Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials. METHODS: We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence. RESULTS: We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio OR,0.73 95% CI, 0.53-1.00; moderate certainty; absolute risk reduction (ARR), -3.35%). Nimodipine (OR, 1.46 95% CI, 1.07-1.99; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 95% CI, 1.14-12.18; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 95% CI, 0.22-0.68; high certainty; ARR, -16.65%), nicardipine (OR, 0.48 95% CI, 0.24-0.94; moderate certainty; ARR, -13.70%), fasudil (OR, 0.55 95% CI, 0.31-0.98; moderate certainty; ARR, -11.54%), and magnesium (OR, 0.66 95% CI, 0.46-0.94; high certainty; ARR, -8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia. CONCLUSIONS: Nimodipine and cilostazol are likely the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019122183.