Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial
Introduction
Even though a large number of compounds have been proven to reduce the size of infarction in animal models, they have almost always failed in patients with acute ischemic stroke. The reasons for the unsuccessful clinical trials have been either the toxic side effects, or a limited therapeutic window [1]. Therefore, potent compounds with little or no side effects that can be administered within a few days after ischemic insult are being sought.
Ischemic stroke triggers secondary injury mechanisms such as inflammatory reactions, hemorheological abnormalities, vasoconstriction, and endothelial dysfunction. There is evidence that such secondary injury mechanisms contribute to the late stages in ischemic injury and results in the worsening of neurologic outcome. Therefore, intervention aimed at decreasing secondary injury mechanisms of the post-ischemic brain over a wide therapeutic window is an attractive therapeutic strategy for stroke.
Fasudil is a Rho-kinase inhibitor (RKI) that has shown clinical effectiveness on cerebral vasospasm in patients after clipping surgery for aneurysmal subarachnoid hemorrhage [2]. Fasudil significantly reduced angiographically demonstrable vasospasm, low-density regions on computerized tomography associated with vasospasm, symptomatic vasospasm, and the number of patients with poor clinical outcome associated with vasospasm. Fasudil was launched and has been widely used in Japan for that indication since 1995. Fasudil and its active metabolite, hydroxyfasudil, inhibit Rho-kinase more effectively than they inhibit other protein kinases; e.g., protein kinase C or myosin light chain kinase [3], [4].
Previous studies provide evidence that Rho-kinase or increased Rho-kinase activity is involved in the pathogenesis of various vascular lesions [5], [6], [7], [8]. Rho-kinase is also thought to play a role in the mechanisms underlying the occurrence of hemodynamic dysfunctions and inflammatory processes [9], [10], [11], [12], [13], [14]. Rho-kinase α (also called Rho-kinase, ROK α or ROCK II) is a Ser/Thr protein kinase that phosphorylates myosin phosphatase, inhibits myosin phosphatase activity, and contracts arterial smooth muscle. Rho-kinase β (AKA p160ROCK, ROK β, ROCK I) is an isoform of Rho-kinase. Rho-kinase is also one of the critical elements involved in: cell (neutrophil and monocyte) migration; endothelial injury through the downregulation of endothelial nitric oxide synthase (eNOS) activity; production of O2− in neutrophils and vessels; and hyperviscosity.
In animal models, fasudil and hydroxyfasudil showed promise in the treatment of acute ischemic stroke [15], [16], [17]. Benefits observed appear to be mediated by various mechanisms; for example, preventing inflammatory response by inhibiting neutrophil and monocyte infiltration [18], [19] and inhibiting the production of O2− in neutrophils and vessels [20], [21]; and improving hemodynamic function by increasing regional cerebral blood flow [22], [23], preventing hyperviscosity [24], and upregulating eNOS activity in endothelial cells [9].
In a Phase IIb, multicenter, double-blind trial, patients with acute cerebral thrombosis and using a 48-h treatment window, received 10, 30 or 60 mg fasudil by intravenous infusion over 60 min, twice daily for 14 days. Fasudil treatment resulted in dose-dependent improvements in neurological functions and clinical outcome (published in Japanese). This Phase IIb trial demonstrated that doses up to 120 mg per day were well-tolerated in patients. We are reporting here the results of a randomized placebo-controlled double-blind (Phase III) trial of fasudil in patients with acute cerebral thrombosis. The endpoints of the trial were neurological status at 2 weeks after the start of treatment, and clinical outcome at 1 month after the onset of symptoms.
Section snippets
Study design and procedures
This was a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of intravenous fasudil in patients with acute ischemic stroke. A total of 160 patients were enrolled at 29 neurological and neurosurgical institutions in Japan. The determination of sample size was calculated from the results of a Phase IIb trial of fasudil in patients with acute ischemic stroke and, based on a 0.9 power to detect a significant difference (p = 0.025, single-sided), 80
Demographic and clinical data
Between July 1998 and February 2002, 160 patients were enrolled in the trial. The trial profile is shown in Fig. 1. A total of 149 patients completed the treatment. Treatment was discontinued in 11 patients (4 in the fasudil group, 7 in the placebo group). Reasons for treatment discontinuation were similar in both groups and included adverse event and request of patient or investigator. All patients enrolled in this trial were included in the assessment of efficacy and safety. The demographic
Discussion
In this trial of 160 patients using a 48-h treatment window, the RKI fasudil produced statistically significant improvements in neurological status and clinical outcome; especially, in reducing the number of worsening patients. This data suggest that the therapeutic window for fasudil at the current dose level is at least 48 h after the onset of an acute ischemic stroke. Acute diseases, such as stroke, are pathophysiological events that initiate a deleterious cascade, which include hemodynamic
Acknowledgements
The authors thank Mark Smith for pertinent comments.
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