How does rivaroxaban compare with dabigatran for stroke, bleeding, and mortality risks in patients with atrial fibrillation?
In a new-user cohort study of 118 891 patients, rivaroxaban treatment was associated with significantly increased intracranial hemorrhage and major extracranial bleeding, including major gastrointestinal bleeding, and nonsignificantly reduced risk of thromboembolic stroke and increased risk of mortality. The absolute increase in intracranial hemorrhage with rivaroxaban treatment exceeded its reduced rate of thromboembolic stroke.
In this observational study, rivaroxaban use was associated with increased intracranial and major extracranial bleeding events compared with dabigatran use.
Dabigatran and rivaroxaban are non–vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes.
To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention.
Design, Setting, and Participants
Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016.
Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily.
Main Outcomes and Measures
Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated.
A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS2 score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke.
Conclusions and Relevance
Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.
Warfarin sodium, a vitamin K antagonist, has been a mainstay of therapy to reduce thromboembolic stroke risk in patients with atrial fibrillation (AF),1-3 but it substantially increases the risk of intracranial and extracranial hemorrhage3 and it can be difficult to maintain patients in the therapeutic range.4Quiz Ref ID Dabigatran etexilate mesylate, a direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, are non–vitamin K antagonist oral anticoagulants (NOACs), which are simpler to dose than warfarin and do not require therapeutic monitoring.5,6 In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran treatment was superior to warfarin treatment for reduction of stroke and intracranial hemorrhage (ICH) in patients with nonvalvular AF but was inferior for major gastrointestinal bleeding, in which risk was increased.7 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), rivaroxaban treatment was noninferior to warfarin treatment for prevention of stroke or systemic embolization.8 Intracranial and fatal bleeding events were reduced while major gastrointestinal bleeding was increased in the rivaroxaban arm.
Using data from RE-LY and ROCKET-AF, an indirect comparison reported that stroke and systemic embolization risk and hemorrhagic stroke risk were significantly reduced with dabigatran use compared with rivaroxaban use.9 However, this analysis did not control for differences in baseline risk of future stroke or in the quality of warfarin anticoagulation between trials.9,10 Another indirect comparison, restricted to the subset of patients from these trials at high risk of future stroke, found a statistically nonsignificant reduction in stroke or systemic embolization risk with dabigatran treatment.10 The question remains unanswered whether these NOACs are therapeutically similar or whether clinically important differences exist that might lead prescribers and patients to prefer one over the other.
Given that 80% of patients with AF are 65 years or older,11,12 we studied elderly Medicare beneficiaries with nonvalvular AF who initiated therapy with dabigatran or rivaroxaban and directly compared their risks of stroke, bleeding, and death. Both NOACs are available in the United States at 2 dosage levels for use in patients with nonvalvular AF, a lower dose for patients with impaired renal function and a standard dose for all other patients.5,6 We compared patients initiating treatment with standard doses of dabigatran (150 mg twice daily) and rivaroxaban (20 mg once daily).
Medicare provides health insurance coverage to persons aged 65 years and older and those younger than 65 years who have end-stage kidney disease or are disabled.13,14 This study was restricted to elderly beneficiaries enrolled in fee-for-service Medicare Part A (hospitalization), Part B (outpatient medical care), and Part D (prescription drugs) because claims from these sources were necessary for research purposes. Patients enrolled in Medicare Advantage (Part C), which provides care through private insurance companies, were not included because claims for medical encounters and hospitalizations were not reliably captured by Medicare during the study period.
A new-user cohort design was used to compare patients initiating dabigatran or rivaroxaban at standard doses for treatment of nonvalvular AF.15 We identified all patients with any inpatient or outpatient diagnoses of AF or atrial flutter, based on International Classification of Diseases, Ninth Revision (ICD-9), coding, who filled their first prescription for either drug from November 4, 2011, when rivaroxaban was approved for AF in the United States, through June 30, 2014. Patients were excluded if they had less than 6 months of enrollment in Medicare Parts A, B, and D, were younger than 65 years, had received prior treatment with warfarin or any NOAC, resided in a skilled nursing facility or nursing home, or were receiving hospice care on the date of their cohort-qualifying prescription (index date). Patients with a hospitalization extending beyond the index date were also excluded, as were kidney transplant recipients and patients undergoing dialysis. Additionally, we excluded patients with diagnoses indicating a potential alternative indication for anticoagulation in the 6 months preceding study entry (mitral valve disease, heart valve repair or replacement, deep vein thrombosis, pulmonary embolism, or joint replacement). Because our purpose was to directly compare dabigatran and rivaroxaban, we did not include a warfarin-treated cohort.
This study was approved by the Research in Human Subjects Committee of the Center for Drug Evaluation and Research. Informed consent was not required due to the retrospective nature of the study.
During the 6 months preceding cohort entry, Medicare claims data on chronic medical conditions, cardiovascular disease, risk factors for cardiovascular, stroke, and bleeding events, and health care utilization were collected for each patient, as were data on prescriptions for medications used for treatment of these disorders, as well as potentially interacting medications that could alter dabigatran or rivaroxaban pharmacokinetics. We also calculated the CHADS2 score,16 which predicts stroke risk in patients with AF and was used in RE-LY and ROCKET-AF,7,8 and the HAS-BLED score,17 which predicts bleeding risk in patients with AF treated with warfarin.
To adjust for potential confounding due to baseline imbalances in study covariates while preserving sample size, we used inverse probability of treatment weighting (IPTW) based on the propensity score.18-22 With this method, the propensity score (predicted probability of initiating dabigatran treatment given baseline characteristics) was used to generate patient-specific stabilized weights that control for covariate imbalances.20,21 Covariate balance between the weighted cohorts was assessed using standardized mean differences.22-24 A standardized difference of 0.1 or less indicates a negligible difference between groups.22-24 The distributions of propensity scores and stabilized weights were inspected for outliers.
Follow-up began on the day after cohort entry and continued until disenrollment from Medicare, a gap in anticoagulant days of supply exceeding 3 days, a prescription fill for a different anticoagulant, kidney transplantation or initiation of dialysis, admission to a skilled nursing facility or nursing home, transfer to hospice care, end of the study period, or occurrence of a study outcome, whichever came first. We chose a 3-day gap allowance because of the short half-lives of dabigatran (12-17 hours) and rivaroxaban (11-13 hours in the elderly) and our desire to increase the likelihood that patients included in analyses were therapeutically anticoagulated.5,6 We censored for admission to a skilled nursing facility or nursing home due to concerns about incomplete capture of outcomes in these settings, and for transfer to hospice care because most deaths in these patients were expected and therefore unlikely to be due to an acute, anticoagulant-associated event.
Primary outcomes were thromboembolic stroke, ICH, major extracranial bleeding events, including major gastrointestinal bleeding, and mortality. Secondary outcomes were all hospitalized extracranial bleeding events and acute myocardial infarction. Outcomes were defined using previously validated algorithms based on ICD-9 diagnosis codes. These algorithms have reported positive predictive values ranging from 86% to 97% (eTable 1 in the Supplement).25-35 Hospital records were not obtained to independently validate these outcomes. Major extracranial bleeding was defined as a fatal bleeding event, a hospitalized bleeding event requiring transfusion, or hospitalization with hemorrhage into an extracranial critical site (ie, intraspinal, intraarticular, intraocular, pericardial, retroperitoneal, or intramuscular with compartment syndrome).8,9 This definition differed from that in RE-LY and ROCKET-AF because we lacked data to document a decrease in hemoglobin concentration of at least 2 g/dL (to convert to grams per liter, multiply by 10.0) or the number of units transfused.36 Mortality was ascertained by linkage to Social Security files, which provide the date, but not cause, of death and capture more than 95% of deaths for persons 65 years or older in the United States.37 Our death outcome included deaths occurring as the first study outcome or within 30 days after hospitalization for another primary outcome event.
All analyses were based on IPTW-adjusted cohorts and therefore accounted for potential confounding by baseline factors. Weighted Kaplan-Meier cumulative incidence plots were generated to characterize risk over time. Weighted Cox proportional hazards regression with robust estimation was used to estimate time-to-event in rivaroxaban compared with dabigatran (reference) cohorts. Adjusted incidence rate differences were estimated using weighted event counts and follow-up time within cohorts. Statistical significance was determined using 95% confidence intervals (CIs) and 2-tailed P values (P ≤ .05). For all outcomes except mortality, the 30-day case fatality rate, defined as the number of deaths within 30 days of outcome occurrence divided by the total number of patients with that outcome, was determined.
Prespecified subgroup analyses were performed for all outcomes in categories defined by age, sex, hospitalization within the prior 30 days, concomitant use of antiplatelet agents, chronic kidney disease, and CHADS2 and HAS-BLED scores. In a secondary analysis, Cox models were generated to examine risk during predefined intervals of time during therapy because bleeding risks may be greatest during the first 3 months after anticoagulant initiation.29,38 We performed a number of sensitivity analyses. To assess whether the main analyses were affected by misclassification of exposed time, we restricted analysis to patients with at least 2 prescription fills of a study drug, and increased the gap allowance between anticoagulant prescriptions from 3 to 14 days. We repeated the main analysis using multivariable Cox regression, which included all covariates used in the weighted analysis. In post hoc sensitivity analyses, the CHA2DS2-VASc was substituted for the CHADS2 score39; we no longer censored for initiation of dialysis or kidney transplantation, or admission to a nursing home, skilled nursing facility, or hospice; and we adjusted for the competing risks of death using the subdistribution of hazards approach.40
Analyses were performed using R 3.2.0 (R Foundation for Statistical Computing, Vienna, Austria) and SAS v. 9.4 (SAS Institute Inc).
A total of 52 240 dabigatran and 66 651 rivaroxaban initiators contributed 15 524 and 20 199 person-years of on-treatment follow-up (mean [range] duration, 108 [0-969] and 111 [0-923] days), respectively. Before adjustment, there were minor differences in income status, geographic residence, emergency department visits in the prior 30 days, and prior use of injectable anticoagulants, antiplatelet agents, and digoxin. There were more substantial differences in prescriber specialty, with greater prescribing of rivaroxaban by cardiologists and less prescribing by family practitioners (Table 1 and eTable 2 in the Supplement). After IPTW adjustment, the cohorts were well balanced across all covariates.
During follow-up, there were 2537 primary outcome events including 306 thromboembolic strokes, 176 intracranial bleeding events, 1209 major extracranial bleeding events of which 1018 (84.2%) were gastrointestinal, and 846 deaths (724 as the first outcome and 122 within 30 days of another primary outcome event). Cumulative incidence plots showed early separation of event rates with continued divergence throughout follow-up for ICH, major gastrointestinal bleeding, and mortality, but convergence of event rates for thromboembolic stroke after day 240 (Figure 1). Quiz Ref IDRivaroxaban use was associated with a statistically nonsignificant decrease in thromboembolic stroke (hazard ratio [HR], 0.81; 95% CI, 0.65-1.01; P = .07); statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001); and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051) (Table 2). Results for the primary outcomes comparing the lower (renal) doses of rivaroxaban (15 mg once daily) vs dabigatran (75 mg twice daily) showed a similar pattern (eTable 3 in the Supplement). For secondary outcomes, there was a statistically significant increase in all hospitalized extracranial bleeding events with rivaroxaban and no difference in acute myocardial infarction risk between drugs. Adjusted incidence rate differences were 1.8 fewer cases of thromboembolic stroke, 2.3 excess cases of ICH, 13.0 excess cases of major extracranial bleeding including 9.4 excess cases of major gastrointestinal bleeding, and 3.1 excess deaths per 1000 person-years with rivaroxaban treatment. The rate differences for thromboembolic stroke and mortality were not statistically significant. Of note, the increased rate of ICH with rivaroxaban treatment exceeded its decreased rate of thromboembolic stroke. The 30-day case fatality rates were 9.2% (thromboembolic stroke), 31.8% (ICH), 3.1% (major extracranial bleeding), 3.3% (major gastrointestinal bleeding), 2.7% (all hospitalized extracranial bleeding), and 9.7% (acute myocardial infarction), with little difference between cohorts.
Hazard ratios were generally consistent among subgroups with a few exceptions (Figure 2). For major gastrointestinal bleeding, the increased risk with rivaroxaban treatment diminished with increasing age, and for mortality, rivaroxaban risk was significantly increased in patients aged 75 years and older and in those with a CHADS2 score greater than 2 (eTable 4 in the Supplement). The secondary analysis found no differences over time for any of the study outcomes except thromboembolic stroke, for which rivaroxaban risk may have been decreased during the first 90 days of use but not thereafter (HR, 0.71; 95% CI, 0.55-0.93 vs HR, 1.14; 95% CI, 0.74-1.75; P for interaction = .07) (eTable 5 in the Supplement). Sensitivity analyses yielded results similar to the main analysis (eTable 6 in the Supplement).
In a direct comparison of patients with nonvalvular AF treated with standard doses of dabigatran or rivaroxaban, the risks of ICH and major extracranial bleeding, including major gastrointestinal bleeding, were significantly increased in patients treated with rivaroxaban. Quiz Ref IDAlthough the risk of mortality was nonsignificantly increased with rivaroxaban across all age groups in the main analysis, it was significantly increased in patients aged 75 years or older or with CHADS2 greater than 2, compared with dabigatran treatment. These latter results must be interpreted cautiously given that we examined multiple subgroups. Also, the net increase in ICH, the outcome with the highest case fatality rate, exceeded the net reduction in thromboembolic stroke for rivaroxaban treatment. Of note, in 2014, rivaroxaban was used 2 to 3 times more often than dabigatran in US patients with AF,41 perhaps partly because of prescriber misperceptions about bleeding risks with dabigatran, arising from US Food and Drug Administration receipt of a large number of postmarketing case reports following its approval.42 Ironically, we found substantially higher bleeding risks with use of rivaroxaban than dabigatran. Our results are consistent with a recently published small study from Denmark that reported no difference in stroke risk but increased bleeding and mortality risks with rivaroxaban 20 mg once daily compared with dabigatran 150 mg twice daily in patients with AF.43
Our results differ from those based on indirect comparisons of clinical trials, which suggested that stroke risk might be higher with rivaroxaban use but with no difference in mortality or bleeding risks between the 2 NOACs.9,10 This highlights the importance of head-to-head studies when evaluating comparative effectiveness of competing therapies. Indirect comparisons can be unreliable.44 For example, rivaroxaban-treated patients in ROCKET-AF were older and had higher baseline CHADS2 scores than dabigatran-treated patients in RE-LY while time in therapeutic range for warfarin-treated patients in RE-LY was greater than in ROCKET-AF.9,10,44 These differences, and perhaps others not measured, could confound an indirect comparison. Whereas a randomized direct comparison between dabigatran and rivaroxaban would be optimal, such a study is unlikely to be undertaken by the manufacturer of either product.
Our findings suggest that standard-dose rivaroxaban produced a greater anticoagulant effect than standard-dose dabigatran. While plasma half-lives of dabigatran and rivaroxaban are each approximately 12 hours, dabigatran is dosed twice daily and rivaroxaban only once daily.5,6 Once-daily dosing of rivaroxaban would be expected to achieve higher peak and lower trough serum concentrations than twice-daily administration of the same total daily dose.45 Reduction of the once-daily dose or adoption of a twice-daily regimen might reduce the excess bleeding and subgroup mortality risks that we observed. However, effects of such dose adjustment on both thrombotic and bleeding events would need to be evaluated through clinical testing. It is also possible that our results arose because some patients taking dabigatran did so only once daily rather than twice daily, leading to dabigatran-treated patients being inadequately anticoagulated. We believe that this is unlikely for 2 reasons. In a previous study of patients with AF initiating warfarin or standard-dose dabigatran treatment, using the same Medicare database and outcome definitions as in this study, results similar to those of the RE-LY trial were obtained, suggesting that adherence to the twice-daily dabigatran regimen by Medicare beneficiaries was comparable to that of patients in RE-LY.38 Also, our sensitivity analysis restricted to patients filling 2 or more NOAC prescriptions yielded results similar to the primary analysis. This analysis included only dabigatran-treated patients who filled their second prescription by the date expected had they been taking it twice daily. Patients taking dabigatran once daily would not be expected to fill their second prescription by this date because they would still have a large remaining medication supply. Finally, the lower dose of dabigatran is recommended for patients with a creatinine clearance (CrCl) of 15 to 30 mL/min/1.73 m2, whereas for rivaroxaban, it is a broader range of 15 to 50 mL/min/1.73 m2 (to convert to milliliters per second per square meter, multiply by 0.0167).5,6 In our standard-dose analysis, we excluded patients treated with the lower dose. We cannot exclude the possibility that a higher proportion of rivaroxaban-treated patients with renal impairment were treated off-label with the standard dose because of the broader CrCl range guiding rivaroxaban dosing. If this occurred, a greater anticoagulant effect with rivaroxaban might be observed in our data. Medicare claims do not capture CrCl or other laboratory results so we cannot definitively evaluate this. With a broader CrCl range, we would expect a higher proportion of rivaroxaban than dabigatran users to be treated with the lower dose, which was present in our data, with 19.6% of dabigatran- and 26.8% of rivaroxaban-treated patients treated with the renal dose (eTable 7 in the Supplement).
This study had several limitations. Quiz Ref IDThe mean duration of on-treatment follow-up was less than 4 months, thereby reducing sample size at longer durations of use. Other studies of NOAC safety using other US databases have had mean follow-up shorter than 6 months, indicating a limited capacity to study longer-term risks.46-48 Despite this, we had a larger number of patients still receiving therapy at 6 or 8 months than the number who started NOAC therapy in these and other studies.43,46-49Quiz Ref ID This study was observational and may be subject to residual confounding by unmeasured factors. This could lead to biased estimates of risk. Also, our study was restricted to patients aged 65 years or older, the age group accounting for 80% of patients with AF. The comparative effects of dabigatran and rivaroxaban treatment could be different in younger populations. Finally, our study examined warfarin-naive first-time users of dabigatran or rivaroxaban for stroke prevention in AF. Results could differ in patients switching from warfarin to a NOAC.
In this large direct comparison of patients with AF treated with dabigatran or rivaroxaban, rivaroxaban use was associated with statistically significant increases in the risk of ICH and major extracranial bleeding, including major gastrointestinal bleeding, and possibly with increased mortality in older patients or those with higher baseline risk of stroke. The greater anticoagulant effect observed with rivaroxaban treatment may be due to the higher dose required for once-daily dosing. A contribution to this effect by off-label use of standard-dose rivaroxaban in patients with impaired renal function cannot be excluded.
Accepted for Publication: August 12, 2016.
Correction: This article was corrected on October 17, 2016, to fix mislabeled graph lines in Figure 1, panels B, C, and D.
Corresponding Author: David J. Graham, MD, MPH, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Bldg 22, Room 4314, Silver Spring, MD 20993-0002 (email@example.com).
Published Online: October 3, 2016. doi:10.1001/jamainternmed.2016.5954
Author Contributions: Dr MaCurdy had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Graham, Reichman, Wernecke, Hsueh, Izem, Southworth, Wei, Goulding, Mott, Chillarige, MaCurdy, Kelman.
Acquisition, analysis, or interpretation of data: Graham, Reichman, Wernecke, Hsueh, Izem, Southworth, Wei, Liao, Goulding, Chillarige, MaCurdy, Worrall, Kelman.
Drafting of the manuscript: Graham, Reichman, Hsueh, Wei, Liao, Mott, Kelman.
Critical revision of the manuscript for important intellectual content: Graham, Reichman, Wernecke, Izem, Southworth, Wei, Goulding, Chillarige, MaCurdy, Worrall, Kelman.
Statistical analysis: Reichman, Wernecke, Hsueh, Izem, Wei, Liao, Chillarige.
Administrative, technical, or material support: Reichman, Wernecke, Hsueh, Southworth, Worrall, Kelman.
Study supervision: Graham, Reichman, Wernecke, Izem, Goulding, MaCurdy, Kelman.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was performed as part of the SafeRx project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS) and the US Food and Drug Administration (FDA), and was funded through an interagency agreement.
Role of the Funder/Sponsor: The authors are employees or contractors of the CMS or the FDA; however, other officials at the CMS and the FDA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views expressed are the authors’ and not necessarily those of the FDA, the CMS, or the Department of Health and Human Services.
Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med
. 1994;154(13):1449-1457.PubMedGoogle ScholarCrossref
R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev
. 2005;(3):CD001927.PubMedGoogle Scholar
MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med
. 2007;146(12):857-867.PubMedGoogle ScholarCrossref
et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest
. 2004;126(6):1938-1945.PubMedGoogle ScholarCrossref
et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med
. 2009;361(12):1139-1151.PubMedGoogle ScholarCrossref
et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med
. 2011;365(10):883-891.PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
J. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes
. 2012;5(4):480-486.PubMedGoogle ScholarCrossref
et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA
. 2001;285(18):2370-2375.PubMedGoogle ScholarCrossref
PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. JAMA
. 1994;271(11):840-844.PubMedGoogle ScholarCrossref
MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA
. 2001;285(22):2864-2870.PubMedGoogle ScholarCrossref
R, de Vos
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.PubMedGoogle ScholarCrossref
JC. Propensity score techniques and the assessment of measured covariate balance to test causal associations in psychological research. Psychol Methods
. 2010;15(3):234-249.PubMedGoogle ScholarCrossref
D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health
. 2010;13(2):273-277.PubMedGoogle ScholarCrossref
B. Marginal structural models and causal inference in epidemiology. Epidemiology
. 2000;11(5):550-560.PubMedGoogle ScholarCrossref
PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res
. 2011;46(3):399-424.PubMedGoogle ScholarCrossref
et al. Reader’s guide to critical appraisal of cohort studies: 2. assessing potential for confounding. BMJ
. 2005;330(7497):960-962.PubMedGoogle ScholarCrossref
JJ. A diagnostic routine for the detection of consequential heterogeneity of causal effects. Sociol Methodol
. 2008;38:231-281.Google Scholar
MR. Validation of ICD-9 codes with a high positive predictive value for incident strokes resulting in hospitalization using Medicaid health data. Pharmacoepidemiol Drug Saf
. 2008;17(1):20-26.PubMedGoogle ScholarCrossref
MD. Coding of stroke and stroke risk factors using International Classification of Diseases, Revisions 9 and 10. Stroke
. 2005;36(8):1776-1781.PubMedGoogle ScholarCrossref
WA. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf
. 2011;20(6):560-566.PubMedGoogle ScholarCrossref
S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation
. 2007;115(21):2689-2696.PubMedGoogle ScholarCrossref
et al. Validation of claims-based diagnostic and procedure codes for cardiovascular and gastrointestinal serious adverse events in a commercially-insured population. Pharmacoepidemiol Drug Saf
. 2010;19(6):596-603.PubMedGoogle ScholarCrossref
J. Positive predictive value of the diagnosis of acute myocardial infarction in an administrative database. J Gen Intern Med
. 1999;14(9):555-558.PubMedGoogle ScholarCrossref
JA. Coding accuracy of hospital discharge data for elderly survivors of myocardial infarction. Can J Cardiol
. 1999;15(11):1277-1282.PubMedGoogle Scholar
JV. A multicenter study of the coding accuracy of hospital discharge administrative data for patients admitted to cardiac care units in Ontario. Am Heart J
. 2002;144(2):290-296.PubMedGoogle ScholarCrossref
DH. Accuracy of Medicare claims-based diagnosis of acute myocardial infarction: estimating positive predictive value on the basis of review of hospital records. Am Heart J
. 2004;148(1):99-104.PubMedGoogle ScholarCrossref
et al. An algorithm to identify incident myocardial infarction using Medicaid data. Pharmacoepidemiol Drug Saf
. 2009;18(11):1064-1071.PubMedGoogle ScholarCrossref
C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost
. 2005;3(4):692-694.PubMedGoogle ScholarCrossref
I. The Social Security Administration’s Death Master File: the completeness of death reporting at older ages. Soc Secur Bull
. 2001-2002;64(1):45-51.PubMedGoogle Scholar
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.PubMedGoogle ScholarCrossref
HJ; The Euro Heart Survey on Atrial Fibrillation. 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(2):263-272.PubMedGoogle ScholarCrossref
RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc
. 1999;94:496-509.Google ScholarCrossref
ZD. National trends in ambulatory oral anticoagulant use. Am J Med
. 2015;128(12):1300-5.e2.PubMedGoogle ScholarCrossref
EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med
. 2013;368(14):1272-1274.PubMedGoogle ScholarCrossref
GYH, Bjerregaard Larsen
T. Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care. Pharmacoepidemiol Drug Saf
. 2016.PubMedGoogle Scholar
S. Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study. BMJ
. 2015;350:h1585.PubMedGoogle ScholarCrossref
Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med
. 2015;175(1):18-24.PubMedGoogle ScholarCrossref
JJ. Prediction of rates of thromboembolic and major bleeding outcomes with dabigatran or warfarin among patients with atrial fibrillation: new initiator cohort study. BMJ
. 2016;353:i2607.PubMedGoogle ScholarCrossref
et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ
. 2015;350:h1857.PubMedGoogle ScholarCrossref