Introduction
Materials and methods
Type of studies included
Types of outcome measures
Search strategy
Study selection and data extraction
Statistical analysis and assessment for bias
Results
Trial selection and characteristics
Included study/year | Center/area | Participants (age/grade) | Number of participants (ETRA/placebo) | Treatment of aneurysm | ETRA (time of initiation, routine) | Dose (n) | Duration of treatment | Primary outcome | Secondary outcomes |
---|---|---|---|---|---|---|---|---|---|
Shaw and colleagues, 2000 [23] | Multicenter/Europe | >18 years old, WFNS 1 to 4 (79% grade 1 to 2) | 420 (207/213) | 75% clipped, 9% coiled | TAK-044 (within 96 hours, intravenously) | ≤50 mg three times per day | 10 days | DND within 3 months | DND within 10 days; DCI within 3 months; GOS at 3 months; adverse events |
Vajkoczy and colleagues, 2005[24] | Multicenter/Germany | 18 to 65 years old, HH 3 to 4 | 29 (13/16) | 100% clipped | Clazosentan (within 48 hours, intravenously) | 0.2 mg/kg/hour | 14 days | Incidence and severity of angiographic vasospasm on day 8 post SAH | DCI at 14 days; adverse events |
CONSCIOUS-1, 2008 [25] | Multicenter/North America and Europe | 18 to 70 years old, WFNS 1 to 4 (74% grade 1 to 2) | 409 (313/96) | 45% clipped | Clazosentan (within 56 hours, intravenously) | 1 mg/hour (108), 5 mg/hour (111), 15 mg/hour (98) | 14 days | Moderate or severe vasospasm within 14 days | Morbidity and mortality at 6 and 12 weeks; DIND at 14 days; DCI at 6 weeks; rescue therapy within 14 days; adverse events |
CONSCIOUS-2, 2011 [16] | Multicenter/North America and Europe | 18 to 75 years old, WFNS 1 to 4 (78% grade 1 to 2) | 1,147 (764/383) | 100% clipped | Clazosentan (within 56 hours, intravenously) | 5 mg/hour | 14 days | Mortality and vasospasm-related morbidity within 6 weeks post SAH | Dichotomized GOSE score at 12 weeks; DCI, DIND, rescue therapy at 6 weeks; adverse events |
CONSCIOUS-3, 2012 [26] | Multicenter/North America and Europe | 18 to 75 years old, WFNS 1 to 4 (80% grade 1 to 2) | 571 (382/189) | 100% coiling | Clazosentan (within 56 hours, intravenously) | 5 mg/hour (194), 15 mg/hour (188) | 14 days | Mortality and vasospasm-related morbidity within 6 weeks post SAH | Dichotomized GOSE score at 12 weeks; DCI, DIND, rescue therapy at 6 weeks; death at 12 weeks; adverse events |
Assessment of trial quality
Quality indicators/studies | Shaw and colleagues[23] | Vajkoczy and colleagues[24] | CONSCIOUS-1[25] | CONSCIOUS-2[16] | CONSCIOUS-3[26] |
---|---|---|---|---|---|
Randomized controlled study | Yes | Yes | Yes | Yes | Yes |
Appropriate random sequence generation | Yes | Unclear | Unclear | Yes | Yes |
Allocation concealment | Unclear | Unclear | Unclear | Yes | Yes |
Blinding of participants and personnel | Yes | Yes | Yes | Yes | Yes |
Blinding of outcome assessment | Unclear | Yes | Yes | Yes | Yes |
Explanation for withdrawals and dropouts | No | Yes | Yes | Yes | Yes |
Jadad scale | 4 | 4 | 4 | 5 | 5 |
Effects of interventions
Mortality and unfavorable outcome
Angiographic vasospasm
Delayed cerebral infarction and delayed ischemic neurological deficit
Adverse events
Subgroup analysis
Discussion
Conclusion
Key messages
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Pilot studies suggested that ETRAs prevent both radiographic vasospasm and DINDs after SAH, but did not indicate that they could improve clinical outcome. Owing to recently published phase 3 clinical trials, the previous meta-analysis on the use of ETRAs to treat aneurysmal SAH has become outdated.
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An up-to-date systemic review and meta-analysis indicates that ETRAs associated with increased adverse events and did not benefit clinical outcome in patients with SAH. Further clinical trials of ETRAs in SAH patients should be more carefully formulated and designed.