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HAMLET 3-year

Surgical Decompression for Space-Occupying Cerebral Infarction: Outcomes at 3 Years in the Randomized HAMLET Trial

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Year of Publication: 2013

Authors: Marjolein Geurts, H. Bart van der Worp, L. Jaap Kappelle, ..., on behalf of the HAMLET Steering Committee

Journal: Stroke

Citation: Stroke. 2013;44:2506-2508

PDF: https://www.ahajournals.org/doi/reader/1...EAHA.113.002014

Clinical Question

Are the effects of surgical decompression for space-occupying hemispheric infarction observed at 1 year sustained at 3 years?

Bottom Line

The effects of decompressive surgery on case fatality and functional outcome in patients with space-occupying hemispheric infarction are sustained at 3 years. Surgery continues to reduce mortality (26% vs 63%, p=0.002) but does not improve functional outcomes (mRS >3 in 74% surgery vs 75% medical). More surgically treated patients lived at home (52% vs 25%). Quality of life improved between 1 and 3 years in patients treated with surgery.

Major Points

  • First long-term (3-year) follow-up of randomized trial of decompressive surgery for malignant MCA infarction
  • Sustained mortality benefit at 3 years: 26% surgery vs 63% medical (ARR 37%, p=0.002)
  • No effect on poor functional outcome: 74% surgery vs 75% medical (p=0.94)
  • More surgical patients lived at home: 52% vs 25% (ARR 27%, p=0.051)
  • Quality of life (SF-36 physical summary score) improved significantly between 1-3 years in surgical patients
  • Quality of life improvement also seen on visual analogue scale in surgical patients
  • Median Barthel Index: 70 (surgery) vs 93 (medical), p=0.16
  • Quality of life acceptable for majority of survivors in both groups
  • Recovery continued beyond 1 year, challenging conventional view that stroke recovery plateaus after 6 months
  • One additional death in each group between 1 and 3 years
  • Mean follow-up duration 3.1 years (SD 0.1)
  • Results consistent across subgroups (≤48 hours vs >48 hours from onset to treatment)
  • Study nurse assessed outcomes, open to treatment allocation

Design

Study Type: Long-term follow-up study of randomized controlled trial (HAMLET)

Randomization: 1

Blinding: Unblinded at 3-year assessment (study nurse open to treatment allocation)

Enrollment Period: Original HAMLET enrollment period

Follow-up Duration: 3 years (mean 3.1 years, SD 0.1)

Centers: Multiple centers (original HAMLET trial)

Countries: The Netherlands

Sample Size: 64

Analysis: Mean differences and absolute risk reductions with 95% confidence intervals. Independent t-test, Mann-Whitney test, χ²-test, paired t-test, or McNemar test as appropriate. Comparisons between 1 and 3 years performed only in patients with outcome data at both time points. Predefined subgroup analyses by interval from stroke onset to treatment (≤48 vs >48 hours). Treatment allocation not blinded at 3-year assessment

Inclusion Criteria

  • Participants from original HAMLET trial
  • Original HAMLET inclusion: adult patients ≤60 years of age
  • Space-occupying hemispheric infarction
  • Enrolled within 4 days (96 hours) after stroke onset in original trial
  • Written informed consent obtained (original trial)

Exclusion Criteria

  • Not specified for 3-year follow-up (used original HAMLET exclusion criteria)

Baseline Characteristics

CharacteristicControlActive
Number randomized3232
Alive at 1 year1325
Alive at 3 years1223
Lost to follow-up at 3 years01

Arms

FieldControlDecompressive Surgery
InterventionConservative medical management for space-occupying hemispheric infarction as per original HAMLET trial protocol. All patients received assigned treatment. Follow-up at 3 years included assessment of: functional outcome (modified Rankin Scale), death, functional dependence (Barthel Index), quality of life (SF-36 and visual analogue scale), symptoms of depression (Montgomery and Åsberg Depression Rating Scale), caregiver strain (Caregiver Strain Index), and place of residence. Study nurse visited each patient and caregivers for outcome assessments at 1 and 3 years, open to treatment allocationSurgical decompression (hemicraniectomy) for space-occupying hemispheric infarction as per original HAMLET trial protocol (within 96 hours of stroke onset). All patients received assigned treatment. Follow-up at 3 years included assessment of: functional outcome (modified Rankin Scale), death, functional dependence (Barthel Index), quality of life (SF-36 and visual analogue scale), symptoms of depression (Montgomery and Åsberg Depression Rating Scale), caregiver strain (Caregiver Strain Index), and place of residence. Study nurse visited each patient and caregivers for outcome assessments at 1 and 3 years, open to treatment allocation
Duration3 years follow-up from original randomization3 years follow-up from original randomization

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Poor functional outcome defined as modified Rankin Scale score >3 (mRS 4-6, including death) at 3 yearsPrimary24/32 (75%)23/31 (74%)0.81%0.94
Death at 3 yearsSecondary20/32 (63%)8/31 (26%)ARR 37%95% CI 14-60, p=0.002
Barthel Index at 3 years (median, range)Secondary93 (15-100)70 (10-100)p=0.16
Quality of life - SF-36 Physical summary score (mean, SD)Secondary35 (12)32 (10)Mean difference -3 (95% CI -12 to 6)p=0.48
Quality of life - SF-36 Mental summary score (mean, SD)Secondary53 (9)56 (10)Mean difference 3 (95% CI -4 to 11)p=0.36
Quality of life - Visual analogue scale (mean, SD)Secondary61 (29)67 (20)Mean difference 6 (95% CI -16 to 28)p=0.56
VAS ≥60 at 3 yearsSecondary8/11 (73%)19/23 (83%)ARR -10% (95% CI -40 to 21)p=0.42
Symptoms of depression - MADRS ≥7Secondary7/10 (70%)13/23 (57%)ARR 14% (95% CI -21 to 48)p=0.69
Symptoms of depression - MADRS ≥19Secondary2/10 (20%)2/23 (9%)ARR 11% (95% CI -16 to 39)p=0.83
Caregiver strain (CSI >6)Secondary6/7 (86%)14/20 (70%)ARR 16% (95% CI -17 to 49)p=0.41
Living at home at 3 yearsSecondary8/32 (25%)16/31 (52%)ARR -27% (95% CI -50 to -4)p=0.051
Change in SF-36 physical summary between 1 and 3 years (surgical patients)SecondaryNot separately reported for medicalStatistically significant improvementSignificant (exact p-value in supplement)
Change in VAS between 1 and 3 years (surgical patients)SecondaryNot separately reported for medicalStatistically significant improvementSignificant (exact p-value in supplement)
Deaths between 1 and 3 yearsAdverse1 additional death1 additional death
Lost to follow-upAdverse01

Subgroup Analysis

Predefined subgroup analyses by interval from stroke onset to treatment (≤48 hours vs >48 hours) showed results consistent with overall analysis. Subgroup analyses limited by smaller patient numbers but support main findings. Results presented in online supplement (Figures and Tables II-III)

Criticisms

  • Small sample size insufficient to detect small differences between groups and small changes over time
  • Comparisons between treatment groups other than case fatality and functional outcome should be interpreted with caution due to large differences in case fatality
  • Outcome assessment at 3 years was unblinded (study nurse open to treatment allocation)
  • Limited statistical power for subgroup analyses
  • Only 64 patients in total - HAMLET was largest randomized trial but still underpowered for some outcomes
  • Comparisons between survivors difficult due to differential mortality between groups
  • No adjustment for multiple comparisons across numerous secondary outcomes
  • Surgery continues to result in survival with severe disability for many patients
  • Quality of life comparisons between groups confounded by survival bias
  • Limited generalizability - only patients ≤60 years included in original trial
  • Single country study (Netherlands)
  • No blinding of outcome assessors at 3 years
  • One patient lost to follow-up in surgical group
  • Baseline characteristics for 3-year cohort not fully described

Funding

Original HAMLET trial supported by Dutch Heart Foundation (grant 2002B138). Drs Geurts and van der Worp supported by Dutch Heart Foundation (2010B239 and 2010T075, respectively) at time of publication

Based on: HAMLET 3-year (Stroke, 2013)

Authors: Marjolein Geurts, H. Bart van der Worp, L. Jaap Kappelle, ..., on behalf of the HAMLET Steering Committee

Citation: Stroke. 2013;44:2506-2508

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