A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage

2021 ◽  
Author(s):  
Ross P Martini ◽  
Dominic Siler ◽  
Justin Cetas ◽  
Nabil J. Alkayed ◽  
Elyse Allen ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Epoxide Hydrolase ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Soluble Epoxide Hydrolase ◽  
Double Blind

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 Genetic variation in soluble epoxide hydrolase: association with outcome after aneurysmal subarachnoid hemorrhage

2014 ◽  
Vol 121 (6) ◽  
pp. 1359-1366 ◽  
Author(s):  
Ross P. Martini ◽  
Jonathan Ward ◽  
Dominic A. Siler ◽  
Jamie M. Eastman ◽  
Jonathan W. Nelson ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Scale Score ◽  
Glasgow Outcome Scale ◽  
Epoxide Hydrolase ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Soluble Epoxide Hydrolase ◽  
Neurological Deterioration ◽  
Wild Type ◽  
Functional Polymorphisms

Object Patients with aneurysmal subarachnoid hemorrhage (SAH) are at high risk for delayed cerebral ischemia (DCI) and stroke. Epoxyeicosatrienoic acids (EETs) play an important role in cerebral blood flow regulation and neuroprotection after brain injury. Polymorphisms in the gene for the enzyme soluble epoxide hydrolase (sEH), which inactivates EETs, are associated with ischemic stroke risk and neuronal survival after ischemia. This prospective observational study of patients with SAH compares vital and neurologic outcomes based on functional polymorphisms of sEH. Methods Allelic discrimination based on quantitative real-time polymerase chain reaction was used to differentiate wild-type sEH from K55R heterozygotes (predictive of increased sEH activity and reduced EETs) and R287Q heterozygotes (predictive of decreased sEH activity and increased EETs). The primary outcome was new stroke after SAH. Secondary outcomes were death, Glasgow Outcome Scale score, and neurological deterioration attributable to DCI. Results Multivariable logistic regression models adjusted for age at admission and Glasgow Coma Scale scores revealed an increase in the odds of new stroke (OR 5.48 [95% CI 1.51–19.91]) and death (OR 7.52 [95% CI 1.27–44.46]) in the K55R group, but no change in the odds of new stroke (OR 0.56 [95% CI 0.16–1.96]) or death (OR 3.09 [95% CI 0.51–18.52]) in patients with R287Q genotype, compared with wild-type sEH. The R287Q genotype was associated with reduced odds of having a Glasgow Outcome Scale score of ≤ 3 (OR 0.23 [95% CI 0.06–0.82]). There were no significant differences in the odds of neurological deterioration due to DCI. Conclusions Genetic polymorphisms of sEH are associated with neurological and vital outcomes after aneurysmal SAH.

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.

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).

scholarly journals Long-acting statin for aneurysmal subarachnoid hemorrhage: A randomized, double-blind, placebo-controlled trial

2017 ◽  
Vol 38 (7) ◽  
pp. 1190-1198 ◽  
Author(s):  
Masato Naraoka ◽  
Naoya Matsuda ◽  
Norihito Shimamura ◽  
Kenichiro Asano ◽  
Kenichi Akasaka ◽  
...  
Keyword(s):  
Placebo Group ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Pleiotropic Effects ◽  
Neurological Deficits ◽  
Double Blind ◽  
Long Acting

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11–0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage

2020 ◽  
Vol 133 (2) ◽  
pp. 351-359
Author(s):  
Natasha Ironside ◽  
Brandon Christophe ◽  
Samuel Bruce ◽  
Amanda M. Carpenter ◽  
Trae Robison ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Phase Ii ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Study Drug ◽  
Double Blind ◽  
Clinical Trial Registration

OBJECTIVEDelayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH.METHODSIn this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH.RESULTSOf the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm.CONCLUSIONSThe power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov)

scholarly journals Effect of Pregabalin on Perioperative Headache in Patients with Aneurysmal Subarachnoid Hemorrhage: A Randomized Double-Blind, Placebo-Controlled Trial

2019 ◽  
Vol 10 (03) ◽  
pp. 438-443
Author(s):  
Karen Ruby Lionel ◽  
Manikandan Sethuraman ◽  
Mathew Abraham ◽  
Smita Vimala ◽  
Unnikrishnan Prathapadas ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Perioperative Period ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Significant Difference ◽  
Daily Headache ◽  
Sedation Scores ◽  
Effective Adjunct

Abstract Background Patients with acute aneurysmal subarachnoid hemorrhage (aSAH) experience excruciating headache that is difficult to manage in resource-constrained settings. Pregabalin’s (β-isobutyl-GABA) analgesic, antiepileptic, and antiemetic properties make it an attractive adjuvant in pain management for these patients. Methods We conducted a double-blind, placebo-controlled, randomized clinical trial on 40 aSAH patients undergoing aneurysmal clipping to assess the effect of perioperative pregabalin in decreasing perioperative headache, anesthetic, and opioid requirement. Patients received either pregabalin (75 mg) or placebo twice daily soon after admission till 24-hour postoperative, in addition to paracetamol 650 mg thrice daily. Headache assessed using a visual analog scale (VAS) at five time points was compared using a mixed effects regression model. Results Pain assessed by VAS declined significantly more from the baseline in pregabalin recipients compared with placebo at preinduction (–3.6 vs.–1.8; p = 0.004), 12-hour (4.3 vs. 2.8; p = 0.014), and 24-hour postsurgery (4.7 vs. 2.9; p = 0.007), but not at the 6-hour postoperation (4.9 vs. 3.8; p = 0.065). Pregabalin recipients required a lower minimum alveolar concentration of sevoflurane to maintain a prespecified bispectral index of 40 and 60 (0.8 vs. 0.9; p = 0.014) and required fewer rescue analgesic doses in the 24  hours following surgery (1.8 vs. 3.3; p = 0.005). The intraoperative fentanyl requirement was not significantly different between the groups (10 μg/kg vs. 11.4 μg/kg; p = 0.065). There was no significant difference in the sedation scores. Conclusions Pregabalin 75 mg administered twice daily, during the perioperative period, was an effective adjunct in the management of the severe headache experienced by patients with aSAH and decreased the opioid and anesthetic requirement without significantly increasing sedation.

Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial

2009 ◽  
Vol 111 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Ming-Yuan Tseng ◽  
Peter J. Hutchinson ◽  
Hugh K. Richards ◽  
Marek Czosnyka ◽  
John D. Pickard ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
National Institutes Of Health ◽  
Neuroprotective Effects ◽  
Double Blind ◽  
End Points ◽  
Age Range ◽  
To Receive

Object Delayed ischemic deficits (DIDs), a major source of disability following aneurysmal subarachnoid hemorrhage (aSAH), are usually associated with severe cerebral vasospasm and impaired autoregulation. Systemic erythropoietin (EPO) therapy has been demonstrated to have neuroprotective properties acting via EPO receptors on cerebrovascular endothelia and ischemic neurons. In this trial, the authors explored the potential neuroprotective effects of acute EPO therapy following aSAH. Methods Within 72 hours of aSAH, 80 patients (age range 24–82 years) were randomized to receive intravenous EPO (30,000 U) or placebo every 48 hours for a total of 90,000 U. Primary end points were the incidence, duration, and severity of vasospasm and impaired autoregulation on transcranial Doppler ultrasonography. Secondary end points were incidence of DIDs and outcome at discharge and at 6 months. Results Randomization characteristics were balanced except for age, with the EPO group being older (mean age 59.6 vs 53.3 years, p = 0.034). No differences were demonstrated in the incidence of vasospasm and adverse events; however, patients receiving EPO had a decreased incidence of severe vasospasm from 27.5 to 7.5% (p = 0.037), reduced DIDs with new cerebral infarcts from 40.0 to 7.5% (p = 0.001), a shortened duration of impaired autoregulation (ipsilateral side, p < 0.001), and more favorable outcome at discharge (favorable Glasgow Outcome Scale score, p = 0.039). Among the 71 survivors, the EPO group had fewer deficits measured with National Institutes of Health Stroke Scale (median Score 2 vs 6, p = 0.008). Conclusions This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.

Sign in / Sign up

Export Citation Format

Share Document