Edited by: Yuli Huang, Southern Medical University, China
Reviewed by: Wanling Xuan, Augusta University, United States; Jianqing She, The First Affiliated Hospital of Xi'an Jiaotong University, China; Xina Xie, Shenzhen Second People's Hospital, China
This article was submitted to General Cardiovascular Medicine, a section of the journal Frontiers in Cardiovascular Medicine
†These authors have contributed equally to this work and share first authorship
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Atrial fibrillation (AF) has a prevalence of 2–3% worldwide (
Direct oral anticoagulants (DOACs), including dabigatran, apixaban, edoxaban, and rivaroxaban (
This was a prospective observational study using data from AF patients who were admitted to the First Affiliated Hospital of Shantou University Medical College from 2019 to 2020. The inclusion criteria were above 18 years of age, had medical conditions that required anticoagulation, received either rivaroxaban, warfarin, or no anticoagulation therapy, and consented to follow-up after the index discharge date. AF patients with the following characteristics were excluded: (1) pregnant; (2) used warfarin with no INR values; (3) used rivaroxaban with missing dosing information; (4) were missing baseline risk factors or demographic information. Patients with evidence of AF from electronic health records or electrophysiologic evaluations were considered as having AF. AF was defined as a supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequent ineffective atrial contraction. The electrocardiographic characteristics of AF include irregular R-R intervals (when atrioventricular conduction is not impaired), absence of distinct repeating P-waves, and irregular atrial activations (
Subject characteristics at baseline, including medical histories, prior and concomitant medications, demographic characteristics, alcohol, smoking, CHA2DS2-VASc score, HAS-BLED score, and other clinical characteristics, as well as the usage of treatments and baseline INR, were collected from the medical records. Follow-up INR records, and anticoagulant treatments were procured from telephone visits and the hospital system's outpatient-based electronic medical records. The baseline comorbidities were rheumatic heart disease (RHD), malignancy, chronic kidney disease (CKD), chronic obstructive pulmonary disease diastolic (COPD), thyroid disease, congestive heart failure (CHF), gastrointestinal (GI) bleeding, hypertension, diabetes mellitus, coronary disease, and ischemic stroke. Other clinical characteristics were systolic blood pressure (SBP), diastolic blood pressure (DBP), creatinine (Cr), prothrombin time-international normalized ratio (PT-INR), and ejection fraction (EF). Prior medications were aspirin, clopidogrel, and statin. For quantifying thromboembolic risk, we combined comorbidity information into the CHA2DS2-VASc score (
Follow-ups were carried out by medical record review and/or telephone interviews at 30, 90, 180, and 365 days after discharge. The follow-up period for patients using rivaroxaban started from the index date of rivaroxaban prescription. The follow-up period of patients without anticoagulants started from the index date of hospital discharge. The follow-up period of patients receiving warfarin began from the last discharge date with warfarin prescription. Patient information, including survival status, INR, and anticoagulant treatment was collected during follow-up through electronic medical records. All INR values were collected during follow-up, independent of the follow-up visits. Patients with missing medical records were contacted via telephone interviews with patients or their family members to collect their information. If patients could not be followed up through electronic medical records or telephone interview, such patients were recorded as lost to follow-up. All patients were followed up to the occurrence of death, switching of treatment (i.e., received OAC for the anticoagulant-untreated group; received an alternative OAC, including dabigatran and apixaban, for the warfarin group and rivaroxaban group), were lost to follow-up, and the end of the study period, whichever came first. For patients who switched anticoagulant treatments during follow-up, only information collected from study enrollment to the day of switching anticoagulant treatments was used for the analysis.
The primary outcome of this study was all-cause mortality, collected using telephone visits and medical records of subjects.
The warfarin treatment groups were categorized based on the PT-INR (PT-INR <2, 2 ≤ PT-INR ≤ 3, PT-INR>3) collected at the last hospital discharge before the occurrence of death or last contact date. The warfarin treatment groups were also categorized based on the percentage of INR measurements in the therapeutic range (PINRR), with a PINRR ≤ 56.1% regarded as poor INR control and a PINRR > 56.1% regarded as good INR control. PINRR was the number of INR values of 2.0–3.0 of the total number of INR values measured. A cut-off value of PINRR ≤ 56.1% was shown to be a good discriminator of a time to therapeutic range (TTR) <65% (
For continuous variables, data are shown as mean ± standard deviation or median with interquartile ranges. For categorical variables, data are shown as counts with percentages. The baseline characteristics of the anticoagulant-untreated groups were compared with warfarin groups and rivaroxaban groups using the Kruskal-Wallis test for continuous variables and chi-square tests for categorical variables.
Cumulative incidence of mortality was estimated using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to compare the risk of mortality of patients without anticoagulants to patients using warfarin, as well as patients receiving rivaroxaban. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented. Multivariable models for the comparison of patients using warfarin and patients without anticoagulant medication was adjusted for gender, age, TIA/stroke, malignancy, CKD, and GI bleeding. Multivariable models for the comparison of patients receiving rivaroxaban and patients without anticoagulants were adjusted for gender, age, coronary disease, TIA/stroke, aspirin, CHF, malignancy, CKD, and statin. Statistical analyses were performed using SPSS version 22.0 (SPSS Inc., Chicago, Illinois, USA), and figures were constructed using R software version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Two-tailed
A total of 2092 patients with AF, who were discharged between 2019 and 2020, were enrolled in this cohort. Among the 2092 participants, 204 patients were excluded because of lack of follow-up data, 49 patients in the warfarin-treated group were excluded because of missing INR values, 86 patients in the rivaroxaban-treated group were excluded because of missing dosing information, and 26 patients were excluded owing to lack of baseline risk factors or demographic information. The final analysis included 1,727 patients with diagnosed AF, of which 873 patients did not use any anticoagulant, 457 patients received warfarin and 397 patients used rivaroxaban. Baseline characteristics of patients without anticoagulants, patients using warfarin (PT-INR < 2, 2 ≤ PT-INR ≤ 3, PT-INR > 3, PINRR > 56.1%, PINRR ≤ 56.1%), and NVAF patients receiving rivaroxaban (≤ 10, 15, 20 mg) are shown in
Baseline characteristics of enrolled patients (A) warfarin and (B) rivaroxaban.
Gender (female) | 345 (39.5%) | 179 (54.2%) | 41 (44.1%) | 19 (55.9%) | <0.001 | 187 (52.8%) | 52 (50.5%) | <0.001 |
Age (years) | 70.45 ± 12.61 | 64.16 ± 11.45 | 64.75 ± 10.56 | 67.15 ± 7.97 | <0.001 | 64.42 ± 11.30 | 64.51 ± 9.87 | <0.001 |
CHA2DS2-VASc score | 3.48 ± 1.85 | 3.06 ± 1.68 | 2.95 ± 1.39 | 3.24 ± 1.5 | <0.001 | 2.85 ± 1.64 | 2.92 ± 1.49 | <0.001 |
HAS-BLED score | 2.7 ± 1.19 | 2.34 ± 1.19 | 2.36 ± 1.14 | 2.61 ± 1.14 | <0.001 | 2.28 ± 1.08 | 2.45 ± 1.20 | <0.001 |
RHD | 34 (3.95%) | 100 (30.9%) | 38 (41.3%) | 11 (34.4%) | <0.001 | 105 (29.7%) | 44 (42.7%) | <0.001 |
CKD | 122 (14.2%) | 33 (10.2%) | 10 (10.9%) | 7 (21.9%) | 0.11 | 39 (11.0%) | 11 (10.7%) | 0.49 |
COPD | 64 (7.4%) | 10 (3.1%) | 4 (4.4%) | 1 (3.1%) | 0.031 | 11 (3.1%) | 4 (3.9%) | 0.0358 |
CHF | 401 (45.9%) | 225 (68.2%) | 70 (75.3%) | 24 (70.6%) | <0.001 | 245 (6.9%) | 74 (7.2%) | <0.001 |
GI bleeding | 32 (3.7%) | 4 (1.2%) | 1 (1.1%) | 2 (6.3%) | 0.06 | 6 (1.7%) | 1 (1.0%) | 0.14 |
Hypertension | 541 (62.9%) | 149 (46.0%) | 37 (40.2%) | 13 (40.6%) | <0.001 | 157 (44.4%) | 42 (40.8%) | <0.001 |
Diabetes mellitus | 238 (27.7%) | 79 (24.9%) | 24 (26.1%) | 12 (37.5%) | 0.37 | 89 (25.1%) | 26 (25.2%) | 0.75 |
Coronary disease | 326 (37.9%) | 77 (23.8%) | 20 (21.7%) | 4 (12.5%) | <0.001 | 84 (23.7%) | 17 (16.5%) | <0.001 |
Ischemic stroke | 228 (26.5%) | 72 (22.2%) | 16 (17.4%) | 4 (12.5%) | 0.05 | 74 (20.9%) | 18 (17.5%) | 0.095 |
Smoking | 270 (30.9%) | 70 (21.2%) | 23 (24.7%) | 5 (14.7%) | 0.002 | 76 (21.5%) | 22 (21.4%) | 0.0173 |
SBP (mmHg) | 139.6 ± 47.0 | 131.6 (23.1) | 128.5 ± 24.8 | 130.4 ± 24.2 | 0.032 | 131.8 ± 22.7 | 129.3 ± 22.0 | <0.001 |
DBP (mmHg) | 86.29 ± 41.0 | 84 ± 18.1 | 79.45 ± 15.2 | 84.17 ± 12.7 | 0.53 | 83.5 ± 17.1 | 81.1 ± 14.2 | 0.17 |
Cr (μmol/L) | 126.96 ± 91.1 | 118.07 ± 98.0 | 115.36 ± 57.1 | 127.42 ± 42.6 | <0.001 | 116.4 ± 81.3 | 116.6 ± 52.0 | 0.23 |
PT-INR | 1.16 ± 0.54 | 1.5 ± 1.31 | 2.22 ± 0.95 | 3.79 ± 0.95 | 0.013 | 1.61 ± 1.46 | 2.11 ± 0.94 | <0.001 |
EF (%) | 58.01 ± 12.2 | 57.71 ± 12.6 | 58.17 ± 12.6 | 59.31 ± 11.8 | 0.19 | 57.84 ± 11.07 | 57.47 ± 9.84 | 0.61 |
Aspirin-clopidogrel | 467(53.5%) | 95(28.8%) | 13(14.0%) | 4 (11.8%) | <0.001 | 98 (27.7%) | 14 (13.6%) | <0.001 |
Statin | 489 (56.0%) | 158 (47.9%) | 39 (41.9%) | 10 (29.4%) | <0.001 | 166 (46.9%) | 41 (39.8%) | 0.0021 |
Sex (Female) | 316 (38.9%) | 58 (42.3%) | 82 (42.9%) | 30 (28.0%) | 0.0276 | |||
Age (years) | 70.70 ± 12.41 | 74.74 ± 9.0 | 71.12 ± 9.80 | 62.06 ± 10.30 | <0.001 | |||
CHA2DS2-VASc score | 3.43 ± 1.83 | 4.22 ± 1.50 | 3.35 ± 1.64 | 2.09 ± 1.60 | <0.001 | |||
HAS-BLED score | 2.66 ± 1.16 | 2.91 ± 1.12 | 2.45 ± 1.05 | 1.8 ± 1.11 | <0.001 | |||
RHD | 8 (0.98%) | 3 (2.2%) | 5 (2.6%) | 2 (1.9%) | 0.37 | |||
CKD | 98 (12.05%) | 21 (15.7%) | 16 (8.4%) | 7 (6.7%) | 0.0302 | |||
COPD | 56 (6.89%) | 11 (8.2%) | 18 (9.4%) | 3 (2.9%) | 0.20 | |||
CHF | 308 (37.9%) | 81 (59.1%) | 99 (51.8%) | 26 (24.3%) | 0.0017 | |||
GI bleeding | 25 (3.08%) | 6 (4.5%) | 1 (0.5%) | 0 (0) | 0.081 | |||
Hypertension | 505 (62.1%) | 100 (74.6%) | 125 (65.5%) | 55 (52.4%) | <0.001 | |||
Diabetes mellitus | 230 (28.3%) | 46 (34.3%) | 43 (22.5%) | 20 (19.1%) | 0.0076 | |||
Coronary disease | 308 (37.9%) | 65 (48.5%) | 84 (44.0%) | 36 (34.3%) | 0.0017 | |||
Ischemic stroke | 219 (26.9%) | 44 (32.8%) | 38 (19.9%) | 17 (16.2%) | <0.001 | |||
Smoking | 257 (31.6%) | 29 (21.2%) | 45 (23.6%) | 37 (34.6%) | 0.0084 | |||
SBP (mmHg) | 138.86 ± 46.3 | 139.6 ± 21.1 | 138.1 ± 24.0 | 130.7 ± 20.6 | <0.001 | |||
DBP (mmHg) | 85.97 ± 39.95 | 84.3 ± 14.4 | 87.0 ± 16.5 | 83.2 ± 12.1 | 0.25 | |||
Cr (μmol/L) | 118.89 ± 61.56 | 119.2 ± 43.3 | 105.4 ± 28.3 | 104.2 ± 25.1 | 0.072 | |||
PT-INR | 1.18 ± 0.46 | 1.13 ± 0.31 | 1.14 ± 0.71 | 1.07 ± 0.24 | 0.41 | |||
EF (%) | 58.1 ± 9.98 | 57.51 ± 13.2% | 58.36 ± 12.28 | 61.46 ± 10.14 | 0.27 | |||
Aspirin-clopidogrel | 444 (54.6%) | 72 (52.6%) | 80 (41.9%) | 31 (29.0%) | <0.001 | |||
Beta-blocker | 484 (59.5%) | 73 (54.9%) | 106 (64.5%) | 66 (70.2%) | 0.097 | |||
Statin | 476 (58.6%) | 101 (73.7%) | 110 (57.6%) | 54 (50.5%) | <0.001 |
The cumulative incidence of mortality in patients using warfarin (PT-INR < 2, 2 ≤ PT-INR ≤ 3, PT-INR > 3), as well as PINRR (>56.1%, ≤ 56.1%), was lower than that of patients not using anticoagulants (log-rank
Cumulative mortality of warfarin groups and the anticoagulant-untreated group (PT-INR).
Cumulative mortality of warfarin groups and the anticoagulant-untreated group (PINRR).
Univariate and multivariable analysis comparing the mortality of patients receiving warfarin vs. no anticoagulant treatment.
Reference | Reference | |||
<2 | 0.274 (0.158, 0.475) | <0.0001 | 0.309 (0.170, 0.560) | 0.0001 |
2–3 | 0.444 (0.196, 1.007) | 0.052 | 0.539 (0.236, 1.229) | 0.14 |
>3 | 0.571 (0.182, 1.794) | 0.34 | 0.652 (0.207, 2.052) | 0.46 |
≤ 56.1% | 0.345 (0.211, 0.562) | <0.0001 | 0.363 (0.220, 0.599) | <0.0001 |
>56.1% | 0.428 (0.189, 0.969) | 0.0418 | 0.387 (0.170, 0.882) | 0.0238 |
There was a clear trend showing that NVAF patients using rivaroxaban (≤ 10, 15, 20 mg) had a significantly lower incidence of mortality than patients without anticoagulant treatment (log-rank test
Cumulative mortality of rivaroxaban groups and the anticoagulant-untreated group.
Univariate and multivariable analysis comparing the mortality of patients receiving rivaroxaban vs. no anticoagulant treatment.
No anticoagulant | Reference | Reference | ||
Rivaroxaban ≤ 10 mg | 0.529 (0.300, 0.935) | 0.0285 | 0.454 (0.256, 0.804) | 0.0068 |
Rivaroxaban 15 mg | 0.136 (0.050, 0.368) | <0.0001 | 0.139 (0.051, 0.376) | 0.0001 |
Rivaroxaban 20 mg | 0.171 (0.055, 0.538) | 0.0025 | 0.276 (0.087, 0.874) | 0.0286 |
In this study, we investigated the risk of mortality in Asians with AF who received warfarin, rivaroxaban, or no anticoagulant therapy. The main findings of this study are as follows: (1) among patients taking warfarin, patients with an INR lower than 2, as well as PINRR ≤ 56.1% and PINRR > 56.1%, had a significantly lower risk of mortality than that of patients without anticoagulant therapy, suggesting that warfarin still noticeably reduces the risk of mortality in Asians despite not achieving a target standard-intensity INR of 2–3; (2) low-dose rivaroxaban treatment (10 mg/day) is associated with a significantly lower risk of mortality than in patients not treated with anticoagulants, indicating that low-dose rivaroxaban may have survival benefits for Asians.
Previous studies have found a high percentage of AF patients do not follow the practice guidelines, especially in the Asian population (
Intake of direct oral anticoagulants for the prevention of stroke in patients with AF is increasing rapidly worldwide, but varies widely, depending mainly but not exclusively on the socioeconomic status of the country under consideration (
Furthermore, several studies have shown that DOACs are more commonly studied in low-risk populations (
Due to the complex clinical profile of patients with AF, certain patients were usually excluded from previous randomized controlled trials, making it challenging for physicians to prescribe anticoagulation therapy in clinical practice. On the one hand, our study includes a wide range of AF patients encountered in clinical practice. Therefore, our study could, to some extent, reflect the treatment patterns and associated risks of mortality in the Chinese population. On the other hand, our study observes treatment patterns and outcomes after discharge, and as such, it examines the associations of post-hospitalization anticoagulant dosage use patterns and death. The drug dose of OACs was as per the attending physician's discretion based on the patients' conditions and was collected from the medical records. Non-compliance with guidelines for warfarin and rivaroxaban use may be influenced by many factors. First, the perceived risks of bleeding impeded clinicians from prescribing anticoagulants and patients to adhere to therapy. Second, some patients with low body weight and/or renal impairment were underdosed because of a fear of toxicity. Finally, the high cost of rivaroxaban limited the options for some patients in the cohort. Nevertheless, there are limitations to this study. First, our patients are from a hospital that may have introduced selection bias. Second, our study does not include clinical information, such as bleeding events, thrombosis events, and BMI because of unclear or incomplete data. Third, although TTR has been recommended by the main international guidelines (
In Asian patients with AF, the risk of death is significantly lower in both patients receiving rivaroxaban and patients using warfarin with an INR below 2 in comparison with patients without anticoagulant therapy. These findings show that, despite effects being smaller than obtained with recommended doses, the use of warfarin below the standard INR target and the use of low-dose rivaroxaban still provide survival benefits, suggesting viable alternatives to physicians to better resolve decisional conflicts with the risks and benefits of anticoagulant therapy, as well as to patients in need of anticoagulant therapy but are not receiving it due to bleeding risk or other factors, such as financial burden, concerns of adverse outcomes, as well as low treatment compliance and persistence.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by Ethics Committee of the First Affiliated Hospital of Shantou University Medical College. The patients/participants provided their written informed consent to participate in this study.
XT and YC: contributed to the conception and design of the work. DL, JY, SW, YZ, and WL: contributed to the data collection and data management. YC and DL: contributed to the analysis, interpretation of data, and drafted the manuscript. XT, RL, and YC: reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.
This study was supported by projects from Grant for Key Disciplinary Project of Clinical Medicine under the High-level University Development Program (2020), Innovation Team Project of Guangdong Universities (2019KCXTD003), Li Ka Shing Foundation Cross-Disciplinary Research Grant (2020LKSFG19B), Funding for Guangdong Medical Leading Talent (2019–2022), National Natural Science Foundation of China (82073659), and Dengfeng Project for the construction of high-level hospitals in Guangdong Province—the First Affiliated Hospital of Shantou University Medical College (202003-2).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The authors would like to express their appreciation to the staffs of the First Affiliated Hospital of Shantou University Medical College for their assistance.