Oral Anticoagulant Users Research Articles

Association between warfarin and direct oral anticoagulants users and risk of mortality: cohort studies in England and Hong Kong

Abstract Background The evidence of the association between warfarin and risk of mortality compared with direct oral anticoagulants (DOACs) has been mixed in current literature. Purpose To investigate the association between all-cause mortality and warfarin, compared with DOACs. Methods Population-based cohort studies were conducted using the data from the Hong Kong Clinical Data Analysis and Reporting System (CDARS) and United Kingdom Clinical Practice Research Datalink (CPRD) Aurum. People with atrial fibrillation aged ≥18 years who initiated warfarin or a DOAC during the study period (1st Jan 2014 - 31st Dec 2019) were identified. Follow-up started from the first date of oral anticoagulant prescription and ended at earliest of the date of death, the day before drug switching (between warfarin and DOACs), transferring out of the practice (CPRD Aurum only), last data collection date for the practice (CPRD Aurum only) or the end of study period. We estimated propensity score (PS) based on the list of potential confounders including demographics, co-morbidities, co-medications and polypharmacy. Cox proportional hazards regression model with PS-weighting was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Among 227,190 new oral anticoagulant users, 54,367 (23.93%) died. The median follow-up was 2.96 and 2.45 years in CPRD and CDARS, respectively. Compared with DOAC use, a lower hazard of all-cause mortality was found in warfarin use (PS-weighted hazard ratio [HR]=0.94, 95% confidence interval [CI]=0.89-0.99) in CPRD; while a higher hazard was observed in warfarin users (PS-weighted HR=1.31, 95% CI=1.24-1.39) in CDARS, versus DOAC users. Consistent results were seen in both databases when stratified warfarin users by Time in Therapeutic Range (TTR). We observed a lower hazard of all-cause mortality in warfarin users with TTR≥65% (PS-weighted HR=0.90, 95% CI=0.85-0.94 in CPRD; 0.87, 0.79-0.96 in CDARS) and increased hazard in warfarin users with TTR<65% (PS-weighted HR=1.37, 95% CI=1.25-1.49 in CPRD; 1.57, 1.48-1.66 in CDARS), versus DOAC users. Conclusions The hazard of all-cause mortality associated with warfarin compared with DOACs were found to be conflicting across databases. However, both databases consistently showed that an increased hazard of all-cause mortality was only found in warfarin users with TTR<65% but not in those with TTR≥65%, suggesting that the differences in hazard of all-cause mortality associated with warfarin compared with DOAC, in part may depend on anticoagulation control in warfarin users. We recommend that warfarin users with poor INR control warrant closer clinical attention and could be considered for a switch to DOACs.

Risk of thromboembolic and haemorrhagic events associated with anticoagulation among 11,355 patients with non-valvular atrial fibrillation and thrombocytopenia

Abstract Background Oral anticoagulation (OAC) is the mainstay for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF). Management is challenging among patients with NVAF complicated with thrombocytopenia. Purpose We compared risk of thromboembolic and hemorrhagic events between vitamin-k antagonist (VKA) and direct oral anticoagulants (DOAC) users. Methods We retrospectively analyzed patients with thrombocytopenia and NVAF prescribed VKA (N=5,251, 46.2%) and DOAC (N=6,104, 53.8%) between January 2012 and July 2022 in 16 public hospitals in Hong Kong. Mild to moderate thrombocytopenia was defined as mean platelet count (PLT) 100-150 × 10^9/L and 50-100 × 10^9/L respectively, during the year of OAC initiation. Propensity-matched cohorts of VKA and DOAC were generated on the basis of age, sex, baseline co-morbidities (components of CHA2DS2VASC and HAS-BLED scores) and medications. Time to intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB) and ischemic stroke (IS) was analyzed using competing risk regression, accounting for death as competing risk. Subgroup analysis was performed to detect heterogeneity of effect across mild and moderate thrombocytopenia. Secondary outcome included (i) comparisons between 4 DOAC agents with full dose; (ii) Full-dose DOAC vs. reduced-dose DOAC. Results Of the whole cohort (N=11,355, mean age 75.8±10.5, female 38.6%), 10.3% (n=1,174) and 89.7% (n=10,181) had moderate and mild thrombocytopenia, respectively. After propensity-score matching, VKA and DOAC (n=4,302 each cohort) users were well balanced at baseline characteristics, with a median follow-up of 4.0 (IQR: 1.6-7.3) years. Overall, utilization of DOAC was associated with reduced risk of ICH [Hazards Ratio (HR) 0.56 (95% CI 0.45-0.70)] and GIB [HR 0.60 (95% CI 0.48-0.75)], compared with VKA. No difference in risk of IS was observed [HR 1.00 (95%CI 0.83-1.20)]. Dosing reduction of DOAC made no difference in all outcomes. Subgroup analysis demonstrated the benefit in decreasing GIB might be more marked in moderate thrombocytopenia [(HR 0.24 (95%CI 0.09-0.61)], than in mild thrombocytopenia [HR 0.64 (95%CI 0.51-0.81)]. Conclusion In patients with NVAF and thrombocytopenia, DOAC has similar efficacy but better safety profile than VKA. In terms of GIB, the superiority appeared to be more pronounced in patients with more significant thrombocytopenia.

Antibiotic prescribing patterns and risk of antibiotic-resistant infections and Clostridium difficile in Warfarin and Direct Oral Anticoagulant users: matched population-based cohort study

BackgroundWarfarin and Direct Oral Anticoagulant (DOAC) users may have more frequent antibiotic prescriptions than non-users. The aim of this study was to estimate rates of common and resistant infections, and antibiotic prescribing amongst warfarin and DOAC users versus non-users.MethodsThis matched retrospective cohort study used data from patients registered with General practices in England contributing to the Clinical Practice Research Datalink GOLD. We included 61,750 adults who initiated warfarin or a DOAC between 1st January 2011 and 31st December 2019, matched 1:1 to non-users. We estimated Incident Rate Ratios (IRR) and 95% Confidence Intervals for three common infections and all-cause antibiotic prescribing. We estimated hazard ratios (HRs) and 95% CIs for the risk of methicillin resistance Staphylococcus aureus (MRSA), other antibiotic-resistant organisms, or Clostridium difficile. We assessed the extent to which any of the effect of warfarin and DOAC use on antibiotic resistant infections or Clostridium difficile was mediated by antibiotic prescribing patterns.Results37,143 warfarin users and 24,607 DOAC users were matched 1:1 to non-users. Warfarin and DOAC users had greater relative consultation rates for respiratory, urinary, and skin infections. All-cause antibiotic prescribing was greater in warfarin and DOAC users (warfarin; adjusted IRR 1.47, 95% CI 1.45–1.50, DOAC; adjusted IRR 1.66, 95% CI 1.63–1.69). Largest effect sizes were observed for flucloxacillin (adjusted IRR 2.11, 95% CI 2.01–2.20), and erythromycin (adjusted IRR 2.32, 95% CI 2.00–2.70). Warfarin users had significantly higher risk of MRSA (adjusted HR 1.68, 95% CI 1.38–2.05) and hospital admission with antibiotic resistant infections (adjusted HR 1.91, 95% CI 1.11–3.30). DOAC users had significantly higher risk of MRSA (adjusted HR 1.57, 95% CI 1.20–2.06), hospital admission with antibiotic resistant infections (adjusted HR 2.13, 95% CI 1.61–2.82), and Clostridium difficile (adjusted HR 1.45, 95% CI 1.10–1.92). We found little evidence to suggest that the increased risks of studied outcomes were mediated by rates of antibiotic prescription.ConclusionWarfarin and DOAC use was associated with greater rates of infection consultations, all-cause antibiotic prescribing, antibiotic resistant infections, and Clostridium difficile, but there was little evidence that antibiotic prescribing rates mediated risk of resistant infections or Clostridium difficile.

Exploring bleeding in oral anticoagulant users: assessing incidence by indications and risk factors in the entire nationwide cohort.

Oral anticoagulants (OACs) are essential for the prevention and treatment of thromboembolic disorders, but bleeding, a major complication, can have a fatal impact on the patient's treatment. We aimed to estimate the nationwide, real-world incidence rate of bleeding in patients taking OACs and confirm the incidence by indications and risk factors. This cross-sectional study identified OAC users from April 1 to December 31, in both 2019 and 2020, using the HIRA-NPS database. The primary outcome variables were the incidence rate of major bleeding events during OAC treatment and within 30 days of treatment discontinuation. We estimated the adjusted incidence rate ratio (aIRR) in subpopulations. Among 18,822 OAC users, the incidence rate of major bleeding was 27.9 (95% CI: 24.6-31.5) per 1,000 person-years. The incidence rate of major bleeding was higher in patients with a bleeding history, with an aIRR of 11.51; those at high bleeding risk (HAS-BLED score ≥3), with an aIRR of 1.51; those with high CCI scores ≥3, with an aIRR of 1.88; and those with liver disease, with an aIRR of 1.41. For indications, compared to patients with nonvalvular atrial fibrillation (NVAF), the aIRR of major bleeding was significantly higher at an aIRR of 2.35 in patients undergoing VTE treatment. Patients with ischemic stroke showed a higher incidence of major bleeding with an aIRR of 2.13 than NVAF patients. The aIRR of major bleeding in the oral anticoagulant group, compared to the matched control group, was 2.25 (95% CI: 1.93-2.63). These findings may be useful for implementing strategies to improve the evaluation and management of anticoagulation-related bleeding.

Anticoagulant-related bleeding as a sign of underlying tumoural lesions in patients with atrial fibrillation: a nationwide cohort study.

Bleeding events are a well-known complication of oral anticoagulant (OAC) use in patients with atrial fibrillation (AF). While these are undesirable, bleedings could have a warning potential for underlying tumoural lesions. Therefore, we aimed to investigate the association between anticoagulant-related bleeding and newly diagnosed tumoural lesions in a nationwide cohort study. Using Belgian nationwide data, AF patients without any tumoural lesions were included when initiating OACs between 2013 and 2019. The absolute and relative risks of newly diagnosed tumoural lesions were investigated in OAC users with vs. without an OAC-related bleeding event. Analyses were additionally stratified by tumoural lesion, location-specific bleeding, and OAC type. A total of 230 386 OAC users were included, among whom 35 192 persons were diagnosed with a tumoural lesion during follow-up. Persons with a clinically relevant bleeding during OAC use had a tumoural lesion incidence of 15.33 per 100 person-years compared to an incidence of 5.22 per 100 person-years in persons without bleeding. Site-specific gastrointestinal, urogenital, respiratory, and intracranial bleeding events were respectively associated with a significantly increased risk of incident gastrointestinal [adjusted hazard ratio (aHR) 8.13 (95% confidence interval (CI): 7.08-9.34)], urological [aHR 12.73 (95% CI: 10.56-15.35)], respiratory [aHR 4.91 (95% CI: 3.24-7.44)], and intracranial tumoural lesions [aHR 27.89 (95% CI: 16.53-47.04)]. Bleeding events in AF patients initiated on OAC were associated with an increased risk of tumoural lesions. Therefore, OAC-related bleeding events could unmask an underlying tumoural lesion.

Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users.

We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P-glycoprotein (P-gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P-gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10days of 0.67 (95% confidence interval [CI]: 0.42-1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39-1.4), suggesting reduced oral absorption via increased P-gp expression. In vitro, dicloxacillin raised P-gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72-1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51-1.5). Dicloxacillin increases expression of intestinal P-gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug-drug interaction between dicloxacillin/flucloxacillin and DOACs.

Comparison of Oral Anticoagulant Users with Non-users Admission Laboratory Parameters, Length of Hospital Stay and Outcomes in COVID-19 Infection

Comparison of Oral Anticoagulant Users with Non-users Admission Laboratory Parameters, Length of Hospital Stay and Outcomes in COVID-19 Infection

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.

Impact of Direct Oral Anticoagulant Levels on Functional Independence Following Endovascular Thrombectomy in Patients With Atrial Fibrillation

Background In direct oral anticoagulant (DOAC) users with stroke due to large artery occlusion, endovascular thrombectomy is an effective treatment when intravenous thrombolytic therapy is unsuitable. The purpose of this study is to investigate the association between emergent DOAC levels and endovascular thrombectomy outcomes. Methods Participants with atrial fibrillation, who had a premorbid modified Rankin Scale score of ≤3 and had undergone endovascular thrombectomy for acute stroke, were enrolled. Drug levels upon hospital arrival were measured in the prestroke DOAC users. Head noncontrast computed tomography and computed tomographic angiography images were used to quantify thrombus permeability. The primary outcome was functional independence at 3 months (modified Rankin Scale 0–2 or a return to premorbid status for patients with a premorbid modified Rankin Scale of 3). Results The study included 250 patients (antithrombotic agent nonusers, 42.0%; oral anticoagulant users, 34.0%; and antiplatelet users, 24.0%). The primary outcomes did not differ among the 3 groups. Among oral anticoagulant users, 78.8% were DOAC users. Of the 59 DOAC users with available drug level measurements, 62.7% had low levels (&lt;50 ng/mL). Low‐level patients were less likely to achieve functional independence than high‐level patients (adjusted odds ratio, 0.26 [0.08–0.87]). Compared with antithrombotic nonusers, oral anticoagulant users with therapeutic anticoagulation were more likely to achieve functional independence (adjusted odds ratio, 2.83 [1.18–6.78]), whereas those with inadequate anticoagulation did not. Symptomatic intracerebral hemorrhage occurred in 3 DOAC users in the low‐level group (8.1%), 1 DOAC user in the high‐level group (4.5%), and 4 antithrombotic nonusers (3.8%). Thrombus permeability was similar between antithrombotic nonusers and low‐ or high‐level DOAC users. Conclusion Among patients who underwent DOAC therapy and endovascular thrombectomy, those with low DOAC levels were less likely to achieve functional independence. Furthermore, oral anticoagulant users with therapeutic anticoagulation displayed better functional outcomes than antithrombotic nonusers.

Thinking Three-Dimensionally: A Self- and Externally-Controlled Approach to Screening for Drug-Drug-Drug Interactions Among High-Risk Populations.

The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self-controlled estimates were adjusted using negative cases (external "control" DOAC users with the same outcomes but co-dispensings for non-interacting AHDs or ASMs). Signal thresholds were set based on P-values and false discovery rate q-values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self-controlled assessments with q-value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the P-value threshold and no signals from the q-value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with P-value thresholds yielded 3 3DI and 26 DDI signals following self-control, as well as 4 3DI signals following adjustment. No 3DI signals met the q-value threshold. The presented self- and externally-controlled approach aimed to advance paradigms for real-world higher order drug interaction screening among high-susceptibility populations with pre-existent DDI risk.

Antithrombotic Treatment and Clinical Outcomes After Intracerebral Hemorrhage: A Retrospective Cohort Study from the Swedish Stroke Register.

A rapid shift has occurred from vitamin K antagonists toward direct oral anticoagulants, which have a lower risk of intracerebral hemorrhage (ICH). However, effects on clinical outcomes after ICH are understudied. We aimed to describe the prevalence of antithrombotic drugs and to study the prognosis among prestroke functionally independent Swedish patients with ICH. We identified all patients diagnosed with nontraumatic ICH in 2017 to 2021 from the Swedish Stroke Register (n=13 155) and assessed death and functional outcome at 3 months after ICH in prestroke functionally independent patients (n=10 014). Functional outcome was estimated among 3-month survivors on the basis of self-reported activities of daily living scores. Risks of outcomes were estimated using Poisson regression. In 13 155 patients, 14.5% used direct oral anticoagulant, 10.1% vitamin K antagonists, and 21.6% antiplatelets at ICH onset. Among 10 014 pre-stroke activities of daily living-independent patients, oral anticoagulants and antiplatelets were associated with increased mortality risk (adjusted risk ratio, 1.27 [95% CI, 1.13-1.43]; P<0.001; and adjusted risk ratio, 1.23 [95% CI, 1.13-1.34]; P<0.001 respectively). Mortality risk did not statistically differ between antiplatelets and oral anticoagulants nor between direct oral anticoagulant and vitamin K antagonists. Among 5126 patients with nonmissing functional outcome (69.1% of survivors), antiplatelets (adjusted risk ratio, 1.06 [95% CI, 0.99-1.13]; P=0.100) and oral anticoagulants (adjusted risk ratio, 1.01 [95% CI, 0.92-1.12]; P=0.768) were not statistically significantly associated with functional dependence. There was no statistically significant difference in mortality risk between direct oral anticoagulant and vitamin K antagonists in prestroke functionally independent patients (unadjusted for oral anticoagulant class indication). Furthermore, mortality risk in antiplatelet and oral anticoagulant users might differ less than previously suggested.

Risk of bleeding amongst warfarin and direct oral anticoagulant users prescribed immediate antibiotics for respiratory tract infection: Cohort study.

Incidence of bleeding amongst warfarin and direct oral anticoagulant (DOAC) users is greater following a respiratory tract infection (RTI). It is unclear whether immediate antibiotics modify this association. We estimated the risk of bleeding amongst warfarin and DOAC users with RTI by antibiotic treatment. This retrospective cohort study used data from the Clinical Practice Research Datalink (CPRD) GOLD for adults in England prescribed warfarin or a DOAC, who sought primary care for an RTI between 1st January 2011 and 31st December 2019. Outcomes were major bleeding (hospital admission for intracranial or gastrointestinal bleeding), and non-major bleeding (hospital admission or General Practice consult for epistaxis, haemoptysis, or haematuria). Cox models derived hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, adjusting for confounders using inverse probability of treatment weighting. Of 14 817 warfarin and DOAC users consulting for an RTI, 8768 (59%) were prescribed immediate antibiotics and 6049 (41%) were not. Approximately 49% were female, and median age was 76 years. Antibiotics were associated with reduced risk of major bleeding (adjusted HR 0.38, 95% CI 0.25 to 0.58). This was consistent across several sensitivity analyses. Antibiotics were also associated with a reduced risk of non-major bleeding (adjusted HR 0.78, 95% CI 0.61 to 0.99). Immediate antibiotics were associated with reduced risk of bleeding amongst warfarin and DOAC users with an RTI. Further work is needed to understand mechanisms and confirm whether a lower threshold for antibiotic use for RTI in this population may be beneficial.

Gastrointestinal bleeding in elderly patients with atrial fibrillation: prespecified All Nippon Atrial Fibrillation in the Elderly (ANAFIE) Registry subgroup analysis

Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88–1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

Percutaneous left atrial appendage occlusion and risk of stroke, hospitalized bleeding and death in Medicare beneficiaries.

Among patients with atrial fibrillation (AF), a nonpharmacologic option (e.g., percutaneous left atrial appendage occlusion [LAAO]) is needed for patients with oral anticoagulant (OAC) contraindications. Among beneficiaries in the Medicare fee-for-service coverage 20% sample databases (2015-18) who had AF and an elevated CHA2DS2-VASc score, we assessed the association between percutaneous LAAO versus OAC use and risk of stroke, hospitalized bleeding, and death. Patients undergoing percutaneous LAAO were matched to up to five OAC users by sex, age, date of enrollment, index date, CHA2DS2-VASc score, and HAS-BLED score. Overall, 17 156 patients with AF (2905 with percutaneous LAAO) were matched (average ± SD 78 ± 6 years, 44% female). Cox proportional hazards model were used. Median follow-up was 10.3 months. After multivariable adjustments, no significant difference for risk of stroke or death was noted when patients with percutaneous LAAO were compared with OAC users (HRs [95% CIs]: 1.14 [0.86-1.52], 0.98 [0.86-1.10]). There was a 2.94-fold (95% CI: 2.50-3.45) increased risk for hospitalized bleeding for percutaneous LAAO compared with OAC use. Among patients 65 to <78 years old, those undergoing percutaneous LAAO had higher risk of stroke compared with OAC users. No association was present in those ≥78 years. In this analysis of real-world AF patients, percutaneous LAAO versus OAC use was associated with similar risk of death, nonsignificantly elevated risk of stroke, and an elevated risk of bleeding in the post-procedural period. Overall, these results support results of randomized trials that percutaneous LAAO may be an alternative to OAC use for patients with contraindications.

Anticoagulation in patients with end-stage kidney disease and atrial fibrillation: a national population-based study.

The prevalence of atrial fibrillation (AF) in patients with end-stage kidney disease (ESKD) is high and increasing. However, evidence regarding oral anticoagulant (OAC) use in these patients is insufficient and conflicting. This retrospective cohort study included patients in the Korea National Health Insurance System diagnosed with AF after ESKD onset from January 2007 to December 2017. The primary outcome was all-cause death. Secondary outcomes were ischaemic stroke, hospitalization for major bleeding and major adverse cardiovascular events (MACE). Outcomes were compared between OAC users and non-users using 6-month landmark analysis and 1:3 propensity score matching (PSM). Among patients with ESKD and AF, the number of prescribed OACs increased 2.3-fold from 2012 (n=3579) to 2018 (n=8341) and the proportion of direct OACs prescribed increased steadily from 0% in 2012 to 51.4% in 2018. After PSM, OAC users had a lower risk of all-cause death {hazard ratio [HR] 0.67 [95% confidence interval (CI) 0.55-0.81]}, ischaemic stroke [HR 0.61 (95% CI 0.41-0.89)] and MACE [HR 0.70 (95% CI 0.55-0.90)] and no increased risk of hospitalization for major bleeding [HR 0.99 (95% CI 0.72-1.35)] compared with non-users. Unlike warfarin, direct OACs were associated with a reduced risk of all-cause death and hospitalization for major bleeding. In patients with ESKD and AF, OACs were associated with reduced all-cause death, ischaemic stroke and MACE.

Effectiveness and safety of prophylactic anticoagulation among hospitalized patients with inflammatory bowel disease

AbstractHospitalized patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE). We aimed to evaluate the effectiveness and safety of prophylactic anticoagulation compared with no anticoagulation in hospitalized patients with IBD. We conducted a retrospective cohort study using a hospital-based database. We included patients with IBD who had a length of hospital stay ≥2 days between 1 January 2016 and 31 December 2019. We excluded patients who had other indications for anticoagulation, users of direct oral anticoagulants, warfarin, therapeutic-intensity heparin, and patients admitted for surgery. We defined exposure to prophylactic anticoagulation using charge codes. The primary effectiveness outcome was VTE. The primary safety outcome was bleeding. We used propensity score matching to reduce potential differences between users and nonusers of anticoagulants and Cox proportional-hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The analysis included 56 194 matched patients with IBD (users of anticoagulants, n = 28 097; nonusers, n = 28 097). In the matched sample, prophylactic use of anticoagulants (vs no use) was associated with a lower rate of VTE (HR, 0.62; 95% CI, 0.41-0.94) and with no difference in the rate of bleeding (HR, 1.05; 95% CI, 0.87-1.26). In this study of hospitalized patients with IBD, prophylactic use of heparin was associated with a lower rate of VTE without increasing bleeding risk compared with no anticoagulation. Our results suggest potential benefits of prophylactic anticoagulation to reduce the burden of VTE in hospitalized patients with IBD.

Anticoagulation-Associated Bleeding in Patients Screened for Atrial Fibrillation versus Usual Care-A Post Hoc Analysis from the LOOP Study.

Background Atrial fibrillation (AF) prevalence is rising; however, data on the bleeding risks associated with the detection of subclinical AF are needed. Objective Our objective was to determine the bleeding increment associated with implantable loop recorder (ILR) screening for subclinical AF and subsequent anticoagulation initiation compared with usual care. Methods This post hoc study utilized LOOP trial data from 6,004 elderly patients with stroke risks randomized to either ILR ( n = 1,503) or usual care ( n = 4,503). The mean follow-up time was 64.5 months, and none were lost to follow-up. The primary exposure was the initiation of oral anticoagulation, and the main outcome was the risk of major bleeding events following initiation of oral anticoagulants (OACs), determined by time-dependent cox regression. Second, we investigated antithrombotic prescription patterns and major bleeding events after antiplatelet treatment and in subgroups. Results OAC was initiated in 1,019 participants with a mean age (years) of 78.8 (± 4.67) in control versus 77.0 (± 4.84) in ILR, p < 0.0001. Altogether did 202 participants end or pause OAC treatment. Among AF patients (n = 910) had 40 (28%) completely ended OAC and 105 (72%) temporarily paused OAC during follow-up. Major bleeding events totaled 221 (3.7%). Forty-seven major bleeding events followed an OAC initiation in 1,019 participants (4.6%); 26 versus 21 events in the control and ILR groups, respectively. The hazard ratio (HR) for major bleeding after OAC initiation compared with before initiation was 2.08 (1.50-2.90) p < 0.0001 overall, 2.81 (1.82-4.34) p < 0.0001 for control and 1.32 (0.78-2.23) p = 0.31 for the ILR group ( p = 0.07 for interaction). Antiplatelet treatment resulted in an overall adjusted HR of 1.3 (0.96-1.75) p = 0.09. For OAC users aged ≥75 years in the ILR group, the rate of major bleeding was 1.73 (0.92-2.96) compared with 0.84 (0.36-1.66) for an age <75 years, and the rate of the corresponding control subgroup aged ≥75 years was 2.20 (1.23-3.63) compared with 1.64 (0.82-2.93) for an age <75 years. Conclusion The individual risk of major bleeding increased twofold after initiation of oral anticoagulation for all patients in this study. However, the patients screened for subclinical AF did not have a higher bleeding risk after initiation of anticoagulation compared with those in usual care. Trial Registration: The LOOP study is registered at ClinicalTrials.gov, identifier: NCT020364 50.

Stroke and bleeding risk in atrial fibrillation with CHA2DS2-VASC risk score of one: the Norwegian AFNOR study.

The benefit of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) and intermediate stroke risk is debated. In a nationwide Norwegian cohort with a non-sex CHA2DS2-VASc risk score of one, this study aimed to investigate (i) stroke and bleeding risk in AF patients with and without OAC treatment, and (ii) the risk of stroke in non-anticoagulated individuals with and without AF. A total of 1 118 762 individuals including 34 460 AF patients were followed during 2011-18 until ischaemic stroke, intracranial haemorrhage, increased CHA2DS2-VASc score, or study end. One-year incidence rates (IRs) were calculated as events per 100 person-years (%/py). Cox regression models provided adjusted hazard ratios (aHRs [95% confidence intervals]). Among AF patients, the ischaemic stroke IR was 0.51%/py in OAC users and 1.05%/py in non-users (aHR 0.47 [0.37-0.59]). Intracranial haemorrhage IR was 0.28%/py in OAC users and 0.19%/py in non-users (aHR 1.23 [0.88-1.72]). Oral anticoagulant use was associated with an increased risk of major bleeding (aHR 1.37 [1.16-1.63]) but lower risk of the combined outcome of ischaemic stroke, major bleeding, and mortality (aHR 0.57 [0.51-0.63]). Non-anticoagulated individuals with AF had higher risk of ischaemic stroke compared to non-AF individuals with the same risk profile (aHR 2.47 [2.17-2.81]). In AF patients at intermediate risk of stroke, OAC use was associated with overall favourable clinical outcomes. Non-anticoagulated AF patients had higher risk of ischaemic stroke compared to the general population without AF with the same risk profile.

Anticoagulation-associated bleeding in patients randomised to screening for atrial fibrillation or usual care

Abstract Background Atrial fibrillation (AF) prevalence is rising, strongly aided by population ageing and increased awareness. Detection and treatment of subclinical AF may help mitigate stroke risk, but could increase iatrogenic complications. Purpose To evaluate whether detection of subclinical AF using implantable loop recorder (ILR) and subsequent initiation of oral anticoagulant (OAC) enhances the risk of major bleeding in elderly individuals with stroke risk factors. Methods This was a post-hoc analysis of a trial which randomised 6004 participants without known AF but with stroke risk factors in a 1:3 ratio to either ILR-screening for AF and OAC initiation upon AF episodes lasting ≥6 minutes or usual care (Control group). We examined the risk of major bleeding using OAC initiation as a time-varying exposure (figure 1) in Cox regression models, and similarly for the use of antiplatelets. Further, we estimated the incidence rates of OAC/antiplatelet initiation and discontinuation along with the distribution of major bleeding events according to drug exposure and subgroups. Results A total of 1019 participants (17%) initiated OAC; 578 (12.8%) in Control group vs. 441 (29.4%) in ILR group, with a mean age of 78.8 (±4.7) years in Control vs. 77.0 (±4.8) in ILR group, p&amp;lt;0.0001. Major bleeding events totalled 221 (3.7%) with 47 of these occurring after OAC initiation (4.6% of all OAC-users); 26 (4.5%) vs. 21 (4.8%) in Control and ILR group, respectively. Without the use of OAC or antiplatelets the overall rate of major bleeding was 0.44 (0.33-0.57) per 100-perosn years compared to 1.54 (1.13-2.05) after OAC initiation. For the individual person, the hazard ratio for major bleeding after OAC initiation was 2.08 (1.50-2.90) p&amp;lt;0.0001 compared to before initiation (Control: 2.81 (1.82-4.34) p&amp;lt;0.0001, ILR: 1.32 (0.78-2.23) p=0.31, p=0.07 for interaction)(table 1), similarly was usage of antiplatelet associated with a hazard ratio of 1.3 (0.96-1.75) p=0.09. For OAC users ≥75 years, the rate of major bleeding was 1.96 (1.30-2.83)(Control: 2.20 (1.23-3.63), ILR: 1.73 (0.92-2.96)), compared to 1.17 (0.70-1.83) among users &amp;lt;75 years (Control: 1.64 (0.82-2.93), ILR: 0.84 (0.36-1.66)). After OAC initiation, the discontinuation rate in the Control and ILR group was 9.60 (7.9-11.6) and 6.15 (4.95-7.55), respectively, while the rate of antiplatelet discontinuation was 7.44 (6.92-7.99) and 12.24 (10.9-13.4) in the Control and ILR group. Conclusion This post-hoc study of a randomised study found a two-fold risk increase of major bleeding after OAC initiation on individual basis compared with before, but this increase did not seem augmented by AF screening and treatment. A weaker signal was seen for antiplatelets. The OAC-associated bleeding risk was markedly higher in the elderly population. Finally, discontinuations of OAC and antiplatelets were common throughout follow-up.

Oral Anticoagulant Use in Patients with Atrial Fibrillation at Low Risk of Stroke and Associated Bleeding Complications.

The use of oral anticoagulants (OACs) in patients with atrial fibrillation (AF) and low stroke risk might cause more harm than benefit. Little attention has been given to address its prevalence and associated consequences. This study aimed to investigate the prescription rate of OACs, identify associated factors, and describe incident bleeding events in low-risk patients. We included patients with a new diagnosis of AF between 1 January 2011 and 31 December 2018 having a low risk of stroke (CHA2DS2-VASc score of 0 for males and 1 for females) from Australian general practice data (MedicineInsight). Patients were classified as OAC users if there was a recorded prescription of an OAC within 60 days of AF diagnosis, and factors associated with the prescription of an OAC were assessed using logistic regression. Recorded incident bleeding events were identified within 6 months after AF diagnosis or after OAC initiation for OAC non-users and users, respectively. The risk of bleeding was compared between the two groups by adjusting their baseline differences using propensity score matching. The study included 2810 low-risk patients (62.3% male) with a mean age of 49.3 ± 10.8 years. Of the total, 705 (25.1%) patients had a record of OAC prescription within 60 days of diagnosis of AF. Older age (odds ratio [OR] 1.03; 95% confidence interval [CI] 1.03-1.04) and diagnosis periods (2015-2016 [OR 1.46; 95% CI 1.10-1.94] and 2017-2018 [OR 1.65; 95% CI 1.17-2.23] vs. 2011-2012) were associated with higher odds of OAC initiation. Female sex (OR 0.71; 95% CI 0.59-0.85), higher bleeding risk (ORBIT score; OR 0.80; 95% CI 0.68-0.94), and higher socioeconomic index for areas (SEIFA) quintiles (SEIFA quintiles; 2 [OR 0.65; 95% CI 0.48-0.88], 3 [OR 0.74; 95% CI 0.56-0.98], 4 [OR 0.70; 95% CI 0.52-0.94], 5 [OR 0.69; 95% CI 0.52-0.91] compared with quintile 1) were associated with lower odds of OAC prescription. A total of 52 (in 1.8% of patients) incident bleeds were identified, with 18 (2.6%) among OAC users. The rate of bleeding was not significantly different between users and non-users after matching. However, within OAC users, commencement of OAC was associated with an increased risk of bleeding compared to the period before OAC initiation (p = 0.006). One in four patients at low risk of stroke received an OAC within 60 days of AF diagnosis. Older age and the period following the widespread availability of direct-acting OACs were associated with an increased likelihood of OAC prescription. Positively, using OACs was not associated with an increased rate of bleeding compared to non-users.