Antithrombotic therapy for stable coronary artery disease and atrial fibrillation in patients with and without revascularisation: the AFIRE trial.

BACKGROUND: The Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial demonstrated non-inferior efficacy endpoints for rivaroxaban monotherapy versus combination therapy (rivaroxaban plus a single antiplatelet) and superior safety endpoints in patients with atrial fibrillation and stable coronary artery disease. AIMS: This post hoc analysis investigated whether the AFIRE trial results reflected the presence or absence of prior revascularisation. METHODS: Among 2,215 patients, 1,697 (76.6%) had previously undergone revascularisation, and the remaining 518 (23.4%) had not undergone prior revascularisation. The primary efficacy endpoint was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation, or death from any cause, while the primary safety endpoint was major bleeding. RESULTS: In 1,697 patients with prior revascularisation, the efficacy and safety endpoints were superior for monotherapy versus combination therapy (efficacy: hazard ratio [HR] 0.62, 95% confidence interval [CI]: 0.45-0.85; p=0.003; safety: HR 0.62, 95% CI: 0.39-0.98; p=0.042). Among 518 without prior revascularisation, there were no significant differences in endpoints (efficacy: HR 1.19, 95% CI: 0.67-2.12; p=0.554; safety: HR 0.47, 95% CI: 0.18-1.26; p=0.134). There was borderline interaction of the efficacy endpoints (p=0.055) between two treatments. The safety benefit of monotherapy on any bleeding was significant in patients without prior revascularisation (HR 0.59, 95% CI: 0.38-0.93; p=0.022). CONCLUSIONS: In high-risk thrombosis patients with a history of prior revascularisation, rivaroxaban monotherapy versus combination therapy demonstrated favourable safety and efficacy outcomes.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH) Study: A Multicenter, Open-Label, Prospective, Interventional Study.

INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).

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.

Thrombocytopenia as a Bleeding Risk Factor in Atrial Fibrillation and Coronary Artery Disease: Insights From the AFIRE Study.

Background Thrombocytopenia poses a risk of bleeding in patients with chronic coronary syndrome after coronary intervention. However, whether thrombocytopenia also increases the bleeding risk in patients with atrial fibrillation and chronic coronary syndrome remains unclear. Methods and Results This study evaluated the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial. Thrombocytopenia was defined as platelet count <100 000/mm3 level at enrollment. Primary end points included incidence of major bleeding based on the International Society on Thrombosis and Hemostasis criterion and major adverse cardiovascular ischemic events (cardiac death, myocardial infarction, and stroke). A total of 2133 patients were classified into the thrombocytopenia (n=70) and nonthrombocytopenia (n=2063) groups. Major bleeding was significantly higher in the thrombocytopenia group than in the nonthrombocytopenia group (10.0% versus 4.1%, P=0.027). The thrombocytopenia group tended to have a higher risk of major adverse cardiovascular ischemic events (11.4% versus 6.2%, P=0.08). The bleeding incidence was significantly higher in patients with thrombocytopenia receiving combination therapy with rivaroxaban and a single antiplatelet drug (thrombocytopenia group, 14.3%, versus nonthrombocytopenia group, 5.0%; hazard ratio, 3.18 [95% CI, 1.27-7.97], P=0.014). Thrombocytopenia was an independent predictor of major bleeding (hazard ratio, 2.57 [95% CI, 1.19-5.56], P=0.017). Conclusions Among patients with atrial fibrillation and chronic coronary syndrome, thrombocytopenia was significantly associated with increased risk of major bleeding. Selecting drugs for patients with thrombocytopenia continuing antithrombotic therapy should be given special consideration. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02642419. https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000016612.

Risk prediction score for clinical outcome in atrial fibrillation and stable coronary artery disease.

OBJECTIVE: Antithrombotic therapy is essential for patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) because of the high risk of thrombosis, whereas a combination of antiplatelets and anticoagulants is associated with a high risk of bleeding. We sought to develop and validate a machine-learning-based model to predict future adverse events. METHODS: Data from 2215 patients with AF and stable CAD enrolled in the Atrial Fibrillation and Ischaemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease trial were randomly assigned to the development and validation cohorts. Using the random survival forest (RSF) and Cox regression models, risk scores were developed for net adverse clinical events (NACE) defined as all-cause death, myocardial infarction, stroke or major bleeding. RESULTS: Using variables selected by the Boruta algorithm, RSF and Cox models demonstrated acceptable discrimination and calibration in the validation cohort. Using the variables weighted by HR (age, sex, body mass index, systolic blood pressure, alcohol consumption, creatinine clearance, heart failure, diabetes, antiplatelet use and AF type), an integer-based risk score for NACE was developed and classified patients into three risk groups: low (0-4 points), intermediate (5-8) and high (≥9). In both cohorts, the integer-based risk score performed well, with acceptable discrimination (area under the curve 0.70 and 0.66, respectively) and calibration (p>0.40 for both). Decision curve analysis showed the superior net benefits of the risk score. CONCLUSIONS: This risk score can predict the risk of NACE in patients with AF and stable CAD. TRIAL REGISTRATION NUMBERS: UMIN000016612, NCT02642419.

Febuxostat and renal outcomes: post-hoc analysis of a randomized trial.

Effect of urate-lowering on renal outcomes in patients at high-risk for cardiovascular disease with hyperuricemia without gout is not known. We conducted a post hoc analysis of a randomized trial (Febuxostat for Cerebral and　CaRdiorenovascular Events PrEvEntion StuDy [FREED]). The FREED trial enrolled 1070 asymptomatic, hyperuricemic elderly patients with at least one risk factor for cardiovascular disease, divided into febuxostat (n = 537) and non-febuxostat (n = 533) groups. We compared the effect of these treatments on renal outcomes including 40% decline in estimated glomerular filtration rate, new onset of microalbuminuria and development or worsening macroalbuminuria. The relative risk of developing or worsening macroalbuminuria was 56% lower in the febuxostat group (hazard ratio, 0.44; 95% CI, 0.24-0.82; P = 0.0098). However, the risks for other outcomes were comparable. In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of development or worsening of macroalbuminuria.

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.

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.

Trends and future projections of cervical cancer-related outcomes in Japan: What happens if the HPV vaccine program is not implemented?

Contrary to other developed countries, in Japan, recent years have seen increases in cervical cancer incidence and mortality among young people. However, the human papillomavirus (HPV) vaccine program, a key measure for avoiding cervical cancer, has been virtually suspended. Temporal changes in cervical cancer profiles in this unique situation have not been fully investigated epidemiologically. Our study aimed to determine the current status and future trends of the incidence and mortality of cervical cancer and precancerous lesions in Japan. Mortality rates of cervical cancer during 1975 to 2016 and incidence rates of cervical cancer and cervical intraepithelial neoplasia (CIN) 3 during 1975 to 2013 were examined using vital statistics and population-based cancer registry data in Japan. Bayesian age-period-cohort analyses were performed to analyze temporal changes of the three cervical cancer-related outcomes. We also calculated projections to 2028 for the three outcomes, assuming that HPV vaccination coverage and screening rates in Japan would be maintained at the current level after the resumption of the national vaccination program. The risk of occurrence of the three outcomes showed similar changes by birth cohort, peaking in the mid-1890s to 1900s birth cohorts, declining sharply in the 1940s birth cohort, and persistently increasing in the 1950s and later birth cohorts. Projections to 2028 show increases in cervical cancer incidence and mortality in the 30 to 69 age group, with a particular increase in CIN3 incidence in the 25 to 49 age group, if HPV vaccine programs and screening are not effectively implemented. These findings revealed an increasing cervical disease burden among reproductive age females in Japan.

Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease: A Post Hoc Secondary Analysis of the AFIRE Trial.

Importance: Appropriate regimens of antithrombotic therapy for patients with atrial fibrillation (AF) and coronary artery disease (CAD) have not yet been established. Objective: To compare the total number of thrombotic and/or bleeding events between rivaroxaban monotherapy and combined rivaroxaban and antiplatelet therapy in such patients. Design, Setting, and Participants: This was a post hoc secondary analysis of the Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease (AFIRE) open-label, randomized clinical trial. This multicenter analysis was conducted from February 23, 2015, to July 31, 2018. Patients with AF and stable CAD who had undergone percutaneous coronary intervention or coronary artery bypass grafting 1 or more years earlier or who had angiographically confirmed CAD not requiring revascularization were enrolled. Data were analyzed from September 1, 2020, to March 26, 2021. Interventions: Rivaroxaban monotherapy or combined rivaroxaban and antiplatelet therapy. Main Outcomes and Measures: The total incidence of thrombotic, bleeding, and fatal events was compared between the groups. Cox regression analyses were used to estimate the risk of subsequent events in the 2 groups, with the status of thrombotic or bleeding events that had occurred by the time of death used as a time-dependent variable. Results: A total of 2215 patients (mean [SD] age, 74 [8.2] years; 1751 men [79.1%]) were included in the modified intention-to-treat analysis. The total event rates for the rivaroxaban monotherapy group (1107 [50.0%]) and the combination-therapy group (1108 [50.0%]) were 12.2% (135 of 1107) and 19.2% (213 of 1108), respectively, during a median follow-up of 24.1 (IQR, 17.3-31.5) months. The mortality rate was 3.7% (41 of 1107) in the monotherapy group and 6.6% (73 of 1108) in the combination-therapy group. Rivaroxaban monotherapy was associated with a lower risk of total events compared with combination therapy (hazard ratio, 0.62; 95% CI, 0.48-0.80; P < .001). Monotherapy was an independent factor associated with a lower risk of subsequent events compared with combination therapy. The mortality risk after a bleeding event (monotherapy, 75% [6 of 8]; combination therapy, 62.1% [18 of 29]) was higher than that after a thrombotic event (monotherapy, 25% [2 of 8]; combination therapy, 37.9% [11 of 29]). Conclusions and Relevance: Rivaroxaban monotherapy was associated with lower risks of total thrombotic and/or bleeding events than combination therapy in patients with AF and stable CAD. Tapered antithrombotic therapy with a sole anticoagulant should be considered in these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02642419.

Rivaroxaban Underdose for Atrial Fibrillation with Stable Coronary Disease: The AFIRE Trial Findings.

BACKGROUND: Rivaroxaban monotherapy was noninferior to combination therapy (rivaroxaban plus antiplatelet therapy) in efficacy but superior in safety in the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial. Among 2,215 patients with atrial fibrillation (AF) and stable coronary artery disease (CAD), 1,378 had baseline creatinine clearance (CrCl) ≥50 mL/min and received 10 (underdose) or 15 mg/d (standard-dose) rivaroxaban. We aimed to assess the effects of rivaroxaban underdose on clinical outcomes. METHODS: We assessed efficacy endpoint (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and death from any cause) and major bleeding in the subgroup of patients with preserved renal function in the AFIRE trial. RESULTS: Age ≥75 years, female sex, lower CrCl, heart failure, and percutaneous coronary intervention history were associated with the underdose prescription. The underdose group had a similar incidence of the efficacy endpoint (3.62 vs. 3.51% per patient-year; p = 0.871) and significantly lower incidence of major bleeding (0.82 vs. 2.17% per patient-year; p = 0.022) than the standard-dose group. In patients receiving monotherapy, the incidences of efficacy endpoint and major bleeding were similar between the groups, whereas in those receiving combination therapy, the incidence of major bleeding was significantly lower in the underdose group than that in the standard-dose group. CONCLUSION: In patients with AF, stable CAD, and preserved renal function, rivaroxaban underdose was associated with similar rates of thrombotic events but a lower incidence of hemorrhagic events than the standard dose. CLINICAL TRIAL REGISTRATION: AFIRE UMIN Clinical Trials Registry (https://www.umin.ac.jp/ctr/), number UMIN000016612, and ClinicalTrials.gov, number NCT02642419.

The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial.

BACKGROUND: The success of antithrombotic therapies is assessed based on thrombotic and bleeding events. Simultaneously assessing both kinds of events might be challenging, and recurrent bleeding events are often ignored. We tried to confirm the effects of kidney function on outcome events in patients undergoing antithrombotic therapy. METHODS: As a post hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, a randomized clinical trial with a median follow-up of 36 months, patients were divided into high and low estimated glomerular filtration rate (eGFR) groups with a cutoff value of 50 mL/min. The cumulative incidence of bleeding and crude incidence of recurrent bleeding per 100 patient-years were calculated. We used the Cox regression model with multiple failure time data for recurrent bleeding events. RESULTS: Among 2092 patients, 1386 (66.3%) showed high eGFR. The cumulative bleeding events per 100 patients at 1 year were 5.4 and 6.2 in the high and low eGFR groups, respectively. The difference continued to increase over time. The hazard ratio for time to the first bleeding event in the high eGFR group was 0.875 (95% confidence interval 0.701-1.090, p = .234) and that for the first composite event was 0.723 (95% confidence interval 0.603-0.867, p < .000). The recurrent bleeding events per 100 person-years were 11.3 and 15.3 in the high and low eGFR groups, respectively, with a rate ratio of 0.738 (95% confidence interval 0.615-0.886, p = .001). During the observation period, the risk of bleeding changed with time. It peaked soon after the study enrollment in both groups. It decreased continuously in the high eGFR group but remained high in the low eGFR group. CONCLUSIONS: We reaffirmed that kidney function affects bleeding events in patients on antithrombotic therapy, considering recurrent events. Patients should have detailed discussions with physicians regarding the possible bleeding events when continuing antithrombotic therapy, especially in patients with decreased kidney function. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000016612 . ClinicalTrials.gov, NCT02642419 . Registered on 21 October 2015.

Rationale and Design of the Efficacy and Safety of Esaxerenone in Hypertensive Patients With Left Ventricular Hypertrophy (ESES-LVH) Study　- Protocol for a Multicenter, Open-Label, Exploratory Interventional Study.

Background: The complication of left ventricular (LV) hypertrophy (LVH) is associated with increased incidence of major cardiovascular events. Hypertension is an independent risk factor among several factors contributing to the development of LVH, and thus appropriate treatment of both hypertension and LVH reduces the risk of developing heart failure. Mineralocorticoid-receptor blockers (MRBs) have been reported to improve the prognosis of LVH, but use of currently available MRBs is limited by adverse events. Esaxerenone is a novel selective nonsteroidal MRB recently approved for treatment of hypertension. Although the renoprotective effect of esaxerenone has been demonstrated in both preclinical and clinical studies, little data is available in terms of its cardioprotective effects. Methods and Results: This multicenter, open-label, exploratory interventional study was designed to evaluate the safety and efficacy of esaxerenone in combination with renin-angiotensin system (RAS) inhibitors or calcium-channel blockers (CCBs). Eligible criteria are hypertensive patients with LVH, and target blood pressure (BP) not reached with an RAS inhibitor or a CCB. The primary endpoints are change from baseline in seated home BP (early morning systolic/diastolic BPs), and change and %change from baseline in the LV mass index at the end of treatment. Conclusions: This study will provide the first clinical evidence of the antihypertensive effect and safety of esaxerenone in hypertensive patients with LVH.

Rivaroxaban Monotherapy in Atrial Fibrillation and Stable Coronary Artery Disease Across Body Mass Index Categories.

Background: The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial showed both noninferiority for efficacy and superiority for safety endpoints of rivaroxaban monotherapy compared with those of rivaroxaban plus antiplatelet therapy (combination therapy) in patients with atrial fibrillation and stable coronary artery disease. Objectives: This study sought to evaluate outcomes of rivaroxaban monotherapy in those patients across body mass index (BMI) categories. Methods: Patients were categorized into 4 groups: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5 to <25 kg/m2), overweight (BMI 25 to <30 kg/m2), and obesity (BMI ≥30 kg/m2). Efficacy (a composite of all-cause death, myocardial infarction, unstable angina requiring revascularization, stroke, or systemic embolism) and safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria) were compared between rivaroxaban monotherapy and combination therapy across BMI categories. Results: This study analyzed 2,054 patients with a median age of 75.0 years and CHA2DS2-VASc score of 4. A significant interaction was not observed between BMI categories and effect of monotherapy for efficacy (P = 0.83) and safety (P = 0.07), although monotherapy was superior to combination therapy for efficacy in normal weight (HR: 0.64; 95% CI: 0.44-0.95) and safety in overweight (HR: 0.25; 95% CI: 0.10-0.62), whereas a significant difference in the endpoints was not observed in the other BMI categories. Conclusions: Rivaroxaban monotherapy had a similar effect on prognosis across all BMI categories in patients with atrial fibrillation and stable coronary artery disease. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease [AFIRE]; UMIN000016612, NCT02642419).

Effect of febuxostat on clinical outcomes in patients with hyperuricemia and cardiovascular disease.

BACKGROUND: 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). METHODS: We performed a post hoc subgroup analysis of 1070 patients randomized to the febuxostat or non-febuxostat group and followed for 36 months. RESULTS: 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). CONCLUSIONS: 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.

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.

Rivaroxaban Monotherapy in Patients With Atrial Fibrillation After Coronary Stenting: Insights From the AFIRE Trial.

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).