DESTINY II: Hemicraniectomy in Older Patients with Malignant MCA Infarction (2014)

“Although decompressive hemicraniectomy increased the number of patients who survived, it also increased the number of patients who survived with severe disability.”

  • The DESTINY II Investigators

1. Publication Details

  • Trial Title: Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II (DESTINY II): a randomized, open-label trial
  • Citation: Jüttler E, Unterberg A, Woitzik J, et al. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. N Engl J Med. 2014;370(12):1091-1100. DOI: 10.1056/NEJMoa1311367
  • Published: March 20, 2014, in The New England Journal of Medicine
  • Author: Eric Jüttler, M.D.
  • Funding: German Research Foundation.

2. Keywords

  • Ischemic Stroke, Malignant Middle Cerebral Artery Infarction, Decompressive Hemicraniectomy, Elderly, Neurosurgery, Randomized Controlled Trial

3. The Clinical Question

  • In older adult patients (>60 years) with malignant middle cerebral artery (MCA) territory infarction (Population), does early decompressive hemicraniectomy (Intervention) compared to standard medical care (Comparison) improve the rate of survival without severe disability at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The original DESTINY trial (2007) and its pooled analysis had definitively shown that decompressive hemicraniectomy was a life-saving procedure in patients under the age of 60 with malignant MCA stroke.
  • Knowledge Gap: Older patients have a worse prognosis after stroke and were excluded from the original trials. It was completely unknown if the survival benefit of this major surgery would extend to patients older than 60, and if it did, what the quality of that survival would be.
  • Proposed Hypothesis: The authors hypothesized that early decompressive hemicraniectomy would be superior to standard medical care in reducing the risk of death or severe disability in patients older than 60 years.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 13 neurological and neurosurgical intensive care units (ICUs) in Germany.
  • Trial Period: Enrollment ran from August 2009 to February 2013.
  • Population:
    • Inclusion Criteria: Adult patients aged 61 years or older with clinical signs of a severe MCA stroke and a large infarct volume on CT/MRI, who could be randomized within 48 hours of symptom onset.
    • Exclusion Criteria: Included pre-existing severe disability (modified Rankin Scale score >1), bilateral fixed and dilated pupils, and severe comorbidities.
  • Intervention: Patients received a large decompressive hemicraniectomy (at least 12 cm in diameter) plus standard medical care.
  • Control: Patients received standard medical care alone, which included sedation, osmotherapy, and other measures to control intracranial pressure.
  • Management Common to Both Groups: All patients received best medical management for stroke according to guidelines at the time.
  • Power and Sample Size: The authors calculated that a sample size of 160 patients would be required to have 80% power to detect a 26% absolute 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: Survival without severe disability, defined as a modified Rankin Scale (mRS) score of 0 to 4, at 6 months.
    • Secondary Outcomes: Included mortality at 6 months and the distribution of mRS scores.

6. Key Results

  • Enrollment and Baseline: 112 patients were randomized (62 to hemicraniectomy and 50 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board after an interim analysis showed a clear survival benefit, but also a high rate of survival with disability.
  • Primary Outcome: There was no significant difference in the primary outcome of survival without severe disability (mRS 0-4). This outcome occurred in 23 of 61 patients (38%) in the hemicraniectomy group and in 18 of 49 patients (37%) in the control group (p=0.99).
  • Secondary Outcomes: Mortality at 6 months was dramatically lower in the hemicraniectomy group (33% vs. 70%; p<0.001). However, the majority of the additional survivors in the surgery group were left with severe disability (mRS score of 4).
  • Adverse Events: The study reported on complications related to the surgery, which were managed as expected.

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 chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who survived without severe disability between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.99 for the primary outcome indicates no difference whatsoever between the groups and is far from the 0.05 threshold for statistical significance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the outcome of survival):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk of Death in Control Group) – (Risk of Death in Intervention Group)
      • Calculation: ARR = 70% – 33% = 37%.
      • Clinical Meaning: For every 100 older patients treated with hemicraniectomy, about 37 additional deaths were prevented at 6 months.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.37 = 2.7, which is rounded up to 3.
      • Clinical Meaning: You would only need to treat 3 older patients with decompressive hemicraniectomy to prevent one additional death.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The inclusion of multiple centers increases the applicability of the findings.
  • Statistical Power: Although stopped early, the trial had a large enough sample size to detect a statistically significant difference in mortality.
  • Patient-Centered Outcomes: The study focused on the crucial outcomes of mortality and long-term functional status.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which is an unavoidable limitation for a major surgical trial.
  • External Validity (Generalizability): The findings are specific to patients over the age of 60.
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect. The most important limitation is the ethical complexity of the outcome: the intervention was highly effective at preventing death but did so at the cost of increasing the number of survivors with severe disability.

10. Conclusion of the Authors

  • The authors concluded that while hemicraniectomy reduces mortality in patients older than 60 with malignant MCA infarction, it also increases the number of patients who survive with moderate to severe disability (mRS scores of 3 to 4).

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that extended the indication for a life-saving therapy to an older population, but it did so with a profound ethical and clinical trade-off. It has forced a major shift in how clinicians discuss this intervention with families.
  • Specific Recommendations:
    • Patient Selection: For adult patients aged >60 years with malignant MCA infarction.
    • Actionable Intervention: Decompressive hemicraniectomy can be considered as a life-saving therapy.
    • Expected Benefit: The intervention has a very large effect on survival, with an NNT of only 3 to prevent one death.
  • What This Trial Does NOT Mean: This trial does NOT mean that all older patients should automatically receive this surgery.
  • Implementation Caveats: The decision to proceed with surgery requires a very careful and explicit shared decision-making process with the patient’s family, clearly outlining the high probability that survival will come at the cost of significant, life-altering disability.

12. Context and Related Studies

  • Building on Previous Evidence: The DESTINY II trial (2014) was the direct successor to the original DESTINY trial (2007) and its pooled analysis, specifically designed to answer the question of efficacy in the elderly population.
  • Influence on Subsequent Research: The findings of this trial have been highly influential in shaping guidelines and, more importantly, in emphasizing the critical role of shared decision-making and goals-of-care discussions in neurocritical care.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from this trial is not a scientific one, but an ethical one: how do patients, families, and societies value survival with severe disability?
  • Future Directions: Future research is focused on improving neuro-rehabilitation and on identifying which older patients might be more likely to have a more favorable functional recovery after this life-saving surgery.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing the applicability of a proven life-saving therapy to a large and growing elderly population.
  • Methods: The multicenter RCT design was of high quality. The main methodological limitation is the open-label design, though this is unavoidable for this type of surgical intervention. The primary outcome, combining survival and function, was well-chosen.
  • Results: The study reported a clear and dramatic reduction in mortality. However, it also clearly showed that this survival benefit did not translate into an increase in survival without severe disability. This complex and nuanced result is the most important finding of the trial.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial is a landmark in neurocritical care, not just for its scientific findings, but for the profound ethical and clinical questions it raises about the goals of care. Its applicability is high, but it comes with the major caveat that the intervention must be preceded by a detailed discussion about the likely outcomes.

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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