Apixaban For Reduction In Stroke Research Articles

Safety and efficacy of apixaban versus warfarin in peritoneal dialysis patients with non-valvular atrial fibrillation: protocol for a prospective, randomised, open-label, blinded endpoint trial (APIDP2)

IntroductionSeveral randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in...

Heart Failure Risk Assessment Using Biomarkers in Patients With Atrial Fibrillation: Analysis From COMBINE-AF

BackgroundHeart failure (HF) is common among patients with atrial fibrillation (AF), and accurate risk assessment is clinically important. ObjectivesThe goal of this study was to investigate the incremental prognostic performance of N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and growth differentiation factor (GDF)-15 for HF risk stratification in patients with AF. MethodsIndividual patient data from 3 large randomized trials comparing direct oral anticoagulants (DOACs) with warfarin (ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48], and RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy]) from the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) cohort were pooled; all patients with available biomarkers at baseline were included. The composite endpoint was hospitalization for HF (HHF) or cardiovascular death (CVD), and secondary endpoints were HHF and HF-related death. Cox regression was used, adjusting for clinical factors, and interbiomarker correlation was addressed using weighted quantile sum regression analysis. ResultsIn 32,041 patients, higher biomarker values were associated with a graded increase in absolute risk for CVD/HHF, HHF, and HF-related death. Adjusting for clinical variables and all biomarkers, NT-proBNP (HR per 1 SD: 1.68; 95% CI: 1.59-1.77), hs-cTnT (HR: 1.39; 95% CI: 1.33-1.44), and GDF-15 (HR: 1.20; 95% CI: 1.15-1.25) were significantly associated with CVD/HHF. The discrimination of the clinical model improved significantly upon addition of the biomarkers (c-index: 0.70 [95% CI: 0.69-0.71] to 0.77 [95% CI: 0.76-0.78]; likelihood ratio test, P < 0.001). Using weighted quantile sum regression analysis, the contribution to risk assessment was similar for NT-proBNP and hs-cTnT for CVD/HHF (38% and 41%, respectively); GDF-15 provided a statistically significant but lesser contribution to risk assessment. Results were similar for HHF and HF-related death, individually, and across key subgroups of patients based on a history of HF, AF pattern, and reduced or preserved left ventricular ejection fraction. ConclusionsNT-proBNP, hs-cTnT, and GDF-15 contributed significantly and independently to the risk stratification for HF endpoints in patients with AF, with hs-cTnT being as important as NT-proBNP for HF risk stratification. Our findings support a possible future use of these biomarkers to distinguish patients with AF at low or high risk for HF.

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF

BackgroundThe extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition...

Direct Oral Anticoagulants Versus Warfarin Across the Spectrum of Kidney Function: Patient-Level Network Meta-Analyses From COMBINE AF.

There is uncertainty surrounding the use of direct oral anticoagulants (DOACs) in patients with kidney dysfunction. Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY [Randomized Evaluation of Long-term Anticoagulation Therapy], 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], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), we performed an individual patient-level network meta-analysis to evaluate the safety and efficacy of DOACs versus warfarin across continuous creatinine clearance (CrCl). A multivariable Cox model including treatment-by-CrCl interaction with random effects was fitted to estimate hazard ratios for paired treatment strategies (standard-dose DOAC, lower-dose DOAC, and warfarin). Outcomes included stroke and systemic embolism (S/SE), major bleeding, intracranial hemorrhage (ICH), and death. Among 71 683 patients (mean age, 70.6±9.4 years; 37.3% female; median follow-up, 23.1 months), the mean CrCl was 75.5±30.5 mL/min. The incidence of S/SE, major bleeding, ICH, and death increased significantly with worsening kidney function. Across continuous CrCl values down to 25 mL/min, the hazard of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin (Pinteraction=0.61). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of ICH at CrCl values <122 mL/min, with a trend for increased safety with DOAC as CrCl decreased (6.2% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl <87 mL/min, with a significant treatment-by-CrCl effect (4.8% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with CrCl <77 mL/min, with a trend toward increasing benefit with lower CrCl (2.1% decrease in hazard ratio per 10-mL/min decrease in CrCl; Pinteraction=0.08). Use of lower-dose rather than standard-dose DOACs was not associated with a significant difference in incident bleeding or ICH in patients with reduced kidney function but was associated with a higher incidence4 of death and S/SE. Standard-dose DOACs are safer and more effective than warfarin down to a CrCl of at least 25 mL/min. Lower-dose DOACs do not significantly lower the incidence of bleeding or ICH compared with standard-dose DOACs but are associated with a higher incidence of S/SE and death. These findings support the use of standard-dose DOACs over warfarin in patients with kidney dysfunction.

Abstract 9290: Relationship Between Body Weight and Pharmacokinetics of Apixaban in Patients With Atrial Fibrillation: Insights from the ARISTOTLE Trial

Introduction: Apixaban dosing in atrial fibrillation (AF) is 5 mg BID or 2.5 mg BID in patients with ≥2 dose-reduction criteria: age &gt;80 years, weight &lt;60 kg, or creatinine &gt;1.5 mg/dl. There is a question of whether drug monitoring might be useful to guide dosing, particularly in patients with extremely high or low body weight (BW). Previous work has demonstrated that the effects of apixaban versus warfarin are similar across BWs. We aimed to investigate the relationship between BW and exposure to apixaban in patients with AF. Methods: Exposure to apixaban was assessed as area under the curve steady state (AUC SS ) using population pharmacokinetics (PK) data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. The relationship between BW and AUC SS was assessed continuously and by BW categories of ≤60kg, &gt;60-120kg, or &gt;120kg overall and by apixaban dose. Results: Of patients with PK data (n=2924), 8.9% were ≤60kg, and 5.8% &gt;120kg. Compared to the overall group, patients ≤60kg were more likely to be older (74 vs 70 years), female (67 vs 33%), had lower creatinine (0.92 vs 1.02 mg/dL) and higher CHA 2 DS 2 -VASc scores (3.9 vs 3.4). There was a weak but significant correlation between BW and AUC SS assessed continuously (correlation -0.38, p&lt;0.001) and by BW group: ≤60kg [median AUCSS 4089 (25 th 3073, 75 th 5148 ng•hr/ml)], &gt;60-120kg [3566 (2926, 4286 ng•hr/ml)], and &gt;120kg [2699 (2284, 3226 ng•hr/ml)] (p&lt;0.001) (Figure). This relationship persisted with stratification by apixaban dose (data not shown). Conclusions: There is a significant relationship between body weight and predicted exposure to apixaban, including at the extremes of BW, but with wide variation in exposure at every weight. This variation, and the absence of an association between body weight and apixaban’s observed safety and efficacy compared with warfarin, make it unlikely that routine therapeutic monitoring of apixaban will be clinically useful.

Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation

AimsThe ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought...

Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas

ObjectivesGrowth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the...

Correction: Blood Pressure Control and Risk of Stroke or Systemic Embolism in Patients With Atrial Fibrillation: Results From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

Correction: Blood Pressure Control and Risk of Stroke or Systemic Embolism in Patients With Atrial Fibrillation: Results From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

Thromboembolic and Hemorrhagic Outcomes in the Direct Oral Anticoagulant Trials Across the Spectrum of Kidney Function.

Chronic kidney disease is a common comorbidity among patients taking direct-acting oral anticoagulants (DOACs). Herein, we evaluate the influence of kidney function on stroke or systemic embolism (SEE), hemorrhage, and composite end points (stroke/SEE/hemorrhage/death and stroke/SEE/death) among patients on DOACs and warfarin. Baseline kidney function was categorized as glomerular filtration rate (GFR)≥60 (reference), 45-59, and <45mL/min/1.73m2 for participants in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) (n=18,049), Apixaban for Reduction in Stroke and Other Thromboembolic Events (ARISTOTLE) (n=18,187), and The Effective Anticoagulation with Factor Xa Next Generation in AF (ENGAGE AF) (n=20,798) trials. Incidence of events was compared across GFR categories. Hazard ratios for events were estimated using Cox regression using intention-to-treat analysis adjusting for known predictors. A large proportion of participants had GFR<60 (25-29% had 45 ≤ GFR < 60 and 9.5-12.6% with GFR<45). Compared with patients with GFR≥60, warfarin users across the trials with GFR≥45-59 and GFR<45 had a higher incidence of hemorrhage (P values<0.0001) and warfarin users in the ARISTOTLE and ENGAGE trials had higher incidence of stroke/SEE (P values≤0.05). Compared with patients with GFR≥60, dabigatran users with GFR≥45-59 and GFR<45 had a higher incidence of stroke/SEE (P≤0.02), hemorrhage (P<0.001), and both composite end points (P<0.0001). Compared with patients with GFR≥60, apixaban and edoxaban users with GFR≥45-59 and GFR<45 had a higher incidence of hemorrhage (P values≤0.05) and composite end points (P values≤0.05). After adjustment, compared with patients with GFR≥60, warfarin users with GFR<60 in the ARISTOTLE and RE-LY trials had a higher risk of hemorrhage (P<0.05), as did dabigatran (P<0.001) and edoxaban (P≤0.005) users, while apixaban users did not exhibit an increased risk (P=0.08 GFR≥45-59; P=0.71 GFR<45). Kidney function significantly influences the safety and efficacy of oral anticoagulants.

10 лет исследованию ARISTOTLE: итоги и уроки

In 2021, the world cardiology community celebrates the anniversary of one of the greatest research in clinical medicine – the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study. The study showed that in patients with atrial fibrillation, the use of apixaban was more effective than the use of warfarin in the prevention of stroke or systemic embolism, was accompanied by a lower frequency of bleeding and was associated with lower mortality from all causes. To date, 77 subanalyses of this ambitious study have been published, a brief overview of which is given in the article. As shown by the post-hoc analysis of the ARISTOTLE study, apixaban was equally effective and safe both in patients without comorbidities and in polymorbid patients. The efficacy and safety of apixaban has been demonstrated in atrial fibrillation and in the presence of comorbidities, including diabetes mellitus, chronic kidney disease, obesity, and coronary heart disease. A number of subanalyses of the ARISTOTLE study are devoted to the prognostic assessment of biomarkers such as cardiac troponins, growth differentiation factor-15, pro-B-type N-terminal natriuretic peptide, D-dimer, asymmetric and symmetric dimethylarginine, interleukin-6, C-reactive protein. Based on the study of biomarkers, new, more informative scales for assessing the risk of stroke, death and bleeding were created: the ABC-stroke scale, the ABC-lethal outcome scale and the ABC-bleeding scale. The data of the corresponding sub-analyzes confirmed the greater efficacy and/or safety of apixaban treatment compared with warfarin, regardless of the level of various biomarkers in blood plasma and the degree of risk of stroke, death and bleeding, assessed using both traditional and new scales.

Evaluation of the Age, Biomarkers, and Clinical History–Bleeding Risk Score in Patients With Atrial Fibrillation With Combined Aspirin and Anticoagulation Therapy Enrolled in the ARISTOTLE and RE-LY Trials

Most patients with atrial fibrillation (AF) and coronary artery disease have indications for preventing stroke with oral anticoagulation therapy and preventing myocardial infarction and stent thrombosis with platelet inhibition. To evaluate whether the recently developed ABC (age, biomarkers, and clinical history)-bleeding risk score might be useful to identify patients with AF with different risks of bleeding during concomitant aspirin and anticoagulation therapy. The biomarkers in the ABC-bleeding risk score (growth differentiation factor 15, hemoglobin, and troponin) were measured in blood samples collected at randomization between 2006 and 2010 in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial and between 2005 and 2009 in the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, both of which were multinational randomized clinical trials. The trials were reported 2011 and 2009, respectively. A total of 24 349 patients with AF (14 980 patients from the ARISTOTLE trial and 9369 patients from the RE-LY trial) were analyzed in the present cohort study. The median (interquartile range) length of follow-up was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3) years in the RE-LY cohort. Data analysis was performed from February 2018 to June 2019. Concomitant aspirin treatment during study follow-up. Time to first occurrence of a major bleeding was determined according to International Society on Thrombosis and Hemostasis definition. Hazard ratios were estimated with Cox models adjusted for ABC-bleeding risk score and randomized treatment. The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort (5238 patients [35.6%] in the ARISTOTLE cohort and 3086 patients [36.4%] in the RE-LY cohort were women). The total number of patients with a first major bleeding event was 651 (207 with aspirin and 444 without) in ARISTOTLE and 463 (238 with aspirin and 225 without) in RE-LY. For both cohorts, in those with a low ABC-bleeding risk score, the absolute bleeding rate was low even with concomitant aspirin treatment, whereas in those with a higher ABC-bleeding risk score, the rate of bleeding was higher with concomitant aspirin compared with oral anticoagulation alone (ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; P < .001; RE-LY, hazard ratio, 1.70; 95% CI, 1.42-2.04; P < .001). Thus, a low annual ABC-bleeding risk (eg, 0.5% without aspirin use) would with concomitant aspirin result in an annual rate of 0.8%, and a high estimated ABC-bleeding risk (eg, 3.0%) would result in a substantially higher rate of 5.0%. These findings suggest that the ABC-bleeding risk score identifies patients with different risks of bleeding when combining aspirin and oral anticoagulation. The ABC-bleeding risk score may, therefore, be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease.

Serial measurement of interleukin‐6 and risk of mortality in anticoagulated patients with atrial fibrillation: Insights from ARISTOTLE and RE‐LY trials

BackgroundThe inflammatory biomarker interleukin‐6 (IL‐6) is associated with mortality in atrial fibrillation (AF). ObjectiveTo investigate if repeated IL‐6 measurements improve the prognostication for stroke or systemic embolism, major bleeding, and mortality in anticoagulated patients with AF. MethodsIL‐6 levels by ELISA were measured at study entry and at 2 months in 4830 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with 1.8 years median follow‐up. In the Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) trial, IL‐6 was measured at study entry, 3, 6, and 12 months in 2559 patients with 2.0 years median follow‐up. Associations between a second IL‐6 measurement and outcomes, adjusted for baseline IL‐6, clinical variables, and other cardiovascular biomarkers, were analyzed by Cox regression. ResultsMedian IL‐6 levels were 2.0 ng/L (interquartile range [IQR] 1.30‐3.20) and 2.10 ng/L (IQR 1.40‐3.40) at the two time‐points in ARISTOTLE, and, in RE‐LY, 2.5 ng/L (IQR 1.6‐4.3), 2.5 ng/L (IQR 1.6‐4.2), 2.4 ng/L (IQR 1.6, 3.9), and 2.4 ng/L (IQR 1.5, 3.9), respectively. IL‐6 was associated with mortality; hazard ratios per 50% higher IL‐6 at 2 or 3 months, respectively, were 1.32 (95% confidence interval, 1.23‐1.41; P < .0001) in ARISTOTLE, and 1.11 (1.01‐1.22, P = .0290) in RE‐LY; with improved C index from 0.74 to 0.76 in ARISTOTLE, but not in the smaller RE‐LY cohort. There were no consistent associations with second IL‐6 and stroke or systemic embolism, or major bleeding. ConclusionsPersistent systemic inflammatory activity, assessed by repeated IL‐6 measurements, is associated with mortality independent of established clinical risk factors and other strong cardiovascular biomarkers in anticoagulated patients with AF.

Association of Different Estimates of Renal Function With Cardiovascular Mortality and Bleeding in Atrial Fibrillation.

BackgroundWe compared different methods of estimated glomerular filtration rate (eGFR) and their association with cardiovascular death and major bleeding in 14 980 patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.Methods and ResultseGFR was calculated using equations based on creatinine (Cockcroft‐Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration [CKD‐EPI]) and/or cystatin C (CKD‐EPICysC and CKD‐EPICysC+Creatinine). These 5 eGFR equations, as well as the individual variables that are used in these equations, were assessed for correlation and discriminatory ability for cardiovascular death and major bleeding. The median age was 70.0 years, and 35.6% were women. The median eGFR was highest with Cockcroft‐Gault (74.1 mL/min) and CKD‐EPICysC (74.2 mL/min), and lowest with Modification of Diet in Renal Disease (66.5 mL/min). Correlation between methods ranged from 0.49 (Cockroft‐Gault and CKD‐EPICysC) to 0.99 (Modification of Diet in Renal Disease and CKD‐EPI). Among the eGFR equations, those based on cystatin C yielded the highest C indices for cardiovascular death and major bleeding: 0.628 (CKD‐EPICysC) and 0.612 (CKD‐EPICysC+Creatinine), respectively. A model based on the variables within the different eGFR equations (age, sex, weight, creatinine, and cystatin C) yielded the highest discriminatory value for both outcomes, with a C index of 0.673 and 0.656, respectively.ConclusionsIn patients with atrial fibrillation on anticoagulation, correlation between eGFR calculated using different methods varied substantially. Cystatin C–based eGFRs seem to provide the most robust information for predicting death and bleeding. A model based on the individual variables within the eGFR equations, however, provided the highest discriminatory value. Our findings may help refine risk stratification in patients with atrial fibrillation and define how renal function should be determined in future atrial fibrillation studies.RegistrationURL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00412984.

Clinical and Pharmacological Effects of Apixaban Dose Adjustment in the ARISTOTLE Trial

BackgroundIn the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and ≥2 dose-adjustment criteria (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dl [133 μmol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin. ObjectivesThe purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes. MethodsPatients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily). ResultsPatients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p < 0.0001) than those receiving the standard dose. In patients with ≥2 dose-adjustment criteria, reductions in D-dimers (p interaction = 0.20) and PF1+2 (p interaction = 0.55) were consistent with those observed in the standard-dose population. Patients with ≥2 dose-adjustment criteria (n = 751) were at higher risk for stroke/systemic embolism, major bleeding, and all-cause death than the standard-dose population (0 or 1 dose-adjustment criterion, n = 17,322). The effect of apixaban 2.5 mg twice daily versus warfarin in the ≥2 dose-adjustment criteria population was consistent with the standard dose in the reductions in stroke or systemic embolism (p interaction = 0.26), major bleeding (p interaction = 0.25), and death (p interaction = 0.72). ConclusionsApixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984)

Patients With Atrial Fibrillation Taking Nonsteroidal Anti-Inflammatory Drugs and Oral Anticoagulants in the ARISTOTLE Trial.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin. The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models. Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11-2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16-2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome. A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Effects of apixaban compared with warfarin as gain in event-free time - a novel assessment of the results of the ARISTOTLE trial.

A novel approach to determine the effect of a treatment is to calculate the delay of event, which estimates the gain of event-free time. The aim of this study was to estimate gains in event-free time for stroke or systemic embolism, death, bleeding events, and the composite of these events, in patients with atrial fibrillation randomized to either warfarin or apixaban in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial (ARISTOTLE). The ARISTOTLE study was a randomized double-blind trial comparing apixaban with warfarin. Laplace regression was used to estimate the delay in time to the outcomes between the apixaban and the warfarin group in 6, 12, 18 and 22 months of follow-up. The gain in event-free time for apixaban versus warfarin was 181 (95% confidence interval 76 to 287) days for stroke or systemic embolism and 55 (-4 to 114) days for death after 22 months of follow-up. The corresponding gains in event-free times for major and intracranial bleeding were 206 (130 to 281) and 392 (249 to 535) days, respectively. The overall gain for the composite of all these events was a gain of 116 (60 to 171) days. In patients with atrial fibrillation, 22 months of treatment with apixaban, as compared with warfarin, provided gains of approximately 6 months in event-free time for stroke or systemic embolism, 7 months for major bleeding and 13 months for intracranial bleeding.

Gastrointestinal bleeding in patients with atrial fibrillation treated with Apixaban or warfarin: Insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial

A history of gastrointestinal bleeding (GIB) in patients with atrial fibrillation (AF) may impact decisions about anticoagulation treatment. We sought to determine whether prior GIB in patients with AF taking anticoagulants was associated with an increased risk of stroke or major hemorrhage. We analyzed key efficacy and safety outcomes in patients with prior GIB in ARISTOTLE. Centrally adjudicated outcomes according to GIB history were analyzed using Cox proportional hazards models adjusted for randomized treatment and established risk factors. A total of 784 (4.3%) patients had prior GIB events (321 [41%] lower, 463 [59%] upper); 215 (27%) occurred <1 year before study enrollment. Patients with prior GIB were older, had more comorbidities, and higher CHADS2 and HAS-BLED scores than those with no GIB. Major GIB occurred more frequently in those with prior GIB (lower: aHR 1.72, 95% CI 0.86-3.42; upper: aHR 3.13, 95% CI 1.97-4.96). This association with major GIB was more pronounced in patients with GIB <1 year before randomization versus no recent GIB (recent lower: aHR 2.58, 95% CI 0.95-7.01; recent upper: aHR 5.16, 95% CI 2.66-10.0). There was no association between prior GIB and risk of stroke/systemic embolism or all-cause death. In those with prior GIB, the apixaban versus warfarin relative risks for stroke/systemic embolism, hemorrhagic stroke, death, or major bleeding were consistent with the results of the overall trial. In patients with AF on oral anticoagulants, prior GIB was associated with an increased risk of subsequent major GIB but not stroke, intracranial bleeding, or all-cause mortality. For the key outcomes of stroke, hemorrhagic stroke, death, and major bleeding, we found no evidence that the treatment effect (apixaban vs. warfarin) was modified by a history of GIB.

Characteristics and Outcomes of Atrial Fibrillation in Patients With Thyroid Disease (from the ARISTOTLE Trial)

Whether patients with atrial fibrillation (AF) and thyroid disease are clinically distinct from those with AF and no thyroid disease is unknown. Furthermore, the effectiveness of anticoagulation for prevention of AF-related thromboembolic events in patients with thyroid disease has not been adequately studied. Patients enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, which compared apixaban with warfarin in patients with AF (n = 18,201), were categorized by thyroid disease history at randomization (hypothyroidism, hyperthyroidism, and no thyroid disease). Adjusted hazard ratios derived from Cox models were used to compare outcomes by thyroid disease history. Associations between randomized treatment and outcomes by thyroid disease history were examined using Cox models with interaction terms. A total of 18,021/18,201 (99%) patients had available thyroid disease history at randomization: 1,656 (9%) had hypothyroidism, 321 (2%) had hyperthyroidism, and 16,044 (89%) had no thyroid disease. When compared with those without a history of thyroid disease, patients with hypo- or hyperthyroidism were more likely to be female (60.4% vs 32.1%; 52.0% vs 32.1%; both p <0.0001). Patients with hypothyroidism were older (73 vs 70 years, p <0.0001) and more likely to have had previous falls (8.7% vs 4.3%, p <0.0001). There was no difference in clinical outcomes by thyroid disease history. The benefit of apixaban compared with warfarin was similar regardless of thyroid disease history (interaction p >0.10). In conclusion, despite differences in baseline characteristics of patients with and without thyroid disease, their clinical outcomes were similar. The benefit of apixban compared with warfarin was preserved regardless of thyroid disease history.

How does blood pressure change in hypertensive patients with atrial fibrillation after successful electrical cardioversion?

How does blood pressure change in hypertensive patients with atrial fibrillation after successful electrical cardioversion?

The efficacy and safety of apixaban versus warfarin are preserved in patients with atrial fibrillation and extreme body weight: Insights from the ARISTOTLE Study

The use of anticoagulation therapy for obese patients with atrial fibrillation (AF) who are at increased risk for stroke is challenging. Recent guidelines caution against the use of non-vitamin K antagonists oral anticoagulants (NOACs) in patients with extreme body weight (≥ 120 kg) due to lack of data in this group. Our aim is to study the efficacy and safety of apixaban versus warfarin in obese patients with AF. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study was a randomized trial, comparing apixaban with warfarin in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary efficacy and safety outcomes were stroke or systemic embolism and ISTH major bleeding. Death from any cause was a secondary endpoint. We estimated the randomized treatment effect (apixaban vs. warfarin) stratified by body weight (< 120 kg, ≥ 120 kg) using a Cox regression model. Of the 18,139 patients who had weight and outcomes data recorded, 17,104 (94%) patients were < 120 kg and 1035 (6%) had a weight ≥ 120 kg. Fifty percent of patients ≥ 120 kg were randomized to apixaban. Patients in the extreme body weight group were younger (median 62 years, IQR 56–97 vs 70 years, IQR 63–76; P < 0.001), less commonly female (15.8% vs 36.4%; P < 0.001), with a lower CHADS2 (mean 1.95, SD 0.93 vs 2.13, SD 1.11) than patients < 120 kg. The efficacy and safety of apixaban versus warfarin appear to be similar in patients with extreme body weight when compared with non-obese subgroup of patients. Larger studies of patients with extreme body weight treated with NOACs are warranted.