HAMLET: Hemicraniectomy in Malignant MCA Infarction (2009)

“Although surgical decompression reduces the risk of death, about half of the survivors are left with moderately severe or severe disability. The decision to undertake surgical decompression should, therefore, be made on an individual basis and in discussion with patients’ relatives.”

  • The HAMLET Investigators

1. Publication Details

  • Trial Title: Surgical Decompression for Space-Occupying Cerebral Infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial
  • Citation: Hofmeijer J, Kappelle LJ, Algra A, et al. Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial. Lancet Neurol. 2009;8(4):326-333. DOI: 10.1016/S1474-4422(09)70044-8
  • Published: April 2009, in The Lancet Neurology
  • Author: J. Hofmeijer, M.D., Ph.D.
  • Funding: The Netherlands Heart Foundation and others.

2. Keywords

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

3. The Clinical Question

  • In adult patients (18-60 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 favorable functional outcome at 1 year (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Malignant MCA infarction is a devastating form of ischemic stroke characterized by massive cerebral edema, leading to brain herniation and death in up to 80% of patients treated with medical therapy alone. Decompressive hemicraniectomy, a surgical procedure to remove a large part of the skull, was known to reduce intracranial pressure.
  • Knowledge Gap: While physiologically plausible, there was no high-quality evidence from randomized controlled trials to determine if this major surgical intervention improved patient-centered outcomes like functional recovery.
  • Proposed Hypothesis: The authors hypothesized that early decompressive hemicraniectomy (within 96 hours) would be superior to standard medical care in improving functional outcomes.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 13 medical centers in the Netherlands.
  • Trial Period: Enrollment ran from October 2002 to December 2006.
  • Population:
    • Inclusion Criteria: Adult patients aged 18 to 60 years with a large MCA stroke who had a decreased level of consciousness (NIHSS score > 15) and who could be randomized within 96 hours of symptom onset.
    • Exclusion Criteria: Included pre-existing severe disability (modified Rankin Scale score >2), bilateral fixed and dilated pupils, and severe comorbidities.
  • Intervention: Patients received a large decompressive hemicraniectomy 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 trial was designed as part of a pre-planned pooled analysis with two other similar European trials (DESTINY and DECIMAL) to achieve adequate statistical power.
  • Outcomes:
    • Primary Outcome: Favorable functional outcome at 1 year, defined as a score of 0 to 3 on the modified Rankin Scale (mRS).
    • Secondary Outcomes: Included mortality at 1 year and the distribution of mRS scores.

6. Key Results

  • Enrollment and Baseline: 64 patients were randomized (32 to hemicraniectomy and 32 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early due to slow enrollment and after the positive results of the pooled analysis with the other two trials became available.
  • Primary Outcome: There was no statistically significant difference in the primary outcome in this trial alone. A favorable outcome (mRS 0-3) occurred in 8 of 32 patients (25%) in the hemicraniectomy group and in 7 of 32 patients (22%) in the control group.
  • Secondary Outcomes: Mortality at 1 year was significantly lower in the hemicraniectomy group: 7 of 32 patients (22%) died, compared with 19 of 32 patients (59%) in the control group (p=0.002).
  • 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 with a favorable outcome between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary and secondary outcomes and the associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value for the primary outcome was not statistically significant. The p-value of 0.002 for the secondary outcome of mortality was highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the outcome of mortality):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 59% – 22% = 37%.
      • Clinical Meaning: For every 100 patients treated with hemicraniectomy, about 37 additional deaths were prevented at 1 year.
    • 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 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. The pre-planned pooled analysis with other trials was a major strength.
  • Generalizability: The inclusion of 13 centers increases the applicability of the findings.
  • 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 trial had a strict upper age limit of 60 years. Therefore, the results cannot be directly generalized to older patients.
  • Other: The trial was stopped early and was severely underpowered on its own to detect a difference in the primary functional outcome. Its results are most meaningful as part of the pooled analysis.

10. Conclusion of the Authors

  • The authors concluded that in patients aged 18-60 with malignant MCA infarction, decompressive hemicraniectomy reduces the risk of death but that many survivors are left with significant disability.

11. To Summarize

  • Impact on Current Practice: This trial, as part of the pooled European analysis, was profoundly practice-changing. It provided definitive evidence that decompressive hemicraniectomy saves lives in younger patients with malignant MCA stroke, establishing it as a standard of care.
  • Specific Recommendations:
    • Patient Selection: For adult patients aged 18-60 years with malignant MCA infarction.
    • Actionable Intervention: Proceed with emergent decompressive hemicraniectomy.
    • Expected Benefit: This 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 survivors will have a good functional outcome. A significant proportion of patients saved by the surgery are left with moderate to severe disability.
  • Implementation Caveats: This is a major neurosurgical procedure that requires a comprehensive stroke center with neurosurgical and neurocritical care expertise. The decision to proceed with surgery requires a careful discussion with the patient’s family about the high likelihood of survival with significant disability.

12. Context and Related Studies

  • Building on Previous Evidence: The HAMLET trial (2009), along with DESTINY (2007) and DECIMAL, was one of three key European trials designed to provide high-quality RCT evidence for hemicraniectomy.
  • Influence on Subsequent Research: The definitive positive survival benefit in younger patients in the pooled analysis led directly to the design of the DESTINY II trial (2014), which was specifically designed to test the same intervention in patients older than 60 years.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from this trial was whether the survival benefit of hemicraniectomy would extend to older patients (>60 years), who have a worse prognosis at baseline.
  • Future Directions: The DESTINY II trial was the direct successor to this study, designed to answer the question of efficacy in the elderly population.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a devastating condition with extremely high mortality.
  • Methods: The multicenter RCT design and pre-planned pooled analysis were of high quality. The main methodological limitation is the open-label design, though this is unavoidable for this type of surgical intervention. The trial was underpowered on its own.
  • Results: The study reported a clear and dramatic reduction in mortality. However, it failed to show a statistically significant improvement in its primary outcome of favorable functional recovery, highlighting the difficult trade-off of the intervention.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial is a landmark in stroke 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 strictly limited to the younger patient population studied.

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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