Dabigatran Users Research Articles

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.

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.

#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.

Identifying treatment heterogeneity in atrial fibrillation using a novel causal machine learning method

Lifelong oral anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent stroke. Over the last decade, multiple new oral anticoagulants (OACs) have expanded the number of treatment options for these patients. While population-level effectiveness of OACs has been compared, it is unclear if there is variability in benefit and risk across patient subgroups. We analyzed claims and medical data for 34,569 patients who initiated a nonvitamin K antagonist oral anticoagulant (non-vitamin K antagonist oral anticoagulant (NOAC); apixaban, dabigatran, and rivaroxaban) or warfarin for nonvalvular AF between 08/01/2010 and 11/29/2017 from the OptumLabs Data Warehouse. A machine learning (ML) method was applied to match different OAC groups on several baseline variables including, age, sex, race, renal function, and CHA2DS2 -VASC score. A causal ML method was then used to discover patient subgroups characterizing the head-to-head treatment effects of the OACs on a primary composite outcome of ischemic stroke, intracranial hemorrhage, and all-cause mortality. The mean age, number of females and white race in the entire cohort of 34,569 patients were 71.2 (SD, 10.7) years, 14,916 (43.1%), and 25,051 (72.5%) respectively. During a mean follow-up of 8.3 (SD, 9.0) months, 2,110 (6.1%) of patients experienced the composite outcome, of whom 1,675 (4.8%) died. The causal ML method identified 5 subgroups with variables favoring apixaban over dabigatran; 2 subgroups favoring apixaban over rivaroxaban; 1 subgroup favoring dabigatran over rivaroxaban; and 1 subgroup favoring rivaroxaban over dabigatran in terms of risk reduction of the primary endpoint. No subgroup favored warfarin and most dabigatran vs warfarin users favored neither drug. The variables that most influenced favoring one subgroup over another included Age, history of ischemic stroke, thromboembolism, estimated glomerular filtration rate, Race, and myocardial infarction. Among patients with AF treated with a NOAC or warfarin, a causal ML method identified patient subgroups with differences in outcomes associated with OAC use. The findings suggest that the effects of OACs are heterogeneous across subgroups of AF patients, which could help personalize the choice of OAC. Future prospective studies are needed to better understand the clinical impact of the subgroups with respect to OAC selection.

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...

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.

Effect of tramadol and DOACs with special attention to dabigatran on concomitant use, on the risk of mayor bleeding using BIFAP database in Spain.

Tramadol, a weak opioid, inhibits the reuptake of serotonin, a key feature on vascular homeostasis. A suspected interaction exists between dabigatran and tramadol, which might trigger an excess on risk of bleeding however, there is a gap in knowledge on this topic. To estimate the effects of tramadol, dabigatran and concomitant use on the risk of hospitalized major bleeds (Gastrointestinal bleeding and intra-extracranial bleeds). Among a validated established cohort of new users of oral anticoagulants for non-valvular atrial fibrillation (NVAF) aged 18 years or older, we identified all hospitalized bleed episodes (GIB and extra/intracranial bleeds) within 2008-2015. A nested case-control analysis was conducted using conditional logistic regression. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated for dabigatran, tramadol, and concomitant use. Several sensitivity analyses were carried out. aORs (95%CIs) for current use of only dabigatran, only tramadol and concomitant users were 1.73 (1.37-2.18) and 1.38 (1.13-1.67) and 2.04 (0.74-5.67) compared with non-users of both drugs (>365 days). aORs for current continuers and non-continuer users of dabigatran were 1.36 (1.00-1.86) and 2.19 (1.61-2.98), respectively. For the latter, non-continuer users with a short duration of dabigatran cumulated the highest risk (3.36 [1.88-5.99]). There also was an increased risk with concomitant use of tramadol and rivaroxaban (2.24 [1.19-4.21]), or antagonist of vitamin K (1.30 [1.00-1.69]). There was a trend towards and increased risk of excess bleeds when using concomitantly with dabigatran. The effect decreases with a narrower definition of current use.

Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base.

BackgroundAge-related macular degeneration (AMD), the leading cause of irreversible blindness in elderly Caucasian populations, includes destruction of the blood-retina barrier (BRB) generated by the retinal pigment epithelium-Bruch’s membrane complex (RPE/BrM), and complement activation. Thrombin is likely to get access to those structures upon BRB integrity loss. Here we investigate the potential role of thrombin in AMD by analyzing effects of the thrombin inhibitor dabigatran.Material and MethodsMarketScan data for patients aged ≥65 years on Medicare was used to identify association between AMD and dabigatran use. ARPE-19 cells grown as mature monolayers were analyzed for thrombin effects on barrier function (transepithelial resistance; TER) and downstream signaling (complement activation, expression of connective tissue growth factor (CTGF), and secretion of vascular endothelial growth factor (VEGF)). Laser-induced choroidal neovascularization (CNV) in mouse is used to test the identified downstream signaling.ResultsRisk of new wet AMD diagnosis was reduced in dabigatran users. In RPE monolayers, thrombin reduced TER, generated unique complement C3 and C5 cleavage products, led to C3d/MAC deposition on cell surfaces, and increased CTGF expression via PAR1-receptor activation and VEGF secretion. CNV lesion repair was accelerated by dabigatran, and molecular readouts suggest that downstream effects of thrombin include CTGF and VEGF, but not the complement system.ConclusionsThis study provides evidence of association between dabigatran use and reduced exudative AMD diagnosis. Based on the cell- and animal-based studies, we suggest that thrombin modulates wound healing and CTGF and VEGF expression, making dabigatran a potential novel treatment option in AMD.

Safety and efficacy of direct oral anticoagulants in patients with atrial fibrillation on concomitant treatment with dronedarone

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The use of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is associated with bleedings. Interactions with dronedarone may increase this risk, but data on concomitant treatment of DOACs with dronedarone are limited. Purpose The primary endpoint was to compare the survival free from the composite endpoint of clinically relevant bleeding, thromboembolic event and all-cause death, between AF patients on treatment with dronedarone and different DOACs. The secondary endpoints were to compare the survival free from i) clinically relevant bleeding and ii) clinically relevant major bleeding. Methods A retrospective study was conducted at our Local Health Unit, from January 1st 2016 to December 31st 2020. The population included AF patients with concomitant prescriptions of DOACs and dronedarone. Patients were divided into 4 groups (rivaroxaban, apixaban, edoxaban, dabigatran). Clinically relevant major bleedings were defined as fatal bleeding or bleeding leading to transfusion of ≥2 units of blood. Clinically relevant non-major bleedings were defined as any sign of hemorrhage that does not fit the criteria for major bleeding but does lead to hospitalization or emergency room admission. Thromboembolic events were defined as ischemic stroke, transient ischemic attack (TIA), and systemic embolism. Results 165 patients were included: 46/165 (28%) on rivaroxaban, 66/165 (40%) on apixaban, 45/165 (27%) on edoxaban, and 8/165 (5%) on dabigatran (Fig.1). Over a median follow-up of 339 days, 14/165 (8%) met the primary composite endpoint: 8/165 (5%) had clinically relevant bleedings, of which 1/165 (0.6%) was a clinically relevant major bleeding (i.e., fatal spontaneous intracerebral hemorrhage), 2/165 (1%) had TIAs, and 5/165 (3%) died. We found no difference in survival free from the primary composite endpoint and from clinically relevant bleeding between groups (p=0.19 and p=0.69, respectively) (Fig. 2A-B). However, survival free from clinically relevant major bleeding was significantly lower in dabigatran users (p=0.003) (Fig. 2C). At a secondary analysis, DOACs contraindicated by 2015 EHRA guide (dabigatran, edoxaban 60 mg), and not by 2018/2021 EHRA guides (rivaroxaban, dabigatran, edoxaban 60 mg), were associated with lower survival from either clinically relevant bleeding or clinically relevant major bleeding (p=0.03 and p&amp;lt;0.001, respectively). Conclusions In our study on patients on concomitant treatment with DOACs and dronedarone, there was no difference in survival free from the primary composite endpoint and from clinically relevant bleeding between groups of coadministration. However, survival free from clinically relevant major bleeding was significantly lower in dabigatran users. DOACs contraindicated by 2015 EHRA guide (and not by the latest 2018/2021 EHRA guides) are associated with lower survival from either clinically relevant bleeding or clinically relevant major bleeding.

C51 SAFETY AND EFFICACY OF DIRECT ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION ON CONCOMITANT TREATMENT WITH DRONEDARONE

Abstract Background The use of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is associated with bleedings. Interactions with dronedarone may increase this risk, but data on concomitant treatment of DOACs with dronedarone are limited. Aim The primary endpoint was to compare the survival free from the composite endpoint of clinically relevant bleeding, thromboembolic event and death, between AF patients on treatment with dronedarone and different DOACs. The secondary endpoints were to compare the survival free from i) clinically relevant bleeding and ii) clinically relevant major bleeding. Methods A retrospective study was conducted at the Local Health Unit “Ulss3 Serenissima” of Venice, Italy, from January 1st 2016 to December 31st 2020. The eligible population included AF patients with concomitant prescriptions of DOACs and dronedarone. Patients were divided in 4 groups (rivaroxaban, apixaban, edoxaban, dabigatran). Results 165 patients were included: 46/165 (28%) on rivaroxaban, 66/165 (40%) on apixaban, 45/165 (27%) on edoxaban, and 8/165 (5%) on dabigatran (Fig.1). Over a median follow–up of 339 days, 14/165 (8%) met the primary composite endpoint: 8/165 (5%) had clinically relevant bleedings, of which 1/165 (0.6%) was a clinically relevant major bleeding, 2/165 (1%) had TIAs, and 5/165 (3%) died. We found no difference in survival free from the primary composite endpoint and from clinically relevant bleeding between groups (log–rank test p = 0.19 and p = 0.69, respectively) (Fig. 2A–B). However, survival free from clinically relevant major bleeding was significantly lower in dabigatran users (p = 0.003) (Fig. 2C). At a secondary analysis, DOACs contraindicated by 2015 EHRA guide (dabigatran, edoxaban 60 mg), and not by 2018/2021 EHRA guides (rivaroxaban, dabigatran, edoxaban 60 mg), were associated with lower survival from either clinically relevant bleeding or clinically relevant major bleeding (log–rank test p = 0.03 and p &amp;lt; 0.001, respectively) (Fig. 3). Conclusions In our study, there was no difference in survival free from the primary composite endpoint and from clinically relevant bleeding between groups of coadministration. However, survival free from clinically relevant major bleeding was significantly lower in dabigatran users. DOACs contraindicated by 2015 EHRA guide (and not by the latest 2018/2021 EHRA guides) are associated with lower survival from either clinically relevant bleeding or clinically relevant major bleeding.

Warfarin is associated with higher rates of epistaxis compared to direct oral anticoagulants: A nationwide propensity score-weighted study.

Although epistaxis is one of the most common side effects of oral anticoagulation, it is unclear whether epistaxis rates vary between different oral anticoagulants (OAC). To compare rates of clinically relevant epistaxis between OAC. Epistaxis event rates were compared between new users of apixaban, dabigatran, rivaroxaban, and warfarin in a nationwide population-based cohort study over a 5-year study period, 2014-2019. Data was collected from the Icelandic Medicine Registry and the five major hospitals in Iceland. Inverse probability weighting (IPW) was used to yield balanced baseline characteristics, and epistaxis rates were compared using Kaplan-Meier survival estimates and Cox regression. During the study period, 2098 patients received apixaban, 474 dabigatran, 3106 rivaroxaban, and 1403 warfarin. In total, 93 patients presented with clinically relevant epistaxis, including 11 (12%) major epistaxis events and one fatal epistaxis episode. Furthermore, seven patients (9%) with non-major epistaxis later presented with major bleeding during the follow-up period. Warfarin use was associated with higher rates of epistaxis compared to apixaban (2.2 events per 100-person years (events/100-py) vs. 0.6 events/100-py, hazard ratio [HR] 4.22, 95% confidence interval [CI] 2.08-8.59, p < 0.001), rivaroxaban (2.2 events/100-py vs. 1.0 events/100-py, HR 2.26, 95% CI 1.28-4.01, p = 0.005), and dabigatran (2.2 events/100-py vs. no events, HR n/a, p < 0.001). Warfarin treatment was associated with higher rates of clinically relevant epistaxis compared to direct oral anticoagulants.

Abstract P135: Adherence To Direct Oral Anticoagulants Across Chronic Kidney Disease Status

Background: Adherence to anticoagulants is critical for effective stroke prevention for patients with atrial fibrillation (AF). Whether adherence to direct oral anticoagulants (DOACs) differs by chronic kidney disease (CKD) status remains uncertain. Methods: Using data from the Geisinger, we identified patients with AF initiating a DOAC between 2010-2019 and had at least one-year engagement prior and 3-month after initiation. To assess medication adherence, we compared proportion of days covered (PDC) by DOAC at 3, 6, 9, 12, and 18-month between patients with and without CKD, defined as estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73 m 2 . Poor adherence was defined as PDC &lt;0.8, indicating that a patient used the drug &lt;80% of the time. Results: Among the 4082 patients who initiated dabigatran (n=574), rivaroxaban (n=1502), or apixaban (n=2006), the mean (SD) age was 72 (12) years, 1083 (44%) were female, and the average eGFR was 73 (21) mL/min/1.73 m 2 . Overall, patients with CKD had lower adherence to DOAC compared to those without CKD (mean PDC: 0.89 vs. 0.91 at 3-month [P=0.03]; 0.87 vs. 0.89 at 6-month [P=0.04]; 0.84 vs. 0.87 at 9-month [P=0.02]; 0.83 vs. 0.86 at 12-month [P=0.05]; and 0.80 vs. 0.83 at 18-month [P=0.04]). For individual DOAC, only adherence to rivaroxaban was significantly lower in patients with CKD compared to those without CKD ( Figure ). Poor adherence to rivaroxaban was more common in CKD, particularly in the long-term (31% vs. 24% at 18-month [P=0.04]). Adherence to apixaban was highest and did not differ by CKD (CKD vs. non-CKD, mean PDC: 0.88 vs. 0.88 at 6-month; 0.85 vs. 0.85 at 12-month; and 0.81 vs. 0.83 at 18-month). Adherence to dabigatran was lowest and did not differ by CKD (CKD vs. non-CKD, mean PDC: 0.83 vs. 0.83 at 6-month; 0.76 vs. 0.78 at 12-month; and 0.73 vs. 0.74 at 18-month). Conclusion: Medication adherence was highest in apixaban users, followed by rivaroxaban and dabigatran users. Patients with CKD had lower adherence to rivaroxaban compared to those without CKD.

A94 PERI-PROCEDURAL MANAGEMENT OF PATIENTS RECEIVING A DIRECT ORAL ANTICOAGULANT UNDERGOING A DIGESTIVE ENDOSCOPY

BackgroundThe peri-procedural management of patients on a direct oral anticoagulant (DOAC) requiring an elective digestive (GI) endoscopic procedure remains uncertain.AimsTo investigate the safety of a standardized peri-procedural DOAC management strategy.MethodsThe Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study was conducted at 23 clinical centers in North America and Europe. Participants (n=3007) all had atrial fibrillation (AF), were >18 years old, long-term users of Apixaban, Rivaroxaban, or Dabigatran, and scheduled for an elective procedure or surgery; all could adhere to the DOAC interruption protocol. This analysis focuses on the 579 patients undergoing a digestive endoscopic procedure. The DOAC interruption (1–2 days pre-endoscopy) and resumption (1–3 days post-endoscopy) strategy is based on the DOAC molecule, patient renal function, with most GI procedures considered at low-risk for bleeding. Follow-up occurred at 30 days. Outcomes included GI bleeding and thromboembolic events (ischemic stroke, transient ischemic attack, myocardial infarction, systemic embolism, deep vein thrombosis, and pulmonary embolism) and mortality.ResultsOf the 556 patients (72.5 +8.6 yrs; 37.4 % female), 38.9%) were on Apixaban, 36.9% on Rivaroxaban, and 24.3% on Dabigatran; 10.1% were on anti-platelet therapy. The overall CHADS score was 1.7 +1.0. Overall, 525 patients were categorized as having a low risk for bleeding, and 31 were at high-risk. DOAC were stopped 2.0 +0.5 days pre-procedure and restarted 1.9 +1.5 days post-procedure. Overall rates were: all bleeding 4.4% (2.9–6.4), GI bleeding 2.5% (1.4–4.2%), while 0.7% (0.3–1.8%) experienced a thromboembolic event. Additional results are listed in Table 1.ConclusionsPatients with AF undergoing a standardized DOAC therapy interruption management protocol for elective digestive endoscopy experienced low rates of major bleeding and arterial thromboembolism.Variable;Patient cohort N=556High-risk group for bleeding N=31 Low risk group for bleeding N=525* Diagnostic procedure N=430 Therapeutic procedure N=21 Mortality0.5 (0.2; 1.6)0.0 (0.0; 11.0)0.6 (0.2; 1.7)0.5 (0.1; 1.7)0.0 (0.0; 15.5)Thromboembolic event0.7 (0.3; 1.8)0.0 (0.0; 11.0)0.8 (0.3; 2.0)0.9 (0.4; 2.4)0.0 (0.0; 15.5)All Bleeding event4.4 (2.9; 6.4)16.1 (7.1; 32.6)3.7 (2.4; 5.6)3.7 (2.3; 6.0)19.1 (7.7; 40.0)GI Bleed2.5 (1.4; 4.2)9.7 (3.3; 24.9)2.1 (1.2; 3.7)2.1 (1.1; 3.9)4.8 (0.8; 22.7)All results reported as % and 95% CI * outcomes were missing for 4 patients that had the procedureFunding AgenciesNone

Impact of different renal function equations on direct oral anticoagulant concentrations

The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft–Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.