Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis

Abstract

As it is often assumed that delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is caused by vasospasm, clinical trials often focus on prevention of vasospasm with the aim to improve clinical outcome. However, the role of vasospasm in the pathogenesis of DCI and clinical outcome is possibly smaller than previously assumed. We performed a systematic review and meta-analysis on all randomized, double-blind, placebo-controlled trials that studied the effect of pharmaceutical preventive strategies on vasospasm, DCI, and clinical outcome in SAH patients to further investigate the relationship between vasospasm and clinical outcome. Effect sizes were expressed in pooled risk ratio (RR) estimates with corresponding 95% confidence intervals (CI). A total of 14 studies randomizing 4,235 patients were included. Despite a reduction of vasospasm (RR 0.80 (95% CI 0.70 to 0.92)), no statistically significant effect on poor outcome was observed (RR 0.93 (95% CI 0.85 to 1.03)). The variety of DCI definitions did not justify pooling the DCI data. We conclude that pharmaceutical treatments have significantly decreased the incidence of vasospasm, but not of poor clinical outcome. This dissociation between vasospasm and clinical outcome could result from methodological problems, sample size, insensitivity of clinical outcome measures, or from mechanisms other than vasospasm that also contribute to poor outcome.

Pharmacologic Reduction of Angiographic Vasospasm in Experimental Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis

“…The end points in human clinical trials are usually clinical outcome and delayed cerebral ischemia but neurological and functional examination after experimental SAH is still uncommonly used (Jeon et al, 2009;Takata et al, 2008). There is some evidence that reduction of angiographic vasospasm does not correlate with improved outcome in humans (Etminan et al, 2011;Macdonald, 2011;Macdonald et al, 2008). Unfortunately, if this is true and not due to other reasons, such as efficacy of rescue therapy in placebo groups, insensitive outcome measures, drug side-effects and such, animal models will have to be reassessed to ensure they reflect relevant human features if they are to be used to decide whether to advance drugs into clinical trials.…”

“…We did not include studies where drugs were administered to reverse established angiographic vasospasm. For selecting drugs, we considered a systematic review of drug treatments for humans with SAH and included all drugs tested in randomized, blinded clinical trials (Etminan et al, 2011).…”

“…To assess the effect of each drug in human trials, the data were obtained from Etminan et al (2011). The outcome measure was radiographic vasospasm, which was defined as a focal or generalized reduction of cerebral arterial caliber on catheter cerebral angiography, or increased cerebral blood flow velocities on transcranial Doppler ultrasound.…”

“…Transcranial Doppler vasospasm was defined as flow velocity of at least 120 cm/s or peak flow velocity of > 200 cm/s. If studies reported angiographic and transcranial Doppler vasospasm, the data on angiographic vasospasm were used (Etminan et al, 2011).…”

Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca 2+ -activated K + (BK) channels

“…Improving outcome for SAH patients has proven to be an elusive goal, and current pharmacological therapies remain ineffective (1,3). For decades, delayed blood-induced vasospasm of brain surface arteries was considered the major underlying cause of SAH-induced DINDs (4,5).…”