Outcomes of apixaban versus rivaroxaban in patients with nonvalvular atrial fibrillation

Introduction

Atrial fibrillation (AFib) is a common irregular cardiac rhythm that affects approximately 2.3 million adults in the United States (1). Abnormal electrical activity causes the atria to contract ineffectively, leading to reduced atrial systolic stroke volume and increasing the risk of clot formation. Current management of AFib includes the use of daily oral anticoagulants, commonly the vitamin K antagonist warfarin or direct oral anticoagulants (DOACs), such as apixaban or rivaroxaban. Both apixaban and rivaroxaban are direct factor Xa inhibitors, approved by the Food and Drug Administration (FDA) in 2012 and 2011, respectively. These newer alternatives to warfarin offer the advantage of not requiring routine anticoagulation monitoring and having fewer adverse drug-drug and food-drug interactions (2).

Given these advantages, current guidelines recommend the use of DOACs over vitamin K antagonists in patients with AFib (3). However, there are a few smaller studies showing direct comparisons between apixaban and rivaroxaban in AFib/AFlutter patients with mixed results (4,5). Understanding the risks and benefits of these two frequently prescribed oral anticoagulants is critical for informing patients about their treatment options (6). Previous research on this topic falls into three main categories: randomized controlled trials (RCTs), observational studies, and meta-analyses, which include both direct and indirect comparisons. While these studies offer valuable insights, most focus on comparing DOACs to warfarin, highlighting the need for updated investigations specifically comparing apixaban and rivaroxaban (7-9).

To date, no head-to-head RCT comparing DOACs exists (5,10). Furthermore, RCTs are often limited by highly selective patient populations, which may not reflect real-world clinical practice (3,11). Observational studies and meta-analyses have consistently suggested that there is no significant difference in effectiveness between DOACs (3,6,11). A 2016 pairwise comparison found no significant difference between apixaban and rivaroxaban regarding stroke/systemic embolism, ischemic stroke, hemorrhagic stroke, myocardial infarction (MI), or all-cause mortality (10). However, bleeding risk profiles differ, with previous studies suggesting that apixaban is associated with a lower risk of major bleeding, including gastrointestinal (GI) bleeding, urogenital bleeding, and intracranial bleeding (3,6,11,12), while rivaroxaban has been linked to a higher risk of major bleeding (11).

The objective of this study is to compare the rates of all-cause mortality, stroke, MI, emboli, and bleeding in non-valvular AFib and/or atrial flutter (AFlutter) patients aged 60 years and older, who are initially treated with either apixaban or rivaroxaban. We present this article in accordance with the STROBE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2024-216/rc).

Methods

TriNetX is a global federated health research network providing access to de-identified electronic medical records (EMRs) from large healthcare organizations (HCOs). For this retrospective, propensity-matched, cross-sectional study, we utilized data from the U.S. Collaborative Network, comprising 64 HCOs and 115,946,908 patients. The study period for the index event ranged from January 1, 2013 to September 30, 2021.

Cohort selection

Cohort selection is outlined in Figure 1. The study population consisted of patients aged 60 years or older who were diagnosed with AFib and/or AFlutter and treated with any dose of either rivaroxaban or apixaban. AFib and/or AFlutter patients were identified by the diagnosis code for atrial fibrillation and flutter [International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM): I48]. Patients had to be initiated on apixaban or rivaroxaban therapy within 3 months of their AFib and/or AFlutter diagnosis to be included. Apixaban patients were identified using RxNorm code 1364430, and rivaroxaban patients were identified using RxNorm code 1114195. Among patients in the TriNetX database, apixaban and rivaroxaban were selected because more than 96% of those taking DOACs were using one of these two agents.

Figure 1 Study cohort flow chart of primary analysis for patients with atrial fibrillation and/or atrial flutter. hx, history; ICH, intracranial hemorrhage; MI, myocardial infarction.

There were 16,107 patients excluded due to being prescribed both apixaban and rivaroxaban after their AFib and/or AFlutter diagnosis. Additionally, patients taking other anticoagulants such as dabigatran etexilate, warfarin, or edoxaban (identified through corresponding RxNorm codes) were excluded. Patients were also excluded if they had medical histories of prosthetic heart valve replacement, rheumatic or nonrheumatic mitral valve disorders, cerebral infarction, arterial embolism, thrombosis, nontraumatic intracerebral hemorrhage, blood transfusions, acute MI, GI hemorrhage, hematemesis, or melena before the index event. These conditions and medications were identified based on their ICD-10-CM and RxNorm codes (3) (Appendix 1, Table S1 and Figure 2).

Figure 2 Comorbidity propensity matching ICD-10-CM codes and diagnoses. ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modification.

Primary analysis was done on those with AFib and/or AFlutter, which included the following two cohorts:

• AFib and/or AFlutter patients treated with apixaban (157,888 patients).
• AFib and/or AFlutter patients treated with rivaroxaban (67,087 patients).

Outcomes

The outcomes analyzed across these cohorts included all-cause mortality, stroke, peripheral emboli, intracranial hemorrhage (ICH), blood transfusion, GI bleed, and MI within 3 years of the index event. These outcomes were defined by corresponding ICD-10 and Current Procedural Terminology (CPT) codes: cerebral infarction (ICD-10-CM: I63), arterial embolism and thrombosis (ICD-10-CM: I74), nontraumatic intracerebral hemorrhage (ICD-10-CM: I61), blood transfusion (CPT: 36430), acute myocardial infarction (ICD-10-CM: I21), and GI bleeds, including hematemesis (ICD-10-CM: K92.0), melena (ICD-10-CM: K92.1), and gastrointestinal hemorrhage, unspecified (ICD-10-CM: K92.2). All-cause mortality was determined based on patients listed as deceased in the EMR and confirmed by national death registries. There is a minor risk of missed death events when patients die outside of the TriNetX-affiliated network. However, as of now, 94% of HCOs within TriNetX are linked to national death registries, with this coverage increasing over time.

Outcomes were measured by the number of occurrences in each cohort. The AFib and/or AFlutter cohort taking apixaban was compared to the cohort taking rivaroxaban. Relative risk (RR) and confidence intervals (CIs) were calculated for both comparisons. To mitigate confounding, propensity score matching was applied based on demographic variables including age, race/ethnicity, and pre-existing conditions associated with mortality (Figure 2), along with prior administration of heparin or enoxaparin (Table 1).

Statistical analysis

A 1:1 propensity score match was performed using a caliper width of 0.1 to reduce bias from potentially confounding risk factors. Propensity score matching analysis was completed using linear regression for variables such as age, and logistic regression for binary variables such as demographics and pre-existing conditions. The greedy nearest neighbor algorithm pairs patients between cohorts with the closest scores based on these variables as outlined in Table 1 and were completed using the balanced cohort tool in TriNetX. Covariate balance between matched groups was assessed using standardized mean differences, with values less than 0.1 indicating acceptable balance. Outcomes were reported as risk, RR, 95% CI, and P values. Statistical significance was set at a 2-sided alpha <0.05. Outcomes were calculated by univariate analysis which was performed using the measure of association tool in TriNetX and all data was obtained on September 23, 2024. The analysis compared outcomes within the set time frame for each cohort.

Ethical considerations

This is a retrospective cohort study based on pre-existing EMRs. As the data are de-identified, utilization of TriNetX data does not require review by the University of Texas Medical Branch (UTMB) Institutional Review Board (IRB). The UTMB IRB classified this project as “not human subjects research”.

Results

A total of 3,749,821 patients with AFib and/or AFlutter were identified at the time of data extraction. After applying inclusion and exclusion criteria, 241,082 patients remained, from which propensity-matched sub-cohorts were formed (Figure 1). Over 75% of participants were White. Before propensity score matching, the mean age of the apixaban cohort was 72.7 years, with a male-to-female ratio of 1.3, while the rivaroxaban cohort had a mean age of 71.5 years and a male-to-female ratio of 1.5. After propensity score matching, the apixaban cohort had a mean age of 71.6 years and a male-to-female ratio of 1.5, similar to the rivaroxaban cohort. Common comorbidities included hypertensive diseases, ischemic heart disease, diabetes mellitus, obesity, chronic kidney disease, and heart failure. After matching, standardized differences were all less than 5%, indicating similarity between cohorts in terms of demographic and comorbidity factors (Table 1).

Before propensity score matching, all outcomes except for ICH were significant. Regarding effectiveness, the RR for stroke was 1.36 (95% CI: 1.27–1.45), and for MI, the RR was 1.41 (95% CI: 1.33–1.51). In terms of bleeding risk, apixaban was associated with a higher risk of all-cause mortality, embolism, bleeding events, and GI bleeding compared to rivaroxaban. After propensity score matching, rivaroxaban remained associated with a reduced risk of stroke, all-cause mortality, embolism, and MI. The RRs for stroke and MI were 1.31 (95% CI: 1.22–1.42) and 1.30 (95% CI: 1.21–1.40), respectively. The results for ICH remained non-significant, and outcomes for GI bleeding and bleeding events became insignificant (Table 2).

Discussion

This study compared seven clinical outcomes for AFib and/or AFlutter patients prescribed apixaban or rivaroxaban within three months of diagnosis using data from the U.S. Collaborative Network in the TriNetX database (2013–2021). Before propensity score matching, rivaroxaban was associated with significantly lower rates of 3-year all-cause mortality, stroke, MI, embolism, bleeding events, and GI bleeding. After propensity score matching, rivaroxaban was still associated with lower rates of all-cause mortality, stroke, MI, and peripheral embolism, though no significant differences were found for ICH, bleeding events or GI bleeding.

The difference in outcomes before and after propensity score matching underscores the importance of adjusting for baseline differences between apixaban and rivaroxaban users to minimize the impact of confounding variables. After propensity score matching, rivaroxaban was associated with better outcomes, particularly in reducing stroke, peripheral embolism, and MI, contradicting some previous studies. For instance, a similar study by Noseworthy et al., using U.S. claims data from 2010–2015, found no significant difference in stroke reduction between the two drugs (11). Furthermore, a 2021 meta-analysis suggested apixaban had a lower hazard ratio for stroke, although it included subgroup analysis of dosing regimens. Similarly, several observational studies did not find significant differences between these drugs in terms of MI risk (13).

This study, however, found stronger evidence for rivaroxaban’s effectiveness, distinguishing it as the only study to our knowledge to suggest improved outcomes with rivaroxaban over apixaban. Notably, this study also evaluated risk of peripheral embolism, with significantly lower risk of peripheral embolism in the rivaroxaban cohort, suggesting a potential new dimension to DOAC safety evaluation.

In terms of death, rivaroxaban was associated with reduced risk of all-cause mortality compared to apixaban. However no significant differences were observed for some other outcomes such as bleeding events, ICH, and GI bleeding, diverging from prior meta-analyses, which have shown a lower risk of major and GI bleeding with apixaban (3,6,10,11). These previous studies considered bleeding risk scores and included data from RCTs, which often involve higher-risk patients. Noseworthy et al. found that rivaroxaban was still associated with more bleeding across a broader patient spectrum, including lower-risk individuals (11). Additionally, U.S. Medicare data linked rivaroxaban to a higher risk of ICH (12).

A key distinction between apixaban and rivaroxaban lies in their dosing schedules: apixaban is administered twice daily, whereas rivaroxaban is taken once daily, which may enhance patient adherence and convenience. Both agents are direct factor Xa inhibitors; however, rivaroxaban is slightly more selective, while apixaban exhibits a broader range of activity. Both rivaroxaban and apixaban bind tightly to factor Xa; however, rivaroxaban has a faster dissociation rate and a more rapid onset of action (14). This difference in binding could influence their efficacy. RCTs have shown that apixaban has less fluctuation in plasma concentration and reduced variability in Cmax compared to rivaroxaban (15), which may influence differences in outcomes. Baseline comorbidities, as limited by available data, might make certain patients more susceptible to differences in anticoagulant bleeding risk and effectiveness. The lack of analysis on site and provider distribution further restricts our understanding of how marketing and provider preferences might influence prescribing patterns.

Limitations

First, the retrospective design of this study limits our ability to infer causality. Second, although we applied propensity score matching to adjust for demographic and clinical characteristics, there is still potential for residual confounding. This study matched for demographics, hypertension, ischemic heart disease, diabetes, obesity, acute and chronic kidney disease, heart failure, cardiac arrest, various valve diseases, and heparin or enoxaparin use. However, other unmeasured factors, such as lifestyle characteristics (e.g., smoking, over-the-counter aspirin use), procedures, change in prescription practices over time, and laboratory values (e.g., renal function, hemoglobin), were not consistently available for inclusion in the analysis. AFib is much more common than AFlutter and has a slightly worse prognosis, however 50–58% of individuals diagnosed with AFlutter go on to develop AFib. This study for the most part was evaluating patients with AFib and the overall percentage of patients with AFib and AFlutter were fairly similar between our apixaban and rivaroxaban cohorts.

Additionally, site clustering or hospital distribution could not be evaluated due to privacy restrictions in the TriNetX database, preventing assessment of healthcare access variability and geographic prescribing patterns. Third, studies based on electronic health records inherently risk misclassification bias due to coding errors. Fourth, we did not account for dosage differences between high and low doses of anticoagulants, which previous studies have identified as influential (10), thus limiting the generalizability of our findings. Furthermore, anticoagulant use was based on prescription data at the time of index event (AFib/AFlutter), which may not reflect actual adherence or prior DOAC use, complicating inferences regarding real-world treatment. Finally, we did not adjust for bleeding risk scores [e.g., HAS-BLED (bleeding score: hypertension, abnormal liver/renal, stroke, bleeding, labile international normalized ratios, elderly, drugs), CHADS2 (risk of stroke: congestive heart failure, hypertension, age >74 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism)] due to their unavailability in the database, which might have impacted the assessment of bleeding risks (6).

Conclusions

This study indicates that, compared to apixaban, rivaroxaban is associated with lower all-cause mortality, risk of MI, stroke, and peripheral emboli, and may be the preferred DOAC for patients aged 60 years and older diagnosed with non-valvular AFib and/or AFlutter.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2024-216/rc

Data Sharing Statement: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2024-216/dss

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2024-216/prf

Funding: This research was supported by the Institute for Translational Sciences at the University of Texas Medical Branch, and in part by a Clinical and Translational Science Award from the National Center for Advancing Translational Sciences at the National Institutes of Health (NIH) (No. UL1 TR001439). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2024-216/coif). D.E.G. reports grants support from NIH (NIA) and serves on three Data Safety Monitoring Boards for trials that are funded by NIH (NIDA, NIA, NHLBI). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This is a retrospective cohort study based on pre-existing EMRs. As the data are de-identified, utilization of TriNetX data does not require review by the University of Texas Medical Branch (UTMB) Institutional Review Board (IRB). The UTMB IRB classified this project as “not human subjects research”.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kumar K. Atrial fibrillation: Overview and management of new-onset atrial fibrillation. UpToDate 2023. Available online: https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation#H1
2. Amin A. Choosing Non-Vitamin K Antagonist Oral Anticoagulants: Practical Considerations We Need to Know. Ochsner J 2016;16:531-41.
3. Grymonprez M, De Backer TL, Bertels X, et al. Long-term comparative effectiveness and safety of dabigatran, rivaroxaban, apixaban and edoxaban in patients with atrial fibrillation: A nationwide cohort study. Front Pharmacol 2023;14:1125576. [Crossref] [PubMed]
4. Jaksa A, Gibbs L, Kent S, et al. Using primary care data to assess comparative effectiveness and safety of apixaban and rivaroxaban in patients with nonvalvular atrial fibrillation in the UK: an observational cohort study. BMJ Open 2022;12:e064662. [Crossref] [PubMed]
5. Hill NR, Sandler B, Bergrath E, et al. A Systematic Review of Network Meta-Analyses and Real-World Evidence Comparing Apixaban and Rivaroxaban in Nonvalvular Atrial Fibrillation. Clin Appl Thromb Hemost 2020;26:1076029619898764. [Crossref] [PubMed]
6. Mamas MA, Batson S, Pollock KG, et al. Meta-Analysis Comparing Apixaban Versus Rivaroxaban for Management of Patients With Nonvalvular Atrial Fibrillation. Am J Cardiol 2022;166:58-64. [Crossref] [PubMed]
7. Dion J, Costedoat-Chalumeau N, Sène D, et al. Relapsing Polychondritis Can Be Characterized by Three Different Clinical Phenotypes: Analysis of a Recent Series of 142 Patients. Arthritis Rheumatol 2016;68:2992-3001. [Crossref] [PubMed]
8. Chan YH, Chen SW, Chan CY, et al. Comparative safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation: A network meta-analysis. J Formos Med Assoc 2024;123:578-86. [Crossref] [PubMed]
9. Patel SM, Braunwald E, Steffel J, et al. Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation. Circulation 2024;149:932-43. [Crossref] [PubMed]
10. 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. [Crossref] [PubMed]
11. 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;150:1302-12. [Crossref] [PubMed]
12. Graham DJ, Baro E, Zhang R, et al. Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation. Am J Med 2019;132:596-604.e11. [Crossref] [PubMed]
13. Abraham NS, Noseworthy PA, Yao X, et al. Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study. Gastroenterology 2017;152:1014-1022.e1. [Crossref] [PubMed]
14. Samama MM. The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants. Thromb Res 2011;127:497-504. [Crossref] [PubMed]
15. Dawwas GK, Cuker A, Barnes GD, et al. Apixaban Versus Rivaroxaban in Patients With Atrial Fibrillation and Valvular Heart Disease : A Population-Based Study. Ann Intern Med 2022;175:1506-14. [Crossref] [PubMed]