Apixaban Users Research Articles

Assessing methods to ascertain persistence and adherence of oral anticoagulants in patients with atrial fibrillation

BackgroundPersistence and adherence to oral anticoagulants (OACs) is crucial for its effectiveness in stroke prevention in atrial fibrillation (AF). We aimed to assess the impact of different ascertainment methods on estimated persistence rates. MethodsWe conducted a retrospective cohort study based on the Medicare claims data (01/01/2013-12/31/2019). We built an incident user cohort of OAC (apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin) prescription filling. We measured OAC medication persistence and adherence using the following approaches: 1) treatment-anniversary based persistence: if there is an active prescription overlapping the 180th and 365th day with vs. without a 15-day buffer period (i.e., overlapping with 165th-195th and 350th-380th day); 2) dispensing-gap-based persistence: if there is OAC discontinuation defined as having gap between prescriptions more than a threshold (e.g., 5 to 60 days) and secondarily, 3) proportion of days covered (PDC) adherence: proportion of days in which patient had filled medication available over the 365-day interval. ResultsWe identified 1,398,692 patients who initiated OACs during the study interval. With the treatment-anniversary based approach, only 51.2 to 65.4% of the patients persisted with the medication for either warfarin or DOACs at 180 days, and the number dropped to 43.4 to 60.7% at one year. Adding a 15-day buffer period increased the treatment-anniversary based persistence rates by 6.5 to 10.5%. When the allowable gap increased from 5 to 60 days, the persistence rates increased by 36.3 to 42.4% for all OACs. Apixaban users had the highest PDC (74 to 75%) over the 365 days, compared to other OACs (60 to 69%). ConclusionsWe found that the estimated persistence rates are sensitive to the choice of ascertainment methods. When reporting and comparing persistence findings using the claims database, definitions of OAC discontinuation must be clearly delineated.

Comparative effectiveness and safety of direct oral anticoagulants and warfarin in atrial fibrillation patients with dementia.

Developing an effective stroke prevention strategy is crucial for elderly atrial fibrillation (AF) patients with dementia. This is due to the limited and inconsistent evidence available on this topic. In this nationwide, population-based cohort study, we aim to compare the effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin in AF patients with dementia. We identified AF patients with dementia, aged 50 years or older, from Taiwan's National Health Insurance Research Database between 2010 and 2019. The primary outcome was a composite of hospitalizations due to ischemic stroke, acute myocardial infarction, intracranial hemorrhage, or major bleeding, as well as all-cause mortality. We used 1:1 propensity score matching and Cox proportional hazard models to adjust for confounding factors when comparing outcomes between warfarin and DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) users or warfarin and each individual DOAC. There were 2952 patients in the DOAC-warfarin matched cohort. The apixaban-, dabigatran-, edoxaban-, and rivaroxaban-warfarin matched cohorts had 2346, 2554, 1684, and 2938 patients, respectively. The DOAC group, when compared to warfarin, was associated with a lower risk of both the composite outcome (hazard ratio (HR), 0.81; 95% confidence interval (CI) 0.69-0.95) and ischemic stroke (HR 0.65; 95% CI 0.48-0.87). Apixaban (HR 0.79; 95% CI 0.66-0.94), dabigatran (HR 0.64; 95% CI 0.53-0.77), and rivaroxaban (HR 0.82; 95% CI 0.70-0.97) were also associated with a lower risk of the composite outcome. Compared to warfarin, DOACs, whether as a group or apixaban, dabigatran, or rivaroxaban individually, were associated with a reduced risk of the composite outcome in elderly patients with concurrent AF and dementia.

Comparison of oral anticoagulants for stroke prevention in atrial fibrillation using the UK clinical practice research Datalink Aurum: A reference trial (ARISTOTLE) emulation study.

Stroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results. Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR. Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.

Apixaban vs rivaroxaban in patients with atrial fibrillation at high or low bleeding risk: A population-based cohort study

BackgroundDespite many atrial fibrillation (AF) patients being at risk of bleeding, very limited data are available on bleeding rates of different direct oral anticoagulants based on the spectrum of bleeding risk. ObjectiveWe aimed to compare the risk of major bleeding and thromboembolic events with apixaban vs rivaroxaban for AF patients stratified by bleeding risk. MethodsWe conducted a population-based, retrospective cohort study of all adult patients (66 years or older) with AF in Ontario, Canada, who were treated with apixaban or rivaroxaban between April 1, 2011, and March 31, 2020. Bleeding risk was estimated by the HAS-BLED score, with high bleeding risk defined as a score of ≥3. The primary safety outcome was major bleeding, and the primary efficacy outcome was thromboembolic events. Comparisons were adjusted for baseline comorbidities by inverse probability of treatment weighting. ResultsThis study included 18,156 AF patients with high bleeding risk and 55,186 AF patients with low bleeding risk. Apixaban use was more common in patients with high bleeding risk; 63% of high-risk patients used apixaban compared with 56% of low-risk patients. Apixaban users had lower rates of major bleeding in high-risk patients (2.9% vs 4.2% per year; hazard ratio [HR], 0.69; 95% CI, 0.58–0.81) and in low-risk patients (1.8% vs 2.9% per year; HR, 0.63; 95% CI, 0.56–0.70) compared with rivaroxaban. There were no differences in rates of thromboembolic events, 3.1% vs 3.0% per year (HR, 1.02; 95% CI, 0.86–1.22) in high-risk patients and 1.9% vs 1.9% per year (HR, 1.00; 95% CI, 0.89–1.14) in low-risk patients. ConclusionIn older AF patients with high or low bleeding risk, treatment with apixaban was associated with lower rates of major bleeding with no difference in risk for thromboembolic events compared with rivaroxaban.

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...

Left atrial appendage thrombus in patients with atrial fibrillation who underwent oral anticoagulation.

Electric cardioversion of atrial fibrillation (AF) is associated with an increased risk of embolism, with embolic material existing in the heart cavities. The initiation of oral anticoagulation therapy reduces the risk of thromboembolic events. The aims of this study were to evaluate the prevalence of left atrial appendage (LAA) thrombi in non-valvular AF, to compare vitamin K antagonists (VKAs) and non-vitamin K oral anticoagulants (NOACs) with respect to thrombus prevalence, and to evaluate the rate of LAA thrombus persistence on repeat transesophageal echocardiography (TEE) after treatment change. We enrolled 160 consecutive AF patients who presented with an AF duration > 48 h and had undergone TEE before cardioversion. Left atrial appendage thrombus was observed in 12 (7.5%) patients, and spontaneous echo contrast 4 was observed in 19 (11.8%) patients; the incidence was similar between the NOAC and VKA groups (8.9% vs. 3.6% and 12.4% vs. 18.5 %, respectively). Among patients on NOAC, thrombus prevalence was detected in 8.4% of users of rivaroxaban, 8% of users of dabigatran, and 12.5% of users of apixaban. The LAA thrombus developed in 7.5% of patients despite anticoagulation therapy, demonstrating similar prevalence rates among patients either on NOAC or VKA. Lower mean LAA flow velocity and a history of vascular disease were independent predictors of embolic material in the LAA. It seems that in the case of embolic materials in LAA under NOAC treatment, switching to VKA provides additional clinical benefit to the patients.

Time-in-therapeutic-range defined warfarin and direct oral anticoagulants in atrial fibrillation: a Nationwide Cohort Study

Background Little is known how individual time-in-therapeutic-range (TTR) impacts the effectiveness and safety of warfarin therapy compared to direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF). Objective To compare the effectiveness and safety of standard dose DOACs to warfarin in patients with AF, while categorizing warfarin treated patients into quartiles based on their individual TTR. Materials and methods We conducted a nationwide study including all patients with new-onset AF between 2011 and 2018 in Finland. Hazard ratios (HR) were calculated using Cox regression analysis with the inverse probability of treatment weighted method to assess the risks of ischaemic stroke (IS), intracranial haemorrhage (ICH) and mortality for users of apixaban (n = 12,426), dabigatran (n = 4545), rivaroxaban (n = 12,950) and warfarin (n = 43,548). Results The median TTR for warfarin users was 72%. Compared to the second best TTR quartile (reference), the risk of IS was higher in the two poorest TTR quartiles, and lower in the best TTR quartile and on rivaroxaban [2.35 (95% confidence interval, 1.85–2.85), 1.44 (1.18–1.75), 0.60 (0.47–0.77) and 0.72 (0.56–0.92)]. These differences were non-significant for apixaban and dabigatran. HR of ICH was 6.38 (4.88–8.35) and 1.87 (1.41–2.49) in the two poorest TTR groups, 1.44 (1.02–1.93) on rivaroxaban, and 0.58 (0.40–0.85) in the best TTR group compared to the reference group. Mortality was higher in the two poorest TTR groups and lowest in the best TTR group. Conclusions The outcome was unsatisfactory in the two lowest TTR quartiles – in half of the patients treated with warfarin. The differences between the high TTR groups and standard dose DOACs were absent or modest.

Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban

Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation. To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol. This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024. Diltiazem and metoprolol. The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting. The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26). In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Utilization outcomes of direct oral anticoagulants in Medicare patients

ObjectiveTo compare the adherence, persistence, discontinuation and switching rates of direct oral anticoagulants (DOACs) for Medicare patients with non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). MethodsThis was retrospective observational cohort study design. Medicare Part D claims files were used for the study duration (2015–2018). Inclusion-exclusion criteria were applied to identify the NVAF and VTE sample using dabigatran, rivaroxaban, apixaban, edoxaban and warfarin during the identification period (2016–2017). Outcomes of adherence, persistence, time to non-persistence and time to discontinuation were assessed in those who did not switch the index drug in the follow-up period (365 days from the index date). Switching rates were assessed in those who switched the index drug at least once in the aforementioned follow-up period. Descriptive statistics were conducted for all the outcomes, and comparisons were made using t-tests, chi-square, and ANOVA. Logistic regression was conducted to compare the odds of being adherent and the odds of switching in NVAF and VTE patient cohorts. ResultsOf all the DOACs, patients with NVAF or VTE were most adherent to apixaban (PDC = 76.88). Among all the DOACs, non-persistence and discontinuation rates were highest for warfarin. Majority of the switches were reported from dabigatran to other DOAC and to apixaban from other DOAC. Despite the better utilization outcomes reported for apixaban users, Medicare plans covered rivaroxaban favorably. It was associated with the lowest mean amount paid by the patient (NVAF: $76; VTE: $59), and the highest mean amount paid by the plans (NVAF: $359; VTE: $326). ConclusionMedicare plans need to consider adherence, persistence, discontinuation and switching rates of DOACs to make the coverage decisions.

Risk Profiles of New Users of Oral Anticoagulants Between 2011 and 2019 in Germany.

Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes over time among persons with non-valvular atrial fibrillation initiating treatment with different DOACs or phenprocoumon (vitamin K antagonist) between 2011 and 2019 in Germany. Using the German Pharmacoepidemiological Research Database (GePaRD; claims data of ~20% of the German population), we identified persons with a first dispensing of phenprocoumon or a DOAC and a diagnosis of non-valvular atrial fibrillation between August 2011 and December 2019. We described the morbidity of included patients prior to treatment initiation, stratified by year of treatment initiation. Overall, we included 448,028 new users (phenprocoumon: N = 118,117, rivaroxaban: N = 130,997, apixaban: N = 130,300, edoxaban: N = 38,128, dabigatran: N = 30,486). Comparing new DOAC users in 2019, the proportion with prior ischemic stroke was highest for dabigatran (17%) and lowest for rivaroxaban (8%). The proportion with prior major bleeding was also highest for dabigatran (25%) and lowest for edoxaban (20%). New users of apixaban were oldest and, eg, showed the highest prevalence of congestive heart failure. Changes over time were most pronounced for phenprocoumon. For example, among persons initiating phenprocoumon in 2012 vs 2019, the proportion with prior major bleeding increased from 18% to 35%; the proportion with renal disease increased from 20% to 36% and the proportion with liver disease from 18% to 24%. This study demonstrated differences in risk profiles between new users of different oral anticoagulants and substantial changes over time among new phenprocoumon users. These differences have to be considered in head-to-head comparisons of these drugs based on observational data, especially regarding potential unmeasured confounding.

#3207 KIDNEY FUNCTION ESTIMATORS FOR DRUG DOSE ADJUSTMENT OF DIRECT ORAL ANTICOAGULANTS IN OLDER ADULTS WITH ATRIAL FIBRILLATION

Abstract Background and Aims The Food and Drug Administration and the European Medicines Agency (EMA) recommend using the Cockcroft-Gault equation (CG) for drug dose adjustment of direct oral anticoagulant drugs (DOACs) in non-valvular atrial fibrillation (NVAF), whereas Cardiology guidelines recommend using estimated glomerular filtration rate (eGFR). This issue is of great importance in older adults, which are more prone to adverse drug reactions and have higher prevalence of atrial fibrillation as compared to younger adults, and in whom CG has worse diagnostic performance than most eGFR equations. We aimed to assess if prognosis was similar according to drug dose status using different kidney function estimators based on creatinine and/or cystatin C in older adults with NVAF. Method We used data from the Berlin Initiative Study (BIS): a population-based prospective cohort study initiated in 2009, with five biennial study visits. Participants with a history of NVAF (based on ICD-10 codes) and a dispensed prescription of DOAC four months prior to baseline or a follow-up visit according to claims data were included. Drug dose status was defined according to the EMA guidelines. CG, deindexed (in ml/min) creatinine and/or cystatin C-based CKD-EPI, and deindexed BIS 1 (creatinine-based) and BIS 2 (creatinine and cystatin C-based) equations were included. Associations between dosing status and mortality, stroke or systemic embolism, and bleeding events were assessed using marginal structural Cox models with time-varying variables and taking account of various confounders. Subgroup analyses were performed in rivaroxaban and apixaban users, but not in dabigatran and edoxaban users because of too small sample sizes. Results Two hundred twenty four patients treated with DOACs were included in this analysis (median age 87 years, median eGFRCKD-EPIcr 56 ml/min/1.73m², median follow-up length 40 months for the mortality analysis). Of those, 99 (44%) were taking rivaroxaban, 86 (38%) apixaban, 21 (9%) edoxaban, and 18 (8%) dabigatran. Using CG, 154 (69%) had appropriate DOAC dose at baseline, 52 (23%) were underdosed, and 18 (8%) were overdosed. Discrepancies were found by comparing dosing status according to CG and eGFR equations (Figure 1). During the follow-up period, 109 (14.9/100 person-years) participants died, 25 (3.6/100 person-years) experienced a stroke or systemic embolism, and 60 (9.9/100 person-years) experienced a bleeding event. Drug dose status was not significantly associated with mortality and the occurrence of stroke or systemic embolism, whatever equation was used. Underdose status was associated with a significantly lower risk of bleeding events with all the equations but overdose status was not associated with a higher risk of bleeding events (Figure 2). In subgroup analyses, drug dose status was not associated with mortality and bleeding event in apixaban users, whatever equation was used. In rivaroxaban users, underdose status was associated with a significant higher risk of death by using CG, eGFRCKD-EPIcys, and BIS 2, and a lower risk of bleeding event by using eGFRCKD-EPIcr. Conclusion In this population of very old adults with NVAF, drug dose status of DOAC was not associated with mortality or the occurrence of stroke or systemic embolism for any of the studied equations. However, underdose status was associated with bleeding events occurrence regardless of the equation used. These associations differed according to the used drug, but this should be interpreted with cautious due to small sample sizes. Our results do not allow us to provide any guidance which equation to use in this context. A study including a larger group of patients with discrepancy in dose status according to the used equations would be of great interest.

Adherence and clinical outcomes for twice-daily versus once-daily dosing of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: Is dosing frequency important?

Twice-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) may reduce drug adherence compared with once-daily dosing of NOACs in patients with atrial fibrillation (AF), thus worsening clinical outcomes. We evaluated adherence to apixaban and dabigatran requiring twice-daily dosing compared with edoxaban or rivaroxaban with a once-daily dosing regimen and the subsequent clinical outcomes in patients with AF. Adherence to each NOAC and outcomes were compared between patients who were diagnosed with AF and initiated NOACs between 2016 and 2017 using Korean claims data. High adherence was defined as the proportion of days covered (PDC) of the index NOAC ≥80%. The clinical outcomes included stroke, acute myocardial infarction, death, and composite outcome. A total of 33,515 patients were analyzed (mean follow-up, 1.7 ± 1.3 years). The proportion of patients with high adherence to NOACs was 95%, which did not significantly differ according to the dosing regimen. The mean PDC for NOACs was as high as ~96%, which was the highest for apixaban users, intermediate for edoxaban or rivaroxaban users, and lowest for dabigatran users, regardless of the dosing regimen. Adverse outcomes in low adherence patients for each NOAC were higher than that of high adherence patients, regardless of the dosing frequency. Adherence between once- and twice-daily dosing NOACs in patients with AF was high and similar among both dosing regimens. Patients with low NOAC adherence had poorer clinical outcomes, regardless of the dosing frequency.

Comparative Effectiveness and Safety of Oral Anticoagulants by Dementia Status in Older Patients With Atrial Fibrillation

The development of an optimal stroke prevention strategy, including the use of oral anticoagulant (OAC) therapy, is particularly important for patients with atrial fibrillation (AF) who are living with dementia, a condition that increases the risk of adverse outcomes. However, data on the role of dementia in the safety and effectiveness of OACs are limited. To assess the comparative safety and effectiveness of specific OACs by dementia status among older patients with AF. This retrospective comparative effectiveness study used 1:1 propensity score matching among 1 160 462 patients 65 years or older with AF. Data were obtained from the Optum Clinformatics Data Mart (January 1, 2013, to June 30, 2021), IBM MarketScan Research Database (January 1, 2013, to December 31, 2020), and Medicare claims databases maintained by the Centers for Medicare & Medicaid Services (inpatient, outpatient, and pharmacy; January 1, 2013, to December 31, 2017). Data analysis was performed from September 1, 2021, to May 24, 2022. Apixaban, dabigatran, rivaroxaban, or warfarin. Composite end point of ischemic stroke or major bleeding events over the 6-month period after OAC initiation, pooled across databases using random-effects meta-analyses. Among 1 160 462 patients with AF, the mean (SD) age was 77.4 (7.2) years; 50.2% were male, 80.5% were White, and 7.9% had dementia. Three comparative new-user cohorts were established: warfarin vs apixaban (501 990 patients; mean [SD] age, 78.1 [7.4] years; 50.2% female), dabigatran vs apixaban (126 718 patients; mean [SD] age, 76.5 [7.1] years; 52.0% male), and rivaroxaban vs apixaban (531 754 patients; mean [SD] age, 76.9 [7.2] years; 50.2% male). Among patients with dementia, compared with apixaban users, a higher rate of the composite end point was observed in warfarin users (95.7 events per 1000 person-years [PYs] vs 64.2 events per 1000 PYs; adjusted hazard ratio [aHR], 1.5; 95% CI, 1.3-1.7), dabigatran users (84.5 events per 1000 PYs vs 54.9 events per 1000 PYs; aHR, 1.5; 95% CI, 1.2-2.0), and rivaroxaban users (87.4 events per 1000 PYs vs 68.5 events per 1000 PYs; aHR, 1.3; 95% CI, 1.1-1.5). In all 3 comparisons, the magnitude of the benefits associated with apixaban was similar regardless of dementia diagnosis on the HR scale but differed substantially on the rate difference (RD) scale. The adjusted RD of the composite outcome per 1000 PYs for warfarin vs apixaban users was 29.8 (95% CI, 18.4-41.1) events in patients with dementia vs 16.0 (95% CI, 13.6-18.4) events in patients without dementia. The corresponding adjusted RD estimates of the composite outcome were 29.6 (95% CI, 11.6-47.6) events per 1000 PYs in patients with dementia vs 5.8 (95% CI, 1.1-10.4) events per 1000 PYs in patients without dementia for dabigatran vs apixaban users and 20.5 (95% CI, 9.9-31.1) events per 1000 PYs in patients with dementia vs 15.9 (95% CI, 11.4-20.3) events per 1000 PYs in patients without dementia for rivaroxaban vs apixaban users. The pattern was more distinct for major bleeding than for ischemic stroke. In this comparative effectiveness study, apixaban was associated with lower rates of major bleeding and ischemic stroke compared with other OACs. The increased absolute risks associated with other OACs compared with apixaban were greater among patients with dementia than those without dementia, particularly for major bleeding. These findings support the use of apixaban for anticoagulation therapy in patients living with dementia who have AF.

Variability in Nonvitamin K Oral Anticoagulant Dose Eligibility and Adjustment According to Renal Formulae and Clinical Outcomes in Patients With Atrial Fibrillation With and Without Chronic Kidney Disease: Insights From ORBIT‐AF II

Background Nonvitamin K oral anticoagulants require dose adjustment based on kidney function.The most common estimate of kidney function employed in clinical practice is estimated glomerular filtration rate (eGFR); however, product monographs recommend the use of the Cockcroft-Gault estimated creatinine clearance (eCrCl) for dose adjustment. Methods and Results The authors included patients enrolled in the ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation AF II) trial. Dosing was considered inappropriate when use of eGFR resulted in a lower (undertreatment) or higher (overtreatment) dose than that recommended by the eCrCl. The primary outcome of major adverse cardiovascular and neurological events was a composite of cardiovascular death, stroke or systemic embolism, new-onset heart failure, and myocardial infarction. Among 8727 in the overall cohort, agreement between eCrCl and eGFR was observed in 93.5% to 93.8% of patients. Among 2184 patients with chronic kidney disease (CKD), the agreement between eCrCl and eGFR was 79.9% to 80.7%. Dosing misclassification was more frequent in the CKD population (41.9% of rivaroxaban users, 5.7% of dabigatran users, and 4.6% apixaban users). At 1 year, undertreated patients in the CKD group had significantly greater major adverse cardiovascular and neurological events (adjusted hazard ratio, 2.93 [95% CI, 1.08-7.92]) compared with the group with appropriate nonvitamin K oral anticoagulants dosing (P=0.03). Conclusions The prevalence of misclassification of nonvitamin K oral anticoagulants dosing was high when using eGFR, particularly among patients with CKD. Among patients with CKD, potential undertreatment due to inappropriate and off-label renal formulae may result in worse clinical outcomes. These findings highlight the importance of using eCrCl, and not eGFR, for dose adjustment in all patients with AF receiving nonvitamin K oral anticoagulants.

Outcomes with direct-acting oral anticoagulants in patients with a history of bariatric surgery: a retrospective cohort study

<h2>Abstract</h2><h3>Background</h3> Patients who undergo bariatric surgery have major physiologic changes in their gastrointestinal tract, which can theoretically alter drug absorption and pharmacokinetics. This is especially concerning for drugs with a narrow therapeutic index, as small changes in absorption can have significant effects on safety and efficacy. One class of interest is direct-acting oral anticoagulants (DOACs), for which there is a paucity of data in this population. <h3>Objective</h3> To characterize the use of DOACs (apixaban, dabigatran, rivaroxaban) in patients with a history of bariatric surgery and incidence of clotting and bleeding events. <h3>Setting</h3> Public healthcare system/university hospital, United States. <h3>Methods</h3> This retrospective cohort study included adult patients who were prescribed a DOAC for the prophylaxis or treatment of venous thromboembolism or for stroke and systemic embolism prevention in atrial fibrillation between January 2011 and December 2018. <h3>Results</h3> A total of 191 patients with a history of bariatric surgery were included. Clotting events occurred in 11 of 191 patients (5.8%) receiving DOAC therapy, with a calculated clotting rate of 3.9 clots per 100 person-years. Bleeding events occurred in 42 of 191 patients (22%) receiving a DOAC, with a calculated bleeding rate of 17.1 bleeds per 100 person-years. The use of rivaroxaban versus apixaban was associated with a statistically significant increased risk of bleeding in patients with a history of bariatric surgery. <h3>Conclusion</h3> In this retrospective cohort of bariatric surgery patients receiving DOACs, we found clotting rates consistent with expected rates and bleeding rates above expected rates based on historical data. We also found an increased risk of bleeding in rivaroxaban users compared with apixaban users. Careful evaluation of bleeding risks in bariatric surgery patients is encouraged.

Abstract P431: Comparative Safety and Effectiveness of Direct Oral Anticoagulants versus Warfarin in Patients With Non-Valvular Atrial Fibrillation and Severe Chronic Kidney Disease

Background: Landmark trials of direct oral anticoagulants (DOACs) versus warfarin for non-valvular atrial fibrillation (NVAF) excluded patients with severe chronic kidney disease (CKD). Real-world data on safety and effectiveness of DOACs in severe CKD is limited. Methods: New users of DOACs (apixaban, rivaroxaban, and dabigatran) or warfarin with NVAF and severe CKD between 2010 and 2020 were identified using the de-identified electronic health records form the Optum Labs Data Warehouse. We estimated the risks of bleeding, ischemic stroke, and death for apixaban and rivaroxaban separately (vs. warfarin) using Cox regression models. Incidence rate (IR) and hazard ratio (HR) were adjusted for baseline characteristics by inverse probability of treatment weighting (IPTW). Dabigatran users were not included for the analysis due to small sample size (n=318). Results: Compared with warfarin users (n=7548), apixaban users (n=3719) were older (mean age 77 vs. 76 years) and had more hypertension (94% vs. 90%). In IPTW analysis, apixaban was associated with a lower risk of any bleeding (HR [95% CI], 0.71 [0.56, 0.89]), as well as major bleeding (HR [95% CI], 0.61 [0.46, 0.81]). There were no significant differences in ischemic stroke and death between apixaban and warfarin users ( Figure A ). Rivaroxaban users (n=920) were older (mean age 76 vs. 75 years) and had higher estimated glomerular filtration rate than warfarin users (mean: 25 vs. 23 ml/min/1.73 m 2 ). In IPTW analysis, risks of bleeding were higher among rivaroxaban users than warfarin users (any bleeding: HR [95% CI], 1.43 [1.05, 1.95]; major bleeding: HR [95% CI], 1.54 [1.09, 2.17]), with no significant differences in ischemic stroke and death ( Figure B ). Conclusion: Apixaban was associated with a lower risk of bleeding, but rivaroxaban was associated with a higher risk of bleeding, compared with warfarin in patients with NVAF and severe CKD. Risks of ischemic stroke and death were similar between agents. Apixaban may be a preferable oral anticoagulant in this population.

Comparison of medication adherence to different oral anticoagulants: population-based cohort study

ObjectivePrevious observational studies have yielded conflicting results on whether medication adherence differs between patients receiving warfarin and direct oral anticoagulants (DOACs). Importantly, no study has adequately accounted for warfarin dosing...

Effectiveness and safety of low-dose versus standard-dose rivaroxaban and apixaban in patients with atrial fibrillation.

Low-dose direct oral anticoagulant (DOAC) use is quite prevalent in clinical practice, but evidence of its effectiveness and safety compared with high-dose DOAC in patients with atrial fibrillation (AF) remains limited. We aimed to assess the effectiveness and safety of low-dose and high-dose DOACs in patients with AF with similar baseline characteristics. We used a cohort of hospitalized patients with a primary or secondary diagnosis of AF after discharge to the community, whose data were stored in the Quebec administrative databases, from 2011 to 2017. Older adults with AF newly prescribed with rivaroxaban (15 or 20 mg) or apixaban (2.5 mg or 5 mg) were classified as under treatment (UT) and intent to treat (ITT). We used an inverse probability treatment weighting study of new users of rivaroxaban and apixaban to address confounding by indication. The primary effectiveness outcome was ischemic stroke/systemic embolism (SE), while the primary safety outcome was major bleeding (MB). We used Cox proportional models to estimate the marginal hazard ratios (HRs). A total of 1,722 and 4,639 patients used low-dose and standard-dose rivaroxaban, respectively, while 3,833 and 6,773 patients used low-dose and standard-dose apixaban, respectively. No significant difference was observed in the incidence of comparative stroke/SE and MB between low-dose and standard-dose rivaroxaban, except for the risk of acute myocardial infarction (AMI), which was increased with the low dose in the UT analysis. For apixaban, no difference was found in the bleeding rates, but the risk of stroke/SE (HR: 1.95; 95% confidence interval (CI): 1.38-2.76) and death (HR: 1.99; 95% CI: 1.46-2.70) were greater in the low-dose group than in the standard-dose group in the UT analysis. Similar results were observed for the ITT analysis. No significant differences were observed in the effectiveness or safety outcome between low-dose and standard-dose rivaroxaban, except for AMI. However, low-dose apixaban was associated with a greater risk of stroke/SE and death without a reduction in the bleeding rates.

Direct Oral Anticoagulant (DOAC) Dosing in Patients with Non-valvular Atrial Fibrillation (NVAF) in the United Kingdom: A Retrospective Cohort Study Using CPRD Gold Database.

Per-label dosing of direct oral anticoagulants (DOACs) is important for the prevention of stroke and systemic embolism among patients with non-valvular atrial fibrillation (NVAF), especially those with poor renal function, advanced age, low body weight or concomitant P-glycoprotein inhibitors. The study described DOAC use and dosing patterns in patients with NVAF in the UK. Using Clinical Practice Research Datalink (CPRD Gold), patients' profiles were described at DOAC initiation (1 January 2016-31 March 2021) and followed for a mean [standard deviation (SD)] 2 (1) years. Patients were categorised as under-dosing: received a lower dose with no indication for a reduced dose; over-dosing: received a standard dose with an indication for a reduced dose; per-label dosing, according to Summary Product Characteristics (SmPC). Forty thousand seven hundred forty-four adult patients with NVAF were identified (mean age: 75.3 (11.2) years; males: 55.4%); 22,827 (56.0%) initiated treatment with apixaban, 930 (2.3%) dabigatran, 5633 (13.8%) edoxaban and 11,354 (27.9%) rivaroxaban. Baseline Charlson comorbidity index ≥ 4 was 65.1%; CHA2DS2-VASc score ≥ 4 was 22.5%; HAS-BLED score ≥ 3 was 18.3%; ~ 2% had prior major bleed and 4.4% a stroke ≤ 2years before DOAC initiation. Overall, 18.0% of patients received incorrect dosing (~ one in five). Under-dosing was highest for dabigatran (156, 16.8%) and over-dosing was highest for rivaroxaban (1084, 9.6%). Per-label dosing was highest for edoxaban (4773, 84.7%), followed by apixaban (18,756, 82.2%), rivaroxaban (9161, 80.7%) and dabigatran (732, 78.7%). Treatment persistence (no switching or discontinuation) was 79% among edoxaban users, followed by 75% for apixaban, 69% for rivaroxaban and 62% for dabigatran. About 15% of dabigatran users, 10% of rivaroxaban users, 5% of apixaban users and 4% of edoxaban users switched treatment to another DOAC during follow-up. Although most patients received per-label dosing, ~ one in five patients was incorrectly dosed with DOAC, which may lead to serious clinical consequences and increased healthcare burden.

Protocols for perioperative management of direct oral anticoagulants in hospitals: opportunities for improvement

Objectives To investigate and describe the protocolized perioperative management in patient using Direct oral anticoagulants (DOACs) in Dutch hospitals. Methods Between August and December 2020, a nationwide survey in 70 hospitals in the Netherlands was conducted. We asked hospital pharmacists to submit their protocols for perioperative management of DOAC (apixaban, dabigatran, edoxaban and rivaroxaban) users. The protocols were assessed for a number of parameters divided into categories: interruption and restart timetables DOACs for elective procedures, criteria for the start of an urgent procedure without antidotes, criteria for the use of antidotes and advised antidotes for urgent procedures. Results A total of 49 hospitals (70%) sent a protocol for perioperative management of DOACs. Two pairs of protocols were identical because hospitals cooperated closely, leaving 47 individual protocols for analysis. Thirty-five of these protocols contained a policy for both elective and urgent procedure; five protocols contained only a policy for elective and seven only for urgent procedures. In protocols for elective procedure, we found great variation in interruption and restart timetables intended for patients with renal impairment (Estimated Glomerular Filtration Ratio < 80 ml/min). In case of urgent procedures, there is variation in choice of antidote, criteria for administration of an antidote and antidote dosing. Conclusion This study provides an overview of the current state of the perioperative protocols in the Netherlands in patients treated with direct oral anticoagulants. Protocols are often not complete and show important and unwanted variation. We have found that national guidelines do not provide unambiguous advice on all points (urgent procedures) and are therefore often elaborated at a local level. The results of this research can help in improving and harmonizing the perioperative protocols on a national level.