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Concomitant Use of Direct Oral Anticoagulants with Antiplatelet Agents and the Risk of Major Bleeding in Patients with Nonvalvular Atrial Fibrillation

  • Antonios Douros
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada

    Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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  • Christel Renoux
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada

    Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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  • Hui Yin
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
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  • Kristian B. Filion
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada

    Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Samy Suissa
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
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  • Laurent Azoulay
    Correspondence
    Requests for reprints should be addressed to Laurent Azoulay, PhD, Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine Road, H425.1, Montreal, QC H3T 1E2, Canada.
    Affiliations
    Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

    Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada

    Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
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Published:October 25, 2018DOI:https://doi.org/10.1016/j.amjmed.2018.10.008

      Abstract

      Purpose

      Patients with nonvalvular atrial fibrillation commonly have comorbidities requiring concurrent use of oral anticoagulants and antiplatelets. There are no real-world data on the comparative safety of concomitant antithrombotic treatments in the era of direct oral anticoagulant (DOACs). Thus, we compared the incidence of intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding between concomitant DOAC-antiplatelet use and concomitant vitamin K antagonist (VKA)-antiplatelet use in patients with nonvalvular atrial fibrillation.

      Methods

      Using computerized health care databases from Québec, we conducted a cohort study among patients newly diagnosed with nonvalvular atrial fibrillation between January 2011 and March 2014. Cox proportional hazards models yielded hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for disease risk score, of the study outcomes comparing current concomitant use of DOACs with ≥1 antiplatelet vs current concomitant use of VKAs with ≥1 antiplatelet.

      Results

      A total of 5301 patients initiated concomitant DOAC-antiplatelet use, while 9106 patients initiated concomitant VKA-antiplatelet use. During a median follow-up of 1.6 months, concomitant DOAC-antiplatelet use was associated with a similar risk of gastrointestinal bleeding (HR 1.08; 95% CI, 0.81-1.45), but with a decreased risk of intracranial hemorrhage (HR 0.46; 95% CI, 0.24-0.91) and other major bleeding (HR 0.68; 95% CI, 0.51-0.91) compared with concomitant VKA-antiplatelet use.

      Conclusions

      Concomitant DOAC-antiplatelet use was associated with a similar risk of gastrointestinal bleeding, and a lower risk of intracranial hemorrhage and other major bleeding than concomitant VKA-antiplatelet use. These findings could inform physician decision-making in patients requiring concomitant treatment with oral anticoagulants and antiplatelets.

      Keywords

      Clinical Significance
      • Direct oral anticoagulants with antiplatelets are associated with a similar risk of gastrointestinal bleeding compared with vitamin K antagonists and antiplatelets.
      • Direct oral anticoagulants with antiplatelets are associated with a decreased risk of intracranial hemorrhage and other major bleeding compared with vitamin K antagonists and antiplatelets.
      • There were no duration–response relations for the 3 bleeding outcomes.
      • Age, sex, or baseline bleeding risk did not modify the associations.

      Background

      Direct oral anticoagulants (DOACs) are increasingly being used for ischemic stroke prevention among patients with nonvalvular atrial fibrillation,
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • et al.
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      • Barnes GD
      • Lucas E
      • Alexander GC
      • Goldberger ZD
      National trends in ambulatory oral anticoagulant use.
      partly because of their favorable efficacy and safety compared with vitamin K antagonists (VKAs).
      • Ruff CT
      • Giugliano RP
      • Braunwald E
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      However, the safety of DOACs in patients with nonvalvular atrial fibrillation requiring additional use of antiplatelet agents remains uncertain. This is important, as up to 30% of patients with nonvalvular atrial fibrillation may receive concomitant treatments of oral anticoagulants with antiplatelets due to comorbid cardiovascular conditions.
      • Steinberg BA
      • Kim S
      • Piccini JP
      • et al.
      Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry.
      • Gupta M
      • Singh N
      • Verma S
      • et al.
      High rates of concomitant antiplatelet use in patients with atrial fibrillation treated with oral anticoagulation: insights from the stroke prevention and rhythm interventions in atrial fibrillation (SPRINT-AF) registry.
      • Lip GY
      • Laroche C
      • Dan GA
      • et al.
      'Real-world' antithrombotic treatment in atrial fibrillation: the EORP-AF pilot survey.
      • Bennaghmouch N
      • de Veer A
      • Bode K
      • et al.
      Efficacy and safety of the use of non-vitamin K antagonist oral anticoagulants in patients with nonvalvular atrial fibrillation and concomitant aspirin therapy: a meta-analysis of randomized trials.
      While concomitant use of VKAs with antiplatelets has previously been shown to increase the risk of bleeding compared with VKAs alone,
      • Lamberts M
      • Gislason GH
      • Lip GY
      • et al.
      Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study.
      • Azoulay L
      • Dell'Aniello S
      • Simon T
      • Renoux C
      • Suissa S
      The concurrent use of antithrombotic therapies and the risk of bleeding in patients with atrial fibrillation.
      data are lacking on the comparative safety of concomitant use of antithrombotic drugs in the era of DOACs.
      In a meta-analysis of randomized controlled trials (RCTs) assessing the efficacy of DOACs in nonvalvular atrial fibrillation, use of acetylsalicylic acid (ASA) with DOACs was associated with a similar risk of major bleeding (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.69-1.01), but a decreased risk of intracranial hemorrhage (HR 0.38; 95% CI, 0.26-0.56), compared with use of ASA with VKAs.
      • Bennaghmouch N
      • de Veer A
      • Bode K
      • et al.
      Efficacy and safety of the use of non-vitamin K antagonist oral anticoagulants in patients with nonvalvular atrial fibrillation and concomitant aspirin therapy: a meta-analysis of randomized trials.
      However, the analysis was limited to use of ASA at randomization not accounting for use during follow-up.
      • Bennaghmouch N
      • de Veer A
      • Bode K
      • et al.
      Efficacy and safety of the use of non-vitamin K antagonist oral anticoagulants in patients with nonvalvular atrial fibrillation and concomitant aspirin therapy: a meta-analysis of randomized trials.
      Moreover, 2 RCTs evaluating concomitant use of DOACs with antiplatelets restricted inclusion to patients with nonvalvular atrial fibrillation undergoing coronary intervention.
      • Cannon CP
      • Bhatt DL
      • Oldgren J
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      • Gibson CM
      • Mehran R
      • Bode C
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      Finally, a recently published cohort study addressing the safety of such regimes in real-world clinical practice had methodological limitations such as inclusion of prevalent users and did not report results on specific types of major bleeding.
      • Sindet-Pedersen C
      • Lamberts M
      • Staerk L
      • et al.
      Combining oral anticoagulants with platelet inhibitors in patients with atrial fibrillation and coronary disease.
      Thus, to address this important safety issue, we conducted a population-based study to compare the incidence of intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding between concomitant DOAC-antiplatelet use and concomitant VKA-antiplatelet use in patients with nonvalvular atrial fibrillation.

      Methods

      Data Sources

      This study was conducted by linking 3 computerized health care databases from the Canadian province of Québec: Régie de l'assurance maladie du Québec (RAMQ), Maintenance et exploitation des données pour l’étude de la clientèle hospitalière (MEDÉCHO), and the Institut de la statistique du Québec (ISQ).
      • Renoux C
      • Patenaude V
      • Suissa S
      Incidence, mortality, and sex differences of non-valvular atrial fibrillation: a population-based study.
      The RAMQ databases collect information on demographics, medical services (coded using the International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] or enhanced version of ICD-10 for Canada ICD-10-CA), and dispensed outpatient prescriptions. Under the universal health care program, medical services are covered for all Québec residents, while coverage in the Public Prescription Drug Insurance Plan is limited to residents (and their children) with no private drug insurance plans, those at least 65 years of age, and recipients of financial assistance.

      Régie de l'assurance maladie Quebec (RAMQ). Public prescription drug insurance plan. Available at: http://www.ramq.gouv.qc.ca/en/citizens/prescription-drug-insurance/Pages/prescription-drug-insurance.aspx. Accessed March 9, 2018.

      RAMQ data quality has been previously documented.
      • Tamblyn R
      • Lavoie G
      • Petrella L
      • Monette J
      The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec.
      • Wilchesky M
      • Tamblyn RM
      • Huang A
      Validation of diagnostic codes within medical services claims.
      MEDÉCHO contains records of all hospitalizations occurring in Québec and includes date and type of admission and discharge, as well as primary and secondary diagnoses (coded using ICD-10-CA). Finally, ISQ contains vital statistics including date and cause of death. The study protocol was approved by the Research Ethics Committee of the Jewish General Hospital, Montreal, Canada. No informed consent was required.

      Base Cohort of Patients with Incident Nonvalvular Atrial Fibrillation

      Using the databases above, we identified all patients at least 18 years of age with a first inpatient or outpatient diagnosis of atrial fibrillation between January 1, 2011 (when the first DOAC, dabigatran, was approved for stroke prevention in nonvalvular atrial fibrillation in Québec) and March 31, 2014. All patients were required to have been covered by the RAMQ Public Prescription Drug Insurance Plan for at least 1 year prior to the diagnosis of atrial fibrillation. We restricted inclusion to patients with nonvalvular atrial fibrillation by excluding patients with a history of mitral or aortic stenosis or valvular repair, and those with a history of hyperthyroidism, at any time prior to the diagnosis of atrial fibrillation. Finally, we excluded patients dispensed VKAs or DOACs in the year prior to the nonvalvular atrial fibrillation diagnosis to maximize the inclusion of new users during the study period.

      Study Cohort of Concomitant Oral Anticoagulant-Antiplatelet Users

      Using the base cohort defined above, we identified all patients initiating concomitant use of an oral anticoagulant (DOAC [dabigatran, rivaroxaban, or apixaban] or VKA) with at least one antiplatelet agent (ASA, dipyridamole, clopidogrel, prasugrel, or ticagrelor) during the study period. Thus, concomitant users comprised 3 types of patients: 1) those on antiplatelets with a prescription overlapping a new prescription for an oral anticoagulant; 2) those on an oral anticoagulant with a prescription overlapping a new prescription for at least one antiplatelet; and 3) patients initiating treatment with an oral anticoagulant and at least one antiplatelet on the same day (Supplementary Figure 1, available online). Cohort entry was defined as the first day of concomitant use during the study period. We excluded patients with any bleeding-related hospitalization in the 3 months prior to cohort entry, to exclude events related to precohort entry antithrombotic exposure. Patients were followed until an event (described in detail below), discontinuation of concomitant use (described in detail below), end of registration with the Public Prescription Drug Insurance Plan, death, or end of study period (December 31, 2014), whichever occurred first.

      Exposure Groups

      We compared patients initiating concomitant use of a DOAC with at least one antiplatelet with patients initiating concomitant use of a VKA with at least one antiplatelet. The latter group served as reference as this represented a clinically relevant comparator, while minimizing potential confounding by indication.
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • et al.
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      An as-treated exposure definition was used where patients were considered continuously exposed to concomitant use if the prescription durations of the drugs of interest were overlapping each other. We allowed for a 30-day grace period in the event of nonoverlapping prescriptions.

      Bleeding Outcomes

      We conducted 3 analyses; for intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding separately (ICD-10 codes in Supplementary Table 1, available online). The bleeding outcomes were defined by inpatient diagnoses (captured in MEDÉCHO in primary or secondary position), or bleeding-related deaths (captured in MEDÉCHO or ISQ).

      Disease Risk Score

      To control for confounding, we calculated disease risk scores (DRS) using a historical cohort from the same data source.
      • Arbogast PG
      • Ray WA
      Performance of disease risk scores, propensity scores, and traditional multivariable outcome regression in the presence of multiple confounders.
      This historical cohort comprised patients newly diagnosed with nonvalvular atrial fibrillation between January 1, 2007 and December 31, 2010 who were on concomitant VKA-antiplatelet use. The DRS included the following variables measured at cohort entry: age, sex, alcohol-related disorders, hypertension, ischemic stroke or transient ischemic attack, congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, renal or liver disease, all diagnosed at any time prior to cohort entry. We also considered time from nonvalvular atrial fibrillation diagnosis to initiation of oral anticoagulation, cancer (other than nonmelanoma skin cancer) diagnosed in the year prior to cohort entry, and history of major bleeding 3 to 15 months prior to cohort entry. Moreover, the model included use of nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, proton pump inhibitors, and H2 blockers in the year prior to cohort entry, because these drugs have been associated with bleeding. Finally, we measured the number of nonantithrombotic drugs in the year prior to cohort entry as a proxy for overall health. For each bleeding outcome, we fitted a Cox proportional hazards model to the historical cohort, which was then applied to the study cohort to estimate the relative hazard of bleeding for each cohort member.
      • Arbogast PG
      • Ray WA
      Performance of disease risk scores, propensity scores, and traditional multivariable outcome regression in the presence of multiple confounders.

      Statistical Analysis

      Crude incidence rates and rate differences for the bleeding outcomes with 95% CIs based on the Poisson distribution were calculated for each exposure group. We used Cox proportional hazards models to estimate HRs and 95% CIs for each bleeding outcome (intracranial hemorrhage, gastrointestinal bleeding, other major bleeding) associated with concomitant DOAC-antiplatelet use compared with concomitant VKA-antiplatelet use. The models were adjusted for DRS by including an interaction term between DRS modeled as a categorical variable (quintiles for intracranial hemorrhage and deciles for gastrointestinal bleeding and other major bleeding) and DRS as a continuous variable, as well as year of cohort entry.

      Secondary Analyses

      We conducted 7 secondary exploratory analyses. First, we repeated the primary analyses for the individual DOACs (dabigatran, rivaroxaban, and apixaban). Second, to assess a possible duration–response relation between concomitant DOAC-antiplatelet use and the incidence of the bleeding outcomes, we estimated HRs for 3 prespecified duration categories (<3, 3-6, and >6 months). Third, we assessed whether the risk of the bleeding outcomes associated with concomitant DOAC-antiplatelet use varies among patient subgroups (age ≤75 vs >75 years, males vs females, or a modified HAS-BLED [uncontrolled hypertension, abnormal renal or liver function, previous stroke, bleeding history or predisposition, age >65 years, alcohol-related disorders] score
      • Pisters R
      • Lane DA
      • Nieuwlaat R
      • de Vos CB
      • Crijns HJ
      • Lip GY
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      of 0-2 vs 3-7). Fourth, we assessed the association between concomitant DOAC-antiplatelet use and risk of genitourinary bleeding, a common complication of antithrombotic treatment.
      • Bhatt NR
      • Davis NF
      • Nolan WJ
      • et al.
      Incidence of visible hematuria among antithrombotic agents: a systematic review of over 175,000 patients.
      Fifth, we assessed the risk of the bleeding outcomes associated with concomitant DOAC-ASA use vs concomitant VKA-ASA use. This analysis was limited to patients using ASA as the only antiplatelet at cohort entry and censored upon addition or switch to another antiplatelet during follow-up. Sixth, we assessed the risk of the bleeding outcomes in patients on DOACs with at least 2 antiplatelets compared with patients on VKAs with at least 2 antiplatelets. Finally, we assessed whether the risk of the bleeding outcomes differed between patients entering the study cohort upon addition of an oral anticoagulant, an antiplatelet, or both.

      Sensitivity Analyses

      We conducted 6 sensitivity analyses to assess the robustness of our findings. First, to assess potential exposure misclassification, we repeated the primary analyses using a 15-day grace period between successive prescriptions. Second, we used a stricter outcome definition considering only primary diagnoses for hospitalized bleeding or fatal bleeding events. Third, to assess potential informative censoring, as discontinuation of antithrombotic treatment could be related to the outcome, we repeated the primary analyses using an intention-to-treat approach, where exposure is defined based on the drug used at cohort entry, and limiting follow-up to 6 months. Fourth, we excluded patients with a history of both VKA and DOAC use between nonvalvular atrial fibrillation diagnosis and cohort entry. Fifth, we repeated the primary analyses after accounting for competing risk due to death.
      • Fine JP
      • Gray RJ
      A proportional hazards model for the subdistribution of a competing risk.
      Finally, we censored on the first major bleeding event during follow-up, thus not allowing patients to contribute events to multiple types of bleeds. All analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC) and R (R Foundation for Statistical Computing, Vienna, Austria).

      Results

      A total of 5301 patients initiated concomitant DOAC-antiplatelet use and 9106 patients initiated concomitant VKA-antiplatelet use during the study period (Figure 1). The median duration of follow-up was 1.4 months for concomitant DOAC-antiplatelet use and 1.7 months for concomitant VKA-antiplatelet use (1.6 months overall), generating a total of 14,751 person-years. This follow-up period was primarily driven by discontinuation of antiplatelets (60%) (Supplementary Table 2, available online). During the follow-up period, 65 patients had an intracranial hemorrhage, 253 had a gastrointestinal bleeding, and 308 had other major bleeding episodes.
      Figure 1
      Figure 1Flowchart describing the construction of base and study cohorts.
      DOAC = direct oral anticoagulant; VKA = vitamin K antagonist.
      Table 1 presents the characteristics of the nonvalvular atrial fibrillation patients on concomitant DOAC-antiplatelet use vs concomitant VKA-antiplatelet use at cohort entry. Patients on concomitant DOAC-antiplatelet use were less likely to have renal or vascular disease or congestive heart failure than patients on concomitant VKA-antiplatelet use, and they also had slightly lower HAS-BLED scores. In both groups, most patients were on single antiplatelet treatment (92% in the DOAC group vs 86% in the VKA group) and the most common antiplatelet was ASA (94% in the DOAC group vs 93% in the VKA group).
      Table 1Baseline Demographics and Clinical Characteristics of the Cohort Stratified by Concomitant Use of Antithrombotic Drugs at Cohort Entry
      CharacteristicConcomitant DOAC-Antiplatelet UseConcomitant VKA-Antiplatelet Use
      Total53019106
      Age, y (mean, SD)75.5 (9.1)78.0 (9.0)
      Male, n (%)2819 (53.2)4709 (51.7)
      Time from NVAF diagnosis to VKA/DOAC initiation, d (mean, SD)77.0 (180.2)38.6 (116.3)
      History of alcohol-related disorders, n (%)210 (4.0)427 (4.7)
      History of arterial hypertension, n (%)4544 (85.7)8337 (91.6)
      History of cancer, n (%)787 (14.9)1399 (15.4)
      History of congestive heart failure, n (%)1043 (19.7)2804 (30.8)
      History of coronary artery disease, n (%)2577 (48.6)5588 (61.4)
      History of diabetes mellitus, n (%)1685 (31.8)3577 (39.3)
      History of liver disease, n (%)269 (5.1)676 (7.4)
      History of peripheral vascular disease, n (%)556 (10.5)1718 (18.9)
      Prior ischemic stroke or transient ischemic attack, n (%)486 (9.2)1105 (12.1)
      Prior major bleeding
      Assessed 3-15 months prior to cohort entry.
      70 (1.3)171 (1.9)
      History of renal disease, n (%)457 (8.6)2210 (24.3)
      CHA2DS2-VASC score, mean (SD)
      We calculated a CHA2DS2-VASc21 score and a modified HAS-BLED18 score for each patient, defining uncontrolled arterial hypertension as intake of two or more antihypertensive drugs in the year prior to cohort entry.
      3.7 (1.5)4.3 (1.5)
      Modified HAS-BLED score, mean (SD)
      We calculated a CHA2DS2-VASc21 score and a modified HAS-BLED18 score for each patient, defining uncontrolled arterial hypertension as intake of two or more antihypertensive drugs in the year prior to cohort entry.
      1.4 (0.8)1.7 (1.0)
      Number of antiplatelets at cohort entry, mean (SD)1.1 (0.3)1.1 (0.4)
       One, n (%)4886 (92.2)7862 (86.3)
       Two or more, n (%)415 (7.8)1244 (13.7)
      Class of antiplatelets at cohort entry, n (%)
       Acetylsalicylic acid4972 (93.8)8487 (93.2)
       P2Y12 inhibitors744 (14.0)1863 (20.5)
      H2 blockers, n (%)85 (1.6)185 (2.0)
      Nonsteroidal anti-inflammatory drugs, n (%)947 (17.9)1527 (16.8)
      Proton pump inhibitors, n (%)2752 (51.9)5577 (61.3)
      Selective serotonin reuptake inhibitors, n (%)457 (8.6)901 (9.9)
      Number of non-antithrombotic drugs, mean (SD)11.5 (6.0)13.7 (6.6)
      CHA2DS2-VASc = congestive heart failure, arterial hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female sex; DOAC = direct oral anticoagulant; HAS-BLED = abnormal renal or liver function, previous stroke or transient ischemic attack, bleeding history or predisposition, age >65 years, alcohol-related disorders or drugs; NVAF = nonvalvular atrial fibrillation; SD = standard deviation; VKA = vitamin K antagonist.
      low asterisk Assessed 3-15 months prior to cohort entry.
      We calculated a CHA2DS2-VASc
      • Lip GY
      • Nieuwlaat R
      • Pisters R
      • Lane DA
      • Crijns HJ
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
      score and a modified HAS-BLED
      • Pisters R
      • Lane DA
      • Nieuwlaat R
      • de Vos CB
      • Crijns HJ
      • Lip GY
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      score for each patient, defining uncontrolled arterial hypertension as intake of two or more antihypertensive drugs in the year prior to cohort entry.
      Table 2 shows the results related to concomitant DOAC-antiplatelet use and the risk of the bleeding outcomes (18,21). Concomitant DOAC-antiplatelet use was associated with a similar risk of gastrointestinal bleeding (HR 1.08; 95% CI, 0.81-1.45), but with a decreased risk of intracranial hemorrhage (HR 0.46; 95% CI, 0.24-0.91) and other major bleeding (HR 0.68; 95% CI, 0.51-0.91), compared with concomitant VKA-antiplatelet use. Cumulative incidence curves for the bleeding outcomes are presented in Supplementary Figures 2-4, available online.
      Table 2Crude and Adjusted Hazard Ratios for the Association Between the DOAC-Antiplatelet Concomitant Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation
      PatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Rate Difference (95% CI)Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year. References: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093-1100. 18 Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137:263-272. 21
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use91065435081.5 (1.2-2.0)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53011114610.8 (0.4-1.4)−0.3 (-1.6-1.1)0.47 (0.25-0.91)0.46 (0.24-0.91)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use910618134625.2 (4.5-6.1)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53017214485.0 (3.9-6.3)−0.8 (-1.4–0.2)0.87 (0.66-1.14)1.08 (0.81-1.45)
      Other major bleeding
       Current concomitant VKA-antiplatelet use910624634217.2 (6.3-8.2)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53016214504.3 (3.3-5.5)−2.9 (-4.3–1.5)0.56 (0.43-0.74)0.68 (0.51-0.91)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.References:Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093-1100.
      • Pisters R
      • Lane DA
      • Nieuwlaat R
      • de Vos CB
      • Crijns HJ
      • Lip GY
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137:263-272.
      • Lip GY
      • Nieuwlaat R
      • Pisters R
      • Lane DA
      • Crijns HJ
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
      Supplementary Table 1ICD-10 Codes for Different Types of Major Bleeding
      Type of BleedingICD-10 CodeDescription
      ICHI60Subarachnoid
      I61Intracerebral
      I620Subdural
      I621Nontraumatic extradural (acute)
      I629Unspecified intracranial hemorrhage (nontraumatic)
      I690Sequelae of subarachnoid hemorrhage
      I691Sequelae of intracerebral hemorrhage
      I692Sequelae of intracranial hemorrhage
      S0636Traumatic hemorrhage of cerebrum
      S064Epidural hemorrhage
      S065Subdural (traumatic)
      S066Subarachnoid (traumatic)
      GIBI850Esophageal varices with bleeding
      K920Hematemesis
      K921Melena
      K922Gastrointestinal hemorrhage (unspecified)
      K226Gastro-esophageal laceration-hemorrhage syndrome
      K228Hemorrhage of esophagus NOS
      K250Acute gastric ulcer with hemorrhage
      K252Acute gastric ulcer with hemorrhage/perforation
      K254Chronic gastric ulcer with hemorrhage
      K256Chronic gastric ulcer with hemorrhage/perforation
      K260Acute duodenal ulcer with hemorrhage
      K262Acute duodenal ulcer with hemorrhage/perforation
      K264Chronic duodenal ulcer with hemorrhage
      K266Chronic duodenal ulcer with hemorrhage/perforation
      K270Acute peptic ulcer with hemorrhage
      K272Acute peptic ulcer with hemorrhage/perforation
      K274Chronic peptic ulcer with hemorrhage
      K276Chronic peptic ulcer with hemorrhage/perforation
      K280Acute gastrojejunal ulcer with hemorrhage
      K282Acute gastrojejunal ulcer with hemorrhage/perforation
      K284Chronic gastrojejunal ulcer with hemorrhage
      K286Chronic gastrojejunal ulcer with hemorrhage/perforation
      K290Acute hemorrhagic gastritis
      K2921Alcoholic gastritis (with hemorrhage)
      K2961Other gastritis with bleeding
      K2971Gastritis (unspecified with bleeding)
      K2991Gastroduodenitis (unspecified with bleeding)
      K2981Duodenitis (with hemorrhage)
      K3181Angiodysplasia of stomach and duodenum with hemorrhage
      K5521Angiodysplasia of colon with hemorrhage
      K5711Diverticulosis of small intestine without perforation or abscess with bleeding
      K5713Diverticulitis of small intestine without perforation or abscess with bleeding
      K5731Diverticulosis of large intestine without perforation or abscess with bleeding
      K5733Diverticulitis of large intestine without perforation or abscess with bleeding
      K625Hemorrhage of anus and rectum
      K661Hemoperitoneum
      OtherD683Hemorrhagic disorder due to circulating anticoagulants
      D699Unspecified hemorrhagic conditions
      H0523Orbital hemorrhage
      H113Conjunctival hemorrhage
      H313Choroidal hemorrhage and rupture
      H356Retinal hemorrhage
      H431Vitreous hemorrhage
      H44819Hemophthalmos, unspecified eye
      H450Vitreous hemorrhage in diseases classified elsewhere
      H922Otorrhagia
      I230Hemopericardium as current complication following acute myocardial infarction
      I312Hemopericardium NEC
      J942Hemothorax
      M250Hemarthrosis
      M7981Nontraumatic hematoma of soft tissue
      N02Recurrent and persistent hematuria
      N421Congestion and hemorrhage of prostate
      N836Hematosalpinx
      N837Hematoma of broad ligament
      N857Hematometra
      N897Hematocolpos
      N92Excessive, frequent and irregular menstruation
      N93Other abnormal uterine and vaginal bleeding
      N950Postmenopausal bleeding
      R04Hemorrhage from respiratory passages
      R31Unspecified hematuria
      R233Spontaneous ecchymoses
      R58Hemorrhage NEC
      T810Hemorrhage and hematoma complicating a procedure NEC
      T792Traumatic secondary and recurrent hemorrhage and seroma, initial encounter
      GIB = gastrointestinal bleeding; ICD = International Classification of Diseases; ICH = intracranial hemorrhage; NEC = not elsewhere classified NOS = not otherwise specified.
      Supplementary Table 2Reasons for Censoring
      Type of Bleeding Event
      Reasons for CensoringIntracranial HemorrhageGastrointestinal BleedingOther Major Bleeding
      Total number14,40714,40714,407
      Discontinuation of concomitant use, n (%)
       DOAC/VKA2947 (20.5)2861 (19.9)2859 (19.8)
       Antiplatelet8591 (59.6)8529 (59.2)8518 (59.1)
       Both3 (0.02)3 (0.02)3 (0.02)
      Switch of use, n (%)
       From DOAC to VKA1 (0.01)1 (0.01)1 (0.01)
       From VKA to DOAC1 (0.01)1 (0.01)1 (0.01)
      End of registration, n (%)29 (0.2)28 (0.2)27 (0.2)
      Death, n (%)427 (3.0)424 (2.9)416 (2.9)
      End of study period, n (%)2136 (14.8)2108 (14.6)2084 (14.5)
      DOAC = direct oral anticoagulant; VKA = vitamin K antagonist.
      Drug-specific analyses revealed similar associations for the 3 DOACs, although these were based on fewer events (Supplementary Table 3, available online). We observed no duration–response relations for the bleeding outcomes (Supplementary Table 4, available online), and age, sex, or HAS-BLED score did not modify the associations (Supplementary Tables 5-7, available online). Concomitant DOAC-antiplatelet use was associated with a trend toward an increased risk of genitourinary bleeding compared with concomitant VKA-antiplatelet use (HR 1.42; 95% CI, 0.88-2.27), with the difference being driven by rivaroxaban and apixaban (Supplementary Table 8, available online). Comparing concomitant DOAC-ASA use vs concomitant VKA-ASA use, or concomitant use of a DOAC with at least 2 antiplatelet agents vs concomitant use of a VKA with at least 2 antiplatelet agents yielded results similar with those of the primary analysis (Supplementary Tables 9, 10, available online). Finally, we observed no effect modification for the bleeding outcomes after stratifying patients based on how they entered the cohort (Supplementary Table 11, available online). The results of the sensitivity analyses were consistent with those of the primary analysis (summarized in Figure 2 and presented in detail in Supplementary Tables 12-17, available online).
      Supplementary Table 3Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Drug-Specific Analysis)
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use91065435081.5 (1.2-2.0)[Reference][Reference]
       Current concomitant dabigatran-antiplatelet use257599271.0 (0.4-1.8)0.63 (0.31-1.28)0.64 (0.32-1.30)
       Current concomitant rivaroxaban-antiplatelet use220714460.2 (0.01-1.3)0.13 (0.02-0.97)0.12 (0.02-0.88)
       Current concomitant apixaban-antiplatelet use5191581.7 (0.04-9.6)0.90 (0.12-6.64)0.72 (0.09-5.61)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use910618134625.2 (4.5-6.1)[Reference][Reference]
       Current concomitant dabigatran-antiplatelet use2575449184.8 (3.5-6.4)0.91 (0.66-1.27)1.10 (0.79-1.54)
       Current concomitant rivaroxaban-antiplatelet use2207264425.9 (3.8-8.6)0.89 (0.59-1.35)1.18 (0.75-1.87)
       Current concomitant apixaban-antiplatelet use5192583.5 (0.4-12.5)0.45 (0.11-1.81)0.54 (0.13-2.24)
      Other major bleeding
       Current concomitant VKA-antiplatelet use910624634217.2 (6.3-8.2)[Reference][Reference]
       Current concomitant dabigatran-antiplatelet use2575309223.3 (2.2-4.7)0.45 (0.31-0.66)0.54 (0.37-0.80)
       Current concomitant rivaroxaban-antiplatelet use2207284426.3 (4.2-9.2)0.77 (0.52-1.14)1.01 (0.66-1.56)
       Current concomitant apixaban-antiplatelet use5194586.9 (1.9-17.7)0.74 (0.28-2.01)0.96 (0.34-2.66)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 4Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Duration-Response Analysis)
      Exposure< 3 Months HR (95% CI)3-5.9 Months HR (95% CI)≥6 Months HR (95% CI)P for Interaction
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use[Reference][Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.37 (0.15-0.92)0.35 (0.04-2.82)0.63 (0.22-1.87).73
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference][Reference]
       Current concomitant DOAC-antiplatelet use1.09 (0.75-1.57)1.18 (0.61-2.29)0.90 (0.48-1.70).83
      Other major bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.67 (0.46-0.97)0.84 (0.43-1.64)0.62 (0.34-1.12).77
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      Supplementary Table 5Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Interaction with Age)
      Exposure≤75 Years of Age HR (95% CI)>75 Years of Age HR (95% CI)P for Interaction
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use[Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.23 (0.05-0.99)0.63 (0.30-1.33).22
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use1.00 [Reference][Reference]
       Current concomitant DOAC-antiplatelet use1.32 (0.86-2.04)0.94 (0.64-1.37).22
      Other major bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.78 (0.52-1.18)0.61 (0.41-0.91).38
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      Supplementary Table 6Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Interaction with Sex)
      ExposureFemale HR (95% CI)Male HR (95% CI)P for Interaction
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use[Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.66 (0.24-1.80)0.37 (0.15-0.88).38
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference]
       Current concomitant DOAC-antiplatelet use1.34 (0.88-2.03)0.93 (0.63-1.36).19
      Other major bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.53 (0.32-0.89)0.77 (0.54-1.09).24
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      Supplementary Table 7Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Interaction with HAS-BLED
      We used a modified HAS-BLED score including uncontrolled arterial hypertension, abnormal renal or liver function, previous stroke or transient ischemic attack, bleeding history or predisposition, age >65 years, and alcohol-related disorders, because all patients were exposed to antiplatelets, and international normalized ratio values were not available. We defined uncontrolled arterial hypertension as intake of ≥2 antihypertensive drugs in the year prior to cohort entry.
      Score)
      ExposureHAS-BLED Score 0-2 HR (95% CI)HAS-BLED Score 3-7 HR (95% CI)P for Interaction
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use[Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.62 (0.31-1.24).98
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference]
       Current concomitant DOAC-antiplatelet use1.25 (0.91-1.73)0.72 (0.36-1.46).16
      Other major bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference]
      Current concomitant DOAC-antiplatelet use0.68 (0.49-0.94)0.79 (0.42-1.49)0.69
      CI = confidence interval; DOAC = direct oral anticoagulant; HAS-BLED = uncontrolled arterial hypertension, abnormal renal function, abnormal liver function, previous stroke, bleeding history or predisposition, labile international normalized ratio, age >65 years old, alcohol-related disorders or drugs; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk We used a modified HAS-BLED score including uncontrolled arterial hypertension, abnormal renal or liver function, previous stroke or transient ischemic attack, bleeding history or predisposition, age >65 years, and alcohol-related disorders, because all patients were exposed to antiplatelets, and international normalized ratio values were not available. We defined uncontrolled arterial hypertension as intake of ≥2 antihypertensive drugs in the year prior to cohort entry.
      Supplementary Table 8Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Genitourinary Bleeding Among Patients with Nonvalvular Atrial Fibrillation
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
       Current concomitant VKA-antiplatelet use91065934841.7 (1.3-2.2)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53012914582.0 (1.3-2.9)1.15 (0.74-1.81)1.42 (0.88-2.27)
      DOAC types
       Current concomitant VKA-antiplatelet use91065934841.7 (1.3-2.2)[Reference][Reference]
       Current concomitant dabigatran-antiplatelet use2575149251.5 (0.8-2.5)0.90 (0.50-1.62)1.04 (0.58-1.87)
       Current concomitant rivaroxaban-antiplatelet use2207134452.9 (1.6-5.0)1.67 (0.90-3.08)2.81 (1.35-5.81)
       Current concomitant apixaban-antiplatelet use5192583.4 (0.4-12.4)1.87 (0.45-7.81)3.57 (0.78-16.38)
      CI = confidence interval; DOAC = direct oral anticoagulants; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 9Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-ASA Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-ASA use72434125681.6 (1.2-2.2)[Reference][Reference]
       Current concomitant DOAC-ASA use4557911810.8 (0.4-1.5)0.47 (0.23-0.97)0.47 (0.22-0.99)
      Gastrointestinal bleeding
       Current concomitant VKA-ASA use724312125434.8 (4.0-5.7)[Reference][Reference]
       Current concomitant DOAC-ASA use45575411714.6 (3.5-6.0)0.89 (0.65-1.23)1.15 (0.82-1.62)
      Other major bleeding
       Current concomitant VKA-ASA use724315525226.1 (5.2-7.2)[Reference][Reference]
       Current concomitant DOAC-ASA use45574811734.1 (3.0-5.4)0.63 (0.45-0.87)0.75 (0.54-1.06)
      ASA = acetylsalicylic acid; CI = confidence interval; DOAC = direct oral anticoagulants; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 10Crude and Adjusted Hazard Ratios for the Association Between Concomitant Use of a DOAC with Multiple Antiplatelets and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant use of a VKA with multiple antiplatelets124487671.0 (0.5-2.1)[Reference][Reference]
       Current concomitant use of a DOAC with multiple antiplatelets4150209---
      Gastrointestinal bleeding
       Current concomitant use of a VKA with multiple antiplatelets1244527497.0 (5.2-9.1)[Reference][Reference]
       Current concomitant use of a DOAC with multiple antiplatelets415162067.8 (4.4-12.6)1.04 (0.59-1.82)1.13 (0.63-2.04)
      Other major bleeding
       Current concomitant use of a VKA with multiple antiplatelets12447673710.3 (8.1-12.9)[Reference][Reference]
       Current concomitant use of a DOAC with multiple antiplatelets415112085.3 (2.6-9.5)0.49 (0.26-0.93)0.56 (0.29-1.07)
      CI = confidence interval; DOAC = direct oral anticoagulants; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 11Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Interaction with the Way Patients Entered the Cohort)
      ExposureAddition of Antiplatelets HR (95% CI)Addition of an Oral Anticoagulant HR (95% CI)Concomitant Initiation of an Oral Anticoagulant and Antiplatelets HR (95% CI)P for Interaction
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use[Reference][Reference][Reference]
       Current concomitant DOAC-antiplatelet use0.61 (0.06-5.85)0.46 (0.23-0.92).97
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference][Reference]
       Current concomitant DOAC-antiplatelet use1.66 (0.44-6.22)1.03 (0.76-1.40)1.65 (0.54-5.06).58
      Other major bleeding
       Current concomitant VKA-antiplatelet use[Reference][Reference][Reference]
       Current concomitant DOAC-antiplatelet use1.96 (0.65-5.87)0.63 (0.46-0.86)0.78 (0.23-2.62).14
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      Figure 2
      Figure 2Forest plot summarizing the results of the primary analysis and sensitivity analyses, showing adjusted hazard ratios and 95% confidence intervals for the association between DOAC-antiplatelet concomitant use and risk of the three bleeding outcomes.
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio.
      Supplementary Figure 1
      Supplementary Figure 1Diagram depicting cohort entry with different patterns of initiation of concomitant use of antithrombotic drugs. The black line represents person-time prior to cohort entry spanning from the diagnosis of nonvalvular atrial fibrillation to the initiation of the first antithrombotic drug (either an antiplatelet or an oral anticoagulant). The blue line represents person-time prior to cohort entry exposed to an oral anticoagulant (either a vitamin K antagonist [VKA] or a direct oral anticoagulant [DOAC]). Red line represents person-time prior to cohort entry exposed to at least one antiplatelet. Cohort entry corresponded to the initiation of DOAC-antiplatelet or VKA-antiplatelet concomitant use. Red-and-blue line represents person-time after cohort entry. Scenario A corresponds to cohort entry upon addition of a DOAC or a VKA to at least one antiplatelet, scenario B corresponds to cohort entry upon addition of at least one antiplatelet to a DOAC or a VKA, and scenario C corresponds to cohort entry upon concomitant initiation of a DOAC or a VKA and at least one antiplatelet.
      AP = antiplatelet; DOAC = direct oral anticoagulant; NVAF = nonvalvular atrial fibrillation; VKA = vitamin K antagonist.
      Supplementary Figure 2
      Supplementary Figure 2Cumulative incidence of intracranial hemorrhage among concomitant DOAC-antiplatelet and VKA-antiplatelet users. DOAC = direct oral anticoagulant; VKA = vitamin K antagonist.
      Supplementary Figure 3
      Supplementary Figure 3Cumulative incidence of gastrointestinal bleeding among concomitant DOAC-antiplatelet and VKA-antiplatelet users. DOAC = direct oral anticoagulant; VKA = vitamin K antagonist.
      Supplementary Figure 4
      Supplementary Figure 4Cumulative incidence of other major bleeding among concomitant DOAC-antiplatelet and VKA-antiplatelet users. DOAC = direct oral anticoagulant; VKA = vitamin K antagonist.
      Supplementary Table 12Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (15-Day Grace Period)
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use88144025681.6 (1.1-2.2)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use5144711570.6 (0.2-1.3)0.39 (0.18-0.88)0.39 (0.17-0.89)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use881414725415.8 (4.9-6.8)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use51445811485.1 (3.8-6.5)0.82 (0.60-1.11)1.02 (0.74-1.40)
      Other major bleeding
       Current concomitant VKA-antiplatelet use881418725177.4 (6.4-8.6)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use51444711514.1 (3.0-5.4)0.52 (0.38-0.72)0.61 (0.44-0.86)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 13Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Stricter Outcome Definition)
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use91064035081.1 (0.8-1.6)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use5301914610.6 (0.3-1.2)0.51 (0.25-1.06)0.47 (0.22-0.99)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use91067434882.1 (1.7-3.3)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53013414572.3 (1.6-3.3)1.00 (0.66-1.50)1.21 (0.79-1.85)
      Other major bleeding
       Current concomitant VKA-antiplatelet use91067734812.2 (1.8-2.8)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53011314610.9 (0.5-1.5)0.39 (0.22-0.70)0.42 (0.23-0.78)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 14Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Intention-to-Treat)
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use91069175791.2 (1.0-1.5)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53012437630.6 (0.4-1.0)0.53 (0.34-0.83)0.58 (0.36-0.93)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use910626674773.6 (3.1-4.0)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use530111537173.1 (2.6-3.7)0.84 (0.68-1.05)1.05 (0.83-1.33)
      Other major bleeding
       Current concomitant VKA-antiplatelet use910638574225.2 (4.7-5.7)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use530110837222.9 (2.4-3.5)0.54 (0.44-0.67)0.67 (0.54-0.84)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 15Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Excluding Patients with a Switch Between a VKA and a DOAC Prior to Cohort Entry)
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use90925435031.5 (1.2-2.0)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use52481114440.8 (0.4-1.4)0.48 (0.25-0.92)0.47 (0.24-0.91)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use909218034585.2 (4.5-6.0)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use52487014324.9 (3.8-6.2)0.85 (0.65-1.13)1.08 (0.81-1.45)
      Other major bleeding
       Current concomitant VKA-antiplatelet use909224534167.2 (6.3-8.1)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use52486114334.3 (3.3-5.5)0.56 (0.42-0.74)0.68 (0.51-0.91)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 16Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Competing Risk)
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use91065435081.5 (1.2-2.0)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53011114610.8 (0.4-1.4)0.48 (0.25-0.92)0.47 (0.24-0.93)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use910618134625.2 (4.5-6.1)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53017214485.0 (3.9-6.3)0.88 (0.67-1.15)1.09 (0.82-1.45)
      Other major bleeding
       Current concomitant VKA-antiplatelet use910624634217.2 (6.3-8.2)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53016214504.3 (3.3-5.5)0.57 (0.43-0.75)0.69 (0.52-0.92)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.
      Supplementary Table 17Crude and Adjusted Hazard Ratios for the Association Between Concomitant DOAC-Antiplatelet Use and the Risk of Bleeding Outcomes Among Patients with Nonvalvular Atrial Fibrillation (Censoring on First Bleeding Event)
      ExposurePatientsEventsPerson-YearsIncidence Rate
      Per 100 person-years.
      (95% CI)
      Crude HR (95% CI)Adjusted HR (95% CI)
      Adjusted for disease risk score and calendar year.
      Intracranial hemorrhage
       Current concomitant VKA-antiplatelet use91065133781.5 (1.1-2.0)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53011114380.8 (0.4-1.4)0.49 (0.25-0.94)0.49 (0.25-0.96)
      Gastrointestinal bleeding
       Current concomitant VKA-antiplatelet use910617833785.3 (4.5-6.1)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53017014384.9 (3.8-6.2)0.85 (0.64-1.12)1.05 (0.78-1.41)
      Other major bleeding
       Current concomitant VKA-antiplatelet use910624033787.1 (6.2-8.1)[Reference][Reference]
       Current concomitant DOAC-antiplatelet use53016114384.2 (3.2-5.5)0.57 (0.43-0.75)0.68 (0.51-0.91)
      CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; VKA = vitamin K antagonist.
      low asterisk Per 100 person-years.
      Adjusted for disease risk score and calendar year.

      Discussion

      Our study assessed the risk of intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding associated with concomitant DOAC-antiplatelet use in patients with nonvalvular atrial fibrillation. Compared with concomitant VKA-antiplatelet use, concomitant DOAC-antiplatelet use was associated with a similar risk of gastrointestinal bleeding (HR 1.08; 95% CI, 0.81-1.45), but with a decreased risk of intracranial hemorrhage (HR 0.46; 95% CI, 0.24-0.91) and other major bleeding (HR 0.68; 95% CI, 0.51-0.91). The findings of the primary analyses remained consistent in several sensitivity analyses.
      Our results on intracranial hemorrhage are congruent with a recent meta-analysis of RCTs, which showed that in patients using ASA at baseline, DOACs were associated with a decreased risk compared with VKAs (HR 0.38; 95% CI, 0.26-0.56). Importantly, the incidence rates of intracranial hemorrhage in our study were approximately twofold higher than the ones reported in the trials comparing different DOACs with VKAs in monotherapy.
      • Ruff CT
      • Giugliano RP
      • Braunwald E
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      This increase in the absolute risk of intracranial hemorrhage combined with the strong reduction in the relative risk associated with concomitant DOAC-antiplatelet use highlight the importance of choosing the appropriate oral anticoagulant in patients with nonvalvular atrial fibrillation requiring additional use of antiplatelets.
      Our results on gastrointestinal bleeding showing a similar risk among concomitant DOAC-antiplatelet use and concomitant VKA-antiplatelet use are opposed to the previously reported increased risk with DOACs in monotherapy compared with VKAs in monotherapy.
      • Ruff CT
      • Giugliano RP
      • Braunwald E
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      A possible explanation could be the preferential concomitant prescribing of VKAs and antiplatelets instead of DOACs and antiplatelets in high-risk patients, as the higher prevalence of proton-pump inhibitors in the VKA group alludes. However, the pharmacologic properties of the different antithrombotic medications could also account for this phenomenon.
      • Desai JC
      • Chatterjee P
      • Friedman K
      • Aisenberg J
      Incidence and clinical presentation of gastrointestinal bleeding in atrial fibrillation patients taking direct oral anticoagulants.
      Indeed, while bleeding episodes related to VKAs and antiplatelets usually occurs in the upper gastrointestinal tract, bleeding episodes related to dabigatran and rivaroxaban, the 2 most prevalent DOACs in our cohort, originate more often in the lower gastrointestinal tract.
      • Desai JC
      • Chatterjee P
      • Friedman K
      • Aisenberg J
      Incidence and clinical presentation of gastrointestinal bleeding in atrial fibrillation patients taking direct oral anticoagulants.
      Thus, the common localization of VKA and antiplatelet-related gastrointestinal bleeding could lead to a higher additive risk due to concomitant antiplatelet use with VKAs than with DOACs.
      Recently, 2 RCTs compared the risk of major bleeding between concomitant DOAC-antiplatelet use and concomitant VKA-antiplatelet use,
      • Cannon CP
      • Bhatt DL
      • Oldgren J
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      • Gibson CM
      • Mehran R
      • Bode C
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      while a third one is ongoing.

      ClinicalTrials.gov. NIH U.S. National Library of Medicine. A study of apixaban in patients with atrial fibrillation, not caused by a heart valve problem, who are at risk for thrombosis (blood clots) due to having had a recent coronary event, such as a heart attack or a procedure to open the vessels of the heart. Available at: https://clinicaltrials.gov/ct2/show/NCT02415400. Accessed April 9, 2018.

      Although they have considerably expanded our knowledge about concomitant antithrombotic treatment, a direct comparison with our study is challenging. First, these trials were restricted to nonvalvular atrial fibrillation patients undergoing coronary intervention.
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • et al.
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      • January CT
      • Wann LS
      • Alpert JS
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
      Second, while trial participants randomized to VKAs received dual antiplatelet treatment, patients randomized to DOACs received either single antiplatelet treatment
      • Cannon CP
      • Bhatt DL
      • Oldgren J
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      • Gibson CM
      • Mehran R
      • Bode C
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      or dual antiplatelet treatment with a low-dose DOAC.
      • Gibson CM
      • Mehran R
      • Bode C
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      Finally, effect estimates for intracranial hemorrhage and gastrointestinal bleeding were based on very few events
      • Cannon CP
      • Bhatt DL
      • Oldgren J
      • et al.
      Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.
      or were not reported.
      • Gibson CM
      • Mehran R
      • Bode C
      • et al.
      Prevention of bleeding in patients with atrial fibrillation undergoing PCI.
      Nevertheless, the lower risk of major bleeding among concomitant DOAC-antiplatelet use shown in the RCTs is congruent with our findings.
      Our study has several strengths. First, the use of an as-treated exposure definition for both oral anticoagulants and antiplatelets allowed us to assess concomitant use with high precision. This is particularly important in drug–drug interaction studies aiming to investigate the effects associated with the concurrent use of 2 or more medications. Second, the population-based setting and the few exclusion criteria applied during study cohort assembly make the results of this study highly generalizable. Finally, we defined bleeding events based on related hospitalization or death likely maximizing the sensitivity and specificity of this outcome definition.
      Our study also has some limitations. First, given its observational nature, residual confounding is possible. To mitigate this potential bias, we adjusted for DRS, including 18 clinically important risk factors. Of note, adjustment had only a minor effect on the point estimates of the bleeding outcomes. Second, the median follow-up in our study was short (1.6 months). However, this was expected given current recommendations limiting concomitant use of oral anticoagulants with antiplatelets to few months for most patients.
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • et al.
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      • January CT
      • Wann LS
      • Alpert JS
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
      Finally, our drug-specific analyses should be interpreted cautiously given the low number of exposed events.
      In summary, the results of this population-based study indicate that compared with concomitant VKA-antiplatelet use, concomitant DOAC-antiplatelet use is associated with a similar risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage and other major bleeding. These findings could help physician decision-making in patients requiring concomitant treatment with oral anticoagulants and antiplatelets.

      Acknowledgments

      AD is a recipient of a Research Fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft). SS is the recipient of the James McGill Professorship award. KBF and LA are recipients of a Chercheur-Boursier Award from the Fonds de recherche du Québec – Santé (FRQS) and William Dawson Scholar awards from McGill University.

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