Interaction of neurovascular protection of erythropoietin with age, sepsis, and statin therapy following aneurysmal subarachnoid hemorrhage

2010 ◽  
Vol 112 (6) ◽  
pp. 1235-1239 ◽  
Author(s):  
Ming-Yuan Tseng ◽  
Peter J. Hutchinson ◽  
Peter J. Kirkpatrick
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Statin Therapy ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Potential Interaction ◽  
Repeated Measurements ◽  
Unfavorable Outcome ◽  
Phase Iii ◽  
Neurovascular Protection ◽  
Phase Iii Trials

Object In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy. Methods The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-β or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or ≥ 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements. Results Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 × 109/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO. Conclusions Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.

Economic Analysis of Tirilazad Mesylate for Aneurysmal Subarachnoid Hemorrhage: Economic Evaluation of a Phase III Clinical Trial in Europe and Australia

1998 ◽  
Vol 14 (1) ◽  
pp. 145-160 ◽  
Author(s):  
Henry Glick ◽  
Richard Willke ◽  
Daniel Polsky ◽  
Ted Llana ◽  
Wayne M. Alves ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cost Effectiveness ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Cost Of Care ◽  
Phase Iii ◽  
Double Blind ◽  
Additional Information ◽  
Tirilazad Mesylate ◽  
The Cost

AbstractThis study used data from a multinational phase III randomized, double-blind, vehicle-controlled trial to evaluate the cost-effectiveness of tirilazad mesylate (Freedox®) in the treatment of aneurysmal subarachnoid hemorrhage. In men, therapy with 6 mg/kg per day of tirilazad mesylate was associated with significantly increased survival, increased cost of care, and ratios of cost per death averted that compare favorably with the ratios of other life and death interventions. In women, it appeared to have no effects on costs or survival. Further clinical studies may provide additional information about the cost-effectiveness of this intervention.

Abstract TMP105: Endovascular Treatment of Severe and Refractory Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage Improves Outcome: A Systematic Review and Meta-analysis of Different Treatment Options Evaluated Since 2006 for Cerebral Vasospasm

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Gregoire Boulouis ◽  
Marc-Antoine Labeyrie ◽  
Jean Raymond ◽  
Christine Rodriguez-Regent ◽  
Anne-Claire Lukaszewicz ◽  
...  
Keyword(s):  
Systematic Review ◽  
Subarachnoid Hemorrhage ◽  
Clinical Outcome ◽  
Endovascular Treatment ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Meta Analysis ◽  
Route Of Administration ◽  
Unfavorable Outcome ◽  
Q Value

Introduction: To report clinical outcome of aneurysmal subarachnoid hemorrhage (aSAH) patients exposed to cerebral vasospasm (CVS) targeted treatments in a systematic review and meta-analysis and compare the efficacy of endovascular and non-endovascular treatments in severe / refractory vasospasm patients. Methods: The literature was searched using PubMed, EMBASE, and The Cochrane Library database. Eligibility criteria were (1) Rated clinical outcome; (2) at least 10 patients; (3) aSAH; (4) study published in English or French (January 2006 - October 2014); and (5) methodological quality score > 10, according to STROBE criteria. Endpoint included unfavorable outcome rate, defined as mRS 3-6, GOS 1-3 or GOSE 1-4 at latest follow-up. Analyses included stratification per route of administration (oral, i.v., intra-arterial or cisternoventricular) and per study inclusion criteria (severe, CVS, refractory CVS or high risk for CVS). Univariate and multivariate subgroup analyses were performed to identify interventions associated with a better outcome. Results: Sixty-two studies, including 26 randomized controlled trials, were included (8976 patients). Overall 2490 patients had unfavorable outcome including death (random-effect weighted average: 33.7%, 99%CI, 28.1-39.7%; Q-value: 806.0, I 2 =92.7%). Clinical outcome was significantly better in severe or refractory patients for whom, on top of best medical treatment, endovascular intervention was performed (RR=0.76, IC95% [0.66-0.89], p <0.00001) whereas other route of administration didn’t show significant differences. RR of unfavorable outcome was significantly lower, vs control groups, in patients treated with Cilostazol (RR=0.46 (IC99% [0.25-0.85], P = 0.001, Q value 1.5, I 2 = 0). Conclusion: In case of CVS following aSAH, endovascular treatment in severe / refractory vasospasm patients. including intra-arterial injection of pharmacological agents or balloon angioplasty, improves outcome as compared to other route of administration.

Abstract T P352: Dantrolene for the Prevention and Treatment of Cerebral Vasospasm after Subarachnoid Hemorrhage - A Randomized Placebo-Controlled Trial to Assess Safety, Tolerability and Feasibility

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Susanne Muehlschlegel ◽  
Raphael Carandang ◽  
Wiley Hall ◽  
Kini Nisha ◽  
Saef Izzy ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Liver Toxicity ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Delayed Cerebral Ischemia ◽  
Double Blind ◽  
Outcome Differences ◽  
Infusion Period

Introduction: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) after aneurysmal subarachnoid hemorrhage (aSAH) in humans. We evaluated safety/tolerability and feasibility of intravenous dantrolene (IV-D) after aSAH. Methods: In this single-center, randomized, double-blind, placebo-controlled trial, 31 patients with acute aSAH were randomized to IV-D 1.25 mg IV every 6 hours x 7 days (n=16) or placebo (n=15). Primary endpoint was incidence of hyponatremia (sNa ≤ 134 mmol/L) and liver toxicity (% patients with ALT, AST and AlkPhos >5x upper limit of normal). Secondary safety endpoints included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored by clinical, transcranial Doppler (TCD) or angiographic cVSP occurrence, delayed cerebral ischemia (DCI) and 3-month modified-Rankin-Scale, Glasgow Outcome Scale and Barthel Index. Statistical analysis was performed using non-parametric tests, generalized estimating equations and mixed models. Results: Between IV-D vs. placebo, no differences were observed in the primary outcome (hyponatremia: 44% vs. 67% [p=0.29]; liver toxicity 6% vs. 0% [p=1.0]). Numerically more AEs and SAEs were seen in the IV-D group, but did not reach statistical significance (16 vs. 5 AEs, of which 5 vs. 2 were severe; RR 2.2; 95% CI 0.7-6.7; p=0.16). Three IV-D vs. two placebo patients reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain edema requiring osmotherapy. No differences in angiographic, TCD, clinical cVSP, DCI, or 3-month functional outcomes were seen. Quantitative angiogram analysis revealed a trend towards increased vessel diameters in the IV-D group after the 7-day infusion-period (p=0.05). Conclusion: In this small trial, IV-Dantrolene after aSAH was feasible, tolerable and safe, but was underpowered to show efficacy or outcome differences.

scholarly journals A new era for stroke therapy: Integrating neurovascular protection with optimal reperfusion

2018 ◽  
Vol 38 (12) ◽  
pp. 2073-2091 ◽  
Author(s):  
Ligen Shi ◽  
Marcelo Rocha ◽  
Rehana K Leak ◽  
Jingyan Zhao ◽  
Tarun N Bhatia ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Cell Types ◽  
Phase Iii ◽  
Preclinical Studies ◽  
New Era ◽  
Stroke Research ◽  
Neuroprotective Strategies ◽  
Neurovascular Protection ◽  
Phase Iii Trials

Recent advances in stroke reperfusion therapies have led to remarkable improvement in clinical outcomes, but many patients remain severely disabled, due in part to the lack of effective neuroprotective strategies. In this review, we show that 95% of published preclinical studies on “neuroprotectants” (1990–2018) reported positive outcomes in animal models of ischemic stroke, while none translated to successful Phase III trials. There are many complex reasons for this failure in translational research, including that the majority of clinical trials did not test early delivery of neuroprotectants in combination with successful reperfusion. In contrast to the clinical trials, >80% of recent preclinical studies examined the neuroprotectant in animal models of transient ischemia with complete reperfusion. Furthermore, only a small fraction of preclinical studies included long-term functional assessments, aged animals of both genders, and models with stroke comorbidities. Recent clinical trials demonstrate that 70%–80% of patients treated with endovascular thrombectomy achieve successful reperfusion. These successes revive the opportunity to retest previously failed approaches, including cocktail drugs that target multiple injury phases and different cell types. It is our hope that neurovascular protectants can be retested in future stroke research studies with specific criteria outlined in this review to increase translational successes.

Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery

1991 ◽  
Vol 74 (1) ◽  
pp. 8-13 ◽  
Author(s):  
Juha Öhman ◽  
Antti Servo ◽  
Olli Heiskanen
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Ct Scanning ◽  
Long Term Effects ◽  
Cerebral Infarcts ◽  
Double Blind ◽  
Content Type

✓ A total of 213 patients with verified aneurysmal subarachnoid hemorrhage (SAH) of Grades I to III (Hunt and Hess classification) were enrolled in a double-blind placebo-controlled trial to determine the effect of intravenous nimodipine on delayed ischemic deterioration and computerized tomography (CT)-visualized infarcts after SAH and surgery. The administration of the drug or matching placebo was started immediately after the radiological diagnosis of a ruptured aneurysm had been made. Of the 213 patients enrolled in the study, 58 were operated on early (within 72 hours after the bleed: Days 0 to 3), 69 were operated on subacutely (between Days 4 and 7), and 74 had late surgery (on Day 8 or later). Eleven patients died before surgery was undertaken and one was not operated on. A follow-up examination with CT scanning, performed 1 to 3 years after the SAH (mean 1.4 years), revealed no significant differences in the overall outcome between the groups. However, nimodipine treatment was associated with a significantly lower incidence of deaths caused by delayed cerebral ischemia (p = 0.01) and significantly lower occurrence of cerebral infarcts visualized by CT scanning in the whole population (p = 0.05), especially in patients without an associated intracerebral hemorrhage on admission CT scan (p = 0.03).

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