RESUMEN
BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.
Asunto(s)
Hemorragias Intracraneales/inducido químicamente , Inhibidores de Agregación Plaquetaria/efectos adversos , Accidente Cerebrovascular/prevención & control , Tetrazoles/efectos adversos , Cilostazol , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Factores de Riesgo , Tetrazoles/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS: Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS: Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564-0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296-0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION: Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING: Otsuka Pharmaceutical.
Asunto(s)
Aspirina/administración & dosificación , Infarto Cerebral/prevención & control , Prevención Secundaria/métodos , Accidente Cerebrovascular/prevención & control , Tetrazoles/administración & dosificación , Adulto , Anciano , Infarto Cerebral/complicaciones , Infarto Cerebral/tratamiento farmacológico , Cilostazol , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: The results of the Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS), a randomized double-blind study of sarpogrelate (selective 5-HT(2A) receptor antagonist) versus aspirin in 1510 Japanese patients, have been reported. But S-ACCESS failed to demonstrate noninferiority of sarpogrelate to aspirin for preventing the recurrence of cerebral infarction. Here we compare the characteristics of sarpogrelate and aspirin in various subgroups. METHODS: Subgroups were predefined from patients' baseline characteristics. Hazard ratio (HR) and 95% confidence interval (CI) for sarpogrelate versus aspirin were calculated for primary (cerebral infarction) and secondary (serious vascular events) end points. Interactions between treatment effects and subgroup variables were examined by post hoc analysis. RESULTS: No significant difference in outcome between sarpogrelate and aspirin was found across multiple predefined subgroups. In post hoc analysis, a qualitative treatment interaction with diabetes mellitus was detected (P=0.166 for recurrence of cerebral infarction; P=0.098 for serious vascular events). HR for the recurrence of cerebral infarction with sarpogrelate versus that with aspirin was 0.87 (95% CI: 0.48 to 1.60) in diabetic patients and 1.51 (95% CI: 0.98 to 2.31) in nondiabetic patients. For serious vascular events, the corresponding HRs were 0.73 (95% CI: 0.42 to 1.25) and 1.28 (95% CI: 0.89 to 1.83). CONCLUSIONS: No specific baseline characteristic resulting in a significant difference between the effects of sarpogrelate and aspirin was identified. Aspirin was superior in most subgroups, except diabetics. Sarpogrelate may be a useful treatment option for Japanese patients with diabetes.
Asunto(s)
Aspirina/uso terapéutico , Infarto Cerebral/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Prevención Secundaria/métodos , Succinatos/uso terapéutico , Anciano , Aspirina/efectos adversos , Infarto Cerebral/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prevención Secundaria/tendencias , Succinatos/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Although antiplatelets are known to be effective for secondary prevention of cerebral infarction, the number needed to treat is rather large and the effects in stroke patients with complications such as hypertension or diabetes are inadequately defined. This study was conducted to examine the effect of such complications on recurrence of cerebral infarction, and to assess the effect of cilostazol, an antiplatelet agent, in these high-risk subjects. METHODS: A post hoc subgroup analysis of the already reported Cilostazol Stroke Prevention Study, which was a placebo-controlled double-blind trial, has been carried out to clarify the influence of various complications on recurrence in the placebo group and the effects of cilostazol in 1,095 patients with noncardioembolic ischemic cerebrovascular disease. Treatment continued for an average of 1.8 +/- 1.3 years (maximum 4.8 years). RESULTS: The recurrence rate of the diabetic stroke patients was significantly higher compared with the nondiabetics in the placebo group (9.4 vs. 4.7%/year, p = 0.01). Furthermore, our study showed that the relative risk reduction (RRR) for recurrence of infarction was 41.7% with cilostazol. This treatment provided a significant benefit in patients with lacunar infarction (RRR 43.4%, p = 0.04), with diabetes (RRR 64.4%, p = 0.008), or with hypertension (RRR 58.0%, p = 0.003). CONCLUSIONS: Diabetic patients are particularly at risk for recurrence of cerebral infarction. Cilostazol is useful for the prevention of the recurrence of vascular events in patients with lacunar infarction, and is probably effective in high-risk patients with diabetes and/or hypertension.
Asunto(s)
Isquemia Encefálica/prevención & control , Infarto Cerebral/prevención & control , Complicaciones de la Diabetes/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tetrazoles/uso terapéutico , Anciano , Isquemia Encefálica/complicaciones , Infarto Cerebral/etiología , Cilostazol , Método Doble Ciego , Femenino , Humanos , Hipertensión/complicaciones , Japón , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Prevención Secundaria , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: The antiplatelet agent sarpogrelate is a selective inhibitor of 5-hydroxytryptamine receptors. The purpose of this study was to compare the efficacy and safety of sarpogrelate with those of aspirin in Japanese ischemic stroke patients. METHODS: In total, 1510 patients with recent cerebral infarction (1 week to 6 months after onset) were randomly assigned to receive either sarpogrelate (100 mg TID) or aspirin (81 mg/d). Mean follow-up period was 1.59 years. The primary efficacy end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event-related death) were selected as secondary end points. The aim of the primary efficacy analysis was to demonstrate the noninferiority of sarpogrelate with respect to aspirin, with the criterion that the upper limit of the 95% CI of the hazard ratio (sarpogrelate vs aspirin) for recurrence of cerebral infarction should not exceed 1.33. RESULTS: Cerebral infarction recurred in 72 patients (6.09%/y) in the sarpogrelate group and in 58 (4.86%/y) in the aspirin group (hazard ratio=1.25; 95% CI, 0.89 to 1.77; P=0.19). A serious vascular event occurred in 90 (7.61%/y) and in 85 (7.12%/y) patients, respectively (hazard ratio=1.07; 95% CI, 0.80 to 1.44; P=0.65). The overall incidences of bleeding events were 89 (11.9%) and 131 (17.3%), respectively (P<0.01). CONCLUSIONS: Sarpogrelate was not noninferior to aspirin for prevention of recurrence of cerebral infarction. Bleeding events were significantly fewer with sarpogrelate than aspirin. The effect of aspirin in Japanese patients was similar to that in Western studies.
Asunto(s)
Aspirina/administración & dosificación , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/prevención & control , Inhibidores de Agregación Plaquetaria/administración & dosificación , Succinatos/administración & dosificación , Anciano , Aspirina/efectos adversos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/epidemiología , Método Doble Ciego , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Prevención Secundaria , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/efectos adversos , Succinatos/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: It is widely accepted that antiplatelet therapy is effective for secondary prevention of atherosclerotic vascular diseases. We performed a double-blind, controlled clinical-pharmacological study to investigate the antiplatelet efficacy of sarpogrelate, a selective 5-hydroxytryptamine (5-HT(2A)) receptor antagonist, in patients with ischemic stroke, using a new assessment system employing combinations of 5-HT and epinephrine as agonists. METHODS: Forty-seven patients with ischemic stroke were randomly assigned to three groups: 15 patients received 25 mg sarpogrelate (group L), 16 patients received 50 mg (group M), and 15 patients received 100 mg (group H) orally, three times daily for 7 days. The effect was expressed as maximum intensity of platelet aggregation on the last day of medication. Two combinations of agonists, 0.5 micromol/l 5-HT plus 3 micromol/l epinephrine, and 1 micromol/l 5-HT plus 3 micromol/l epinephrine, were used to induce platelet aggregation. RESULTS: With both combinations of agonists, sarpogrelate treatment inhibited platelet aggregation dose-dependently (p < 0.025, Jonckheere test). In multiple-group comparison, the effect in group H was greater than that in group L or M (p < 0.025, Wilcoxon rank-sum test). CONCLUSION: Sarpogrelate treatment inhibited platelet aggregation dose-dependently in patients with ischemic stroke, as judged by a new assessment system employing combinations of 5-HT and epinephrine as agonists.
Asunto(s)
Plaquetas/efectos de los fármacos , Isquemia Encefálica/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT2 , Antagonistas de la Serotonina/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Succinatos/uso terapéutico , Administración Oral , Anciano , Plaquetas/metabolismo , Isquemia Encefálica/sangre , Isquemia Encefálica/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Epinefrina/metabolismo , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Pruebas de Función Plaquetaria/métodos , Receptor de Serotonina 5-HT2A/metabolismo , Serotonina/metabolismo , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/efectos adversos , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Succinatos/administración & dosificación , Succinatos/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Some of the cerebral microlesions less than 3 mm in diameter observed on magnetic resonance imaging (MRI) are considered to represent pathological processes. The present study investigated changes due to aging in microlesions according to anatomical regions and phenotypes. PATIENTS: A total of 390 cases without localized lesions other than lacune less than 15 mm in diameter were studied. METHOD: Microlesion type on MRI was categorized into hypo-, iso-, and hyper-intensities on T1-weighted (T1WI), T 2-weighted (T2WI), and proton-weighted or fluid-attenuated inversion recovery (proton/FLAIR) images. Correlations between unidentified bright objects (UBO) in white matter and vascular risk factors were analyzed using logistic regression analysis. RESULTS: Microlesions of the upper basal ganglia showing low intensity on T1WI, high intensity on T2WI and iso intensity on proton/FLAIR, and showing low intensity on T1WI, high intensity on T2WI and low intensity on proton/FLAIR increased with age, whereas those showing low intensity on T1WI, iso intensity on T2WI, and low intensity on proton/FLAIR of the upper basal ganglia decreased. In subcortical white matter, microlesions of the first two types: and those showing iso intensity on T1WI, high intensity on T2WI and iso intensity on proton/FLAIR decreased with age. Conversely, UBO increased with age, and significantly correlated with hypertension. CONCLUSION: Although microlesions in the upper basal ganglia increase with age, those in the subcortical white matter decrease with age. These observations suggest pathological changes surrounding small arteries with aging in the brain.