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PLOS ONE logoLink to PLOS ONE
. 2021 Apr 8;16(4):e0249940. doi: 10.1371/journal.pone.0249940

Effectiveness and safety of rivaroxaban versus warfarin in Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation: A real-world nationwide cohort study

Yi-Cheng Lin 1,2, Bi-Li Chen 1,2, Chun-Ming Shih 3,4,5,6, Feng-Yen Lin 3,4,5,6, Chih-Wei Chen 3,4,5,6, Chien-Yi Hsu 3,4,5,6, Yung-Ta Kao 3,4,5,6,7, Wei-Fung Bi 3,4,5,6, Li-Ying Chen 8, Li-Nien Chien 9,*,#, Te-Chao Fang 10,11,12,*,#, Chun-Yao Huang 3,4,5,6,*,#
Editor: Yoshihiro Fukumoto13
PMCID: PMC8031437  PMID: 33831130

Abstract

Background

The optimal anticoagulant for end-stage renal disease patients for stroke prophylaxis is unknown. The efficacy and safety of warfarin in this population are debatable. In addition, real-world evidence of direct oral anticoagulants in patients with end-stage renal disease is limited. The aim of this study was to evaluate the clinical outcomes of rivaroxaban compared with warfarin in Taiwanese patients with end-stage renal disease with nonvalvular atrial fibrillation in a real-world setting.

Methods and results

This was a retrospective population-based cohort study conducted using Taiwan’s National Health Insurance Research Database. Patients with nonvalvular atrial fibrillation and end-stage renal disease who started on rivaroxaban or warfarin between February 2013 and September 2017 were eligible to participate in the study. The inverse probability of treatment weighting approach was used to balance baseline characteristics. Bleeding and thromboembolic outcomes were compared using competing risk analyses. The study population consisted of 3358 patients (173 and 3185 patients on rivaroxaban and warfarin, respectively). In the rivaroxaban group, 50.8%, 38.7%, and 10.4% of the patients received 10, 15, and 20 mg of the drug, respectively. The cumulative incidence of major bleeding was similar between the two groups; however, the gastrointestinal bleeding rate was lower in the rivaroxaban group (adjusted subdistribution hazard ratio [SHR]: 0.56, 95% confidence interval [CI]: 0.34–0.91) than in the warfarin group. Furthermore, the composite risk of ischemic stroke or systemic embolism was significantly lower in the rivaroxaban group (adjusted SHR: 0.36, 95% CI: 0.17–0.79). Similar findings were observed for patients who received 10 mg of rivaroxaban.

Conclusions

In Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation, rivaroxaban may be associated with a similar risk of major bleeding but a lower risk of thromboembolism compared with warfarin. The potential benefit of 10 mg of rivaroxaban in this population requires further investigation.

Introduction

Nonvalvular atrial fibrillation (NVAF) is common in patients with chronic kidney disease, and the prevalence markedly increases as renal function declines [1, 2]. An estimated 13%–27% of patients with end-stage renal disease (ESRD) have NVAF [3, 4], a substantially higher prevalence than in the general population. In addition, chronic kidney disease increases the stroke risk independent of other risk factors in patients with NVAF [5]. Despite an increased thromboembolism risk in patients with ESRD and NVAF, anticoagulant use in this population has been controversial because it lacks sufficient benefits, and anticoagulant users have had more adverse effects than nonusers [6, 7]. Moreover, stroke prevention is complex because renal dysfunction is an independent risk factor for major bleeding [1, 8].

To date, the optimal anticoagulant for the ESRD population for stroke prophylaxis is unknown. The efficacy and safety of warfarin in patients with ESRD for stroke prophylaxis are debatable. Numerous observational studies and meta-analyses have suggested that warfarin has no clear benefit and indicated that it is associated with increased bleeding compared with no anticoagulant and direct oral anticoagulant use in patients with ESRD [6, 913]. Direct oral anticoagulants have been demonstrated to be beneficial over warfarin in patients with NVAF in phase 3 clinical trials [1418]. However, patients with ESRD were excluded from these trials, considering that direct oral anticoagulants are primarily eliminated through the kidney and that this population has high mortality and morbidity risks. A recent randomized controlled trial compared the efficacy and safety of apixaban with warfarin for stroke prevention in patients with NVAF and ESRD [19]. However, the trial was stopped early, leaving the results inconclusive. Direct oral anticoagulant use in this population has been investigated using real-world data in the United States, but Caucasians were the large majority in these study populations, and conflicting results were obtained [2023].

In Taiwan, rivaroxaban is approved for stroke prophylaxis in NVAF patients with creatinine clearance of ≥15 mL/min. In addition to 15 mg of rivaroxaban, 10 mg of rivaroxaban is approved in Taiwan and Japan for patients with creatinine clearance between 15 and 50 mL/min. The approval was based on the findings of a phase 3 randomized controlled trial in Japan [24], and in that trial, a lower dosage was chosen for investigation based on previous pharmacokinetic data in Japanese patients. The elimination of rivaroxaban is less dependent on renal clearance compared with dabigatran and edoxaban [2528], which makes it a potential option for patients with severe renal dysfunction. To our knowledge, no real-world data are available regarding the evaluation of the off-label use of rivaroxaban for stroke prophylaxis in Asian patients with ESRD. The study objective was to investigate the effectiveness and safety of rivaroxaban compared with warfarin in Asian patients with NVAF and ESRD in a real-world setting.

Methods

Study design and data sources

This was a retrospective population-based cohort study conducted using Taiwan’s National Health Insurance Research Database. This database contains insurance claims from 99% of Taiwan residents. The database captures enrollment records; International Classification of Diseases, Ninth and Tenth Revision (ICD-9 and ICD-10) diagnosis codes; procedure codes; and prescription records from both inpatient and outpatient services. This study was approved by the Joint Institutional Review Board of Taipei Medical University (TMU-JIRB No. N201911006). Because all data were de-identified, the Institutional Review Board waived the need for informed consent.

Study cohort

We used prescriptions records to select a study cohort to minimize the possibility of underreporting and incomplete diagnosis coding because the National Health Insurance Research Database only captured up to five diagnoses for each visit. We selected patients who received oral anticoagulant prescriptions between February 2013 and September 2017. We excluded patients from the cohort if (1) they were aged <20 years; (2) their anticoagulant prescription was filled only once during the study period; (3) anticoagulants were not prescribed by neurologists or cardiologists; (4) they received a diagnosis of pulmonary embolism or deep vein thrombosis within 6 months before the index date; and (5) they received joint replacement or valvular surgery within 6 months before the index date [29]. Among patients on oral anticoagulants with a diagnosis of NVAF or atrial flutter, we selected patients on rivaroxaban or warfarin with an ESRD diagnosis as our final study cohort. ESRD, which was defined based on a diagnosis of stage 5 chronic kidney disease or patients being on regular dialysis in this study, was identified through ICD-9 codes in the Registry of Catastrophic Illness and medical records indicating the use of erythropoiesis-stimulating agents. According to National Health Insurance policies, patients who have received renal replacement therapy for at least 3 months are eligible for catastrophic illness certification, and the use of erythropoiesis-stimulating agents is limited to patients with ESRD regardless of the dialysis status. For erythropoiesis-stimulating drug users, we specifically included those with an ESRD diagnosis identified through ICD-9 codes to eliminate patients using these agents for off-label indications. The patient selection process is shown in Fig 1. The study cohort was followed from the date of the first anticoagulant prescription to the date of the clinical event of interest or until December 31, 2017, whichever came first.

Fig 1. Patient selection process.

Fig 1

A total of 3358 patients with NVAF and ESRD receiving either rivaroxaban or warfarin were enrolled in this study, consisting of 173 and 3185 rivaroxaban and warfarin users, respectively. NVAF = nonvalvular atrial fibrillation; DVT = deep vein thrombosis; PE = pulmonary embolism.

Comorbidities and medications

Thromboembolic and bleeding risks at the baseline were assessed using established scoring systems, namely the CHA2DS2-VASc and ORBIT scores. The CHA2DS2-VASc score outperformed the CHADS2 score in predicting thromboembolic risk in the Taiwanese population with NVAF [30]. The ORBIT score had better accuracy than other bleeding risk scoring systems in predicting major bleeding in patients with NVAF and was validated in a large cohort of patients receiving rivaroxaban or warfarin [31]. Specific diagnosis and medication codes for comorbidities and medications are listed in S1 Table.

Study outcomes

The outcomes of interest are safety and efficacy [29]. Safety outcomes include hospitalization for major bleeding, defined as fatal bleeding, symptomatic bleeding in a critical area or organ, or bleeding leading to transfusions, and non-major clinically relevant bleeding. The definition of major bleeding was based on the recommendations of the International Society on Thrombosis and Haemostasis [32]. Non-major clinically relevant bleeding was defined as any hemorrhage that did not satisfy the criteria for major bleeding but led to hospitalization or medical visits. Efficacy outcomes included the composite endpoint of ischemic stroke or systemic embolism and individual components of the composite endpoint. Study outcomes were identified based on disease diagnosis codes and procedure codes, which are provided in S1 Table. Because 10 mg of rivaroxaban accounted for a large proportion of usage and is only approved in Taiwan and Japan, we performed analyses comparing clinical outcomes between users of 10 mg of rivaroxaban and warfarin.

Statistical analysis

To reduce potential selection bias, we used inverse probability of treatment weighting (IPTW) based on the propensity score to balance the baseline characteristics of patients receiving warfarin and rivaroxaban, resulting in similar baseline characteristics between the two groups. Instead of matching two treatment groups based on the selected confounders, IPTW involves using the entire cohort and can address numerous confounding variables. IPTW allows for the estimation of marginal hazard ratios with minimal bias while retaining data from all participants [33, 34]. Each patient was assigned a weight based on the likelihood of exposure to the treatment effect, which was estimated through logistic regression. We considered all baseline characteristics when estimating the weight. Standardized mean difference was used to compare baseline characteristics between the two groups, and a value of <0.1 indicated a negligible difference between the variables of the treatment groups. Because the outcomes of interest were thromboembolic and bleeding events, we considered death as a competing risk. Therefore, the cumulative incidence of competing risk was used to estimate the incidence of the selected outcomes. The adjusted subdistribution hazard ratio (SHR) was calculated using the competing risk model adjusted for sex, age, comorbidities, and prescribed medications. The warfarin group served as the reference cohort. During the follow-up period, patients who switched from rivaroxaban to warfarin and vice versa were excluded. Analyses were performed using SAS/STAT 9.4 software (SAS Institute Inc., Cary, NC, USA) and STATA 14 software (Stata Corp LP, College Station, TX, USA). A p-value of <0.05 was considered statistically significant.

Results

A total of 286,767 patients were selected from February 2013 to September 2017. Of these, 3358 patients met the eligibility criteria and were included in the analysis (173 and 3185 patients receiving rivaroxaban or warfarin, respectively). In the rivaroxaban group, 88 (50.8%), 67 (38.7%), and 18 (10.4%) patients received 10, 15, and 20 mg of the drug, respectively. The mean follow-up durations for the rivaroxaban and warfarin groups were 19.1 and 27.4 months, respectively. Before IPTW, patients in the rivaroxaban group were older and had more comorbidities than those in the warfarin group. The mean CHA2DS2-VASc and ORBIT scores of those in the rivaroxaban group were higher than those in the warfarin group (CHA2DS2-VASc and ORBIT scores were 4.0 vs. 3.7 and 2.9 vs. 2.7, respectively). After IPTW, the baseline characteristics were balanced between the two groups. Detailed baseline characteristics are listed in Table 1.

Table 1. Baseline characteristics of eligible patients received rivaroxaban and warfarin.

Before IPTW After IPTW
Rivaroxaban (n = 173) Warfarin (n = 3185) Rivaroxaban (n = 173) Warfarin (n = 3185)
% % SMD % % SMD
Male 55 51 0.08 43 49 0.13
Age, mean ± SD (y) 75 ± 9 69 ± 12 0.54 69 ± 11 69 ± 12 0.02
2064 15 35 0.49 39 34 0.09
6574 32 31 0.04 29 31 0.03
75+ 53 34 0.39 32 35 0.06
Charlson–Deyo index, mean ± SD 6 ± 3 5 ± 2 0.35 5 ± 2 5 ± 2 0.13
02 9 13 0.13 7 13 0.18
3 13 18 0.16 17 18 0.02
4+ 78 69 0.22 76 69 0.14
CHA2DS2-VASc score, mean ± SD 4.0 ± 1.5 3.7 ± 1.6 0.18 3.8 ± 1.5 3.7 ± 1.6 0.05
02 20 25 0.12 20 25 0.11
3 17 25 0.13 24 22 0.03
4+ 63 52 0.21 56 53 0.06
ORBIT score 2.9 ± 1.4 2.7 ± 1.4 0.13 2.8 ± 1.5 2.7 ± 1.4 0.05
02 49 55 0.14 54 55 0.02
3 22 20 0.07 20 20 0.004
4+ 29 25 0.09 26 25 0.02
Comorbidities
 Ischemic stroke 19 13 0.15 16 13 0.08
 GI bleeding 13 12 0.03 15 12 0.09
 Myocardial infarction 10 7 0.09 11 8 0.12
 Congestive heart failure 33 37 0.08 43 37 0.13
 Peptic ulcer disease 29 22 0.16 24 22 0.04
 Hypertension 82 78 0.09 78 78 0.02
 Diabetes 41 51 0.19 51 50 0.02
 Chronic liver disease 9 7 0.08 6 7 0.07
 Hyperlipidemia 28 23 0.11 18 23 0.13
 COPD 16 13 0.08 10 13 0.10
 Valvular heart disease 11 11 0.002 12 11 0.04
 Malignancy 47 14 0.77 13 16 0.08
Medication history
 NSAID 35 27 0.17 24 28 0.08
 Glucocorticoids 23 15 0.20 14 16 0.05
 Antiplatelet agents 57 52 0.09 50 53 0.06
 PPI 19 14 0.14 16 14 0.06
 HMG-CoA reductase inhibitors 25 21 0.10 17 21 0.10
 ACE inhibitors 9 6 0.12 8 6 0.08
 Angiotensin II antagonists 43 34 0.19 35 35 0.003

ACE = angiotensin-converting enzyme; CHA2DS2-VASc score was based on the presence of congestive heart failure, hypertension, age ≥ 75 years, diabetes, stroke/transient ischemic attack, vascular disease, age 65–74 years, sex category (female); Charlson–Deyo index was based on the presence of myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatologic disease, peptic ulcer disease, mild liver disease, diabetes, diabetes with chronic complications, hemiplegia or paraplegia, renal disease, moderate or severe liver disease, acquired immune deficiency syndrome; COPD = chronic obstruction pulmonary disease; GI = gastrointestinal; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; IPTW = inverse probability of treatment weighting; NSAID = nonsteroidal anti-inflammatory drugs; ORBIT score was based on the presence of age ≥ 74 years, anemia, bleeding history, chronic kidney disease, treatment with antiplatelet; PPI = proton pump inhibitor; SD = standard deviation; SMD = standardized mean difference.

The cumulative incidence and competing risk of safety outcomes are shown in Fig 2 and Table 2. The major bleeding risk was similar between rivaroxaban and warfarin users (adjusted SHR: 0.86, 95% confidence interval [CI]: 0.50–1.47, p = 0.59). No significant difference was observed in the risk of non-major clinically relevant bleeding (adjusted SHR: 0.74, 95% CI: 0.48–1.13, p = 0.16). We further classified these bleeding events based on bleeding origin. The gastrointestinal bleeding risk was significantly lower in the rivaroxaban group than in the warfarin group (adjusted SHR: 0.56, 95% CI: 0.34–0.91, p = 0.02), whereas the intracranial bleeding risk was similar between the groups (adjusted SHR: 0.62, 95% CI: 0.24–1.61, p = 0.33).

Fig 2. Bleeding and thromboembolic outcomes: Rivaroxaban versus warfarin.

Fig 2

Compared with warfarin users, rivaroxaban users were associated with similar risks of major bleeding (A) and non-major clinically relevant bleeding (B), but a lower risk of ischemic stroke or systemic embolism (C). CI = confidence interval; SHR = subdistribution hazard ratio.

Table 2. Cumulative incidence and SHR of bleeding and thromboembolic outcomes: Rivaroxaban versus warfarin.

Outcomes Rivaroxaban (n = 173) Warfarin (n = 3185) Crude SHR (95% CI) P-value Adjusted SHR* (95% CI) P-value
Major bleeding
No. of events 23 560 0.88 (0.51–1.51) 0.64 0.86 (0.50–1.47) 0.59
CICR (%) 21.5 24.1
Non-major clinically relevant bleeding
 No. of events 53 1267 0.79 (0.53–1.18) 0.25 0.74 (0.48–1.13) 0.16
 CICR (%) 41.4 49.3
Gastrointestinal bleeding
 No. of events 32 1010 0.62 (0.39–0.99) 0.04 0.56 (0.34–0.91) 0.02
 CICR (%) 27.1 40.1
Intracranial bleeding
 No. of events 7 236 0.62 (0.24–1.61) 0.32 0.62 (0.24–1.61) 0.33
 CICR (%) 6.2 9.8
Composite endpoints of ischemic stroke or systemic embolism
 No. of events 10 520 0.38 (0.17–0.82) 0.01 0.36 (0.17–0.79) 0.01
 CICR (%) 8.4 20.9
Ischemic stroke
 No. of events 7 236 0.62 (0.24–1.61) 0.32 0.62 (0.24–1.61) 0.33
 CICR (%) 6.2 9.8
Systemic embolism
 No. of events 6 311 0.38 (0.12–1.24) 0.10 0.36 (0.11–1.12) 0.08
 CICR (%) 4.9 12.2

*Adjusted for sex, age, Charlson–Deyo index, CHA2DS2-VASc score, ORBIT score, comorbidities, and medications listed in Table 1. CI = confidence interval; CICR = cumulative incidence for competing risk; SHR = subdistribution hazard ratio.

The cumulative incidence and competing risk of efficacy outcomes are shown in Fig 2 and Table 2. The composite risk of ischemic stroke or systemic embolism was significantly lower in the rivaroxaban group than in the warfarin group (adjusted SHR: 0.36, 95% CI: 0.17–0.79, p = 0.01), whereas the individual components of the composite endpoint were similar between the two groups.

Because 10 mg rivaroxaban 10 is approved in Taiwan for stroke prevention in NVAF patients with mild to moderate renal insufficiency, we further performed a subgroup analysis of patients receiving 10 mg rivaroxaban to evaluate its effectiveness and safety in patients with ESRD compared with warfarin (Table 3). Although no significant difference was observed in overall bleeding events (major bleeding adjusted SHR: 0.58, 95% CI: 0.24–1.37, p = 0.21; non-major clinically relevant bleeding adjusted SHR: 0.75, 95% CI: 0.40–1.39, p = 0.36), gastrointestinal bleeding risk was lower in the 10 mg rivaroxaban group (adjusted SHR: 0.43, 95% CI: 0.22–0.83, p = 0.01) than in the warfarin group. Furthermore, the composite risk of ischemic stroke or systemic embolism was significantly lower in the 10 mg rivaroxaban group than in the warfarin group (adjusted SHR: 0.32, 95% CI: 0.12–0.85, p = 0.02). The reduction in the thromboembolism risk was primarily driven by ischemic stroke (adjusted SHR: 0.31, 95% CI: 0.11–0.86, p = 0.03).

Table 3. Cumulative incidence and SHR of bleeding and thromboembolic outcomes: Rivaroxaban 10 mg versus warfarin.

Outcomes Rivaroxaban 10 mg (n = 88) Warfarin (n = 3185) Crude SHR (95% CI) P-value Adjusted SHR* (95% CI) P-value
Major bleeding
No. of events 8 559 0.60 (0.25–1.44) 0.25 0.58 (0.24–1.37) 0.21
CICR (%) 15.2 24.0
Non-major clinically relevant bleeding
No. of events 28 1265 0.82 (0.46–1.46) 0.49 0.75 (0.40–1.39) 0.36
CICR (%) 42.4 49.1
Gastrointestinal bleeding
No. of events 13 1009 0.49 (0.25–0.95) 0.04 0.43 (0.22–0.83) 0.01
CICR (%) 22.1 40.1
Intracranial bleeding
No. of events 2 170 0.53 (0.11–2.61) 0.44 0.59 (0.12–2.89) 0.52
CICR (%) 4.2 7.7
Composite endpoints of ischemic stroke or systemic embolism
No. of events 4 521 0.33 (0.13–0.89) 0.03 0.32 (0.12–0.85) 0.02
CICR (%) 7.5 20.9
Ischemic stroke
No. of events 2 235 0.31 (0.11–0.86) 0.02 0.31 (0.11–0.86) 0.03
CICR (%) 3.1 9.8
Systemic embolism
No. of events 3 313 0.34 (0.08–1.43) 0.14 0.32 (0.08–1.33) 0.12
CICR (%) 4.3 12.2

*Adjusted for sex, age, Charlson–Deyo index, CHA2DS2-VASc score, ORBIT score, comorbidities, and medications listed in Table 1. CI = confidence interval; CICR = cumulative incidence for competing risk; SHR = subdistribution hazard ratio.

Discussion

To our knowledge, this was the first study to evaluate the use of rivaroxaban compared with warfarin in Asian ESRD patients with NVAF using real-world data. A phase 3 randomized controlled trial comparing the clinical outcomes of rivaroxaban and warfarin included patients with moderate renal insufficiency, defined as creatinine clearance of 30–49 mL/min, and similar rates of stroke and major bleeding were observed in these patients [35]. A retrospective population-based US study using an ESRD database investigated the prescribing patterns and bleeding rates associated with rivaroxaban, dabigatran, and warfarin in chronic hemodialysis patients with NVAF [20]. Patients on rivaroxaban had a higher rate of major bleeding compared with those on warfarin, especially patients on 20 mg of rivaroxaban. Another retrospective cohort study in the United States compared the effectiveness and safety of rivaroxaban and warfarin in NVAF patients with stage 4 or 5 chronic kidney disease or those on hemodialysis [21]. Most patients in this study were using 20 mg of rivaroxaban. Although the risk of stroke or systemic embolism was similar between the two groups, rivaroxaban was associated with a lower rate of major bleeding compared with warfarin. These conflicting findings reflect the heterogeneity of anticoagulation responses in patients with NVAF and chronic kidney disease. In our study, we did not observe significant differences in major bleeding and non-major clinically relevant bleeding events, except lower gastrointestinal bleeding. Notably, we observed the risk of ischemic stroke or systemic embolism was lower in patients who used rivaroxaban than in those who used warfarin.

Our study revealed a high cumulative incidence of thromboembolism and bleeding in patients with ESRD on warfarin. Although warfarin has been the mainstay therapy for stroke prevention in patients with ESRD, the level of evidence is weak. According to several observational studies and meta-analyses, warfarin is associated with an increased bleeding risk, including intracranial hemorrhage, in patients with ESRD, without providing a protective effect against stroke [6, 912, 36]. In addition, the risk of warfarin-related major bleeding, particularly intracranial bleeding, is significantly higher in Asian populations [37]. Our study did not include patients with no anticoagulation because such a study design imposes a significant confounding effect that cannot be eliminated through statistical adjustments. Furthermore, direct oral anticoagulants have fewer drug and food interactions and monitoring requirements. In addition, some studies have indicated that factor Xa inhibition may ameliorate nephropathy, and rivaroxaban has been associated with a slower decline in renal function compared with warfarin [38, 39]. A pharmacokinetic study of rivaroxaban in chronic hemodialysis patients indicated that 10 mg of the drug administered to such patients had similar outcomes to 20 mg given to healthy volunteers [40], and drug accumulation was absent after multiple doses. Our study showed that 10 mg of rivaroxaban was associated with a lower rate of thromboembolism and gastrointestinal bleeding compared with warfarin, but the use of this dose in patients with NVAF and ESRD requires further investigation, considering the retrospective nature of our study. Other therapies such as antiplatelet drugs have been investigated in retrospective observational studies, and they did not confer stroke prevention benefits in patients with ESRD [41, 42]. The current guidelines do not recommend antiplatelet agent use for stroke prevention [43]. Therefore, our study did not compare clinical outcomes between rivaroxaban and antiplatelet agents.

The present study has several limitations. First, the data source was insurance claims, and thus, information on international normalized ratio levels was unavailable; for this reason, we could not evaluate the time in the therapeutic range of the warfarin group. Information of actual adherence rates were unavailable in our data source. Second, the sample size of the rivaroxaban group was small because rivaroxaban was used off-label. Further studies with a larger Asian ESRD population are required to evaluate the effectiveness and safety of rivaroxaban. Finally, the retrospective study design and differences between rivaroxaban and warfarin users at baseline indicated the potential for confounding effects. Therefore, we used IPTW to minimize the effect of confounding variables, and our analyses were adjusted for baseline characteristics.

Conclusions

In real-world clinical settings, warfarin is associated with a high incidence of thromboembolic and bleeding events in Taiwanese patients with NVAF and ESRD. Rivaroxaban use in this population resulted in fewer thrombotic events but similar major bleeding events when compared with warfarin. A prospective clinical study is required to confirm the findings of the present study.

Supporting information

S1 Table. Disease diagnosis codes according to ICD-9-CM, ATC classification of medications, and reimbursement codes for procedures.

(DOCX)

Acknowledgments

We appreciate the assistance provided by Health and Clinical Data Research Center, College of Public Health, Taipei Medical University, Taipei, Taiwan.

Data Availability

In regards to data availability, our study used National Health Insurance Research Data, a healthcare claims data that provided by the Health and Welfare Science Data Center (HWDC), Ministry of Health and Welfare in Taiwan. The HWDC is a third-party organization. Researchers can submit application to HWDC in order to have access to several health-related databases. Due to legal restrictions imposed by the government of Taiwan in relation to the Personal Information Protection Act, data cannot be made publicly available. Requests for data can be sent as a formal proposal to the HWDC with an IRB approval letter. The contact information of Taipei Medical University Joint IRB is tmujirb@gmail.com. All data were fully anonymized before we access them. In addition, these data can only be access and analyzed in an independent operating area in the HWDC. Only statistical results can be brought out from the operating area. Therefore, original data cannot be shared publicly due to legal restrictions.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Yoshihiro Fukumoto

22 Jan 2021

PONE-D-20-36593

Effectiveness and safety of rivaroxaban versus warfarin in Taiwanese patients with end-stage renal disease and non-valvular atrial fibrillation: A real-world nationwide cohort study

PLOS ONE

Dear Dr. Huang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Yoshihiro Fukumoto

Academic Editor

PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Huang et al. conducted a retrospective observational cohort study using a database of the national health insurance in Taiwan, elucidating the effectiveness and safety of rivaroxaban, in comparison to warfarin, in patients with ESRD and NVAF. There were significantly less thromboembolic episodes in patients taking rivaroxaban whereas bleeding events were comparable between the groups. The authors concluded that rivaroxaban may be associated with a lower risk of thromboembolism compared to warfarin in patients with ESRD and NVAF. The number of studied patient was relatively small and data with regard to drug adherence is not available. There are apparent limitations in the present study due to its study design and data source, although clinically important issues are dealt with.

Major comments:

#1. Setting of the control group:

As the author stated in the manuscript, warfarin therapy is not established in the studied population. Data of patients with ESRD and NVAF NOT taking anticoagulation is important and should be compared. In addition, TTR in the warfarin group was not presented. Is this data unavailable?

#2. Eligible patients:

In the method section, the authors stated that eligible patient were selected by the use of erythropoiesis-stimulating agents, which was limited to ESRD patients. The situation is understandable, however, how can it be proven that they truly extracted patients with ESRD? How do they exclude the possibility of over-indication of erythropoiesis-stimulating agents?

#3. What was the proportion of patients with hemodialysis?

#4. Issue of drug adherence:

The authors should state about this in the discussion and limitations.

Minor comments:

#1. Has the number of patient unchanged after the IPTW (table 1)?

#2. Number of patient receiving 10mg rivaroxaban should be stated in the text and table 3.

#3. The manuscript is basically well written. However, English usage should be revised through the manuscript again.

Reviewer #2: Comments to the Author

Yi-Cheng Lin et al. examined the efficacy and safety of rivaroxaban and warfarin in patients with end-stage renal disease in a population-based cohort study.

The author has clearly shown valuable information that will change future clinical practice. I think this paper is a well-written and informative study.

Major comments

This paper is an important study analyzed in detail by population-based cohort study using National Health Insurance.

If possible, please consider the content of the following papers.

Biol Pharm Bull 2011;34:824-30: The role of PAR2 in the progression of renal function.(This paper is related to the other fact that type Xa DOAC prevents the role of PAR2)

In addition, as shown in Reference paper 20, comparing with antiplatelet drugs and examining dialysis cases leads to deeper consideration..

**********

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Reviewer #1: No

Reviewer #2: No

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Attachment

Submitted filename: PLOS ONE review Comment to Editor.docx

Attachment

Submitted filename: PLOS ONE review Comment to Author.docx

PLoS One. 2021 Apr 8;16(4):e0249940. doi: 10.1371/journal.pone.0249940.r002

Author response to Decision Letter 0


26 Feb 2021

Reviewer #1:

1. Setting of the control group: As the author stated in the manuscript, warfarin therapy is not established in the studied population. Data of patients with ESRD and NVAF NOT taking anticoagulation is important and should be compared.

Authors’ response: Thank you for your valuable suggestions. While comparing rivaroxaban with no anticoagulation in patients with ESRD and NVAF is important, there is a concern of significant confounding effect (confounding by indication) in such study design. For example, clinicians may choose not to use anticoagulants in patients with high bleeding risk, and such risk may not be captured by claims data. Other publication regarding comparison of direct oral anticoagulant and warfarin also raised similar issue (Circulation. 2018;138:1519–1529). Prospective study is needed to answer this important question. According to your comments, we revised the Discussion section of the manuscript as below (page 23 line 225):

Our study did not include patients with no anticoagulation because such a study design imposes a significant confounding effect that cannot be eliminated through statistical adjustments.

2. TTR in the warfarin group was not presented. Is this data unavailable?

Authors’ response: TTR in the warfarin group is not available since our data source does not contain laboratory data. This was included as one of our study limitations (page 24 line 242).

3. Eligible patients: In the method section, the authors stated that eligible patient were selected by the use of erythropoiesis-stimulating agents, which was limited to ESRD patients. The situation is understandable, however, how can it be proven that they truly extracted patients with ESRD? How do they exclude the possibility of over-indication of erythropoiesis-stimulating agents?

Authors’ response: Thank you for your comments. In order to eliminate possibility of over-indication of erythropoiesis-stimulating agents (ESA), we only included ESA users who also had end-stage renal disease (ESRD) diagnosis. To avoid misunderstanding, we revised the Methods section of the manuscript as below (page 8 line 67):

For erythropoiesis-stimulating drug users, we specifically included those with an ESRD diagnosis identified through ICD-9 codes to eliminate patients using these agents for off-label indications.

4. What was the proportion of patients with hemodialysis?

Authors’ response: The proportion of patients on dialysis was 82.5%, with 67 subjects in the rivaroxaban group and 2702 subjects in the warfarin group. We did not perform analyses in patients on dialysis separately because rivaroxaban cannot be eliminated by renal replacement therapy. Drug concentration is likely similar between ESRD patients who are not on dialysis and patients who are on regular dialysis.

5. Issue of drug adherence: The authors should state about this in the discussion and limitations.

Authors’ response: Thank you for your comments. Since the actual adherence rate cannot be determined due to the nature of our data source, we revised the Discussion section of the manuscript as below (Page 24 line 243):

Information of actual adherence rates were unavailable in our data source.

6. Has the number of patient unchanged after the IPTW (table 1)?

Authors’ response: The purpose of IPTW is to create a synthetic sample in which treatment assignment is independent of baseline covariates (Stat Med. 2015 Dec 10; 34(28): 3661–3679). Thus, the number of patients might slightly change after IPTW. The advantage of this method is that it uses the entire cohort rather than selecting some matching subjects. We used this method in our previous published work (J Am Coll Cardiol. 2018 Jul 31;72(5):477-485).

7. Number of patient receiving 10mg rivaroxaban should be stated in the text and table 3.

Authors’ response: Number of patients receiving 10 mg rivaroxaban was stated in the Result section of the manuscript (page 12 line 126). The number was added to Table 3 according to your comment.

8. The manuscript is basically well written. However, English usage should be revised through the manuscript again.

Authors’ response: Thank you for your advice. We submitted our manuscript to English editing service. Revised manuscript with track changes is attached.

Reviewer #2:

1. If possible, please consider the content of the following papers: Biol Pharm Bull 2011;34:824-30: The role of PAR2 in the progression of renal function.(This paper is related to the other fact that type Xa DOAC prevents the role of PAR2)

Authors’ response: Thank you for providing this important paper. We added this paper into the Discussion section of the manuscript as below (page 23 line 227):

Furthermore, direct oral anticoagulants have fewer drug and food interactions and monitoring requirements. In addition, some studies have indicated that factor Xa inhibition may ameliorate nephropathy, and rivaroxaban has been associated with a slower decline in renal function compared with warfarin [38, 39].

2. In addition, as shown in Reference paper 20, comparing with antiplatelet drugs and examining dialysis cases leads to deeper consideration.

Authors’ response: The use of antiplatelet drugs in end-stage renal disease (ESRD) patients with atrial fibrillation for stroke prevention has been seen in clinical practice. However, clinical outcomes of antiplatelet drugs in this population has been unfavorable and is not recommended by clinical guidelines. Therefore, we did not compare rivaroxaban with antiplatelet drugs in the present study. In light of your valuable comments, we revised the Discussion section of the manuscript as below (page 24 line 236):

Other therapies such as antiplatelet drugs have been investigated in retrospective observational studies, and they did not confer stroke prevention benefits in patients with ESRD [41, 42]. The current guidelines do not recommend antiplatelet agent use for stroke prevention [43]. Therefore, our study did not compare clinical outcomes between rivaroxaban and antiplatelet agents.

Decision Letter 1

Yoshihiro Fukumoto

29 Mar 2021

Effectiveness and safety of rivaroxaban versus warfarin in Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation: A real-world nationwide cohort study

PONE-D-20-36593R1

Dear Dr. Huang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Yoshihiro Fukumoto

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript has been much improved. The study results will be informative for readers of the journal. The reviewer has no further comments.

Reviewer #2: Comments to the Author

This manuscript has been improved very much.

This paper is acceptable for publication as is.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Yasushi Mukai, MD, PhD

Reviewer #2: No

Acceptance letter

Yoshihiro Fukumoto

31 Mar 2021

PONE-D-20-36593R1

Effectiveness and safety of rivaroxaban versus warfarin in Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation: A real-world nationwide cohort study

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Disease diagnosis codes according to ICD-9-CM, ATC classification of medications, and reimbursement codes for procedures.

    (DOCX)

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    Submitted filename: PLOS ONE review Comment to Author.docx

    Data Availability Statement

    In regards to data availability, our study used National Health Insurance Research Data, a healthcare claims data that provided by the Health and Welfare Science Data Center (HWDC), Ministry of Health and Welfare in Taiwan. The HWDC is a third-party organization. Researchers can submit application to HWDC in order to have access to several health-related databases. Due to legal restrictions imposed by the government of Taiwan in relation to the Personal Information Protection Act, data cannot be made publicly available. Requests for data can be sent as a formal proposal to the HWDC with an IRB approval letter. The contact information of Taipei Medical University Joint IRB is tmujirb@gmail.com. All data were fully anonymized before we access them. In addition, these data can only be access and analyzed in an independent operating area in the HWDC. Only statistical results can be brought out from the operating area. Therefore, original data cannot be shared publicly due to legal restrictions.


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