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Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa

Giuseppe Lanzino, Neal F. Kassell, Nicholas W. C. Dorsch, Alberto Pasqualin, Lennart Brandt, Peter Schmiedek, Laura L. Truskowski, Wayne M. Alves, and the Participants

Object. Findings from previous multicenter clinical trials have suggested that tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH). This beneficial effect, however, was greater in males than females, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of tirilazad in women with SAH.

Methods. To test the efficacy of a higher tirilazad mesylate dose in female patients, a prospective randomized, doubleblind, vehicle-controlled trial was conducted at 56 neurosurgical centers in Europe, Australia, New Zealand, and South Africa. Eight hundred nineteen patients were randomly assigned to receive either 15 mg/kg/day of tirilazad mesylate or a placebo containing the citrate vehicle. The two groups were similar in prognostic factors for delayed cerebral ischemia and overall outcome. High-dose tirilazad appeared to be well tolerated because no differences in the incidence of untoward medical events were noted between the two groups. Medical and surgical interventions were no different in the two treatment groups except for hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution), which was more often used in the placebo-treated group to counteract symptomatic vasospasm (24% of patients given placebo compared with 18% of patients given tirilazad, p = 0.02).

Mortality rates and overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, were not different between the two groups, despite a significantly lower incidence of delayed cerebral ischemia in patients given tirilazad. Post hoc subgroup analysis by neurological grade also did not reveal significant differences in outcome, although a trend toward a lower mortality rate favoring the study drug was present in patients with neurological Grade IV and V at admission (32% compared with 37%). Symptomatic vasospasm occurred in 33.7% of the placebo-treated patients as opposed to 24.8% of the patients who were given tirilazad (p = 0.005). The severity of symptomatic vasospasm was also attenuated by administration of the study drug (severe symptomatic vasospasm was reported in 11% of the placebo-treated patients compared with 6% of patients in the tirilazad-treated group (p = 0.008). Clinical cerebral infarction from vasospasm was also reduced from 13% in the vehicle-treated group to 8% in the tirilazad-treated group (p < 0.04).

Conclusions. The authors conclude that high-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Although a significant reduction in the incidence of symptomatic vasospasm was observed in the treatment group, the primary end point (mortality rate at 3 months post-SAH) was not affected by the study drug. The use of other potentially effective rescue therapies (that is, hypervolemia, hemodilution, and induced hypertension) to counteract vasospasm may have been responsible for these contrasting observations between the two groups.

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Antifibrinolytic Therapy in Subarachnoid Hemorrhage

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The aspect ratio (dome/neck) of ruptured and unruptured aneurysms

Bryce Weir, Christina Amidei, Gail Kongable, J. Max Findlay, Neal F. Kassell, John Kelly, Lanting Dai, and Theodore G. Karrison

Object. In this retrospective study the authors examined the aspect ratio (AR; the maximum dimension of the dome/width of the neck of an aneurysm) and compared the distribution of this ratio in a group of ruptured and unruptured aneurysms. A similar comparison was performed in relation to the maximum dimension of the aneurysm alone. The authors sought to evaluate the utility of these measures for differentiating ruptured and unruptured aneurysms.

Methods. Measurements were made of 774 aneurysms in 532 patients at three medical centers. One hundred twenty-seven patients harbored only unruptured lesions, 290 only ruptured lesions, and 115 both ruptured and unruptured lesions. Cases were included if angiograms were available for measurement and the status of the individual patient's aneurysm(s) was known.

The odds of a lesion falling in the ruptured aneurysm group increased with both the lesion's maximum size and the AR. The odds ratio for rupture rose progressively only for the AR. The distribution curves showed that ruptured aneurysms were larger and had greater ARs. The mean size of unruptured aneurysms was 7 mm and that of ruptured ones was 8 mm; the corresponding mean ARs were 1.8 and 3.4, respectively. The odds of rupture were 20-fold greater when the AR was larger than 3.47 compared with an AR less than or equal to 1.38. Only 7% of ruptured aneurysms had an AR less than 1.38 compared with 45% of unruptured lesions.

Conclusions. The AR is probably a useful index to calculate. A high AR might reasonably influence the decision to treat actively an unruptured aneurysm independent of its maximum size. Prospective studies are warranted.

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Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials

Clinical article

Don Ilodigwe, M. Stat., Gordon D. Murray, Neal F. Kassell, James Torner, Richard S. C. Kerr, Andrew J. Molyneux, and R. Loch Macdonald

Object

In randomized clinical trials of subarachnoid hemorrhage (SAH) in which the primary clinical outcomes are ordinal, it has been common practice to dichotomize the ordinal outcome scale into favorable versus unfavorable outcome. Using this strategy may increase sample sizes by reducing statistical power. Authors of the present study used SAH clinical trial data to determine if a sliding dichotomy would improve statistical power.

Methods

Available individual patient data from tirilazad (3552 patients), clazosentan (the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage trial [CONSCIOUS-1], 413 patients), and subarachnoid aneurysm trials (the International Subarachnoid Aneurysm Trial [ISAT], 2089 patients) were analyzed. Treatment effect sizes were examined using conventional fixed dichotomy, sliding dichotomy (logical or median split methods), or proportional odds modeling. Whether sliding dichotomy affected the difference in outcomes between the several age and neurological grade groups was also evaluated.

Results

In the tirilazad data, there was no significant effect of treatment on outcome (fixed dichotomy: OR = 0.92, 95% CI 0.80–1.07; and sliding dichotomy: OR = 1.02, 95% CI 0.87–1.19). Sliding dichotomy reversed and increased the difference in outcome in favor of the placebo over clazosentan (fixed dichotomy: OR = 1.06, 95% CI 0.65–1.74; and sliding dichotomy: OR = 0.85, 95% CI 0.52–1.39). In the ISAT data, sliding dichotomy produced identical odds ratios compared with fixed dichotomy (fixed dichotomy vs sliding dichotomy, respectively: OR = 0.67, 95% CI 0.55–0.82 vs OR = 0.67, 95% CI 0.53–0.85). When considering the tirilazad and CONSCIOUS-1 groups based on age or World Federation of Neurosurgical Societies grade, no consistent effects of sliding dichotomy compared with fixed dichotomy were observed.

Conclusions

There were differences among fixed dichotomy, sliding dichotomy, and proportional odds models in the magnitude and precision of odds ratios, but these differences were not as substantial as those seen when these methods were used in other conditions such as head injury. This finding suggests the need for different outcome scales for SAH.

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Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage

Hakan H. Caner, Aij-Lie Kwan, Adam Arthur, Arco Y. Jeng, Rodney W. Lappe, Neal F. Kassell, and Kevin S. Lee

✓ The potent vasoconstrictor peptide, endothelin-1 (ET-1), has been implicated in the pathophysiology of cerebral vasospasm that occurs after subarachnoid hemorrhage (SAH). This peptide is synthesized as a large prepropeptide that requires a series of modifying steps for its activation. The last of these steps involves the proteolytic conversion of a relatively inactive propeptide, Big ET-1, to its active, 21—amino acid peptide form. The enzyme responsible for converting Big ET-1 to ET-1 is a metalloprotease called endothelin-converting enzyme (ECE). In the present study the authors examined the effects of a newly developed inhibitor of ECE on responses to ET peptides in the normal basilar artery and on pathophysiological constriction in the spastic basilar artery after SAH.

In the first series of experiments the authors examined normal basilar arteries in the rabbit, which were exposed transclivally and measured on-line using videomicroscopy. Intravenous administration or topical application of an active inhibitor of ECE, CGS 26303, blocked vasoconstrictor responses to topically applied Big ET-1 but not to ET-1. In contrast, topical application of a structurally related compound that does not inhibit ECE, CGS 24592, was ineffective in blocking vasoconstriction that was elicited by a topical application of Big ET-1. These findings indicate that CGS 26303 when administered systemically is capable of blocking the conversion of Big ET-1 to ET-1 in the basilar artery without affecting the ability of the vessel to respond to ET-1. In the second series of experiments the authors examined the effects of the ECE inhibitor on cerebral vasospasm after experimental SAH. Intraperitoneal administration of CGS 26303 via osmotic minipumps significantly attenuated the delayed spastic response of the basilar artery to an intracisternal injection of autologous blood.

This study provides the first evidence that systemic administration of an inhibitor of ECE is capable of preventing cerebral vasospasm after SAH. The results reinforce a growing body of evidence that ETs play a critical role in the development of spastic constriction after SAH. Moreover, the findings indicate that blocking the conversion of Big ET-1 to its active ET-1 form using CGS 26303 may represent a feasible strategy for ameliorating cerebral vasospasm.

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Treatment of Vasospasm

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Improvement of endothelial function in insulin-resistant carotid arteries treated with pravastatin

Aaron S. Dumont, M. Eric Hyndman, Randall J. Dumont, Paul M. Fedak, Neal F. Kassell, Garnette R. Sutherland, and Subodh Verma

Object. Insulin resistance and hypertension are independent risk factors for stroke. Endothelial dysfunction in response to risk factors and carotid artery (CA) disease are important in the pathogenesis of stroke. Pravastatin may have cholesterol-independent pleiotropic effects. In the present study the authors examined the effects of short-course pravastatin treatment on endothelial function in CAs obtained in control and insulin-resistant rats with fructose-induced hypertension.

Methods. Thirty rats were divided into two experimental groups, in which 14 were fed a regular diet and 16 were fed a fructose-enriched diet for 3 weeks. The rats were then divided into four groups: control, pravastatin-treated control, fructose-fed, and pravastatin-treated fructose-fed. Pravastatin was administered (20 mg/kg/day) for 2 weeks. Excretion of the urinary nitric oxide (NO) metabolite nitrite (NO2 ) was also assayed. The CAs from all rats were subsequently removed and assessed for endothelium-dependent and -independent vascular reactivity in vitro. The rats in the fructose-fed group were insulin resistant, hyperinsulinemic, and hypertensive relative to the rats in the control and pravastatin-treated control groups and exhibited diminished endothelium-dependent vasomotion and urinary NO2 excretion (p < 0.05), with preserved endothelium-independent vasomotion. Strikingly, pravastatin treatment restored endothelium-dependent vasomotion and urinary NO2 excretion in rats in the fructose-fed pravastatin-treated relative to the fructose-fed group (p < 0.05).

Conclusions. The authors report, for the first time, that pravastatin restores endothelial function in CAs from insulin-resistant rats with fructose-induced hypertension. These beneficial effects were ascribed to direct, cholesterol-independent vascular effects of pravastatin and are likely the result of augmentation of NO production. These data provide impetus for further investigation of nonlipid-lowering indications for pravastatin therapy in the prevention and treatment of CA disease.

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Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage

Aij-Lie Kwan, Murad Bavbek, Arco Y. Jeng, Wieslawa Maniara, Tomikatsu Toyoda, Rodney W. Lappe, Neal F. Kassell, and Kevin S. Lee

✓ Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy.

Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

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Editorial

Unruptured aneurysms

David O. Wiebers, David G. Piepgras, Robert D. Brown Jr., Irene Meissner, James Torner, Neal F. Kassell, Jack P. Whisnant, John Huston III, and Douglas A. Nichols

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Attenuation of vasospasm and hemoglobin-induced constriction in the rabbit basilar artery by a novel protease inhibitor

Barbara Cappelletto, Hakan H. Caner, Frank Schottler, Aij-Lie Kwan, David Eveleth, Patricia L. Foley, Neal F. Kassell, and Kevin S. Lee

Calcium-activated proteolysis mediated by the protease inhibitor, calpain, has recently been implicated in the pathogenesis of cerebral vasospasm. The effect of one inhibitor of calcium-activated proteolysis, z-Leu-Phe-CONH-morpholene (zLF), on cerebrovascular constriction was examined in two experimental paradigms. In the first paradigm, the rabbit basilar artery (BA) was visualized via a transclival exposure, and its diameter was monitored using videomicroscopy. In the second experimental paradigm two intracisternal injections of autologous blood were administered to mimic a subarachnoid hemorrhage (SAH). The BA was visualized via the transclival exposure, and its luminal diameter was measured. Topical application of oxyhemoglobin (OxyHb), a known pathogenic agent in cerebral vasospasm, elicited vasoconstriction in normal animals, reducing arterial diameter to approximately 75% of resting levels. Pretreatment with zLF (100, 200, or 300 μM) attenuated vasoconstriction induced by OxyHb. In an experimental model of SAH, the diameter of the BA was reduced after the first injection of blood to approximately 67% of normal resting levels when measured 3 to 4 days later. This vasospastic response was reversed significantly by topical application of zLF (100 μM); vascular diameter was increased to approximately 84% of normal resting levels.

These findings demonstrate that both acute OxyHb-induced constriction and blood-induced vasospasm are sensitive to an inhibitor of the proteolytic enzyme, calpain. Together, these observations indicate an important role for calcium-activated proteolysis in the development and maintenance of vasospasm after SAH. In addition, it may be inferred from the data that inhibitors of calcium-activated proteolysis may be useful therapeutic agents for treating this form of cerebrovascular disease.