PDF: CONSCIOUS-2
(2011)Objective
To investigate whether clazosentan, an endothelin receptor antagonist, reduced vasospasm-related morbidity and all-cause mortality in patients with aneurysmal subarachnoid hemorrhage secured by surgical clipping
Study Summary
• No significant effect on poor functional outcome at 12 weeks (GOSE ≤4: 29% clazosentan vs 25% placebo, p=0.10)
• Subgroup analyses suggested benefit in patients with poor WFNS grade (≥III) or diffuse thick SAH, but this did not translate to better functional outcomes
Intervention
Clazosentan 5 mg/h intravenous infusion for up to 14 days after aneurysmal SAH versus placebo
Inclusion Criteria
Age 18-75 years, SAH due to ruptured saccular aneurysm secured by surgical clipping, diffuse clot on admission CT (long axis ≥20 mm or present in both hemispheres), WFNS grade I-IV SAH before securing procedure
Study Design
Arms: Clazosentan 5 mg/h vs Placebo
Patients per Arm: Clazosentan: 764, Placebo: 383
Outcome
• Poor outcome (GOSE ≤4) at 12 weeks: 29% clazosentan vs 25% placebo (p=0.10)
• Mortality at 12 weeks: 6% in both groups
Bottom Line
Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome in patients with aneurysmal SAH undergoing surgical clipping. Despite proven efficacy in reducing angiographic vasospasm in previous trials, clazosentan did not translate to measurable clinical benefit. Further investigation in patients undergoing endovascular coiling is needed.
Major Points
- Phase 3 randomized, double-blind, placebo-controlled trial across 102 sites in 27 countries
- 1157 patients randomized (2:1 ratio), 1147 received treatment (764 clazosentan, 383 placebo)
- Primary endpoint (mortality and vasospasm-related morbidity) not significantly different: 21% clazosentan vs 25% placebo (RRR 17%, 95% CI -4 to 33, p=0.10)
- No significant effect on poor functional outcome at 12 weeks: 29% clazosentan vs 25% placebo (p=0.10)
- Mortality at 12 weeks identical in both groups (6%)
- Clazosentan reduced need for rescue therapy for vasospasm: 11% vs 16% placebo (RRR 36%, 95% CI 14-53)
- Subgroup analyses suggested benefit in patients with poor WFNS grade (≥III): RRR 33% (95% CI 8-51)
- Benefit also suggested in patients with diffuse thick SAH at baseline: RRR 25% (95% CI 5-41)
- However, these subgroup benefits did not translate to improved functional outcomes
- More adverse events with clazosentan: lung complications (34% vs 18%), anaemia (22% vs 15%), hypotension (12% vs 4%)
- Study enriched for high-risk patients: substantial blood clot thickness and surgical clipping
- Treatment started median 19 hours after aneurysm clipping in both groups
- Study stopped after enrolling 1157 of planned 1200 patients due to recruitment challenges
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind. Randomization using interactive web response system with predefi ned scheme. Randomization code only available to authorized individuals until study completion. Randomization stratified by site. 2:1 allocation (clazosentan:placebo) to maximize safety information
- Sample Size
- 1157
- Follow-up
- 12 weeks
- Centers
- 102
- Countries
- 27 countries across Europe, North America, and Asia
Primary Outcome
Definition: Composite endpoint of all-cause mortality and vasospasm-related morbidity within 6 weeks of aSAH, defined by at least one of: death; vasospasm-related cerebral infarction (where vasospasm was primary cause or relevant contributing factor); DIND due to vasospasm (decrease ≥2 points on modified Glasgow coma scale or increase ≥2 points on abbreviated NIHSS lasting ≥2 hours, or for sedated patients, administration of valid rescue therapy); or neurological signs/symptoms in presence of positive angiogram leading to rescue therapy
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 97/383 (25%) | 161/764 (21%) | - (-4 to 33) | 0.10 |
Limitations & Criticisms
- Study did not meet primary endpoint - no significant reduction in vasospasm-related morbidity and mortality
- No benefit on functional outcome despite reduction in angiographic vasospasm shown in previous trials
- Higher rates of adverse events with clazosentan, particularly lung complications, anaemia, and hypotension
- Combination with oral nimodipine (used in ~78% of patients) may have contributed to adverse events
- Rescue therapy used more frequently in placebo group may have obscured benefit of clazosentan
- Study excluded patients >75 years and those with local thin SAH, limiting generalizability
- Most patients had WFNS grades I-II (good condition), potentially limiting ability to detect benefit
- Patients with WFNS grade V excluded by protocol
- Subgroup benefits in poor WFNS grade and diffuse thick SAH not confirmed in functional outcomes
- Primary endpoint designed for high specificity may have decreased sensitivity by excluding questionable events
- 2:1 randomization ratio reduced precision of placebo arm estimates
- Imbalance in use of rescue therapy between groups may have confounded results
- Study enriched for high-risk patients (surgical clipping, substantial clot) - results may not apply to endovascular coiling patients
- Trial stopped after 1157 of 1200 planned patients due to recruitment challenges
- No assessment of effect on microcirculation (only large vessel vasospasm)
- Other mechanisms (microthromboembolism, cortical spreading ischemia, delayed neuronal injury) may contribute to poor outcome and are not affected by clazosentan
Citation
Lancet Neurol. Published online June 2, 2011