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.

A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America

1997 ◽  
Vol 86 (3) ◽  
pp. 467-474 ◽  
Author(s):  
E. Clarke Haley ◽  
Neal F. Kassell ◽  
Carolyn Apperson-Hansen ◽  
Marie H. Maile ◽  
Wayne M. Alves ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Mortality Rate ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Vehicle Group ◽  
Mortality Data ◽  
Double Blind ◽  
Content Type ◽  
Tirilazad Mesylate ◽  
Fine Print

✓ To test the safety and efficacy of tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, in improving the outcome of patients with aneurysmal subarachnoid hemorrhage (SAH), 902 patients were enrolled in a prospective randomized, double-blind, vehicle-controlled trial at 54 North American neurosurgical centers. Five patients were excluded prior to receiving any study drug. Of 897 patients who received at least one dose of study medication, 300 received a placebo containing a citrate vehicle, 298 received 2 mg/kg per day tirilazad, and 299 received 6 mg/kg per day tirilazad, all administered intravenously beginning within 48 hours of the SAH and continuing through 10 days posthemorrhage. All patients were also treated with orally administered nimodipine. At 3 months post-SAH, there were no significant differences (p < 0.025) among the groups with regard to mortality rate, favorable outcome on the Glasgow Outcome Scale, or employment status. During the first 14 days after the SAH, there were no significant differences among the groups in the incidence or severity of clinically symptomatic or angiographically identifiable cerebral vasospasm. Mortality data stratified by gender and neurological grade on admission (assessed according to a modified World Federation of Neurological Surgeons scale) demonstrated that the men with Grades IV to V had a 33% mortality rate in the vehicle group, 52% in the 2 mg/kg per day tirilazad group (p = 0.29), and 5% in the 6 mg/kg per day tirilazad group (p = 0.03). Tirilazad was well tolerated at both dose levels. Tirilazad mesylate at dosage levels of up to 6 mg/kg per day for 8 to 10 days following SAH did not improve the overall outcome in patients with aneurysmal SAH in this trial. The differences in the efficacy of tirilazad in this trial and a previously reported trial in Europe, Australia, and New Zealand, in which dosage levels of tirilazad of 6 mg/kg per day reduced mortality rates and increased good recovery, may be a result of differences in admission characteristics of the patients and/or differences in management protocols, including the use of anticonvulsant medications.

Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand

1996 ◽  
Vol 84 (2) ◽  
pp. 221-228 ◽  
Author(s):  
Neal F. Kassell ◽  
E. Clarke Haley ◽  
Carolyn Apperson-Hansen ◽  
Wayne M. Alves ◽  
_ _
Keyword(s):  
New Zealand ◽  
Subarachnoid Hemorrhage ◽  
Focal Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Double Blind ◽  
Content Type ◽  
Symptomatic Vasospasm ◽  
Tirilazad Mesylate ◽  
Fine Print

✓ Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, has been shown in experimental models to reduce vasospasm following subarachnoid hemorrhage (SAH) and to reduce infarct size from focal cerebral ischemia. To test whether treatment with tirilazad would reduce ischemic symptoms from vasospasm and improve overall outcome in patients with ruptured aneurysms, a prospective randomized, double-blind, vehicle-controlled trial was conducted at 41 neurosurgical centers in Europe, Australia, and New Zealand. One thousand twenty-three patients were randomly assigned to receive 0.6, 2, or 6 mg/kg per day of intravenously administered tirilazad or a placebo containing the citrate vehicle. All patients were also treated with intravenously administered nimodipine. Patients receiving 6 mg/kg per day of tirilazad had reduced mortality (p = 0.01) and a greater frequency of good recovery on the Glasgow Outcome Scale 3 months after SAH (p = 0.01) than similar patients treated with vehicle. There was a reduction in symptomatic vasospasm in the group that received 6 mg/kg per day tirilazad; however, the difference was not statistically significant (p = 0.048). The benefits of treatment with tirilazad were predominantly shown in men rather than in women. There were no material differences between the outcomes in the groups treated with 0.6 and 2 mg/kg tirilazad per day and the group treated with vehicle. Tirilazad was well tolerated at all three dose levels. These observations suggest that tirilazad mesylate, at a dosage of 6 mg/kg per day, is safe and improves overall outcome in patients (especially in men) who have experienced an aneurysmal SAH.

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.

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.

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).

Abstract TP423: Trends of Hospitalization Cost of Aneurysmal Subarachnoid Hemorrhage in the United States

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Sumul Modi ◽  
Kavit Shah ◽  
Muhammad Affan ◽  
Rizwan Tahir ◽  
Panayiotis Varelas ◽  
...  
Keyword(s):  
United States ◽  
Ischemic Stroke ◽  
Subarachnoid Hemorrhage ◽  
Respiratory Failure ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
The United States ◽  
Male Gender ◽  
Cost Of Care ◽  
Hospitalization Cost ◽  
The Cost

Background: Recent large scale studies describing the trends of hospitalization cost secondary to aneurysmal subarachnoid hemorrhage (aSAH) in the United States are lacking. We performed this study to discover these trends and the factors affecting the cost of hospitalization. Methods: The Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project from year 2002 to 2013 was searched for patients with a primary diagnosis of subarachnoid hemorrhage International Classification of Diseases - Ninth Revision (ICD-9) code 430) who underwent either clipping or coiling of an aneurysm. Patients with traumatic intracranial hemorrhage, arteriovenous malformation, arteriovenous fistula, cost of care ≤ 0, discharge to another hospital, and any missing variables were excluded. The cost of hospitalization was calculated using total charge and cost-to-charge ratio provided by HCUP, and then was adjusted for inflation (for the year 2016) utilizing the Consumer Price Index inflation calculator. Univariate and multivariable linear regression analysis was performed on selected variables to identify the factors associated with a higher cost of care. The multivariable model was adjusted for calendar year, medical comorbidities (using the Charlson Comorbidity Index), hospital location (urban or rural) and hospital teaching status (teaching or non-teaching). Results: We identified 20,905 patients with aSAH over the course of the 12 years. The mean and the median costs of hospitalization were $80,859 and $66,274, respectively. The median cost increased from $53,697 in 2002 to $73,901 in 2013 (p<0.001). Cost was also noted to increase by $2690 with the male gender, $18,877 with the presence of an acute ischemic stroke, $33,942 with the presence of respiratory failure and $18,464 with the requirement of ventriculostomy (all p<0.001). Every decade increase in age was associated with $3022 reduction in the cost (P<0.001). Conclusion: Among the factors we studied, higher hospitalization cost was independently associated with the male gender and the presence of ischemic stroke, respiratory failure and the requirement of ventriculostomy. Older age was associated with a lower hospitalization cost.

Protective effects of tirilazad mesylate and metabolite U-89678 against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury

1996 ◽  
Vol 84 (2) ◽  
pp. 229-233 ◽  
Author(s):  
Sarah L. Smith ◽  
Heidi M. Scherch ◽  
Edward D. Hall
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Blood Brain Barrier ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Brain Barrier ◽  
Phase Iii ◽  
Blue Dye ◽  
Ferrous Ammonium Sulfate ◽  
Protective Effects ◽  
Blood Brain ◽  
Tirilazad Mesylate

✓ The 21-aminosteroid lipid-peroxidation inhibitor, tirilazad mesylate (U-74006F), recently was shown in a large multinational Phase III clinical trial to decrease mortality and improve neurological recovery in patients 3 months after onset of aneurysmal subarachnoid hemorrhage (SAH). A major tirilazad metabolite in animals and man, U-89678 is formed when the 4–5 double bond in the A-ring is reduced and has been postulated to contribute significantly to tirilazad's neuroprotective effects. In the first experiment of the present study, the authors compared the effects of tirilazad and U-89678 on acute blood-brain barrier (BBB) damage in rats subjected to SAH via injection of 300 µl of autologous nonheparinized blood under the dura of the left cortex. The rats were treated by intravenous administration of either 0.3 or 1.0 mg/kg of tirilazad or U-89678 10 minutes before and 2 hours after SAH, and BBB damage was quantified according to the extravasation of the protein-bound Evans' blue dye into the injured cortex 3 hours post-SAH. The results revealed that 0.3 and 1.0 mg/kg tirilazad significantly reduced SAH-induced BBB damage 35.2% (p < 0.05) and 60.6% (p < 0.0001), respectively, in comparison to treatment with vehicle. The 0.3- and 1.0-mg/kg doses of U-89678 also decreased injury by 39.1% (p < 0.05) and 21.3% (not significant), respectively. In the second experiment, the investigators assessed the relative abilities of tirilazad and U-89678 to protect cultured neurons from iron-induced lipid peroxidative injury. Fetal mouse spinal cord cells were pretreated with 3, 10, or 30 µM tirilazad or U-89678 for 1 hour and then exposed to 200 µM ferrous ammonium sulfate (FAS) for 40 minutes. Cell viability was measured in terms of the uptake of [3H]α-(methyl)-aminoisobutyric acid 45 minutes after the FAS treatment. Both compounds enhanced neuronal survival in a concentration-dependent fashion. Although the two were equally efficacious, U-89678 was slightly more potent than its parent. On the basis of these findings, the authors conclude that the tirilazad metabolite, U-89678, possesses vaso- and neuroprotective properties that are essentially equivalent to the parent 21-aminosteroid. Hence, U-89678 probably contributes to the protective effects of tirilazad in SAH and other insults to the central nervous system.

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