Background Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation (AF), which is more prevalent among CKD patients than the general population. AF causes stroke or systemic embolism, leading to increased mortality. The conventional antithrombotic prophylaxis agent warfarin is often prescribed for the prevention of stroke, but risk of bleeding necessitates regular therapeutic monitoring. Recently developed direct oral anticoagulants (DOAC) are expected to be useful as alternatives to warfarin. Objectives To assess the efficacy and safety of DOAC including apixaban, dabigatran, edoxaban, and rivaroxaban versus warfarin among AF patients with CKD. Search methods We searched the Cochrane Kidney and Transplant Specialised Register (up to 1 August 2017) through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. Selection criteria We included all randomised controlled trials (RCTs) which directly compared the efficacy and safety of direct oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) with dose-adjusted warfarin for preventing stroke and systemic embolic events in non-valvular AF patients with CKD, defined as creatinine clearance (CrCl) or eGFR between 15 and 60 mL/min (CKD stage G3 and G4). Data collection and analysis Two review authors independently selected studies, assessed quality, and extracted data. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for the association between anticoagulant therapy and all strokes and systemic embolic events as the primary efficacy outcome and major bleeding events as the primary safety outcome. Confidence in the evidence was assessing using GRADE. Main results Our review included 12,545 AF participants with CKD from five studies. All participants were randomised to either DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) or dose-adjusted warfarin. Four studies used a central, interactive, automated response system for allocation concealment while the other did not specify concealment methods. Four studies were blinded while the other was partially open-label. However, given that all studies involved blinded evaluation of outcome events, we considered the risk of bias to be low. We were unable to create funnel plots due to the small number of studies, thwarting assessment of publication bias. Study duration ranged from 1.8 to 2.8 years. The large majority of participants included in this study were CKD stage G3 (12,155), and a small number were stage G4 (390). Of 12,545 participants from five studies, a total of 321 cases (2.56%) of the primary efficacy outcome occurred per year. Further, of 12,521 participants from five studies, a total of 617 cases (4.93%) of the primary safety outcome occurred per year. DOAC appeared to probably reduce the incidence of stroke and systemic embolism events (5 studies, 12,545 participants: RR 0.81, 95% CI 0.65 to 1.00; moderate certainty evidence) and to slightly reduce the incidence of major bleeding events (5 studies, 12,521 participants: RR 0.79, 95% CI 0.59 to 1.04; low certainty evidence) in comparison with warfarin. Authors' conclusions Our findings indicate that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing risk of major bleeding events among AF patients with kidney impairment. These findings should encourage physicians to prescribe DOAC in AF patients with CKD without fear of bleeding. The major limitation is that the results of this study chiefly reflect CKD stage G3. Application of the results to CKD stage G4 patients requires additional investigation. Furthermore, we could not assess CKD stage G5 patients. Future reviews should assess participants at more advanced CKD stages. Additionally, we could not conduct detailed analyses of subgroups and sensitivity analyses due to lack of data.

/pdf/direct-oral-anticoagulants-versus-warfarin-for-preventing-50xjlr872z.pdf

Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease

SummaryBackground
Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major risk factor for stroke. Rivaroxaban, an oral factor Xa inhibitor, is approved for the prevention of stroke in patients with non-valvular AF. In the pivotal phase III trial ROCKET AF, rivaroxaban demonstrated non-inferiority compared with warfarin for reducing the risk of stroke or systemic embolism (SE) in patients with AF (intention-to-treat analysis), without an increased risk of major bleeding. Superior efficacy vs. warfarin was achieved while patients were on study medication. Other direct oral factor Xa inhibitors have completed phase III clinical trials in this indication. Compared with warfarin, apixaban (in the ARISTOTLE trial) and edoxaban (in the ENGAGE-AF trial) were shown to be superior or non-inferior, respectively, for reduction in stroke or SE risk in patients with AF. Baseline stroke risk, as indicated by CHADS2 scores, was lower in patients in the ARISTOTLE and ENGAGE-AF trials than in ROCKET AF.

Objectives
This review discusses the main findings from ROCKET AF, specifically examining recent subgroup analyses investigating rivaroxaban use across various patient types at high risk for adverse outcomes, including those with prior stroke or transient ischaemic attack, reduced renal function, prior myocardial infarction, peripheral artery disease, heart failure or patients aged ≥ 75 years and those resident in East Asia.

Conclusions
These subgroup analyses demonstrate that the treatment effect for rivaroxaban vs. warfarin is broadly consistent across a wide range of patient groups, with respect to both efficacy and safety.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/ijcp.12631

Stroke prevention with rivaroxaban in higher-risk populations with atrial fibrillation.

Between 1985 and 2011, the prevalence of obesity, defined as body mass index (BMI) of 30 kg/m2 or higher, increased from 6.1% to 18.3% in Canada.1 It is estimated that by 2019, more than 55% of the adult Canadian population will be overweight or obese.1 Obesity is associated with an approximately 2-fold increased risk of venous thromboembolism (VTE).2 The major mechanisms proposed as being responsible for obesityassociated thrombosis are chronic inflammation, impaired fibrinolysis, and clinical factors such as immobility, obstructive sleep apnea, heart failure, and venous stasis.2 Direct oral anticoagulants (DOACs) are indicated for the prevention of acute VTE in patients who have undergone elective hip or knee replacement, for the treatment of acute VTE, for the prevention of recurrent VTE, and for the prevention of stroke or systemic embolism in patients with atrial fibrillation. The Canadian rivaroxaban product monograph states that for patients with extremes of body weight (< 50 kg or > 120 kg), a 10-mg tablet caused less than a 25% change in the plasma concentration of rivaroxaban, and thus no dosage adjustment is required.3 The 2016 guidelines of the International Society on Thrombosis and Haemostasis (ISTH) suggest that DOACs not be used in patients with weight greater than 120 kg or BMI greater than 40 kg/m2 because of the lack of clinical data for this population.4 We present here a case of rivaroxaban use in a patient with class III obesity and review the evidence for use of this medication in obese patients.

/pdf/rivaroxaban-for-a-patient-with-class-iii-obesity-case-report-2kxvod5978.pdf

Rivaroxaban for a Patient with Class III Obesity: Case Report with Literature Review

BACKGROUND
Limited clinical data exists regarding use of direct oral anticoagulants (DOACs) in extreme obesity, specifically those ≥140 kg or having a body mass index (BMI) ≥ 50 kg/m2.


OBJECTIVE
Evaluate the safety and efficacy of DOACs in extreme obesity.


PATIENTS/METHODS
A retrospective chart review was performed at a single center of patients aged 18-89 years and weight ≥140 kg or BMI ≥50 kg/m2 receiving warfarin or DOAC therapy. Patients were followed for 1 year from prescribing/study inclusion. The primary outcome was the difference in rates of any bleed (composite of major, nonmajor clinically relevant, or minor bleeding events as defined by International Society of Thrombosis and Haemostasis (ISTH) criteria) between groups. Secondary outcomes included individual components of the composite primary outcome and effectiveness in preventing thrombotic events within 12 months. Post-hoc multivariate analysis evaluated potential predictors of bleeding events within overall patient population.


RESULTS
Two-hundred eighty-five patients were included, 80 and 205 in the DOAC and warfarin groups, respectively. Rates of any documented bleeding event were comparable in DOAC and warfarin groups (17.5% vs 17.1%, P > .05). No significant difference in rates of minor (P = .067), nonmajor clinically relevant (P = .825), and major (P = 1) bleeding events were observed. Two thrombotic events occurred in the warfarin group compared to none in the DOAC group. Increasing weight was associated with bleeding events in multivariate analysis.


CONCLUSIONS
This data did not demonstrate a difference in safety or efficacy outcomes between DOACs and warfarin when utilized in patients with extreme obesity.

Comparing Safety and Efficacy of Direct Oral Anticoagulants Versus Warfarin in Extreme Obesity.

Influences of Obesity and Bariatric Surgery on the Clinical and Pharmacologic Profile of Rivaroxaban

Obesity paradox for stroke in patients with atrial fibrillation treated with rivaroxaban and warfarin in the rocket af trial

Background: Atrial fibrillation (AF) is associated with increased mortality. Identification of contemporary risk factors for mortality may be helpful to guide interventions. Methods: In ROCKET AF, patients with nonvalvular AF were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination was used to identify the factors at randomization independently associated with the occurrence of all-cause death in the 14,171 intention to treat patients. Results: The median age was 73 yrs and the mean CHADS 2 score was 3.5. Over a median followup of 1.94 years, 1214 (8.6%) patients died. Among these patients, the median age was 76, mean CHADS 2 score was 3.6 and 48% had prior stroke or TIA. The independent, significant predictors of increased mortality were decreasing creatinine clearance, COPD, male sex, peripheral vascular disease, increasing age, diabetes, heart failure, tachycardia, residence in Latin America, and prior stroke/TIA (Table; C-index 0.6770). Alcohol use and higher body mass index were associated with a decreased risk of death. When baseline medications, including prior vitamin K antagonist (HR 0.77; 95% CI 0.68–0.87) and antiarrhythmic drug therapy (HR 1.04; 95% CI 0.87–1.24), were included as candidate variables the C-index improved to 0.6800. Conclusions: In a large population of patients with nonvalvular AF, the strongest predictors of mortality were reduced renal function, COPD, male sex, peripheral vascular disease, and age.

Independent Predictors of Mortality in Patients with Nonvalvular Atrial Fibrillation: Results from ROCKET AF

tive,randomizedclinicaltrialisneededtoestablishthevalue of determining thrombomodulin level in clinical practice.

/pdf/practice-guidelines-chest-physicians-evidence-based-clinical-1giaqzcggd.pdf

Practice Guidelines Chest Physicians Evidence-Based Clinical Thrombosis, 9th ed: American College of : Antithrombotic Therapy and Prevention of Antithrombotic Therapy for Atrial Fibrillation

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Obesity paradox for stroke in patients with atrial fibrillation treated with rivaroxaban and warfarin in the rocket af trial

Independent Predictors of Mortality in Patients with Nonvalvular Atrial Fibrillation: Results from ROCKET AF

tive,randomizedclinicaltrialisneededtoestablishthevalue of determining thrombomodulin level in clinical practice.

Practice Guidelines Chest Physicians Evidence-Based Clinical Thrombosis, 9th ed: American College of : Antithrombotic Therapy and Prevention of Antithrombotic Therapy for Atrial Fibrillation