Predictors of sinus rhythm 6 weeks after cardioversion of atrial fibrillation: a pre-planned post hoc analysis of the X-VeRT trial.

AIMS: Using a pre-planned post hoc analysis of patients included in X-VeRT, we evaluated predictors of sinus rhythm at 6 weeks after planned cardioversion. METHODS AND RESULTS: Receiver operating characteristic curves and logistic regression models were used to evaluate continuous and categorical variables as predictors of sinus rhythm 6 at weeks from cardioversion (end of study). The primary analysis was performed in successfully cardioverted patients with an evaluable electrocardiogram at end of study. A second analysis evaluated additional patients who spontaneously restored sinus rhythm before planned cardioversion. Of the 1504 patients with atrial fibrillation of >48 h or of unknown duration who were randomly assigned to either rivaroxaban or vitamin K antagonist, 1039 (64.6 ± 10.3 years, 73.4% male) underwent planned cardioversion and were included in this study. Patients receiving early cardioversion (i.e. between 1 and 5 days from hospitalization) had a 67% higher probability to have sinus rhythm at end of study than those who received delayed cardioversion (i.e. between 21 and 56 days from hospitalization) [odds ratio (OR) 1.67, confidence interval (CI) 1.27-2.18; P < 0.0001]. In a multivariate analysis of 17 baseline variables, patients with a CHADS2 score of 0 were 33% less likely to be in sinus rhythm than those with a CHADS2 score ≥2 (OR 0.66, CI 0.47-0.94; P = 0.0225). In the secondary analysis, spontaneous restoration of sinus rhythm was also found to predict sinus rhythm at end of study (OR 8.62, CI 1.54-48.16; P = 0.0142). CONCLUSION: In X-VeRT, early cardioversion and high CHADS2 scores predicted sinus rhythm at 6 weeks from cardioversion.

Left atrial thrombus resolution in atrial fibrillation or flutter: Results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF).

BACKGROUND: Data on left atrial/left atrial appendage (LA/LAA) thrombus resolution after non-vitamin K antagonist (VKA) oral anticoagulant treatment are scarce. The primary objective of X-TRA was to explore the use of rivaroxaban for the resolution of LA/LAA thrombi in patients with nonvalvular atrial fibrillation (AF) or atrial flutter, with the CLOT-AF registry providing retrospective data after standard-of-care therapy in this setting. METHODS: X-TRA was a prospective, single-arm, open-label, multicenter study that investigated rivaroxaban treatment for 6 weeks for LA/LAA thrombus resolution in patients with nonvalvular AF or atrial flutter and LA/LAA thrombus confirmed at baseline on a transesophageal echocardiogram (TEE). CLOT-AF retrospectively collected thrombus-related patient outcome data after standard-of-care anticoagulant treatment for 3 to 12 weeks in patients with nonvalvular AF or atrial flutter who had LA/LAA thrombi on TEE recorded in their medical file. RESULTS: In X-TRA, patients were predominantly (95.0%) from Eastern European countries. The adjudicated thrombus resolution rate was 41.5% (22/53 modified intention-to-treat [mITT] patients, 95% CI 28.1%-55.9%) based on central TEE assessments. Resolved or reduced thrombus was evident in 60.4% (32/53 mITT patients, 95% CI 46.0%-73.6%) of patients. In CLOT-AF, the reported thrombus resolution rate was 62.5% (60/96 mITT patients, 95% CI 52.0%-72.2%) and appeared better in Western European countries (34/50; 68.0%) than in Eastern European countries (26/46; 56.5%). CONCLUSION: X-TRA is the first prospective, multicenter study examining LA/LAA thrombus resolution with a non-VKA oral anticoagulant in VKA-naïve patients or in patients with suboptimal VKA therapy. Rivaroxaban could be a potential option for the treatment of LA/LAA thrombi.

Patient-reported treatment satisfaction and budget impact with rivaroxaban vs. standard therapy in elective cardioversion of atrial fibrillation: a post hoc analysis of the X-VeRT trial.

AIMS: We compared patient-reported treatment satisfaction and the economic impact of anticoagulation therapy with rivaroxaban vs. vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation undergoing elective cardioversion procedures. METHODS AND RESULTS: The current study is a post hoc analysis of the prospective, multicentre X-VeRT (EXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in subjects with non-valvular aTrial fibrillation scheduled for cardioversion) trial. Patient-reported treatment satisfaction with anticoagulation therapy was assessed using the Treatment Satisfaction Questionnaire for Medication version II in seven countries (US, UK, Canada, Germany, France, Italy, and the Netherlands). An economic model was also developed to estimate the impact of postponed cardioversions for two countries (UK and Italy). This model estimated the total costs of cardioversion, taking into consideration the costs for drug therapy (including extended treatment duration due to cardioversion postponement), international normalized ratio monitoring of VKAs, the cardioversion procedure, and rescheduling the procedure. These costs were linked to the respective X-VeRT study data to estimate the total costs. Patients receiving rivaroxaban in the delayed cardioversion group had significantly higher scores for Convenience, Effectiveness, and Global satisfaction (81.74 vs. 65.78; 39.41 vs. 32.95; and 82.07 vs. 66.74, respectively; P < 0.0001). Based on the total patient population included in the treatment satisfaction substudy (n = 632) in the delayed cardioversion group in X-VeRT, the use of rivaroxaban was estimated to result in a saving of £421 and €360 per patient in UK and Italian settings, respectively. CONCLUSION: The use of rivaroxaban in the setting of cardioversion resulted in greater patient satisfaction and cost savings, compared with that of VKA.

Rationale and design of a study exploring the efficacy of once-daily oral rivaroxaban (X-TRA) on the outcome of left atrial/left atrial appendage thrombus in nonvalvular atrial fibrillation or atrial flutter and a retrospective observational registry providing baseline data (CLOT-AF).

There are still many unresolved issues concerning patient outcomes and prognostic factors in patients with atrial fibrillation (AF) and left atrial/left atrial appendage (LA/LAA) thrombi. Rivaroxaban (Xarelto®), a potent and highly selective oral, direct factor Xa inhibitor, is a new therapeutic option in this setting. The planned study program will consist of a prospective interventional study (X-TRA) and a retrospective observational registry (CLOT-AF). The primary objective of the X-TRA study is to explore the efficacy of rivaroxaban in the treatment of LA/LAA thrombi in patients with nonvalvular AF or atrial flutter, scheduled to undergo cardioversion or AF ablation, in whom an LA/LAA thrombus has been found on transesophageal echocardiography (TEE) before the procedure. The primary end point is the complete LA/LAA thrombus resolution rate at 6 weeks of end of treatment confirmed by TEE. The secondary objectives are to describe categories of thrombus outcome in patients (resolved, reduced, unchanged, larger, or new) confirmed on TEE at the end of treatment (after 6 weeks of treatment), incidence of the composite of stroke and noncentral nervous system systemic embolism at the end of treatment and during follow-up, and incidence of all bleeding at the end of treatment and during follow-up. The objective of the CLOT-AF registry is to provide retrospective thrombus-related patient outcome data after standard-of-care anticoagulant treatment in patients with nonvalvular AF or atrial flutter, who have TEE-documented LA/LAA thrombi. The data will be used as a reference for the prospective X-TRA study. In conclusion, X-TRA and CLOT-AF will provide some answers to the many unresolved issues concerning patient outcomes and prognostic factors in patients with AF and LAA thrombi. Results from this study program would provide the first prospective interventional study (X-TRA) and a large international retrospective observational registry (CLOT-AF) on the prevalence and natural history of LA/LAA thrombi. Unique data on clot resolution with rivaroxaban in a prospective cohort would be obtained in X-TRA.

Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.

AIMS: X-VeRT is the first prospective randomized trial of a novel oral anticoagulant in patients with atrial fibrillation undergoing elective cardioversion. METHODS AND RESULTS: We assigned 1504 patients to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 mL/min) or dose-adjusted vitamin K antagonists (VKAs) in a 2:1 ratio. Investigators selected either an early (target period of 1-5 days after randomization) or delayed (3-8 weeks) cardioversion strategy. The primary efficacy outcome was the composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group and in 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15-1.73]. In the rivaroxaban group, four patients experienced primary efficacy events following early cardioversion (0.71%) and one following delayed cardioversion (0.24%). In the VKA group, three patients had primary efficacy events following early cardioversion (1.08%) and two following delayed cardioversion (0.93%). Rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs (P < 0.001). Major bleeding occurred in six patients (0.6%) in the rivaroxaban group and four patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21-2.67). CONCLUSION: Oral rivaroxaban appears to be an effective and safe alternative to VKAs and may allow prompt cardioversion. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov; TRIAL REGISTRATION NUMBER: NCT01674647.

Rationale and design of the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prEvention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion trial: A comparison of oral rivaroxaban once daily with dose-adjusted vitamin K antagonists in patients with nonvalvular atrial fibrillation undergoing elective cardioversion.

BACKGROUND: Anticoagulation before, during, and after cardioversion is effective in reducing stroke risk in patients with atrial fibrillation. OBJECTIVE: The objective of this study is to explore the efficacy and safety of rivaroxaban 20 mg once daily (15 mg if creatinine clearance is 30-49 mL/min) compared with dose-adjusted vitamin K antagonists (VKAs; international normalized ratio 2.0-3.0) in patients scheduled for elective cardioversion. METHODS: This is a prospective, randomized, open-label, parallel group comparison of approximately 1,500 patients from 17 countries with hemodynamically stable nonvalvular atrial fibrillation of >48 hours or unknown duration. Patients will be randomized 2:1 (rivaroxaban:VKA) using 2 cardioversion strategies: the first approach is early cardioversion with the precardioversion anticoagulation goal of 1 to 5 days using rivaroxaban or usual therapy (heparin + VKA). In these patients, transesophageal echocardiography will be encouraged to exclude atrial thrombi. The alternative approach is delayed cardioversion. Rivaroxaban or VKA will be administered for 21 to 56 days before cardioversion. All patients will receive study treatment for 6 weeks postcardioversion. The primary efficacy end point is a composite of all strokes, transient ischemic attacks, noncentral nervous system systemic emboli, myocardial infarctions, and cardiovascular deaths. Each primary end point component will be evaluated separately, and additional composites will be investigated. The principal safety end point is major bleeding. CLINICAL CONTEXT: This will be the first prospective study of a novel oral anticoagulant in the setting of cardioversion. It will provide important information regarding the use of rivaroxaban in the periods preceding and after cardioversion in a broad patient population.

Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies.

BACKGROUND: The worldwide EINSTEIN DVT and EINSTEIN PE studies randomized 8282 patients with acute symptomatic deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) and, for the first time in trials in this setting, included patients in China. This analysis evaluates the results of these studies in this subgroup of patients. METHODS: A total of 439 Chinese patients who had acute symptomatic DVT (n=211), or PE with or without DVT (n=228), were randomized to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy of enoxaparin overlapping with and followed by an adjusted-dose vitamin K antagonist, for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or non-major clinically relevant bleeding. RESULTS: The primary efficacy outcome occurred in seven (3.2%) of the 220 patients in the rivaroxaban group and in seven (3.2%) of the 219 patients in the standard-therapy group (hazard ratio, 1.04; 95% confidence interval 0.36-3.0; p=0.94). The principal safety outcome occurred in 13 (5.9%) patients in the rivaroxaban group and in 20 (9.2%) patients in the standard-therapy group (hazard ratio, 0.63; 95% confidence interval 0.31-1.26; p=0.19). Major bleeding was observed in no patients in the rivaroxaban group and in five (2.3%) patients in the standard-therapy group. In fragile patients (defined as age >75 years, creatinine clearance <50 mL/min, and/or body weight ≤50 kg), the principal safety outcome occurred in four (8.9%) of the 45 patients who received rivaroxaban compared with seven (15.2%) of the 46 patients who received standard therapy. CONCLUSIONS: In Chinese patients with acute symptomatic DVT and/or PE, rivaroxaban was as efficacious as enoxaparin followed by vitamin K antagonist therapy, with a similar safety profile. The relative efficacy and safety of rivaroxaban compared with enoxaparin/vitamin K antagonist were consistent with that found in the rest of the world. TRIAL REGISTRATION NUMBER: EINSTEIN PE, ClinicalTrials.gov NCT00439777; EINSTEIN DVT, ClinicalTrials.gov NCT00440193.

Left atrial thrombus resolution in non-valvular atrial fibrillation or flutter: biomarker substudy results from a prospective study with rivaroxaban (X-TRA).

BACKGROUND: Non-vitamin K antagonist oral anticoagulants including rivaroxaban are widely used for stroke prevention in patients with atrial fibrillation (AF). We investigated the relationship between plasma biomarkers (indicative of thrombogenesis, fibrinolysis and inflammation) and left atrial thrombus resolution after rivaroxaban treatment. METHODS: This was an ancillary analysis of the X-TRA study, which was a prospective interventional study evaluating the use of rivaroxaban for left atrial/left atrial appendage (LA/LAA) thrombus resolution in AF patients. We assessed various biomarkers of thrombogenesis/fibrinolysis [D-dimer, plasminogen activator inhibitor-1 (PAI-1), prothrombin fragment 1 + 2 (F1,2), thrombin-antithrombin (TAT) complexes, von Willebrand factor (vWF)] and inflammation [high-sensitivity interleukin-6 (hsIL-6), and high-sensitivity C-reactive protein (hsCRP)], measured at baseline and after 6 weeks' of rivaroxaban treatment. RESULTS: There was a significant decrease in the mean levels of hsCRP, D-dimer, vWF, and TAT from baseline to end of treatment with rivaroxaban. Although none of the thrombogenesis/fibrinolysis biomarkers showed a significant relationship with thrombus resolution, high inflammatory biomarkers at baseline were significantly associated with an increased chance of the thrombus being completely resolved (hsIL-6) or reduced/resolved (hsCRP). CONCLUSIONS: Biomarkers of inflammation are significantly associated with LA/LAA thrombus outcomes in AF patients prospectively treated with rivaroxaban.