Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.

BACKGROUND: The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m2. RESULTS: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. CONCLUSIONS: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.

Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.

BACKGROUND: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs). METHODS: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score. RESULTS: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001). CONCLUSIONS: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

Neutrophil-lymphocyte ratio and clinical outcomes in 19,697 patients with atrial fibrillation: Analyses from ENGAGE AF- TIMI 48 trial.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is the ratio between neutrophil and lymphocyte counts measured in peripheral blood. NLR is easily calculable based on a routine blood test available worldwide and may reflect systemic inflammation. However, the relationship between NLR and clinical outcomes in atrial fibrillation (AF) patients is not well-described. METHODS: We calculated NLR at baseline in ENGAGE AF-TIMI 48, a randomized trial comparing edoxaban versus warfarin in patients with AF followed for 2.8 years (median). The association of baseline NLR with major bleeding events, major adverse cardiac events (MACE), cardiovascular death, stroke/systemic embolism, and all-cause mortality were calculated. RESULTS: The median baseline NLR in 19,697 patients was 2.53 (interquartile range 1.89-3.41). NLR was associated with major bleeding events (HR 1.60; 95% CI 1.41-1.80), stroke/systemic embolism (HR 1.25; 95% CI, 1.09-1.44), MI (HR 1.73; 95% CI 1.41-2.12), MACE (HR 1.70; 95% CI 1.56-1.84), CV (HR 1.93; 95% CI 1.74-2.13) and all-cause mortality (HR 2.00; 95% CI 1.83-2.18). The relationships between NLR and outcomes remained significant after adjustment for risk factors. Edoxaban consistently reduced major bleeding. MACE, and CV death across NLR groups vs. warfarin. CONCLUSIONS: NLR represents a widely available, simple, arithmetic calculation that could be immediately and automatically reported during a white blood cell differential measurement to identify patients with AF at increased risk of bleeding, CV events, and mortality.

Evaluation of the atrial fibrillation better care pathway in the ENGAGE AF-TIMI 48 trial.

AIMS: The Atrial fibrillation Better Care (ABC) pathway is endorsed by guidelines to improve care of patients with atrial fibrillation (AF). However, whether the benefit of ABC pathway-concordant care is consistent across anticoagulants remains unclear. We assessed the association between ABC-concordant care and outcomes in this post hoc analysis from the ENGAGE AF-TIMI 48 trial, which was reported prior to the initial description of the ABC pathway. METHODS AND RESULTS: Patients were retrospectively classified as receiving ABC-concordant care based on optimal anticoagulation, adequate rate control, management of co-morbidities and lifestyle measures. Associations between ABC-concordance and outcomes were assessed with adjustment for components of the CHA2DS2-VASc and HAS-BLED scores. Of 20 926 patients, 7915 (37.8%) satisfied criteria of ABC-concordant care, which was associated with significantly lower incidence of stroke or systemic embolic event [stroke/SEE: hazard ratio (HRadj): 0.54; 95% confidence interval (CI): 0.47-0.63], major bleeding (HRadj 0.66; 95% CI: 0.58-0.75), major adverse cardiac events (HRadj 0.53; 95% CI: 0.48-0.58), primary net clinical outcome (composite of stroke/SEE, major bleeding or death; HRadj 0.61; 95% CI: 0.56-0.65), cardiovascular (CV) hospitalization (HRadj 0.78; 95% CI: 0.74-0.83), CV death (HRadj 0.52; 95% CI: 0.46-0.58), and all-cause mortality (HRadj 0.56; 95% CI: 0.51-0.62), P < 0.001 for each. These associations were qualitatively consistent for both edoxaban and warfarin and across patient subgroups. CONCLUSION: Atrial fibrillation Better Care pathway-concordant care is associated with reductions across multiple CV endpoints and all-cause mortality, with benefit in edoxaban- and warfarin-treated patients and across patient subgroups. Increasing implementation of ABC-concordant care may improve clinical outcomes of patients with AF irrespective of anticoagulant.