DEFUSE 3: Thrombectomy 6 to 16 Hours after Stroke (2018)

“Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes at 90 days and lower mortality than standard medical therapy alone.”

  • The DEFUSE 3 Investigators

1. Publication Details

  • Trial Title: Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging
  • Citation: Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018;378(8):708-718. DOI: 10.1056/NEJMoa1713973
  • Published: February 22, 2018, in The New England Journal of Medicine
  • Author: Gregory W. Albers, M.D.
  • Funding: Stryker Neurovascular.

2. Keywords

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

3. The Clinical Question

  • In adult patients with acute ischemic stroke from a large-vessel occlusion who present 6 to 16 hours after they were last known to be well and who have a favorable perfusion-imaging profile (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—specifically, a small “core” of dead brain tissue but a large “penumbra” of salvageable tissue as identified by perfusion imaging—could still benefit from thrombectomy in an extended time window.
  • Proposed Hypothesis: The authors hypothesized that in patients selected based on a favorable perfusion-imaging mismatch, 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 with blinded outcome assessment (used to test the effectiveness of interventions).
  • Setting: 38 medical centers in the United States.
  • Trial Period: Enrollment ran from May 2016 to May 2017.
  • Population:
    • Inclusion Criteria: Adult patients (18-90 years) 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 16 hours earlier and who had a favorable perfusion-imaging profile (infarct core <70 ml, mismatch ratio ≥1.8, and mismatch volume ≥15 ml).
    • Exclusion Criteria: Included a large infarct core or evidence of intracranial hemorrhage.
  • Intervention: Patients received mechanical thrombectomy 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 approximately 200 patients, which would provide 80% power to detect a significant difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The distribution of functional outcomes on the modified Rankin Scale (mRS) for disability at 90 days.
    • Secondary Outcomes: Included the rate of functional independence (mRS score of 0-2) at 90 days and 90-day mortality.

6. Key Results

  • Enrollment and Baseline: 182 patients were randomized (92 to thrombectomy and 90 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 publication of the DAWN trial, which showed a clear and overwhelming benefit for thrombectomy in a similar extended-window population.
  • Primary Outcome: The distribution of functional outcomes on the mRS at 90 days was significantly better in the thrombectomy group (p<0.001).
  • Secondary Outcomes: The rate of functional independence at 90 days was dramatically higher in the thrombectomy group (45% vs. 17%; p<0.001). 90-day mortality was significantly lower in the thrombectomy group (14% vs. 26%; p=0.05).
  • Adverse Events: The incidence of symptomatic intracranial hemorrhage was not significantly different between the groups (7% in the thrombectomy group vs. 4% 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 an ordinal logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the overall distribution of mRS scores between the two groups.
  • Key Statistic(s) Reported: The key statistics were the rate of functional independence and the associated P-value.
  • 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% – 17%) – (100% – 45%) = 83% – 55% = 28%.
      • Clinical Meaning: For every 100 patients treated with thrombectomy in this extended window, about 28 were saved from death or severe disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.28 = 3.6, which is rounded down to 3.
      • Clinical Meaning: You would only need to treat 3 to 4 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 with blinded outcome assessment provided high-quality evidence. The use of a physiology-based patient selection strategy (perfusion imaging) was a major strength.
  • Generalizability: The inclusion of 38 diverse centers increases the applicability of the findings.
  • Statistical Power: The study showed such a large treatment effect that a benefit was clear even with early termination.
  • Patient-Centered Outcomes: The primary outcome of the mRS distribution is a robust and highly patient-centered endpoint that captures the full spectrum of disability.

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 perfusion-imaging criteria. This requires 24/7 access to advanced imaging and a comprehensive stroke center.
  • Other: The trial was stopped early, which can sometimes lead to an overestimation of the true treatment effect. The trial was funded by the manufacturer of a thrombectomy device.

10. Conclusion of the Authors

  • The authors concluded that among patients with acute stroke who present 6 to 16 hours after they were last known to be well and who have a favorable perfusion-imaging profile, endovascular thrombectomy plus standard medical therapy resulted in a significantly better functional outcome at 90 days than standard medical therapy alone.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. Along with the concurrent DAWN 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 16 hours earlier and who meet specific perfusion-imaging mismatch criteria.
    • Actionable Intervention: Proceed with emergent mechanical thrombectomy.
    • Expected Benefit: This intervention has a very large effect, with an NNT of only 3-4 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 DEFUSE 3 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 DAWN trial (2018) which showed similar results using a different mismatch 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 (perfusion imaging) 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 3-4. 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.
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