy group vs. 3.4 in the control group (p<0.001).
  • Secondary Outcomes: The rate of functional independence at 90 days was dramatically higher in the thrombectomy group (49% vs. 13%; p<0.001).
  • Adverse Events: The incidence of symptomatic intracranial hemorrhage was low and not significantly different between the groups (6% in the thrombectomy group vs. 3% in the control group).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a Bayesian statistical model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean utility-weighted mRS scores between the two groups.
  • Key Statistic(s) Reported: The key statistics were the mean scores for the primary outcome and the rate of functional independence.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of <0.001 for both the primary and key secondary outcomes is extremely low, indicating a highly statistically significant result that is very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (for the outcome of functional dependence):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = (100% – 13%) – (100% – 49%) = 87% – 51% = 36%.
      • Clinical Meaning: For every 100 patients treated with thrombectomy in this extended window, about 36 were saved from death or severe disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.36 = 2.8, which is rounded down to 2.
      • Clinical Meaning: You would only need to treat 2 to 3 patients with thrombectomy in this selected population to achieve one additional case of functional independence.
  • Subgroup Analyses: The benefit was consistent across all subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence. The use of a novel, physiology-based patient selection strategy (clinical-core mismatch) was a major strength.
  • Generalizability: The inclusion of 26 diverse centers increases the applicability of the findings.
  • Statistical Power: The study showed such a large treatment effect that it was stopped early with definitive results.
  • Patient-Centered Outcomes: The primary outcome of a utility-weighted mRS score is a robust and highly patient-centered endpoint that captures both survival and quality of life.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias. However, the primary outcome was assessed by blinded adjudicators, which mitigates this concern.
  • External Validity (Generalizability): The findings are only applicable to the highly selected group of patients who meet the specific clinical-core mismatch criteria. This requires advanced imaging and rapid interpretation, which may not be available at all centers.
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect. The trial was funded by the manufacturer of the thrombectomy device.

10. Conclusion of the Authors

  • The authors concluded that in patients with acute stroke who present in the 6-to-24-hour window and have a clinical-core mismatch, thrombectomy is associated with a significantly better functional outcome at 90 days than standard medical care alone.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It completely overturned the previous 6-hour time window for thrombectomy and ushered in a new era of physiology-based patient selection for stroke intervention.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute ischemic stroke from a large-vessel occlusion who are last known well 6 to 24 hours earlier and who meet specific clinical-core mismatch criteria on imaging.
    • Actionable Intervention: Proceed with emergent mechanical thrombectomy.
    • Expected Benefit: This intervention has a very large effect, with an NNT of only 3 to achieve one additional good outcome.
  • What This Trial Does NOT Mean: This trial does NOT mean that “time is not brain.” Earlier treatment is still always better. It also does NOT mean that all patients who present late are candidates for thrombectomy, only the highly selected group with a favorable imaging profile.
  • Implementation Caveats: The success of this strategy is entirely dependent on having 24/7 access to advanced neuroimaging (CT perfusion or MRI) and a comprehensive stroke center capable of performing emergent thrombectomy.

12. Context and Related Studies

  • Building on Previous Evidence: The DAWN trial (2018) was designed to challenge the established 6-hour time window that had been defined by earlier thrombectomy trials.
  • Influence on Subsequent Research: The definitive positive result of this trial, along with the concurrent DEFUSE 3 trial (2018) which showed similar results using a different imaging paradigm, led to a rapid and major revision of international stroke guidelines, expanding the window for thrombectomy up to 24 hours for selected patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal selection criteria for late-window thrombectomy and whether patients who do not meet the strict DAWN or DEFUSE 3 criteria might still benefit remain areas of investigation.
  • Future Directions: Future research is focused on further refining patient selection, exploring adjunctive neuroprotective therapies, and improving systems of care to get more patients to comprehensive stroke centers faster.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, seeking to expand the treatment window for a highly effective but time-sensitive therapy.
  • Methods: The multicenter RCT design with blinded outcome adjudication was of high quality. The use of a physiology-based inclusion criterion (clinical-core mismatch) was a novel and key strength.
  • Results: The study reported a very large and statistically overwhelming benefit for the intervention, with an extremely low p-value and a very impressive NNT of 3. The trial was appropriately stopped early for efficacy.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in stroke care and a classic example of how a physiology-based approach to patient selection can extend the benefits of a proven therapy to a wider population. The findings are highly applicable to any healthcare system with a well-organized comprehensive stroke center.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
Scroll to Top