scholarly journals Preventive Effect of Clazosentan against Cerebral Vasospasm after Clipping Surgery for Aneurysmal Subarachnoid Hemorrhage in Japanese and Korean Patients

2017 ◽  
Vol 44 (1-2) ◽  
pp. 59-67 ◽  
Author(s):  
Miki Fujimura ◽  
Jin-Yang Joo ◽  
Jong-Soo Kim ◽  
Motonori Hatta ◽  
Yoshinari Yokoyama ◽  
...  
Keyword(s):  
Placebo Group ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Infarction ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Study Drug ◽  
Aneurysm Rupture ◽  
Dose Finding ◽  
Double Blind ◽  
Korean Patients

Background: Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH. Methods: The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared. Results: Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003). Conclusion: These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.

Effect of Cilostazol on Cerebral Vasospasm and Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Randomized, Double-Blind, Placebo-Controlled Trial

2016 ◽  
Vol 42 (1-2) ◽  
pp. 97-105 ◽  
Author(s):  
Naoya Matsuda ◽  
Masato Naraoka ◽  
Hiroki Ohkuma ◽  
Norihito Shimamura ◽  
Katsuhiro Ito ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Infarction ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Control Group ◽  
Independent Factor ◽  
Double Blind ◽  
End Points ◽  
Double Blind Placebo ◽  
Poor Outcome

Background: Several clinical studies have indicated the efficacy of cilostazol, a selective inhibitor of phosphodiesterase 3, in preventing cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). They were not double-blinded trial resulting in disunited results on assessment of end points among the studies. The randomized, double-blind, placebo-controlled study was performed to assess the effectiveness of cilostazol on cerebral vasospasm. Methods: Patients with aneurysmal SAH admitted within 24 h after the ictus who met the following criteria were enrolled in this study: SAH on CT scan was diffuse thick, diffuse thin, or local thick, Hunt and Hess score was less than 4, administration of cilostazol or placebo could be started within 48 h of SAH. Patients were randomly allocated to placebo or cilostazol after repair of a ruptured saccular aneurysm by aneurysmal neck clipping or endovascular coiling, and the administration of cilostazol or placebo was continued up to 14 days after initiation of treatment. The primary end point was the occurrence of symptomatic vasospasm (sVS), and secondary end points were angiographic vasospasm (aVS) evaluated on digital subtraction angiography, vasospasm-related new cerebral infarction evaluated on CT scan or MRI, and clinical outcome at 3 months of SAH as assessed by Glasgow Outcome Scale, in which poor outcome was defined as severe disability, vegetative state, and death. All end points were evaluated with blinded assessment. Results: One hundred forty eight patients were randomly allocated to the cilostazol group (n = 74) or the control group (n = 74). The occurrence of sVS was significantly lower in the cilostazol group than in the control group (10.8 vs. 24.3%, p = 0.031), and multiple logistic analysis showed that cilostazol use was an independent factor reducing sVS (OR 0.293, 95% CI 0.099-0.568, p = 0.027). The incidence of aVS and vasospasm-related cerebral infarction were not significantly different between the groups. Poor outcome was significantly lower in the cilostazol group than in the control group (5.4 vs. 17.6%, p = 0.011), and multiple logistic analyses demonstrated that cilostazol use was an independent factor that reduced the incidence of poor outcome (OR 0.221, 95% CI 0.054-0.903, p = 0.035). Severe adverse events due to cilostazol administration did not occur during the study period. Conclusions: Cilostazol administration is effective in preventing sVS and improving outcomes without severe adverse events. A larger-scale study including more cases was necessary to confirm this efficacy of cilostazol.

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.

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.

Efficacy of transluminal angioplasty for the management of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage

2000 ◽  
Vol 92 (2) ◽  
pp. 284-290 ◽  
Author(s):  
Richard S. Polin ◽  
Volker A. Coenen ◽  
Carolyn Apperson Hansen ◽  
Peter Shin ◽  
Mustafa K. Baskaya ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Scale Score ◽  
Cerebral Vasospasm ◽  
Medical Management ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Conditional Logistic Regression ◽  
Study Drug ◽  
Transluminal Angioplasty ◽  
Content Type ◽  
Fine Print

Object. Transluminal angioplasty has become a widely used adjunct therapy to medical management of symptomatic cerebral vasospasm following subarachnoid hemorrhage (SAH). Despite anecdotal reports of universal, angiographically confirmed reversal of vasospasm and high rates of clinical improvement, no rigorous examination of the efficacy of this procedure has been conducted. In this study the authors assess the efficacy of the aforementioned procedure.Methods. Thirty-eight patients enrolled as part of the North American trial of tirilazad in aneurysmal SAH underwent transluminal angioplasty for symptomatic cerebral vasospasm. Fifty-three percent of these patients showed good recovery or moderate disability based on their 3-month Glasgow Outcome Scale score.Among the 38 patients who underwent angioplasty, the severity and type of vasospasm, use of papaverine in addition to balloon angioplasty, timing of treatment, and dose of study drug did not have an effect on the outcome. The results of their neurological examinations improved in only four of the 38 patients immediately after the procedure. A conditional logistic regression analysis was performed in which these patients were compared with individuals matched for age, sex, dose of study drug, admission neurological grade, and modified Glasgow Coma Scale score at the time of angioplasty. No effect on favorable outcomes was found for this procedure.Conclusions. Transluminal cerebral angioplasty is very effective in reversing angiographically confirmed vasospasm, and anecdotal reports of its clinical utility are numerous. However, in this report the authors conclude that its superiority to medical management for symptomatic cerebral vasospasm is questionable.

scholarly journals Update on endovascular therapies for cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage

2006 ◽  
Vol 21 (3) ◽  
pp. 1-11 ◽  
Author(s):  
Christina M. Sayama ◽  
James K. Liu ◽  
William T. Couldwell
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Infarction ◽  
Cerebral Vasospasm ◽  
Mechanism Of Action ◽  
Clinical Effect ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Calcium Channel Antagonists ◽  
Induced Hypertension

✓Cerebral vasospasm remains a major source of morbidity and death in patients with aneurysmal subarachnoid hemorrhage (SAH). When vasospasm becomes refractory to maximal medical management consisting of induced hypertension and hypervolemia and administration of calcium channel antagonists, endovascular therapies should be considered. The primary goal of endovascular treatment is to increase cerebral blood flow to prevent cerebral infarction. Two of the more frequently studied endovascular treatments are transluminal balloon angioplasty and intraarterial papaverine infusion. These two have been used either alone or in combination for the treatment of vasospasm. Other pharmacological vasodilating agents currently being investigated are intraarterial nimodipine, nicardipine, verapamil, and milrinone. Newer intraarterial agents, such as fasudil and colforsin daropate, have also been investigated. In this article the authors review the current options in terms of endovascular therapies for treatment of cerebral vasospasm. The mechanism of action, technique of administration, clinical effect and outcomes, and complications of each modality are discussed.

CONTROVERSIES IN THE ENDOVASCULAR MANAGEMENT OF CEREBRAL VASOSPASM AFTER INTRACRANIAL ANEURYSM RUPTURE AND FUTURE DIRECTIONS FOR THERAPEUTIC APPROACHES

Neurosurgery ◽  
2008 ◽  
Vol 62 (4) ◽  
pp. 897-907 ◽  
Author(s):  
Ricardo J. Komotar ◽  
Brad E. Zacharia ◽  
Marc L. Otten ◽  
J Mocco ◽  
Sean D. Lavine
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Aneurysm Rupture ◽  
Endovascular Management ◽  
Therapeutic Approaches ◽  
Endovascular Techniques ◽  
Arterial Infusion ◽  
Future Directions ◽  
Maximal Medical Therapy

Abstract CEREBRAL VASOSPASM IS one of the leading causes of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Despite maximal medical therapy, however, up to 15% of patients surviving the ictus of subarachnoid hemorrhage experience stroke or death from vasospasm. For those cases of vasospasm that are refractory to medical treatment, endovascular techniques are frequently used, including balloon angioplasty with or without intra-arterial infusion of vasodilators, combined endovascular modalities, and aortic balloon devices. In this article, we review each of these therapies and their expanding role in the management of this condition. Moving forward, rigorous prospective outcome assessments after endovascular treatment of cerebral vasospasm are necessary to clearly delineate the efficacy and indications for these techniques.

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)

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