Canagliflozin reduces proteinuria by targeting hyperinsulinaemia in diabetes patients with heart failure: A post hoc analysis of the CANDLE trial.

AIM: To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin. MATERIALS AND METHODS: This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models. RESULTS: The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of ß-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011). CONCLUSIONS: In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study.

PURPOSE: Inflammation plays an important role in the initiation and progression of atherosclerosis, leading to poor clinical outcomes. Hyperuricemia is associated with the activation of the Nod-like receptor protein 3 inflammasome. Here, we investigated whether inhibition of inflammation using febuxostat lowered the risk of cardiovascular events. METHODS: This is a post-hoc analysis of the randomized trial, Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED). In total, 1067 patients (736 men and 331 women) were included in the analysis. We compared the serial changes in high-sensitivity C-reactive protein (hs-CRP) levels between febuxostat and non-febuxostat groups and assessed the correlation between the changes in uric acid (UA) and hs-CRP levels after febuxostat treatment. We also determined whether febuxostat could reduce a hard endpoint, defined as a composite of cardiovascular events and all-cause mortality. RESULTS: Serum UA levels in the febuxostat group were significantly lower than those in the non-febuxostat group after randomization (p < 0.05). However, hs-CRP levels were comparable between the two groups during the study. No significant correlation was observed between the changes in UA and hs-CRP levels after febuxostat treatment. The hard endpoints did not differ significantly between the two groups. In patients with baseline hs-CRP levels > 0.2 mg/dL or those administered 40 mg of febuxostat, the drug did not reduce hs-CRP levels or decrease the hard endpoint. CONCLUSION: Febuxostat reduced the UA levels but did not affect the CRP levels, and therefore may fail to improve cardiovascular outcomes after treatment. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01984749). https://clinicaltrials.gov/ct2/show/NCT01984749.

Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomized controlled trial.

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.

New Conversion Formula Between B-Type Natriuretic Peptide and N-Terminal-Pro-B-Type Natriuretic Peptide　- Analysis From a Multicenter Study.

BACKGROUND: Although B-type natriuretic peptide (BNP) and N-terminal (NT)-proBNP are commonly used markers of heart failure, a simple conversion formula between these peptides has not yet been developed for clinical use.Methods and Results: A total of 9,394 samples were obtained from Nara Medical University, Jichi Medical University, and Osaka University. We randomly selected 70% for a derivation set to investigate a conversion formula from BNP to NT-proBNP using estimated glomerular filtration rate (eGFR) and body mass index (BMI); the remaining 30% was used as the internal validation set and we used a cohort study from Nara Medical University as an external validation set. Multivariate linear regression analysis revealed a new conversion formula: log NT-proBNP = 1.21 + 1.03 × log BNP - 0.009 × BMI - 0.007 × eGFR (r2=0.900, P<0.0001). The correlation coefficients between the actual and converted values of log NT-proBNP in the internal and external validation sets were 0.942 (P<0.0001) and 0.891 (P<0.0001), respectively. We applied this formula to samples obtained from patients administered with sacubitril/valsartan. After treatment initiation, NT-proBNP levels decreased and actual BNP levels increased. However, the calculated BNP levels decreased roughly parallel to the NT-proBNP levels. CONCLUSIONS: This new and simple conversion formula of BNP and NT-proBNP with eGFR and BMI is potentially useful in clinical practice.

Effectiveness and Safety of Rivaroxaban by General Practitioners　- A Multicenter, Prospective Study in Japanese Patients With Non-Valvular Atrial Fibrillation (GENERAL).

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<0.001) and history of ischemic stroke (HR; 1.89, P=0.005) as significant risk factors of stroke/SE, with history of major bleeding (HR; 14.9, P<0.001) and warfarin use (HR; 2.15, P=0.002) as risk factors for major bleeding events. Neither cognitive dysfunction, defined by the receipt of anti-dementia medications, nor frailty, evaluated by the classification of the Japanese Long-term Care Insurance system, correlated with stroke/SE or major bleeding events. CONCLUSIONS: The low incidence of adverse events, including stroke/SE and bleeding, in patients prescribed rivaroxaban by general practitioners supports its use as a safe and efficacious treatment in the standard clinical care of high-risk patient populations.

Intensive uric acid-lowering therapy in CKD patients: the protocol for a randomized controlled trial.

BACKGROUND: Hyperuricemia would be a risk factor for the development/progression of CKD. However, several studies showed U-shape association between serum uric acid level and renal impairment, suggesting that hypouricemia was rather associated with renal dysfunction. Perhaps, there is the optimal target level of serum UA for renal function. METHODS: The Target-UA study is a multicenter randomized controlled trial. Eligible CKD patients (eGFR ≥ 30, < 60 mL/min/1.73 m2 and urine protein < 0.5 g/gCr or urine albumin to creatinine ratio (ACR) < 300 mg/gCr) with serum UA ≥ 8.0 mg/dL (≥ 7.0 mg/dl: under the treatment) will be enrolled and be randomly assigned to the intensive therapy group (target serum UA level ≥ 4.0 mg/dL, < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL, < 7.0 mg/dL). Topiroxostat, a new xanthine oxidase inhibitor, will be administered to treat hyperuricemia. The primary endpoint is a change in logarithmic value of urine ACR between baseline and week 52 of treatment. The secondary endpoints include changes in serum UA, eGFR, urine protein, lipid profile, and onset of composite cardiovascular events, renal events, gouty arthritis, and attack of urolithiasis. The number of subjects has been set to be 185 in each group for a total of 370. DISCUSSION: This is the first study, to the best of our knowledge, to determine the optimal target level of serum UA for renal protection and is expected to lead to progress in CKD treatment. TRIAL REGISTRATION: (UMIN000026741 and jRCTs051180146).

Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.

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 < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592-0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562-0.987; P = 0.041). CONCLUSION: Febuxostat lowers uric acid and delays the progression of renal dysfunction. REGISTRATION: ClinicalTrials.gov (NCT01984749).

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial.

BACKGROUND: Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. METHODS: The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. CONCLUSIONS: The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

Assessment of trough rivaroxaban concentrations on markers of coagulation activation in nonvalvular atrial fibrillation population.

Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10 mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1 + 2 (F1 + 2) levels, and protein C activities were measured at 0 (baseline), 12 and 24 weeks of rivaroxaban treatment just before the patient's regular dosing time (trough phase). For 49 patients, D-dimer, F1 + 2, and rivaroxaban concentrations were also measured twice between 28 and 32 weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1 + 2 levels were significantly reduced (p < 0.01) from baseline at 12 and 24 weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (p < 0.01) for F1 + 2. Protein C activity was unchanged in the naive group and was increased (p < 0.01) in the warfarin group. Prothrombin time (r = 0.92, p < 0.0001) and activated partial thromboplastin time (r = 0.54, p < 0.0001) correlated with rivaroxaban concentration, but not D-dimer and F1 + 2 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1 + 2 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1 + 2 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.

Reduction of circulating FABP4 level by treatment with omega-3 fatty acid ethyl esters.

BACKGROUND: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) mainly expressed in adipocytes is secreted and acts as an adipokine. Increased circulating FABP4 level is associated with obesity, insulin resistance and atherosclerosis. However, little is known about the modulation of serum FABP4 level by drugs including anti-dyslipidemic agents. METHODS: Patients with dyslipidemia were treated with omega-3 fatty acid ethyl esters (4 g/day; n = 14) containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 4 weeks. Serum FABP4 level was measured before and after treatment. Expression and secretion of FABP4 were also examined in mouse 3T3-L1 adipocytes treated with EPA or DHA. RESULTS: Treatment with omega-3 fatty acid ethyl esters significantly decreased triglycerides and serum FABP4 level (13.5 ± 1.5 vs. 11.5 ± 1.1 ng/ml, P = 0.017). Change in FABP4 level by omega-3 fatty acids was negatively correlated with change in levels of EPA + DHA (r = -0.643, P = 0.013), EPA (r = -0.540, P = 0.046) and DHA (r = -0.650, P = 0.011) but not change in the level of triglycerides or other fatty acid composition. Treatment of 3T3-L1 adipocytes with EPA or DHA had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by treatment with EPA or DHA. CONCLUSIONS: Omega-3 fatty acids decrease circulating FABP4 level, possibly by reducing expression and consecutive secretion of FABP4 in adipocytes. Reducing FABP4 level might be involved in suppression of cardiovascular events by omega-3 fatty acids.

Reduction of serum FABP4 level by sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes mellitus.

Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP or aP2, is secreted from adipocytes in association with lipolysis as a novel adipokine, and elevated serum FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the modulation of serum FABP4 level by therapeutic drugs. Sitagliptin (50 mg/day), a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases glucagon-like peptide 1 (GLP-1), was administered to patients with type 2 diabetes (n = 24) for 12 weeks. Treatment with sitagliptin decreased serum FABP4 concentration by 19.7% (17.8 ± 1.8 vs. 14.3 ± 1.5 ng/ml, P < 0.001) and hemoglobin A1c without significant changes in adiposity or lipid variables. In 3T3-L1 adipocytes, sitagliptin or exendin-4, a GLP-1 receptor agonist, had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by sitagliptin, which was not mimicked by exendin-4. Treatment with recombinant DPP-4 increased gene expression and long-term secretion of FABP4, and the effects were cancelled by sitagliptin. Furthermore, knockdown of DPP-4 in 3T3-L1 adipocytes decreased gene expression and long-term secretion of FABP4. In conclusion, sitagliptin decreases serum FABP4 level, at least in part, via reduction in the expression and consecutive secretion of FABP4 in adipocytes by direct inhibition of DPP-4.

Therapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy: analysis of leukocyte balance.

Intravenous immunoglobulin (IVIG) therapy has been used to treat several autoimmune or inflammatory diseases. We conducted a clinical trial of immunoglobulin therapy for acute myocarditis. The study consisted of two projects: (1) a comparison of prognosis between patients treated with and those not treated with IVIG in a multi-center study; (2) analyses of inflammatory cytokines and blood cell profiles in a substudy. In (1), 15 patients were treated with IVIG (1-2 g/kg, over 2 days), whereas 26 were untreated. There was a statistically significant difference between the survival curves of the patients treated with IVIG and the survival curves of those not treated with IVIG. There was no significant difference between the IVIG-treated and untreated groups in terms of clinical parameters of the acute and chronic phases. In (2), 10 patients were treated with IVIG and 6 were untreated. In both groups, all of the data except for changes in the fraction of lymphocytes and the fraction of monocytes decreased due to the treatment or during the course. In patients in the IVIG group, the percentage of peripheral eosinophils was decreased and the percentage of peripheral monocytes was increased by this treatment when they were compared with the pretreatment data. Therefore, therapy with IVIG seems to be a promising treatment for acute myocarditis given that it improves the clinical course, which may be due to modulation of inflammatory cytokines and the peripheral leukocyte balance.

Febuxostat (Feburic tablet) in the management of hyperuricemia in a general practice cohort of Japanese patients with a high prevalence of cardiovascular problems.

Hyperuricemia is increasing in prevalence and this is paralleled by an increased incidence of acute gout. In addition, there is growing evidence of an association between high serum levels of uric acid (sUA) and cardiovascular disease (CVD). In this preliminary report, we present 12-16 week results from a multicenter, general practice study in which we evaluated the usefulness of febuxostat in a cohort of untreated patients with hyperuricemia with a high prevalence of CVD. Febuxostat titrated from 10 mg/day up to 40 mg/day resulted in statistically significant and clinically relevant reductions in sUA after 12-16 weeks. A "responder" level of 6.0 mg/dL or lower was achieved in 95 of 100 (95%) patients. Significant reductions in sUA were achieved regardless of the presence/absence of coexisting diseases (e.g. CVD, renal insufficiency, diabetes and obesity) or the class of antihypertensive agent being used by the patient. No serious adverse reactions were noted with febuxostat. Although allopurinol has been used generally for hyperuricemia/gout, it is excreted fully via the kidneys, restricting its use in patients with reduced renal function, and its three-times-daily administration leads to poor adherence. Based on the results of this study, febuxostat may provide an easier option than allopurinol for clinicians specializing in CVDs.

Observational study of frailty in older Japanese patients with non-valvular atrial fibrillation receiving anticoagulation therapy.

The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants to such patients because of possible harm. The effects of frailty on anticoagulant therapy in older Japanese patients with nonvalvular atrial fibrillation (NVAF) are unclear. Herein, we prescribed rivaroxaban to Japanese patients with NVAF and monitored for a mean of 2.0 years. The primary endpoint was stroke or systemic embolism. The secondary endpoints were all-cause or cardiovascular death, composite endpoint, and major or non-major bleeding. Frailty was assessed using the Japanese long-term care insurance system. A multiple imputation technique was used for missing data. The propensity score (PS) was obtained to estimate the treatment effect of frailty and was used to create two PS-matched groups. Overall, 5717 older patients had NVAF (mean age: 73.9 years), 485 (8.5%) were classified as frail. After PS matching, background characteristics were well-balanced between the groups. Rivaroxaban dosages were 10 and 15 mg/day for approximately 80% and the remaining patients, respectively. Frailty was not associated with the primary endpoint or secondary endpoints. In conclusion, frailty does not affect the effectiveness or safety of rivaroxaban anticoagulant therapy in older Japanese patients with NVAF.Trial registration: UMIN000019135, NCT02633982.

Impacts of Febuxostat on Cerebral and Cardiovascular Events in Elderly Patients with Hyperuricemia: Post Hoc Analysis of a Randomized Controlled Trial.

A recent meta-analysis found no benefit of uric acid-lowering therapy including febuxostat on death, cardiovascular events, or renal impairment. However, there may be populations that benefit from febuxostat in reducing mortality and cerebral and cardiovascular events. The aim of the present study was to examine the clinical benefit of febuxostat in elderly patients stratified by age using Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) data. FREED was a randomized study involving patients aged 65 years or older with hyperuricemia and risk factors for cerebral, cardiovascular, or renal diseases. A total of 1,070 patients were included in this post hoc analysis, divided into 2 age groups: 65-74 years and ≥ 75 years. Patients were randomized into febuxostat and non-febuxostat groups, with uric acid levels monitored for 36 months. The primary composite end point included cerebral, cardiovascular, and renal events. In patients aged between 65 and 74 years, febuxostat significantly reduced the risk of future cerebral and cardiorenovascular events. However, no effects of febuxostat were found in the older population aged ≥ 75 years. Heterogeneity in potential interactions between the age and febuxostat treatment was particularly observed in non-fatal cerebral and cardiovascular events and all-cause death. Patients aged ≥ 75 years exhibited more pre-existing factors associated with cerebral and cardiorenovascular events than those aged 65-74 years. The effectiveness of febuxostat varies by age group, with potential benefits for patients aged 65-74 years. The effects of febuxostat are complex and it is important to consider patient characteristics in its clinical use.

The effects of pemafibrate and omega-3 fatty acid ethyl on apoB-48 in dyslipidemic patients treated with statin: A prospective, multicenter, open-label, randomized, parallel group trial in Japan (PROUD48 study).

Background: We compared the lowering effects of pemafibrate and omega-3 fatty acid ethyl on fasting apolipoprotein (apo) B-48 (apoB-48), a marker that reflects postprandial hypertriglyceridemia, which is one of the residual risks for atherosclerotic cardiovascular disease (ASCVD) with statin treatment. Methods: This prospective, multicenter, open-label, randomized, parallel group trial was conducted at 4 medical institutions between April 2020 and May 2022. A total of 126 ambulatory patients with dyslipidemia receiving statin treatment for more than 4 weeks, aged 20-79 years with fasting triglyceride (TG) levels of ≥177 mg/dl were randomly assigned to 16-week pemafibrate 0.4 mg per day treatment group (PEMA, n = 63) or omega-3 fatty acid ethyl 4 g per day treatment group (OMEGA-3, n = 63). The primary endpoint was the percentage change in fasting apoB-48 from baseline to week 16. Results: The percentage changes in fasting apoB-48 in PEMA and OMEGA-3 were -50.8% (interquartile range -62.9 to -30.3%) and -17.5% (-38.3 to 15.3%) (P < 0.001), respectively. As the secondary endpoints, the changes in fasting apoB-48 in PEMA and OMEGA-3 were -3.10 µg/ml (-5.63 to -1.87) and -0.90 µg/ml (-2.95 to 0.65) (P < 0.001), respectively. Greater decreases with significant differences in the percentage changes in TG, remnant lipoprotein cholesterol, apoC-III, fasting plasma glucose, alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase were observed in PEMA, compared with OMEGA-3. Greater increases with significant differences in those in high-density lipoprotein (HDL) cholesterol, apoA-I, and apoA-II were observed in PEMA, compared with OMEGA-3. PEMA showed anti-atherosclerotic lipoprotein profiles in gel-permeation high-performance liquid chromatography analyses, compared with OMEGA-3. Although adverse events occurred in 9 of 63 (14.3%) patients in PEMA and 3 of 63 (4.8%) patients in OMEGA-3, no serious adverse events associated with drug were observed in either group. Conclusions: This is the first randomized trial to compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl on fasting apoB-48. We concluded that pemafibrate was superior to omega-3 fatty acid ethyl in lowering effect of fasting apoB-48. Pemafibrate is expected to reduce the residual risk for ASCVD with statin treatment. Clinical trial registration: https://rctportal.niph.go.jp/en, identifier jRCTs071200011.

Corrigendum: The effects of pemafibrate and Omega-3 fatty acid ethyl on apoB-48 in dyslipidemic patients treated with statin: A prospective, multicenter, open-label, randomized, parallel group trial in Japan (PROUD48 study).

[This corrects the article DOI: 10.3389/fcvm.2023.1094100.].

Clinical characteristics and outcomes of Japanese atrial fibrillation patients with poor medication adherence: A sub-analysis of the GENERAL study.

BACKGROUND: Oral anticoagulation therapy is essential for preventing stroke in patients with atrial fibrillation (AF). However, poor anticoagulant adherence may hamper medication safety and effective prevention of stroke. METHODS: GENERAL is a prospective cohort study of AF patients taking rivaroxaban prescribed by general practitioners in Japan. In this study, anticoagulant adherence was calculated as the proportion of days covered (PDC), and patients were retrospectively divided into two groups: good adherence (PDC ≥80 %) and poor adherence (<80 %). RESULTS: Of 5680 patients in the GENERAL study, the poor adherence group consisted of 223 patients (3.9 %). Baseline clinical characteristics were almost comparable regarding age (PDC ≥80 % vs. <80 %: 73.9 vs. 74.0 years, p = 0.92) and sex (male 64.6 % vs. 66.8 %, p = 0.52). The PDC <80 % group more often had various co-morbidities, and had significantly higher CHADS2 (2.14 vs. 2.28, p = 0.04) and CHA2DS2-VASc scores (3.12 vs. 3.31, p = 0.045). There was no significant difference in HAS-BLED score (1.41 vs. 1.47, p = 0.39). During 2-year follow-up, the incidences of stroke or systemic embolism (1.14 vs. 3.56 % per patient-year, p < 0.01), major bleeding (0.59 vs. 1.78 % per patient-year, p < 0.01), and net clinical outcome (the composite of stroke, systemic embolism, major bleeding, or death) (3.49 vs. 7.78 % per patient-year, p < 0.01) were significantly higher in the poor adherence group; however, there was no significant difference in all-cause (1.89 vs. 2.73 % per patient-year, p = 0.23) and cardiovascular mortality (0.86 vs. 1.49 % per patient-year, p = 0.18). Multivariate analysis revealed that the poor adherence group was independently associated with stroke or systemic embolism (adjusted hazard ratio 3.12, 95 % confidence interval 1.79-5.47), major bleeding (2.87, 1.31-6.34), and net clinical outcome, (2.02, 1.39-2.93), but not with all-cause (1.18, 0.64-2.17) or cardiovascular death (1.39, 0.60-2.93). CONCLUSIONS: Poor anticoagulant adherence, as measured by PDC <80 %, was associated with higher incidence of stroke or systemic embolism and major bleeding in the GENERAL study.