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The Japan Circulation Society launched the STOP-MI campaign in 2014, focusing on immediate hospital arrival for acute myocardial infarction (AMI) treatment. This study aimed to determine the factors influencing longer prehospital time among patients with AMI in Japan.Methods and Results:This study analyzed a total of 4,625 AMI patients enrolled in the Osaka Acute Coronary Insufficiency Study registry from 1998 to 2014. The prehospital time delay was defined as the time interval from the onset of initial symptoms to hospital arrival time ≥2 h. Among eligible patients, 2,927 (63.3%) had a prehospital time ≥2 h. In multivariable analyses, age 65-79 years (adjusted odds ratio [AOR] 1.19, 95% confidence interval [CI] 1.02-1.39), age ≥80 years (AOR 1.42, 95% CI 1.13-1.79), diabetes mellitus (AOR 1.33, 95% CI 1.16-1.52), and onset time of 0:00-5:59 h (AOR 1.63, 95% CI 1.37-1.95) were positively associated with prehospital time ≥2 h, whereas smoking (AOR 0.78, 95% CI 0.68-0.90) and ambulance use (AOR 0.37, 95% CI 0.32-0.43) were negatively associated with prehospital time ≥2 h.Older age, diabetes mellitus, and nighttime onset were associated with prehospital time delay for AMI patients, whereas smoking and ambulance use were associated with no prehospital time delay. Healthcare providers and patients could help reduce the time to get to a medical facility by being aware of these findings.

The prognostic significance of combining intra-aortic balloon pumping (IABP) with extracorporeal membrane oxygenation (ECMO) for acute myocardial infarction (AMI) patients is still unclear. We investigated whether combining IABP with veno-arterial (VA)-ECMO is associated with a lower risk of short-term mortality.Among 12,093 AMI cases enrolled in the Osaka Acute Coronary Insufficiency Study (OACIS), we identified 519 who were administered VA-ECMO during hospitalization. Among these, 459 received IABP support (IABP group) and 60 cases did not (no-IABP group). The primary endpoint was 30-day all-cause death; the secondary endpoint was major bleeding. Logistic regression analysis using original data was conducted. We also established weighted logistic regression models with inverse probability of treatment weighting (IPTW).Logistic regression analysis revealed that IABP use was significantly associated with a reduced risk of 30-day death in the original data [odds ratio (OR) 0.504, 95% confidence interval (CI) 0.282-0.901, p = 0.021]. After IPTW-adjustment for clinically relevant covariates with the use of IABP, patients receiving VA-ECMO with IABP had a lower risk of 30-day death (OR 0.816, 95% CI 0.746-0.892, p0.001) compared to those without IABP. The incidence of major bleeding was comparable between the groups (IABP 29.0% vs. non-IABP 21.7%, p=0.302). However, the risk of major bleeding was higher in the IABP group after IPTW-adjustment (OR 1.092, 95% CI 1.008-1.184, p=0.032).IABP support for AMI patients with VA-ECMO was significantly associated with reduced risk of short-term mortality, suggesting that the addition of IABP support might contribute to improved survival in AMI patients requiring VA-ECMO.

The effect of a history of cancer on the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is poorly understood.From the Osaka Acute Coronary Insufficiency Study (OACIS) registry in Osaka, Japan, we enrolled the case data of a total of 3499 patients with AMI treated with PCI between 1998 and 2014, of whom 462 had a cancer history (cancer group, 13.2%) and 3037 did not (non-cancer group, 86.8%). All of the cases were followed for up to five years from discharge.The Kaplan-Meier curve and multivariate analysis using Cox proportional hazards models revealed that all-cause mortality was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR], 2.43; P < 0.001). Deaths from cardiac, cancer, and other causes were treated as competing events, and competing analysis using the cumulative incidence function (CIF) and Fine-Gray model revealed that mortality due to cancer was higher in the cancer group than in the non-cancer group, whereas cardiac mortality was similar between the two groups. The incidences of cardiovascular events, including stroke, recurrent infarction, and heart failure requiring readmission, were also similar between the two groups, although the Kaplan-Meier analysis and univariate Cox proportional hazards model revealed that the incidence of stroke was higher in the cancer group than in the non-cancer group.A history of cancer increased all-cause and cancer mortality among patients with AMI treated with PCI, although it was not associated with cardiovascular events.

The Japanese high-bleeding-risk criteria (Japanese-HBR), modified criteria of the Academic Research Consortium (ARC) HBR, has been recently proposed. We aimed to investigate the prevalence of the ARC-HBR and the Japanese-HBR, and to assess their prognostic significance in patients with acute myocardial infarction (AMI). We applied the ARC-HBR and the Japanese-HBR criteria to the OACIS prospective multicenter acute myocardial infarction registry (12,093 patients, 66 ± 12 years, 9,096 males). The primary endpoint was fatal bleeding (BARC-5). Median follow-up duration was 4.84 [inter-quartile range 1.35, 5.01] years. Prevalence of the ARC-HBR was 43.8%, while that of the Japanese-HBR was 61.8%. Cumulative incidence of fatal bleeding was higher in the ARC-HBR group than in the no ARC-HBR group at 1 year (1.3 vs. 0.6%) and at 5 years (2.0 vs. 0.7%). The Kaplan–Meier curves stratified by the Japanese-HBR criteria more prominently diverged (1.3 vs. 0.2% at 1 year; and 1.9 vs. 0.3% at 5 years). The Japanese-HBR criteria showed superior discriminative performance over the ARC-HBR criteria (C-statistics: 0.677 vs. 0.598, P

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

Background: Studies comparing the cardiac consequences of hydrophilic and lipophilic statins in experimental and clinical practice settings have produced inconsistent results. In particular, evidence focusing on diabetic patients after acute myocardial infarction (AMI) is lacking. Methods and Results: From the Osaka Acute Coronary Insufficiency Study (OACIS) registry database, 1,752 diabetic patients with AMI who were discharged with a prescription for statins were studied. Long-term outcomes were compared between hydrophilic and lipophilic statins, including all-cause death, recurrent myocardial infarction (re-MI) and admission for heart failure (HF) and a composite of these (major adverse cardiac events; MACE). During a median follow-up period of 1,059 days, all-cause death, non-fatal re-MI, admission for HF, and MACE occurred in 95, 89, 112 and 249 patients, respectively. Although there was no significant difference between statins in the risk of all-cause death, re-MI and MACE, the risk of HF admission was significantly lower in patients with hydrophilic than lipophilic statins before (adjusted hazard ratio [aHR], 0.560; 95% CI: 0.345–0.911, P=0.019) and after (aHR, 0.584; 95% CI: 0.389–0.876, P=0.009) propensity score matching. Hydrophilic statin use was consistently associated with lower risk for HF admission than lipophilic statins across the subgroup categories. Conclusions: In the present diabetic patients with AMI, hydrophilic statins were associated with a lower risk of admission for HF than lipophilic statins.

Aims: This article aimed to examine the cost-effectiveness of rivaroxaban in comparison to warfarin for stroke prevention in Japanese patients with non-valvular atrial fibrillation (NVAF), from a public healthcare payer's perspective.Materials and methods: Baseline event risks were obtained from the J-ROCKET AF trial and the treatment effect data were taken from a network meta-analysis. The other model inputs were extracted from the literature and official Japanese sources. The outcomes included the number of ischaemic strokes, myocardial infarctions, systemic embolisms and bleedings avoided, life-years, quality-adjusted life-years (QALYs), incremental costs and incremental cost-effectiveness ratio (ICER). The scenario analysis considered treatment effect data from the same network meta-analysis.Results: In comparison with warfarin, rivaroxaban was estimated to avoid 0.284 ischaemic strokes per patient, to increase the number of QALYs by 0.535 per patient and to decrease the total costs by ¥118,892 (€1,011.11) per patient (1 JPY = 0.00850638 EUR; XE.com, 7 October 2019). Consequently, rivaroxaban treatment was found to be dominant compared to warfarin. In the scenario analysis, the ICER of rivaroxaban versus warfarin was ¥2,873,499 (€24,446.42) per QALY.Limitations: The various sources of data used resulted in the heterogeneity of the cost-effectiveness analysis results. Although, rivaroxaban was cost-effective in the majority of cases.Conclusion: Rivaroxaban is cost-effective against warfarin for stroke prevention in Japanese patients with NVAF, giving the payer WTP of 5,000,000 JPY.

Aims It is unknown whether Asian and non-Asian patients with atherosclerotic vascular disease derive similar benefits from long-term antithrombotic therapy. Methods and results In patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in The Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, the effects of rivaroxaban 2.5 mg b.i.d. plus aspirin 100 mg o.d. were compared with those of aspirin 100 mg o.d. in Asian vs. non-Asian patients (race was self-identified). Asians (n = 4269) vs. non-Asians (n = 23 126) had similar rates of major adverse cardiovascular events (MACEs) (4.85% vs. 4.83%, P = 0.30) and modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding (2.72% vs. 2.58%, P = 0.22), but higher rates of intracranial haemorrhage (ICH) (0.63% vs. 0.29%, P = 0.01) and minor bleeding (13.61% vs. 6.49%, P Conclusion Asian compared with non-Asian patients with chronic CAD and/or PAD have higher rates of ICH and minor bleeding. The combination of rivaroxaban and aspirin vs. aspirin alone produces similar effects for MACE, modified ISTH major bleeding, and net clinical outcome but may be associated with higher rates of ICH in Asian patients.

Background The previous large‐scale randomized controlled trial showed that routine thrombus aspiration (TA) during percutaneous coronary intervention (PCI) was associated with an increased risk of stroke. However, real‐world clinical evidence is still limited. Methods and Results We investigated the association between manual TA and stroke risk during primary PCI in the OACIS (Osaka Acute Coronary Insufficiency Study) database (N=12 093). The OACIS is a prospective, multicenter registry of myocardial infarction. The primary end point of the present study is stroke at 7 days. A total of 9147 patients who underwent primary PCI within 24 hours of hospitalization were finally analyzed (TA group, n=4448, versus non‐TA group, n=4699 patients). TA was independently associated with risk of stroke at 7 days (odds ratio [OR], 1.92 [95% CI, 1.19‒3.12]; P =0.008) in the simple logistic regression model, while the multilevel random effects logistic regression model with hospital treated as a random effect showed that manual TA was not associated with incremental risk of stroke at 7 days (OR, 0.91 [95% CI, 0.71‒1.16]; P =0.435). The 7‐day stroke risk of manual TA was significantly heterogeneous in different institutions ( P for interaction =0.007). Conclusions Manual TA during primary PCI for patients with acute myocardial infarction was independently associated with the overall increased risk of periprocedural stroke. However, this result was substantially skewed because of institution specific risk variation, suggesting that the periprocedural stroke may be preventable by prudent PCI procedure or appropriate periprocedural management. Registration URL: https://upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000005464 . Unique identifier: UMIN000004575.

To investigate the difference in the prognostic impact of loop diuretics in patients with acute myocardial infarction (AMI) based on plasma volume status, a total of 3,364 survivors of AMI who were registered in the large database of the Osaka Acute Coronary Insufficiency Study (OACIS) were studied. Plasma volume status was assessed by the estimated plasma volume status (ePVS) that was calculated based on a weight- and hematocrit-based formula at discharge. The endpoint was a composite endpoint of all-cause death and rehospitalization due to heart failure for 5 years. During a median follow-up period of 1.9 years, 90 and 223 patients had events in the groups with low ePVS (median value of 4.07%) and high ePVS (≥4.07%), respectively. Multivariable Cox regression analysis showed that loop diuretics use was independently associated with an increased risk of the composite endpoint in the low ePVS group (hazard ratio [HR], 2.572; 95% confidence interval [CI], 1.386-4.771; p = 0.002), but not in the high ePVS group (HR, 1.028; 95% CI, 0.698-1.512; p = 0.890). These results were unchanged even in the propensity-score matched cohorts. There was no heterogeneity in the increased risk of the primary endpoints between various patient characteristics and loop diuretic use in the matched cohorts. In conclusion, prescription of loop diuretics at discharge was associated with increased risk of poor long-term prognosis in patients with AMI without PV expansion, but not with PV expansion. Therefore, careful observation is needed when loop diuretics are prescribed for AMI patients without PV expansion.

Aims We aimed to establish a practical method for the assessment of tradeoff between thrombotic and bleeding risks. Methods We aimed to investigate the balance between bleeding risk and coronary thrombotic risk according to the number of the Academic Research Consortium for high bleeding risk (ARC-HBR) criteria in the multicenter prospective ST/non-ST elevation myocardial infarction (STEMI/NSTEMI) registry (N=12,093). Patients were divided as follows by the number of ARC-HBR criteria fulfilled: group 0, 0 major with ≤ 1 minor (N=6,792); group 1, 1 major with 0 minor (N=1,705); group 2, 0 major with ≥ 2 minors (N=790); group 3, 1 major with ≥ 1 minor (N=1,709); group 4, 2 majors with ≥ 0 minors (N=861); and group 5, ≥ 3 majors with ≥ 0 minor (N=236). We assessed the acute-phase absolute risk differences between bleeding and coronary thrombotic events in each group. Results At 7-day follow-up, all patients (groups 0-5) had a higher risk of major bleeding than that of any myocardial infarction (MI). Patients at ARC-HBR (groups 1-5) had a balanced risk between fatal MI and fatal bleeding, whereas patients at non-ARC-HBR (group 0) had a higher risk of fatal MI than that of fatal bleeding. Conclusions All STEMI/NSTEMI patients have a relatively high risk of major bleeding as compared with the risk of any MI in the acute phase. The ARC-HBR criteria would be a practical tool for assessing the tradeoff between fatal bleeding and fatal MI risks. This practical assessment would be helpful for the optimal decision-making of appropriate treatment strategy considering the balance between bleeding and coronary thrombotic risks.

The effect of a history of cancer on the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is poorly understood.From the Osaka Acute Coronary Insufficiency Study (OACIS) registry in Osaka, Japan, we enrolled the case data of a total of 3499 patients with AMI treated with PCI between 1998 and 2014, of whom 462 had a cancer history (cancer group, 13.2%) and 3037 did not (non-cancer group, 86.8%). All of the cases were followed for up to five years from discharge.The Kaplan-Meier curve and multivariate analysis using Cox proportional hazards models revealed that all-cause mortality was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR], 2.43; P0.001). Deaths from cardiac, cancer, and other causes were treated as competing events, and competing analysis using the cumulative incidence function (CIF) and Fine-Gray model revealed that mortality due to cancer was higher in the cancer group than in the non-cancer group, whereas cardiac mortality was similar between the two groups. The incidences of cardiovascular events, including stroke, recurrent infarction, and heart failure requiring readmission, were also similar between the two groups, although the Kaplan-Meier analysis and univariate Cox proportional hazards model revealed that the incidence of stroke was higher in the cancer group than in the non-cancer group.A history of cancer increased all-cause and cancer mortality among patients with AMI treated with PCI, although it was not associated with cardiovascular events.

Background: Heart rate (HR) reduction by β-blocker might not benefit patients with heart failure and reduced ejection fraction (HFrEF) with atrial fibrillation (AF). Methods and Results: The J-CHF study was a prospective randomized multicenter trial that assigned 360 HFrEF patients to a 2.5 mg/5 mg/20 mg target dose of carvedilol. Carvedilol was uptitrated over 8 weeks and then the dose was fixed. Of 321 patients available for analysis, AF was identified in 65 (20%). Using the median absolute change in HR at 32 weeks (∆HR), the subjects were further divided into group A (∆HR >-6 beats/min) and B (∆HR ≤-6 beats/min). Both in sinus rhythm (SR) and AF, baseline characteristics and achieved carvedilol dose were similar between groups A and B. In SR, the time-dependent change in left ventricular EF (LVEF) and LV end-diastolic dimension (LVEDD) over 56 weeks was more favorable in B compared with A (∆LVEF, P=0.036; ∆LVEDD, P=0.047), and ∆HR was independently associated with ∆LVEF (P=0.040). Group B had a lower rate of the primary endpoint, defined as a composite of death and hospitalization due to cardiovascular causes including acute decompensated HF at 3 years (P=0.002). ∆HR was an independent predictor of the primary endpoint (P=0.01), but this was not observed in AF. Conclusions: Response to the carvedilol HR reduction might differ in HFrEF between SR and AF.

Background: Estimated plasma volume status (ePVS) is a well-validated prognostic indicator in heart failure. However, it remains unclear whether ePVS has prognostic significance in patients with acute myocardial infarction (AMI). Moreover, there is no available information on its additive effect with the Global Registry of Acute Coronary Events (GRACE) risk score in AMI patients. Methods: Data were obtained from the Osaka Acute Coronary Insufficiency Study (OACIS) registry database. Patients whose data were available for ePVS derived from Hakim’s formula and the GRACE risk score were studied. The primary endpoints were in-hospital and 5-year mortality. Results: Of 3930 patients, 206 and 200 patients died during hospitalization and 5 years after discharge, respectively. After adjustment, ePVS remained an independent predictor of in-hospital death (OR:1.02, 95% CI: 1.00–1.04, p = 0.036), and 5-year mortality(HR:1.03, 95% CI: 1.01–1.04, p

The Japanese high-bleeding-risk criteria (Japanese-HBR), modified criteria of the Academic Research Consortium (ARC) HBR, has been recently proposed. We aimed to investigate the prevalence of the ARC-HBR and the Japanese-HBR, and to assess their prognostic significance in patients with acute myocardial infarction (AMI).We applied the ARC-HBR and the Japanese-HBR criteria to the OACIS prospective multicenter acute myocardial infarction registry (12,093 patients, 66 ± 12 years, 9,096 males). The primary endpoint was fatal bleeding (BARC-5). Median follow-up duration was 4.84 [inter-quartile range 1.35, 5.01] years. Prevalence of the ARC-HBR was 43.8%, while that of the Japanese-HBR was 61.8%. Cumulative incidence of fatal bleeding was higher in the ARC-HBR group than in the no ARC-HBR group at 1 year (1.3 vs. 0.6%) and at 5 years (2.0 vs. 0.7%). The Kaplan-Meier curves stratified by the Japanese-HBR criteria more prominently diverged (1.3 vs. 0.2% at 1 year; and 1.9 vs. 0.3% at 5 years). The Japanese-HBR criteria showed superior discriminative performance over the ARC-HBR criteria (C-statistics: 0.677 vs. 0.598, P 0.001).In the real-world Japanese AMI registry, nearly half of the patients fulfilled the criteria of ARC-HBR, and two-thirds met the Japanese-HBR. Our findings support the validity of both ARC- and Japanese-HBR criteria in AMI patients but encourage the future application of the Japanese-HBR criteria to the Japanese AMI cohort.UMIN000004575.

Introduction Heterozygous familial hypercholesterolemia (HeFH) exhibits substantially atherogenic substrate which involves coronary and peripheral arteries. Whether atherosclerosis in HeFH propagates to intracranial arteries causing stroke remains to be determined. Purpose To characterize intracranial artery stenosis (IAS) in subjects with HeFH. Methods 148 HeFH subjects who underwent MRI/MRA imaging to evaluate intracranial arteries were analyzed. IAS was defined as the presence of stenosis with its % diameter stenosis ≥25%. Clinical demographics and cardiovascular events (all-cause death, ACS, stroke and PAD) were compared in those with and without IAS. Results IAS was observed in 24.3% (=36/148) of study subjects. It was more frequently located at middle cerebral artery (30.6%=11/36), followed by internal carotid artery (25.0%=9/36). 47.2% of IAS exhibited % diameter stenosis ≥75%. Furthermore, 58.3% of HeFH patients with IAS exhibited concomitance of CAD, PAD or carotid stenosis. They were more likely to be older (Table). While there was no significant difference in LDL-C level, an elevated triglyceride level was observed in those with IAS (Table). Of note, during the observational period (median=14.1 years), IAS was associated with a greater likelihood of experiencing not only stroke but other cardiovascular events (all-cause death + ACS + PAD) (picture). Multivariate analysis demonstrated triglyceride level ≥1.7mmol/l as an independent predictor of IAS in HeFH patients (HR=5.53, 95% CI: 1.85–16.5, p=0.002). Conclusions Around one-fourth of HeFH patients harboured IAS, which was associated with concomitance of atherosclerosis in other vascular beds and the occurrence of stroke and other cardiovascular events. Given the relationship of IAS with hypertriglyceridemia, this lipid feature may be an important contributor to atherosclerotic formation which involves intracranial artery in HeFH patients. Clinical outcome Funding Acknowledgement Type of funding source: None

Introduction Lipoprotein (a) [Lp (a)] is a plasma lipoprotein which exhibits atherogenic properties. Lp(a) ≥50 mg/dl has been recently shown to associate with a risk of atherosclerotic cardiovascular diseases (ASCVD) in patients with heterozygous familial hypercholesterolemia (HeFH). While current guideline recommends lowering LDL-C as a first-line therapeutic approach in HeFH subjects, it remains to be fully determined whether an elevated level of Lp(a) confers additional ASCVD risks in HeFH patients who achieved a lower LDL-C level. Purpose To investigate cardiovascular outcomes in HeFH subjects with a lower LDL-C but an elevated Lp(a) levels. Methods 182 HeFH patients with on-treatment LDL-C Results The averaged LDL-C and Lp (a) levels were 1.9 mmol/l and 26.8 mg/dl, respectively. 19.2% of study subjects exhibited Lp(a)≥50 mg/dl. HeFH patients with Lp(a) ≥50 mg/dl were more likely to be older and have a history of hypertension, but these comparisons did not meet statistical significance. There was no significant difference in on-treatment LDL-C, HDL-C and Triglyceride level (Table). However, during the observational period (median=4.7 years), there was a 2.7-fold (95% CI, 1.41–5.02; p=0.004) greater likelihood of experiencing MACE in subjects with Lp(a) ≥50 mg/dl (picture). Even after adjusting clinical demographics, Lp(a) ≥50 mg/dl remained an independent predictor for the occurrence of MACE (hazard ratio=2.53, 95% CI: 1.29–4.82, p Conclusions Despite achieving on-treatment LDL-C Clinical outcome Funding Acknowledgement Type of funding source: None

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study (GWAS) of 168,228 Japanese (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,782 CAD cases and 3,148 controls. We detected 9 novel disease-susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a transethnic meta-analysis and discovered 37 additional novel loci. Using the result of the meta-analysis, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European GWAS. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improves clinical characterization of CAD genetics and suggests the utility of transethnic meta-analysis for PRS derivation in non-European populations.

BACKGROUND Anemia portends a poor clinical outcome in patients with chronic heart failure (CHF). However, its mechanism remains unknown. We sought to elucidate the effect of anemia on patients with HF with reduced ejection fraction (HFrEF) who receive carvedilol therapy.Methods and Results:J-CHF study was a prospective, randomized, multicenter trial that assigned 360 HFrEF patients to 2.5 mg/5 mg/20 mg carvedilol groups according to the target dose. At baseline 70 patients (19%) had anemia ([A]) defined as hemoglobin level (Hb)

BACKGROUND: Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy. METHODS: Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo. RESULTS: Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD. CONCLUSIONS: COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy. ispartof: Canadian Journal of Cardiology vol:33 issue:8 pages:1027-1035 ispartof: location:England status: published

Background Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. Methods The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. Results The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. Conclusions Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively.

Introduction The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia (FH)” as a FH phenotype with the highest cardiovascular risk. Coronary artery disease (CAD) represents a major atherosclerotic change in FH patients. Given their higher LDL-C level and atherogenic clinical features, more extensive formation of atherosclerosis cardiovascular disease including not only CAD but stroke/peripheral artery disease (PAD) may more frequently occur in severe FH. Methods 481 clinically-diagnosed heterozygous FH subjects were analyzed. Severe FH was defined as untreated LDL-C>10.3 mmol/l, LDL-C>8.0 mmol/l+ 1 high-risk feature, LDL-C>4.9 mmol/l + 2 high-risk features or presence of clinical ASCVD according to IAS proposed statement. Cardiac (cardiac death and ACS) and non-cardiac (stroke and peripheral artery disease) events were compared in severe and non-severe FH subjects. Results Severe FH was identified in 50.1% of study subjects. They exhibit increased levels of LDL-C and Lipoprotein (a) with a higher frequency of LDLR mutation. Furthermore, a proportion of %LDL-C reduction>50% was greater in severe FH under more lipid-lowering therapy (Table). However, during the observational period (median=6.3 years), severe FH was associated with a 5.9-fold (95% CI, 2.05–25.2; p=0.004) and 5.8-fold (95% CI, 2.02–24.7; p=0.004) greater likelihood of experiencing cardiac-death/ACS and stroke/PAD, respectively (picture). Multivariate analysis demonstrated severe FH as an independent predictor of both cardiac-death/ACS (hazard ratio=3.39, 95% CI=1.12–14.7, p=0.02) and stroke/PAD (hazard ratio=3.38, 95% CI=1.16–14.3, p=0.02) events. Clinical characteristics of severe FH Non-severe FH Severe FH P-value Baseline LDL-C (mmol/l) 5.3±1.5 6.6±2.0 50% 21.3% 49.8% Clinical outcome Conclusions Severe FH subjects exhibit substantial atherosclerotic risks for coronary, carotid and peripheral arteries despite lipid lowering therapy. Our finding underscore the screening of systemic arteries and the adoption of further stringent lipid management in severe FH patients.

In patients with ST-segment elevation myocardial infarction (STEMI), the association between stress-induced hyperglycemia (SIH) and long-term outcomes, as well as the effects of baseline diabetic status on this association remain elusive. To clarify the association between SIH and long-term outcomes, and the effects of baseline diabetic status on this association, we studied 6,287 STEMI patients who were discharged alive. SIH was estimated using the stress hyperglycemia ratio (SHR), which is defined as [(admission glucose (mg/dl))/(28.7 × HbA1c (%) − 46.7)]. End points were all-cause death and admission for heart failure (HF). We compared prognosis between patients in the highest SHR quartile and those in other quartiles of the nondiabetic and diabetic population. Over a follow-up of 5 years (median 1,522 days), 464 (7.4%) and 401 (6.4%) cases of all-cause death and HF admission were observed. In the nondiabetic population, the highest SHR quartile (Q4) group was significantly associated with worse long-term outcomes (adjusted hazard ratio [HR] (95% confidence interval [CI]), all-cause death; 1.45 (1.06 to 1.98), p = 0.021, HF admission; 1.48 (1.04 to 2.10), p = 0.031). However, in the diabetic population, SHR Q4 group was not significantly associated with worse long-term outcomes (adjusted HR (95% CI), all-cause death; 1.00 (0.68 - 1.48), p = 0.996, HF admission; 1.31 (0.90 to 1.89), p = 0.154). In conclusion, in STEMI patients discharged alive, high SHR was significantly associated with worse long-term prognosis in the nondiabetic population. In contrast, high SHR was not significantly associated with worse long-term prognosis in the diabetic population.

Nonvalvular atrial fibrillation (AF) is a risk factor for stroke in elderly patients. Although warfarin has been used to prevent AF-associated stroke for more than 50 years, non-vitamin K antagonist oral anticoagulants (NOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban recently have been developed to overcome the disadvantages of warfarin. Based on the results of NOAC clinical trials, Savelieva and Camm made recommendations regarding selection of NOACs in patients with nonvalvular AF. Recent accumulating evidence indicates that NOACs work differently in Asian and non-Asian individuals. In this review, we discuss the results of the large, randomized, phase 3 international clinical trials on NOACs, the subanalyses of Asians, and a Japanese phase 3 clinical trial of rivaroxaban to discriminate Japanese patient-specific characteristics with regard to their responses to NOACs and make recommendations. Our analysis revealed that rivaroxaban decreased the incidence of gastrointestinal (GI) bleeding compared with warfarin in Japanese patients. The efficacy results showed that rivaroxaban significantly decreased the incidence of ischemic stroke (hazard ratio: 0.40, 95% confidence interval: 0.17-0.96) compared with warfarin. The lower incidence of GI bleeding and ischemic stroke may be specific to Japanese patients. Based on the present and previous results, the following recommendations regarding the selection of NOACs are added in the Camm chart for Japanese patients: edoxaban for patients with a high risk of bleeding and those with a previous stroke; and rivaroxaban for patients with a high risk of ischemic stroke and a low bleeding risk, and those with previous GI bleeding.

Atrial fibrillation (AF) affects an estimated 1.5 million individuals in Japan, increasing their stroke risk and imposing considerable costs on the Japanese healthcare system. To reduce stroke incidence, guidelines recommend using anticoagulants in moderate-to-high risk non-valvular AF (NVAF) patients; however, many patients receive no treatment, aspirin only, or remain poorly-controlled on vitamin K antagonists (VKAs) due to high VKA discontinuation rates and non-adherence to guidelines. A prevalence-based Markov model was developed to estimate the clinical and budgetary impact of treating these patients with Xarelto(TM) (rivaroxaban, Bayer AG) in Japan.Population, baseline risk of events, and associated management costs were estimated using data from Japanese publications where available. Treatment efficacy and safety were derived from published data and the J-ROCKET AF trial. Drug and physician visit costs were based on data from the Ministry of Health, Labor, and Welfare, the J-ROCKET AF trial, and Japanese clinical guidelines.This model demonstrates that increased use of rivaroxaban in inadequately-managed NVAF patients could avoid 456 081 non-fatal ischemic strokes (IS) and 76 975 cardiovascular deaths over 10 years in Japan. This clinical benefit offsets the increased incidence of myocardial infarctions and anticoagulant-related bleeding. Decreased event costs could lead to a ¥188.4 billion decrease in net spending over the analysis time horizon.Introducing rivaroxaban may decrease the burden of NVAF in Japanese society. From a clinical perspective, the reduction in IS and embolic events outweighs the increased risk of anticoagulant-related bleeding; from an economic perspective, reduced event costs offset drug and physician visit costs, resulting in cost savings.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, pINTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.FUNDING: Bayer AG.

Background Autoantibody against β 1 -adrenergic receptors (β 1 -AAb) exerts agonist-like action inducing receptor uncoupling and myocardial damage. We attempted to determine the significance of β 1 -AAb in chronic heart failure (CHF) patients who received carvedilol in a substudy of the Japanese Chronic Heart Failure study. Methods and Results In this prospective, randomized, multicenter trial, 117 patients were assigned to 2.5 mg, 5 mg, and 20 mg (n = 38, 36, and 43) carvedilol groups according to the target dose. β 1 -AAb was positive in 51 patients (44%, P) and negative in 66 (56%, N). The percentage increase of left ventricular ejection fraction over 56 weeks (ΔLVEF) was larger in P than in N ( P = .050) and in the high-titer group (H) than in the low-titer group (L; P = .04). Left ventricular (LV) volume decreased to a greater extent in H than in L over 56 weeks. β 1 -AAb titer was significantly correlated with ΔLVEF and the percentage change of LV volume and was an independent predictor of them. No difference was seen in the composite end point (all-cause mortality and hospitalization for cardiovascular diseases or heart failure). However, in patients with dilated cardiomyopathy, it was more common in the 2.5 mg group than in the other groups in N, and it was similar among the 3 groups in P. Conclusions Our data suggest that the presence of β 1 -AAb is associated with favorable response to carvedilol in CHF.

Background In Asian patients in RE-LY, dabigatran etexilate (DE) was as effective as warfarin, with a significantly lower bleeding risk. We evaluated the relationship between baseline renal function or CHADS2 score and efficacy or safety outcomes in these patients. Methods and results Asian patients (n=2,782) were categorized according to baseline renal function or CHADS2 score, and efficacy and safety outcomes were analyzed for DE (110 mg and 150 mg b.i.d.) vs. warfarin. There was an increase in the rates of stroke/systemic embolism and major bleeding with worsening renal function and CHADS2 score. For stroke/systemic embolism (primary efficacy endpoint), there was no treatment interaction for dabigatran at either 110 or 150 mg b.i.d. compared with warfarin related to patients' baseline renal function (Pinteraction=0.56 for DE 110 mg and 0.62 for DE 150 mg vs. warfarin) or CHADS2 score (Pinteraction=0.68 for DE 110 mg and 0.31 for DE 150 mg vs. warfarin). For major bleeding, there was no treatment interaction by creatinine clearance category observed for either dose (Pinteraction=0.60 and 0.62 for DE 110 mg and DE 150 mg, respectively). Baseline CHADS2 score had no significant effect on bleeding event rates with DE vs. warfarin. Conclusions Bleeding and stroke rates in Asian patients varied according to renal function and CHADS2 score, but the relative benefits of DE over warfarin were preserved when analyzed by subcategories.

Cardiovascular complications, including heart failure, hypertension, ischemic syndromes and venous thromboembolism, have been identified in patients treated with anti-cancer drugs. Oxidative stress, mitochondrial dysfunction and DNA synthesis inhibition are considered to be responsible for the cardiotoxicity induced by these agents. Protein quality control (PQC) has 3 major components, including the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, and participates in protein folding and degradation to maintain protein homeostasis. We have demonstrated that PQC dysfunction is a new causal mechanism for the development of cardiac hypertrophy and failure. Increasing evidence shows that anti-cancer drugs, such as tyrosine kinase inhibitors, proteasome inhibitors, anthracyclines and autophagy inhibitors, cause PQC dysfunction. Here, we provide an overview of the potential role of PQC dysfunction in the development of cardiovascular complications induced by anti-cancer drugs.

Recent advances in laparoscopic surgical technology have made it possible to perform advanced high-level surgery, such as lymph node dissection for malignancy. Grasping the anatomy during such procedures is important for a safe operation. We have developed a new image information system that provides three-dimensional (3D) reconstructed CT images synchronized with the motion of the laparoscope. This study assesses this new navigation system.Enhanced CT using a custom-made software program can provide 3D angiography images reconstructed as a laparoscopic view. A motion sensor mounted on the laparoscope can detect the direction angle of the laparoscope. The real-time rendered 3D CT images are synchronized with the laparoscopic video images according to the motion of the scope. These 3D CT images are projected on another monitor close to the laparoscopic video monitor. Lymph node dissection can be performed with the help of the real-time navigation system that provides a detailed 3D view of the vasculature.Ten laparoscopic gastrectomies were performed using this navigation system. Real-time intraoperative navigation of the vasculature was available, allowing for an excellent surgical outcome. No complications occurred in this series.Our intraoperative navigation system allows for safe laparoscopic gastric lymph node dissection.

BackgroundThe Japanese Diastolic Heart Failure Study (J-DHF) has suggested beneficial effects of the standard-dose prescription of carvedilol in heart failure with preserved ejection fraction (HFPEF). However, it is unclear whether any risk factors modulate the effects of the standard-dose carvedilol.Methods and resultsData from 245 patients with HFPEF in J-DHF were evaluated. Decreased body mass index, diabetes mellitus, and left atrial (LA) dilatation were independent risk factors for both of the primary outcomes (cardiovascular death and unplanned hospitalization for heart failure) and another major composite outcome (cardiovascular death and unplanned hospitalization for any cardiovascular causes) in multivariable analysis. In patients with LA diameter≥the median value (43.2mm), standard-dose carvedilol was associated with unadjusted hazard ratio (HR) 0.263 [95% confidence interval (CI): 0.080–0.859] and covariate adjusted 0.264 (0.080–0.876) for the primary outcome. In those with LA diameter

Introduction Results from the multicenter trial (J-Land study) of landiolol versus digoxin in atrial fibrillation (AF) and atrial flutter (AFL) patients with left ventricular (LV) dysfunction revealed that landiolol was more effective for controlling rapid HR than digoxin. The subgroup analysis for patient characteristics was conducted to evaluate the impact on the efficacy and safety of landiolol compared with digoxin. Methods Two hundred patients with AF/AFL, heart rate (HR) ≥ 120 beats/min, and LV ejection fraction (LVEF) 25–50% were randomized to receive either landiolol (n = 93) or digoxin (n = 107). Successful HR control was defined as ≥20% reduction in HR together with HR

Background: The J-ROCKET AF study found that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcome in patients with atrial fibrillation (AF). The aim of this subgroup analysis was to assess the safety and efficacy of rivaroxaban and warfarin in relation to patient age. Methods and Results: A total of 39.0% were elderly (aged ≥75 years). In elderly patients, the principal safety outcome occurred at 25.05%/year with rivaroxaban vs. 16.95%/year on warfarin (hazard ratio [HR], 1.49; 95% confidence interval [CI]: 1.02–2.16), whereas the primary efficacy endpoint occurred at 2.18%/year vs. 4.25%/year (HR, 0.51; 95% CI: 0.20–1.27), respectively. There were significant interactions in the principal safety outcomes of rivaroxaban compared with warfarin between the elderly and non-elderly groups, but not in the primary efficacy endpoints (P=0.04 and 0.82 for both interactions, respectively). Furthermore, in elderly patients, in the rivaroxaban group there was a trend to increase the principal safety outcome regardless of renal function. In elderly patients with preserved renal function, however, patients on rivaroxaban had a marginally favorable trend in the primary efficacy endpoint incidence rate compared with patients on warfarin. Conclusions: There is a need to carefully consider the risks and benefits of therapy with rivaroxaban in elderly patients with non-valvular AF. (Circ J 2014; 78: 1349–1356)

This study sought to evaluate whether genetic variants in the renin-angiotensin-aldosterone system (RAAS) have an impact on long-term mortality after acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era. We investigated the impacts of individual and combinations of 4 major RAAS genetic variants, angiotensinogen (AGT) T1311C, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensin 2 type 1 receptor A1166C, and aldosterone synthase T4660C on 5-year mortality in 3149 post-AMI patients using multivariate Cox regression analysis. The predictive accuracy of all possible RAAS genetic combinations was evaluated using Cox regression analysis, and the best combination that affected prognosis was determined based on the minimal Akaike Information Criterion. There were 220 deaths during a median follow-up of 4.9 years. Independent analyses of any single RAAS variant did not show signifi cant impacts on 5-year mortality. However, analyses in combination revealed that absence of both AGT CC genotype and ACE D allele was associated with lower 5-year mortality (log-rank P = 0.005). Patients with at least either of the AGT CC or ACE D allele had increased mortality with adjusted hazard ratios of 2.07 (95% confi dence interval 1.18-3.65, P = 0.012), compared with those with neither the AGT CC nor ACE D allele. Among the 4 RAAS genetic variants examined, a combination of AGT and ACE polymorphisms was associated with 5-year mortality after AMI.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.

To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia.In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol.A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs. 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p0.001). Treatment with esomeprazole was generally well tolerated.Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection.NCT01069939.

Background and Purpose— Intracranial hemorrhage rates are higher in Asians than non-Asians, especially in patients receiving warfarin. This randomized evaluation of long-term anticoagulation therapy subgroup analysis assessed dabigatran etexilate (DE) and warfarin effects on stroke and bleeding rates in patients from Asian and non-Asian countries. Methods— There were 2782 patients (15%) from 10 Asian countries and 15 331 patients from 34 non-Asian countries. A Cox regression model, with terms for treatment, region, and their interaction was used. Results— Rates of stroke or systemic embolism in Asians were 3.06% per year on warfarin, 2.50% per year on DE 110 mg BID (DE 110), and 1.39% per year on DE 150 mg BID (DE 150); in non-Asians, the rates were 1.48%, 1.37%, and 1.06% per year with no significant treatment-by-region interactions. Hemorrhagic stroke on warfarin occurred more often in Asians than non-Asians (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3–4.7; P =0.007), with significant reductions for DE compared with warfarin in both Asian (DE 110 versus warfarin HR, 0.15; 95% CI, 0.03–0.66 and DE 150 versus warfarin HR, 0.22; 95% CI, 0.06–0.77) and non-Asian (DE 110 versus warfarin HR, 0.37; 95% CI, 0.19–0.72 and DE 150 versus warfarin HR, 0.28; 95% CI, 0.13–0.58) patients. Major bleeding rates in Asians were significantly lower on DE (both doses) than warfarin (warfarin 3.82% per year, DE 110 2.22% per year, and DE 150 2.17% per year). Conclusions— Hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians, despite similar blood pressure, younger age, and lower international normalized ratio values. Hemorrhagic strokes were significantly reduced by DE in both Asians and non-Asians. DE benefits were consistent across Asian and non-Asian subgroups. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Although clinical guidelines recommend long-term β-blocker (BB) therapy to decrease mortality after acute myocardial infarction, these recommendations are based predominantly on evidence from before the reperfusion and thrombolytic eras. To investigate the effects of BB therapy for patients with acute myocardial infarctions on mortality in the percutaneous coronary intervention era, a total of 5,628 consecutive patients who were admitted

Background: In the percutaneous coronary intervention (PCI) era, little evidence exists regarding the incidence, predictors and long-term mortality of recurrent myocardial infarction (Re-MI) following discharge for acute myocardial infarction (AMI). Methods and Results: A total of 7,870 patients who survived AMI were studied with a median follow-up period of 3.9 years: 353 patients (4.5%) experienced Re-MI, with 7 of those dying within 30 days, which was classified as fatal Re-MI. The incidence of Re-MI per year was 2.65% for the first year, and 0.91–1.42% thereafter up to 5 years. Multivariate Cox regression analyses revealed that predictors of Re-MI were diabetes mellitus (hazard ratio (HR): 2.079, P

Aims The therapeutic strategy for heart failure with preserved ejection fraction (HFPEF) has not been established. The Japanese Diastolic Heart Failure Study (J-DHF) is a multicentre, prospective, randomized, open, blinded-endpoint trial, designed to assess the effects of carvedilol in HFPEF patients. Methods and results A total of 245 patients with heart failure and ejection fraction >40% were randomly assigned into those treated with (carvedilol group, n = 120) and without carvedilol (control group, n = 125). The primary outcome is a composite of cardiovascular death and unplanned hospitalization for heart failure. During a median follow-up of 3.2 years, the primary endpoint occurred in 29 patients in the carvedilol group and in 34 patients in the control group [adjusted hazard ratio (HR) 0.902, 95% confidence interval (CI) 0.546–1.488, P = 0.6854]. Another major composite endpoint, cardiovascular death and unplanned hospitalization for any cardiovascular causes, occurred in 38 patients of the carvedilol group and 52 patients of the control group (HR 0.768, 95% CI 0.504–1.169; P = 0.2178). The target dose of carvedilol was 20 mg/day, but the median prescribed dose was 7.5 mg/day. In the patients treated with standard doses (carvedilol >7.5 mg/day, n = 58), this composite outcome was significantly less than in the controls (HR 0.539, 95% CI 0.303–0.959; P = 0.0356), whereas it was comparable with the controls in the patients treated with carvedilol ≤7.5 mg/day (n = 62, HR 1.070, 95% CI 0.650–1.763; P = 0.7893). Conclusions Carvedilol did not improve prognosis of HFPEF patients overall; however, the standard dose, not the low dose, prescription might be effective. This may facilitate further investigation. UMIN number: C000000318.

Background: A rapid heart rate (HR) during atrial fibrillation (AF) and atrial flutter (AFL) in left ventricular (LV) dysfunction often impairs cardiac performance. The J-Land study was conducted to compare the efficacy and safety of landiolol, an ultra-short-acting β-blocker, with those of digoxin for swift control of tachycardia in AF/AFL in patients with LV dysfunction. Methods and Results: The 200 patients with AF/AFL, HR ≥120beats/min, and LV ejection fraction 25–50% were randomized to receive either landiolol (n=93) or digoxin (n=107). Successful HR control was defined as ≥20% reduction in HR together with HR