Background and Purpose-We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries. Methods-A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition. Results-During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (PϽ0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative riskϭ1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative riskϭ1.37; 95% CI, 1.07 to 1.76). Conclusions-The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.

on behalf of The Bleeding With Antithrombotic Therapy (BAT) Study Group Background and Purpose-A prospective, multicenter, observational cohort study was conducted to clarify the association between major bleeding events and blood pressure (BP) levels during follow-up before development of bleeding events in antithrombotic users. Methods-A total of 4009 patients taking oral antithrombotic agents for cardiovascular or cerebrovascular diseases (2728 men, 69Ϯ10 years old) were followed. Changes in systolic and diastolic BPs between entry and the last clinic visit before intracranial hemorrhage (ICH) or extracranial hemorrhage were assessed. Results-Over a median follow-up of 19 months, ICH developed in 31 patients and extracranial hemorrhage developed in 77. Entry BP levels were similar among patients with ICH, those with extracranial hemorrhage, and those without hemorrhagic events. Both systolic BP and diastolic BP were relatively high during follow-up as compared with the levels at entry in patients with ICH, whereas they showed plateaus in patients with extracranial hemorrhage and patients without hemorrhagic events. Average systolic BP levels between 1 and 6 months (hazard ratio, 1.45; 95% CI, 1.08 to 1.92 per 10-mm Hg increase) and between 7 and 12 months (hazard ratio, 1.47; 95% CI, 1.05 to 2.01) as well as average diastolic BP levels between 7 and 12 months (hazard ratio, 2.05; 95% CI, 1.15 to 3.62) were independently associated with development of ICH after adjustment for established ICH predictors. The optimal cutoff BP level to predict impending risk of ICH was Ն130/81 mm Hg using receiver operating characteristic curve analysis. Conclusions-An increase in BP levels during antithrombotic medication was positively associated with development of ICH, suggesting the importance of adequate BP control for avoiding ICH. BP levels did not appear to be associated with extracranial hemorrhage. (Stroke.

The preventive effect of statins on coronary events is not only associated with the cholesterol-lowering effect of these drugs, but also various direct effects on the vascular wall, which include improvement of endothelial function, antioxidant activity, and anti-inflammatory activity. We investigated whether short-term statin therapy could improve arterial stiffness and assessed its mechanism of action in patients with hypercholesterolemia. We assessed arterial stiffness in 10 patients (mean age: 62.9 +/- 9.0 years) with hypercholesterolemia (total cholesterol > or =220 mg/dl). The patients were treated with cerivastatin (0.15 mg/day) for 4 weeks. Before and after 4 weeks of treatment, we determined arterial stiffness from brachial-ankle pulse wave velocity and the ankle-brachial blood pressure index (ABI) using a FORM apparatus (Colin, Komaki, Japan). We also measured the blood levels of high-sensitivity C-reactive protein (hsCRP) and malondialdehyde low-density lipoprotein (MDA-LDL) as markers of inflammation and oxidation, respectively. After statin therapy, both the right and left abPWV were significantly decreased from 1544.6 +/- 157.1 to 1349.0 +/- 223.9 cm/s and from 1592.1 +/- 164.8 to 1424.8 +/- 245.2 cm/s, respectively (P < 0.05). However, the ABI was unchanged after 4 weeks of cerivastatin therapy. MDA-LDL decreased significantly (from 161.2 +/- 42.4 to 119.4 +/- 33.5 U/l, P < 0.05) and hsCRP also decreased. Total cholesterol and LDL-cholesterol decreased, while triglycerides and high-density lipoprotein-cholesterol were unchanged. Blood pressure was not significantly altered from the baseline value by statin therapy. These results suggest that the preventive effect of statins on coronary events is partly associated with the various actions of these drugs on the vascular wall, and that statins are not only cholesterol-lowering agents but also antiatherosclerotic agents.

A 72-year-old woman was admitted to our hospital with acute exacerbation of chronic heart failure. Her medical history included chronic heart failure, permanent atrial fibrillation, and psychiatric disease. Despite a CHA2DS2-VASc score of 5, poor drug compliance compelled her to warfarin administration. Coarse crackles were evident over both lungs and a chest X-ray showed pulmonary congestion. Electrocardiography showed atrial fibrillation with a ventricular heart rate of 98. Blood tests revealed BNP 775.7 pg/mL and D-dimer 4.0 mg/mL. The heart failure was promptly compensated by intravenous furosemide. However, transthoracic echocardiography (TTE) demonstrated a mobile high echoic mass of 2.6 × 3.0 cm in the left atrium (LA) (Panel A, white arrows; LA, left atrium; LV, left ventricle). We administered heparin and warfarin, and TTE after 1 month showed that the LA mass had shrunk to 1.7 × 1.0 cm, confirming that it was thrombus (Panel B, white arrows). Warfarin was changed to dabigatran 300 mg/day because she had a delusional disorder. She has remained on dabigatran for 4 months without any serious bleeding complications, and TTE confirmed that the thrombus had disappeared (Panel C).Dabigatran is a direct thrombin inhibitor that exerts anticoagulant effects by binding to the active site of thrombin. Since it acts independently of antithrombin, it can inhibit thrombin bound to fibrin and fibrin degradation products, implying that it also has thrombolytic properties. In fact, dabigatran possibly induced thrombolysis in this patient, indicating that this drug could be a therapeutic option for patients with intracardiac thrombus.

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We evaluated the effects of disopyramide in terms of the balance between myocardial oxygen supply and demand in patients with hypertrophic obstructive cardiomyopathy (HOCM). The myocardial oxygen supply was evaluated by measuring coronary flow velocity and the myocardial oxygen demand was assessed by the pressure-volume area (PVA). The time velocity integral of coronary flow did not change significantly (20 +/- 6 to 21 +/- 8 cm), but the peak left ventricular pressure and left ventricular external work decreased significantly (206 +/- 44 to 157 +/- 37 mmHg, P < 0.001; 1.09 +/- 0.33 to 0.80 +/- 0.23 J/beat, P < 0.001) after disopyramide administration. From theoretical analysis using these data, we concluded that disopyramide improves the myocardial oxygen supply-demand balance in patients with HOCM.

The CHADS2 and CHA2DS2-VASc scores, that is, ischemic stroke risk indices for patients having atrial fibrillation (AF), may also be useful as bleeding risk indices. Japanese patients with AF, who routinely took oral antithrombotic agents were enrolled from a prospective, multicenter study. The CHADS2 and CHA2DS2-VASc scores were assessed based on information at entry. Scores of 0, 1 and ⩾2 were defined as the low, intermediate and high ischemic risk categories, respectively, for each index. Of 1221 patients, 873 took warfarin, 114 took antiplatelet agents and 234 took both. The annual incidence of ischemic stroke was 0.76% in the low-risk category, 1.46% in the intermediate-risk category and 2.90% in the high-risk category by CHADS2 scores, and 1.44, 0.42 and 2.50%, respectively, by CHA2DS2-VASc scores. The annual incidence of major bleeding in each category was 1.52, 2.19 and 2.25% by CHADS2, and 1.44, 1.69 and 2.24% by CHA2DS2-VASc. After multivariate adjustment, the CHADS2 was associated with ischemia (odds ratio 1.76, 95% confidence interval 1.03-3.38 per 1-category increase) and the CHA2DS2-VASc tended to be associated with ischemia (2.18, 0.89-8.43). On the other hand, associations of the indices with bleeding were weak. In conclusion, bleeding risk increased gradually as the CHADS2 and CHA2DS2-VASc scores increased in Japanese antithrombotic users, although the statistical impact was rather weak compared with their predictive power for ischemic stroke.

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