Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Real-world comparison of bleeding risks among non-valvular atrial fibrillation patients prescribed apixaban, dabigatran, or rivaroxaban

  • Ping G. Tepper ,

    Roles Conceptualization, Formal analysis, Writing – original draft, Writing – review & editing

    ping@pganalytics.com

    Affiliation Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America

  • Jack Mardekian,

    Roles Conceptualization, Writing – review & editing

    Affiliation Department of Outcomes & Evidence, Pfizer, Inc; New York, New York, United States of America

  • Cristina Masseria,

    Roles Conceptualization, Writing – review & editing

    Affiliation Department of Outcomes & Evidence, Pfizer, Inc; New York, New York, United States of America

  • Hemant Phatak,

    Roles Conceptualization, Writing – review & editing

    Affiliation Department of Global Health Economics and Outcomes Research, Bristol-Myers Squibb; Princeton, New Jersey, United States of America

  • Shital Kamble,

    Roles Conceptualization, Writing – review & editing

    Affiliation Department of Global Health Economics and Outcomes Research, Bristol-Myers Squibb; Princeton, New Jersey, United States of America

  • Younos Abdulsattar,

    Roles Conceptualization, Writing – review & editing

    Affiliation Department of Outcomes & Evidence, Pfizer, Inc; New York, New York, United States of America

  • William Petkun,

    Roles Conceptualization, Writing – review & editing

    Affiliation Department of Global Medical Affairs, Bristol-Myers Squibb; Princeton, New Jersey, United States of America

  • Gregory Y. H. Lip

    Roles Conceptualization, Writing – original draft, Writing – review & editing

    Affiliation Institute of Cardiovascular Sciences, University of Birmingham, City Hospital, Birmingham, United Kingdom

Real-world comparison of bleeding risks among non-valvular atrial fibrillation patients prescribed apixaban, dabigatran, or rivaroxaban

  • Ping G. Tepper, 
  • Jack Mardekian, 
  • Cristina Masseria, 
  • Hemant Phatak, 
  • Shital Kamble, 
  • Younos Abdulsattar, 
  • William Petkun, 
  • Gregory Y. H. Lip
PLOS
x

Abstract

Limited real-world data are available regarding the comparative safety of non-vitamin K antagonist oral anticoagulants (NOACs). The objective of this retrospective claims observational cohort study was to compare the risk of bleeding among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, or rivaroxaban. NVAF patients aged ≥18 years with a 1-year baseline period were included if they were new initiators of NOACs or switched from warfarin to a NOAC. Cox proportional hazards modelling was used to estimate the adjusted hazard ratios of any bleeding, clinically relevant non-major (CRNM) bleeding, and major inpatient bleeding within 6 months of treatment initiation for rivaroxaban and dabigatran compared to apixaban. Among 60,227 eligible patients, 8,785 were prescribed apixaban, 20,963 dabigatran, and 30,529 rivaroxaban. Compared to dabigatran or rivaroxaban patients, apixaban patients were more likely to have greater proportions of baseline comorbidities and higher CHA2DS2-VASc and HAS-BLED scores. After adjusting for baseline clinical and demographic characteristics, patients prescribed rivaroxaban were more likely to experience any bleeding (HR: 1.35, 95% confidence interval [CI]: 1.26–1.45), CRNM bleeding (HR: 1.38, 95% CI: 1.27–1.49), and major inpatient bleeding (HR: 1.43, 95% CI: 1.17–1.74), compared to patients prescribed apixaban. Dabigatran patients had similar bleeding risks as apixaban patients. In conclusion, NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and major inpatient bleeding, compared to apixaban patients. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding risks between patients treated with dabigatran and apixaban.

Introduction

Atrial fibrillation (AF) increases the risk of stroke and systemic embolism, and AF-related strokes have higher mortality, disability, costs, and risk of recurrent stroke compared to non-AF related strokes [1,2]. Oral anticoagulation with warfarin reduces the risk of stroke by 64%, and all-cause mortality by 26%, compared to control or placebo [3]. However, interactions with food and other drugs, variability in metabolism, a delayed onset of action, and the necessity of regular anticoagulation monitoring are limitations of warfarin therapy as well as a significant risk of major bleeding, particularly if anticoagulation control is poorly managed [46]. One population-based cohort study reported a major bleeding rate of 3.8% per person-year over a 5-year follow-up period [7]. This increased risk of bleeding with warfarin may lead to more discontinuations of oral anticoagulants, thus exposing patients to a risk of stroke and mortality.

Currently, non-vitamin K antagonist oral anticoagulants (NOACs) offer relative efficacy, safety, and convenience compared to warfarin. These drugs can be given in fixed doses without routine coagulation monitoring, and they have minimal drug and food interactions [7,8]. In clinical trials, NOACs were non-inferior or superior to warfarin for the prevention of stroke or systemic embolism in moderate-to-high risk patients with non-valvular AF, and were also non-inferior or superior to warfarin in terms of safety, with regard to major and intracranial bleeding [9]. However, clinical trials are limited by strict inclusion/exclusion criteria, and the generalizability to everyday clinical practice requires post-licensing ‘real world’ observational studies.

With the recent licensing and availability of NOACs, including dabigatran etexilate mesylate, rivaroxaban, apixaban, and edoxaban, data are needed on their comparative safety profile in many countries. Dabigatran was approved in the United States in 2010, while rivaroxaban, apixaban, and edoxaban were approved in 2011, 2012, and 2015, respectively.

The objective of this retrospective claims observational cohort study was to compare the risk of bleeding among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, or rivaroxaban.

Materials and methods

This is a retrospective observational cohort study using insurance claims data from the Truven MarketScan Commercial Claims and Encounter and Medicare Supplemental & Coordination of Benefits Early View Database incurred from 01JAN2013-31OCT2014 to capture the real-world experience of NVAF patients who were either new initiators or switchers from warfarin. The database captures person-specific clinical utilization among approximately 100 payers of large employers, health plans, and government and public organizations in the United States, with more than 196 million unique patients since 1995. The database included annual insurance claims of inpatient, outpatient, emergency room, pharmacy, behavioural health care, and enrollment data for more than 94 million insured individuals, their dependents for active employees, early retirees, Consolidated Omnibus Budget Reconciliation Act (COBRA) health plan continuers, and Medicare-eligible retirees with employer-sponsored private health insurance and employer-provided Medicare Supplemental plans in the United States [10]. Data extraction for the purpose of this study was compliant with the Health Insurance Portability and Accountability Act (HIPPA).

The study population consisted of patients with an AF diagnosis claim (N = 1,209,729) during the study period. Patients were identified based on at least 1 inpatient or 2 outpatient claims that were at least 30 days apart, with a primary or secondary diagnosis of AF (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 427.3). The first AF diagnosis claim during the study period was defined as the date of AF diagnosis for this population. As documented in claims data, we excluded transient perioperative AF patients and patients with valvular heart disease or hyperthyroidism at the time of AF diagnosis and women who were pregnant during the study period. Transient perioperative AF patients were identified as patients who had cardiac surgery procedures (ICD-9-CM: 35–39) up to 30 days before the AF diagnosis date. Valvular heart disease was identified based on inpatient or outpatient diagnosis of mitral stenosis or prosthetic heart valve (ICD-9-CM: 394, 396, 424, or 746). Hyperthyroidism was defined as having an inpatient or outpatient diagnosis of hyperthyroidism or thyrotoxicosis (ICD-9-CM: 242).

NVAF patients who had unique pharmacy claims for apixaban, dabigatran, or rivaroxaban on or after their AF diagnosis date were identified (n = 146,141) from 01JAN2013-31OCT2014. The date of the first prescription claim was identified as the index date. The population included new initiators of unique NOACs and those who switched from warfarin. Allowing warfarin experienced patients in the study population makes it more representative of ‘real-world’ practice. All patients had 12 months of continuous enrollment prior to their index date. Patients with bleeding, stroke, or transient ischemic attack (TIA) within 30 days prior to or on the index date were excluded to avoid ambiguity about timing of treatment initiation and occurrence of events. Patients who had a different NOAC prescription 6 months before the index date were excluded (Fig 1).

thumbnail
Fig 1. Patient selection criteria.

AF: atrial fibrillation; NOAC: non-vitamin K antagonist oral anticoagulant; NVAF: non-valvular atrial fibrillation; OAC: oral anticoagulant.

https://doi.org/10.1371/journal.pone.0205989.g001

Follow-up started after the index date and ended with the occurrence of bleeding, health plan disenrollment, discontinuation, switch of therapy, or 6 months after treatment initiation, whichever came first. Discontinuation of therapy was defined as no evidence of index prescriptions for 30 days from the last day of supply of the last filled prescription. The date of discontinuation was the last day of supply of the last filled prescription. During follow-up, if the NOAC initiator had a pharmacy claim for another NOAC, the patient was censored on the first date of the new drug’s pharmacy claim.

Any bleeding, including major and clinically relevant non-major (CRNM) bleeding, was defined using inpatient or outpatient claims with a primary diagnosis of bleeding. Inpatient major bleeding was identified based on inpatient claims, with major bleeding as the primary diagnosis for a hospitalization (any visit to a hospital for haemorrhage). The definition of major bleeding was modified from a published administrative claims-based algorithm and captures major bleeding at key sites including but not limited to intracranial, gastrointestinal (GI), liver, splenic, and ocular hemorrhage requiring hospitalization with a diagnosis for bleeding [11]. Inpatient major bleeding was further categorized into intracranial haemorrhage (ICH), GI, and other bleeding. The ICD-9-CM codes used to identify bleeding are listed in the Supplementary Material.

Baseline patient characteristics during the 12-month period before or on the index date were determined. Demographic factors included age on the index date, sex, health plan type, and geographic region. Baseline comorbidities were identified based on inpatient or outpatient claims with diagnoses of interest. Clinical prediction risk scores, including Charlson Comorbidity Index (CCI), CHADS2 and CHA2DS2-VASc stroke risk, and HAS-BLED bleed risk scores were calculated as allowed by the availability of the data [1215]. The CHADS2 risk index was based on a point system in which 2 points are assigned for a history of stroke or a transit ischemic attack and 1 point each is assigned to age≥75 years, a history of hypertension, a history of diabetes mellitus, or a heart failure. CHADS2-VASc score was calculated with further consideration for vascular disease. The system will include 1 point for congestive heart failure, hypertension, diabetes mellitus, vascular disease (prior myocardial infarction [MI], peripheral artery disease, or aortic plaque), aged 65–74, and female, and 2 points for age ≥75, stroke/TIA/thromboembolic disease. Modified HAS-BLED score was calculated to approximate bleed risk. One point was assigned to patients with 1) hypertension (ideally systolic blood pressure >160 mm hg, but for this study, ICD-9 code was used), 2) abnormal renal function, 3) abnormal liver function, 4) stroke, 5) history of bleeding or predisposition (anemia), 6) elderly (aged >65 years), 7) concomitant antiplatelet or nonsteroidal anti-inflammatory drugs, and 8) alcohol abuse [15].

Prior stroke and bleeding in the baseline period were also reported. Concomitant use of antiplatelets, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting-enzyme (ACE) inhibitors, statins, and other anticoagulants 120 days preceding or on the index date were identified based on pharmacy claims. Patients who switched from warfarin to an NOAC were identified. Index NOAC dosage was categorized as reduced (apixaban 2.5 mg twice a day; dabigatran 75 mg twice a day; rivaroxaban 15 mg once a day), standard (apixaban 5 mg twice a day; dabigatran 150 mg twice a day; rivaroxaban 20 mg once a day), or unknown.

Statistical analysis

Descriptive statistics of patient characteristics were summarized as mean (Standard Deviation, SD), Median (interquartile range, IQR). Pairwise comparisons were conducted between dabigatran and apixaban as well as between rivaroxaban and apixaban using Pearson’s chi-square test and the Kruskal-Wallis test for categorical and continuous variables, respectively. Overall annualized rates of inpatient bleeding were calculated for the first 6 months. Time-to-bleeding was modelled using Cox proportional hazard regression. Multivariate modeling was performed with the adjustment of baseline risk factors including age, gender, baseline comorbidities, and medications. Risk of bleeding, when comparing dabigatran or rivaroxaban versus apixaban, was expressed as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical significance was determined using 2-sided tests with alpha = 0.05 and reported as p-values <0.001 (***), <0.01 (**), <0.05 (*)

Two sensitivity analyses were conducted. First, a sensitivity analysis was conducted using only patients who received the standard dosage (apixaban 5 mg twice a day; dabigatran 150 mg twice a day; rivaroxaban 20 mg once a day). Second, a sensitivity analysis based on inverse probability treatment weighting (IPTW) was performed. A multinomial logistic model with treatment group as response and covariates included in the Cox regression adjusted models was fit to calculate the weights. Weighted Cox proportional hazards models were used to estimate the time-to-inpatient major bleeding in the dabigatran and rivaroxaban cohorts compared with the apixaban cohort. All analyses were conducted using SAS Windows 9.3 (SAS Institute Inc., Cary, NC).

Results

The eligible study population included 8,785 apixaban, 20,963 dabigatran, and 30,529 rivaroxaban patients. Of the 32,800 patients, the median follow-up duration was 184 days (interquartile range [IQR] 89–312) for apixaban, 553 days (IQR 341–619) for dabigatran, and 300 days (IQR 151–505) for rivaroxaban patients. The average age was 70 years for both apixaban and dabigatran patients and 68 years for rivaroxaban patients (Table 1). Clinical comorbidity profiles were more similar between apixaban and rivaroxaban patients than between apixaban and dabigatran patients. Apixaban patients had greater proportions of clinical comorbidities compared to both dabigatran and rivaroxaban patients, with higher overall CCI scores, higher stroke and bleeding risk scores, and greater use of antiplatelet drugs prior to the index medication; apixaban patients were more likely to have switched from warfarin (Table 1).

thumbnail
Table 1. Baseline characteristics of non-valvular atrial fibrillation (NVAF) patients who initiated apixaban, dabigatran, or rivaroxaban.

https://doi.org/10.1371/journal.pone.0205989.t001

The unadjusted bleeding rates are shown in Table 2, and the cumulative incidence of major bleeding is represented in Fig 2. After the adjustment of baseline patient characteristics–medication use, dosage, and switching from warfarin–patients treated with rivaroxaban were significantly more likely to have any bleeding (HR: 1.35, 95% CI: 1.26–1.45) or CRNM bleeding (HR: 1.38, 95% CI: 1.27–1.49) within 6 months of treatment initiation compared to those treated with apixaban (Table 3).

thumbnail
Fig 2. Kaplan-meier curves of any major inpatient bleeding by treatment.

Rivaroxaban has the highest cumulative probability of any inpatient major bleeding. The overall Log-rank is p<0.0001.

https://doi.org/10.1371/journal.pone.0205989.g002

thumbnail
Table 2. Unadjusted annual cumulative incidence of bleeding among non-valvular atrial fibrillation (nvaf) patients who initiated apixaban, dabigatran, or rivaroxaban.

https://doi.org/10.1371/journal.pone.0205989.t002

thumbnail
Table 3. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for any, major, and clinically relevant Non-Major (CRNM) bleeding during the first 6 months after treatment initiation comparing dabigatran and rivaroxaban vs apixaban.

https://doi.org/10.1371/journal.pone.0205989.t003

After adjusting for baseline characteristics, there was a 43% (95% CI: 1.17–1.74) increased adjusted risk of inpatient major bleeding for rivaroxaban patients as compared to apixaban patients (Table 4). This effect was mainly observed in the risk of GI and other inpatient major bleeding with rivaroxaban as compared to apixaban, with a 51% (95% CI: 1.18–1.92) increased adjusted risk of GI inpatient bleeding, and a 58% (95% CI: 1.13–2.22) increased adjusted risk of other inpatient major bleeding.

thumbnail
Table 4. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for inpatient major bleeding during the first 6 months after treatment initiation comparing Dabigatran and Rivaroxaban vs Apixaban among non-valvular atrial fibrillation (NVAF) patients.

https://doi.org/10.1371/journal.pone.0205989.t004

No significant differences were found between dabigatran and apixaban patients for any bleeding, CRNM bleeding, or inpatient major bleeding. The sensitivity analysis to assess the standard dose treatment effect on risk of major bleeding showed similar trends of significantly higher major risk with rivaroxaban compared to apixaban (Table 5). Additionally, the IPTW sensitivity analysis demonstrated consistent trends with the main analysis (Table 6).

thumbnail
Table 5. Sensitivity analysis using only patients initiated with standard dosage adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for inpatient major bleeding during the first 6 months after treatment initiation comparing dabigatran and rivaroxaban vs apixaban among non-valvular atrial fibrillation (NVAF) patients.

https://doi.org/10.1371/journal.pone.0205989.t005

thumbnail
Table 6. Sensitivity analysis—Inverse probability treatment weighting IPTW analyses: Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for inpatient major bleeding during the first 6 months after treatment initiation comparing dabigatran and rivaroxaban vs apixaban among nvaf patients.

https://doi.org/10.1371/journal.pone.0205989.t006

Discussion

In this study, our principal finding was that NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and inpatient major bleeding compared to patients treated with apixaban. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding between dabigatran and apixaban patients.

This large observational cohort study compares inpatient bleeding risks among NVAF patients treated with the three NOACs: rivaroxaban, dabigatran, and apixaban. Despite greater comorbidities and worse bleeding and stroke profiles among apixaban patients, these patients experienced significantly less major inpatient bleeding, CRNM bleeding, or any bleeding events compared to rivaroxaban patients, and had comparable bleeding event rates to dabigatran patients. When compared with apixaban, rivaroxaban patients also showed significantly higher GI and other bleeding risks, and trended towards a higher ICH bleeding risk. Dabigatran had similar risks with apixaban across various bleeding sites.

Previous studies used data from large clinical trials to compare the safety between NOACs, which have been used to inform indirect comparisons and network meta-analyses [16]. Our study is broadly supportive of clinical trial observations, and in the ROCKET-AF trial, rivaroxaban had a comparable risk of bleeding to warfarin, whilst apixaban had significantly lower bleeding risk compared to warfarin [1719]. We also found less bleeding with dabigatran compared to rivaroxaban, consistent with indirect comparison studies [20].

Few direct comparisons have been completed for apixaban, dabigatran, and rivaroxaban patients in a real-world setting. Another observational study using MarketScan data and propensity score matching showed that dabigatran had similar risk of major bleeding compared to apixaban and rivaroxaban, and apixaban had significantly lower risk of major bleeding compared to rivaroxaban [21]. Our study showed consistent results with additional comparisons of types of major bleeding and CRNM. Furthermore, in a more recent claims study using Optum claims data, apixaban patients had a 50% and 61% lower risk of major bleeding compared to dabigatran and rivaroxaban patients, respectively. There was no difference in the risk of ICH between apixaban and dabigatran or rivaroxaban patients [22]. In another study using the same data, apixaban patients also had a significantly lower risk of GI bleeding compared to dabigatran and rivaroxaban patients [23].

In addition, previous real-world studies have compared the risk of major bleeding for NOACs versus warfarin, the standard of care. Several real-world analysis comparing dabigatran to warfarin on adjusted overall bleeding risks showed greater or non-significant differences in overall bleeding, but higher GI bleeding and lower ICH risks [2427]. Nonetheless, a recent study reported significantly lower overall major bleeding and ICH risks among dabigatran patients compared to warfarin patients [28]. Abraham et al. found similar GI bleeding risks when comparing dabigatran and rivaroxaban separately to warfarin using the Optum dataset [29]. Furthermore, real-world studies focused on rivaroxaban versus warfarin have shown no statistically significant difference in bleeding risk [21,28,30]. In addition, apixaban patients have been shown to have consistently lower risk of major bleeding compared to warfarin [21,28,31].

Based on large national claims data, our study adds novel evidence regarding the comparative bleeding risks of apixaban, dabigatran, and rivaroxaban in patients with NVAF. This population includes patients who were warfarin naïve and warfarin experienced, which makes it more representative of true clinical practice. Many prior studies only include treatment-naïve patients. Clearly, more real-world studies regarding bleeding risks and use of NOACs are still warranted.

Limitations

First, health insurance databases include patients with varied risk profiles, and patients with a higher risk of major bleeding were more likely to use apixaban. Second, patients on all dosages of apixaban, dabigatran, and rivaroxaban were included in the study population. As expected, previous studies have shown that increased dosages are positively associated with bleeding events. Sensitivity analysis using only standard dosage found comparable results. Third, compared with clinical trials, no causal relation can be drawn in this retrospective cohort study. Additionally, there are wide ranges of comorbidities among the cohorts, and although baseline characteristics were adjusted, some residual confounding is likely because of unmeasured confounders [32]. The mean length of follow-up for patients treated with apixaban was significantly shorter compared to those treated with dabigatran and rivaroxaban. Survival methodology was used to account for the varied follow-up length; however, apixaban-related bleeding events could have occurred later than the other NOACs, which could have affected the results. Given the distinct separation in the cumulative incidence, we would expect minimal impact on the results.

Furthermore, there are inherent limitations of claim data, such as coding errors and missing data. Comorbidities were presented in the dataset using ICD-9-CM diagnosis codes. Laboratory data, including creatinine clearance, are not available in the claims database, so diagnosis codes were used to determine comorbidities. Additionally, with a claims database, medication as filled may not reflect true medication use [33]. Nonetheless, this study used a large database of nationally representative commercially insured patients and is one of the first studies to compare the safety between NOACs.

Conclusions

In conclusion, NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and major inpatient bleeding compared to patients treated with apixaban. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding between dabigatran and apixaban patients. These data may help guide decision-making in clinical practice.

Acknowledgments

Allison Keshishian and Qisu Zhang of STATinMED Research provided editorial assistance in the preparation of this manuscript.

References

  1. 1. Marini C, De Santis F, Sacco S, Russo T, Olivieri L, Totaro R, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke. 2005;36(6): 1115–1119. pmid:15879330
  2. 2. Benjamin EJ, Chen PS, Bild DE, Mascette AM, Albert CM, Alonso A, et al. Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop. Circulation. 2009;119(4): 606–618. pmid:19188521
  3. 3. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12): 857–867. pmid:17577005
  4. 4. Gallego P, Roldan V, Marín F, Romera M, Valdés M, Vicente V et al. Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation. Thromb Haemost. 2013;110(6): 1189–1198. pmid:24096615
  5. 5. De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III): position paper of the ESC Working Group on Thrombosis—task force on anticoagulants in heart disease. Thromb Haemost. 2013;110(6): 1087–1107. pmid:24226379
  6. 6. Wan Y, Heneghan C, Perera R, Roberts N, Hollowell J, Glasziou P, et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circ Cardiovasc Qual Outcomes. 2008;1(2): 84–91. pmid:20031794
  7. 7. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185(2): E121–E127. pmid:23184840
  8. 8. Hylek EM, Ko D, Cove CL. Gaps in translation from trials to practice: non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. Thromb Haemost. 2014;111(5): 783–788. pmid:24573511
  9. 9. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, 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. Lancet. 2014;383(9921): 955–962. pmid:24315724
  10. 10. Danielson E. Health Research Data for the Real World: The MarketScan® Databases. Ann Arbor, MI, Truven Health Analytics; 2014.
  11. 11. Cunningham A, Stein CM, Chung CP, Daugherty JR, Smalley WE, Ray WA. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf. 2011;20(6): 560–566. pmid:21387461
  12. 12. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383. pmid:3558716
  13. 13. Lip GY, Halperin JL. Improving stroke risk stratification in atrial fibrillation. Am J Med. 2010;123(6): 484–488. pmid:20569748
  14. 14. Roldán V, Marín F, Fernández H, Manzano-Fernandez S, Gallego P, Valdés M, et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a “real-world” population with atrial fibrillation receiving anticoagulant therapy. Chest. 2013;143(1): 179–184. pmid:22722228
  15. 15. 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(5): 1093–1100. pmid:20299623
  16. 16. Skjøth F, Larsen TB, Rasmussen LH, Lip GY. Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation. an indirect comparison analysis. Thromb Haemost. 2014;111(5): 981–988. pmid:24577485
  17. 17. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10): 883–891. pmid:21830957
  18. 18. Halperin JL, Hankey GJ, Wojdyla DM, Piccini JP, Lokhnygina Y, Patel MR, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014;130(2): 138–146. pmid:24895454
  19. 19. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): 981–992. pmid:21870978
  20. 20. Lip GY, Larsen TB, Skjøth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2012;60(8): 738–746. pmid:22575324
  21. 21. Lip GY, Keshishian A, Kamble S, Pan X, Mardekian J, Horblyuk R, et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. Thromb Haemost. 2016;116(5): 975–986. pmid:27538358
  22. 22. Noseworthy PA, Yao X, Abraham NS Sangaralingham LR, McBane RD, Shah ND. Direct comparisons of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in nonvalvular atrial fibrillation. Chest. 2016;150(6): 1302–1312. pmid:27938741
  23. 23. Abraham NS, Noseworthy PA, Yao X, Sangaralingham LR, Shah ND. Gastrointestinal safety of direct oral anticoagulants: a large population-based study. Gastroenterology. 2017;152(5): 1014–1022. pmid:28043907
  24. 24. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015;131(2): 157–164. pmid:25359164
  25. 25. Hernandez I, Baik SH, Piñera A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2015;175(1): 18–24. pmid:25365537
  26. 26. Seeger JD, Bykov K, Bartels DB, Huybrechts K, Zint K, Schneeweiss S. Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation. Thromb Haemost. 2015;114(6): 1277–1289. pmid:26446507
  27. 27. Villines TC, Schnee J, Fraeman K, Siu K, Reynolds MW, Collins J, et al. A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system. Thromb Haemost. 2015;114(6): 1290–1298. pmid:26446456
  28. 28. Yao X, Abraham NS, Sangaralingham LR, Bellolio MF, McBane RD, Shah ND, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016;5(6): e003725. pmid:27412905
  29. 29. Abraham NS, Singh S, Alexander GC, Heien H, Haas LR, Crown W, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ. 2015;350: h1857. pmid:25910928
  30. 30. Laliberté F, Cloutier M, Nelson WW, Coleman CI, Pilon D, Olson WH, et al. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2014;30(7): 1317–1325. pmid:24650301
  31. 31. Adeboyeje G, Sylwestrzak G, White J, Rosenberg A, Abarca J, Crawford G, et al. Comparative effectiveness and safety of anticoagulant therapy with warfarin, dabigatran, apixaban, or rivaroxaban in patients with nonvalvular atrial fibrillation. Circ Card Qual Outcomes. 2016;9(Suppl 2):A2.
  32. 32. Lauffenburger JC, Farley JF, Gehi AK, Rhoney DH, Brookhart MA, Fang G. Factors driving anticoagulant selection in patients with atrial fibrillation in the United States. Am J Cardiol. 2015;115(8): 1095–1101. pmid:25724781
  33. 33. Lauffenburger JC, Balasubramanian A, Farley JF, Critchlow CW, O'Malley CD, Roth MT, et al. Completeness of prescription information in US commercial claims databases. Pharmacoepidemiol Drug Saf. 2013;22(8): 899–906. pmid:23696101