Evaluation Of Long-Term Anticoagulation Therapy Research Articles

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.

Effect of pre-procedural anticoagulation in patients undergoing ablation: a meta-analysis of randomized controlled trials

Abstract Background Atrial fibrillation (AF) is the most common type of arrhythmia seen in a clinical setting. Patients have a high risk of stroke, especially in the first two years of diagnosis. Anticoagulation therapy is prescribed to patients with a high CHAD2S2-VASc score. Based on recent evidence, catheter ablation (CA) is emerging as the preferred first-line treatment of modality. The benefit of interruption of anticoagulation before CA is unclear. Interruption of anticoagulation and insertion of a foreign body during CA can lead to an increased risk of thromboembolism (TE). Anticoagulation is interrupted before the procedure to balance the risk of TE and bleeding. Objective To assess the risk of bleeding and TE in patients undergoing CA with uninterrupted versus interrupted anticoagulation. Methods We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) strategy to search PubMed/MEDLINE, EMBASE, and Cochrane databases from inception till January 2023. We included randomized controlled trials and excluded observational studies. The data was extracted from full texts. Data Random effects model and Mantel-Haenszel method were used to calculate pooled risk ratio and 95% confidence interval. Results A total of 10 studies were included, with 4,584 participants. The risk of TE [1.76; 95% confidence interval (CI): 0.33, 9.46] and bleeding [1.10; 95% CI: 0.59, 2.05] did not change significantly with the interruption of all anticoagulation agents. Similarly, interruption of individual anticoagulants such as heparin [0.81, 95% CI: 0.19, 3.39], vitamin K antagonists (VKA) [9.21, 95% CI: 0.02, 5627.42], and direct oral anticoagulants (DOAC) [1.36, 95% CI: 0.26, 7.23] did not show any change in the risk of TE. There was no significant change in the risk of bleeding with heparin discontinuation (Figure 1). Conclusion Our study supports recent trials such as Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) and emerging data that support uninterrupted anticoagulation prior to ablation as there is no increased risk of bleeding or TE.

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

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). 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. 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). In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

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.

Personalizing the decision of dabigatran versus warfarin in atrial fibrillation: A secondary analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) trial.

The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial demonstrated that higher-risk patients with atrial fibrillation had lower rates of stroke or systemic embolism and a similar rate of major bleeding, on average, when treated with dabigatran 150mg compared to warfarin. Since population-level averages may not apply to individual patients, estimating the heterogeneity of treatment effect can improve application of RE-LY in clinical practice. For 18040 patients randomized in RE-LY, we used patient-level data to develop multivariable models to predict the risk for stroke or systemic embolism and for major bleeding including all three treatment groups (dabigatran 110mg, dabigatran 150mg, and warfarin) over a median follow up of 2.0 years. The mean predicted absolute risk reduction (ARR) for stroke/systemic embolism with dabigatran 150mg compared to warfarin was 1.32% (range 11.6% lower to 3.30% higher risk). The mean predicted ARR for bleeding was 0.41% (range 8.93% lower to 63.4% higher risk). Patients with increased stroke/systemic embolism risk included those with prior stroke/TIA (OR 2.01), diabetics on warfarin (OR 2.00), and older patients on dabigatran 150mg (OR 1.68 for every 10-year increase). Major bleeding risk was higher in patients on aspirin (OR 1.25), with a history of diabetes (OR 1.34) or prior stroke/TIA (OR 1.22), those with heart failure on dabigatran 110mg (OR 1.52), older patients on either dabigatran 110mg or 150mg (OR 1.57 and 1.93, respectively, for each 10-year increase), and heavier patients on dabigatran 110mg or 150mg; patients in a region outside the United States and Canada and with better renal function had lower bleeding risk. There is substantial heterogeneity in the benefits and risks of dabigatran relative to warfarin among patients with atrial fibrillation. Using individualized estimates may enable shared decision making and facilitate more appropriate use of dabigatran; as such, it should be prospectively tested. www.clinicaltrials.gov number, NCT00262600.

Outpatient Prescription Practices in Patients with Atrial Fibrillation (From the NCDR PINNACLE Registry)

This study sought to evaluate inappropriate prescribing practices in an atrial fibrillation (AF) population, as outlined by the 2016 ACC/AHA Clinical Performance and Quality Measures for Adults with Atrial Fibrillation or Atrial Flutter document. The 2016 AF quality measures document specified medications to avoid in certain AF populations, including aspirin and anticoagulant combination therapy in patients without cardiovascular disease, and non-dihydropyridine calcium channel blockers in patients with reduced ejection fraction. Using data from the NCDR PINNACLE registry, a national outpatient cardiology practice registry, we assessed rates of inappropriate prescription of two types of medications among AF outpatients from 5/1/2008-5/1/2016. Overall rates of inappropriate prescription and variation by practice were calculated. Patient and practice factors associated with inappropriate prescription were assessed in adjusted analyses. A total of 107,759 of 658,250 (16.4%) patients without cardiovascular disease were inappropriately prescribed an antiplatelet and anticoagulant together, and 5,731 of 150,079 (3.8%) patients with reduced ejection fraction were inappropriately prescribed a non-dihydropyridine calcium channel blocker. Overall, 14.8% of AF patients were prescribed medications that were not recommended. Both patient and practice factors were associated with inappropriate prescribing, and the adjusted practice-level median odds ratio for inappropriate prescription was 1.70 (95% CI: 1.61-1.82), indicating a 70% likelihood that 2 random practices would treat identical AF patients differently. In a large registry of AF patients treated in cardiology practices, overall rates of inappropriate prescription practices, as defined by the 2016 AF quality measures, were relatively low, but significant practice variation was present.

Comparison of Direct Oral Anticoagulant Use for the Treatment of Non-Valvular Atrial Fibrillation in Pivotal Clinical Trials vs. the Real-World Setting: A Population-Based Study from Southern Italy.

Patients enrolled into pivotal randomized controlled trials (RCTs) may differ substantially from those treated in a real-world (RW) setting, which may result in a different benefit–risk profile. The aim of the study was to assess the external validity of pivotal RCT findings concerning direct oral anticoagulants (DOACs) for the treatment of nonvalvular atrial fibrillation (NVAF) by comparing patients recruited in RCTs to those treated with DOACs registered in a southern Italian local health unit (LHU) in the years 2013–2017. The Palermo LHU claims database was used to describe the baseline characteristics of incident DOAC users (washout > 1 year) with NVAF compared with those of enrolled patients in DOAC pivotal RCTs. In the RW, DOAC treatment discontinuation was calculated during the follow-up and compared with DOAC treatment discontinuation of enrolled patients in DOAC pivotal RCTs. Rates of effectiveness and safety outcomes during the follow-up were calculated in an unmatched and in a simulated RCT population, by matching individual incidental RW and RCT DOAC users (excluding edoxaban users) on age, sex, and CHADS2 score. Overall, 42,336 and 7092 incident DOAC users with NVAF were identified from pivotal RCTs and from the RW setting, respectively. In RCTs, DOAC use was more common among males (62.6%) compared with an almost equal sex distribution in the RW. RCT patients were younger (mean age ± standard deviation: 70.7 ± 9.2 years) than RW patients (76.0 ± 8.6 years). Compared with RCTs, a higher proportion of RW dabigatran users (30.4% vs. 19.6%) and a lower proportion of RW apixaban (15.9% vs. 25.3%) and rivaroxaban (20.4% vs. 23.7%) users discontinued the treatment during the follow-up (p-value < 0.001). The rate of ischemic stroke was lower in RW high-dose dabigatran users (unmatched/-matched population: 0.40–0.11% per year) than in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) population (0.93% per year). Major bleeding rates were lower in RW users than in RCT users. In conclusion, except for dabigatran, a lower proportion of DOAC discontinuers was observed in the real-world than in pivotal RCT settings. This study provides reassurance to practicing physicians that DOAC use appears to be effective in stroke prevention and is likely safer in RW patients than in RCT enrolled patients. These results may be related to a lower burden of comorbidities despite more advanced age in the RW population compared to the pivotal RCT population.

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...

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.

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.

Tailoring anticoagulant treatment of patients with atrial fibrillation using a novel bleeding risk score

ObjectivesCurrent international guidelines advocate the application of bleeding risk scores only to identify modifiable risk factors, but not to withhold treatment in patients at high risk of bleeding. VTE-BLEED (ActiVe...

Use of dabigatran with antiretrovirals.

Theoretical and untested interactions between antiretrovirals and direct-acting oral anticoagulants have limited the use of this new class of anticoagulant in people with HIV infection. This case series, the first of its kind, reports on the successful concurrent use of the direct-acting oral anticoagulant dabigatran and antiretroviral therapy. This series involved 14 patients requiring anticoagulation for management of atrial fibrillation, who were either unable or unwilling to take warfarin, and who were receiving concurrent treatment for HIV infection. Participants were treated with dabigatran with dose monitoring to establish the safety and efficacy of concurrent use with antiretrovirals. All were commenced on 110mg twice daily, increased to 150mg twice daily if the trough level was < 69.3ng/mL. In the 14 patients treated with dabigatran and antiretrovirals, there were no thromboembolic or bleeding complications. Dabigatran treatment was discontinued in one patient because of undetectable dabigatran levels despite dose escalation. Dabigatran levels fell within the fivefold variance seen in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study at a dose of either 110 or 150 mg twice daily. This case series represents the largest published population to date successfully receiving antiretroviral and direct-acting oral anticoagulant therapy. Given the significant health care burden faced by people living with HIV, the availability of safe anticoagulant therapy without the requirement for monitoring is an important option in this patient population.

Reasons for hospitalization and risk of mortality in patients with atrial fibrillation treated with dabigatran or warfarin in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial.

Hospitalizations are common among patients with atrial fibrillation. This article aimed to analyse the causes and consequences of hospitalizations occurring during the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial. The RE-LY database was used to evaluate predictors of hospitalization using multivariate regression modelling. The relationship between hospitalization and subsequent major adverse cardiac events was evaluated in a time dependent Cox proportional-hazard modelling. Of the 18 113 patients in RE-LY, 7200 (39.8%) were hospitalized at least once during a mean follow-up of 2 years. First hospitalization rates were 2312 (39.5%) for dabigatran etexilate (DE) 110, 2430 (41.6%) for DE 150, and 42.6% (N = 2458) for warfarin. Hospitalization was associated with post-discharge death [absolute event rate 9.1% vs. 2.2%; adjusted hazard ratio (HR) 3.6, 95% confidence interval (CI) 3.2-4.0, P < 0.0001], vascular death (adjusted HR 2.9, 95% CI 2.5-3.3, P < 0.0001), and sudden cardiac death (adjusted HR 2.3; 95% CI 1.8-2.9, P < 0.0001). Cardiovascular hospitalization was also associated with an increased risk of post-discharge death (adjusted HR 2.8, 95% CI 2.5-3.2, P < 0.0001), vascular death (adjusted HR 2.8, 95% CI 2.4-3.2, P < 0.0001), and sudden cardiac death (adjusted HR 2.1, 95% CI 1.6-2.7, P < 0.0001) compared with patients not hospitalized for any cardiovascular reason. Hospitalizations are associated an increased risk of with death and cardiovascular death in patients with atrial fibrillation.

Periprocedural Outcomes of Direct Oral Anticoagulants Versus Warfarin in Nonvalvular Atrial Fibrillation.

Direct oral anticoagulants (DOACs) are surpassing warfarin as the anticoagulant of choice for stroke prevention in nonvalvular atrial fibrillation. DOAC outcomes in elective periprocedural settings have not been well elucidated and remain a source of concern for clinicians. The aim of this meta-analysis was to evaluate the periprocedural safety and efficacy of DOACs versus warfarin in patients with nonvalvular atrial fibrillation. We reviewed the literature for data from phase III randomized controlled trials comparing DOACs with warfarin in the periprocedural period among patients with nonvalvular atrial fibrillation. Substudies from 4 trials (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation], and ENGAGE-AF [Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation]) were included in the meta-analysis. DOACs as a group and warfarin were compared in terms of the 30-day pooled risk for stroke/systemic embolism, major bleeding, and death, according to whether the study drug was interrupted or not periprocedurally. The overall relative risk (RR) was estimated with a random-effects model. The I2 test was used to assess heterogeneity in RR among the studies. In the uninterrupted anticoagulant strategy, there were no differences in the rates of stroke/systemic embolism (pooled risk, 0.6% [29 events/4519 procedures] versus 1.1% [31/2971]; RR, 0.70; 95% confidence interval [CI], 0.41-1.18) and death (1.4% versus 1.8%; RR, 0.77; 95% CI, 0.53-1.12) between DOACs and warfarin and significantly fewer major bleeding events (2.0% versus 3.3%; RR, 0.62; 95% CI, 0.47-0.82) with DOACs compared to warfarin. Under an interrupted strategy, there was no significant difference between DOACs versus warfarin for stroke/systemic embolism (0.4% [41/9260] versus 0.5% [31/7168]; RR, 0.95; 95% CI, 0.59-1.55), major bleeding (2.1% versus 2.0%; RR, 1.05; 95% CI, 0.85-1.30), and death (0.7% versus 0.6%; RR, 1.24; 95% CI, 0.76-2.04). The studies were homogeneous ( I2=0.0%) for all calculated pooled associations except for the RR of death in the interrupted strategy ( I2=26.3%). The short-term safety and efficacy of DOACs and warfarin are not different in patients with nonvalvular atrial fibrillation periprocedurally. Under an uninterrupted anticoagulation strategy, DOACs are associated with a 38% lower risk of major bleeding compared with warfarin.

Simulation for Predicting Effectiveness and Safety of New Cardiovascular Drugs in Routine Care Populations.

In the presence of heterogeneity of treatment effect (HTE), the average treatment effect from a randomized controlled trial (RCT) may not be applicable to different patients, such as those in observational settings. Our objective was to develop a novel approach that uses individual-level simulation to expand RCT results to target patient populations in the presence of HTE. For this purpose, we compared the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, and two observational studies that compared benefits and risks of dabigatran to warfarin in patients with atrial fibrillation. We developed a simulation model that replicates the rates of ischemic stroke and major bleeding observed in RE-LY using published outcome risk models and participants' baseline characteristics. We used our validated simulation model to predict what the results of the RCT would have been had it been conducted in populations similar to those in the observational studies.

Predicting Major Bleeding in Ischemic Stroke Patients With Atrial Fibrillation.

Performance of risk scores for major bleeding in patients with atrial fibrillation and a previous transient ischemic attack or ischemic stroke is not well established. We aimed to validate risk scores for major bleeding in patients with atrial fibrillation treated with oral anticoagulants after cerebral ischemia and explore the net benefit of oral anticoagulants among bleeding risk categories. We analyzed 3623 patients with a history of transient ischemic attack or stroke included in the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). We assessed performance of HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count or function, hypertension [uncontrolled], anemia, genetic factors, excessive fall risk, and stroke), Shireman, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and ORBIT scores (older age, reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) with C statistics and calibration plots. Net benefit of oral anticoagulants was explored by comparing risk reduction in ischemic stroke with risk increase in major bleedings on warfarin. During 6922 person-years of follow-up, 266 patients experienced a major bleed (3.8 per 100 person-years). C statistics ranged from 0.62 (Shireman) to 0.67 (ATRIA). Calibration was poor for ATRIA and moderate for other models. The reduction in recurrent ischemic strokes on warfarin was larger than the increase in major bleeding risk, irrespective of bleeding risk category. Performance of prediction models for major bleeding in patients with cerebral ischemia and atrial fibrillation is modest but comparable with performance in patients with only atrial fibrillation. Bleeding risk scores cannot guide treatment decisions for oral anticoagulants but may still be useful to identify modifiable risk factors for bleeding. Clinical usefulness may be best for ORBIT, which is based on a limited number of easily obtainable variables and showed reasonable performance.

Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial

To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial. GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1, <1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3, >1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment. GDF-15 concentrations were <1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and >1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P < .0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P < .0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores. In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.

Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation— the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study

AimWe tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF).Methods and resultsThis is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75–1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49–0.95). In patients with LVH, the rates of primary outcome were 3.21%/year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32–0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29–0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH.ConclusionsLVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status.Clinical trial registration http:www.clinicaltrials.gov. Unique identifier: NCT00262600.

Comparison of Stroke- and Bleed-Specific Healthcare Resource Utilization and Costs Among Patients with Non-Valvular Atrial Fibrillation, Newly Treated with Dabigatran or Warfarin

INTRODUCTION: In the pivotal Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) clinical trial, dabigatran was associated with lower rates of stroke and systemic embolism compared to adjusted-dose warfarin. However, real-world evidence comparing stroke- and bleed-specific healthcare resource utilization (HCRU), costs, length of stay (LOS) per hospitalization and readmissions in non-valvular atrial fibrillation (NVAF) patients newly treated with dabigatran or warfarin is limited.METHODS: Using a nationwide administrative claims database in the US, a retrospective matched-cohort of newly diagnosed NVAF patients aged ≥18 years treated with dabigatran or warfarin in 01/01/2011-12/31/2013 was evaluated. Index date was the first dabigatran or warfarin claim date. All patients had data for 12 months before the index date and a maximum follow-up of 12 months or until discontinuation or switch, disenrollment, end of study period, or inpatient death. Propensity scores were used to match dabigatran and warfarin users 1:1. Stroke or bleed-specific HCRU and costs were defined as hospitalizations with stroke or bleed as the primary discharge diagnosis and outpatient claims with stroke or bleed diagnosis in any position. Percentage and incidence rate (IR) of first stroke or bleed per 100 person-years and associated 95% confidence interval (CI) were reported. Stroke- and bleed-specific per-patient-per-year (PPPY) HCRU and costs were analyzed for all patients. Among those with a hospitalization for stroke or bleed, LOS and readmissions of patients who were admitted and discharged home were reported. Cox regression examined the risk of stroke or bleed and logistic regression assessed the impact on stroke- and bleed-specific readmission between dabigatran and warfarin users.RESULTS: A total of 18,980 dabigatran patients were matched to corresponding warfarin patients. Of these, the percentage of dabigatran patients with stroke (0.5%, n=87 vs 0.8%, n=142; P<0.001) or bleed (1.2%, n=227 vs 1.6%, n=294; P=0.003) was significantly lower than warfarin patients. The IR (95% CI) of stroke [0.65 (0.51-0.78) vs. 1.06 (0.89-1.24)] and bleed [1.69 (1.47-1.91) vs. 2.20 (1.95-2.46)] was also lower in dabigatran patients compared to warfarin patients. After adjustment, compared to warfarin patients, the hazard ratio (HR) of having a first stroke or bleed was significantly lower in dabigatran patients [(HR = 0.60 (95% CI = 0.46-0.79)) and (HR = 0.76 (95% CI = 0.64-0.91)), respectively].Among all NVAF patients, dabigatran users had a significantly lower number of stroke-specific hospitalizations (0.007 vs 0.013, P<0.001) and outpatient visits (0.304 vs 0.450, P<0.001) compared to warfarin patients. Similarly, dabigatran users had significantly lower bleed-specific hospitalizations (0.024 vs 0.035, P=0.008) and outpatient visits (0.820 vs 0.920, P=0.018). Dabigatran users had significantly lower stroke-specific outpatient visit costs ($84 vs $144, P=0.01) and bleed-specific hospitalization costs ($360 vs $612, P=0.007). There was no significant difference observed in stroke-specific hospitalization costs and bleed-specific outpatient costs between the two groups.Among dabigatran patients with a stroke or bleed, average LOS was significantly lower compared to warfarin patients [(4.74 days vs 5.70 days) and (4.30 days vs 4.60 days), both P<0.001]. Stroke-related 30-day readmissions did not significantly differ between dabigatran and warfarin patients (0.4%, n=14 vs 0.6%, n=25, P=0.078). However, the odds of stroke-related readmission were significantly lower in dabigatran compared to warfarin users [Odds Ratio (OR) = 0.59 (95% CI = 0.51-0.69)]. Bleed-related 30-day readmissions were significantly lower for dabigatran than warfarin users (0.8%, n=30 vs. 1.5%, n=59, P=0.002); similar results were found after adjustment [OR=0.54 (95% CI = 0.47-0.63)].CONCLUSION: Using real-world data of newly diagnosed NVAF patients, dabigatran users had a lower risk of stroke or bleed than warfarin users. Dabigatran users had lower stroke- and bleed-specific HCRU (including LOS per hospitalization), and lower odds of stroke- and bleed-specific readmissions compared to warfarin users. Also, costs associated with bleed-specific hospitalizations and stroke-specific outpatient visits were significantly lower for dabigatran users compared to warfarin users. DisclosuresSong:Truven Health Analytics: Employment; Amgen: Other: This study was funded by Amgen.. Gilligan:Truven Health Analytics, an IBM Company: Employment. Sander:Boehringer Ingelheim: Employment. Smith:Truven Health Analytics: Employment.

Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender

The oral anticoagulant prodrug dabigatran etexilate (DABE) is sequentially metabolized by intestinal carboxylesterase 2 (CES2) and hepatic carboxylesterase 1 (CES1) to form its active metabolite dabigatran (DAB). A recent genome-wide association study reported that the CES1 single nucleotide polymorphisms (SNPs) rs2244613 and rs8192935 were associated with lower DAB plasma concentrations in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) study participants. In addition, gender differences in exposure to DAB were observed in clinical studies. The aim of this study was to examine the effect of CES1 genetic polymorphisms and gender on DABE activation using several in vitro approaches. The genotypes of the CES1 SNPs rs2244613, rs8192935, and the known loss-of-function CES1 variant rs71647871 (G143E), and the activation of DABE and its intermediate metabolites M1 and M2 were determined in 104 normal human liver samples. DABE, M1, and M2 activations were found to be impaired in human livers carrying the G143E variant. However, neither rs2244613 nor rs8192935 was associated with the activation in human livers. The incubation study of DABE with supernatant fractions (S9) prepared from the G143E-transfected cells showed that the G143E is a loss-of-function variant for DABE metabolism. Moreover, hepatic CES1 activity on M2 activation was significantly higher in female liver samples than male. Our data suggest that CES1 genetic variants and gender are important contributing factors to variability in DABE activation in humans. A personalized DABE treatment approach based on patient-specific CES1 genotypes and sex may have the potential to improve the efficacy and safety of DABE pharmacotherapy.