Christopher C. Nessel

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

BACKGROUND The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Response to Letter Regarding Article, “Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation: Validation of the R2CHADS2 Index in the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study Cohorts”

Background —We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. Methods and Results —In ROCKET AF, 14,264 patients with nonvalvular AF and creatinine clearance (CrCl) ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system (CNS) embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA, an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 (4.0%) patients experienced primary endpoint events. Reduced CrCl was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack (TIA). Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, and vascular disease of the heart and limbs (C-index 0.635). A model including CrCl (R2CHADS2) improved net reclassification index (NRI) by 6.2% when compared with CHA2DS2VASc (C-statistic=0.578) and 8.2% when compared with CHADS2 (C-statistic=0.575). The inclusion of estimated glomerular filtration rate <60 and prior stroke or TIA in a model with no other covariates led to a C-statistic of 0.590. Validation of R2CHADS2 in an external, separate population improved NRI by 17.4% (95% CI 12.1-22.5%) relative to CHADS2. Conclusions —In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. Clinical Trial Registration Information —ClinicalTrials.gov; Unique identifier: [NCT00403767][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00403767&atom=%2Fcirculationaha%2Fearly%2F2012%2F12%2F03%2FCIRCULATIONAHA.112.107128.atom

Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF

BACKGROUND In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). METHODS In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0-3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. FINDINGS 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77-1·16) and those without (1·44%vs 1·88%; 0·77, 0·58-1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87-1·07) and those without (16·69%vs 15·19%; 1·10, 0·99-1·21; interaction p=0·08). INTERPRETATION There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF. FUNDING Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.

Outcomes After Cardioversion and Atrial Fibrillation Ablation in Patients Treated With Rivaroxaban and Warfarin in the ROCKET AF Trial

OBJECTIVES This study sought to investigate the outcomes following cardioversion or catheter ablation in patients with atrial fibrillation (AF) treated with warfarin or rivaroxaban. BACKGROUND There are limited data on outcomes following cardioversion or catheter ablation in AF patients treated with factor Xa inhibitors. METHODS We compared the incidence of electrical cardioversion (ECV), pharmacologic cardioversion (PCV), or AF ablation and subsequent outcomes in patients in a post hoc analysis of the ROCKET AF (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation) trial. RESULTS Over a median follow-up of 2.1 years, 143 patients underwent ECV, 142 underwent PCV, and 79 underwent catheter ablation. The overall incidence of ECV, PCV, or AF ablation was 1.45 per 100 patient-years (n = 321; 1.44 [n = 161] in the warfarin arm, 1.46 [n = 160] in the rivaroxaban arm). The crude rates of stroke and death increased in the first 30 days after cardioversion or ablation. After adjustment for baseline differences, the long-term incidence of stroke or systemic embolism (hazard ratio [HR]: 1.38; 95% confidence interval [CI]: 0.61 to 3.11), cardiovascular death (HR: 1.57; 95% CI: 0.69 to 3.55), and death from all causes (HR: 1.75; 95% CI: 0.90 to 3.42) were not different before and after cardioversion or AF ablation. Hospitalization increased after cardioversion or AF ablation (HR: 2.01; 95% CI: 1.51 to 2.68), but there was no evidence of a differential effect by randomized treatment (p value for interaction = 0.58). The incidence of stroke or systemic embolism (1.88% vs. 1.86%) and death (1.88% vs. 3.73%) were similar in the rivaroxaban-treated and warfarin-treated groups. CONCLUSIONS Despite an increase in hospitalization, there were no differences in long-term stroke rates or survival following cardioversion or AF ablation. Outcomes were similar in patients treated with rivaroxaban or warfarin. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation [ROCKET AF]; NCT00403767).

Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial

Background Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial. Methods and Results TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i‐TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐TTR was 55.2% (SD 21.3%) and the median i‐TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i‐TTR, dominant determinants were previous warfarin use (mean i‐TTR of 61.1% for warfarin‐experienced versus 47.4% in VKA‐naïve patients) and geographic region where patients were managed (mean i‐TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐TTRs had INR distributions shifted toward lower INR values and had longer inter‐INR test intervals. Conclusions Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐TTR in global studies of warfarin. Regional differences in mean i‐TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00403767.

Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial.

Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation. Methods and results Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6). Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF.

Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial

AIMS There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors. METHODS AND RESULTS Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11). CONCLUSION Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin.

Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial

Aims We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. Methods and results ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55–1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75–1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05–1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94–1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. Conclusions Many patients with ‘non-valvular atrial fibrillation’ have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.

Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial

Background Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons. Methods and Results TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger‐stick point‐of‐care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non‐central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower‐risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non‐major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values. Conclusions The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.

Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial

BACKGROUND Gastrointestinal (GI) bleeding is a common complication of oral anticoagulation. OBJECTIVES This study evaluated GI bleeding in patients who received at least 1 dose of the study drug in the on-treatment arm of the ROCKET AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. METHODS The primary outcome was adjudicated GI bleeding reported from first to last drug dose + 2 days. Multivariable modeling was performed with pre-specified candidate predictors. RESULTS Of 14,236 patients, 684 experienced GI bleeding during follow-up. These patients were older (median age 75 years vs. 73 years) and less often female. GI bleeding events occurred in the upper GI tract (48%), lower GI tract (23%), and rectum (29%) without differences between treatment arms. There was a significantly higher rate of major or nonmajor clinical GI bleeding in rivaroxaban- versus warfarin-treated patients (3.61 events/100 patient-years vs. 2.60 events/100 patient-years; hazard ratio: 1.42; 95% confidence interval: 1.22 to 1.66). Severe GI bleeding rates were similar between treatment arms (0.47 events/100 patient-years vs. 0.41 events/100 patient-years; p = 0.39; 0.01 events/100 patient-years vs. 0.04 events/100 patient-years; p = 0.15, respectively), and fatal GI bleeding events were rare (0.01 events/100 patient-years vs. 0.04 events/100 patient-years; 1 fatal events vs. 5 fatal events total). Independent clinical factors most strongly associated with GI bleeding were baseline anemia, history of GI bleeding, and long-term aspirin use. CONCLUSIONS In the ROCKET AF trial, rivaroxaban increased GI bleeding compared with warfarin. The absolute fatality rate from GI bleeding was low and similar in both treatment arms. Our results further illustrate the need for minimizing modifiable risk factors for GI bleeding in patients on oral anticoagulation.