Chronological Change of the Clinical Features and Treatment Outcomes for Subarachnoid Hemorrhage in Japan: A Multicenter Retrospective Study.

Aneurysmal subarachnoid hemorrhage (SAH) treatment has progressed, and patients are rapidly aging in Japan. Consequently, dynamic changes must have emerged in the clinical practice of SAH. This study aimed to elucidate chronological changes of aneurysmal SAH and the prognostic factors in the previous quarter century in Japan. We conducted a retrospective survey regarding aneurysmal SAH in eight institutions in Japan. The study included 848, 863, and 781 patients in the first (1989-1993), second (1999-2003), and third (2009-2013) periods, respectively. The chronological changes of factors that influenced the poor outcomes and differences between the nonelderly (<75 years) and elderly patients were investigated. Mean age was significantly higher in patients in the third period (61.4 years) than in those in the other two periods (first, 57.8 years; second, 59.5 years). During these periods, the proportion of good outcomes did not change; however, the mortality rate significantly decreased from 19% in the first period to 11% and 9.2% in the second and third periods, respectively. The poor outcome was mainly caused by the significantly higher incidence of systemic complication and procedural complication in the first period and the significantly lower incidence of delayed ischemic neurological deficit in the third period. The elderly patients had significantly poorer clinical outcomes than the nonelderly ones. During the last 25 years, the age of patients with aneurysmal SAH has rapidly increased. The study results may contribute to the improvement of the treatment strategy of SAH in advanced countries with a rapidly aging population.

Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial.

OBJECT: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm. METHODS: Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population. RESULTS: Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period. CONCLUSIONS: Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry.

Platelet aggregometry in the presence of PGE(1) provides a reliable method for cilostazol monitoring.

INTRODUCTION: Cilostazol has been shown to be effective for prevention and treatment of cerebral infarction. However, there appears to be no widely accepted method appropriate for monitoring cilostazol. We attempted to establish an assay system for cilostazol monitoring, using platelet aggregation induced by arachidonic acid (AA) in the presence of PGE(1) which upregulates intracellular cyclic AMP. METHODS: Blood was drawn from stroke patients before and after cilostazol intake. AA-induced platelet aggregation after pretreatment with 0~30nM PGE(1) for 2minutes was measured by light transmittance aggregometry. RESULTS: AA-induced platelet aggregation was 73.1±2.2% in the absence of PGE(1), and pretreatment with 30nM PGE(1) had virtually no inhibitory effect on platelet aggregation prior to cilostazol intake. In contrast, after cilostazol intake, 30nM PGE(1) significantly inhibited platelet aggregation to 12.7±4.5% (p=7.8×10(-11)) , while in the absence of PGE(1) platelet aggregation remained similar to that of prior-to-cilostazol value (70.6±3.5%). The plasma concentration of cilostazol ranged from 0.55 to 3.51µM. In the presence of 30nM PGE(1), all the patients with cilostazol concentrations exceeding 1µM had their platelet aggregation inhibited almost completely. ROC analysis suggests that AA-induced platelet aggregation in the presence of 30nM PGE(1) had the excellent sensitivity (90.5%) and specificity (88.4%) for monitoring cilostazol. CONCLUSIONS: AA-induced platelet aggregation in the presence of 30nM PGE(1) could give good estimate on plasma concentrations of cilostazol. It is suggested that this system is a good tool for monitoring cilostazol.