Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies.
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ABSTRACT: Objective
To establish the risk of major bleeding in direct oral anticoagulant (DOAC) users (overall and by class) versus vitamin K antagonist (VKA) users, using health care databases from four European countries and six provinces in Canada.Methods
A retrospective cohort study was performed according to a similar protocol. First-users of VKAs or DOACs with a diagnosis of non-valvular atrial fibrillation (NVAF) were included. The main outcome of interest was major bleeding and secondary outcomes included gastrointestinal (GI) bleeding and intracranial haemorrhage (ICH). Incidence rates of events per 1000 person years were calculated. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard regression model. Exposure and confounders were measured and analysed in a time-dependant way. Risk estimates were pooled using a random effect model.Results
421 523 patients were included. The risk of major bleeding for the group of DOACs compared to VKAs showed a pooled HR of 0.94 (95% CI: 0.87-1.02). Rivaroxaban showed a modestly increased risk (HR 1.11, 95% CI: 1.06-1.16). Apixaban and dabigatran showed a decreased risk of respectively HR 0.76 (95% CI: 0.69-0.84) and HR 0.85 (95% CI: 0.75-0.96).Conclusions
This study confirms that the risk of major bleeding of DOACs compared to VKAs is not increased when combining all DOACs. However, we observed a modest higher risk of major bleeding for rivaroxaban, whereas for apixaban and dabigatran lower risks of major bleeding were observed compared to VKAs.
SUBMITTER: van den Ham HA
PROVIDER: S-EPMC8456818 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Direct oral anticoagulants (DOACs) are commonly prescribed with antidepressants that may increase bleeding risk. Here we assessed the association between DOACs with and without concurrent antidepressants and major bleeding risk in patients with atrial fibrillation (AF) by a retrospective cohort study included patients with AF who received prescriptions of DOACs in Taiwan's National Health Insurance database between 2012 and 2017. Adjusted rate ratio (ARR) of major bleeding was calculated by comparing incidence rate adjusted with Poisson regression and inverse probability of treatment weighting using the propensity score between patient-times with and without antidepressants. Among 98863 patients with AF, concurrent use of bupropion with DOACs increased the risks of all major bleeding (ARR: 1.49, 95% CI: 1.02-2.16) and gastrointestinal hemorrhage (ARR: 1.57, 95% CI: 1.04-2.33). An increased risk of intracerebral hemorrhage (ICH) was associated with the combinations of DOACs with selective serotonin reuptake inhibitors (SSRIs, ARR: 1.38, 95% CI: 1.08-1.76), particularly in paroxetine (ARR: 2.11, 95% CI: 1.17-3.81), and tetracyclic antidepressants (TeCAs, ARR: 1.34, 95% CI: 1.01-1.78). In subgroup analyses stratified by individual NOACs, SSRIs increased the risk of ICH in the dabigatran-treated patients (ARR: 1.55, 95% CI: 1.04-2.33). The combinations of apixaban and serotonin-norepinephrine reuptake inhibitors (SNRIs) were associated with a higher risk of all major bleeding (ARR: 1.63, 95% CI: 1.04-2.55). These results clearly indicate the drug-drug interactions between DOACs and antidepressants, which should be carefully considered when prescribing DOACs in adult patients. Careful monitoring for bleeding should be performed while concurrently prescribing DOACs with bupropion, SSRI, SNRI, and TeCA. Concomitant use of DOACs and TCAs may be a relatively safe strategy for patients with AF.
| S-EPMC8855103 | biostudies-literature
Project description:BackgroundDespite direct oral anticoagulants (DOACs) being safer than warfarin for stroke prevention in atrial fibrillation (AF), major bleeding concerns persist. Most bleeding risk scores predate DOAC approval.ObjectivesThis study aimed to compare the Age, history of Bleeding, and non-bleeding related Hospitalisation [ABH] score's performance-derived for DOAC-treated patients-with those of 5 other scores (Anticoagulation and Risk Factors in Atrial Fibrillation [ATRIA], Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [>65 years], Drugs/alcohol concomitantly [HAS-BLED], Hepatic, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke [HEMORR2HAGES], Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF], and Congestive heart failure, Hypertension, Age ≥75 [doubled], Diabetes, Stroke [doubled]-Vascular disease, Age 65-74, Sex category [CHA2DS2-VASc]) in predicting DOAC-related major bleeding in patients with AF.MethodsIn this retrospective study of 2364 patients with nonvalvular AF on rivaroxaban or apixaban (median age, 68.3 years; 32.1% women), International Society on Thrombosis and Haemostasis-defined major bleeding (incidence, 4.1%; n = 97) was analyzed. C-statistics from time-dependent receiver operating characteristic (ROC) curves for continuous risk scores were the primary comparison metric, but other metrics, such as decision curves, were also compared.ResultsAt 100 days, C-statistics were highest for ORBIT-AF and ATRIA (0.62 and 0.61, respectively, with other scores having an area under the ROC curve of <0.60); some significant differences favored ORBIT-AF. At 1100 days, C-statistics remained highest for ORBIT-AF and ATRIA (0.62 and 0.61, respectively, with other scores having an area under the ROC curve of <0.60 again), and ORBIT-AF had significantly higher C-statistics than those for all other risk scores (P < .05), except for ATRIA. At 2100 days, all C-statistics were <0.60 with no significant differences. Decision curves showed the greatest net benefit for ORBIT-AF and ATRIA at 100 days and for ATRIA at 1100 days, with no discernible net benefit for any of the scores at 2100 days.ConclusionORBIT-AF and ATRIA provided the best bleeding risk prediction within the first 1100 days. None of the 6 bleeding risk scores provided predictive benefit over 2100 days of DOAC treatment.
| S-EPMC10826825 | biostudies-literature
Project description:BACKGROUND:No scores presently exist to predict bleeding in atrial fibrillation (AF) populations using direct oral anticoagulants (DOACs). We used data from two independent healthcare claims databases to develop and validate a predictive model of major bleeding in a contemporary AF population. METHODS:Patients with non-valvular AF initiating oral anticoagulation were identified in the MarketScan databases from 2007-2014. Using Cox regression models in 1000 bootstrapped samples, we developed a model that selected variables predicting major bleeding in the first year after anticoagulant initiation. The final model was validated in patients with non-valvular AF in the Optum Clinformatics database in the period 2009-2015. The discriminative ability of existing bleeding scores were individually evaluated and compared with the new bleeding model termed Anticoagulation-specific Bleeding Score (ABS) in both MarketScan and Optum. RESULTS:Among 119,083 patients with AF initiating oral anticoagulation in the derivation cohort, 4,030 experienced a bleeding event. The variable selection model identified 15 variables (including individual type of oral anticoagulant) associated with major bleeding. Discrimination of the model was modest [c-statistic 0.68, 95% confidence interval (CI) 0.67-0.69]. The model was subsequently applied to 81,285 AF patients in the validation data set (3,238 bleeding events), showing similar discrimination (c-statistic 0.68, 95% CI 0.67-0.69). In both cohorts, the predictive performance of the ABS was better than the existing models for bleeding prediction in AF. CONCLUSIONS:We developed a model that uses administrative healthcare data for the identification of AF patients at higher risk of bleeding after initiation of oral anticoagulation, taking into account the lower bleeding risk in DOAC compared to warfarin users.
| S-EPMC6130859 | biostudies-literature
Project description:Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring. Direct oral anticoagulant-specific measurements were performed at trough and peak. Patients who developed bleeding events showed higher DOAC plasma levels at peak. This study suggests the need of a more accurate DOAC dose assessment.BackgroundDirect oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C-trough or C-peak plasma levels and bleeding complications in patients with non-valvular atrial fibrillation (NVAF).MethodsFive hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C-trough and at C-peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow-up after blood sampling, were recorded. For each DOAC, interval of C-trough and C-peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated.ResultsTwo hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1-[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C-peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C-peak levels were higher in patients with bleeding than in those without bleeding.ConclusionsBleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C-peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C-trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window.
| S-EPMC6852698 | biostudies-literature
Project description:Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m2. At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m2) (P for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.
| S-EPMC9707838 | biostudies-literature
Project description:AimReal-world predictors of major bleeding (MB) have been well-studied among warfarin users, but not among all direct oral anticoagulant (DOAC) users diagnosed with atrial fibrillation (AF). Thus, our goal was to build a predictive model of MB for new users of all oral anticoagulants (OAC) with AF.MethodsWe identified patients hospitalized for any cause and discharged alive in the community from 2011 to 2017 with a primary or secondary diagnosis of AF in Quebec's RAMQ and Med-Echo administrative databases. Cohort entry occurred at the first OAC claim. Patients were categorized according to OAC type. Outcomes were incident MB, gastrointestinal bleeding (GIB), non-GI extracranial bleeding (NGIB) and intracranial bleeding within 1 year of follow-up. Covariates included age, sex, co-morbidities (within 3 years before cohort entry) and medication use (within 2 weeks before cohort entry). We used logistic-LASSO and adaptive logistic-LASSO regressions to identify MB predictors among OAC users. Discrimination and calibration were assessed for each model and a global model was selected. Subgroup analyses were performed for MB subtypes and OAC types.ResultsOur cohort consisted of 14,741 warfarin, 3,722 dabigatran, 6,722 rivaroxaban and 11,196 apixaban users aged 70-86 years old. The important MB predictors were age, prior MB and liver disease with ORs ranging from 1.37-1.64. The final model had a c-statistic of 0.63 (95% CI 0.60-0.65) with adequate calibration. The GIB and NGIB models had similar c-statistics of 0.65 (95% CI 0.63-0.66) and 0.67 (95% CI 0.64-0.70), respectively.ConclusionsMB and MB subtype predictors were similar among DOAC and warfarin users. The predictors selected by our models and their discriminative potential are concordant with published data. Thus, these models can be useful tools for future pharmacoepidemiologic studies involving older oral anticoagulant users with AF.
| S-EPMC7928472 | biostudies-literature
Project description:BackgroundAnemia is encountered in patients with nonvalvular atrial fibrillation (NVAF) on oral anticoagulants (OACs) but the prognostic impact was not well scrutinized in real-world settings.MethodsWe conducted a historical multicenter registry of patients with NVAF taking OACs at 71 centers in Japan. Those with mechanical heart valves or a history of pulmonary thrombosis or deep venous thrombosis were excluded. Anemic patients were divided into three groups of hemoglobin (Hb) level: moderate/severe (Hb < 11.0 g/dL), mild (men: Hb of 11.0-12.9 g/dL; women: Hb of 11.0-11.9 g/dL), and no anemia. The endpoints included major bleeding, hemorrhagic stroke, ischemic events, ischemic stroke, and all-cause mortality.ResultsAmong 7558 consecutive patients (mean age, 73 years; men 67%) registered in February 2013 and followed until February 2017, 2100 (28%) patients had anemia. The anemic patients were older (moderate/severe: 79 years; mild: 77 years; no anemia: 71 years, p < .001), and HAS-BLED score was significantly higher in the anemic patients (p < .001). The cumulative incidences at 4 years of major bleeding in moderate/severe, mild, and no anemia group, were 14.9%, 10.7%, and 6.4%, respectively. The adjusted hazard ratios (HRs) (95% confidential intervals (CIs)) of major bleeding of moderate/severe and mild anemia group were 1.96 (1.49-2.58) and 1.48 (1.17-1.87) compared to no anemia group. The adjusted HRs (95% CIs) for ischemic events were 0.63 (0.39-0.99) and 1.03 (0.76-1.39).ConclusionsThe severity of anemia in the patients with NVAF on OACs was associated with major bleeding.
| S-EPMC10407181 | biostudies-literature
Project description:In comparison to warfarin, non-vitamin K antagonist oral anticoagulants (NOACs) have the advantages of ease of dosing, fewer drug interactions, and lack of need for ongoing monitoring. We sought to evaluate whether these advantages translate to improved adherence and whether adherence is associated with improved outcomes in patients with atrial fibrillation.We performed a retrospective cohort analysis by using a large US commercial insurance database to identify 64 661 patients with atrial fibrillation who initiated warfarin, dabigatran, rivaroxaban, or apixaban treatment between November 1, 2010, and December 31, 2014. During a median of 1.1 y of follow-up, 47.5% of NOAC patients had a proportion of days covered of ≥80%, compared with 40.2% in warfarin patients (P<0.001). Patients with CHA2DS2-VASc (risk based on the presence of congestive heart failure, hypertension age 65-74 y, age ≥75 y, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, sex category) score ≥4 were at increased risk of stroke when they were not taking anticoagulation ≥1 month versus <1 week (1-3 months: hazard ratio [HR] 1.96, 3-6 months: HR 2.64, ≥6 months: HR 3.66; all P<0.001). Patients with CHA2DS2-VASc score 2 or 3 were at increased risk of stroke when they were not taking anticoagulation ≥6 months (HR 2.73, P<0.001). In these patients with CHA2DS2-VASc score ≥2, nonadherence was not associated with intracranial hemorrhage. Among patients with CHA2DS2-VASc score 0 or 1, time not taking anticoagulation was not associated with stroke, but not taking anticoagulation ≥3 months was associated with a significant reduction of bleeding.Adherence to anticoagulation is poor in practice and may be modestly improved with NOACs. Adherence to therapy appears to be most important in patients with CHA2DS2-VASc score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA2DS2-VASc score 0 or 1.
| S-EPMC4802483 | biostudies-other
Project description:BackgroundStatins are frequently prescribed with direct oral anticoagulants (DOACs), and previous studies have raised concerns about the increased risk of intracerebral hemorrhage or other major bleeding in concurrent statins and DOACs use. The objective of this study is to evaluate the risk of major bleeding in non-valvular atrial fibrillation patients taking DOACs with or without statins.MethodsThis nationwide, retrospective cohort study used data from the Taiwan National Health Insurance Research Database, enrolled a total of 90,731 non-valvular atrial fibrillation patients receiving rivaroxaban, dabigatran, apixaban or edoxaban from January 1st, 2012 to December 31st, 2017. Major bleeding was defined as a hospitalization or emergency department visit with a primary diagnosis of intracerebral hemorrhage, gastrointestinal tract bleeding, urogenital tract bleeding, or other sites of bleeding. Adjusted incidence rate ratios (IRR) and differences of major bleeding between person-quarters of DOACs with or without statins were estimated using a Poisson regression and inverse probability of treatment weighting using the propensity score.Results50,854 (56.0%) of them were male with a mean age of 74.9 (SD, 10.4) years. Using DOACs without statins as a reference, the adjusted IRR for all major bleedings in concurrent use of DOACs and statins was 0.8 (95% CI 0.72-0.81). Lower major bleeding risk was seen in both low-to-moderate-intensity statins (IRR: 0.8, 95% CI 0.74-0.84) and high-intensity statins (IRR: 0.8, 95% CI 0.74-0.88). Concurrent use of DOACs and statins decreased the risk for intracerebral hemorrhage with an IRR of 0.8 (95% CI 0.66-0.93), and gastrointestinal tract bleeding with an IRR of 0.7 (95% CI 0.69-0.79). The protective effect of statins on intracerebral hemorrhage was observed only in female patients (IRR 0.67, 95% CI 0.51-0.89), but not in male patients (IRR 0.87, 95% CI 0.70-1.08).ConclusionsAmong non-valvular atrial fibrillation patients who were taking DOACs, concurrent use of statins decreased major bleeding risk, including intracerebral hemorrhage and gastrointestinal tract bleeding. Considering this and other cardioprotective effects, statins should be considered in all eligible patients prescribed with DOACs.
| S-EPMC9393418 | biostudies-literature
Project description:Polypharmacy is common in patients with atrial fibrillation (AF), making these patients vulnerable to the occurrence of potential drug-drug interactions (DDIs). We assessed the risk of ischemic stroke and major bleeding in the context of concomitant treatment with potential DDIs in patients with AF prescribed direct oral anticoagulants (DOACs). Using the common data model (CDM) based on an electronic health record (EHR) database, we included new users of DOACs from among patients treated for AF between January 2014 and December 2017 (n = 1938). The median age was 72 years, and 61.8% of the patients were males, with 28.2% of the patients having a CHA2DS2-VASc score in category 0-1, 49.4% in category 2-3, and 22.4% in category ≥ 4. The CHA2DS2-VASc score was significantly associated with ischemic stroke occurrence and hospitalization for major bleeding. Multiple logistic regression analysis showed that increased risk of ischemic stroke and hospitalization for major bleeding was associated with the number of DDIs regardless of comorbidities: ≥ 2 DDIs was associated with ischemic stroke (OR = 18.68; 95% CI, 6.22-55.27, P < 0.001) and hospitalization for major bleeding (OR = 5.01; 95% CI, 1.11-16.62, P < 0.001). DDIs can cause reduced antithrombotic efficacy or increased risk of bleeding in AF patients prescribed DOACs.
| S-EPMC8599657 | biostudies-literature