Causes of death in patients with atrial fibrillation anticoagulated with rivaroxaban: a pooled analysis of XANTUS.

AIMS: Anticoagulation can prevent stroke and prolong lives in patients with atrial fibrillation (AF); However, anticoagulated patients with AF remain at risk of death. The aim of this study was to investigate the causes of death and factors associated with all-cause and cardiovascular death in the XANTUS population. METHODS AND RESULTS: Causes of death occurring within a year after rivaroxaban initiation in patients in the XANTUS program studies were adjudicated by a central adjudication committee and classified following international guidance.Baseline characteristics associated with all-cause or cardiovascular death were identified. Of 11,040 patients, 187 (1.7%) died. Almost half of these deaths were due to cardiovascular causes other than bleeding (n = 82, 43.9%), particularly heart failure (n = 38, 20.3%) and sudden or unwitnessed death (n = 24, 12.8%). Fatal stroke (n = 8, 4.3%), which was classified as a type of cardiovascular death, and fatal bleeding (n = 17, 9.1%) were less common causes of death. Independent factors associated with all-cause or cardiovascular death included age, AF type, body mass index, left ventricular ejection fraction, hospitalization at baseline, rivaroxaban dose, and anaemia. CONCLUSION: The overall risk of death due to stroke or bleeding was low in XANTUS. Anticoagulated patients with AF remain at risk of death due to heart failure and sudden death. Potential interventions to reduce cardiovascular deaths in anticoagulated patients with AF, require further investigation, e.g. early rhythm control therapy and AF ablation.

Finerenone in patients across the spectrum of chronic kidney disease and type 2 diabetes by glucagon-like peptide-1 receptor agonist use.

AIMS: To explore the modifying effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO-DKD and FIGARO-DKD. MATERIALS AND METHODS: Patients with T2D and CKD treated with optimized renin-angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin-to-creatinine ratio (UACR), and safety were analysed by GLP-1RA use. RESULTS: Of 13 026 patients, 944 (7.2%) used GLP-1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52-1.11 with GLP-1RA; HR 0.87, 95% CI 0.79-0.96 without GLP-1RA; P-interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45-1.48 with GLP-1RA; HR 0.77, 95% CI 0.67-0.89 without GLP-1RA; P-interaction = 0.79) irrespective of baseline GLP-1RA use. Reduction in UACR with finerenone at Month 4 was -38% in patients with baseline GLP-1RA use compared with -31% in those without GLP-1RA use (P-interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP-1RA use. CONCLUSIONS: The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP-1RA use. Subsequent studies are needed to investigate any potential benefit of this combination.

Real-world vs. randomized trial outcomes in similar populations of rivaroxaban-treated patients with non-valvular atrial fibrillation in ROCKET AF and XANTUS.

AIMS: Based on Phase III data, non-vitamin K antagonist oral anticoagulants are recommended for stroke prevention in patients with atrial fibrillation. To determine whether trial outcomes translate into similar event rates in unselected patients, this analysis compared outcomes from the real-world XANTUS study with those from the Phase III ROCKET AF study. METHODS AND RESULTS: Individual patient data from 4020 XANTUS patients were re-weighted to match the proportion of selected baseline characteristics in 7061 rivaroxaban-treated patients from ROCKET AF, using the matching-adjusted indirect comparison (MAIC) method. For the primary analysis, CHADS2 scores and gender were selected as relevant variables. Adjusted annualized incidence rates for XANTUS were calculated and compared with incidence rates from ROCKET AF-the ratio of these rates ('MAIC ratio') was used as a relative effect estimate. Rates of major bleeding [3.10%/year vs. 3.60%/year; MAIC ratio 0.86; 95% confidence interval (CI) 0.67-1.12] and stroke/non-central nervous system systemic embolism (1.54%/year vs. 1.70%/year; MAIC ratio 0.91; 95% CI 0.62-1.32) were similar between XANTUS and ROCKET AF. The rate of all-cause death was higher in XANTUS (3.22%/year vs. 1.87%/year; MAIC ratio 1.72; 95% CI 1.31-2.27), but the rates of vascular death were similar (1.83%/year vs. 1.53%/year; MAIC ratio 1.19; 95% CI 0.84-1.70). Sensitivity analyses weighted by different baseline characteristics supported these results. CONCLUSION: The low rates of major bleeding and stroke in XANTUS were consistent with results from ROCKET AF. All-cause death, but not vascular death, was higher in XANTUS, as expected in an unselected real-world population.

Outcomes after catheter ablation and cardioversion in patients with non-valvular atrial fibrillation: results from the prospective, observational XANTUS study.

Aims: In patients with atrial fibrillation, catheter ablation and cardioversion carry a risk of peri-procedural thromboembolic events; current guidelines recommend anticoagulation in these settings. This study aimed to report the baseline demographics and clinical characteristics of patients enrolled in the prospective, observational XANTUS study who underwent catheter ablation or cardioversion, and adverse outcomes with each of these procedures in patients treated with rivaroxaban. Methods and results: Data collected included information on catheter ablation and cardioversion, and adverse outcomes occurring within 30 days of these procedures: incidence of treatment-emergent adjudicated symptomatic thromboembolic events and major bleeding; and cardiovascular and all-cause death. Incidence of these adverse outcomes at 42 days after cardioversion was also analysed. Patients undergoing either procedure had significantly lower mean CHA2DS2-VASc and HAS-BLED scores than those who did not, and were more frequently hospitalized at study baseline. Within a period of 30 days after intervention, symptomatic thromboembolic events were reported in 1.2% and 0.6% of patients undergoing ablation or cardioversion, respectively; major bleeding events were reported in 2.9% and 0.4% of patients undergoing ablation or cardioversion, respectively. No patients died within 30 days of intervention. Incidence of symptomatic thromboembolic and major bleeding events remained low at 42 days after cardioversion. Conclusion: Similar to the results of prospective and non-interventional studies, the low rates of symptomatic thromboembolic events and major bleeding in patients with atrial fibrillation undergoing ablation or cardioversion and treated with rivaroxaban in XANTUS suggest that its use is associated with an acceptable benefit-risk profile in this setting. Trial registration number: Clinicaltrials.gov: NCT01606995.

Effect of finerenone on ambulatory blood pressure in chronic kidney disease in type 2 diabetes.

OBJECTIVE: Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist with a short half-life. Its effects on cardiorenal outcomes were thought to be mediated primarily via nonhemodynamic pathways, but office blood pressure (BP) measurements were insufficient to fully assess hemodynamic effects. This analysis assessed the effects of finerenone on 24-h ambulatory BP in patients with chronic kidney disease and type 2 diabetes. METHODS: ARTS-DN (NCT01874431) was a phase 2b trial that randomized 823 patients with type 2 diabetes and chronic kidney disease, with urine albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate of 30-90 ml/min per 1.73 m2 to placebo or finerenone (1.25-20 mg once daily in the morning) administered over 90 days. Ambulatory BP monitoring (ABPM) over 24 h was performed in a subset of 240 patients at screening, Day 60, and Day 90. RESULTS: Placebo-adjusted change in 24-h ABPM systolic BP (SBP) at Day 90 was -8.3 mmHg (95% confidence interval [CI], -16.6 to 0.1) for finerenone 10 mg (n = 27), -11.2 mmHg (95% CI, -18.8 to -3.6) for finerenone 15 mg (n = 34), and -9.9 mmHg (95% CI, -17.7 to -2.0) for finerenone 20 mg (n = 31). Mean daytime and night-time SBP recordings were similarly reduced and finerenone did not increase the incidence of SBP dipping. Finerenone produced a persistent reduction in SBP over the entire 24-h interval. CONCLUSIONS: Finerenone reduced 24-h, daytime, and night-time SBP. Despite a short half-life, changes in BP were persistent over 24 h with once-daily dosing in the morning.

Application of the REVEAL risk score calculator 2.0 in the CHEST study.

BACKGROUND: Currently there are no risk assessment recommendations for chronic thromboembolic pulmonary hypertension (CTEPH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score (RRS), developed for risk assessment in patients with pulmonary arterial hypertension, has previously predicted outcomes in CTEPH. RRS 2.0 was developed to refine the RRS. METHODS: This post hoc analysis of the CHEST study (n = 237), which assessed riociguat in patients with inoperable and persistent/recurrent CTEPH, evaluated RRS 2.0 and its relationship with survival and clinical worsening-free survival (CWFS). RESULTS: At CHEST-1 Week 16, RRS 2.0 significantly improved and more patients moved into the low-risk stratum with riociguat versus placebo; these improvements were maintained at CHEST-2 Week 12. RRS 2.0 at CHEST-1 baseline and Week 16, and change in RRS 2.0 from CHEST-1 baseline to Week 16 were significant predictors of survival and CWFS in CHEST-2. CONCLUSIONS: Our data suggest that RRS 2.0 may have utility in predicting outcomes and monitoring treatment response in patients with inoperable or persistent/recurrent CTEPH.

Change in REVEAL Lite 2 risk score predicts outcomes in patients with pulmonary arterial hypertension in the PATENT study.

BACKGROUND: Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT. METHODS: PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS). RESULTS: REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001). CONCLUSIONS: This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.

Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes.

BACKGROUND: In patients with type 2 diabetes (T2D), risks of cardiovascular mortality and heart failure (HF) increase with decreasing kidney function (estimated glomerular filtration rate [eGFR]) and increasing albuminuria (urine albumin-to-creatinine ratio [UACR]). Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and T2D in FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis). OBJECTIVES: This study sought to evaluate the effects of finerenone on HF outcomes by eGFR and/or UACR categories. METHODS: FIDELITY included 13,026 patients with T2D and CKD (UACR 30-5,000 mg/g and eGFR ≥25 mL/min/1.73 m2) randomized to finerenone or placebo. Time-to-event outcomes were first hospitalization for heart failure (HHF), cardiovascular death or first HHF, recurrent HHF, and cardiovascular death or recurrent HHF, analyzed in subgroups by baseline eGFR (<60 and ≥60 mL/min/1.73 m2) and/or UACR (<300 and ≥300 mg/g). RESULTS: Compared with placebo, finerenone significantly reduced risk of first HHF (HR: 0.78 [95% CI: 0.66-0.92]; P = 0.003), cardiovascular death or first HHF (HR: 0.83 [95% CI: 0.74-0.93]; P = 0.002), recurrent HHF (HR: 0.79 [95% CI: 0.64-0.96]; P = 0.021), and cardiovascular death or recurrent HHF (HR: 0.82 [95% CI: 0.72-0.95]; P = 0.006). The risk of outcomes increased across baseline eGFR and UACR categories; lowest incidences were seen in patients with an eGFR ≥60 mL/min/1.73 m2 and a UACR <300 mg/g. Finerenone improved HF outcomes irrespective of baseline eGFR and/or UACR categories (all P interaction values >0.10). CONCLUSIONS: Compared with placebo, finerenone improved HF-related outcomes in patients with CKD and T2D, with consistent benefits across eGFR and/or UACR categories. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Chronic Kidney Disease [FIGARO-DKD], NCT02545049).

Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Pooled Secondary Analysis.

Importance: Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19-associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19-associated adverse events in patients with chronic kidney disease and type 2 diabetes. Objective: To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Design, Setting, and Participants: This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Exposure: Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. Main Outcomes and Measures: The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Results: Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). Conclusions and Relevance: These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. Trial Registration: ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049.

Application of the REVEAL risk score calculator 2.0 in the PATENT study.

BACKGROUND: Regular risk assessment is recommended in pulmonary arterial hypertension (PAH) management to improve patient outcomes. The REVEAL risk score (RRS) predicts survival in patients with PAH, including those from the PATENT study, which assessed riociguat, a soluble guanylate cyclase stimulator approved for PAH treatment. An updated version, RRS 2.0, has been developed to further refine risk prediction. METHODS: This post hoc analysis of PATENT-1 and its open-label extension PATENT-2 (n = 396) assessed RRS 2.0 score and risk stratum and their association with survival and clinical worsening-free survival (CWFS). RESULTS: At PATENT-1 Week 12, riociguat improved RRS 2.0 versus placebo (least-squares mean difference versus placebo: -1.0 [95% confidence interval - 1.4 to -0.6; p < 0.0001]) and more patients improved risk stratum with riociguat (57%) versus placebo (42%). These improvements were maintained at PATENT-2 Week 12. RRS 2.0 score and risk strata at PATENT-1 baseline and Week 12 were significantly associated with survival and CWFS in PATENT-2 (p < 0.0001); change in RRS 2.0 score from PATENT-1 baseline to Week 12 was also significantly associated with outcomes. CONCLUSIONS: These data suggest that RRS 2.0 has clinical utility in predicting long-term outcomes and monitoring treatment response in patients with PAH.

Impact of gender: Rivaroxaban for patients with atrial fibrillation in the XANTUS real-world prospective study.

BACKGROUND: The XANTUS study (NCT01606995) demonstrated low rates of stroke and major bleeding in patients with atrial fibrillation (AF) receiving rivaroxaban in clinical practice for the prevention of thromboembolic events (N = 6784). HYPOTHESIS: Because previous real-world studies have not reported gender-dependent responses to rivaroxaban treatment, this sub-analysis of the XANTUS study investigated the effect of gender on outcomes. METHODS: The centrally adjudicated outcomes were compared between genders. Primary outcomes were major bleeding and all-cause death. Secondary outcomes included symptomatic thromboembolic events. Multivariable Cox regression analysis was performed to assess the effect of risk factors on outcomes between genders. RESULTS: A total of 2765 female and 4016 male patients were included in the analysis. Baseline characteristics were generally similar. No nominally significant interaction between gender and risk factors for the study outcomes was observed. Rates of major bleeding, all-cause death and symptomatic thromboembolic events in patients with non-valvular AF receiving rivaroxaban for stroke prevention were similar in men and women; no significant differences in risk factors for these outcomes were observed between genders. CONCLUSIONS: Further research is needed to better characterize the relative importance of different risk factors on outcomes in men vs women and to determine whether gender differences exist in patients treated with non-vitamin K antagonist oral anticoagulants.

Impact of Modifiable Bleeding Risk Factors on Major Bleeding in Patients With Atrial Fibrillation Anticoagulated With Rivaroxaban.

Background Reducing major bleeding events is a challenge when managing anticoagulation in patients with atrial fibrillation. This study evaluated the impact of modifiable and nonmodifiable bleeding risk factors in patients with atrial fibrillation receiving rivaroxaban and estimated the impact of risk factor modification on major bleeding events. Methods and Results Modifiable and nonmodifiable risk factors associated with major bleeding events were identified from the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) prospective registry data set (6784 rivaroxaban-treated patients). Parameters showing univariate association with bleeding were used to construct a multivariable model identifying independent risk factors. Modeling was used to estimate attributed weights to risk factors. Heavy alcohol use (hazard ratio [HR]=2.37; 95% CI 1.24-4.53); uncontrolled hypertension (HR after parameter-wise shrinkage=1.79; 95% CI 1.05-3.05); and concomitant treatment with antiplatelets, nonsteroidal anti-inflammatory drugs, or paracetamol (HR=1.80; 95% CI 1.24-2.61) were identified as modifiable, independent bleeding risk factors. Increasing age (HR=1.25 [per 5-year increment]; 95% CI 1.12-1.38); heart failure (HR=1.97; 95% CI 1.36-2.86); and vascular disease (HR=1.91; 95% CI 1.32-2.77) were identified as nonmodifiable bleeding risk factors. Overall, 128 (1.9%) patients experienced major bleeding events; of these, 11% had no identified bleeding risk factors, 50% had nonmodifiable bleeding risk factors only, and 39% had modifiable bleeding risk factors (with or without nonmodifiable risk factors). The presence of 1 modifiable bleeding risk factor doubled the risk of major bleeding. Conclusions Elimination of modifiable bleeding risk factors is a potentially effective strategy to reduce bleeding risk in atrial fibrillation patients receiving rivaroxaban. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01606995.

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals with Mild or Moderate Hepatic Impairment.

BACKGROUND AND OBJECTIVES: Finerenone (BAY 94-8862) is a selective, nonsteroidal mineralocorticoid receptor antagonist. The aim of this study was to assess the effect of mild or moderate hepatic impairment on the pharmacokinetics, safety and tolerability of finerenone. METHODS: The study was conducted in a single-center, nonrandomized, noncontrolled, nonblinded observational design with group stratification. A single oral 5-mg dose of finerenone was administered as a tablet to participants with mild or moderate hepatic impairment (Child-Pugh A, score 5-6 [n = 9], or Child-Pugh B, score 7-9 [n = 9], respectively) and to age-, weight- and sex-matched healthy participants (n = 9). The pharmacokinetics of finerenone and its metabolites were assessed in plasma and urine, and safety and tolerability were monitored. RESULTS: Finerenone area under the plasma concentration-time curve (AUC) and unbound AUC were 38% and 55% greater, respectively, in participants with moderate hepatic impairment than in healthy participants, whereas maximum plasma concentration (Cmax) was unchanged. No clear effects on AUC or Cmax were seen in participants with mild hepatic impairment. Finerenone was safe and well tolerated in all participants. CONCLUSION: The effects of mild or moderate hepatic impairment on systemic exposure of finerenone are small, consistent with its low hepatic extraction and preponderance of gastrointestinal over hepatic first-pass clearance. Considering the small increases in AUC and the absence of changes in Cmax, a dose adaptation does not appear to be warranted in patients with mild or moderate hepatic impairment.

Outcomes associated with non-recommended dosing of rivaroxaban: results from the XANTUS study.

AIMS: In Europe, the approved rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is 20 mg once daily (o.d.), with 15 mg o.d. recommended in patients with creatinine clearance (CrCl) 15-49 mL/min. Non-recommended doses are prescribed in real-world practice. This analysis of the XANTUS study assessed outcomes associated with non-recommended dosing and patient characteristics that may have impacted dose choice. METHODS AND RESULTS: Baseline characteristics and 1 year outcomes were compared in 4464/6784 patients with known CrCl, receiving recommended or non-recommended rivaroxaban doses; 3608 (80.8%) patients received recommended doses (mean CHADS2 score 1.9) and 856 (19.2%) non-recommended doses (mean CHADS2 score 2.5). Incidence rate (events/100 patient-years) for the composite of treatment-emergent adjudicated major bleeding, stroke/systemic embolism, and death was 7.5 [95% confidence interval (CI) 5.7-9.8] and 4.8 (95% CI 4.1-5.7) with non-recommended and recommended doses, respectively [hazard ratio (HR) 1.55, 95% CI 1.2-2.1; P = 0.004]. Incidence rates for the components of the composite were 3.7 and 2.6, 1.4 and 0.9, and 3.5 and 1.9, respectively. Adjustment for baseline characteristics showed similar rates of the composite outcome (HR 1.06, 95% CI 0.77-1.45; P = 0.719). Multivariable analysis identified age, anaemia, congestive heart failure, diabetes mellitus, CrCl, lower body weight, AF type, and vascular disease as predictors of non-recommended dosing. CONCLUSION: Non-recommended rivaroxaban dosing was associated with less favourable outcomes, possibly due to baseline characteristics, in addition to renal function, that may also affect physicians' dosing decisions. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT01606995.

Global Prospective Safety Analysis of Rivaroxaban.

BACKGROUND: The efficacy of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation (AF) has been established in clinical trials. However, well-conducted, prospective, real-world observational studies of the safety and effectiveness of DOACs are needed. OBJECTIVES: This study sought to assess the real-world safety profile of rivaroxaban through a pooled analysis of patients with AF enrolled in the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) program worldwide. METHODS: A pre-planned pooled analysis of the XANTUS, XANAP (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia), and XANTUS-EL (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region) registries was performed. Patients with AF newly starting rivaroxaban for stroke prevention were followed for 1 year. Primary outcomes were treatment-emergent major bleeding, adverse events (AEs)/serious AEs, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and nonmajor bleeding. Major outcomes were centrally adjudicated. RESULTS: Overall, 11,121 patients were included (mean age 70.5 ± 10.5 years; female 42.9%). Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%). Event rates were: events/100 patient-years: major bleeding 1.7 (95% confidence interval [CI]: 1.5 to 2.0; lowest: Latin America 0.7; highest: Western Europe, Canada, and Israel 2.3); all-cause death 1.9 (95% CI: 1.6 to 2.2; lowest: Eastern Europe 1.5; highest: Latin America, Middle East, and Africa 2.7); and stroke or systemic embolism 1.0 (95% CI: 0.8 to 1.2; lowest: Latin America 0; highest: East Asia 1.8). One-year treatment persistence was 77.4% (lowest: East Asia 66.4%; highest: Eastern Europe 84.4%). CONCLUSIONS: This large, prospective, real-world analysis in 11,121 patients from 47 countries showed low bleeding and stroke rates in rivaroxaban-treated patients with AF, with low treatment discontinuation in different regions of the world. Results were broadly consistent across regions. (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation [XANTUS]; NCT01606995; Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region [XANTUS-EL]; NCT01800006; and Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia [XANAP]; NCT01750788).

XANTUS-EL: A real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation in Eastern Europe, Middle East, Africa and Latin America.

BACKGROUND: The prospective, observational XANTUS study demonstrated low rates of stroke and major bleeding in real-world rivaroxaban-treated patients with non-valvular atrial fibrillation (NVAF) from Western Europe, Canada and Israel. XANTUS-EL is a component of the overall XANTUS programme and enrolled patients with NVAF treated with rivaroxaban from Eastern Europe, the Middle East and Africa (EEMEA) and Latin America. METHODS: Patients with NVAF starting rivaroxaban for stroke prevention were consecutively recruited and followed for 1 year, at approximately 3-month intervals, or for ≥30 days after permanent rivaroxaban discontinuation. Primary outcomes were major bleeding, adverse events (AEs), serious AEs and all-cause mortality. Secondary outcomes included stroke, non-central nervous system systemic embolism (non-CNS SE), transient ischaemic attack (TIA), myocardial infarction (MI) and non-major bleeding. All major outcomes were centrally adjudicated. RESULTS: Overall, 2064 patients were enrolled; mean age ±â€¯standard deviation was 67.1 ±â€¯11.32 years; 49.3% were male. Co-morbidities included heart failure (30.9%), hypertension (84.2%), diabetes mellitus (26.5%), prior stroke/non-CNS SE/TIA (16.2%) and prior MI (10.7%). Mean CHADS2, CHA2DS2-VASc and HAS-BLED scores were 2.0, 3.6 and 1.6, respectively. Treatment-emergent event rates were (events/100 patient-years, [95% confidence interval]): major bleeding 0.9 (0.5-1.4); all-cause mortality 1.7 (1.2-2.4); stroke/non-CNS SE 0.7 (0.4-1.2); any AE 18.1 (16.2-20.1) and any serious AE 8.3 (7.0-9.7). One-year treatment persistence was 81.9%. CONCLUSIONS: XANTUS-EL confirmed low stroke and major bleeding rates in patients with NVAF from EEMEA and Latin America. The population was younger but with more heart failure and hypertension than XANTUS; stroke/SE rate was similar but major bleeding lower.