Direct Oral Anticoagulants Users Research Articles

#430 Risk factors for major bleeding in patients with non-valvular atrial fibrillation and CKD G3-G5D on oral anticoagulants

Abstract Background and Aims We previously published a register-based cohort study comparing direct oral anticoagulants (DOAC) and warfarin in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) GFR category 3-5 (G3-G5) including patients on dialysis (G5D) (1). This study showed that DOAC was associated with lower risk of major bleeding but similar risk of ischemic stroke compared to warfarin. Bleedings were however more common than strokes, especially in advanced CKD (G5-G5D) where the risk of major bleeding was up to 10 times higher than the risk of stroke. Subsequently, the stroke- and bleeding risk in patients with AF and advanced CKD must be carefully evaluated when deciding on whether to prescribe oral anticoagulants (OAC) or not. Available stroke- and bleeding scoring systems do not perform well in CKD (2, 3). This study aims to present risk factors associated with major bleeding in a Swedish cohort of OAC-treated patients with CKD G3-G5D. Method Data was collected from high quality Swedish healthcare registers including Swedish Renal Registry and Auricula, a register for atrial fibrillation and oral anticoagulants and the National Patient Register. Patients with eGFR<60 ml/min/1.73m2 and non-valvular atrial fibrillation and either DOAC (apixaban, rivaroxaban, edoxaban and dabigatran) or warfarin treatment between 2009-2018 where included. DOAC treatment periods were collected from the Swedish Prescribed Drug Register (PDR), starting from dispense date covering assumed standard pill use and an additional 30 days grace period. Warfarin treatment periods were collected directly from Auricula. An undefined treatment was a period of no OAC or a period of warfarin from PDR not matching a treatment period in Auricula. All periods of OAC treatment with either DOAC or warfarin were evaluated in a multivariate Cox regression model regarding the risk of major bleeding requiring inpatient care. Time-dependent covariates adjusted for in the model were age, sex, years from study start, GFR category, congestive heart failure, diabetes mellitus, hypertension, excessive alcohol use, liver disease, vascular disease, previous gastrointestinal bleeding, intracranial bleeding, other bleeding, ischemic stroke/ transient ischemic attack (TIA), myocardial infarction, PCI and exposures (DOAC, warfarin and periods of undefined treatment). Results Of 2453 included patients, 59% had warfarin (time in therapeutic range, TTR, 67%) and 41% DOAC at inclusion, predominantly apixaban (81% of DOAC users). The mean age was 77 years, 28.3% had G3, 45.4% G4, 9.1% G5 and 17.3% G5D (Table 1). Mean follow up was 2.2 years. During follow up 424 major bleedings occurred yielding 8.9 (95% confidence interval 8.1-9.8) bleedings per 100 patient-years. Table 2 shows effect estimates of each covariate on the outcome major bleeding. Covariates, besides warfarin, associated with increased risk of major bleeding were GFR category, G5/5D versus G3, hazard ratio 1.92 (95% CI 1.43-2.56), previous GI bleeding, 1.77 (1.39-2.25) and previous other bleeding 1.33 (1.09-1.62). Other factors associated with major bleeding were congestive heart failure 1.36 (1.11-1.68), male sex 1.28 (1.03-1.60) and vascular disease, 1.35 (1.01-1.79). Conclusion Patients with non-valvular atrial fibrillation and CKD G3-G5D on OAC are at high risk of major bleeding. Previous major bleeding and kidney failure are strongly associated with major bleeding, this reiterates the results of many previous studies. The present study also shows an association between OAC-associated major bleeding in CKD and male sex, congestive heart failure and vascular disease. Similar associations have been showed in non-CKD cohorts previously but is inadequately studied in CKD. Knowledge about risk factors for major bleeding on OAC in advanced CKD is essential when deciding on when to anticoagulate or not.

Racial and Ethnic Disparities in Initiation of Direct Oral Anticoagulants Among Medicare Beneficiaries

The influence of race and ethnicity on initiation of direct oral anticoagulants (DOACs) is relatively understudied in Medicare data. To investigate disparities in the initiation of DOACs compared with warfarin by race, ethnicity, and social vulnerability. This retrospective cohort study used a 50% sample of Medicare fee-for-service data from January 1, 2010, to December 31, 2019 (mean patient enrollment duration, 7.7 years). Analysis took place between January 2023 and February 2024. A cohort of older adults (aged ≥65 years) with atrial fibrillation who newly initiated warfarin or DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) was identified. Patients were classified as non-Hispanic White, non-Hispanic Black, and Hispanic. The likelihood of starting use of DOACs compared with warfarin was modeled, adjusting for race, ethnicity, age, sex, county-level social vulnerability, and other clinical factors. Among 950 698 anticoagulation initiations, consisting of 680 974 DOAC users and 269 724 warfarin users (mean [SD] age, 78.5 [7.6] years; 52.6% female), 5.2% were Black, 4.3% were Hispanic, and 86.7% were White. During the 10-year study period, DOAC use increased for all demographic groups. After adjustment, compared with White patients, Black patients were 23% less likely (adjusted odds ratio [AOR, 0.77; 95% CI, 0.75-0.79) and Hispanic patients were 13% less likely (AOR, 0.87; 95% CI, 0.85-0.89) to initiate DOAC use. Disparities in DOAC initiation were greatest among Black patients in the earlier years but attenuated during the study period. For instance, in 2010, the OR of Black patients initiating DOACs was 0.54 (95% CI, 0.50-0.57), attenuating linearly over time to 0.69 by 2013 (95% CI, 0.65-0.74) and 0.83 (95% CI, 0.78-0.89) by 2017. By 2019, these differences became nonsignificant (OR, 1.08; 95% CI, 0.99-1.18). In this cohort study of Medicare patients with atrial fibrillation, Black and Hispanic patients were less likely to initiate DOACs for atrial fibrillation, although these differences diminished over time. Identifying the factors behind these early disparities is crucial for ensuring equitable access to novel therapies as they emerge for Black and Hispanic populations.

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.

A real-world exploration into clinical outcomes of direct oral anticoagulant therapy in people with chronic kidney disease: a large hospital-based study.

There is limited evidence to support definite clinical outcomes of direct oral anticoagulant (DOAC) therapy in chronic kidney disease (CKD). By identifying the important variables associated with clinical outcomes following DOAC administration in patients in different stages of CKD, this study aims to assess this evidence gap. An anonymised dataset comprising 97,413 patients receiving DOAC therapy in a tertiary health setting was systematically extracted from the multidimensional electronic health records and prepared for analysis. Machine learning classifiers were applied to the prepared dataset to select the important features which informed covariate selection in multivariate logistic regression analysis. For both CKD and non-CKD DOAC users, features such as length of stay, treatment days, and age were ranked highest for relevance to adverse outcomes like death and stroke. Patients with Stage 3a CKD had significantly higher odds of ischaemic stroke (OR 2.45, 95% Cl: 2.10-2.86; p = 0.001) and lower odds of all-cause mortality (OR 0.87, 95% Cl: 0.79-0.95; p = 0.001) on apixaban therapy. In patients with CKD (Stage 5) receiving apixaban, the odds of death were significantly lowered (OR 0.28, 95% Cl: 0.14-0.58; p = 0.001), while the effect on ischaemic stroke was insignificant. A positive effect of DOAC therapy was observed in advanced CKD. Key factors influencing clinical outcomes following DOAC administration in patients in different stages of CKD were identified. These are crucial for designing more advanced studies to explore safer and more effective DOAC therapy for the population.

Real-World Risk of Gastrointestinal Bleeding for Direct Oral Anticoagulants and Warfarin Users: A Distributed Network Analysis Using a Common Data Model.

: Early studies on direct oral anticoagulants (DOACs) reported a higher risk of gastrointestinal bleeding (GIB) compared with warfarin; however, recent studies have reported a reduced risk. Therefore, this study was designed to evaluate the risk of GIB in users of DOAC and warfarin. : Using a common data model, we investigated the comparative risk of GIB in subjects from eight hospitals who were newly prescribed DOACs or warfarin. We excluded subjects who had a prior history of GIB or had been prescribed both medications. After propensity score matching, we analyzed 3,347 matched pairs of new DOAC and new warfarin users. : The risk of GIB in new DOAC users was comparable to that in new warfarin users (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.65 to 1.40; p=0.808). New DOAC users had a similar risk of GIB to new warfarin users among older patients >65 years (HR, 1.00; 95% CI, 0.69 to 1.52; p=0.997) and in older patients >75 years (HR, 1.21; 95% CI, 0.68 to 2.10; p=0.509). In addition, the risk of GIB was not significantly different between two groups according to sex. We also found that the risk of GIB in DOAC users was 26% lower in edoxaban or apixaban subgroups compared to rivaroxaban or dabigatran subgroups (HR, 0.74; 95% CI, 0.69 to 1.00; p=0.049). : In real-world practice, the risk of GIB in new DOAC users is comparable to that in new warfarin users. In DOAC users, the risk of GIB was lower in edoxaban or apixaban subgroups than rivaroxaban or dabigatran subgroups.

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.

Reduction of Upper Gastrointestinal Bleeding Risk With Proton Pump Inhibitor Therapy in Asian Patients With Atrial Fibrillation Receiving Direct Oral Anticoagulant: A Nationwide Population-based Cohort Study

Background & AimsIn patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), upper gastrointestinal bleeding (UGIB) is a serious complication. There are limited data on the benefit of preventive proton pump inhibitor (PPI) use to reduce the risk of UGIB in DOAC users. MethodsWe included patients with AF receiving DOAC from 2015 to 2020 based on the Korean Health Insurance Review and Assessment database. The propensity score (PS) weighting method was used to compare patients with PPI use and those without PPI use. The primary outcome was hospitalization for UGIB. Weighted hazard ratios (HR) and corresponding 95% confidence intervals (CI) were evaluated using the Cox proportional hazards regression model. ResultsA total of 165,624 patients were included (mean age: 72±11 years; mean CHA2DS2-VASc score: 4.3±1.8; mean HAS-BLED score: 3.3±1.2). Among them, 99,868 and 65,756 were in the non-PPI group and PPI group, respectively. During a median follow-up of 1.5 years, the PPI group was associated with lower risks of hospitalization for UGIB and UGIB requiring RBC transfusion than non-PPI group [weighted HR (95% CI): 0.825 (0.761-0.894) and 0.798 (0.717-0.887), respectively, both p<0.001]. The benefits of PPI on the risk of hospitalization for UGIB were greater in those with older age (≥75 years), higher HAS-BLED score (≥3), prior UGIB history, and concomitant use of antiplatelet agent (all p-for-interaction<0.1). Low-dose PPI was consistently associated with a lower risk of significant UGIB [adjusted HR: 0.564 (0.504-0.631), p<0.001]. ConclusionsIn this large Asian cohort of patients with AF on DOAC, PPI co-therapy is beneficial for reducing the risk of hospitalization for UGIB, particularly in high-risk patients.

Direct oral anticoagulants and the risk of adverse clinical outcomes among patients with different body weight categories: a large hospital-based study

ObjectiveThrough predictable pharmacokinetics—including a convenient fixed-dose regimen, direct oral anticoagulants (DOACs) are preferred over previous treatments in anticoagulation for various indications. However, the association between higher body weight and the risk of adverse consequences is not well studied among DOAC users. We aim to explore the association of body weight and adverse clinical outcomes in DOAC users.MethodsA total of 97,413 anonymised DOAC users in a tertiary care setting were identified following structured queries on the electronic health records (EHRs) to extract the feature-rich anonymised dataset. The prepared dataset was analysed, and the features identified with machine learning (ML) informed the adjustments of covariates in the multivariate regression analysis to examine the association. Kaplan–Meier analysis was performed to evaluate the mortality benefits of DOACs.ResultsAmong DOAC users, the odds of adverse clinical outcomes, such as clinically relevant non-major bleeding (CRNMB), ischaemic stroke, all-cause mortality, and prolonged hospital stay, were lower in patients with overweight, obesity, or morbid obesity than in patients with normal body weight. The odds of ischaemic stroke (OR 0.42, 95% CI: 0.36–0.88, p = 0.001) and all-cause mortality (OR 0.87, 95% CI: 0.81–0.95, p = 0.001) were lower in patients with morbid obesity than in patients with normal body weight. In the Kaplan–Meier analysis, apixaban was associated with a significantly lower rate of mortality overall and in obesity and overweight subgroups than other DOACs (p < 0.001). However, rivaroxaban performed better than apixaban in the morbid obesity subgroup (p < 0.001).ConclusionThis study shows the positive effects of DOAC therapy on clinical outcomes, particularly in patients with high body weight. However, this still needs validation by further studies particularly among patients with morbid obesity.

Digital dashboards for direct oral anticoagulant surveillance, intervention and operational efficiency: uptake, obstacles, and opportunities

Direct oral anticoagulants (DOAC) are the most widely prescribed oral anticoagulants in the United States. Despite advantages over warfarin, system-level improvements are needed to optimize outcomes. While Veterans Health Administration and others have described successful DOAC management dashboard implementation, the extent of use nationally is unknown. A survey of Anticoagulation Forum’s members was conducted to assess access to digital tools available within a dashboard and to describe implementation models. An Expert Forum was subsequently convened to identify barriers to dashboard development and adoption. Responses were received from 340 targeted recipients (8.5% of invitees). Only a minority of inpatient (25/52, 48.1%) and outpatient (47/133, 35.3%) respondents outside of Veterans Health Administration were able to generate rosters of DOAC users on-demand, and fewer had the ability to digitally display key clinical data elements, identify drug-related problems, document interventions, or generate reports. The lack of regulatory requirements regarding Anticoagulation Stewardship was identified by the Expert Forum as the major barrier to widespread development of digital tools for improved anticoagulation management. While some health systems have demonstrated the feasibility of DOAC dashboards and described their impact on quality and efficiency, these tools do not appear to be widely available in the United States apart from Veterans Health Administration. The lack of regulatory requirements for Anticoagulation Stewardship may be the primary barrier to the development of digital resources to better manage anticoagulants. Efforts to secure regulatory requirements for Anticoagulation Stewardship are needed, and evidence of improvements in clinical and financial outcomes through DOAC dashboard use will likely bolster such efforts.

Impact of cerebral small vessel disease burden and drug level at admission on direct oral anticoagulant associated intracerebral hemorrhage.

Direct oral anticoagulant (DOAC)-associated intracerebral hemorrhage (ICH) is a catastrophic complication. The aim of this study was to investigate the association between computed tomography (CT)-based cerebrovascular small vessel disease (SVD) burden and DOAC-ICH as well as the DOAC concentration upon hospital admission and ICH outcome. The study included two cohorts: (1) DOAC-ICH: patients who suffered from DOAC-ICH and underwent drug level measurements upon admission; (2) DOAC-non-ICH: stable DOAC users who underwent head CT without ICH during treatment. We categorized the DOAC levels of the DOAC-ICH patients as low (<50 ng/mL), medium (50-300 ng/mL), and high (>300 ng/mL). The CT-based SVD burden (including white matter lesions [WML], lacunes, and cerebral atrophy) was evaluated, and SVD scores (range, 0-3) were used to evaluate SVD severity. A total of 43 DOAC-ICH patients and 177 DOAC-non-ICH patients were enrolled. DOAC-ICH patients were more likely to have WML, lacunes, or cerebral atrophy compared to DOAC-non-ICH patients. After adjustment, the SVD burden was associated with DOAC-ICH, with a higher risk of more severe SVD (SVD score of 2; odds ratio [OR], 10.3 [3.17, 33.3]; score of 3; OR, 16.8 [4.50, 62.6]). The proportions of patients with high, medium, and low drug levels in the DOAC-ICH group were 16.3%, 55.8%, and 27.9%, respectively. Additionally, the high-level group displayed a larger hematoma size and had worse functional outcomes at 3 months than the other two groups. The severity of SVD burden was associated with DOAC-ICH. Furthermore, high DOAC levels in ICH were associated with unfavorable clinical outcomes. To address the potential selection bias from these two cohorts, a prospective study to investigate the co-contribution of drug levels and SVD to DOAC-ICH is essential.

Oral anticoagulant treatment and risk of kidney disease-a nationwide, population-based cohort study.

Direct oral anticoagulants (DOACs) are recommended as first-line treatment of atrial fibrillation. Whether DOAC use is associated with lower risks of kidney complications compared with vitamin K antagonists (VKAs) remains unclear. We examined this association in a nationwide, population-based cohort study. We conducted a cohort study including patients initiating oral anticoagulant treatment within 3months after an atrial fibrillation diagnosis in Denmark during 2012-18. Using routinely collected creatinine measurements from laboratory databases, we followed patients in an intention-to-treat approach for acute kidney injury (AKI) and chronic kidney disease (CKD) progression. We used propensity-score weighting to balance baseline confounders, computed weighted risks and weighted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing DOACs with VKAs. We performed several subgroup analyses and a per-protocol analysis. We included 32 781 persons with atrial fibrillation initiating oral anticoagulation (77% initiating DOACs). The median age was 75years, 25% had a baseline estimated glomerular filtration rate <60mL/min/1.73 m2, and median follow-up was 2.3 (interquartile range 1.1-3.9) years. The weighted 1-year risks of AKI were 13.6% in DOAC users and 15.0% in VKA users (HR 0.86, 95% CI 0.82; 0.91). The weighted 5-year risks of CKD progression were 13.9% in DOAC users and 15.4% in VKA users (HR 0.85, 95% CI 0.79; 0.92). Results were similar across subgroups and in the per-protocol analysis. Initiation of DOACs was associated with a decreased risk of AKI and CKD progression compared with VKAs. Despite the potential limitations of observational studies, our findings support the need for increased clinical awareness to prevent kidney complications among patients who initiate oral anticoagulants.

Direct Oral Anticoagulants Affect Activated Clotting Time During and Bleeding Events After Percutaneous Coronary Intervention

Inappropriately high activated clotting time (ACT) during percutaneous coronary intervention (PCI) is associated with an increased risk of bleeding events. However, whether the prescription of direct oral anticoagulants (DOACs) affects ACT kinetics during heparin use and adverse clinical events in patients who underwent PCI remains unclear. We aimed to evaluate the relations between ACT changes during and adverse clinical events after PCI in patients who were prescribed DOAC. This observational study included 246 patients who underwent PCI at the 2 cardiovascular centers who were not receiving warfarin and whose ACT was recorded immediately before and 30minutes after injection of unfractionated heparin. Patients were divided into 2 groups according to DOAC prescription at the time of the index PCI: DOAC users (n=31) and nonusers (n=215). Any bleeding and systemic thromboembolic events were investigated until 30days after PCI. The average age of this population was 70.5years, and 66.3% were male. Average ACT was significantly higher in DOAC users than nonusers both before and 30minutes after unfractionated heparin induction (157.2±30.1 vs 131.8±25.1seconds, p<0.001; 371.1±122.2 vs 308.3±82.2seconds, p<0.001; respectively). The incidence of systemic thromboembolism after PCI was low and comparable between the 2 groups (0% vs 3.7%, p=0.60). However, the rate of any bleeding event was significantly higher in DOAC users than in nonusers (16.1% vs 4.7%, p=0.028). Patients receiving DOAC have higher ACT during PCI and higher incidence of bleeding events than those not receiving DOAC.

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.

Management of anticoagulation in atrial fibrillation patients in Italy: insight from the &lt;i&gt;Atrial Fibrillation-Survey on Anticoagulated Patients Register&lt;/i&gt; (AF-START)

The survey on anticoagulated patients register (START-Register) is an independent, prospective, inception-cohort observational study aimed at providing information on patients on vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in Italy. In this study, we describe the cohort of atrial fibrillation (AF) patients in the START-Register and report outcomes and changes in anticoagulant prescription from 2011 to 2021. The study included 11,078 AF patients, enrolled in 47 Italian centers distributed all over the Country; the median age was 77 years (range 18-99 years); 6029 (54.3%) were men; 5135 (46.4%) were on VKAs, and 5943 (53.6%) were on DOACs. Warfarin was the most prescribed VKA (98.4%), and apixaban was the most prescribed DOAC (31.6%). Among DOAC users, 4022 (67.7%) patients were naive to anticoagulation, and 2562 (43.1%) patients were treated with a reduced dose. DOAC patients were significantly older than VKA patients (median age 79 years vs 76 years respectively, P&lt;0.001), but no gender difference was detected. The mean CHA2DS2VASc score was higher in DOAC users than in VKA users (3.7 vs 3.6; P=0.03). The mean HAS-BLED score was not different between the two groups. During follow-up, 542 bleeding events were recorded [2.44 per 100 patient-years (pt-yrs)]; 240 were major (1.08 per 100 pt-yrs), and 301 were clinically relevant non-major bleedings (1.34 per 100 pt-yrs). 146 thrombotic events were recorded during follow-up (0.66 per 100 pt-yrs). The total mortality rate was 3.5 per 100 pt-yrs; the mortality rate was 4.54 per 100 pt-yrs among patients on VKAs and 2.31 per 100 pt-yrs among patients on DOACs. During the last 10 years, in Italy, AF patient management has changed with the large spread of DOACs all over the Country. DOAC patients are frequently treated with reduced doses and show a lower mortality rate in comparison to patients on VKAs.

Risk of venous thromboembolism or hemorrhage among individuals with chronic kidney disease on prophylactic anticoagulant after hip or knee arthroplasty.

Chronic kidney disease (CKD) confers a high risk of thrombosis and bleeding. However, little evidence exists regarding the optimal choice of postoperative thromboprophylaxis in these patients. We conducted a population-based, retrospective cohort study among adults ≥66 years old with CKD undergoing hip or knee arthroplasty who had filled an outpatient prophylactic anticoagulant prescription between 2010 and 2020 in Ontario, Canada. The primary outcomes of venous thrombosis (VTE) and hemorrhage were identified by validated algorithms using relevant diagnoses and billing codes. Overlap-weighted cause-specific Cox proportional hazard models were used to examine the association of direct oral anticoagulants (DOAC) on the 90-day risk of VTE and hemorrhage compared with low-molecular-weight heparin (LMWH). A total of 27 645 patients were prescribed DOAC (N = 22 943) or LMWH (N = 4702) after arthroplasty. Rivaroxaban was the predominant DOAC (94.5%), while LMWH mainly included enoxaparin (67%) and dalteparin (31.5%). DOAC users had higher eGFRs, fewer co-morbidities, and surgery in more recent years compared to LMWH users. After weighing, DOAC (compared with LMWH) was associated with a lower risk of VTE (DOAC: 1.5% vs. LMWH: 2.1%, weighted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.94) and a higher risk of hemorrhage (DOAC: 1.3% vs. LMWH: 1.0%, weighted HR 1.44, 95% CI 1.04-1.99). Additional analyses including a more stringent VTE defining algorithm, different eGFR cut-offs, and limiting to rivaroxaban and enoxaparin showed consistent findings. Among elderly adults with CKD, DOAC was associated with a lower VTE risk and a higher hemorrhage risk compared to LMWH following hip or knee arthroplasty.

Reimbursement and use of oral anticoagulants during 2014–2022 - A register-based study

BackgroundVitamin K antagonists, warfarin in particular, have been the mainstay of anticoagulation therapy, but their use has declined in many countries since direct oral anticoagulants (DOACs) have entered the market. ObjectiveTo examine utilization trends of oral anticoagulants (OACs) in Finland considering the reimbursement of DOACs and changes to national treatment guidelines for the treatment of atrial fibrillation (AF). MethodsBoth public, aggregated data on reimbursed OAC dispensations and individual-level data on electronic dispensations during 2014–2022 were applied. Data on electronic dispensations during 2015–2016 were used to study OAC initiations. Data on entitlements to reimbursement for DOACs came from public data. ResultsIn 2014, there were almost 20,000 DOAC users, rising to 214,000 in 2022. The number of warfarin users declined since 2015 from over 181,000 to around 59,000 users in 2022, DOACs exceeding warfarin in the number of users in 2019. The total DOAC costs were higher than warfarin costs each year. Rivaroxaban was the most widely used DOAC during 2014–2018, and apixaban during 2019–2022. In 2015, there were more warfarin (56.7%) than DOAC (43.3%) initiators, but the result was opposite for 2016 (warfarin 39.4%, DOACs 60.6%). The number of individuals entitled to reimbursement for DOACs has increased steadily, and in 2022, there were over 196,000 individuals entitled to this reimbursement due to AF. ConclusionsThe uptake of DOACs in Finland appears to have been gradual and slower than in many other countries. During the 2010s, the treatment guidelines for AF were more cautious in recommending DOACs than the European guidelines. The use of DOACs increased as their reimbursement became less restrictive.

Risk of hospitalization for upper gastrointestinal bleeding in Helicobacter pylori eradicated patients newly started on warfarin or direct oral anticoagulants: A population-based cohort study.

To investigate risks of hospitalization for upper gastrointestinal bleeding (UGIB) in H. pylori-eradicated patients newly started on warfarin or direct oral anti-coagulants (DOACs). We identified all patients who had previously received H. pylori eradication therapy or were found to have no H. pylori on endoscopy and were then newly started on warfarin or DOACs from a population-based electronic healthcare database. Primary analysis was the risk of UGIB between warfarin and DOACsusers in H. pylori-eradicated patients. Secondary analysis included the UGIB risk between H. pylori-eradicated and H. pylori-negative patients who were newly started on warfarin or DOACs. The hazard ratio (HR) of UGIB was approximated by pooled logistic regression model incorporating the inverse propensity of treatment weightings with time-varying covariables. Among H. pylori-eradicated patients, DOACs had a significantly lower risk of UGIB (HR: 0.26, 95% CI 0.09-0.71) compared with warfarin. In particular, lower UGIB risks with DOACs were observed among older (≥65 years) patients, female, those without a history of UGIB or peptic ulcer, or ischemic heart disease, and non-users of acid-suppressive agents or aspirin. Secondary analysis showed no significant difference in UGIB risk between H. pylori-eradicated and H. pylori-negative patients newly started on warfarin (HR: 0.63,95% CI 0.33-1.19) or DOACs (HR: 1.37, 95% CI 0.45-4.22). In H. pylori-eradicated patients, new users of DOACs had a significantly lower risk of UGIB than new warfarin users. Furthermore, the risk of UGIB in new warfarin or DOACs users was comparable between H. pylori-eradicated and H. pylori-negative patients.

Reduction of major gastrointestinal bleeding risk with proton pump inhibitor therapy in patients with atrial fibrillation receiving direct oral anticoagulant

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This research was supported by a grant from the Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health &amp; Welfare, Republic of Korea (grant number: HC21C0028). Background In patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), gastrointestinal bleeding (GIB) is itself a serious event for the patient, and it causes an increase in the thromboembolic risk caused by discontinuation of anticoagulation therapy. There are limited data on the benefit of preventive PPI use to reduce the risk of GIB in DOAC users. Methods We included patients with AF receiving DOAC from 2013 to 2020 based on the Korean Health Insurance Review and Assessment database. For comparison between patients with and without PPI, propensity score (PS) weighting method was used. Primary outcome was major GIB and secondary outcomes were major upper GIB and upper GIB requiring transfusion. Results A total of 171,494 patients were included (mean 72±10 years, mean CHA2DS2-VASc 4.3±1.8; 50,577 of rivaroxaban, 23,010 of dabigatran, 54,461 of apixaban, and 43,446 of edoxaban). Among the total population, 40% of patients were prescribed PPI and 55% of PPI users were prescribed low dose PPI. After PS weighting, patients with PPI were associated with lower risks of major GIB, major upper GIB, and upper GIB requiring transfusion than those without PPI (hazard ratio [95% confidence interval]; 0.816 [0.758-0.878], 0.834 [0.770-0.901], and 0.814 [0.734-0.902], respectively, Figure A). Patients with low dose PPI showed significant risk reduction for major GIB, major upper GIB, and upper GIB requiring transfusion than those without PPI (0.570 [0.515-0.632], 0.563 [0.505-0.628], and 0.505 [0.435-0.587], respectively). The protective effect of PPI was slightly different among DOAC types (Figure B). In the subgroup analyses, major GIB risk reduction of PPI co-therapy was more accentuated in patients older than 75 years and those with underlying GI disease or symptoms. Conclusion In this largest Asian cohort of patients with AF receiving DOAC, PPI co-therapy might be beneficial to reduce the risk of major GIB and upper GIB. This was consistently observed with low-dose PPI. The protective effect of PPI was more pronounced in the high bleeding risk patients.

Venous thromboembolism recurrence among one-and-done direct oral anticoagulant users: a retrospective longitudinal study.

Direct oral anticoagulants (DOACs) are the American Society of Hematology guideline-recommended treatment for venous thromboembolism (VTE) in the United States (US). To compare risk of VTE recurrence between patients who, following the first fill, discontinued ("one-and-done") versus those who continued ("continuers") DOACs. Open source US insurance claims data (04/1/2017 to 10/31/2020) were used to select adult patients with VTE initiated on DOACs (index date). Patients with only one DOAC claim during the 45-day landmark period (starting on the index date) were classified as one-and-done and the remaining as continuers. Inverse probability of treatment weighting was used to reweight baseline characteristics between cohorts. VTE recurrence based on the first post-index deep vein thrombosis or pulmonary embolism event was compared using weighted Kaplan-Meier and Cox proportional hazard models from landmark period end to clinical activity or data end. 27% of patients initiating DOACs were classified as one-and-done. After weighting, 117,186 and 116,587 patients were included in the one-and-done and continuer cohorts, respectively (mean age 60years; 53% female; mean follow-up 15months). After 12months of follow-up, the probability of VTE recurrence was 3.99% and 3.36% in the one-and-done and continuer cohorts; the risk of recurrence was 19% higher in the one-and-done cohort (hazard ratio [95% confidence interval] = 1.19 [1.13, 1.25]). Substantial proportion of patients discontinued DOAC therapy after the first fill, which was associated with significantly higher risk of VTE recurrence. Early access to DOACs should be encouraged to reduce the risk of VTE recurrence.