Search

Objectives The aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting. Background Of 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment. Methods The benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment. Results Efficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097). Conclusions In patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612 , NCT02642419 )

Objectives Hyperuricaemia is recognized as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes is unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia. Methods This was a post hoc analysis of a randomized trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the endpoint (withdrawal or study completion) SUA levels and clinical outcomes. Primary endpoint was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events. Results In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% CI: 1.05, 3.87]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >5 to ≤6 mg/dl (P = 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (P = 0.007 [Gray’s test]) and was not significant in the non-febuxostat treatment group (P = 0.212 [log-rank test]). Conclusion Optimal SUA level by febuxostat treatment is 5–6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations. Trial Registration ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749

ObjectivePatients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y12 inhibitors and aspirin in patients also receiving anticoagulant therapy.MethodsWe evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician’s discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y12 inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria.ResultsA total of 1075 patients were included (P2Y12 inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456).ConclusionsThere were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y12 inhibitors or aspirin in the chronic phase.Trial registration numberUMIN000016612; NCT02642419.

Background In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. Methods In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. Results Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. Conclusions The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. Clinical Trial Registration UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.

Aim: Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM. Methods: The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9–12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL. Results: In DM patients, the monotherapy group (n = 13) and the DLLT group (n = 12) showed a similar prevalence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: −2.77 ± 3.47% vs. −0.77 ± 2.51%, P = 0.11; non-DM: −2.01 ± 3.36% vs. −0.08 ± 2.66%, P = 0.008). The change in LDL-C level was not correlated with ΔPAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r = 0.52, P = 0.008). Conclusions: ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.

To evaluate whether combinatorial use of abatacept (ABT) and tacrolimus (Tac) increases the risk of adverse events compared to their individual use in Japanese rheumatoid arthritis (RA) patients. We conducted a retrospective cohort study of RA patients using the Japanese multicenter database and analyzed the data of RA patients registered from April 2010 to March 2019 by comparing three treatment groups who received Tac, ABT, or a combination of both. We included patients who had initiated treatment with ABT or Tac and excluded patients who used tumor necrosis factor inhibitors, IL-6 inhibitors, and Jak inhibitors in the first year of our study. The primary outcome was the occurrence of adverse events such as infections that required hospitalization, newly diagnosed malignancy, or death from any cause after initiation of ABT or Tac. Of the 27,032 RA patients in the registry, 2009 patients were included. The Tac, ABT, and combination groups consisted of 1328, 563, and 118 patients, respectively. Primary outcome occurred in 149 (13.4%), 62 (13.5%), and 14 (13.9%) patients of the Tac, ABT, and combination groups, respectively. The incidence of adverse events between groups was not significantly different (p = 0.638). A Cox regression analysis which was adjusted for potential confounders such as age, disease activity, and concomitant use of prednisolone revealed no significant differences between groups. The combinatorial use of ABT and Tac, or ABT alone does not increase the risk of adverse events when compared to the use of Tac alone in RA patients in Japan. Key Points • This study included Japanese rheumatoid arthritis data and found that there was no significant risk when patients were treated with a combination of Tac and ABT or each drug alone.

To test our hypothesis that the magnitude of reduction in hsCRP achieved by antihypertensive medications may predict the benefit for cardiovascular outcomes in hypertensive individuals, we performed subanalysis of the ATTEMPT-CVD study. The hypertensive participants enrolled in the ATTMEPT-CVD study were categorized into two groups according to whether achieved reduction in hsCRP levels at 6 months after initiation of antihypertensive medications from baseline was equal to or greater than 40% (responder group) or less than 40% (non-responder group). Baseline characteristics and blood pressure during follow-up period were similar between the groups. For women, the incidence of cardiovascular events was significantly less in responder group than non-responder group (P This trial was registered with ClinicalTrials.gov, number NCT01075698.

New/worsening cognitive and physical impairments following critical care pose significant problems. Multidisciplinary cardiac rehabilitation (CR) can improve physical function after cardiac intensive care (CIC). This observational study aimed to evaluate cognitive function in patients participating in multidisciplinary CR and to identify correlates of impaired cognitive function after CIC. We analyzed 111 consecutive patients admitted to our comprehensive care ward at least 7 days after CIC and assessed factors associated with cognitive function using the Functional Independence Measure (FIM). Patients were stratified into two groups based on the median FIM-Cognitive scores: impaired (n = 56) and preserved cognition (n = 55) groups. Multiple logistic regression analysis identified age [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.00–1.13; p = 0.042], Mini-Nutrition Assessment-Short Form (MNA-SF; OR 0.73; 95% CI 0.56–0.95; p = 0.017), and FIM-Physical scores (OR: 0.94; 95% CI 0.90–0.99; p = 0.012) as significant and independent factors associated with impaired cognition. The median length of hospital stay was 28 (interquartile range: 18, 43) days. The FIM-Cognitive and FIM-Physical scores significantly increased from admission to discharge [32.0 (27.0, 35.0) vs. 34.0 (29.0, 35.0) points; p

AIMS The prediction of future heart failure (HF) in stable outpatients is often difficult for general practitioners and cardiologists. Recently, the H2 FPEF score (0-9 points) has been proposed for the discrimination of HF with preserved ejection fraction from non-cardiac causes of dyspnoea. The six clinical and echocardiographic variables that constitute the H2 FPEF score include the following: (i) obesity (H); (ii) the use of ≥2 antihypertensive drugs (H); (iii) atrial fibrillation (F); (iv) pulmonary hypertension (P); (v) an age > 60 years (E); and (vi) E/e' > 9 (F). We performed an external validation study that investigated whether the H2 FPEF score could predict future HF-related events in stable outpatients with cardiovascular risk factor(s) in Japan. METHODS AND RESULTS In this prospective cohort study, after exclusion of 195 from 551 consecutive, stable Japanese outpatients with at least one cardiovascular risk factor who were enrolled between September 2010 and July 2013, the remaining 356 outpatients (171 men, 185 women, mean age 73.2 years) were eligible for the analysis. We calculated the H2 FPEF score (0-9 points), and followed up the patients for an average of 517 days. In all of the 356 patients, the mean H2 FPEF score was 3.1 ± 1.8, and 15 developed HF-related events during the follow-up period, including cardiovascular death (n = 2) and hospitalization for HF decompensation (n = 13). Multivariate Cox proportional hazards analysis showed that the H2 FPEF score was an independent predictor of future HF-related events (P < 0.001 for all three models). Kaplan-Meier survival curves showed a significantly higher probability of HF-related events in the outpatients with a high H2 FPEF score (P < 0.001). In receiver operating characteristic (ROC) curve analysis, the H2 FPEF score was significantly associated with the occurrence of future HF-related events (P < 0.001). In ROC curve analysis, the sensitivity, specificity, and positive likelihood ratio of a H2 FPEF score of 7 points to predict HF-related events were 47%, 96%, and 11.4%, respectively. CONCLUSIONS The H2 FPEF score could provide useful information for future HF-related events in stable outpatients with cardiovascular risk factor(s) in Japan.

Background Among patients with atrial fibrillation and stable coronary artery disease, those with histories of atherothrombotic disease are at high‐risk for future ischemic events. This study investigated the efficacy and safety of rivaroxaban monotherapy in patients with atrial fibrillation, coronary artery disease, and histories of atherothrombotic disease. Methods and Results This was a post hoc subanalysis of the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial. Patients with non‐valvular atrial fibrillation and coronary artery disease were recruited and randomized to receive the rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. For the purpose of this sub‐study, participants were divided into 2 subgroups, including the atherothrombosis group (those with histories of myocardial infarction, stroke, and/or peripheral artery disease; n=1052, 47.5%) and non‐atherothrombosis group (n=1163, 52.5%). The efficacy end point included cardiovascular events or all‐cause death, while the safety end point was major bleeding. Net adverse events consisted of all‐cause death, myocardial infarction, stroke, or major bleeding. In the atherothrombosis group, rivaroxaban monotherapy was significantly associated with a lower risk of net adverse events when compared with combination therapy (hazard ratio [HR], 0.50; 95% CI, 0.34–0.74; P P =0.044) and safety (HR, 0.37; 95% CI, 0.19–0.71; P =0.003) end points. By contrast, there were no differences between treatment outcomes for the non‐atherothrombosis group. Conclusions Rivaroxaban monotherapy significantly reduced net adverse events as compared with combination therapy for patients with atrial fibrillation, coronary artery disease, and prior atherothrombotic disease. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000016612. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02642419.

Background: Early bleeding after percutaneous coronary intervention is associated with increased risk of death and myocardial infarction; however, the association between bleeding and subsequent major adverse cardiac and cerebrovascular events (MACCE) remains unclear in patients with atrial fibrillation and stable coronary artery disease. We thus aimed to investigate this association. Methods: The AFIRE trial (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) was a multicenter, open-label trial conducted in Japan. This post hoc analysis included 2215 patients with atrial fibrillation and stable coronary artery disease treated with rivaroxaban or rivaroxaban plus an antiplatelet agent. MACCE was defined as a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. The association of bleeding with subsequent MACCE risk was investigated using time-adjusted Cox multivariate analysis after adjusting for baseline characteristics and time from bleeding. Bleeding events were classified according to the International Society on Thrombosis and Haemostasis criteria. Results: Among the 2215 patients, 386 (17.4%) had bleeding during follow-up, of whom 63 (16.3%) also experienced MACCE; MACCE incidence was higher in patients with bleeding than in those without (8.38% versus 4.20% per patient-year; hazard ratio, 2.01 [95% CI, 1.49–2.70]; P Conclusions: In patients with atrial fibrillation and stable coronary artery disease, major bleeding was strongly associated with subsequent MACCE. Thus, it is important to prevent major bleeding to avoid cardiovascular events and death. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000016612. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02642419. Graphic Abstract: A graphic abstract is available for this article.

Aims To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. Methods and results This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat (n = 537) and non-febuxostat groups (n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively (P Conclusion Febuxostat lowers uric acid and delays the progression of renal dysfunction. Registration ClinicalTrials.gov (NCT01984749).

AIM Whether young cervical cancer patients have poorer prognosis compared to older ones has remained controversial over the past half century. The last three decades have seen a rise in morbidity and mortality among young Japanese women with cervical cancer. This reflects the fact that the importance of prevention has not been fully recognized due to limited clinical studies. We examined the relationship between age and prognosis in cervical cancer. METHODS We retrospectively examined medical records of consecutive patients with International Federation of Gynecology and Obstetrics stage IB and IIB cervical cancer at a hospital in Japan. Patients were divided into two age groups: less than or equal to 39 years (adolescent and young adult [AYA] group) and greater than or equal to 40 years (older adult group). We compared prognosis and clinical factors associated with prognosis between AYA and older adult patients. RESULTS Data from 182 patients (AYA n = 71; older adults n = 111) treated between 2004 and 2011 were analyzed. The proportion of loss to follow-up was 6.0%. Significant differences were observed in stage and lymph node metastasis between the two groups at baseline. However, despite the older adult group having a higher proportion of advanced cancer patients, the overall survival rate of stage IIB patients in the AYA group at the 3-year follow-up was significantly lower (AYA 53.6%, older adults 86.3%, P < 0.05). Multivariate analysis adjusted for clinical factors revealed that AYA patients had a 3.7-3.9 times greater mortality risk compared to older adults. CONCLUSION AYA patients with stage IB and IIB cervical cancer may have a prognostic disadvantage.

Exposure to ambient air pollution increases mortality and is a leading contributor to the global disease burden [1]. Epidemiological studies have elucidated a relationship between out-of-hospital cardiac arrests (OHCAs) and air pollutants, especially particulate matter (diameter ≤2.5 μm; PM2.5) [2, 3]. The causes of OHCA are broadly categorised as cardiac and non-cardiac [4]. A 10 µg·m−3 increase in PM2.5 exposure yielded a 1.6% increase in the incidence of cardiac origin OHCA [3, 5]. However, few studies on OHCAs of non-cardiac origin, including intrinsic respiratory diseases (COPD/pneumonia/asthma) are available. We examined the association between short-term exposure to PM2.5 and bystander-witnessed respiratory origin OHCAs, including eventual prognosis. We also investigated differences between PM2.5 exposure-related cardiac and respiratory origin OHCAs., Particulate matter is a potential risk factor for out-of-hospital cardiac arrests (OHCAs) of respiratory origin. The percent increase in incidence of OHCA of respiratory origin is equivalent to that of PM2.5 exposure-related OHCAs of cardiac origin. http://bit.ly/3tDXym0

BACKGROUND Direct oral anticoagulants have become a standard therapy for non-valvular atrial fibrillation (NVAF). However, little is known about their effectiveness/safety when prescribed by general practitioners to treat high-risk populations such as the elderly, those who are frail or have cognitive dysfunction.Methods and Results:In this multicenter, prospective study, a total of 5,717 NVAF patients (mean age 73.9 years) receiving rivaroxaban were registered by general practitioners, with a maximum 3-year follow up (mean 2.0±0.5 years). The primary endpoint was a composite of stroke and systemic embolism (SE). The annual incidence (per 100 person-years) of stroke/SE was 1.23% and for major bleeding, it was 0.63%. Multivariate analyses identified age ≥75 years (hazard ratio [HR]; 2.67, P

We previously reported on the FREED study, which found that febuxostat reduced the risk of adverse clinical outcome in patients with asymptomatic hyperuricemia without gout. We have now investigated outcomes in subgroups of FREED patients with and without a history of cardiovascular disease (CVD).We performed a post hoc subgroup analysis of 1070 patients randomized to the febuxostat or non-febuxostat group and followed for 36 months.At baseline, 234 patients (21.9%) had a history of CVD, including 86 patients with stroke (36.8%), 90 with coronary artery disease (38.5%), 74 with heart failure (31.6%), and 25 with vascular disease (10.7%). The risk for the primary composite endpoint, i.e., cerebral, cardiovascular, and renal events and all deaths, was higher in patients with CVD than in those without CVD (34.2% vs 23.7%; p 0.001). Treatment with febuxostat lowered rates of the primary composite endpoint in patients with CVD (hazard ratio [HR] 0.601, 95% CI 0.384 to 0.940, p = 0.026), and these effects were consistently observed in subgroups with and without CVD (p = 0.227 for treatment by subgroup interaction). Furthermore, in the subgroup with CVD, all-cause mortality was significantly lower in the febuxostat group than in the non-febuxostat group (HR 0.160, 95% CI 0.047 to 0.547, p = 0.004), with a significant subgroup interaction (p = 0.007 for treatment by subgroup interaction).In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of the composite of cerebral, cardiovascular, and renal events and death in the secondary prevention setting.

This case-control study assesses exposure to ambient air pollution, presenting cardiac arrest rhythms, initial resuscitation efforts, and patient and onset factors in individuals who experienced out-of-hospital cardiac arrests in Japan., Key Points Question What is the association of short-term exposure to fine particulate matter (with a diameter of ≤2.5 μm [PM2.5]) with bystander-witnessed out-of-hospital cardiac arrests of cardiac origin and with the development of initial cardiac arrest rhythm? Findings In this case-control study of 103 189 bystander-witnessed out-of-hospital cardiac arrests, every 10 μg/m3 increase in PM2.5 levels was associated with a 1.6% increase in out-of-hospital cardiac arrests and with a 1.4% increase in out-of-hospital cardiac arrests initially presenting with a nonshockable rhythm. Meaning Results of this study support the implementation of measures to reduce PM2.5 exposure for the prevention of out-of-hospital cardiac arrests of cardiac origin., Importance Out-of-hospital cardiac arrests (OHCAs) are a major public health concern and a leading cause of death worldwide. Exposure to ambient air pollution is associated with increases in morbidity and mortality and has been recognized as a leading contributor to global disease burden. Objective To examine the association between short-term exposure to particulate matter with a diameter of 2.5 μm or smaller (PM2.5) and the incidence of OHCAs of cardiac origin and with the development of initial cardiac arrest rhythm. Design, Setting, and Participants This case-control study used data from cases registered between January 1, 2005, and December 31, 2016, in the All-Japan Utstein Registry, a prospective, nationwide, population-based database for OHCAs across all 47 Japanese prefectures. These OHCA cases included patients who had bystander-witnessed OHCAs and for whom emergency medical services responders initiated resuscitation before hospital transfer. A case-crossover design was employed for the study analyses. A prefecture-specific, conditional logistic regression model to estimate odds ratios was applied, and a random-effects meta-analysis was used to obtain prefecture-specific pooled estimates. All analyses were performed from May 7, 2019, to January 23, 2020. Main Outcomes and Measures The main outcome was the association of short-term PM2.5 exposure with the incidence of bystander-witnessed OHCAs of cardiac origin. The differences in the distribution of initial cardiac arrest rhythm in OHCAs among those with exposure to PM2.5 were also examined. Results In total, 103 189 OHCAs witnessed by bystanders were included in the final analysis. Among the patients who experienced such OHCAs, the mean (SD) age was 75 (15.5) years, and 62 795 (60.9%) were men. Point estimates of the percentage increase for a 10-μg/m3 increase in PM2.5 at lag0-1 (difference in mean PM2.5 concentrations measured on the case day and 1 day before) demonstrated a statistically significantly higher incidence of OHCA across most of the 47 prefectures, without significant heterogeneity (I2 = 20.1%; P = .12). A stratified analysis found an association between PM2.5 exposure and OHCAs (% increase, 1.6; 95% CI, 0.1%-3.1%). An initial shockable rhythm, such as ventricular fibrillation or pulseless ventricular tachycardia (% increase, 0.6; 95% CI, –2.0% to 3.2%), was not associated with PM2.5 exposure. However, an initial nonshockable rhythm, such as pulseless electrical activity and asystole, was associated with PM2.5 exposure (% increase, 1.4; 95% CI, 0.1%-2.7%). Conclusions and Relevance Findings from this study suggest that increased PM2.5 concentration is associated with bystander-witnessed OHCA of cardiac origin that commonly presents with nonshockable rhythm. The results support measures to reduce PM2.5 exposure to prevent OHCAs of cardiac origin.

Chronic kidney disease (CKD) deteriorates the prognosis of patients undergoing percutaneous coronary intervention (PCI). Because coronary artery disease (CAD) is the major cause of death in CKD patients, cardiovascular risk reduction has been clinically important in CKD. We hypothesized intensive lipid-lowering with statin/ezetimibe attenuated coronary atherosclerotic development even in patients with CKD.In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound (IVUS)-guided PCI were randomly assigned to receive atorvastatin/ezetimibe combination or atorvastatin alone (the dosage of atorvastatin was up-titrated to achieve the level of low-density lipoprotein cholesterol 70 mg/dL). Serial volumetric IVUS findings obtained at baseline and 9-12 month follow-up to quantify the coronary plaque response in 202 patients were compared stratified by the presence or absence of CKD.CKD was observed in 52 patients (26%) among 202 enrolled patients. Compared with the non-CKD group, the CKD group was significantly older (71.5 ± 8.6 years vs. 64.4 ± 9.6 years, P 0.001) with similar prevalence of comorbid coronary risk factors and lipid profiles. Similar to the non-CKD group (-1.4 [-2.8 to -0.1]% vs. -0.2 [-1.7 to 1.0]%, P = 0.002), the atorvastatin/ezetimibe combination significantly reduced ∆PAV compared with atorvastatin alone even in the CKD group (-2.6 [-5.6 to -0.4]% vs. -0.9 [-2.4 to 0.2]%, P = 0.04).As with non-CKD, intensive lipid-lowering therapy with atorvastatin/ezetimibe demonstrated stronger coronary plaque regression effect even in patients with CKD compared with atorvastatin monotherapy.NCT01043380 (ClinicalTrials.gov).

Background and aims We aimed to examine the effect of serum sitosterol, a cholesterol absorption marker, on clinical outcomes in acute coronary syndrome patients with dyslipidaemia. Methods This is a sub-analysis of the HIJ-PROPER trial that assesses the effect of aggressive low-density lipoprotein cholesterol (LDL-C) lowering treatment with pitavastatin + ezetimibe in 1734 acute coronary syndrome (ACS) patients with dyslipidaemia. Patients were divided into two groups based on sitosterol level at enrolment (cut-off value was 2.2 μg/mL; a median of baseline sitosterol level), and clinical outcomes were examined. Results The mean LDL-C level after 3 years in the low sitosterol group was 84.8 ± 20.1 mg/dL with pitavastatin-monotherapy and 64.6 ± 20.3 mg/dL with pitavastatin + ezetimibe, while corresponding values in the high sitosterol group were 91.0 ± 22.9 mg/dL and 71.1 ± 23.3 mg/dL, respectively. In the high sitosterol group, the Kaplan-Meier event rate for the primary endpoint at 3 years was 26.0% in the pitavastatin + ezetimibe group, as compared with 34.3% in the pitavastatin-monotherapy group (hazard ratio, 0.71; 95% confidence interval, 0.56–0.91; p = 0.006, p-value for interaction = 0.010). However, in the low sitosterol group, there was no significant reduction of the primary endpoint by pitavastatin + ezetimibe therapy. Conclusions Aggressive lipid-lowering treatment with ezetimibe had a positive effect on clinical outcomes in the high sitosterol subset of ACS patients with dyslipidaemia, but not in the low sitosterol subset. This effect was independent of LDL-C reduction and suggests that sitosterol measurement on admission in ACS patients might contribute to a “personalised” lipid-lowering approach.

There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease.In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority.The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority).As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).

Background and Purpose— Renal denervation (RD) may protect against cardiovascular diseases regardless of blood pressure (BP)–lowering effect. We hypothesized that RD can improve the outcome of acute ischemic stroke (AIS) in hypertensive rats. Methods— An AIS model of spontaneously hypertensive stroke-prone rats (SHRSPs) was prepared by 90-minute middle cerebral artery occlusion followed by reperfusion. At 30 minutes poststroke, the SHRSPs were subjected to (1) sham operation or (2) RD to determine the beneficial effects of RD posttreatment. In addition, we evaluated the neuroprotective effects of RD posttreatment in Wistar Kyoto rats and RD pretreatment in SHRSPs with AIS. Results— RD significantly ameliorated neurological deficit and infarct volume at 1 and 7 days after middle cerebral artery occlusion. RD immediately and continuously normalized elevated BP during 24 hours. This normalization of BP by RD was associated with the reduction of cerebral blood flow during both middle cerebral artery occlusion and reperfusion periods. Thus, RD-induced BP normalization seems to ameliorate cerebrovascular overperfusion in SHRSPs with AIS. On the contrary, RD did not affect cerebral vascular resistance or cerebral vasoreactivity and did not increase Akt and endothelial NO synthase phosphorylation, thereby indicating no apparent change of cerebrovascular function. RD significantly attenuated cerebral oxidative stress as estimated by dihydroethidium staining and gp91 phox expression. The beneficial effects were not seen in Wistar Kyoto rats, whereas RD pretreatment improved neurological function in SHRSPs. Conclusions— RD posttreatment improved outcome in the hypertensive AIS rat model. Therefore, we suggest that BP normalization by RD may be a promising therapeutic strategy for AIS.

Aims To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L). Methods and results The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C

Background Rivaroxaban, a direct oral anticoagulant (DOAC), has become available for stroke prevention in patients with non-valular atrial fibrillation (NVAF). However, little is known about its effectiveness and safety when prescribed by general practitioners in real-life settings. Methods GENERAL is a multicenter, prospective, non-interventional observational study of patients receiving rivaroxaban for NVAF in daily clinical practice prescribed specifically by general practitioners. The target number of participating medical institutions is 500–700 clinics with fewer than 20 beds and the target number of participants is 5000. The baseline clinical data, including antidementia medication and frailty, and follow-up data including concomitant treatment and outcomes until September 2018 (maximum three years) will be collected. The primary efficacy endpoints will be stroke and/or systemic embolism and the secondary endpoints will be major bleeding meeting the ISTH guidelines, non-major and clinically relevant bleeding, onset of symptomatic stroke (ischemic/hemorrhagic), systemic embolism, deep vein thrombosis/pulmonary thromboembolism, myocardial infarction and/or cardiovascular death, and systemic embolism. Based on the provided information, the event assessment committee will investigate the endpoint-related events. The annual incidence and predictive factors for primary/secondary endpoint will be investigated based on underlying disease, age, renal function, and CHADS 2 , CHA 2 DS 2 -VASC, and HAS-BLED scores using Cox regression. We will also compare the incidence of the primary/secondary endpoint between the present study, EXPAND study, and FUSHIMI AF registry study. Results The results of this study are currently under investigation. Conclusion This study will provide important information regarding the effectiveness and safety of rivaroxaban treatment in Japanese patients with NVAF among general practitioners.

The predictive value of serum adiponectin for hypertensive cardiovascular outcomes is unknown. This study was performed to investigate the association of adiponectin with incident cardiovascular and renal events (CV events) in hypertensive patients. We performed post-hoc analysis on 1,228 hypertensive patients enrolled in the ATTEMPT-CVD study, a prospective randomized study comparing the effects of two antihypertensive therapies. The participants were divided into quartiles of baseline serum total adiponectin or high molecular weight (HMW) adiponectin. Multivariable Cox proportional hazards analysis was performed to determine the prognostic factors associated with CV events. Kaplan-Meier analysis for CV events by quartiles of baseline total adiponectin showed that patients in the highest total adiponectin quartile (Q4) had more CV events (P = 0.0135). On the other hand, no significant difference was noted regarding the incidence of CV events among patients stratified by HMW adiponectin quartile (P = 0.2551). Even after adjustment for potential confounders, the highest total adiponectin quartile (Q4) remained independently associated with incident CV events in hypertensive patients (HR = 1.949: 95%CI 1.051–3.612; P = 0.0341). These results showed that total adiponectin, but not HMW adiponectin, was independently associated with the incidence of CV events in treated hypertensive patients, thereby highlighting total adiponectin as a valuable predictor for hypertensive cardiovascular outcomes.

Supplemental Digital Content is available in the text, Although attention has been paid to the relationship between malignant diseases and cardiovascular diseases, few data have been reported. Moreover, there have also been few reports in which the preventive factors were examined in patients with or without malignant disease histories requiring percutaneous coronary intervention (PCI). This was a retrospective, single-center, observational study. A total of 1003 post-PCI patients were divided into a malignant group, with current or past malignant disease, and a nonmalignant group. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, revascularization, and admission due to heart failure within 5 years of PCI. Kaplan–Meier analysis showed a significantly higher probability of the primary endpoint in the malignant group (P = .002). Multivariable Cox hazard analyses showed that in patients without a history of malignant, body mass index (BMI) and the presence of dyslipidemia were independent and significant negative predictors of the primary endpoint (BMI: hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.53–0.99, P = .041; prevalence of dyslipidemia: HR 0.72, 95% CI 0.52–0.99, P = .048), and the presence of multi-vessel disease (MVD) and the prevalence of peripheral artery disease (PAD) were independent and significant positive predictors of the primary endpoint (prevalence of MVD: HR 1.68, 95% CI 1.18–2.40, P = .004; prevalence of PAD: HR 1.51, 95% CI 1.03–2.21, P = .034). In patients with histories of malignancy, no significant independent predictive factors were identified. Patients undergoing PCI with malignancy had significantly higher rates of adverse cardiovascular events but might not have the conventional prognostic factors.

Increasing attention is being paid to the relationship between cancer and cardiovascular diseases. In this study, we examined arterial stenosis and stiffness in patients with malignant diseases requiring percutaneous coronary intervention.This was a retrospective, single-center, observational study. Participants (n = 1003) were divided into a malignant group, with current or past malignant disease, and a nonmalignant group. The ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) were evaluated. The endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, and revascularization within 1 year.We observed significantly impaired ABI and baPWV in the malignant group. A total of 148 patients had a cardiovascular event. Kaplan-Meier analysis showed a significantly higher probability of cardiovascular events in the malignant group (P = 0.012). The combination of malignancy with ABI/baPWV identified subgroups with significantly different probabilities of cardiovascular events. Multivariate Cox hazard analysis identified malignancy as an independent predictor of cardiovascular events (hazard ratio, 1.54; 95% confidence interval, 1.06-2.26; P = 0.025) with an increased hazard ratio by adding the status of low ABI/high baPWV to malignancy (hazard ratio, 2.36; 95% confidence interval, 1.35-4.12; P = 0.003). We found significantly higher follow-up baPWV values in the malignancy group (P = 0.016).Atherosclerosis is advanced and accelerated in patients with malignancy, and these patients had significantly higher rates of adverse cardiovascular events, and their risk might be stratified by ABI and baPWV.University Hospital Medical Information Network-CTR (http://www.umin.ac.jp/ctr/).Kumamoto University Malignancy and Atherosclerosis study (UMIN000028652).Opt-out materials are available at the following website: http://www.kumadai-junnai.com/home/wp-content/uploads/akusei.pdf.

Introduction Mortality in hemodialysis patients is relatively high; thus, its risk stratification is very important. There are insufficient data describing the current status of the management of serum phosphate and calcium levels. Methods We conducted a multicenter, prospective, registry study throughout the Kumamoto Prefecture in Japan. We enrolled 1993 patients at 58 facilities with complete explanatory data, including serum phosphate, corrected calcium, and intact parathyroid hormone levels. We categorized subjects into nine categories according to low, normal, and high levels of phosphate and corrected calcium levels. The endpoint was all-cause mortality. Results Of the total number of subjects, 56.1% of the patients were in the normal phosphate and calcium category, and 72% and 77.1% had controlled serum phosphate and calcium levels, respectively. Two hundred twenty-six deaths occurred during the follow-up period. In the nine categories, the highest mortality rates were observed in the highest corrected calcium and lowest phosphate categories. Stepwise backward multivariate regression analyses identified the serum corrected calcium level (OR, 1.38; 95% CI, 1.06-1.79; P = 0.016) and the serum phosphate level (OR, 1.26; 95% CI, 1.08-1.48; P = 0.003) as significant and independent predictors of all-cause mortality. Conclusions The corrected serum calcium and phosphate levels are associated with mortality in our dialysis population, with poorest survival in patients with high corrected serum calcium and low serum phosphorus.

Background: Sudden cardiac arrest is a leading cause of cardiovascular death. We aimed to examine the association of short-term exposure to particulate matter of diameter ≤2·5 μm (PM2·5) with factors including incidence of out-of-hospital cardiac arrests (OHCAs) of cardiac origin, efficacy of basic life support measures, and eventual prognosis. Methods: We utilised data from the prospective, nationwide, population-based All-Japan Utstein Registry of OHCAs occurring throughout all 47 Japanese prefectures. We obtained PM2·5 concentrations and other air pollutants from atmospheric environmental database of the National Institute for Environmental Studies. A time-stratified, case-crossover design was applied to study the association of prefecture-specific estimates of PM2·5 with OHCA-related factors using a conditional logistic regression analysis. Estimations were combined with a random-effects meta-analysis for higher accuracy. Findings: The study included 103 189 bystander-witnessed OHCAs of cardiac origin that occurred from April 2011 to December 2016. A 10-μg/m3 increase in the average PM2·5 concentration on the day of OHCA over that on the day prior was associated with a 1·6 (95% CI, 0·1-3·1)% increase. PM2·5-exposure was closely associated with OHCAs presenting with asystole (2·1 [0·2-4·1]%) as compared to those with other initial cardiac rhythms. Occurrence of unfavourable prognosis such as 1-month mortality (1·5 [0·0-3·2]%) was estimated, and both chest compressions and rescue breathing were associated with higher 1-month mortality (4·6 [0·4-9·0]%) than chest-compression-only type of cardiopulmonary resuscitation (1·2 [-0·7-3·1]%) in OHCA patients with PM2·5-exposure. Interpretation: Increase in PM2·5 concentrations triggers OHCAs of cardiac origin, which commonly present with initial asystole, leading to poor outcomes. The impact of rescue breathing for cardiac origin-OHCA patients affected by short-term exposure to PM2·5, requires further study. Funding: Environment Research and Technology Development Fund (5-1751) of the Ministry of Environment, Japan, and Grants-in-Aid for Scientific Research (17K19821) of the Japan Society for Promotion of Science. Declaration of Interest: None. Ethical Approval: They conducted the study with approval from the Ethics Committee of Kawasaki Medical School (Approved Number: 3383).

Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the association of CYP2C19 polymorphisms and EETs on microvascular angina (MVA) caused by coronary microvascular dysfunction. We examined CYP2C19 genotypes in patients with MVA ( n = 71) and healthy subjects as control ( n = 71). MVA was defined as the absence of coronary artery stenosis and epicardial spasms and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. MVA group showed significantly higher CYP2C19 PM incidence (35% vs. 16%; P = 0.007) and high sense C-reactive protein (hs-CRP) levels (0.127 ± 0.142 vs. 0.086 ± 0.097 mg/dl; P = 0.043) than those of controls. Moreover, in MVA group, hs-CRP levels in CYP2C19 PM were significantly higher than that of non-PM (0.180 ± 0.107 vs. 0.106 ± 0.149 mg/dl, P = 0.045). Multivariate analysis indicated that smoking, hypertension, high hs-CRP, and CYP2C19 PM are predictive factors for MVA. In MVA group, DHET levels for CYP2C19 PM were significantly lower than that of non-PM [10.9 ± 1.64 vs. 14.2 ± 5.39 ng/ml, P = 0.019 (11,12-DHET); 15.2 ± 4.39 vs. 17.9 ± 4.73 ng/ml, P = 0.025 (14,15-DHET)]. CYP2C19 variants are associated with MVA. The decline of EET-based defensive mechanisms owing to CYP2C19 variants may affect coronary microvascular dysfunction.

Background and aims Although dual low-density lipoprotein cholesterol (LDL-C)-lowering therapy (DLLT) with statin-ezetimibe combination showed clinical benefit in patients with acute coronary syndrome (ACS) confirming "the lower, the better," the underlying mechanisms of DLLT are still unknown. Methods PRECISE-IVUS trial evaluated the effects of DLLT on IVUS-derived coronary atherosclerosis and lipid profile, compared with atorvastatin monotherapy, quantifying the coronary plaque response in 100 ACS patients. We explored the potential predictors of plaque regression. Results Lower total cholesterol, LDL-C, triglyceride, remnant-like particles cholesterol, and stronger reduction of small dense LDL-C and cholesterol absorption markers were observed in patients with plaque regression compared to those with progression. Multivariate analysis revealed that achieved LDL-C was the strongest predictor for coronary plaque regression (95% CI: 0.944–1.000, p = 0.05), followed by age (95% CI: 0.994–1.096, p = 0.09). Conclusions Incremental LDL-C lowering by DLLT was associated with stronger coronary plaque regression, reconfirming that lowering LDL-C to levels below previous targets provided additional clinical benefit.

Background Host genetic factors of interleukin (IL)-1 polymorphisms influence Helicobacter pylori infection pathogenic activity. We examined whether H. pylori-infected patients with IL-1 polymorphisms are associated with myocardial infarction (MI). Materials and methods We recruited 594 consecutive coronary artery disease patients and excluded those who met exclusion criteria. After matching age and sex, 82 cases with MI and 82 controls were enrolled. Immunoglobulin G antibodies against H. pylori and IL-1 polymorphisms (IL-1 beta-511 base pairs and IL-1 receptor antagonist) were analyzed. We assessed high sensitivity C-reactive protein (hs-CRP) level and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index (RHI) using the EndoPAT2000 system. Results The simultaneous prevalence of H. pylori-seropositivity and IL-1 polymorphisms was 45.1% and 19.5% in the cases and controls, respectively (P = 0.001). H. pylori-positive patients with IL-1 polymorphisms showed significantly higher serum levels of natural logarithm of hs-CRP in the cases and controls (− 2.8 ± 1.0 vs. − 3.4 ± 0.6, respectively; P = 0.003 and − 2.8 ± 0.9 vs. − 3.2 ± 0.6, respectively; P = 0.02) and significantly lower levels of natural logarithm of RHI in the cases and controls (0.51 ± 0.13 vs. 0.61 ± 0.23, respectively; P = 0.039 and 0.47 ± 0.13 vs. 0.69 ± 0.23, respectively; P = 0.005). H. pylori-seropositivity with IL-1 polymorphisms was significantly associated with MI by logistic regression analysis (odds ratio, 4.83; 95% confidence interval, 1.99–11.7; P Conclusions H. pylori-positive patients with IL-1 polymorphisms showed higher levels of hs-CRP and lower levels of RHI, and were significantly correlated with the MI.

Objective The purpose of this study was to examine the cardiovascular protective effects of candesartan in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). Background Candesartan has been reported to reduce cardiovascular events when therapy was started 6 months after PCI with bare-metal stents in patients who survived restenosis. Candesartan started immediately after PCI with DESs was also effective in preventing cardiovascular events. Methods The 4C trial was a multicenter, prospective, randomized, open-label study. A total of 1145 patients at 39 centers in Japan were randomly assigned to receive candesartan plus standard medical treatment or standard medical treatment alone. The primary endpoints were all-cause death, and a composite of non-fatal myocardial infarction (MI), unstable angina pectoris (uAP), congestive heart failure (CHF), and non-fatal cerebrovascular events. The follow-up period was up to 3 years after the index PCI (ClinicalTrials.gov NCT00139386 ). Results The incidence of total death, one of the primary endpoints, was comparable between the two treatment groups (3.8% each, p = 0.9702). Another primary endpoint, non-fatal major cardiovascular events, tended to occur more often in the control group than in the candesartan group (9.2% vs. 12.5%, p = 0.0985). In contrast, candesartan significantly reduced one of the pre-specified secondary endpoints: cardiovascular events that included non-fatal MI, uAP, and CHF (4.4% vs. 6.7%, p = 0.0136). Furthermore, candesartan significantly reduced another secondary endpoint that included cardiovascular events and cardiovascular death (5.0% vs. 7.7%, p = 0.0493). Conclusions The 4C trial showed that candesartan administered immediately after PCI with DESs did not improve the prognosis after the index procedure, but did reduce some cardiac-related events for 3 years.

The evidence suggests that mentoring is one of useful teaching methods in academic medicine but it is not clear for which outcome mentoring is effective. In this study, the authors investigated the number of original research articles that the participants had published in peer-reviewed English-language journals (as a first or a corresponding author) within one year prior to investigation and what characteristics of the participants who published at least one paper would be like compared to those who did not. In March 2015, the authors recruit early- and mid-career Japanese physicians (238 men and 240 women; mean age 40.6 years old) in a web survey. In total, 23.9% of physicians had published at least one original research article as a first author, 10.0% had published as a corresponding author, and 23.4% had a research mentor. A multivariate logistic regression model adjusting for variables selected at p < 0.15 in univariable models showed that even after adjusting for their motivation levels for clinical research, physicians with a research mentor [odds ratio (OR) 6.68; 95% confidence interval (CI), 3.74-11.93], physicians who obtained DMSc, roughly equivalent to PhD in the West (OR, 2.17; 95% CI, 1.26-3.72), and physicians who worked at teaching hospitals (OR 6.39; 95% CI, 2.54-16.04) were more likely to publish an original paper in a peer-reviewed journal. Having a research mentor or DMSc is associated with an experience of successfully publishing original papers in peer-reviewed journals for young and mid-career physician-researchers.

Background There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients receiving dual antiplatelet therapy (DAPT). Peripheral endothelial dysfunction has recently been reported to predict adverse cardiovascular events. We hypothesized that CYP2C19 loss-of-function (LOF) allele carriers with peripheral endothelial dysfunction had worse prognosis. The aim of this study was to evaluate an additive effect of peripheral endothelial dysfunction on clinical outcome following percutaneous coronary intervention (PCI) in patients with a CYP2C19 variant. Methods We enrolled 434 patients on DAPT following PCI. CYP2C19 genotype was examined, and we divided patients into two groups: carriers, who had at least one CYP2C19 LOF allele, and non-carriers. Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low and high RHI. Thus, subjects were divided into four groups, and clinical events were followed up. Results A total of 55 patients had a cardiovascular event. Kaplan–Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers with low RHI (log-rank test: p = 0.007). Multivariate Cox proportional hazards analysis identified both CYP2C19 LOF allele possession (hazard ratio (HR): 1.94; 95% confidence interval (CI): 1.1–3.69; p = 0.045) and low RHI (HR: 2.15; 95% CI: 1.22–3.78; p = 0.008) as independent and significant predictors of future cardiovascular events. Conclusions CYP2C19 LOF allele carriers with peripheral endothelial dysfunction were significantly correlated with cardiovascular events. The additional evaluation of peripheral endothelial function along with CYP2C19 polymorphism might improve risk stratification after coronary stent implantation.

Numb chin syndrome (NCS) is defined as reduced or absent sensation in an area of the chin and lower lip within the distribution of the mental or inferior alveolar nerves. The causes of NCS may be neoplastic, traumatic, dental, toxic, drug-induced, inflammatory, autoimmune or infectious. NCS may be the preliminary symptom of malignancy or recurrence/metastasis in patients with cancer. Therefore, the occurrence of NCS warrants careful examination and monitoring of such patients. This article presents two cases of NCS reported in a patient with prostate cancer and in a patient with Burkitt lymphoma/leukaemia.

To investigate whether anemia is an independent risk factor for cardiovascular and renal events in hypertensive outpatients, we performed a subgroup analysis of the ATTEMPT-CVD study based on baseline hemoglobin. The ATTEMPT-CVD study was a multicenter, prospective, randomized study of hypertensive outpatients that compared the efficacy of angiotensin receptor blocker (ARB)-based antihypertensive treatment with non-ARB antihypertensive treatment over 3 years. In the present subanalysis, ATTEMPT-CVD study participants (n = 1213) were categorized into the anemic group and nonanemic group according to their baseline hemoglobin. We compared the anemic and nonanemic groups mainly in regard to the incidence of cardiovascular and renal events and blood pressure. We also performed a multivariable Cox proportional hazards analysis to determine the prognostic factors that were independently associated with cardiovascular and renal events. Of the 1213 patients enrolled in the ATTEMPT-CVD, 194 patients had anemia (mostly mild anemia) and 1019 patients did not. Blood pressure was well-controlled during the 3 years of antihypertensive therapy in both the anemic and nonanemic groups. However, the incidence of cardiovascular and renal events was significantly greater in the anemic group than in the nonanemic group (HR = 1.945: 95%CI 1.208–3.130; P = 0.0062). Even after adjustment, anemia was independently associated with cardiovascular and renal events (HR = 1.816: 95%CI 1.116–2.955; P = 0.0163) in overall hypertensive patients with well-controlled blood pressure. Anemia, even mild anemia, is an independent risk factor for cardiovascular and renal events in hypertensive outpatients whose blood pressure is well-controlled. Thus, anemia may be a novel therapeutic target for cardiovascular and renal diseases in hypertensive outpatients with anemia.

BACKGROUND Patients with reduced-function CYP2C19 genotypes on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel show higher clinical risk for acute myocardial infarction (AMI). We investigated the effect of CYP2C19 genotype-tailored adjunctive cilostazol therapy on treatment of AMI.Methods and Results:The study group of 138 patients with suspected AMI were screened for CYP2C19 genotype immediately after percutaneous coronary intervention (PCI) using a SPARTAN RX point-of-care device. Carriers of the CYP2C19 reduced-function allele were randomized into DAPT (Carrier/DAPT) and DAPT plus 14-day cilostazol (Carrier/DAPT+Cilostazol) groups, while noncarriers were treated with DAPT (Noncarrier/DAPT). After exclusion of 10 patients, the remaining 128 patients were analyzed for P2Y12 reaction unit (PRU) using VerifyNow®P2Y12 system, and levels of biomarkers immediately after, and 1, 14, and 28 days after PCI. DAPT+Cilostazol reduced PRU levels in carriers (n=46) to those found in the Noncarrier/DAPT group (n=40), and significantly lower than those of the Carrier/DAPT group (n=42) at 14 days post-PCI. Discontinuation of cilostazol for 14 days was associated with a significant rise in PRU levels to those of the Carrier/DAPT group at 28 days post-PCI. Plasma B-type natriuretic peptide levels at 14 days post-PCI were lower in Carrier/DAPT+Cilostazol than in the other 2 groups, and the levels increased to those of the other groups at 28 days post-PCI after withdrawal of cilostazol. CONCLUSIONS Adjunctive cilostazol therapy tailored to CYP2C19 genotype seemed useful in AMI patients with the CYP2C19 reduced-function allele.

The ATTEMPT-CVD study was prospective randomized active-controlled trial and the main findings had been reported. According to baseline GFR and albuminuria categories, we divided the patients of the ATTEMPT-CVD study into 2 subgroups: (Group 1) the patients with at least one of eGFR of 2 and UACR of ≥300 mg/g creatinine, defined as G3b and/or A3; (Group 2) the patients except for Group 1, defined as the other patients. In patients with G3b and/or A3, the incidence of cardiovascular events was significantly less in ARB group than in non-ARB group (11 vs 22, respectively) (HR = 0.465: 95%CI = 0.224–0.965; P = 0.040). UACR was significantly less in ARB group than in non-ARB group during follow-up period in patients with G3b and/or A3 (P = 0.0003), while eGFR, plasma BNP levels, and blood pressure were comparable between ARB and non-ARB groups. Allocation to ARB therapy was a significant independent prognostic factor for cardiovascular events in patients with G3b and/or A3 (P = 0.0268). On the other hand, in the other patients, the occurrence of cardiovascular events was comparable between ARB and non-ARB groups. In patients with advanced CKD, ARB-based therapy may confer greater benefit in prevention of cardiovascular events than non-ARB therapy.

Background Although the positive association between achieved low-density lipoprotein cholesterol (LDL-C) level and the risk of coronary artery disease (CAD) has been confirmed by randomized studies with statins, many patients remain at high residual risk of events suggesting the necessity of novel pharmacologic strategies. The combination of ezetimibe/statin produces greater reductions in LDL-C compared to statin monotherapy. Purpose The Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS) trial was aimed at evaluating the effects of ezetimibe addition to atorvastatin, compared with atorvastatin monotherapy, on coronary plaque regression and change in lipid profile in patients with CAD. Methods The study is a prospective, randomized, controlled, multicenter study. The eligible patients undergoing IVUS-guided percutaneous coronary intervention will be randomly assigned to receive either atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily using a web-based randomization software. The dosage of atorvastatin will be increased by titration within the usual dose range with a treatment goal of lowering LDL-C below 70 mg/dL based on consecutive measures of LDL-C at follow-up visits. IVUS will be performed at baseline and 9–12 months follow-up time point at participating cardiovascular centers. The primary endpoint will be the nominal change in percent coronary atheroma volume measured by volumetric IVUS analysis. Conclusion PRECISE-IVUS will assess whether the efficacy of combination of ezetimibe/atorvastatin is noninferior to atorvastatin monotherapy for coronary plaque reduction, and will translate into increased clinical benefit of dual lipid-lowering strategy in a Japanese population.

Background Coronary artery spasm contributes to the pathogenesis of variant angina and ischemic heart disease and may play a role in the progression of atherosclerosis. It is unclear whether the location of spasm is related to outcome. Objectives This study compared the clinical features and prognosis of patients with coronary spasm at the site of significant atherosclerotic stenosis with patients with spasm at sites without stenosis or nonsignificant stenosis. Methods This was a retrospective, observational study of 1,877 consecutive patients with typical or atypical angina-like chest pain undergoing acetylcholine (ACh)-provocation testing. A total of 1,760 patients were eligible for analysis. ACh-provoked coronary spasm and significant organic stenosis were observed in 873 and 358 patients, respectively. Results In patients with significant atherosclerotic stenosis, ACh-positive patients (n = 233) were younger and without diabetes mellitus compared with nonspasm patients (n = 125). In patients without organic stenosis, ACh-positive patients (n = 640) were older, had dyslipidemia, and were more likely to have a family history of ischemic heart disease than nonspasm patients (n = 762). Multiple logistic regression analysis identified ST-segment elevation during anginal attacks, organic stenosis of the left anterior descending artery, and multivessel spasm as correlates of spasm at sites of significant organic stenosis (n = 192). Multivariate analysis identified ACh-provoked spasm at the site of significant stenosis and use of nitrates as the 2 prognostic factors for major adverse cardiac events. Conclusions The clinical features and prognosis of patients with ACh-provoked coronary spasm were different when it occurred at the site of significant atherosclerotic stenosis compared with patients with spasm elsewhere. Both spasm at the site of significant organic stenosis and nitrate use were significant predictors of major adverse cardiac events.

Background Despite standard statin therapy, a majority of patients retain a high “residual risk” of cardiovascular events. Objectives The aim of this study was to evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention (PCI). Methods This trial was a prospective, randomized, controlled, multicenter study. Eligible patients who underwent PCI were randomly assigned to atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily. Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol (LDL-C) Results The combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 ± 16.3 mg/dl vs. 73.3 ± 20.3 mg/dl; p Conclusions Compared with standard statin monotherapy, the combination of statin plus ezetimibe showed greater coronary plaque regression, which might be attributed to cholesterol absorption inhibition–induced aggressive lipid lowering. (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound [PRECISE-IVUS]; NCT01043380 )

Background The CHADS 2 score has mainly been used to predict the likelihood of cerebrovascular accidents in patients with atrial fibrillation. However, increasing attention is being paid to this scoring system for risk stratification of patients with coronary artery disease. We investigated the value of the CHADS 2 score in predicting cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. Methods and Results This was a multicenter, observational cohort study. The subjects had been admitted to one of the participating institutions with coronary artery disease requiring percutaneous coronary intervention. We calculated the CHADS 2 scores for 7082 patients (mean age, 69.7 years; males, 71.9%) without clinical evidence of atrial fibrillation. Subjects were subdivided into low‐ (0–1), intermediate‐ (2–3), and high‐score (4–6) groups and followed for 1 year. The end point was a composite of cardiovascular/cerebrovascular death, nonfatal myocardial infarction, and ischemic stroke at 1‐year follow‐up. Rates of triple‐vessel/left main trunk disease correlated positively with CHADS 2 score categories. CHADS 2 scores among single, double, and triple‐vessel/left main trunk groups were 2 (1–2), 2 (1–3), and 2 (2–3), respectively ( P CHADS 2 score (log‐rank test, P CHADS 2 score (per 1 point) as an independent predictor of cardiovascular/cerebrovascular events (hazard ratio, 1.31; 95% CI , 1.17–1.47; P Conclusions This large cohort study indicated that the CHADS 2 score is useful for the prediction of cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation.

Background Mean amplitude of glycemic excursion ( MAGE ) is commonly used to gauge the degree of glucose level fluctuations. MAGE plays a significant role in vascular endothelial dysfunction and cardiovascular events in patients with diabetes mellitus ( DM ), but its significance is not clear in non‐ DM patients. Thus, we examined the impact of MAGE and vascular endothelial dysfunction on clinical outcomes in non‐ DM patients with coronary artery disease. Methods and Results We followed non‐ DM patients (n=65) for 12 months who underwent percutaneous coronary intervention and assessed the relationship among MAGE , reactive hyperemia index ( RHI ) measured by reactive hyperemia peripheral arterial tonometry as endothelial function, and cardiovascular events. Cardiovascular events analyzed were cardiovascular death, myocardial infarction, unstable angina, and revascularizations. Compared with patients with MAGE MAGE ≥ 65 mg/dL (high glycemic excursions) had significantly higher high‐sensitivity C‐reactive protein (0.10±0.11 mg/dL versus 0.18±0.13 mg/dL, P =0.006) and lower RHI (0.64±0.21 versus 0.51±0.22, P =0.035). The multivariable analysis identified high MAGE and low RHI (≤0.56) as risk factors associated with cardiovascular events (hazard ratio, 5.6; 95% RI, 1.72–18.4 [ P =0.004] versus hazard ratio, 4.5; 95% RI, 1.37–14.9 [ P =0.013]). When the prognosis was classified by combination with MAGE and RHI , the incidence of cardiovascular events was 46.7% (high MAGE +low RHI ), 26.7% (high MAGE +high RHI ), 20.0% (low MAGE +low RHI ), and 6.6% (low MAGE +high RHI ) in descending order ( P =0.014). Receiver operating characteristic curve analysis revealed that MAGE , RHI , and MAGE + RHI were each associated with cardiovascular events (area under the curve 0.780, 0.727, and 0.796, respectively). Conclusions MAGE was associated with cardiovascular events in non‐ DM patients with coronary artery disease. Furthermore, the combination with MAGE and RHI was useful for further subdivision of the risk of cardiovascular events.

Background Experimental studies suggest that angiotensin II-receptor blockers can influence atrial remodeling and may prevent atrial fibrillation (AF). Therefore, we hypothesized that irbesartan may prevent the recurrence of AF following either catheter ablation or electrical cardioversion of AF. Methods Study on the Effect of Irbesartan on Atrial Fibrillation Recurrence in Kumamoto (SILK study) is a prospective, multicenter, randomized, and open-label comparative evaluation of the effects of irbesartan and amlodipine on AF recurrence in hypertensive patients with AF who are scheduled to undergo catheter ablation or electrical cardioversion of AF. The primary end point was either AF or atrial tachycardia (AT) recurrence. AF/AT recurrence was evaluated for 6 months using 24-h Holter electrocardiogram and portable electrocardiogram. The secondary endpoints included the change in blood pressure, the interval from the procedure to the first AF/AT recurrence, cardiovascular events, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), and changes in the biomarkers [brain natriuretic polypeptide (BNP), high-sensitivity C-reactive protein (hs-CRP), urinary albumin/creatinine]. Results The study enrolled 98 patients (irbesartan; n = 47, amlodipine; n = 51). The recurrence of AF/AT was observed in 8 patients (17.0%) in the irbesartan group and in 10 patients (19.6%) in the amlodipine group. There was no significant difference in the AF/AT recurrence between the irbesartan and amlodipine groups. Blood pressure decreased similarly in both groups. There were no significant differences between the two groups as regards to the interval from the procedure to the first AF/AT recurrence, occurrence of cardiovascular events, changes in LAD and LVEF. BNP and urinary albumin/creatinine significantly decreased similarly in both groups, but no significant difference was found in hs-CRP between the two groups. Conclusions In hypertensive patients with AF, treatment with irbesartan did not have any advantage over amlodipine in the reduction of AF/AT recurrence after catheter ablation or electrical cardioversion.

The OSCAR study was a multicenter prospective randomized study that examined the relative benefit of combined ARB (olmesartan 20 mg per day) plus calcium channel blocker (CCB) therapy vs. high-dose ARB monotherapy (olmesartan 40 mg per day) for prevention of cardiovascular events in elderly Japanese hypertensive patients. The present subanalysis of patients enrolled in the OSCAR study (n = 1078) was performed to assess whether baseline eGFR coupled with cardiovascular disease (CVD) could predict the relative benefit of these two treatments. Patients with baseline CVD (n = 769) and patients without baseline CVD (n = 309) were divided into two groups based on baseline eGFR; (i) patients with eGFR of < 60 ml min(-1) 1.73 m(-)(2) and (ii) those with eGFR of ⩾ 60 ml min(-1) 1.73 m(-2). There was a significant treatment-subgroup interaction among these four subgroups in relation to the incidence of primary outcome events(P = 0.007 for interaction). In patients with CVD and with eGFR of

Pericardial fat (PF) and complex fractionated atrial electrogram (CFAE) are both associated with atrial fibrillation (AF). Therefore, we examined the relation between PF and CFAE area in AF.The study population included 120 control patients without AF and 120 patients with AF (80 paroxysmal AF and 40 persistent AF) who underwent catheter ablation. Total cardiac PF volume, representing all adipose tissue within the pericardial sac, was measured by contrast-enhanced computed tomography. The location and distribution of CFAE region were identified by left atrial endocardial mapping using a three-dimensional mapping system. We analyzed the significance of total cardiac PF volume and total area of CFAE region on AF, persistence of AF from paroxysmal to persistent form, and the relation between total cardiac PF volume and total CFAE area. We also evaluated the regional distribution of PF volume and CFAE area in five areas of the left atrium (LA).Total cardiac PF volume correlated with AF (odds ratio [OR]: 1.024, p0.001). Total cardiac PF volume and total CFAE area were both independently associated with persistence of AF (OR: 1.018, p=0.018, OR: 1.144, p=0.002, respectively). Multivariate linear regression analysis identified total cardiac PF volume as a significant and independent determinant of total CFAE area (r=0.488, p0.001). Furthermore, regional PF volume correlated with local CFAE area in an each LA area.PF volume correlated significantly with CFAE area in patients with AF. This finding suggests that PF is directly related to the progression of CFAE area and promotes the pathogenic process of AF.

High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy.We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively.The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/*1), 46 % in intermediate metabolizers (IM; *1/*2, *1/*3), and 25 % in poor metabolizers (PM; *2/*2, *2/*3, *3/*3). Platelet reactivity levels in during the early and late phases were 3,793 ± 1,476 and 2,960 ± 1,410, respectively, in EM, 4,706 ± 1,417 and 3,239 ± 1,479, respectively, in IM, and 5,402 ± 776 and 4,736 ± 1,356 aggregation units (AU)•min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of-function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963 ± 1,436 and 5,100 ± 1,190 AU•min in Expressor and Non-expressor, respectively (P0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM.Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19.