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Review

Comparative Effectiveness and Safety of Rivaroxaban in Adults With Nonvalvular Atrial Fibrillation

Aronow, Wilbert S. MD1; Shamliyan, Tatyana A. MD, MS2,*

Author Information
doi: 10.1097/MJT.0000000000000890

Abstract

BACKGROUND

Despite guideline recommendations, actual utilization of novel oral anticoagulants (NOACs) for stroke prevention in adults with nonvalvular atrial fibrillation remains low.1–6 Multiple reviews of a few pivotal randomized controlled trials (RCTs) comparing NOACs with warfarin did not address real-life experience or the direct comparative effectiveness and safety of apixaban, dabigatran, edoxaban, or raviroxaban.7–14 Clinicians' confidence in the quality of evidence and balance between benefits and harms of oral anticoagulants was lowered by the publications suggesting inaccurate data collection in studies of rivaroxaban.15–17

Rivaroxaban is a factor Xa inhibitor approved in 2011 based on a single multinational, double-blind RCT: “Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for the Prevention of Stroke and Embolism Trial in Atrial Fibrillation” (ROCKET AF) [NCT00403767].18 This RCT compared rivaroxaban at a dose of 20 mg/daily with warfarin in adults with nonvalvular atrial fibrillation and preserved renal function.19 The trial enrolled 14,269 adults with a history of previous stroke or transient ischemic attack (TIA) or ≥2 stroke risk factors including older age, arterial hypertension, heart failure, or diabetes.19 The trial was designed to demonstrate that rivaroxaban has more than 50% of warfarin's effectiveness on a composite outcome of stroke and non–central nervous system (CNS) systemic embolism.19 The most recent reviews of published RCTs compared major outcomes, including stroke prevention and the risk of major bleeding after rivaroxaban in adults with nonvalvular atrial fibrillation, but did not include unpublished data or large nationally representative observational studies and did not address the comparative effectiveness and safety of rivaroxaban in patient subpopulations.14,20,21 We aimed at consistent appraisal of the quality of evidence regarding the comparative effectiveness and safety of rivaroxaban, warfarin, apixaban, dabigatran, and edoxaban based on all available studies, regardless of publication status or study design.

METHODS

We conducted a rapid systematic literature review following a priori developed protocol (CRD42014007013).22 We appraised the evidence from primary RCTs, observational studies, published systematic reviews, and network meta-analyses.23–25 We appraised the quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our objective was to test null hypotheses of no differences in patient outcomes after rivaroxaban versus warfarin, apixaban, dabigatran, or edoxaban in adults with nonvalvular atrial fibrillation.26

We refined the clinical questions about the comparative effectiveness and safety of the oral anticoagulant rivaroxaban compared with warfarin or other anticoagulants and non–vitamin K antagonists in preventing stroke in adults with nonvalvular atrial fibrillation. Eligible interventions included licensed doses of rivaroxaban (20 mg), apixaban (5 mg), dabigatran (150–300 mg), and edoxaban (60 mg). We analyzed the role of patient demographics, residency, baseline renal function, history of stroke or TIA, comorbidities, and concurrent and concomitant medications, if reported in the studies. Eligible outcomes included stroke, all-cause and cardiovascular mortality and morbidity, quality of life, bleeding events, and all other adverse effects.

We conducted a comprehensive search in PubMed, EMBASE, the Cochrane Library, PharmaPendium, the World Health Organization's VigiBase, and the clinicaltrials.gov trial registry up to October 2018 to find systematic reviews and meta-analyses, published and unpublished RCTs, and large controlled observational studies with adjusted effect estimates. We excluded uncontrolled studies and studies that examined rivaroxaban in patients undergoing surgery for various conditions.

The data were extracted from the Clinical Trials Transformation Initiative (https://www.ctti-clinicaltrials.org/aact-database), checked for quality, and stored in the High-Performance Computing Cluster platform (https://hpccsystems.com/). We abstracted the information about study population, interventions, comparators, and outcomes. We abstracted minimum data sets (eg, hazard ratios in log scale, number of subjects in treatment groups, and number of patients experiencing outcomes) to estimate absolute risk difference, relative risk (RR), and number needed to treat for categorical variables. Statistical significance was evaluated at a 95% confidence level. All authors have access to the data.

We performed meta-analyses when definitions of active and control interventions and patient outcomes were deemed similar.27 We used random effects meta-analyses to address inevitable differences across the primary studies. We examined consistency in results across studies with chi-square tests and I2 statistics and concluded statistically significant heterogeneity if I2 was greater than 50%.26 Statistically significant heterogeneity did not preclude statistical pooling but was explored using available study and patient characteristics.27

We defined harms as the totality of all possible adverse consequences, regardless of how investigators related them to treatments.

We calculated treatment effect estimates using STATA software (StataCorp LP, College Station, TX).28 Correction coefficients for zero events were used as a default option, and intention to treat was used for evidence synthesis.27 Superiority of interventions under comparison was hypothesized.29

We used consensus method guidelines for systematic review and meta-analyses that do not recommend conducting post hoc analyses of statistical power.30–32 Instead, we downgraded our confidence in true treatment effects based on calculated optimal information size as the number of patients required for an adequately powered individual trial.33 Because power is more closely related to the number of events than to sample size, we concluded imprecision in treatment effects if fewer than 250 patients experienced the event.33 Treatment effect estimates were defined as precise when pooled estimates had reasonably narrow 95% confidence intervals and the number of events was greater than 250.34 Justification of the sample size was not included in grading of the evidence.

We assessed reporting bias as a proportion of unpublished among all registered studies, unreported outcomes compared with published protocols, or unreported minimum data sets to ensure reproducibility of the results.35 We did not conduct formal statistical tests for publication bias because of the questionable validity of such tests.36

We evaluated the risk of bias in RCTs using the Cochrane risk-of-bias tool on a 3-point scale: high bias, low bias, and unclear.26 We upgraded the risk of bias in the body of evidence from low to high if at least 1 RCT had a high risk of bias.37,38 We defined indirectness in comparisons between rivaroxaban and other medications when head-to-head randomized trials were not available.39

In assessing the quality of evidence in all studies, the authors looked for the strength of association and evidence of any reporting bias.40 The strength of the association was evaluated, defining a priori a large effect when the RR was greater than 2 and a very large effect when the RR was greater than 5.40 A small treatment effect was found when the RR was significant but less than 2.40

The authors assigned the quality of evidence ratings as high, moderate, low, or very low, according to risk of bias in the body of evidence, directness of comparisons, precision and consistency in treatment effects, and the evidence of reporting bias, using GRADE methodology.40 A high quality of evidence was assigned to well-designed RCTs with consistent findings. The quality of evidence was downgraded to moderate if at least 1 of 4 quality of evidence criteria were not met; for example, moderate quality of evidence was assigned if there was a high risk of bias in the body of evidence or if the results were not consistent or precise.40 The quality of evidence was downgraded to low if 2 or more criteria were not met.

A low quality of evidence was assigned to nonrandomized studies and upgraded for the rating if there was a strong association. Evidence was defined as insufficient when no studies provided valid information about treatment effects. This approach was applied regardless of whether the results were statistically significant.

RESULTS

Our comprehensive search in PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov identified published and unpublished data from 2 head-to-head RCTs (15,549 patients) included in multiple reviews, 30 large observational studies with multivariate adjustment, and multiple case reports after rivaroxaban administration in adults with nonvalvular atrial fibrillation.7,9–12,14,20,21,41–71,72–101,102–136 We excluded 180 references after screening the abstracts and 45 references at full-text review, mostly because of the ineligible target population or nonsystematic nature of the reviews.137–160,161–181

Low-quality direct evidence suggests that rivaroxaban and warfarin have comparable effectiveness for stroke prevention, and rivaroxaban reduces the risk of hemorrhagic stroke, fatal bleeding, and cardiac arrest at the expense of increased risk of major gastrointestinal bleeding (Table 1). The differences in absolute risk of stroke and bleeding are small, with large numbers needed to treat to avoid an outcome in 1 patient (Table 1). The risk of bleeding is dose responsive, with a 16% relative increase in the risk of major bleeding after the larger versus the lower dose of the drug (HR 1.16, 95% confidence interval, 0.82–1.63).124 Rivaroxaban increases the risk of bleeding within the first week of treatment, with no differences after that in both warfarin-naive and warfarin-experienced patients (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/AJT/A54).

Table 1-a
Table 1-a:
Rivaroxaban versus warfarin for stroke prevention in adults with nonvalvular atrial fibrillation.
Table 1-b
Table 1-b:
Rivaroxaban versus warfarin for stroke prevention in adults with nonvalvular atrial fibrillation.
Table 1-c
Table 1-c:
Rivaroxaban versus warfarin for stroke prevention in adults with nonvalvular atrial fibrillation.

Multiple subgroup analyses of RCTs suggest that age, sex, baseline body mass index, and renal function do not modify the effect of rivaroxaban when compared with warfarin for stroke prevention in adults with nonvalvular atrial fibrillation (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/AJT/A54). The comparative effectiveness and safety of rivaroxaban and warfarin are the same, regardless of baseline hypertension, heart failure, diabetes, peripheral arterial disease, carotid artery disease, type of atrial fibrillation, history of myocardial infarction, chronic obstructive pulmonary disease, implantable cardioverter defibrillator, or biventricular-implantable cardioverter defibrillator.41–44,55 Rivaroxaban when compared with warfarin increases the risk of bleeding in the residents of North America, with no differences in the rest of the world (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/AJT/A54). Rivaroxaban is superior to warfarin in reducing the risk of intracranial hemorrhage in East Asian patients, with no differences in the rest of the world (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/AJT/A54). In patients with higher risk of bleeding, warfarin is superior to rivaroxaban, resulting in lower risk of major or clinically relevant nonmajor bleeding (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/AJT/A54). The risk of stroke, fatal stroke, fatal bleeding, and intracerebral hemorrhage is lower after rivaroxaban than after warfarin in patients without previous stroke or TIA (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/AJT/A54). The risk of major bleeding, intracranial hemorrhage, or fatal bleeding is lower after rivaroxaban than after warfarin in patients taking fewer than 5 concurrent medications (see Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/AJT/A54). Concurrent digoxin and nondihydropyridine calcium channel blockers are associated with an increased risk of mortality and bleeding but do not modify the comparative effectiveness and safety of rivaroxaban when compared with warfarin.46,61 Concurrent antiplatelet agents increase the risk of gastrointestinal bleeding in people taking either warfarin or rivaroxaban.95

Large European studies suggest a higher risk of all-cause mortality associated with rivaroxaban when compared with warfarin (Table 2). In contrast, a large Asian study and the recent analysis of Medicare beneficiaries suggests that rivaroxaban is associated with a lower risk of death when compared with warfarin in adults with nonvalvular atrial fibrillation and in older adults with high baseline comorbidity score (Table 2). Large observational studies also provide low-quality evidence that rivaroxaban is associated with a lower risk of ischemic stroke or systemic embolism, intracranial hemorrhage, acute myocardial infarction, acute kidney injury, and drug discontinuation at the expense of a higher risk of gastrointestinal bleeding and hematuria (Table 2). The most recent analysis of Medicare beneficiaries suggests that there are no differences in the risk of ischemic stroke and major bleeding between rivaroxaban and warfarin regardless of baseline comorbidity score (Table 2). At the same time, this study confirms the higher risk of gastrointestinal bleeding associated with rivaroxaban versus warfarin regardless of baseline comorbidity score (Table 2).

Table 2-a
Table 2-a:
Rivaroxaban versus warfarin for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from observational studies.
Table 2-b
Table 2-b:
Rivaroxaban versus warfarin for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from observational studies.

No trials directly compared rivaroxaban with edoxaban, apixaban, or dabigatran. Therefore, we included indirect evidence from network meta-analyses of pivotal phase III RCTs, comparing the adjusted dose of warfarin with licensed doses of rivaroxaban, edoxaban, apixaban, or dabigatran.10,14,53,68,70,99,100,105,128,160,182–187

When compared with apixaban, indirect evidence from RCTs suggests that there are no differences in mortality or stroke between rivaroxaban and apixaban in adults with nonvalvular atrial fibrillation (Table 3). However, rivaroxaban increases the risk of bleeding when compared with apixaban (Table 3). Direct evidence from large observational studies suggests that rivaroxaban is associated with a higher risk of bleeding and treatment discontinuation because of adverse effects when compared with apixaban, with no differences in stroke outcomes (Table 4).

Table 3-a
Table 3-a:
Rivaroxaban vs. non–vitamin K oral anticoagulants for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from indirect comparisons in network meta-analyses of RCTs.
Table 3-b
Table 3-b:
Rivaroxaban vs. non–vitamin K oral anticoagulants for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from indirect comparisons in network meta-analyses of RCTs.
Table 3-c
Table 3-c:
Rivaroxaban vs. non–vitamin K oral anticoagulants for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from indirect comparisons in network meta-analyses of RCTs.
Table 3-d
Table 3-d:
Rivaroxaban vs. non–vitamin K oral anticoagulants for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from indirect comparisons in network meta-analyses of RCTs.
Table 4-a
Table 4-a:
Rivaroxaban vs. non–vitamin K antagonists apixaban, dabigatran, and edoxaban for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from large observational studies, direct comparison.
Table 4-b
Table 4-b:
Rivaroxaban vs. non–vitamin K antagonists apixaban, dabigatran, and edoxaban for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from large observational studies, direct comparison.
Table 4-c
Table 4-c:
Rivaroxaban vs. non–vitamin K antagonists apixaban, dabigatran, and edoxaban for stroke prevention in adults with nonvalvular atrial fibrillation; low-quality evidence from large observational studies, direct comparison.

When compared with dabigatran, indirect evidence from RCTs suggests that rivaroxaban increases the risk of stroke or systemic embolism, hemorrhagic stroke, intracranial hemorrhage, and any bleeding, but reduces the risk of treatment discontinuation when compared with dabigatran (Table 3). Direct evidence from large observational studies suggests that rivaroxaban is associated with a higher risk of all-cause mortality and bleeding events when compared with dabigatran, with no consistent differences in stroke outcomes (Table 4). Rivaroxaban is associated with higher risk of major bleeding compared with dabigatran regardless of baseline comorbidity score (Table 4).

When compared with edoxaban, indirect evidence from RCTs suggests that there are no differences in mortality or stroke between rivaroxaban and edoxaban in adults with nonvalvular atrial fibrillation (Table 3). However, rivaroxaban increases the risk of bleeding when compared with edoxaban (Table 3). We found no observational studies that directly compared outcomes in association with rivaroxaban versus edoxaban.

Recent postmarketing analyses suggest an increased risk of severe liver injury, bleeding, and specifically gastrointestinal hemorrhage in patients taking rivaroxaban among other medications (see Appendix Table 2, Supplemental Digital Content 2, http://links.lww.com/AJT/A55).115,134,188 Postmarketing surveillance suggests multiple cases of bleeding adverse events associated with oral non–vitamin K antagonists in adults taking these drugs among other multiple medications (see Appendix Table 2, Supplemental Digital Content 2, http://links.lww.com/AJT/A55). The absolute number of rivaroxaban-associated case reports may differ because of different utilization of oral non–vitamin K antagonists (see Appendix Table 2, Supplemental Digital Content 2, http://links.lww.com/AJT/A55).

No reliable monitoring for edoxaban, apixaban, rivaroxaban, or dabigatran is available.189 Andexanet alfa has been approved as an antidote to the factor Xa inhibitors,190–192 and idarucizumab has been approved as an antidote to dabigatran.193–196

DISCUSSION

We found direct evidence that rivaroxaban and warfarin have comparable effectiveness for stroke prevention, and rivaroxaban reduces the risk of hemorrhagic stroke, fatal bleeding, and cardiac arrest at the expense of an increased risk of major gastrointestinal bleeding in a dose-response manner. The balance between benefits and harms favors rivaroxaban in Asian patients and patients without previous history of stroke or TIA and favors warfarin in patients with a higher baseline risk of bleeding. Evidence from observational studies suggests that rivaroxaban is associated with higher risk of all-cause mortality and severe liver injury, which requires further investigation. Direct comparative evidence from observational studies suggests that rivaroxaban is associated with higher risk of bleeding when compared with apixaban, dabigatran, or edoxaban.

We downgraded the quality of evidence because of high risk of bias, imprecision of the effect estimates, indirectness in statistical comparisons, and heterogeneity in treatment effects, specifically in observational studies. Exact definitions of bleeding events and measures of coagulation differ across the studies.197 Indirect comparisons were made based on a very few pivotal RCTs.97–99,107,108,110,111,113,114,198–200 The evidence regarding comparative benefits and harms of rivaroxaban in patients with severe renal impairment is insufficient.4 Dosing recommendations in these patients are based on pharmacologic models rather than well-designed clinical studies.18,201–203

Available guidelines recommend US Food and Drug Administration–approved NOACs including rivaroxaban, apixaban, and dabigatran in patients who cannot take warfarin or do not adhere to coagulation monitoring under warfarin treatment.3,4,197,204–207 Guidelines do not recommend specific NOACs but highlight the importance of patient engagement and adherence and individualized treatment choice based on drug cost and the assessment of baseline risk for outcomes in each patient.208–211

Our review has clinical implications. Baseline risk of stroke and bleeding should be assessed using validated scales, including HAS-BLED, CHA2DS2-VASc, and multimarker risk score and documented in all adults with nonvalvular atrial fibrillation.212–215 Baseline risk of warfarin-induced bleeding based on genetic variants in the CYP2C9 and VKORC1 genes should be examined to predict the balance between benefits and harms after warfarin versus NOACs.216

Our review has research implications. Coagulation measurements and bleeding definitions should be standardized in future RCTs and when collecting real-life evidence in clinical settings.217,218 Well-conducted individual patient data analyses from electronic health records and national registries should provide valid evidence regarding the long-term effectiveness and safety of oral anticoagulants in patient subpopulations with various demographics, genotype, baseline risk of stroke and bleeding, comorbidities, and concomitant treatments. Future research should shed light on the quality of life in patients treated with rivaroxaban versus other NOACs.

Our review has policy implications that aimed at better patient safety and evidence-based decisions regarding the cost-effectiveness of available treatments. In contrast with passive collection of case reports, proactive multinational standardized pharmacovigilance for all adverse effects of NOACs should be implemented and available for decision making.219,220 Patients should have complete and accurate information about all harms associated with NOACs to ensure optimal drug choice and patient safety.60,61,221

Our review has several limitations. We do not know how many unregistered and unpublished studies have been conducted. Available information did not allow valid explanation of the heterogeneity in treatment effects in observational studies. Different study designs, length, adjustment methods, and various definitions of clinical events made comparisons difficult. Off-label use of the drugs and drug errors resulting in serious harms were beyond our scope.222 The lack of patient-level data presented additional challenges in assessing comparative benefits and harms of NOACs.223 Instead of reproducing published analyses, we explored consistency in indirect treatment estimates from available network meta-analyses. We addressed these limitations in the ranking of the evidence with GRADE criteria.

We concluded that to reduce the risk of stroke or embolic events in patients with nonvalvular atrial fibrillation, clinicians may recommend rivaroxaban in patients who cannot take warfarin or do not adhere to coagulation monitoring under warfarin treatment. The higher risk of all-cause mortality, bleeding, and liver injury requires urgent investigation.

REFERENCES

1. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719–2747.
2. Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:2064–2089.
3. Culebras A, Messe SR, Chaturvedi S, et al. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82:716–724.
4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071–2104.
5. Marzec LN, Wang J, Shah ND, et al. Influence of direct oral anticoagulants on rates of oral anticoagulation for atrial fibrillation. J Am Coll Cardiol. 2017;69:2475–2484.
6. Barnes GD, Lucas E, Alexander GC, et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:1300–1305 e1302.
7. Caldeira D, Barra M, Ferreira A, et al. Systematic review with meta-analysis: the risk of major gastrointestinal bleeding with non-vitamin K antagonist oral anticoagulants. Aliment Pharmacol Ther. 2015;42:1239–1249.
8. Caldeira D, Barra M, Pinto FJ, et al. Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis. J Neurol. 2015;262:516–522.
9. Chai-Adisaksopha C, Hillis C, Isayama T, et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015;13:2012–2020.
10. Cope S, Clemens A, Hammes F, et al. Critical appraisal of network meta-analyses evaluating the efficacy and safety of new oral anticoagulants in atrial fibrillation stroke prevention trials. Value Health. 2015;18:234–249.
11. Sardar P, Chatterjee S, Lavie CJ, et al. Risk of major bleeding in different indications for new oral anticoagulants: insights from a meta-analysis of approved dosages from 50 randomized trials. Int J Cardiol. 2015;179:279–287.
12. Tornyos A, Kehl D, D'Ascenzo F, et al. Risk of myocardial infarction in patients with long-term non-vitamin K antagonist oral anticoagulant treatment. Prog Cardiovasc Dis. 2015;58:483–494.
13. Xiong Q, Lau YC, Senoo K, et al. Non-vitamin K antagonist oral anticoagulants (NOACs) in patients with concomitant atrial fibrillation and heart failure: a systemic review and meta-analysis of randomized trials. Eur J Heart Fail. 2015;17:1192–1200.
14. Lip GY, Mitchell SA, Liu X, et al. Relative efficacy and safety of non-Vitamin K oral anticoagulants for non-valvular atrial fibrillation: network meta-analysis comparing apixaban, dabigatran, rivaroxaban and edoxaban in three patient subgroups. Int J Cardiol. 2016;204:88–94.
15. Cohen D. Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ. 2016;354:i5131.
16. Cohen D. Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device. BMJ. 2015;351:h6431.
17. Baruch L, Sherman O. Inaccuracy of point-of-care international normalized ratio in rivaroxaban-treated patients. Ann Pharmacother. 2013;47:1210–1212.
18. FDA Cardiovascular and Renal Drugs Advisory Committee. XARELTO® (rivaroxaban) Tablets. Indication for Use: Prevention Of Stroke and Systemic Embolism in Patients With Non-valvular Atrial Fibrillation. 2011; Title of Study: The ROCKET AF Trial (Rivaroxaban) Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.
19. Investigators RAS. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340–347.e341.
20. López-López JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058.
21. Guo L, Li S, Wang P, et al. Comparative efficacy of clinical events prevention of five anticoagulants in patients with atrial fibrillation: a network meta-analysis. Am J Cardiol. 2017;119:585–593.
22. Hartling L, Guise JM, Kato E, et al. EPC Methods: an Exploration of Methods and Context for the Production of Rapid Reviews. Rockville, MD: AHRQ Comparative Effectiveness Reviews; 2015.
23. Robinson KA, Chou R, Berkman ND, et al. Integrating bodies of evidence: existing systematic reviews and primary studies. In: Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
24. Robinson KA, Chou R, Berkman ND, et al. Twelve recommendations for integrating existing systematic reviews into new reviews: EPC guidance. J Clin Epidemiol. 2016;70:38–44.
25. Lunny C, Brennan SE, McDonald S, et al. Toward a comprehensive evidence map of overview of systematic review methods: paper 1—purpose, eligibility, search and data extraction. Syst Rev. 2017;6:231.
26. Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. London, United Kingdom: The Cochrane Collaboration; 2011. Cochrane Book Series.
27. Fu R, Gartlehner G, Grant M, et al. Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program. J Clin Epidemiol. 2011;64:1187–1197.
28. Palmer TM; SJAC. Meta-Analysis in Stata. 2nd ed. Stata Press; 2016. Available at: https://www.stata.com/bookstore/meta-analysis-in-stata/. Accessed November 11, 2018.
29. Treadwell JR, Uhl S, Tipton K, et al. Assessing equivalence and noninferiority. J Clin Epidemiol. 2012;65:1144–1149.
30. Yuan KH, Maxwell S. On the post hoc power in testing mean differences. J Educ Behav Stat. 2005;30:141–167.
31. Goodman SN, Berlin JA. The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results. Ann Intern Med. 1994;121:200–206.
32. Levine M, Ensom MH. Post hoc power analysis: an idea whose time has passed? Pharmacotherapy. 2001;21:405–409.
33. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines 6: rating the quality of evidence—imprecision. J Clin Epidemiol. 2011;64:1283–1293.
34. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol. 2013;66:719–725.
35. Balshem HSA, Ansari M, Norris S, et al. Finding grey literature evidence and assessing for outcome and analysis reporting biases when comparing medical interventions: AHRQ and the effective health care program. In: AHRQ and the Effective Health Care Program Methods Guide for Comparative Effectiveness Reviews. 2013; Prepared by the Oregon Health and Science University and the University of Ottawa Evidence-based Practice Centers under Contract Nos. 290-2007-10057-I and 290-2007-10059-I. (AHRQ Publication No. 13(14)-EHC096-EF): Rockville, MD: Agency for Healthcare Research and Quality; November 2013. http://www.effectivehealthcare.ahrq.gov/reports/final.cfm.
36. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.
37. Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol. 2011;64:407–415.
38. Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. Rating the quality of evidence—publication bias. J Clin Epidemiol. 2011;64:1277–1282.
39. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 8. Rating the quality of evidence—indirectness. J Clin Epidemiol. 2011;64:1303–1310.
40. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. Available at: http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html#h.fueh5iz0cor4.
41. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013;61:1998–2006.
42. van Diepen S, Hellkamp AS, Patel MR, et al. Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrillation: insights from ROCKET AF. Circ Heart Fail. 2013;6:740–747.
43. Goodman SG, Wojdyla DM, Piccini JP, et al. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2014;63:891–900.
44. Kochar A, Hellkamp AS, Lokhnygina Y, et al. Efficacy and safety of rivaroxaban compared with warfarin in patients with carotid artery disease and nonvalvular atrial fibrillation: insights from the ROCKET AF trial. Clin Cardiol. 2018;41:39–45.
45. Balla SR, Cyr DD, Lokhnygina Y, et al. Relation of risk of stroke in patients with atrial fibrillation to body mass index (from patients treated with rivaroxaban and warfarin 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 trial). Am J Cardiol. 2017;119:1989–1996.
46. Washam JB, Hellkamp AS, Lokhnygina Y, et al. Efficacy and safety of rivaroxaban versus warfarin in patients taking nondihydropyridine calcium channel blockers for atrial fibrillation (from the ROCKET AF trial). Am J Cardiol. 2017;120:588–594.
47. Sun Y, Hu D, Stevens S, et al. Efficacy and safety of rivaroxaban versus warfarin in patients from mainland China with nonvalvular atrial fibrillation: a subgroup analysis from the ROCKET AF trial. Thromb Res. 2017;156:184–190.
48. Leef GC, Hellkamp AS, Patel MR, et al. Safety and efficacy of rivaroxaban in patients with cardiac implantable electronic devices: observations from the ROCKET AF trial. J Am Heart Assoc. 2017;6.
49. Chen ST, Hellkamp AS, Becker RC, et al. Outcome of patients receiving thrombolytic therapy while on rivaroxaban for nonvalvular atrial fibrillation (from rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). Am J Cardiol. 2017;120:1837–1840.
50. Pokorney SD, Piccini JP, Stevens SR, et al. Cause of death and predictors of all-cause mortality in anticoagulated patients with nonvalvular atrial fibrillation: data from ROCKET AF. J Am Heart Assoc. 2016;5:e002197.
51. Piccini JP, Hellkamp AS, Washam JB, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation. 2016;133:352–360.
52. Fordyce CB, Hellkamp AS, Lokhnygina Y, et al. On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF. Circulation. 2016;134:37–47.
53. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.
54. Halperin JL, Hankey GJ, Wojdyla DM, 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;130:138–146.
55. Jones WS, Hellkamp AS, Halperin J, et al. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF. Eur Heart J. 2014;35:242–249.
56. Piccini JP, Garg J, Patel MR, et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014;35:1873–1880.
57. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from ROCKET AF. Circulation. 2014;129:1850–1859.
58. Mahaffey KW, Wojdyla D, Hankey GJ, et al. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013;158:861–868.
59. Bansilal S, Bloomgarden Z, Halperin JL, et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: 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 trial). Am Heart J. 2015;170:675–682.e678.
60. Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF trial. J Am Coll Cardiol. 2015;66:2271–2281.
61. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of 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). Lancet. 2015;385:2363–2370.
62. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32:2387–2394.
63. DeVore AD, Hellkamp AS, Becker RC, et al. Hospitalizations in patients with atrial fibrillation: an analysis from ROCKET AF. Europace. 2016;18:1135–1142.
64. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (rivaroxaban once-daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2013;61:651–658.
65. Wong KS, Hu DY, Oomman A, et al. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke. 2014;45:1739–1747.
66. Hori M, Matsumoto M, Tanahashi N, et al. Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation—subanalysis of J-ROCKET AF for patients with moderate renal impairment. Circ J. 2013;77:632–638.
67. Uchiyama S, Hori M, Matsumoto M, et al. Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup Analysis of J-ROCKET AF. J Stroke Cerebrovasc Dis. 2014;23:1142–1147.
68. Tanahashi N, Hori M, Matsumoto M, et al. Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation for the secondary prevention of stroke: a subgroup analysis of J-ROCKET AF. J Stroke Cerebrovasc Dis. 2013;22:1317–1325.
69. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation in relation to the CHADS2 score: a subgroup analysis of the J-ROCKET AF trial. J Stroke Cerebrovasc Dis. 2014;23:379–383.
70. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation—the J-ROCKET AF study. Circ J. 2012;76:2104–2111.
71. Matsumoto M, Hori M, Tanahashi N, et al. Rivaroxaban versus warfarin in Japanese patients with non-valvular atrial fibrillation in relation to hypertension: a subgroup analysis of the J-ROCKET AF trial. Hypertens Res. 2014;37:457–462.
72. Hori M, Matsumoto M, Tanahashi N, et al. Predictive factors for bleeding during treatment with rivaroxaban and warfarin in Japanese patients with atrial fibrillation—subgroup analysis of J-ROCKET AF. J Cardiol. 2016;68:523–528.
73. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age. Circ J. 2014;78:1349–1356.
74. Efficacy and Safety of Rivaroxaban for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation. 2010. Available at: https://clinicaltrials.gov/ct2/show/NCT00494871. Accessed November 11 2018.
75. An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation. 2010. Available at: https://clinicaltrials.gov/ct2/show/NCT00403767, Accessed November 11, 2018.
76. Hankey GJ, Patel MR, Stevens SR, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11:315–322.
77. Lee HF, Chan YH, Tu HT, et al. The effectiveness and safety of low-dose rivaroxaban in Asians with non-valvular atrial fibrillation. Int J Cardiol. 2018;261:78–83.
78. Larsen TB, Skjoth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 2016;353:i3189.
79. Lee CJY, Gerds TA, Carlson N, et al. Risk of myocardial infarction in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2018;72:17–26.
80. Hernandez I, Zhang Y, Saba S. Comparison of the effectiveness and safety of apixaban, dabigatran, rivaroxaban, and warfarin in newly diagnosed atrial fibrillation. Am J Cardiol. 2017;120:1813–1819.
81. Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ. 2015;350:h1857.
82. Chang HY, Zhou M, Tang W, et al. Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study. BMJ. 2015;350:h1585.
83. Laliberte F, Cloutier M, Nelson WW, et al. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2014;30:1317–1325.
84. Weir MR, Haskell L, Berger JS, et al. Evaluation of clinical outcomes among nonvalvular atrial fibrillation patients treated with rivaroxaban or warfarin, stratified by renal function. Clin Nephrol. 2018;89:314–329.
85. Maura G, Blotiere PO, Bouillon K, et al. Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study. Circulation. 2015;132:1252–1260.
86. Lip GY, Keshishian A, Kamble S, et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin: a propensity score matched analysis. Thromb Haemost. 2016;116:975–986.
87. Yao X, Abraham NS, Sangaralingham LR, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016;5:e003725.
88. Gorst-Rasmussen A, Lip GY, Bjerregaard Larsen T. Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care. Pharmacoepidemiol Drug Saf. 2016;25:1236–1244.
89. Lip GYH, Pan X, Kamble S, et al. Discontinuation risk comparison among “real-world” newly anticoagulated atrial fibrillation patients: apixaban, warfarin, dabigatran, or rivaroxaban. PLoS One. 2018;13:e0195950.
90. Laliberte F, Cloutier M, Crivera C, et al. Effects of rivaroxaban versus warfarin on hospitalization days and other health care resource utilization in patients with nonvalvular atrial fibrillation: an observational study from a cohort of matched users. Clin Ther. 2015;37:554–562.
91. Lip GY, Pan X, Kamble S, et al. Major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin: a “real-world” observational study in the United States. Int J Clin Pract. 2016;70:752–763.
92. Vinogradova Y, Coupland C, Hill T, et al. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ. 2018;362:k2505.
93. Wasserlauf G, Grandi SM, Filion KB, et al. Safety of rivaroxaban versus vitamin K antagonists: a systematic review and meta-analysis. Circulation. 2018;126:A16558.
94. Tahir F, Riaz H, Riaz T, et al. The new oral anti-coagulants and the phase 3 clinical trials—a systematic review of the literature. Thromb J. 2013;11:18.
95. Sobieraj DM, White CM, Alikhanov S, et al. The impact of antiplatelet and anticoagulant therapies on gastrointestinal symptoms in patients with atrial fibrillation: a systematic review. Ann Pharmacother. 2012;46:1220–1231.
96. Simpson EL, Stevenson MD, Scope A, et al. Echocardiography in newly diagnosed atrial fibrillation patients: a systematic review and economic evaluation. Health Tech Assess. 2013;17:1–263.
97. Schneeweiss S, Gagne JJ, Patrick AR, et al. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2012;5:480–486.
98. Mitchell SA, Simon TA, Raza S, et al. The efficacy and safety of oral anticoagulants in warfarin-suitable patients with nonvalvular atrial fibrillation: systematic review and meta-analysis. Clin Appl Thromb Hemost. 2013;19:619–631.
99. Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110:453–460.
100. Mantha S, Ansell J. An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost. 2012;108:476–484.
101. Liu T, Korantzopoulos P, Li L, et al. Survival benefit of new anticoagulants compared with warfarin in patients with atrial fibrillation: a meta-analysis. Int J Cardiol. 2012;156:96–97.
102. Limone BL, Baker WL, Kluger J, et al. Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models. PLoS One. 2013;8:e62183.
103. Lane DA, Raichand S, Moore D, et al. Combined anticoagulation and antiplatelet therapy for high-risk patients with atrial fibrillation: a systematic review. Health Technol Assess. 2013;17:1–188.
104. Holster IL, Valkhoff VE, Kuipers EJ, et al. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology. 2013;145:105–112.e115.
105. Harenberg J, Marx S, Diener HC, et al. Comparison of efficacy and safety of dabigatran, rivaroxaban and apixaban in patients with atrial fibrillation using network meta-analysis. Int Angiol. 2012;31:330–339.
106. Gomez-Outes A, Terleira-Fernandez A, Suarez-Gea ML, et al. New oral anticoagulants versus warfarin on primary and secondary prevention of stroke in patients with atrial fibrillation: a metaanalysis. Basic Clin Pharmacol Toxicol. 2012;111:32.
107. Dogliotti A, Paolasso E, Giugliano RP. Current and new oral antithrombotics in non-valvular atrial fibrillation: a network meta-analysis of 79,808 patients. Heart. 2013;100:396.
108. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation. 2012;126:2381–2391.
109. Chatterjee S, Sardar P, Biondi-Zoccai G, et al. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol. 2013;70:1486–1490.
110. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev. 2013;8:Cd008980.
111. Biondi-Zoccai G, Malavasi V, D'Ascenzo F, et al Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. HSR Proc Intensive Care Cardiovasc Anesth. 2013;5:40–54.
112. Biondi Zoccai G, Marietta M, Malavasi V, et al. Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin controlled network meta analyses. Blood Transfus. 2012;10:s61.
113. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2012;5:711–719.
114. Assiri A, Al-Majzoub O, Kanaan AO, et al. Mixed treatment comparison meta-analysis of aspirin, warfarin, and new anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation. Clin Ther. 2013;35:967–984.e962.
115. Russmann S, Niedrig DF, Budmiger M, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol. 2014;61:293–300.
116. Yao X, Abraham NS, Alexander GC, et al. Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with atrial fibrillation. J Am Heart Assoc. 2016;5:e003074.
117. Uyhazi KE, Miano T, Pan W, et al. Association of novel oral antithrombotics with the risk of intraocular bleeding. JAMA Ophthalmol. 2018;136:122–130.
118. Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27,467 patients taking rivaroxaban. Clin Cardiol. 2015;38:63–68.
119. Shinohara M, Fujino T, Yao S, et al. Assessment of the bleeding risk of anticoagulant treatment in non-severe frail octogenarians with atrial fibrillation. J Cardiol. 2018. doi: .
120. Shimokawa H, Yamashita T, Uchiyama S, et al. The EXPAND study: efficacy and safety of rivaroxaban in Japanese patients with non-valvular atrial fibrillation. Int J Cardiol. 2018;258:126–132.
121. Sherid M, Sifuentes H, Sulaiman S, et al. Risk of gastrointestinal bleeding with dabigatran: a head-to-head comparative study with rivaroxaban. Digestion. 2014;90:137–146.
122. Ogawa S, Ikeda T, Kitazono T, et al. Present profiles of novel anticoagulant use in Japanese patients with atrial fibrillation: insights from the Rivaroxaban Postmarketing Surveillance Registry. J Stroke Cerebrovasc Dis. 2014;23:2520–2526.
123. Noseworthy PA, Yao X, Abraham NS, et al. Direct comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in nonvalvular atrial fibrillation. Chest. 2016;150:1302–1312.
124. Lin YC, Chien SC, Hsieh YC, et al. Effectiveness and safety of standard- and low-dose rivaroxaban in Asians with atrial fibrillation. J Am Coll Cardiol. 2018;72:477–485.
125. Laliberte F, Cloutier M, Crivera C, et al. Effect of rivaroxaban versus warfarin on health care costs among nonvalvular atrial fibrillation patients: observations from rivaroxaban users and matched warfarin users. Adv Ther. 2015;32:216–227.
126. Kirchhof P, Radaideh G, Kim YH, et al. Global prospective safety analysis of rivaroxaban. J Am Coll Cardiol. 2018;72:141–153.
127. Jacobs V, May HT, Bair TL, et al. Long-term population-based cerebral ischemic event and cognitive outcomes of direct oral anticoagulants compared with warfarin among long-term anticoagulated patients for atrial fibrillation. Am J Cardiol. 2016;118:210–214.
128. Skjøth F, Larsen TB, Rasmussen LH, et al. 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;111:981–988.
129. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2018;361:k2295.
130. Verdecchia P, Angeli F, Lip GY, et al. Edoxaban in the evolving scenario of non vitamin K antagonist oral anticoagulants imputed placebo analysis and multiple treatment comparisons. PLoS One. 2014;9–.
131. Wasserlauf G, Grandi SM, Filion KB, et al. Meta-analysis of rivaroxaban and bleeding risk. Am J Cardiol. 2013;112:454–460.
132. Clemens A, Noack H, Brueckmann M, et al. Twice- or once-daily dosing of novel oral anticoagulants for stroke prevention: a fixed-effects meta-analysis with predefined heterogeneity quality criteria. PLoS One. 2014;9:.
133. Cameron C, Coyle D, Richter T, et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation. BMJ Open. 2014;4:.
134. Liakoni E, Ratz Bravo AE, Terracciano L, et al. Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban. JAMA Intern Med. 2014;174:1683–1686.
135. Chan YH, Yeh YH, Hsieh MY, et al. The risk of acute kidney injury in Asians treated with apixaban, rivaroxaban, dabigatran, or warfarin for non-valvular atrial fibrillation: a nationwide cohort study in Taiwan. Int J Cardiol. 2018;265:83–89.
136. Mentias A, Shantha G, Chaudhury P, et al. Assessment of outcomes of treatment with oral anticoagulants in patients with atrial fibrillation and multiple chronic conditions: a comparative effectiveness analysis. JAMA Netw Open. 2018;1:.
137. Sobieraj-Teague M, Odonnell M, Eikelboom J. New anticoagulants for atrial fibrillation. Semin Thromb Hemost. 2009;35:515–524.
138. Zolfaghari S, Harenberg J, Marx S, et al. Indirect comparisons of the new oral anticoagulants in patients with non-valvular atrial fibrillation. Blood. 2012;120:4363.
139. Miller CS, Grandi SM, Shimony A, et al. The efficacy and safety of new oral anticoagulants versus warfarin in patients with atrial fibrillation: a systematic review and meta-analysis. J Popul Ther Clin Pharmacol. 2012;19:e124.
140. Castellucci LA, Cameron C, Le Gal G, et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ. 2013;347:f5133.
141. Marx S, Diener HC, Harenberg J, et al. Network meta-analysis of efficacy and safety of dabigatran, rivaroxaban and apixaban in patients with non-valvular atrial fibrillation. Eur Heart J. 2012;33:815.
142. Roversi S, Malavasi V, D'Ascenzo F, et al. Picking the best novel oral anticoagulant for atrial fibrillation: evidence from a warfarin-controlled network meta-analysis. J Am Coll Cardiol. 2012;59:E598.
143. Harenberg J, Marx S, Krejczy M, et al. Indirect comparison of new oral anticoagulants for patients with atrial fibrillation using network meta-analysis. Hamostaseologie. 2012;32:A72.
144. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta analysis of the literature. Blood Transfus. 2012;10:s60–s61.
145. Gibson CM, Chakrabarti AK, Mega J, et al. Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51. J Am Coll Cardiol. 2013;62:286–290.
146. Investigators E, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–2510.
147. Kubitza D, Mueck W, Becka M. Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Saf. 2008;31:67–77.
148. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors in Atrial fibrillation) study cohorts. Circulation. 2013;127:224–232.
149. Spencer RJ, Amerena JV. Rivaroxaban in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: clinical implications of the ROCKET AF trial and its subanalyses. Am J Cardiovasc Drugs. 2015;15:395–401.
150. Mobius-Winkler S, Sandri M, Mangner N, et al. The WATCHMAN left atrial appendage closure device for atrial fibrillation. J Vis Exp. 2012. doi: .
151. Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction-51). J Am Coll Cardiol. 2013;61:1853–1859.
152. Hurley C, Dai S, Sobieraj DM. The impact of inpatient rivaroxaban versus warfarin on hospital-based outcomes when used for stroke prevention in patients with anticoagulant naive, new-onset nonvalvular atrial fibrillation. Int J Cardiol. 2015;192:1–2.
153. Deshpande CG, Kogut S, Willey C. Real-world health care costs based on medication adherence and risk of stroke and bleeding in patients treated with novel anticoagulant therapy. J Manag Care Spec Pharm. 2018;24:430–439.
154. Cataldo N, Pegoraro V, Ripellino C, et al. Non-persistence risk and health care resource utilization of Italian patients with non-valvular atrial fibrillation. Recenti Prog Med. 2018;109:113–121.
155. Lam YY, Ma TKW, Yan BP. Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation. Int J Cardiol. 2011;150:4–11.
156. Cairns JA, McMurtry MS. Oral antithrombotic therapy in atrial fibrillation associated with acute or chronic coronary artery disease. Can J Cardiol. 2013;29(7 suppl):S60–S70.
157. Beyer-Westendorf J, Buller H. External and internal validity of open label or double-blind trials in oral anticoagulation: better, worse or just different? J Thromb Haemost. 2011;9:2153–2158.
158. Lip GYH, Lane DA. Stroke prevention with oral anticoagulation therapy in patients with atrial fibrillation: focus on the elderly. Circ J. 2013;77:1380–1388.
159. Lee S, Monz BU, Clemens A, et al. Representativeness of the dabigatran, apixaban and rivaroxaban clinical trial populations to real-world atrial fibrillation patients in the United Kingdom: a cross-sectional analysis using the General Practice Research Database. BMJ Open. 2012;2:e001768.
160. Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, et al. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups. Thrombosis. 2013;2013:640723.
161. Perez A, Eraso LH, Merli GJ. Implications of new anticoagulants in primary practice. Int J Clin Pract. 2013;67:139–156.
162. Paikin JS, Wright DS, Eikelboom JW. Effectiveness and safety of combined antiplatelet and anticoagulant therapy: a critical review of the evidence from randomized controlled trials. Blood Rev. 2011;25:123–129.
163. Hart RG, Eikelboom JW, Brimble KS, et al. Stroke prevention in atrial fibrillation patients with chronic kidney disease. Can J Cardiol. 2013;29(7 suppl):S71–S78.
164. Haas S, Spannagl M, Schellong SM. Novel oral anticoagulants—key messages for the angiologist. Vasa. 2012;41:177–191.
165. Connolly SJ, Eikelboom J, O'Donnell M, et al. Challenges of establishing new antithrombotic therapies in atrial fibrillation. Circulation. 2007;116:449–455.
166. Tendera M, Syzdol M, Parma Z. ARISTOTLE RE-LYs on the ROCKET: what's new in stroke prevention in patients with atrial fibrillation? Cardiol J. 2012;19:4–10.
167. Barco S, Cheung YW, Eikelboom JW, et al. New oral anticoagulants in elderly patients. Best Pract Res Clin Haematol. 2013;26:215–224.
168. Woodhouse C, Evans G, Muller AF. The new oral anticoagulants: practical management for patients attending for endoscopic procedures. Frontline Gastroenterol. 2013;4:213–218.
169. Tzeis S, Andrikopoulos G. Novel anticoagulants for atrial fibrillation: a critical appraisal. Angiology. 2012;63:164–170.
170. Shameem R, Ansell J. Disadvantages of VKA and requirements for novel anticoagulants. Best Pract Res Clin Haematol. 2013;26:103–114.
171. O'Dell KM, Igawa D, Hsin J. New oral anticoagulants for atrial fibrillation: a review of clinical trials. Clin Ther. 2012;34:894–901.
172. Noheria A, Asirvatham SJ. Periprocedural dabigatran anticoagulation for atrial fibrillation ablation: do we have enough information to make a rational decision. J Interv Card Electrophysiol. 2013;37:209–211.
173. Mattle HP, Brainin M, Chamorro A, et al. European stroke science workshop. Cerebrovasc Dis. 2012;34:95–105.
174. Manolis AJ, Poulimenos LE. Prevention of stroke by antithrombotic therapy in patients with atrial fibrillation. J Atrial Fibrillation. 2013;5:84–92.
175. Lip GY, Felmeden DC, Dwivedi G. Antiplatelet agents and anticoagulants for hypertension. Cochrane Database Syst Rev. 2011:Cd003186.
176. Hollands JM, Gowan M, Riney JN, et al. Role of new drugs for management of atrial fibrillation. Ann Pharmacother. 2012;46:1656–1670.
177. Haas S, Schellong S. New anticoagulants: from bench to bedside. Hamostaseologie. 2007;27:41–47.
178. Haas S. Rivaroxaban—an oral, direct Factor Xa inhibitor: lessons from a broad clinical study programme. Eur J Haematol. 2009;82:339–349.
179. Cohen AT, Dobromirski M. The use of rivaroxaban for short- and long-term treatment of venous thromboembolism. Thromb Haemost. 2012;107:1035–1043.
180. Cayla G, Morange PE, Chambost H, et al. Management of cardiovascular disease in haemophilia. Thromb Res. 2013;132:8–14.
181. Camm AJ. The RE-LY study: randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin. Eur Heart J. 2009;30:2554–2555.
182. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol. 2007;100:1419–1426.
183. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.
184. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875–1876.
185. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128:237–243.
186. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J. 2013;34:2464–2471.
187. Lee S, Mullin R, Blazawski J, et al. Cost-effectiveness of apixaban compared with warfarin for stroke prevention in atrial fibrillation. PLoS One. 2012;7:e47473.
188. Lambert A, Cordeanu M, Gaertner S, et al. Rivaroxaban-induced liver injury: results from a venous thromboembolism registry. Int J Cardiol. 2015;191:265–266.
189. Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis. 2015;39:288–294.
190. Gold AM, Crowther M, Levy G, et al. Annexatm-R: a phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of rivaroxaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor xa (fXa) inhibitors. J Am Coll Cardiol. 2015;65:A23.
191. Jones D. Anticoagulant antidotes start yielding Phase III promise. Nat Rev Drug Discov. 2015;14:5–6.
192. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–2424.
193. Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113:943–951.
194. Reilly PA, van Ryn J, Grottke O, et al. Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects. Am J Med. 2016;129:S64–S72.
195. Syed YY. Idarucizumab: a review as a reversal agent for dabigatran. Am J Cardiovasc Drugs. 2016;16:297–304.
196. Wang RR, Yu H, Zheng YL, et al. Idarucizumab, a specific dabigatran reversal agent. Chin J New Drugs. 2016;25:361–365.
197. Lip GYH, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients: executive summary# of a position document from the European heart rhythm association [EHRA], endorsed by the European society of cardiology [ESC] working group on thrombosis. Thromb Haemost. 2011;106:997–1011.
198. Capodanno D, Capranzano P, Giacchi G, et al. Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: a meta-analysis of 50,578 patients. Int J Cardiol. 2013;167:1237–1241.
199. Dogliotti A, Paolasso E, Giugliano RP. Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin. Clin Cardiol. 2013;36:61–67.
200. Baker WL, Phung O. Do differences exist between oral anticoagulants in patients with nonvalvular atrial fibrillation? an adjusted indirect comparison meta-analysis. J Am Coll Cardiol. 2012;59:E597.
201. Boehringer Ingelheim Pharmaceuticals I. Pradaxa (Dabigatran) Package Insert. Ridgefield, CT: 2015; Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022512s028lbl.pdf. Accessed November 11, 2018.
202. Lehr T, Haertter S, Liesenfeld KH, et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol. 2012;52:1373–1378.
203. Hariharan S, Madabushi R. Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment. J Clin Pharmacol. 2012;52(1 suppl):119S–125S.
204. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e531S–575S.
205. Pengo V, Crippa L, Falanga A, et al. Questions and answers on the use of dabigatran and perspectives on the use of other new oral anticoagulants in patients with atrial fibrillation; a consensus document of the Italian federation of thrombosis centers (FCSA). Thromb Haemost. 2011;106:868–876.
206. Cairns JA, Connolly S, McMurtry S, et al. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol. 2011;27:74–90.
207. Gillis AM, Skanes AC. Comparing the 2010 North American and European atrial fibrillation guidelines. Can J Cardiol. 2011;27:7–13.
208. National Institute for Health and Care Excellence (NICE). Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation. 2015; Available at: https://www.nice.org.uk/guidance/ta355. Accessed November 11, 2018.
209. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37:2893–2962.
210. Hauk L. Newly detected atrial fibrillation: AAFP updates guideline on pharmacologic management. Am Fam Physician. 2017;96:332–333.
211. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the american College of cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70:3042–3067.
212. Wang SV, Franklin JM, Glynn RJ, et al. 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.
213. Hijazi Z, Oldgren J, Lindback J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet. 2016;387:2302–2311.
214. Chang YT, Hu YF, Liao JN, et al. The assessment of anticoagulant activity to predict bleeding outcome in atrial fibrillation patients receiving dabigatran etexilate. Blood Coagul Fibrinolysis. 2016;27:389–395.
215. Ruff CT, Giugliano RP, Braunwald E, et al. Cardiovascular biomarker score and clinical outcomes in patients with atrial fibrillation: a subanalysis of the engage AF-TIMI 48 randomized clinical trial. JAMA Cardiol. 2016;1:999–1006.
216. Mega JL, Walker JR, Ruff CT, et al. Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015;385:2280–2287.
217. Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625–651.
218. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013;34:2094–2106.
219. Bohm R, von Hehn L, Herdegen T, et al. OpenVigil FDA—inspection of U.S. American adverse drug events pharmacovigilance data and novel clinical applications. PLoS One. 2016;11:e0157753.
220. Pitts PJ, Louet HL, Moride Y, et al. 21st century pharmacovigilance: efforts, roles, and responsibilities. Lancet Oncol. 2016;17:e486–e492.
221. UTTS v. BRISTOL-MYERS SQUIBB CO. 16cv5668(DLC) 251 F.Supp.3d 644 (2017) United States District Court, S.D. New York. Signed May 8, 2017. Applicable Law: 28 U.S.C. § 1332pl Cause: 28 U.S.C. § 1332pl Diversity - Product Liability Nature of Suit: 367 Personal Injury: Health Care/Pharmaceutical Personal Injury Product Liability. Available at https://www.leagle.com/decision/infdco20170509b61. Accessed November 11, 2018.
222. Henriksen JN, Nielsen LP, Hellebek A, et al. Medication errors involving anticoagulants: data from the Danish patient safety database. Pharmacol Res Perspect. 2017;5:e00307.
223. Marciniak TA, Cherepanov V, Golukhova E, et al. Drug discontinuation and follow-up rates in oral antithrombotic trials. JAMA Intern Med. 2016;176:257–259.
Keywords:

atrial fibrillation; stroke; mortality; rivaroxaban; warfarin; edoxaban; apixaban; dabigatran; evidence-based medicine

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