Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

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.

[Nicotine replacement therapy].

For the habitual smokers with nicotine dependence, it is difficult for them to quit smoking. The nicotine replacement therapy (NRT) is a helpful measure for the persons who want to quit smoking. The concept, medication and practice of the NRT are described.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial.

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.

Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial.

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.

Clinical profile and prognosis of hospitalized patients with congestive heart failure in Isehara, Japan.

Since the clinical profile and prognosis of heart failure depending on time of the study performed, regional characteristics of background population and different race, we attempted to evaluate the prognosis of symptoms and life expectancy of Japanese patients with heart failure. We evaluated the clinical profiles and prognoses of 1,015 consecutive patients with congestive heart failure (CHF) for whom hospitalization was required. A total of 1,015 consecutive CHF patients (584 males and 431 females) were enrolled in this study, however the total number of events investigated was 1,409. Of these patients, survival was confirmed in 413 patients, death was confirmed in 299 patients, and the prognoses of 303 patients remained unknown due to transfer to other hospitals or for some other reasons. The mean age on admission was 68.4 +/- 14.9 years. In both males and females, the peak age at the onset of CHF was in the seventies, and for patients in their eighties, the number of female patients with CHF was larger than that of male patients. Major underlying heart diseases consisted of ischemic heart disease (34%), valvular heart disease (22%), dilated cardiomyopathy (11%), and hypertension (10%). Most CHF patients who had dilated cardiomyopathy as an underlying disease were hospitalized several times, and 45% of them were hospitalized 3 times or more. The life expectancy of patients with CHF caused by ischemic heart disease was the poorest, and their 5-year and 10-year survival rates were 55% and 38%, respectively. Similarly, 5-year and 10-year survival rates of patients with CHF caused by valvular heart disease, hypertension, and dilated cardiomyopathy were 62% and 44%, 58% and 53%, and 70% and 65%, respectively. In 299 deceased patients, the mean age at death was 72.2 +/- 13.9 years. In all these deceased patients, direct causes of death were sudden death (16.1%), CHF (42.2%), others (31.4%), and unknown (10.4%). The frequency of sudden death was highest (25%) in patients with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by valvular heart disease (18%) and those with CHF caused by ischemic heart disease (17.5%). In addition, the frequency of death from CHF was highest (60%) in those with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by ischemic heart disease (49.2%).

A case of familial hypercholesterolemia; secession from LDL-apheresis by the drug treatment with potent statin and resin.

Low density lipoprotein (LDL)-apheresis is a useful tool for the treatment of familial hypercholesterolemia (FH) with coronary artery disease (CAD). However, it gives economic, physical and mental burdens for the patients. We reports a case of FH in whom LDL-apheresis treatment was seceded with drug treatment with a potent statin and bile acid-sequestering resin. A 54-year-old woman was admitted for evaluation of atherosclerotic lesion after 4 years of LDL-apheresis and 1 year of drug medication with a potent statin, atorvastatin and resin, cholestimide with coronary angiography. She had been diagnosed as heterozygous FH when she was 46 years old. Oral medication was initiated at the outpatient clinic. LDL-cholesterol (C) level was not successfully controlled despite the administration of a statin, pravastatin, a fibrate, clinofibrate and probucol at maximum doses Concomitantly. Therefore, as combination therapy, LDL-apheresis was introduced in May 1997. However, the patient strongly complained of the economic, physical, and mental burdens of LDL-apheresis and requested discontinuation of apheresis. Therefore, LDL-apheresis was discontinued in July 2000, and oral medication was subsequently changed to a combination of atorvastatin and cholestimide, resulting in successful control of serum LDL-C level by oral medication alone. We compared coronary arteriographic findings between 1997 and 2001. No advancement of lesions was observed. We think that strong drug treatment can secede from the LDL-apheresis for treatment of patients with FH.

Detection of right to left shunting through a patent foramen ovale in Japanese patients with ischemic stroke by transesophageal echocardiography using a standardized Valsalva maneuver.

We attempted to clarify the usefulness of transesophageal echocardiography performed using a standardized Valsalva maneuver to detect the presence of a patent foramen ovale in Japanese patients with ischemic stroke. Four hundred ninety six patients with ischemic stroke who were admitted to the Yokohama City Brain and Stroke Center between September 1999 and February 2002 were enrolled for the study. All the enrolled patients underwent transesophageal echocardiography with contrast injection and color Doppler imaging. During the procedure, a standardized Valsalva maneuver was performed to induce right to left shunting through a patent foramen ovale. Other related structural abnormalities, such as atrial septal aneurysm and the Chiari network anomaly, were also detected by the test. Transesophageal echocardiography without the Valsalva maneuver revealed a functional right to left communication in only 8.2% of the ischemic stroke patients, whereas the procedure conducted using a standardized Valsalva maneuver to provoke shunting revealed a patent foramen ovale in 15.3% of the patients. The presence of an atrial septal aneurysm or the Chiari network anomaly was not sensitive or specific enough to predict the presence of a patent foramen ovale as diagnosed by transesophageal echocardiography using the standardized Valsalva maneuver. Our results suggest that the standardized Valsalva maneuver is a safe and useful technique to detect the presence of a patent foramen ovale, which is potentially known to be associated with paradoxical embolism.

Platelets, after exposure to a high shear stress, induce IL-10-producing, mature dendritic cells in vitro.

There is evidence for immune system involvement in atherogenesis. In the present study the effect of platelets on dendritic cells (DC), an important immunologic regulator, was examined in vitro. Platelet-rich plasma, after exposure to shear stress, was added to human monocyte-derived immature DC, which were then examined for surface Ag expression, allogeneic T lymphocyte stimulatory activity, and cytokine production. After exposure, the number of anti-CD40 ligand (anti-CD40L) and anti-P-selectin IgG molecules bound per platelet was increased. These activated platelets induced DC maturation, as revealed by significant up-regulation of CD83, CD80, and CD86 Ags. The addition of platelets in the presence of IFN-gamma plus LPS significantly enhanced IL-10 production from immature DC. After platelet addition, mature DC provoked a significant proliferation of allogeneic naive T lymphocytes. These activated T cells showed lower IFN-gamma production than those stimulated by LPS- and IFN-gamma-treated DC. CD40L on the platelet surface was not involved in maturation of DC, as mAb to CD40L failed to block maturation. The effect of platelets was observed even if platelets and DC were separated using large pore-sized membranes or when platelets were depleted from plasma by centrifugation. Furthermore, it was abrogated after the depletion of protein fraction. Thus, soluble protein factors excreted from activated platelets contribute to IL-10-producing DC maturation.

Specific inhibiting effects of Ilexonin A on von Willebrand factor-dependent platelet aggregation under high shear rate.

BACKGROUND: Ilexonin A (IA), purified from the Chinese herbal medicine Maodongqing (Ilex pubescens Hook, et Arn) has been commonly used in south China to treat thrombotic disorders. In this study, we aimed to study the inhibiting effects and mechanism of IA on von Willebrand factor (vWF)-dependent high shear-induced platelet aggregation. METHODS: vWF-dependent high shear (10,800 s(-1)) induced aggregation of platelets obtained from normal donors in the presence or absence of IA was measured by a modified cone-plate viscometer and shear-induced vWF binding was measured by quantitative flow cytometry with monoclonal antibody known to bind exclusively to the C-terminal domain of vWF (LJ-C3) directly labeled with fluorescein isothiocyanate (FITC). P-selectin surface expression was also measured by a similar method with FITC conjugated anti-P-selectin monoclonal antibody (WGA1). RESULTS: Shear-induced platelet aggregation was inhibited by IA in a dose-dependent manner. The extent of aggregation decreased from (78.6 +/- 4.6)% in the absence of IA to (36.5 +/- 2.1)% in the presence of IA (3.3 mmol/L) (P < 0.0001, n = 9) with a high shear rate of 10800 s(-1). vWF binding and P-selectin expression were also inhibited by IA in a dose dependent manner. The number of binding FITC-LJ-C3 molecules increased after exposure of platelet-rich plasma to a high shear rate of 10800 s(-1) for 6 minutes, but this shear-induced increased binding platelet surface vWF molecules and P-selectin expression can be decreased in the presence of IA. CONCLUSION: vWF binding and vWF mediated platelet activation, aggregation occurring under high shear rate were inhibited by IA. IA may be a unique antithrombotic drug inhibiting the vWF-GP Ibalpha interaction, and may thus facilitate drug design targeting arterial thrombosis.

Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.

BACKGROUND: The efficacy and optimum dose of beta-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a beta-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF. METHODS: After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class. RESULTS: Carvedilol therapy achieved dose-dependent improvement of all end points (P for linear trend, range.002 to <.001). Both carvedilol groups showed marked risk reduction (71% to 91%) for cardiovascular and CHF hospitalization and for death or cardiovascular hospitalization (P range,.024 to <.001 for pairwise comparisons with placebo). No significant differences were observed for noncardiovascular hospitalization or adverse events. CONCLUSIONS: In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.

Possible contribution of acetylamrinone and its enhancing effects on platelet aggregation under shear stress conditions in the onset of thrombocytopenia in patients treated with amrinone.

BACKGROUND: Thrombocytopenia is recognized as one of the most common complications when the patients with severe heart failure are treated with cardiotropic phosphodiesterase (PDE)-3 inhibitors. To understand the mechanism of the onset of this complication, we focused on the effects of various PDE-3 inhibitors and its stable metabolite of acetylamrinone on platelet aggregation occurring under physiological shear stress conditions. METHOD: Blood specimens were obtained from eight apparently healthy adult donors. Platelet-rich plasma was separated after anticoagulation by citrate. The effects of PDE-3 inhibitors of amrinone and olprinone, as well as the stable metabolite of the former of acetylamrinone, on platelet aggregation induced by its exposure to a shear rate of 1200 and 10,800 s(-1) were determined by optically modified cone-plate viscometer. RESULTS: Both olprinone and amrinone inhibited platelet aggregation at 10,800 s(-1) in a dose-dependent manner with the IC(50) value of 14 +/- 1 and 61 +/- 8 microM (mean +/- S.D.), respectively, while amrinone significantly inhibited platelet aggregation at 1200 s(-1) only at highest concentration tested (100 microM). Contrary to the effects shown with PDE-3 inhibitors, acetylamrinone did not inhibit platelet aggregation at all. Moreover, it even enhanced the aggregation at 1200 s(-1) when used with 5 microM. CONCLUSIONS: Our results demonstrate possible contribution of the enhancing effects of acetylamrinone on platelet aggregation occurring under blood flow conditions, which reduced the platelet count when occurring in real circulation, to the higher incidence of thrombocytopenia in patients treated with amrinone.

[Efficacy of Nifekalant hydrochloride for life-threatening ventricular tachyarrhythmias in patients with resistance to lidocaine: a study of patients with out-of-hospital cardiac arrest].

OBJECTIVES: Class I antiarrhythmic agents are not always effective in the treatment of life-threatening ventricular tachycardia/ventricular fibrillation (VT/VF) especially in patients with cardiopulmonary arrest. Nifekalant hydrochloride(NIF) is a novel class III antiarrhythmic agent for malignant VT/VF. This study prospectively evaluated NIF efficacy for life-threatening VT/VF observed after cardiopulmonary arrest. METHODS: Thirty-two of 145 patients who were transferred to the emergency room in Tokai University Hospital showed VT/VF after resuscitation from cardiopulmonary arrest from June 2000 to March 2001. These 32 patients were treated with 12 mg (mean) epinephrine and 1.0-2.0 mg/kg lidocaine following direct current application(200 to 360J), and then classified into two groups. Eleven patients received intravenous 0.15 to 0.3 mg/kg NIF followed by intravenous infusion of 0.3 to 0.4 mg/kg/hr NIF(NIF group). The other 21 patients received 1.0 to 2.0 mg/kg of lidocaine(non-NIF group). RESULTS: Sinus rhythm was restored in the nine patients(82%) in the NIF group but only four patients (19%) in the non-NIF group. QTc was not prolonged(0.45 +/- 0.04 sec, n = 9) and no torsades de pointes was observed in the NIF group. Two patients survived but the remaining nine patients died in the NIF group. Five patients died of cardiac standstill following sinus bradycardia and repeated sinus arrest within 2 to 27 hr after admission, two patients died of sudden cardiac arrest from sinus rhythm, and two patients died of persistent VT/VF. In contrast, all 21 patients in the non-NIF group died. Seventeen patients died of persistent VT/VF before hospitalization, one patient died of recurrent VT/VF, and three patients died of cardiac standstill following sinus bradycardia. CONCLUSIONS: NIF effectively suppresses VT/VF which is refractory to direct current shock in patients with cardiopulmonary arrest. However, NIF may rather worsen electrophysiological function in the sinus node after administration of high doses of epinephrine, and may induce sinus bradycardia and/or sinus arrest. Careful observation, such as monitoring of electrocardiography and blood pressure and temporary cardiac pacemaker use, is needed to prevent death in patients surviving after cardiopulmonary arrest if NIF is administered following high dose epinephrine infusion.

[Significance of electrocardiographic QRS width in patients with congestive heart failure: a marker for biventricular pacing].

OBJECTIVES: Biventricular pacing may be valuable for the treatment of patients with intractable heart failure, but how many patients in Japan would benefit from this type of therapy remains uncertain. This study investigated the incidence of intraventricular conduction delay in the electrocardiogram(ECG) as a marker of the need for biventricular pacing, as well as the underlying etiology of heart failure in patients admitted with congestive heart failure. METHODS: Patients with heart failure admitted to the Tokai University Hospital from January 1990 to September 2000 were studied retrospectively. The distribution of age, sex and underlying diseases, and that of the rhythm and the QRS width in ECG recordings were analyzed. Patients with a QRS width of over 121 msec in the ECG were classified as the 'wide QRS' group. RESULTS: Of a series of 1,200 consecutive patients with heart failure, 872 patients, 499 males and 373 females (mean age 67.9 +/- 13.9 years) were admitted to the hospital and 71 had 'wide QRS' by ECG. Among those in the 'wide QRS' group, 37% had ischemic heart disease and 14% had dilated cardiomyopathy. The widest QRS complexes were encountered in patients with dilated cardiomyopathy and the largest number of wide QRS complexes was encountered in patients with ischemic heart disease. CONCLUSIONS: The most frequent causes of heart failure among patients considered suitable for biventricular pacing were ischemic heart disease and dilated cardiomyopathy, which is consistent with previous reports. Compared with the statistics reported from western countries, the incidence of ischemic heart disease and the incidence of intraventricular conduction delay were lower in Japanese patients with heart failure. The incidence of intraventricular conduction delay among patients with heart failure was 8.6%. Therefore, fewer patients need biventricular pacing in Japan than in western countries. Nevertheless, patients with heart failure resistant to other therapies might still benefit from this type of therapy.

Application of ex vivo flow chamber system for assessment of stent thrombosis.

OBJECTIVE: Factors influencing platelet accumulation around stents were to be investigated by an ex vivo flow chamber system. METHODS AND RESULTS: Platelet accumulations on collagen surfaces under flow conditions were augmented in the presence of stents, especially at sites downstream from coil stents. Densitometric analysis revealed that 4.9+/-0.8 times more platelets accumulated downstream from coil stents than were formed downstream from tube stents (P<0.01), suggesting that stent morphology is an important determinant factor of its thrombogenicity. Platelet accumulations around stents were significantly inhibited by a combination of ticlopidine and aspirin, whereas aspirin alone produced only modest inhibition. Anti-glycoprotein IIb/IIIa (abciximab) inhibited platelet accumulation around stents in a dose-dependent manner, whereas the antibody blocking von Willebrand factor binding to glycoprotein Ib(alpha), which had been shown to inhibit platelet thrombus formation under high shear rates, did not inhibit the accumulation downstream from the coil stents. Our results suggest that the important characteristics of in vivo stent thrombosis, ie, augmented platelet accumulation with coil stents and the strong antithrombotic effect of the combination antiplatelet agents and an anti-glycoprotein IIb/IIIa, can be reproduced in ex vivo perfusion model. CONCLUSIONS: We conclude that an ex vivo perfusion system is useful in the assessment of the thrombogenicity of various stents and in the screening of effective antiplatelet agents.