Anticoagulation is a well-established treatment for patients with atrial fibrillation (AF) for the prevention of stroke/systemic embolism (SE). However, although nearly all elderly patients with AF are at risk for thrombotic events, they also have a heightened risk of bleeding, and evidence regarding the optimal anticoagulation regimen in very elderly patients remains limited. This study aimed to evaluate the safety and effectiveness of apixaban versus warfarin in a cohort of very elderly patients with AF in Japan. This was a retrospective analysis of administrative claims for patients with AF newly initiated on apixaban or warfarin from acute care hospitals. Clinical and demographic characteristics were balanced between cohorts using an inverse probability of treatment weighting with stabilized weights (s-IPTW) method. Prespecified subgroup analyses were also conducted to assess treatment interaction with some baseline/demographic factors. A total of 77,814 eligible patients with AF were balanced between the apixaban group (N = 33,834) and warfarin group (N = 43,671) using s-IPTW. The incidence of stroke/SE—primary effectiveness outcome—was 55.8 and 75.2 per 1000 person-years and that of major bleeding—primary safety outcome—was 17.3 and 25.3 per 1000 person-years in the apixaban and warfarin groups, respectively. Apixaban was associated with a significantly lower risk of stroke/SE (hazard ratio [HR], 0.75; 95

Very elderly patients with nonvalvular atrial fibrillation (NVAF) are at high risk for both ischemic and hemorrhagic events. This study aimed to understand the characteristics and real-world treatment of very elderly patients with NVAF in Japan. We conducted a retrospective analysis of electronic health records and claims data from acute care hospitals for very elderly patients with NVAF with medical records available on or after their 80th birthday. The outcomes of interest were (1) characteristics of very elderly patients and (2) patterns of anticoagulation and impact of clinical condition on anticoagulation. Of 1,278,404 patients with newly diagnosed atrial fibrillation (AF), 443,820 were eligible for the analysis. Mean ± standard deviation age was 84.5 ± 5.5 years, CHADS2 score was 2.4 ± 1.0, and CHA2DS2-VASc score was 4.3 ± 1.3. Among patients diagnosed with NVAF before age 80 years, 39.1

Abstract Background: Hypertriglyceridemia is one of the causes of idiopathic acute pancreatitis and atherosclerotic cardiovascular diseases. Most guidelines define fasting triglyceride levels greater than 150 mg/dL as hypertriglyceridemia; however the triglyceride level of patients with acute pancreatitis is not clear, nor is it known how much triglyceride level reduction can reduce cardiovascular events. This study aimed to characterize patients with acute idiopathic pancreatitis and especially focused on triglyceride levels, patient characteristics, pharmaceutical treatment, and prognosis. Methods: In this retrospective analysis of an administrative claims database, patients hospitalized due to acute pancreatitis were selected, and idiopathic pancreatitis was identified using specific pre-determined ICD-10 codes. A Wilcoxon rank sum test was performed for the comparison of the means of the two cohorts, and Fisher's exact test was used to compare proportions between the cohorts. The comparison between idiopathic and non-idiopathic pancreatitis was performed using a log-rank test. Results: Between April 1, 2008, and July 31, 2021, 44,005 patients were hospitalized for the treatment of pancreatitis; among them, 30,814 cases (70.0%) were categorized as idiopathic. The mean age of patients with idiopathic pancreatitis was 62.7±18.8 years, 68.8% of the patients were male, and the mean triglyceride levels within 3 days after hospitalization were 293.1±816.6 mg/dL. Rehospitalization due to recurrent pancreatitis and the incidence rates of cardiovascular events were 39.5% and 3.3%, respectively. Conclusions: Patients with idiopathic pancreatitis had elevated triglyceride levels at admission. Even if triglyceride levels are not extremely high, hypertriglyceridemia might cause idiopathic pancreatitis. Therefore, there is a need for intervention in terms of triglyceride levels in patients with hypertriglyceridemia, not only to prevent cardiovascular disease, but also to prevent the onset and recurrence of acute pancreatitis. Trial registration: Not applicable

The time course of reduction in the risk of venous thromboembolism (VTE) in patients who were diagnosed with cancer, treated with anticancer therapy, and in remission is unclear. We hypothesized that the risk of VTE will decrease over time after cancer remission. We conducted a retrospective analysis using claims data for cancer remission in Japan. Background information of patients who developed VTE after cancer remission was collected, and the VTE incidence rate after cancer remission was analyzed. Subgroup analysis based on VTE history, cancer type, and the presence or absence of surgery during hospitalization was conducted. A total of 638,908 patients were eligible for the analysis. VTE occurred in 5533 of 638,908 cases, pulmonary embolism occurred in 779 cases, and deep vein thrombosis occurred in 5084 cases after cancer remission. The mean age of patients who developed VTE was 70.1 ± 12.5 years, and the proportion of men was 47.5

Previous studies on anticoagulation treatment trends have mostly focused on hospitalized patients. This study aimed to clarify the treatment status of patients with venous thromboembolism (VTE) in Japan from 2011 to 2018, including outpatients, and to assess adherence with current guidelines. Data of inpatients and outpatients who were treated for VTE were extracted from a nationwide claims database (Medical Data Vision Co., Ltd., Tokyo, Japan) and analyzed. The study included 79,330 patients with VTE; half were diagnosed during hospitalization for diseases other than VTE. The proportion of outpatient treatment increased significantly from 2015 to 2018 (Cochran–Armitage trend test, P < 0.0001), while 80

Aim: Nonvalvular atrial fibrillation (NVAF) is associated with an increased risk of stroke however many patients are diagnosed after onset. This study assessed the potential of machine-learning algorithms to detect NVAF. Materials & methods: A retrospective database study using a Japanese claims database. Patients with and without NVAF were selected. 41 variables were included in different classification algorithms. Results: Machine learning algorithms identified NVAF with an area under the curve of >0.86; corresponding sensitivity/specificity was also high. The stacking model which combined multiple algorithms outperformed single-model approaches (area under the curve ≥0.90, sensitivity/specificity ≥0.80/0.82), although differences were small. Conclusion: Machine-learning based algorithms can detect atrial fibrillation with accuracy. Although additional validation is needed, this methodology could encourage a new approach to detect NVAF.

ObjectiveTo assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs.MethodsWe conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted.ResultsA total of 73 989 patients were eligible for analysis. Notably, 52.8%–81.9% of patients received reduced doses of NOACs. After applying s-IPTW, patient characteristics were well balanced across warfarin/NOAC cohorts. The mean within-cohort age, CHADS2 score and CHA2DS2-VASc score were 76 years, 2.2–2.3 and 3.8, respectively. In all age categories, the majority of the HRs for major bleeding, any bleeding and stroke/SE were equal to or below 1 for all NOACs versus warfarin. Apixaban was the only NOAC associated with a significantly lower risk of any bleeding. There was a trend towards increased risk reduction with NOACs versus warfarin in patients with body weight ≥60 kg. In patients with renal disease, the HRs for apixaban versus warfarin were below 1 for major bleeding, any bleeding and stroke/SE, with statistical significance observed for the risk reduction in stroke/SE versus warfarin. In the sensitivity analysis, there were no large differences in HRs between the two observational periods.ConclusionsIn patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.

ObjectivesThe purpose of this study was to investigate the effects of smoking on prognosis after elective surgeries. Incidence of 30-day postoperative complications was compared between propensity score-matched ‘ever-smoker’ and ‘never-smoker’ cohorts. Thirty-day mortality and medical costs during the hospital stay were also compared.Design and settingA large-scale retrospective study using deidentified administrative claims data obtained from 372 acute care hospitals across Japan using the Diagnosis Procedure Combination system (ie, a flat-fee payment system).ParticipantsInpatients who were hospitalised to undergo elective surgery.Primary and secondary outcome measuresThe primary endpoint of this study was incidence of 30-day postoperative complications. Secondary endpoints were 30-day mortality and total medical costs during hospitalisation. Comparison between ever-smokers and never-smokers was conducted using matched cohorts created by 1:1 propensity score matching.ResultsUsing 561 598 eligible patients, matched ever-smoker and never-smoker cohorts (n=1 55 593 each) were created. Ever-smokers were defined as patients with Brinkman Index ≥1. The percentage of patients who were male was 76.7%, and mean ages for ever-smokers and never-smokers were 65.1±13.8 years old and 66.4±15.3 years old, respectively. The Brinkman Index of the ever-smoker cohort was 677.6±553.4. Smoking was significantly associated with higher risk of 30-day postoperative complications compared with not smoking (OR 1.15, 95% CI 1.13 to 1.17, p<0.001). Similarly, smoking was significantly associated with postoperative 30-day mortality, with OR of 1.22 (95% CI 1.08 to 1.39, p=0.002).ConclusionsOur results suggest that smoking could be associated with risk of poor postoperative outcomes. In particular, a history of smoking may increase the risk of 30-day postoperative complications as well as that of 30-day mortality. The results suggest that smoking might have a harmful effect on postoperative outcomes irrespective of types of surgery.

Objective: To investigate the risk of bleeding events and stroke/systemic embolism (SE) among Japanese patients with nonvalvular atrial fibrillation (NVAF), focusing on the initial dosage of apixaban and patient age. Methods: This retrospective cohort study used de-identified electronic health records based claims data from 314 acute-care hospitals in Japan. NVAF patients newly initiated on warfarin or apixaban, with no prescription during the 180-day blanking period, were eligible. Patients were allocated to receive warfarin or 5 or 2.5 mg twice daily (BID) apixaban. One-to-one propensity-score matching was used to balance patient characteristics between apixaban and warfarin. Results: Among 31,006 eligible patients, 11,972 matched pairs were identified for apixaban versus warfarin. Mean age +/- standard deviation was 77.7 +/- 10.0 and 77.6 +/- 10.0 years and CHADS 2 score was 2.2 +/- 1.4 and 2.2 +/- 1.4 for warfarin and apixaban, respectively. In the apixaban cohort, 39.4% of patients received the standard dose (5 mg BID) and 60.6% received the reduced dose (2.5 mg BID). Incidence rates (events per 100 person-years) of major bleeding, any bleeding and stroke/SE were 3.7, 23.1 and 3.1, and 2.5, 18.6 and 2.0 for warfarin and apixaban cohorts, respectively. Apixaban was associated with a significantly lower risk of any bleeding (hazard ratio [HR] 0.809, 95% confidence interval [CI] 0.731-0.895; p< .001), major bleeding (HR 0.655, 95% CI 0.505-0.849; p=.001) and stroke/SE (HR 0.637, 95% CI 0.478-0.850; p=.002). Conclusions: Our observational data from clinical practice broadly confirms the safety and efficacy results of pivotal randomized controlled trials of apixaban for stroke prevention among NVAF patients.

Objectives: There is scarce evidence comparing novel oral anticoagulants (NOACs) with warfarin in real-world settings in Japan. This study compared the risk of bleeding events among patients with non-valvular atrial fibrillation (NVAF) initiating treatment with NOACs versus warfarin. Methods: A retrospective cohort study was conducted using a de-identified electronic health record based database of health claims and Diagnosis Procedure Combination data from 275 consenting hospitals in Japan. NVAF patients newly initiated on oral anticoagulants were eligible. Based on the first prescription, patients were assigned to 5/2.5 mg BID apixaban, 150/110 mg BID dabigatran, 15/10 mg QD rivaroxaban (approved dose lower in Japan compared to Western countries [20/15 mg QD]) or warfarin groups. One-to-one propensity score matching (PSM) was used to balance patient characteristics between warfarin and each NOAC. Patients were followed up to 1 year post-first prescription. Results: Among 38,662 eligible patients, a total of 5977, 5090, and 6726 matched pairs were identified for warfarin versus apixaban, warfarin versus dabigatran, and warfarin versus rivaroxaban, respectively after PSM. Compared to warfarin, apixaban (hazard ratio [HR] 0.586; 95% CI 0.421–0.815), dabigatran (HR 0.617; 0.425–0.895) and rivaroxaban (HR 0.693; 0.514–0.933) were associated with a significantly lower risk of major bleeding. The risk of any bleeding was significantly lower for apixaban (HR 0.782; 0.682–0.896), but not for dabigatran (HR 0.988; 0.860–1.135) or rivaroxaban (HR 0.938; 0.832–1.057) when comparing to warfarin. Conclusions: Among Japanese patients with NVAF, treatment with apixaban 5/2.5 mg BID was associated with a significantly lower risk of major bleeding and any bleeding when compared to warfarin. Treatment with dabigatran 150/110 mg BID or rivaroxaban 15/10 mg QD was associated with a significantly lower risk of major bleeding, but not any bleeding, than warfarin. The potential benefit of individual NOACs in real-world practice needs to be assessed further.

Background—The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)–dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II–independent remodeling is unclear. Methods and Results—Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor–knockout (AT1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT1A-KO mice. In AT1A-KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized. Conclusions—Our results indicate that genetic blockade of AT1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II–independent mechanisms.

Postoperative peritoneal adhesion represents a major complication of surgery, but the molecular mechanism underlying pathogenesis of adhesion is not fully understood. The present study investigated the roles of cyclooxygenase (COX)-1 and COX-2 in peritoneal adhesion induced by scraping the surface of the cecum and abdominal wall in mice. Slight, but macroscopically observable, peritoneal adhesion was induced even on day 1, and the extent of adhesion reached a maximum on day 7 and beyond. COX-1 mRNA was constitutively expressed in the intact cecum, and its expression level was not altered after the mechanical stimulus. In contrast, expression of the COX-2 gene was markedly increased after the stimulus, and maximum expression was observed on days 3 to 7. Mofezolac, a specific COX-1 inhibitor, had no effect on peritoneal adhesion at 30 mg/kg and had only marginal effects on prostaglandin (PG)E2 levels in the cecum or peritoneal fluid. On the other hand, two highly selective inhibitors for COX-2, NS-398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide) and CAY10404 [3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole], dose-dependently inhibited both adhesion formation and the increase in PGE2 levels (3-30 mg/kg). The effects of NS-398 were eliminated when PGE2 or (R)-butaprost was administered exogenously. A COX-2 antisense oligonucleotide also attenuated adhesion formation. Activation of p38 mitogen-activated protein (MAP) kinase was observed in the traumatized cecum, and an MAP kinase inhibitor, SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole], inhibited adhesion formation (54% inhibition at 15 μM) and also reduced the COX-2 mRNA level and PGE2 levels. In conclusion, COX-2, but not COX-1, plays a significant role in mechanical stimulus-induced peritoneal formation in the mouse cecum.

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.