Abstract
Background
Dose adjustment of non‐vitamin K antagonist oral anticoagulants (NOACs) is indicated in some patients with atrial fibrillation (AF), based on selected patient factors or concomitant medications. We assessed the frequency of label adherence of NOAC dosing among AF patients and the associations between off‐label NOAC dosing and clinical outcomes.
Methods and Results
We evaluated 53 649 AF patients treated with an NOAC using Korean National Health Insurance Service database during the period from 2013 to 2016. NOAC doses were classified as either underdosed or overdosed, consistent with Korea Food and Drug Administration labeling. Cox proportional hazards regression was performed to investigate the effectiveness and safety outcomes including stroke or systemic embolism, major bleeding, and all‐cause mortality. Overall, 16 757 NOAC‐treated patients (31.2%) were underdosed, 4492 were overdosed (8.4%), and 32 400 (60.4%) were dosed appropriately according to drug labeling. Compared with patients with label adherence, those who were underdosed or overdosed were older (aged 71±8 and 75±7 years versus 70±9 years, respectively; P<0.001) and had higher CHA 2 DS 2‐VASc scores (4.6±1.7 and 5.3±1.7 versus 4.5±1.8, respectively; P<0.001). NOAC overdosing was associated with increased risk for stroke or systemic embolism (5.76 versus 4.03 events/100 patient‐years, P<0.001), major bleeding (4.77 versus 2.94 events/100 patient‐years, P<0.001), and all‐cause mortality (5.43 versus 3.05 events/100 patient‐years, P<0.001) compared with label‐adherent use.
Conclusions
In real‐world practice, a significant proportion (almost 2 in 5) of AF patients received NOAC doses inconsistent with drug labeling. NOAC overdosing is associated with worse clinical outcomes in Asian AF patients.
Keywords: atrial fibrillation, label adherence, non‐vitamin K antagonist oral anticoagulants, overdosing, underdosing
Subject Categories: Atrial Fibrillation, Epidemiology, Ischemic Stroke
Nonstandard Abbreviations and Acronyms
- AF
atrial fibrillation
- OAC
oral anticoagulation
- NOAC
non‐vitamin K antagonist oral anticoagulants
- NHIS
national health insurance system
- ICD‐10
International Classification of Diseases, Tenth Revision
Clinical Perspective
What Is New?
The real‐world label adherence of non‐vitamin K antagonist oral anticoagulants (NOAC) dosing across all 4 NOACs and their clinical effects in Asian atrial fibrillation patients were investigated.
Of those treated, only 60% of patients were dosed appropriately, with 30% of patients underdosed in real‐world practice.
What Are the Clinical Implications?
NOAC overdosing was associated with increased risk for adverse outcomes compared with label‐adherent dosing.
There was no safety benefit of underdosing compared with the appropriate dosing of NOACs.
Label adherence of NOAC dosing is important to improve the clinical outcomes in atrial fibrillation patients.
The prevalence of atrial fibrillation (AF) is rapidly increasing globally, especially in the Asian population,1, 2 and oral anticoagulation (OAC) is the principal management for stroke prevention in patients with AF.3, 4 The efficacy and safety of the non‐vitamin K antagonist oral anticoagulants (NOAC) have all been shown at least as effective and safe as warfarin in large randomized controlled trials.5, 6, 7, 8
Dose adjustment of NOACs is indicated in some AF patients, based on selected patient factors such as renal function, age, body weight, or concomitant medications.9 However, whether these dose recommendations are adhered to in community practice remains a major concern. In a study with ORBIT‐AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) database,10 NOAC over‐ and underdosing were shown to be associated with increased risk for adverse events. In addition, a previous study using a large US administrative database with about 15 000 AF patients revealed that the prescribed doses were often inconsistent with the renal dose recommendation by Food and Drug Administration labeling.11 In that study, inappropriate dose reduction was related to reduced effectiveness for stroke prevention without any safety benefit. Recently, we reported the real‐world effectiveness and safety of edoxaban in Korean AF patients in relationship to renal function.12 Interestingly, low‐dose edoxaban had lower effectiveness for stroke prevention compared with warfarin at higher levels of creatinine clearance, which is called super normal renal function.
Therefore, in the current study, we sought to assess the frequency of label adherence of NOAC dosing among Korean AF patients, and to analyze the associations between off‐label NOAC dosing and clinical outcomes in real‐world clinical practice.
Methods
Data Source
This study is based on the national health claims database established by the national health insurance system (NHIS) of Republic of Korea.13, 14 The NHIS is the single insurer managed by the Korean government, and the majority (97.1%) of the Korean population are mandatory subscribers, with the remaining 3% of the population being medical aid subjects. The NHIS database contains the information of medical aid subjects, therefore it is based on the entire Korean population. All data and materials have been made publicly available at the National Health Insurance Sharing Service and can be accessed at (https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do).
The NHIS also provides regular health check‐up programs for the public. Subscribers of the NHIS are recommended to undergo this check‐up at least biennially, and it includes blood tests, chest X‐ray examinations, physical examinations of the patients, and questionnaires on their medical history. Every population in the NHIS database was linked by the Korean social security numbers, and all social security numbers were deleted after constructing the cohort by giving serial numbers to prevent leakage of personal information. This study was approved by the Institutional Review Board of Yonsei University Health System (4‐2016‐0179), and informed consent was waived.
Study Population
We identified a total of 866 363 patients with prevalent AF who were aged ≥18 years from January 1, 2013 to December 31, 2016. AF was diagnosed using the International Classification of Diseases, Tenth Revision (ICD‐10) codes, I48 (AF and atrial flutter), I48.0 (AF), and I48.1 (atrial flutter). Moreover, patients were diagnosed with AF only when it was a discharge diagnosis or confirmed more than twice in the outpatient department to ensure diagnostic accuracy.15 The diagnosis of AF has previously been validated in the NHIS database with a positive predictive value of 94.1%.16, 17, 18 Definitions of other comorbidities are presented in Table S1. The following were exclusion criteria: (1) those with valvular AF (with a diagnosis of mitral stenosis [ICD‐10: I05.0, I05.2, and I34.2] or prosthetic heart valves [ICD‐10: Z95.2–Z95.4], and insurance claims for valve replacement or valvuloplasty) (n=8646), (2) those who ever underwent catheter ablation (n=5607), (3) those ever diagnosed with end‐stage renal disease (n=933), (4) no OAC or OAC use <30 days (n=717 946), (5) OAC use for acute coronary syndrome or deep vein thrombosis prophylaxis (n=4188), or (6) warfarin users (n=34 851) (Figure 1).
Figure 1. Flowchart of study population enrollment.
ACS indicates acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; ESRD, end‐stage renal disease; NOAC, non‐vitamin K antagonist oral anticoagulants; NVAF, non‐valvular atrial fibrillation; OAC, oral anticoagulants; and RFCA, radiofrequency catheter ablation.
Among the 94 192 patients, patients without baseline anthropometric and laboratory measurements for evaluation of compliance with labeled dosing were excluded (n=40 543). Finally, we identified 53 649 non‐valvular AF patients in this study. We defined the date of the first oral anticoagulant prescription as the index date. The follow‐up period was defined as from the index date until the first occurrence of any study outcome or the end date of the study period (December 31, 2016), whichever came first.
NOAC Dose Reduction Criteria and Dosing According to Label
A standard dose was defined, according to each NOAC, as dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Approved dose reduction criteria were specific to each NOAC, according to the following patient characteristics: age, body weight, serum creatinine level at the patients’ enrollment, and concomitant medications. Creatinine clearance was calculated using the Cockcroft‐Gault equation. The adherence with labeled dosing of each NOAC in each study patient was evaluated based on the Ministry of Food and Drug Safety labeling (Table S2). Patients were categorized into 3 groups based on NOAC dose and dose recommendation adherence: labeled use (n=32 400), underdosing (n=16 757), and overdosing (n=4492).
Study Outcomes
The primary study outcomes were stroke or systemic embolism, major bleeding, and death from any cause. Secondary outcomes were intracranial bleeding, gastrointestinal bleeding, and myocardial infarction. The clinical events that occurred after 1 week of quarantine periods after initial OAC prescription were counted as the study outcomes. The ICD codes for the study outcomes are summarized in Table S3. Data on vital status and date of death were reconfirmed, and the cause of death was determined from the National Population Registry of the Korea National Statistical Office with the use of a unique personal identification number, in which central registration of death was conducted on the basis of death certificates.19 This approach provides a complete event ascertainment.
Statistical Analysis
Continuous variables were presented as means and standard deviations. Comparison of continuous variables was performed using an independent t test or, in case of a non‐normal distribution, the Mann–Whitney test. Categorical variables were represented with numbers and percentages using the Chi‐square test of Fisher exact test. Incidence rates were estimated using the total number of study outcomes during the follow‐up period divided by person‐years at risk. The risk for clinical outcomes for study groups were obtained using survival analysis (Kaplan–Meier method and log‐rank test for univariate analysis and Cox proportional hazards regression for multivariate analysis). Cox proportional hazards regression was used to estimate the unadjusted and adjusted hazard ratio for the association between label adherence of NOAC dosing and clinical outcomes. To control for confounding, we added age, sex, chronic kidney disease, dyslipidemia, and other risk factors included in CHA2DS2‐VASc risk score factors (heart failure, hypertension, diabetes mellitus, stroke or transient ischemic attack, and vascular disease) to our multivariable models. Statistical significance was indicated by a P<0.05. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and SPSS version 23.0 statistical package (SPSS Inc., Chicago, IL, USA).
Results
Baseline Characteristics
Baseline characteristics of study population are presented in Table. We evaluated 53 649 AF patients treated with NOACs (dabigatran 30.5%, rivaroxaban 37.5%, apixaban 22.2%, and edoxaban 9.7%). The mean age was 70.5±8.9 years, 60.3% were men, and the mean CHA2DS2‐VASc score was 4.6±1.8. Four thousand three hundred fifty‐four (8.1%) patients had chronic kidney disease at baseline, and 16.2% and 9.3% of patients were prescribed concomitant aspirin and P2Y12 inhibitors, respectively.
Table 1.
Baseline Characteristics
| Overall (n=53 649) | Underdosing (n=16 757) | Labeled Use (n=32 400) | Overdosing (n=4492) | P Value | |
|---|---|---|---|---|---|
| Age, y | 70.5±8.9 | 70.7±7.9 | 69.8±9.5 | 74.8±7.2 | <0.001 |
| Age <65 y | 11 699 (21.8) | 3086 (18.4) | 8273 (25.5) | 340 (7.6) | <0.001 |
| 65≤ Age <75 y | 22 763 (42.4) | 7809 (46.6) | 13 302 (41.1) | 1652 (36.7) | <0.001 |
| Age ≥75 y | 19 187 (35.8) | 5862 (35.0) | 10 825 (33.4) | 2500 (55.7) | <0.001 |
| Men | 32 350 (60.3) | 10 230 (61.0) | 20 016 (61.8) | 2104 (46.8) | <0.001 |
| Comorbidities | |||||
| Heart failure | 32 845 (61.2) | 10 257 (60.4) | 19 574 (60.4) | 3014 (67.1) | <0.001 |
| Hypertension | 50 921 (96.3) | 15 966 (95.3) | 30 629 (94.5) | 4326 (96.3) | <0.001 |
| Diabetes mellitus | 16 952 (31.6) | 5406 (32.3) | 10 189 (31.4) | 1357 (30.2) | 0.021 |
| Stroke or TIA | 24 411 (45.5) | 6968 (41.6) | 15 096 (46.6) | 2347 (52.2) | <0.001 |
| Vascular disease | 15 443 (28.8) | 4983 (29.7) | 9045 (27.9) | 1415 (31.5) | <0.001 |
| Previous MI | 6285 (11.7) | 2096 (12.5) | 3625 (11.2) | 564 (12.6) | <0.001 |
| PAD | 10 935 (20.4) | 3476 (20.7) | 6443 (19.9) | 1016 (22.6) | <0.001 |
| CKD | 4354 (8.1) | 1279 (7.6) | 2613 (8.1) | 462 (10.3) | <0.001 |
| Dyslipidemia | 49 406 (92.1) | 15 464 (92.3) | 29 773 (91.9) | 4169 (92.8) | 0.055 |
| CHA2DS2‐VASc score | 4.6±1.8 | 4.6±1.7 | 4.5±1.8 | 5.3±1.7 | <0.001 |
| NOAC type | |||||
| Dabigatran | 16 379 (30.5) | 6428 (38.4) | 8934 (27.6) | 1017 (22.6) | <0.001 |
| Rivaroxaban | 20 143 (37.5) | 5426 (32.4) | 12 332 (38.1) | 2385 (53.1) | <0.001 |
| Apixaban | 11 933 (22.2) | 4002 (23.9) | 7673 (23.7) | 258 (5.7) | <0.001 |
| Edoxaban | 5194 (9.7) | 901 (5.4) | 3461 (10.7) | 832 (18.5) | <0.001 |
| Other medication use | |||||
| Aspirin | 8714 (16.2) | 2916 (17.4) | 5079 (15.7) | 719 (16.0) | <0.001 |
| P2Y12 inhibitors | 5005 (9.3) | 1766 (10.5) | 2792 (8.6) | 447 (10.0) | <0.001 |
| ACEi/ARB | 27 535 (51.3) | 8537 (50.9) | 16 714 (51.6) | 2284 (50.8) | 0.323 |
| Beta‐blockers | 30 773 (57.4) | 9698 (57.9) | 18 589 (57.4) | 2486 (55.3) | 0.010 |
| CCBs | 9875 (18.4) | 3173 (18.9) | 5869 (18.1) | 833 (18.5) | 0.081 |
| Digoxin | 9766 (18.2) | 3117 (18.6) | 5617 (17.3) | 1032 (23.0) | <0.001 |
| Diuretics | 24 852 (46.3) | 7866 (46.9) | 14 632 (45.2) | 2354 (52.4) | <0.001 |
| Statins | 31 067 (57.9) | 9560 (57.1) | 18 917 (58.4) | 2590 (57.7) | 0.017 |
| AAD (class Ic) | 8730 (16.3) | 2657 (15.9) | 5590 (17.3) | 483 (10.8) | <0.001 |
| AAD (class III) | 5838 (10.9) | 1697 (10.1) | 3614 (11.2) | 527 (10.9) | <0.001 |
Values are mean±SD or n (%). AAD indicates anti‐arrhythmic drug; ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCBs, calcium channel blockers; CKD, chronic kidney disease; MI, myocardial infarction; PAD, peripheral artery disease; and TIA, transient ischemic attack.
Label Adherence of NOAC Dosing
In the total study population, 31% NOAC‐treated patients were underdosed, 8.4% were overdosed, and 60% were dosed appropriately according to drug labeling. (Table) The overdosing group were older (74.8±7.2 years versus 69.8±9.5 years in labeled use group and 70.7±7.9 years in underdosing group), tended to be women (53.2% versus 38.2% in labeled use group and 39.0% in underdosing group), and had a higher CHA2DS2‐VASc score (5.3±1.7 versus 4.5±1.8 in labeled use group and 4.6±1.7 in underdosing group) than the other groups. Patients taking dabigatran or apixaban were prescribed with underdosing more frequently than those taking rivaroxaban or edoxaban, whereas patients taking rivaroxaban or edoxaban were more frequently prescribed with overdosing than those taking dabigatran or apixaban (Figure 2).
Figure 2. Label adherence of NOAC dosing.
Clinical Outcomes According to Label Adherence
The cumulative incidence of stroke and systemic embolism, major bleeding, intracranial bleeding, gastrointestinal bleeding, acute myocardial infarction and all‐cause death is shown in Figure 3. There was a significantly higher rate of stroke and systemic embolism, major bleeding, gastrointestinal bleeding, and all‐cause death in patients with NOAC overdosing in comparison with labeled use or underdosing.
Figure 3. Cumulative incidence of clinical outcomes according to label adherence.
ICH indicates intracranial bleeding; and MI, myocardial infarction.
In reference with labeled use group, the adverse event in terms of stroke and systemic embolism were higher in overdosing group (5.76 versus 4.03 events/100 patient‐years; hazard ratio [HR], 1.45; 95% CI, 1.01–1.34; adjusted HR [aHR], 1.16; 95% CI, 1.01–1.34) (Figure 4). Major bleeding was significantly higher in the overdosing group (4.77 versus 2.94 events/100 patient‐years; HR, 1.63; 95% CI, 1.39–1.90; aHR, 1.18; 95% CI, 1.01–1.38). Mortality was also significantly higher in the overdosing group (5.43 versus 3.05 events/100 patient‐years; HR, 1.81; 95% CI, 1.56–2.09; aHR, 1.19; 95% CI, 1.02–1.38). The incidence rates of intracranial bleeding, gastrointestinal bleeding, or acute myocardial infarction were comparable between overdosing and labeled use group (Figure 4). On the other hand, underdosing was not associated with worse clinical outcomes in comparison with labeled NOAC use (Figure 5).
Figure 4. Incidence rates and hazard ratios of clinical outcomes in the overdosing group. Each HR was adjusted for age, sex, chronic kidney disease, dyslipidemia, and other risk factors included in CHA 2 DS 2‐VASc risk score factors (heart failure, hypertension, diabetes mellitus, stroke or transient ischemic attack, and vascular disease).
HR indicates hazard ratio; ICH, intracranial bleeding; IR, incidence rate; MI, myocardial infarction; and S/SE, stroke or systemic embolism. *P value for adjusted HR.
Figure 5. Incidence rates and hazard ratios of clinical outcomes in the underdosing group.
Each HR was adjusted for age, sex, chronic kidney disease, dyslipidemia, and other risk factors included in CHA 2 DS 2‐VASc risk score factors (heart failure, hypertension, diabetes mellitus, stroke or transient ischemic attack, and vascular disease). HR indicates hazard ratio; ICH, intracranial bleeding; IR, incidence rate; MI, myocardial infarction; and S/SE, stroke or systemic embolism. *P value for adjusted HR.
The effectiveness and safety outcomes of 4 individual NOACs in terms of over‐/underdosing were also assessed (Figure S1). In reference with labeled use group, overdosing of dabigatran was associated with increasd risk of major bleeding (aHR, 1.39; 95% CI, 1.04–1.88) and gastrointestinal bleeding (aHR, 1.52; 95% CI, 1.10–2.11). Overdosing of apixaban was associated with increased risk of gastrointestinal bleeding (aHR, 1.83; 95% CI, 1.04–3.24) and all‐cause death (aHR, 1.72; 95% CI, 1.10–1.88). In addition, underdosing of rivaroxaban was associated with increasd risk of all‐cause death (aHR, 1.37; 95% CI, 1.16–1.63) compared with labeled use of rivaroxaban.
Discussion
In the current study, we analyzed the label adherence of NOAC dosing across four NOACs and the associations between off‐label NOAC dosing and clinical outcomes in patients with AF in routine clinical practice. We found that off‐label NOAC dosing was not uncommon in the real‐world practice: 31% NOAC‐treated patients were underdosed, 8.4% were overdosed, and 60% were dosed appropriately according to drug labeling. Compared with patients with label adherence, those who were underdosed or overdosed were older, more likely female, and had a higher CHA2DS2‐VASc scores. According to the current analysis, underdosing was not associated with worse clinical outcomes in comparison with labeled NOAC dosing, but there was no benefit in terms of safety either. However, NOAC overdosing was associated with increased risk for stroke or systemic embolism, major bleeding, and all‐cause mortality compared with label‐adherent dosing. These findings could give us meaningful messages of the real‐world NOAC dosing patterns in patients with AF.
Label Adherence of NOAC Dosing in Real‐World Practice
The appropriate dosing of NOACs for stroke prevention in AF has become an important issue. Currently, there are several data on the prescribed doses of NOACs in clinical practice of stroke prevention in AF. In a small Australian analysis, inappropriate NOAC dosing was identified in 34% and renal dysfunction was the primary driver of inappropriate dosing for those patients.20 In larger analysis, in the ORBIT‐AF II registry, 9.4% were underdosed, 3.4% were overdosed, and 87% were dosed according to US labeling.10 Using a large US claims database with 14 865 patients, Yao et al11 reported that 43.0% were potentially overdosed among the patients with a renal indication for dose reduction, and 13.3% were potentially underdosed among the patients with no renal indication for dose reduction. The use of low‐dose NOAC is known to be more frequent among Asian AF patients. In Taiwanese nationwide data, 87% and 90% of the total study subjects were shown to be taking low‐dose rivaroxaban (10–15 mg once daily) and dabigatran (110 mg twice daily), respectively.21 In a recent Korean report using the Comparison Study of Drugs for Symptom Control and Complication Prevention of AF (CODE‐AF) registry,22 the label adherence of NOAC dosing was about 60%, and more than one third of patients with NOAC prescription received an off‐label reduced dose. However, neither studies reported the clinical outcome according to inappropriate NOAC dosing. In the present study, we first reported the real‐world label adherence of NOAC dosing across all 4 NOACs and their clinical effects in Asian AF patients.
Clinical Implication of Label Adherence of NOAC Dosing
There are several studies that have reported clinical outcomes according to label adherence of NOAC dosing. Previously we reported lower relative effectiveness for the prevention of thromboembolic events with low‐dose edoxaban regimen (30 mg daily) compared with warfarin in patients with a creatinine clearance >95 mL/min in real‐world setting.12 In that study, a 30‐mg dosage of edoxaban was used in 31% of patients with supranormal renal clearance and ≈40% of patients were using lower doses of edoxaban inappropriately when analyzed based on body weight and creatinine clearance criteria of label‐recommended edoxaban dosing. In the ORBIT‐AF II registry, NOAC over‐ and underdosing were associated with increased risk for adverse events such as stroke or systemic embolism, myocardial infarction, major bleeding, and all‐cause mortality compared with the recommended dosing of NOACs.10 Especially, inappropriate dose reduction of NOAC was associated with a reduced effectiveness for stroke prevention without any safety benefit.11 Recently, a meta‐analysis of pivotal randomized controlled trials showed that NOACs had an improved benefit‐harm profile compared with warfarin when appropriately dose‐adjusted.23 Efficacy and safety of reduced‐dose NOACs compared with warfarin in patients eligible for reduced‐dose NOACs were consistent with those of full‐dose NOACs relative to warfarin in those eligible for full‐dose NOACs. In our current study, the adverse clinical consequence was higher in the overdosing group compared with the on‐label dosing group, and there was no safety benefit of underdosing compared with the appropriate dosing of NOACs. Based on the results so far, label adherence of NOAC dosing is important to improve the clinical outcomes in AF patients, and further investigation is needed to assess the optimal dosing of NOACs in the Asian AF population.
Study Limitations
There are several limitations in the present study. First, we classified NOAC dosing groups based on patients’ baseline clinical characteristics, there is the possibility that other confounding factors and changes in patient status during the follow‐up period may have influenced the physician's prescription decisions. Especially changes in NOAC dosing during the follow‐up period was not captured in the present analysis, which may in turn affect the findings of the study. Second, the poor clinical outcome of patients in overdosing group might be affected by their older age and higher prevalence of comorbidities, although the NOAC dosing label already reflects factors such as age, body weight, and kidney function. However, because we thought that differences in base characteristics and comorbidities such as patient age or renal function were important factors in determining appropriate NOAC dosing, we present the analysis without matching among groups to show the results as they are in the real world practice setting. Finally, the present nationwide study only enrolled the entire Korean population, whether the results can be extrapolated to other populations remains uncertain. Despite these limitations, our findings reflect the real‐world practice pattern of NOAC dosing in Asian AF patients and the clinical consequences of label adherence of NOAC dosing.
Conclusions
In routine clinical practice, a significant proportion of AF patients received NOAC doses inconsistent with drug labeling. NOAC overdosing is associated with increased risk for stroke or systemic embolism, major bleeding, and all‐cause mortality in Asian AF patients. NOAC underdosing was not significantly associated with increased risk of stroke, but there was no safety benefit in comparison with label‐adhered NOAC dosing.
Sources of Funding
This study was supported by a research grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF‐2017R1A2B3003303, 2017R1C1B1008292) and grants from the Korean Healthcare Technology R&D project funded by the Ministry of Health & Welfare (HI16C0058, HI15C1200).
Disclosures
Dr Lip has served as a consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi‐Sankyo and as a speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi‐Sankyo. No fees are directly received personally. Dr Joung has served as a speaker for Bayer, BMS/Pfizer, Medtronic, and Daiichi‐Sankyo and has received research funds from Medtronic and Abbott. The remaining authors have no disclosures to report.
Supporting information
Tables S1–S3 Figure S1
Acknowledgments
The National Health Information Database was provided by the NHIS of Korea (NHIS‐2018‐4‐025). The authors thank the NHIS for its cooperation.
(J Am Heart Assoc. 2020;9:e014177 DOI: 10.1161/JAHA.119.014177.)
For Sources of Funding and Disclosures, see page 8.
Contributor Information
Gregory Y. H. Lip, Email: cby6908@yuhs.ac.
Boyoung Joung, Email: gregory.lip@liverpool.ac.uk.
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Supplementary Materials
Tables S1–S3 Figure S1