Publication

• Title: Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke
• Acronym: DESTINY II
• Year: 2014
• Journal published in: The New England Journal of Medicine
• 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.

Context & Rationale

• Background

  • “Malignant” middle cerebral artery (MCA) infarction causes rapidly progressive cerebral oedema with life-threatening mass effect and historically very high case fatality under best medical management.
  • Earlier randomised trials in younger adults showed decompressive hemicraniectomy can reduce mortality, but most survivors remain moderately-to-severely disabled.
  • Older patients (a large proportion of malignant MCA cases) were largely excluded from earlier trials, leaving major uncertainty about benefit–harm balance, acceptable outcomes, and shared decision-making.
• Research Question/Hypothesis

  • In patients aged ≥61 years with malignant MCA infarction, does early decompressive hemicraniectomy plus intensive care increase survival without “severe disability” (pre-specified as modified Rankin Scale [mRS] 0–4 at 6 months) compared with intensive care alone?
• Why This Matters

  • Defines whether the mortality benefit of surgery extends to older adults and quantifies the disability profile among survivors.
  • Directly informs time-critical neurosurgical referral pathways and ethically fraught discussions about survival with dependency.
  • Provides trial data for guideline recommendations, counselling, and resource planning for neurocritical care and rehabilitation.

Design & Methods

• Research Question: Among patients ≥61 years with malignant MCA infarction, does early decompressive hemicraniectomy (within 48 hours of symptom onset) plus maximum conservative intensive care improve the proportion with mRS 0–4 at 6 months versus maximum conservative intensive care alone?
• Study Type: Prospective, randomised, controlled, open-label, multicentre trial (Germany); 1:1 allocation; sequential design with interim analyses and a pre-specified stopping boundary.
• Population:
  • Setting: Neurocritical care units at participating hospitals.
  • Key inclusion criteria:
    • Age ≥61 years.
    • Acute unilateral MCA infarction involving ≥2/3 of the MCA territory (CT or MRI), including basal ganglia involvement on imaging criteria used for “malignant” infarction prediction.
    • Severe stroke with high NIHSS (dominant hemisphere: NIHSS ≥20; non-dominant hemisphere: NIHSS ≥15).
    • Reduced level of consciousness (NIHSS item 1a ≥1).
    • Ability to start assigned treatment within 6 hours after randomisation and within 48 hours after symptom onset.
  • Key exclusion criteria:
    • Pre-stroke disability (mRS >1).
    • Contraindication to surgery/anaesthesia or anticipated poor life expectancy due to severe comorbidity.
    • Other causes of impaired consciousness or major competing neurological pathology (e.g., intracranial haemorrhage, tumour).
    • Known coagulopathy or ongoing anticoagulation not correctable within the required timeframe (as per trial criteria).
• Intervention:
  • Early decompressive hemicraniectomy plus maximum conservative intensive care.
  • Surgery performed as soon as possible after randomisation (target within 6 hours) and within 48 hours of symptom onset.
  • Standardised surgical approach: large fronto-temporo-parietal craniectomy (typically ≥12 cm diameter) with dural opening and duraplasty; bone flap removed and stored; subsequent cranioplasty later.
• Comparison:
  • Maximum conservative intensive care without early decompressive surgery.
  • Conservative management included protocolised neurocritical care (airway/ventilation as needed, haemodynamic targets, temperature and glucose management, osmotherapy/ICP-directed measures, and management of complications), with no planned hemicraniectomy unless protocol deviation/rescue.
• Blinding: Open-label treatment; outcome assessment was performed by investigators not involved in acute care, but full blinding was not feasible (risk of performance and detection bias for subjective endpoints).
• Statistics: Sequential (triangular) design; assumed an increase in the primary endpoint (mRS 0–4 at 6 months) from 8.6% (control) to 31.0% (surgery); alpha 5% (two-sided) and 90% power; maximum sample size 160; primary analysis by intention-to-treat with bias-corrected estimates appropriate for sequential monitoring.
• Follow-Up Period: Primary outcome at 6 months (±14 days); key secondary outcomes at 12 months (±14 days).

Key Results

This trial was stopped early. Recruitment was halted after a pre-specified interim analysis (sequential monitoring boundary crossed for efficacy once sufficient patients had reached the 6‑month endpoint); a total of 112 patients were randomised (including “overrun” patients already enrolled).

• The primary endpoint improvement reflected a large reduction in mortality, with most survivors living with substantial dependency (mRS 4–5 predominated).
• At 12 months, surgery remained associated with higher survival and better (but still impaired) health-related quality of life; depressive symptom scores were lower in the surgical arm.
• Serious infections were more frequent after surgery, whereas neurological deterioration/herniation events were more frequent with conservative care.

Internal Validity

• Randomisation and allocation:
  • Central randomisation stratified by centre; sealed envelopes were available as back-up (allocation concealment likely adequate up to assignment).
  • Sequential monitoring increases risk of overestimating treatment effects; trial used bias-corrected estimates for the primary endpoint.
• Dropout or exclusions (post-randomisation):
  • Primary endpoint data were available for the full analysis set at 6 months.
  • At 12 months, outcome denominators were reduced (mRS available: 47/49 vs 62/63), introducing potential attrition bias for longer-term endpoints.
• Performance/Detection bias:
  • Open-label treatment could influence co-interventions (e.g., intensity of supportive care, timing of limitation of therapy) and subjective outcomes.
  • The primary outcome (mRS) is semi-structured but still subject to assessment bias; assessors were not part of acute care, which may reduce but not eliminate bias.
• Protocol adherence:
  • Protocol compliance was high: 48/49 (98.0%) received assigned surgery; 62/63 (98.4%) in the conservative arm remained without early surgery.
  • Per-protocol set excluded protocol deviations (n=5 surgery; n=6 control); per-protocol primary endpoint OR 3.61; 95% CI 1.20 to 9.80; P=0.024 (directionally consistent).
• Baseline characteristics:
  • Groups were broadly similar in age (median 70 vs 71 years), sex distribution, pre-stroke function (mRS 0–1), stroke severity (NIHSS median 18 vs 19), and imaging infarct extent.
• Heterogeneity:
  • Multicentre design improves robustness; however, surgical technique and ICU practices may vary across sites (mitigated by protocolised surgical standards and ICU care guidance).
• Timing:
  • Randomisation occurred early (median 25 hours from symptom onset in both groups).
  • Time from randomisation to hemicraniectomy was short (median 1.3 hours; IQR 0.7–2.2), supporting biological plausibility for oedema prevention rather than rescue only.
• Dose (intervention fidelity):
  • Surgical “dose” (large hemicraniectomy with duraplasty) was standardised; separation from control was strong (minimal crossover).
• Separation of the variable of interest:
  • Assigned treatment delivered: 48/49 received surgery vs 1/63 in the conservative arm receiving hemicraniectomy (protocol deviation/rescue).
  • Time to randomisation: median 25 hours (IQR 18–30) vs 26 hours (IQR 20–30).
• Crossover:
  • Crossovers were rare (1 patient in each arm received the opposite strategy), limiting dilution of effect.
• Outcome assessment:
  • Primary endpoint (mRS dichotomised 0–4 vs 5–6) is clinically interpretable but embeds a value judgement about what constitutes “severe disability”.
  • Secondary endpoints included survival, mRS distribution, and patient-centred measures (EQ‑5D, SF‑36, HDRS), improving interpretability beyond mortality alone.
• Statistical rigour:
  • Sequential design with pre-specified stopping boundaries was appropriate for an invasive intervention and high-mortality condition, but early stopping can exaggerate effect sizes and widen uncertainty.
  • Confidence intervals were wide for the primary OR (reflecting modest sample size and stopping).

Conclusion on Internal Validity: Moderate-to-strong. Randomisation, high protocol adherence, and strong treatment separation support internal validity, but open-label delivery and early stopping (with modest sample size and wide CIs) limit certainty about the precise magnitude of benefit and the disability trade-off.

External Validity

• Population representativeness:
  • Enrolled a typical “malignant MCA infarction” phenotype with very severe deficits (high NIHSS, depressed consciousness, large infarct burden) and low pre-morbid disability.
  • Applies primarily to older patients who are independent pre-stroke and can undergo major neurosurgery within a narrow time window.
• Applicability:
  • Findings generalise best to well-resourced neurocritical care settings with rapid neurosurgical access and rehabilitation capacity.
  • Conducted largely before widespread modern thrombectomy pathways; malignant oedema still occurs despite reperfusion therapy, but incidence and case-mix may differ today.
  • Patients with substantial pre-stroke disability, major comorbidity, or delayed presentation were excluded; extrapolation to these groups is limited.

Conclusion on External Validity: Good for independent older adults with true malignant MCA infarction managed in neurocritical care systems capable of rapid surgery; limited for frail patients, delayed presenters, and health systems without consistent neurosurgical capacity.

Strengths & Limitations

• Strengths:
  • Addresses a major evidence gap in older adults, a group under-represented in earlier decompressive surgery trials.
  • Clear physiological rationale with tight timing and high protocol adherence; strong separation between strategies.
  • Patient-centred secondary outcomes (quality of life, mood) and retrospective consent data enrich clinical interpretation.
  • Sequential monitoring ethically appropriate for high-risk surgery with high baseline mortality.
• Limitations:
  • Open-label design; potential influence on co-interventions and treatment limitation decisions.
  • Early stopping and modest sample size yield wide confidence intervals and potential overestimation of effect.
  • Primary endpoint uses a disability threshold (mRS 0–4) that may not align with all patients’ values, particularly given high rates of mRS 4–5 among survivors.
  • Missing data for some 12‑month outcomes and available-case analyses for quality-of-life measures.

Interpretation & Why It Matters

• Clinical decision-making

  Early decompressive hemicraniectomy in older adults substantially increases survival, but most additional survivors live with dependency (commonly mRS 4–5); this must be explicitly discussed with patients’ families using clear prognostic framing.
• Practical pathway implication

  Because time to randomisation and surgery was short, systems need pre-defined triggers (imaging + NIHSS + reduced consciousness) to facilitate urgent neurosurgical consultation within the first day after symptom onset.
• Outcome nuance

  Survival benefit is clear; quality-of-life and mood data at 12 months suggest survivors are not uniformly “worse off”, but the disability burden remains high and preferences vary widely.

Controversies & Subsequent Evidence

• Disability threshold and value judgements:
  • The pre-specified primary outcome (mRS 0–4) treats mRS 5 as an “unfavourable” outcome, yet many surgical survivors were mRS 4–5; critics emphasised that the clinical meaning of “benefit” depends on patient values and acceptable dependency levels.¹
• Early stopping and effect-size inflation:
  • Stopping at an interim analysis can inflate apparent benefit and increase uncertainty around the true treatment effect size, particularly for disability outcomes where CIs were wide.
• Open-label care and withdrawal/limitation decisions:
  • Letters highlighted that differential expectations and treatment limitation practices could influence mortality and disability outcomes in unblinded surgical trials; this remains a critical interpretive lens for any surgery-versus-medical management study.²
• Subsequent evidence base:
  • Individual patient data meta-analysis of randomised trials (including older cohorts) supports a mortality benefit of decompressive surgery with outcome trade-offs that vary by age and disability thresholds, reinforcing the need for preference-sensitive decisions.³
  • European Stroke Organisation guidance on space-occupying brain infarction incorporates DESTINY II and recommends decompressive surgery in carefully selected patients, with explicit attention to expected disability and shared decision-making.⁴
  • AHA/ASA acute ischaemic stroke guidance recognises decompressive hemicraniectomy as a key option for malignant cerebral oedema in appropriately selected patients, framing it as time-sensitive and preference-dependent.⁵

Summary

• DESTINY II tested early decompressive hemicraniectomy versus conservative ICU care in patients aged ≥61 years with malignant MCA infarction.
• The trial stopped early for efficacy; hemicraniectomy increased survival without “severe disability” (mRS 0–4) at 6 months (38.5% vs 17.7%; OR 2.91; 95% CI 1.06 to 7.49).
• Mortality was markedly lower with surgery at 6 months (32.7% vs 73.0%) and survival remained higher at 12 months (57.4% vs 24.2%).
• Most survivors in the surgical arm were dependent (mRS 4–5), underscoring the need for nuanced counselling rather than “mortality-only” framing.
• Serious infections were more frequent after surgery, while neurological deterioration/herniation events were more frequent with conservative management; QoL and depressive symptoms at 12 months favoured surgery among assessed survivors.

Overall Takeaway

DESTINY II established that early decompressive hemicraniectomy in older adults with malignant MCA infarction substantially improves survival, with a corresponding increase in survivors living with significant dependency. Its landmark contribution is not merely demonstrating a mortality signal, but quantifying the disability profile and patient-centred outcomes that underpin modern shared decision-making and guideline recommendations in neurocritical care.

Bibliography

• 1.Ropper AH. Hemicraniectomy — to halve or halve not. N Engl J Med. 2014;370(12):1159-1160.
• 2.Kelly AG, et al. Hemicraniectomy for middle-cerebral-artery stroke. N Engl J Med. 2014;370(24):2346-2347.
• 3.Reinink H, Jüttler E, Hacke W, et al. Surgical decompression for space-occupying hemispheric infarction: an individual patient data meta-analysis of randomized clinical trials. JAMA Neurol. 2021;78(2):208-216.
• 4.van der Worp HB, Hofmeijer J, Jüttler E, et al. European Stroke Organisation (ESO) guidelines on the management of space-occupying brain infarction. Eur Stroke J. 2021;6(4):IV-XLVII.
• 5.Powers WJ, Rabinstein AA, Ackerson T, et al. 2019 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke. 2019;50(12):e344-e418.