BACKGROUND:Compared with the general population, patients with advanced chronic kidney disease have a >10-fold higher burden of atrial fibrillation. Limited data are available guiding the use of ...nonvitamin K antagonist oral anticoagulants in this population.
METHODS:We compared the safety of apixaban with warfarin in 269 patients with atrial fibrillation and advanced chronic kidney disease (defined as creatinine clearance CrCl 25 to 30 mL/min) enrolled in the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). Cox proportional models were used to estimate hazard ratios for major bleeding and major or clinically relevant nonmajor bleeding. We characterized the pharmacokinetic profile of apixaban by assessing differences in exposure using nonlinear mixed effects models.
RESULTS:Among patients with CrCl 25 to 30 mL/min, apixaban caused less major bleeding (hazard ratio, 0.34 95% CI, 0.14–0.80) and major or clinically relevant nonmajor bleeding (hazard ratio, 0.35 95% CI, 0.17–0.72) compared with warfarin. Patients with CrCl 25 to 30 mL/min randomized to apixaban demonstrated a trend toward lower rates of major bleeding when compared with those with CrCl >30 mL/min (P interaction=0.08) and major or clinically relevant nonmajor bleeding (P interaction=0.05). Median daily steady-state areas under the curve for apixaban 5 mg twice daily were 5512 ng/(mL·h) and 3406 ng/(mL·h) for patients with CrCl 25 to 30 mL/min or >30 mL/min, respectively. For apixaban 2.5 mg twice daily, the median exposure was 2780 ng/(mL·h) for patients with CrCl 25 to 30 mL/min. The area under the curve values for patients with CrCl 25 to 30 mL/min fell within the ranges demonstrated for patients with CrCl >30 mL/min.
CONCLUSIONS:Among patients with atrial fibrillation and CrCl 25 to 30 mL/min, apixaban caused less bleeding than warfarin, with even greater reductions in bleeding than in patients with CrCl >30 mL/min. We observed substantial overlap in the range of exposure to apixaban 5 mg twice daily for patients with or without advanced chronic kidney disease, supporting conventional dosing in patients with CrCl 25 to 30 mL/min. Randomized, controlled studies evaluating the safety and efficacy of apixaban are urgently needed in patients with advanced chronic kidney disease, including those receiving dialysis.
REGISTRATION:URLhttps://www.clinicaltrials.gov; Unique identifierNCT00412984.
Most patients with atrial fibrillation (AF) and risk factors for stroke require oral anticoagulation (OAC) to decrease the risk of stroke or systemic embolism. This is now best achieved with direct ...oral anticoagulants that decrease the risk of intracranial bleeding compared with vitamin K antagonists. Of note, approximately 5% to 10% of patients undergoing percutaneous coronary intervention have AF, which complicates antithrombotic therapy in daily practice, because the guidelines recommend that these patients also receive dual antiplatelet therapy (DAPT) to reduce the risk of ischemic complications. However, combining OAC with DAPT, a strategy also known as triple antithrombotic therapy, is known to increase the risk of bleeding compared with the use of OAC or DAPT alone. Studies of direct oral anticoagulants are now emerging that show the favorable safety profile of double antithrombotic therapy with OAC and a P2Y
inhibitor in comparison with triple antithrombotic therapy including the use of vitamin K antagonists. The scope of this review is to provide an update on this topic as well as to discuss future directions in the management of antithrombotic therapy after percutaneous coronary intervention in AF patients requiring chronic OAC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level ...data.
We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (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), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs 95% CIs) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex.
A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 3.01% versus 1080/29 229 3.69%; HR, 0.81 95% CI, 0.74-0.89), death (2276/29 312 7.76% versus 2460/29 229 8.42%; HR, 0.92 95% CI, 0.87-0.97), and intracranial bleeding (184/29 270 0.63% versus 409/29 187 1.40%; HR, 0.45 95% CI, 0.37-0.56), but no statistically different hazard of major bleeding (1479/29 270 5.05% versus 1733/29 187 5.94%; HR, 0.86 95% CI, 0.74-1.01), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 3.96% versus 1080/29 229 3.69%; HR, 1.06 95% CI, 0.95-1.19) but a lower hazard of intracranial bleeding (55/12 985 0.42% versus 409/29 187 1.40%; HR, 0.28 95% CI, 0.21-0.37), death (1082/13 049 8.29% versus 2460/29 229 8.42%; HR, 0.90 95% CI, 0.83-0.97), and major bleeding (564/12 985 4.34% versus 1733/29 187 5.94%; HR, 0.63 95% CI, 0.45-0.88). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (
=0.01) and lower creatinine clearance (
=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (
=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction
=0.02) and lower-dose DOACs (interaction
=0.01) versus warfarin.
Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.
This study sought to characterize major bleeding on the basis of the components of the major bleeding definition, to explore major bleeding by location, to define 30-day mortality after a major ...bleeding event, and to identify factors associated with major bleeding.
Apixaban was shown to reduce the risk of major hemorrhage among patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.
All patients who received at least 1 dose of a study drug were included. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. Factors associated with major hemorrhage were identified using a multivariable Cox model.
The on-treatment safety population included 18,140 patients. The rate of major hemorrhage among patients in the apixaban group was 2.13% per year compared with 3.09% per year in the warfarin group (hazard ratio HR 0.69, 95% confidence interval CI: 0.60 to 0.80; p < 0.001). Compared with warfarin, major extracranial hemorrhage associated with apixaban led to reduced hospitalization, medical or surgical intervention, transfusion, or change in antithrombotic therapy. Major hemorrhage followed by mortality within 30 days occurred half as often in apixaban-treated patients than in those receiving warfarin (HR 0.50, 95% CI: 0.33 to 0.74; p < 0.001). Older age, prior hemorrhage, prior stroke or transient ischemic attack, diabetes, lower creatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal anti-inflammatory drugs were independently associated with an increased risk.
Apixaban, compared with warfarin, was associated with fewer intracranial hemorrhages, less adverse consequences following extracranial hemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of major hemorrhage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events ...in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves.
We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio HR, 0.70; 95% confidence interval CI, 0.51-0.97 and HR, 0.84; 95%, CI 0.67-1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61-1.04 and HR, 0.65; 95% CI, 0.55-0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84-1.22 and HR, 0.84; 95% CI, 0.73-0.96; interaction P=0.10).
More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.
Atrial fibrillation (AF) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists (VKAs). Vitamin K antagonist use is limited, in part, by the high incidence of ...complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor, apixaban, is noninferior to warfarin at reducing the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine treatment duration. The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38; apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with apixaban is >1.38 times higher than with warfarin. ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism; whether apixaban has particular benefits in the warfarin-naïve population; whether it reduces the combined rate of stroke, systemic embolism, and death; and whether it impacts bleeding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objectives The aim of this study was to evaluate the prognostic value of high-sensitivity troponin T (hs-TnT) in addition to clinical risk factors and the CHA2 DS2 VASc (congestive heart failure, ...hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) risk score in patients with atrial fibrillation (AF). Background The level of troponin is a powerful predictor of cardiovascular events and mortality. Methods A total of 14,897 patients with AF were randomized to treatment with apixaban or warfarin in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial. The associations between baseline hs-TnT levels and outcomes were evaluated using adjusted Cox regression models. Results Levels of hs-TnT were measurable in 93.5% of patients; 75% had levels >7.5 ng/l, 50% had levels >11.0 ng/l, and 25% had levels >16.7 ng/l. During a median 1.9-year period, the annual rates of stroke or systemic embolism ranged from 0.87% in the lowest hs-TnT quartile to 2.13% in the highest hs-TnT quartile (adjusted hazard ratio HR: 1.94; 95% confidence interval CI: 1.35 to 2.78; p = 0.0010). The annual rates in the corresponding groups ranged from 0.46% to 4.24% (adjusted HR: 4.31; 95% CI: 2.91 to 6.37; p < 0.0001) for cardiac death and from 1.26% to 4.21% (adjusted HR: 1.91; 95% CI: 1.43 to 2.56; p = 0.0001) for major bleeding. Adding hs-TnT levels to the CHA2 DS2 VASc score improved the C statistic from 0.620 to 0.635 for stroke or systemic embolism (p = 0.0226), from 0.592 to 0.711 for cardiac death (p < 0.0001), and from 0.591 to 0.629 for major bleeding (p < 0.0001). Apixaban reduced rates of stroke, mortality, and bleeding regardless of the hs-TnT level. Conclusions Levels of hs-TnT are often elevated in patients with AF. The hs-TnT level is independently associated with an increased risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA2 DS2 VASc risk score. The benefits of apixaban as compared with warfarin are consistent regardless of the hs-TnT level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation ARISTOTLE; NCT00412984 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Device-detected atrial fibrillation (also known as subclinical atrial fibrillation or atrial high-rate episodes) is a common finding in patients with an implanted cardiac rhythm device and is ...associated with an increased risk of ischemic stroke. Whether oral anticoagulation is effective and safe in this patient population is unclear.
We performed a systematic review of MEDLINE and Embase for randomized trials comparing oral anticoagulation with antiplatelet or no antithrombotic therapy in adults with device-detected atrial fibrillation recorded by a pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy device, or implanted cardiac monitor. We used random-effects models for meta-analysis and rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). The review was preregistered (PROSPERO CRD42023463212).
From 785 citations, we identified 2 randomized trials with relevant clinical outcome data: NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes; 2536 participants) evaluated edoxaban, and ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; 4012 participants) evaluated apixaban. Meta-analysis demonstrated that oral anticoagulation with these agents reduced ischemic stroke (relative risk RR, 0.68 95% CI, 0.50-0.92; high-quality evidence). The results from the 2 trials were consistent (I
statistic for heterogeneity=0%). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85 95% CI, 0.73-0.99; I
=0%; moderate-quality evidence). There was no reduction in cardiovascular death (RR, 0.95 95% CI, 0.76-1.17; I
=0%; moderate-quality evidence) or all-cause mortality (RR, 1.08 95% CI, 0.96-1.21; I
=0%; moderate-quality evidence). Oral anticoagulation increased major bleeding (RR, 1.62 95% CI, 1.05-2.50; I²=61%; high-quality evidence).
The results of the NOAH-AFNET 6 and ARTESiA trials are consistent with each other. Meta-analysis of these 2 large randomized trials provides high-quality evidence that oral anticoagulation with edoxaban or apixaban reduces the risk of stroke in patients with device-detected atrial fibrillation and increases the risk of major bleeding.
Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed ...the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.
The association between cancer and clinical outcomes was assessed using Cox regression models. At baseline, 1236 patients (6.8%) had a history of cancer; 12.7% had active cancer, and 87.3% had remote cancer.
There were no significant associations between history of cancer and stroke/systemic embolism, major bleeding, or death. The effect of apixaban versus warfarin for the prevention of stroke/systemic embolism was consistent among patients with a history of cancer (event/100 patient-years = 1.4 vs 1.2; hazard ratio HR, 1.09; 95% confidence interval CI, 0.53-2.26) and no cancer (1.3 vs 1.6; HR, 0.77; 95% CI, 0.64-0.93) (P interaction = .37). The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, myocardial infarction, and death in active cancer (HR, 0.30; 95% CI, 0.11-0.83) versus without cancer (HR, 0.86; 95% CI, 0.78-0.95), but not in remote cancer (HR, 1.46; 95% CI, 1.01-2.10) (interaction P = .0028).
Cancer was not associated with a higher risk of stroke. The superior efficacy and safety of apixaban versus warfarin were consistent in patients with and without cancer. Our positive findings regarding apixaban use in patients with atrial fibrillation and cancer are exploratory and promising, but warrant further evaluation.
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