Magnesium sulfate for aneurysmal subarachnoid hemorrhage: the end of the road or more trials?

Delayed cerebral ischemia (DCI) is a feared complication and an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). In the current study, Wong and colleagues performed a systematic review and meta-analysis of randomized controlled trials that investigated the efficacy of magnesium sulfate in patients with aneurysmal SAH. Outcome measures were DCI, cerebral infarction, and functional outcome 3 and 6 months after SAH. Magnesium sulfate decreased the rate of cerebral infarction, but not of DCI or poor functional outcome. Regarding outcome, a beneficial effect of magnesium sulfate on outcome can not be ruled out because of sample size limitations. Even if this meta-analysis had shown an effect on outcome, the question remains which treatment protocol should be applied in daily practice, since the administration of magnesium sulfate differed between most included studies. The present meta-analysis also underlines the importance of defining clinically relevant endpoints in SAH trials. Clinical deterioration due to DCI is more subject to inter-observer bias compared to cerebral infarction, which represents the ultimate outcome of the ischemic event. The Magnesium in Aneurysmal Subarachnoid Hemorrhage-II (MASH-II: ISRCTN68742385) phase III clinical trial nears completion. It aims to include 1,200 patients, and its results are urgently awaited

Aneurysm treatment within 6 h versus 6-24 h after rupture in patients with subarachnoid hemorrhage

BACKGROUND The risk of rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) is the highest during the initial hours after rupture. Emergency aneurysm treatment may decrease this risk, but is a logistic challenge and economic burden. We aimed to investigate whether aneurysm treatment <6 h after rupture is associated with a decreased risk of poor functional outcome compared to aneurysm treatment 6-24 h after rupture. METHODS We used data of patients included in the ULTRA trial (NCT02684812). All patients in ULTRA were admitted within 24 h after aneurysm rupture. For the current study, we excluded patients in whom the aneurysm was not treated <24 h after rupture. We calculated crude and adjusted risk ratios (aRR) with 95% confidence intervals using Poisson regression analyses for poor functional outcome (death or dependency, assessed by the modified Rankin Scale) after aneurysm treatment <6 h versus 6-24 h after rupture. Adjustments were made for age, sex, clinical condition on admission (WFNS scale), amount of extravasated blood (Fisher score), aneurysm location, tranexamic acid treatment, and aneurysm treatment modality. RESULTS We included 497 patients. Poor outcome occurred in 63/110 (57%) patients treated within 6 h compared to 145/387 (37%) patients treated 6-24 h after rupture (crude RR: 1.53, 95% CI: 1.24-1.88; adjusted RR: 1.36, 95% CI: 1.11-1.66). CONCLUSION Aneurysm treatment <6 h is not associated with better functional outcome than aneurysm treatment 6-24 h after rupture. Our results do not support a strategy aiming to treat every patient with a ruptured aneurysm <6 h after rupture

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

Despite an undisputed association between vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH), there is debate if this association implies causality. It has been suggested that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies. To further investigate the relationship between infarction and outcome, we performed a systematic review and meta-analysis of all randomized, double-blind, placebo-controlled trials that studied the efficacy of pharmaceutical preventive strategies in SAH patients, and had both cerebral infarction and clinical outcome as outcome events. Effect sizes were expressed in (pooled) risk ratio (RR) estimates with corresponding 95% confidence intervals (CIs). Sensitivity analyses were performed for studies with a low risk of bias and for those who reported outcome at 3 months after SAH. Twenty-four studies including 8,552 patients were included. Pharmaceutical treatments decreased the incidence of both cerebral infarction (RR: 0.83; 95% CI: 0.74 to 0.93) and of poor functional outcome (RR: 0.92; 95% CI: 0.86 to 0.98). The sensitivity analyses did not change the results essentially. These data suggest that the previously observed association between cerebral infarction and functional outcome implies causality, and that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies

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

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

Endovascular coiling versus neurosurgical clipping for people with aneurysmal subarachnoid haemorrhage

Background: Around 30% of people who are admitted to hospital with aneurysmal subarachnoid haemorrhage (SAH) will rebleed in the initial month after the haemorrhage if the aneurysm is not treated. The two most commonly used methods to occlude the aneurysm for prevention of rebleeding are microsurgical clipping of the neck of the aneurysm and occlusion of the lumen of the aneurysm by means of endovascular coiling. This is an update of a systematic review that was previously published in 2005. Objectives: To compare the effects of endovascular coiling versus neurosurgical clipping in people with aneurysmal SAH on poor outcome, rebleeding, neurological deficit, and treatment complications. Search methods: We searched the Cochrane Stroke Group Trials Register (March 2018). In addition, we searched CENTRAL (2018, Issue 2), MEDLINE (1966 to March 2018), Embase (1980 to March 2018), US National Institutes of Health Ongoing Trials Register (March 2018), and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (last searched March 2018). We also contacted trialists. Selection criteria: We included randomised trials comparing endovascular coiling with neurosurgical clipping in people with SAH from a ruptured aneurysm. Data collection and analysis: Two review authors independently extracted data, and assessed trial quality and risk of bias using the GRADE approach. We contacted trialists to obtain missing information. We defined poor outcome as death or dependence in daily activities (modified Rankin scale 3 to 6 or Glasgow Outcome Scale (GOS) 1 to 3). In the special worst-case scenario analysis, we assumed all participants in the group with better outcome with missing follow-up information had a poor outcome and those in the other group with missing data a good outcome. Main results: We included four randomised trials involving 2458 participants (range per trial: 20 to 2143 participants). Evidence is mostly based on the largest trial. Most participants were in good clinical condition and had an aneurysm on the anterior circulation. None of the included trials was at low risk of bias in all domains. One trial was at unclear risk in one domain, two trials at unclear risk in three domains, and one trial at high risk in one domain. After one year of follow-up, 24% of participants randomised to endovascular treatment and 32% of participants randomised to the surgical treatment group had poor functional outcome. The risk ratio (RR) of poor outcome (death or dependency) for endovascular coiling versus neurosurgical clipping was 0.77 (95% confidence interval (CI) 0.67 to 0.87; 4 trials, 2429 participants, moderate-quality evidence), and the absolute risk reduction was 7% (95% CI 4% to 11%). In the worst-case scenario analysis for poor outcome, the RR for endovascular coiling versus neurosurgical clipping was 0.80 (95% CI 0.71 to 0.91), and the absolute risk reduction was 6% (95% CI 2% to 10%). The RR of death at 12 months was 0.80 (95% CI 0.63 to 1.02; 4 trials, 2429 participants, moderate-quality evidence). In a subgroup analysis of participants with an anterior circulation aneurysm, the RR of poor outcome was 0.78 (95% CI 0.68 to 0.90; 2 trials, 2157 participants, moderate-quality evidence), and the absolute risk decrease was 7% (95% CI 3% to 10%). In subgroup analysis of those with a posterior circulation aneurysm, the RR was 0.41 (95% CI 0.19 to 0.92; 2 trials, 69 participants, low-quality evidence), and the absolute decrease in risk was 27% (95% CI 6% to 48%). At five years, 28% of participants randomised to endovascular treatment and 32% of participants randomised to surgical treatment had poor functional outcome. The RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.87 (95% CI 0.75 to 1.01, 1 trial, 1724 participants, low-quality evidence). At 10 years, 35% participants allocated to endovascular and 43% participants allocated to surgical treatment had poor functional outcome. At 10 years RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.81 (95% CI 0.70 to 0.92; 1 trial, 1316 participants, low-quality evidence). The RR of delayed cerebral ischaemia at two to three months for endovascular coiling versus neurosurgical clipping was 0.84 (95% CI 0.74 to 0.96; 4 trials, 2450 participants, moderate-quality evidence). The RR of rebleeding for endovascular coiling versus neurosurgical clipping was 1.83 (95% CI 1.04 to 3.23; 4 trials, 2458 participants, high-quality evidence) at one year, and 2.69 (95% CI 1.50 to 4.81; 1 trial, 1323 participants, low-quality evidence) at 10 years. The RR of complications from intervention for endovascular coiling versus neurosurgical clipping was 1.05 (95% CI 0.44 to 2.53; 2 trials, 129 participants, low-quality evidence). Authors' conclusions: The evidence in this systematic review comes mainly from one large trial, and long-term follow-up is available only for a subgroup of participants within that trial. For people in good clinical condition with ruptured aneurysms of either the anterior or posterior circulation the data from randomised trials show that, if the aneurysm is considered suitable for both neurosurgical clipping and endovascular coiling, coiling is associated with a better outcome. There is no reliable trial evidence that can be used directly to guide treatment in people with a poor clinical condition

Aneurysm characteristics and risk of rebleeding after subarachnoid haemorrhage

Introduction: Knowledge of risk factors for rebleeding after aneurysmal subarachnoid haemorrhage can help tailoring ultra-early aneurysm treatment. Previous studies have identified aneurysm size and various patient-related risk factors for early (≤24 h) rebleeding, but it remains unknown if aneurysm configuration is also a risk factor. We investigated whether irregular shape, aspect- and bottleneck ratio of the aneurysm are independent risk factors for early rebleeding after aneurysmal subarachnoid haemorrhage. Patients and methods: From a prospectively collected institutional database, we investigated data from consecutive aneurysmal subarachnoid haemorrhage patients who were admitted ≤24 h after onset between December 2009 and January 2015. The admission computed tomographic angiogram was used to assess aneurysm size and configuration. With Cox regression, we calculated stepwise-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for irregular shape, aspect ratio ≥1.6 mm and bottleneck ratio ≥1.6 mm. Results: Of 409 included patients, 34 (8%) patients had in-hospital rebleeding ≤24 h after ictus. Irregular shape was an independent risk factor for rebleeding (HR: 3.9, 95% CI: 1.3-11.3) after adjustment for age, sex, PAASH score, aneurysm location, aneurysm size and aspect- and bottleneck ratio. Aspect ratio ≥1.6 mm (HR: 2.3, 95% CI: 0.8-6.5) and bottleneck ratio ≥1.6 mm (HR: 1.7, 95% CI: 0.8-3.6) were associated with an increased risk of rebleeding, but were not independent risk factors after multivariable adjustment. Conclusions: Irregular shape is an independent risk factor for early rebleeding. However, since the majority of subarachnoid haemorrhage patients have an irregular aneurysm, additional risk factors have to be found for aneurysm treatment prioritisation

Impact of time to start of tranexamic acid treatment on rebleed risk and outcome in aneurysmal subarachnoid hemorrhage

INTRODUCTION: The ULTRA-trial investigated effectiveness of ultra-early administration of tranexamic acid (TXA) in subarachnoid hemorrhage (SAH) and showed that TXA reduces the risk of rebleeding without concurrent improvement in clinical outcome. Previous trials in bleeding conditions, distinct from SAH, have shown that time to start of antifibrinolytic treatment influences outcome. This post-hoc analysis of the ULTRA-trial investigates whether the interval between hemorrhage and start of TXA impacts the effect of TXA on rebleeding and functional outcome following aneurysmal SAH. PATIENTS AND METHODS: A post-hoc comparative analysis was conducted between aneurysmal SAH patients of the ULTRA-trial, receiving TXA and usual care to those receiving usual care only. We assessed confounders, hazard ratio (HR) of rebleeding and odds ratio (OR) of good outcome (modified Rankin Scale 0-3) at 6 months, and investigated the impact of time between hemorrhage and start of TXA on the treatment effect, stratified into time categories (0-3, 3-6 and >6 h). RESULTS: Sixty-four of 394 patients (16.2%) in the TXA group experienced a rebleeding, compared to 83 of 413 patients (19.9%) with usual care only (HR 0.86, 95% confidence interval (CI): 0.62-1.19). Time to start of TXA modifies the effect of TXA on rebleeding rate (p < 0.001), with a clinically non-relevant reduction observed only when TXA was initiated after 6 h (absolute rate reduction 1.4%). Tranexamic acid treatment showed no effect on good outcome (OR 0.96, 95% CI: 0.72-1.27) with no evidence of effect modification on the time to start of TXA (p = 0.53). DISCUSSION AND CONCLUSIONS: This study suggests that the effect of TXA on rebleeding is modified by time to treatment, providing a protective, albeit clinically non-relevant, effect only when started after 6 h. No difference in functional outcome was seen. Routine TXA treatment in the aneurysmal SAH population, even within a specified time frame, is not recommended to improve functional outcome

Hospital case-volume is associated with case-fatality after aneurysmal subarachnoid hemorrhage

BACKGROUND: Inverse association between hospital case-volume and case-fatality has been observed for various nonsurgical interventions and surgical procedures. AIMS: To study the impact of hospital case-volume on outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We included aSAH patients who underwent aneurysm coiling or clipping from tertiary care medical centers across three continents using the Dr Foster Stroke GOAL database 2007-2014. Hospitals were categorized by annual case-volume (low volume: 70/year). Primary outcome was 14-day in-hospital case-fatality. We calculated proportions, and used multiple logistic regression to adjust for age, sex, differences in comorbidity or disease severity, aneurysm treatment modality, and hospital. RESULTS: We included 8525 patients (2363 treated in low volume hospitals, 3563 treated in intermediate volume hospitals, and 2599 in high-volume hospitals). Crude 14-day case-fatality for hospitals with low case-volume was 10.4% (95% confidence interval (CI) 9.2-11.7%), for intermediate volume 7.0% (95% CI 6.2-7.9%; adjusted odds ratio (OR) 0.63 (95%CI 0.47-0.85)) and for high volume 5.4% (95% CI 4.6-6.3%; adjusted OR 0.50 (95% CI 0.33-0.74)). In patients with clipped aneurysms, adjusted OR for 14-day case-fatality was 0.46 (95% CI 0.30-0.71) for hospitals with intermediate case-volume and 0.42 (95% CI 0.25-0.72) with high case-volume. In patients with coiled aneurysms, adjusted OR was 0.77 (95% CI 0.55-1.07) for hospitals with intermediate case-volume and 0.56 (95% CI 0.36-0.87) with high case-volume. CONCLUSIONS: Even within a subset of large, tertiary care centers, intermediate and high hospital case-volume is associated with lower case-fatality after aSAH regardless of treatment modality, supporting centralization to higher volume centers.status: publishe