Non-Vitamin K Antagonist Anticoagulants versus Warfarin in newly diagnosed Atrial Fibrillation and CKD: the Korean National Health Insurance Data

doi:10.21203/rs.3.rs-1706182/v2

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Non-Vitamin K Antagonist Anticoagulants versus Warfarin in newly diagnosed Atrial Fibrillation and CKD: the Korean National Health Insurance Data

https://doi.org/10.21203/rs.3.rs-1706182/v2

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Background

Despite the benefits of non-vitamin K antagonist oral anticoagulants (NOACs), whether NOAC therapy has a better risk-benefit profile than warfarin therapy in patients with non-valvular atrial fibrillation (AF) and chronic kidney disease (CKD), including end-stage renal disease (ESRD), remains uncertain. We investigated the efficacy and safety of NOACs compared to warfarin in these patients using a nationwide database.

Methods

We evaluated patients with incident non-valvular AF and CKD in the Korea National Health Insurance Database from 2013 to 2018. The primary and secondary efficacy outcomes were ischemic stroke and all-cause mortality, respectively. The primary safety outcomes included intracranial hemorrhage, gastrointestinal bleeding, and extracranial or unclassified major bleeding.

Results

Among the 1,885 patients, 970 (51.5%) initiated warfarin therapy, whereas 915 (48.5%) initiated NOAC therapy. Although NOAC users had a lower proportion of patients with ESRD than warfarin users (6.6% vs. 32.5%, p < 0.001), NOAC users had a higher Charlson comorbidity index, CHA₂DS₂-VAS_C score, and modified HAS-BLED score compared with warfarin users. During a mean follow-up period of 23.8 months, there were 293 and 214 cases of ischemic stroke and all-cause death, respectively. There was no difference in ischemic stroke between the two groups. However, Kaplan-Meier survival analysis showed that all-cause mortality was significantly lower in NOAC users than in warfarin users. In multivariate Cox regression analyses, the hazard ratio for all-cause mortality compared to warfarin therapy was 0.41 (95% CI, 0.30–0.56; p < 0.001) in NOAC therapy. Additionally, NOAC therapy significantly reduced intracranial hemorrhage and gastrointestinal bleeding in multivariate Cox regression analyses.

Conclusions

This study showed that NOAC therapy had a better risk-benefit profile than warfarin therapy in patients with AF and CKD. To clarify the benefits of NOACs in patients with AF and CKD, further well-designed clinical trials are needed.

atrial fibrillation

chronic kidney disease

non-vitamin K antagonist oral anticoagulants

and warfarin.

Atrial fibrillation (AF), which increases the risk of ischemic stroke and mortality compared to patients with sinus rhythm, is the most common sustained cardiac arrhythmia [1–3]. It occurs more often in patients with advanced age, hypertension, diabetes, heart failure, and vascular disease [4, 5]. Chronic kidney disease (CKD) frequently occurs in aging patients with comorbidities such as diabetes or hypertension [6, 7]. As such, AF and CKD share several common risk factors and are straightly related. Usually, the prevalence of AF increases with deterioration of kidney function, and when patients with pre-dialytic CKD develop end-stage renal disease (ESRD), it reaches approximately 15%, which is more than three times that of age-matched controls [8]. In addition, ischemic stroke clearly increases mortality in patients with CKD compared to those without CKD [9].

The prevention of ischemic stroke is the cornerstone of AF management. Therefore, clinical guidelines recommend oral anticoagulant therapy in patients with AF [3, 10]. However, patients with CKD are not only at a higher risk of ischemic stroke but also at an increased risk of bleeding even without oral anticoagulants [11]. Although vitamin K antagonists (VKAs), such as warfarin, are highly effective in the prevention of ischemic stroke, the narrow therapeutic window requiring frequent monitoring and dose adjustments may result in potentially subtherapeutic or toxic effects, particularly in patients with CKD. In fact, observational studies failed to demonstrate clear benefits of VKAs compared with no treatment in patients with non-valvular AF undergoing hemodialysis[12–14]. Recently, non-vitamin K antagonist oral anticoagulants (NOACs) have been developed as alternatives to VKAs. They have a low risk of bleeding but have an effect similar to that of VKAs. Theoretically, NOACs are expected to have a better risk-benefit profile than VKAs in patients with AF and CKD. However, because of the lack of efficacy and safety data of NOACs in patients with AF and CKD including ESRD, VKAs are more commonly prescribed than NOACs in these patients, despite the high bleeding risk. Therefore, this study aimed to investigate the efficacy and safety of warfarin and NOACs in patients with non-valvular AF and CKD, including ESRD, using the Korean National Health Insurance Database.

Data sources

This cohort study was performed using data from the Republic of Korea National Health Insurance Service (NHIS). It is a nationwide universal healthcare insurer that covers the entire Korean population. All clinics, hospitals, and pharmacies in Korea are required to participate in the NHIS, and they are reimbursed for their services through the NHIS after filing claims electronically. Claims are accompanied by data regarding demographic characteristics, diagnostic codes classified by the 10th revision of the International Classification of Disease (ICD-10), procedure codes, and prescription records. The NHIS constructs a nationwide claims database called the National Health Insurance Database (NHID), which contains data on death compiled by Statistics Korea. These data are publicly available at https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do. Based on these data, we constructed comprehensive datasets of baseline demographics, clinical covariates on diagnosis, study medications, and outcomes.

Study population

Among patients with chronic kidney disease (CKD) aged 18 years or older from January 1, 2013 to December 31, 2017, patients newly diagnosed with AF were eligible. The target study cohort included patients with non-valvular AF who had initiated oral anticoagulant therapy, either NOACs or warfarin, since 2014. Of note, to identify baseline comorbidities, we started the sample in 2013 and to look for treatment in 2014. Exclusion criteria included the use of anticoagulants for less than 90 days, cancer patients, or previous history of pulmonary thromboembolism, deep vein thrombosis, ischemic stroke, or hemorrhage (intracranial hemorrhage, gastrointestinal bleeding, extracranial or unclassified major bleeding). It is important to note that, in the Korean healthcare system, most doctors are not willing to remove an existing diagnostic code because they may not be reimbursed for their claim if they do not enter an appropriate diagnostic code. As a result, once a diagnostic code is entered, it is almost always maintained. Therefore, to extract diagnostic codes as outcomes, the patient had to be established as event-naive. Supplemental Table 1 shows ICD-10 codes for diagnosing diseases to extract the study population.

Data collection and study design

Baseline characteristics and clinical outcomes of the patients were evaluated according to NOAC users or warfarin users. The index date was defined as the first date of prescription of NOACs or warfarin. Baseline demographic characteristics were recognized from insurance claims at the index date, and baseline comorbidities referred to any claim with diagnostic codes at the index date or in the prior 1 year at the index date. Supplemental Table 2 shows the ICD-10 codes for comorbidities. Patients with CKD were stratified into pre-dialytic CKD and ESRD groups. Pre-dialytic CKD was identified by insurance claims with diagnostic codes, and ESRD was identified by insurance claims with the diagnostic code and regular dialysis (hemodialysis and/or peritoneal dialysis) procedure codes (Supplement Table 2). The Charlson comorbidity index (CCI), CHA₂DS₂-VASc score, and modified HAS-BLED (mHAS-BLED) score were calculated to evaluate the general comorbidity status, ischemic stroke risk, and major bleeding risk, respectively. Because factors such as H (uncontrolled hypertension with systolic blood pressure >160 mmHg), L (labile international normalized ratios), and D (alcohol), were not known on the index date, they were not included in the calculation of the mHAS-BLED score. Therefore, the maximum mHAS-BLED score was 5 [15, 16]. The use of medications, defined as lasting for > 90 cumulative days after the index date, was identified by insurance claims with prescription records. The follow-up period was from the index date until the first occurrence of any clinical outcomes, date of ceasing or changing anticoagulant from warfarin to NOACs, or end date of the study period (December 31, 2018), based on whichever came first. It is noteworthy that if patients with pre-dialytic CKD had changed to patients with ESRD during the study follow-up period, these patients were defined as patients with pre-dialytic CKD and were followed up at the time of change. In other word, they were censored when dialysis was begun.

Outcome assessment

We assessed the following incident outcomes: The primary efficacy outcome was ischemic stroke, and the secondary efficacy outcome was all-cause mortality. The primary safety outcomes included intracranial hemorrhage, gastrointestinal bleeding, and extracranial or unclassified major bleeding. Outcomes were also recognized from insurance claims using the diagnostic codes (Supplement Table 1).

Statical analysis

Categorical variables are presented as frequencies with percentages and continuous variables as means and standard deviations (SDs). Differences between treatment groups were evaluated by the t-test for continuous variables and by the χ2 or Fisher exact test for categorical variables. The cumulative incidence of outcomes between NOAC therapy and warfarin therapy was calculated using the Kaplan-Meier estimation method with the log-rank test. Event-free survival times and times to events during the total observation period were compared between the two groups using Cox proportional hazards models. We performed a series of models that sequentially adjusted for categories of potential explanatory variables: Model 1 (age, sex, dialysis dependency, CCI), Model 2 (Model 1 + baseline use of medications [antiplatelets, beta blocker, calcium channel blocker, renin-angiotensin-aldosterone system blocker, diuretics, statin]), and Model 3 (Model 2 + CHA₂DS₂-VASc score, mHAS-BLED score). Additionally, efficacy and safety outcomes between the two groups were assessed in important clinical subgroups: age < 65 vs. age ≥ 65, male vs. female, pre-dialytic CKD vs. ESRD, CHA₂DS₂-VASc ≤ 3 vs. CHA₂DS₂-VASc > 3 (higher ischemic stroke risk), andmHAS-BLED ≤ 2 vs. mHAS-BLED > 2 (higher major bleeding risk). All statistical tests were evaluated using a two-tailed 95% confidence interval (CI), and statistical significance was set at P < 0.05. All analyses were performed using SAS software (version 9.3, SAS Institute) and R programming language version 3.3.1.

Study population

Among patients with chronic kidney disease (CKD) aged 18 years or older from January 1, 2013 to December 31, 2017, 43,840 patients newly diagnosed with AF were identified in the Korean NHIS database. A total of 29,706 patients initiated anticoagulant therapy, NOACs, or warfarin and were eligible for inclusion since 2014. Of these patients, 27,821 patients were excluded for the following reasons: valvular AF, such as those with rheumatic mitral stenosis, or surgery heart valves (n = 165); the use of anticoagulants for less than 90 days (n = 21,469); cancer patients (n = 3,142); previous history of pulmonary thromboembolism (n =229), deep vein thrombosis (n = 213), ischemic stroke (n = 789), intracranial hemorrhage (n = 640), gastrointestinal bleeding (n = 721), and extracranial or unclassified major bleeding (n = 453). Thus, a total of 1,885 patients were included in the analysis (Figure 1).

Non-Vitamin K Antagonist Oral Anticoagulants

Prescribed drug doses according to the type of NOAC, as shown in Supplement Table 3, were as follows: low-dose apixaban (2.5 mg twice daily), low-dose rivaroxaban (15 mg once daily), and low-dose edoxaban (30mg twice daily) were prescribed in 60, 183, and 174 patients, respectively.

Baseline Characteristics

The baseline characteristics are shown in Table 1. The mean age was 71.1 ± 11.1 years, and 1,060 (56.2%) were men. Among the 1,885 patients, 970 patients (51.5%) initiated warfarin therapy, whereas 915 (48.5%) initiated NOAC therapy. Compared to warfarin users, NOAC users were significantly older and had a lower proportion of men. Although NOAC users had a lower proportion of patients with ESRD than warfarin users (6.6% vs. 32.5%, p <0.001), NOAC users had higher CCI, CHA₂DS₂-VAS_Cscore_,andmHAS-BLED score than warfarin users. Meanwhile, although the use of beta blocker was more frequent in NOAC users than in warfarin users, the use of aspirin, other antiplatelets, renin-angiotensin-aldosterone system blocker, calcium channel blocker, and diuretics was comparable between the two groups.

Ischemic stroke

During a mean follow-up duration of 23.8 ± 15.2 months, ischemic stroke occurred in 293 patients (15.5 %). The incidence of ischemic stroke was comparable between warfarin and NOAC users (1.73 vs. 1.96 per 1,000 patient-years, P = 0.89). In Kaplan-Meier survival analysis and Cox regression analyses, there was also no difference in ischemic stroke between warfarin and NOAC users (Figure 2A and Table 2). Of note, when the entire study population was divided by important clinical subgroups, in patients with ESRD and with pre-dialytic CKD, there was also no difference in ischemic stroke between warfarin and NOAC users (Figure 3A).

All-cause death

A total of 214 all-cause deaths occurred during the follow-up period. The incidence of all-cause death occurred less frequently in NOAC users than in warfarin users (1.93 vs. 2.15 per 1,000 patient-years, P < 0.001). Kaplan-Meier survival analysis showed that all-cause mortality was significantly lower in NOAC users than in warfarin users (Figure 2B). In Cox regression analyses, NOAC therapy significantly reduced the all-cause mortality compared with warfarin therapy. The impact of NOAC therapy on all-cause death remained significant even after adjustments for age, sex, dialysis dependency, medications, CCI, CHA₂DS₂-VAS_Cscore_,andmHAS-BLED score (hazard ratio [HR],0.41; 95% CI, 0.30 to 0.56; P < 0.001) (Table 2). However, the subgroup analysis showed that NOAC therapy did not reduce all-cause mortality compared to warfarin therapy in patients with pre-dialytic CKD and with ESRD, respectively (Figure 3B).

Hemorrhage

During the follow-up period, intracranial hemorrhage, gastrointestinal bleeding, and extracranial or unclassified major bleeding occurred in 45 (2.4 %), 258 (13.7%), and 180 (9.5 %) patients, respectively. The incidences of intracranial hemorrhage (1.92 vs. 2.12 per 1000 patient-years, P = 0.02), gastrointestinal bleeding (1.82 vs. 1.93 per 1000 patient-years, P = 0.02), and extracranial or unclassified major bleeding (1.84 vs. 1.99 per 1000 patient-years, P = 0.04) were significantly lower in NOAC users than warfarin users. Kaplan-Meier survival analysis also showed that the occurrence rate of intracranial hemorrhage, gastrointestinal bleeding, and extracranial or unclassified major bleeding were significantly lower in NOAC users than in warfarin users (Figure 2C, D, E). Meanwhile, compared with warfarin therapy, NOAC therapy significantly reduced only intracranial hemorrhage and gastrointestinal bleeding in univariate and multivariate Cox regression analyses (Table 3). Especially, in the subgroup analysis, NOAC therapy significantly reduced hemorrhagic risk compared to warfarin therapy in patients with higher major bleeding risk (mHAS-BLED>2). However, NOAC therapy did not reduce hemorrhagic risk compared to warfarin therapy in patients with pre-dialytic CKD and with ESRD, respectively (Figure 3C, D, E).

This study evaluated ischemic stroke, all-cause mortality, and hemorrhagic risk in AF patients with CKD according to NOAC or warfarin therapy using a large-scale, nationwide population-based database. In particular, because of the concern that NOAC therapy or warfarin therapy would not convey the same safety and efficacy in patients with ESRD compared with pre-dialytic CKD, subgroup analyses of AF patients with ESRD were conducted.

The results of the present study showed that NOAC therapy reduced hemorrhagic risk and all-cause mortality in patients with AF and CKD compared to warfarin therapy. However, there was no significant difference between NOAC therapy and warfarin therapy in reducing ischemic stroke in these patients. Meanwhile, in subgroup analyses of AF patients with ESRD,there were no significant differences between NOAC therapy and warfarin therapy for ischemic stroke, all-cause mortality, and hemorrhagic risk.

Although the AF guidelines recommend warfarin therapy differently in patients with CKD [17–19], warfarin is still widely used in patients with AF and CKD. When clinical practice guidelines recommend warfarin therapy in patients with CKD, it is suggested that drug dose adjustment is not necessary because warfarin is eliminated by hepatic metabolism [17, 20]. However, considering warfarin’s narrow therapeutic window and its susceptibility to multiple drug and food interactions, interpretation of dose adjustment solely on the basis of estimated glomerular filtration rate (eGFR) may be an over-simplified approach under uremia and downregulation of CYP450 in these patients [11, 21]. In fact, several clinical studies have shown that patients with CKD require lower warfarin dosages to maintain therapeutic anticoagulation compared to patients with normal kidney function [22, 23]. Another caveat to warfarin therapy is that higher risk of major bleeding events for greater fluctuations in international normalized ratio (INR) values, or any given INR value, were commonly observed in these patients [24, 25]. In addition, there are concerns about increased vascular calcification and calciphylaxis with warfarin, as it reduces the function of vitamin K-dependent vascular calcification inhibitors, such as matrix G1a proteins [26, 27].

Recently, NOACs such as direct thrombin inhibitors or factor Xa inhibitors have been developed as alternatives to VKAs. Compared with VKAs, NOACs have a more predictable anticoagulant response, more rapid onset/offset of action, and fewer drug or food interactions [28]. In addition, although the dose of VKAs to maintain therapeutic anticoagulation is determined on an individual basis, NOACs are administered at a fixed dose and do not require regular coagulation monitoring [28]. Because of this difference between VKAs and NOACs, NOACs are associated with lower bleeding risk than VKAs. In fact, many clinical studies have shown that NOAC therapy had a better risk-benefit profile in patients with non-valvular AF [28–31]. Despite these advantages of NOACs over VKAs, NOAC therapy requires caution in patients with CKD. Although varying in degrees, all NOACs are dependent on the kidney for elimination, so their use makes dose adjustment mandatory in patients with CKD [11, 32]. Unfortunately, there is no standardized test for monitoring NOACs to confirm maintenance of therapeutic anticoagulation in these patients after dose adjustment.

Despite several shortcomings of NOACs in patients with CKD, post-analyses of key efficacy randomized control trials (RCTs) in AF demonstrated equivalent or superior efficacy and safety of NOACs compared with VKAs, provided that the recommended dose reductions are made [33–35]. In line with these findings, in the present study, we observed superior safety of NOAC therapy compared with warfarin therapy even in situations where NOAC users were at a higher risk of bleeding than warfarin users. On the other hand, evidence of the safety and efficacy of NOACs in patients with ESRD is lacking because the key RCTs excluded these patients [36–39]. For this reason, clinicians are reluctant to use NOACs, and warfarin is commonly prescribed despite the high bleeding risk. Of note, in this study, warfarin users were also more common than NOAC users in patients with ESRD. Generally, because bleeding risk with warfarin is more pronounced in patients with ESRD than in those with CKD, clinicians tend to prescribe warfarin at a subtherapeutic dose. In fact, Laura et al. reported that these patients were three times more likely to be below the target INR range [40]. This finding suggests that clinicians are conservative with their warfarin dosing strategies in patients with ESRD; therefore, these patients are more often encountering inadequate efficacy of warfarin compared to NOACs. Recently, a valkyrie trial clearly showed that in patients with ESRD, a reduction in rivaroxaban significantly decreased cardiovascular disease and major bleeding compared to VKA [41]. However, in this study, subgroup analyses of patients with ESRD showed that NOAC therapy did not reduce the risk of all-cause death and hemorrhage compared with warfarin therapy. This finding was probably due to the relatively small number of patients with ESRD enrolled in this study.

Our study had several limitations. First, propensity score adjustment for NOAC users should be performed especially given the differences in the baseline characteristics of the patients. Second, the present work was conducted based on insurance claims data from the NHICD. The extractions of all variables and outcome events were retrieved from the electronic database; thus, a precise review of clinical presentations was not available. In addition, any information on CKD stage, serum creatinine, and eGFR could not be obtained. Therefore, it is not known whether the dose reduction of NOACs based on eGFR is appropriate. Third, laboratory data or alcohol consumption were not available; thus, the measurement of mHAS-BLED scores and the adequacy of warfarin dosage could be biased. Fourth, for other major bleeding sites that were defined by the International Society on Thrombosis and Hemostasis criteria [42], there were many limitations in extraction by the insurance database.

Despite these limitations, in the current study, a relatively large number of incident patients were enrolled and had a long follow-up period. The findings based on these major strengths showed that NOAC therapy had a better risk-benefit profile than warfarin therapy in patients with AF and CKD. To clarify the benefits of NOACs in patients with AF and CKD, further well-designed clinical trials are needed.

AF; Atrial fibrillation, BB; beta blocker, CCB; calcium channel blocker, CCI; Charlson comorbidity index, CKD; Chronic kidney disease, CYP450; cytochrome P450, eGFR; estimated glomerular filtration rate, ESRD; end-stage renal disease, IRB; Institutional Review Board, mHAS-BLED; modified HAS-BLED, NHIS; National Health Insurance Service, NHID; National Health Insurance Database, NOAC; non-vitamin K antagonist oral anticoagulant, RASB; renin-angiotensin-aldosterone system blocker, RCTs; randomized control trials, SDs; standard deviations, VKA; vitamin K antagonist

Ethics approval and consent to participate

The current study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Kangdong Sacred Heart Hospital (Ref. no. 2019-08-005).

Consent for publication

Anonymous and de-identified data were used for the analysis; therefore, informed consent was not obtained. Because of retrospective nature of the study Informed consent is waived by Institutional Review Board (IRB) of Kangdong Sacred Heart Hospital.

Competing interests

The authors declare no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors’ contributions

Y.K.K and D.H.S were involved in the conception and design of the study. D.K and J.L performed data analysis. All authors were involved in interpretation of data analysis and in manuscript preparation.

Acknowledgments

We would like to thank Editage (www.editage.co.kr) for English language editing.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to the permission to access the data is restricted to research and subjects to consent of national health insurance but available from corresponding author on reasonable request.

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Table 1. Baseline characteristics of subjects

	Total (n =1,885)	Warfarin user (n =970)	NOAC user (n =915)	P-value
Age, y	71.1 ± 11.1	68.4 ± 12.0	73.7 ± 10.1	<0.001
Male, n (%)	1,060 (56.2)	573 (59.1)	487 (53.2)	<0.001
Comorbid disease, n (%)
Pre-dialytic CKD	1,510 (80.1)	655 (67.5)	855 (93.4)	<0.001
ESRD	375 (19.9)	315 (32.5)	60 (6.6)
Diabetes mellitus	1,340 (71.1)	675 (69.6)	665 (72.7)	0.14
Congestive heart failure	1,073 (56.9)	551 (56.8)	522 (57.0)	0.93
Myocardial infarction	222 (11.8)	111 (11.4)	111 (12.1)	0.67
Peripheral vascular disease	773 (41.0)	361 (37.2)	412 (45.0)	0.001
Charlson's comobidity index	4.39 ± 2.03	4.08 ± 2.02	4.69 ± 2.04	<0.001
CHA₂DS₂-VASc	4.91 ± 1.66	4.64 ± 1.63	5.17 ± 1.68	<0.001
CHA₂DS₂-VASc ≤ 3, n (%)	428 (22.7)	257 (26.5)	171 (18.7)	<0.001
CHA₂DS₂-VASc > 3, n (%)	1,457 (77.3)	713 (73.5)	744 (81.3)
mHAS-BLED^*	2.90 ± 0.85	2.72 ± 0.90	3.07 ± 0.79	<0.001
mHAS-BLED^* ≤ 2, n (%)	148 (7.9)	107 (11.0)	41 (0.04)
mHAS-BLED^* > 2, n (%)	1,737 (92.1)	863 (89.0)	874 (0.96)
Medication, n (%)
Aspirin	902 (47.9)	449 (46.3)	453 (49.5)	0.17
Other antiplatelets	367 (19.5)	178 (18.4)	189 (20.7)	0.22
BB	937 (49.7)	521 (53.7)	416 (45.5)	<0.001
CCB	1,163 (61.7)	593 (61.1)	570 (62.3)	0.64
RASB	1,342 (71.2)	687 (70.8)	655 (71.6)	0.72
Diuretics	1,056 (56.0)	536 (55.3)	520 (56.8)	0.52
Statin	968 (51.4)	465 (47.9)	503 (55.0)	0.002

NOACs, non-vitamin K antagonist oral anticoagulants; RASB, renin-angiotensin-aldosterone system blocker; CCB, calcium channel blocker; BB, beta blocker

^*Modified HAS-BLED

Table 2. Primary and secondary efficacy outcomes

Outcome	Group	Events	Person-year	Unadjusted		Adjusted^*		Adjusted^**		Adjusted^***
	(n)	(n)	(per 1,000)	HR	P value	HR	P value	HR	P value	HR	P value
				(95% CI)		(95% CI)		(95% CI)		(95% CI)
Ischemic stoke	Warfarin user
	915	137	1.73	ref		ref		ref		ref
	NOAC user
	970	156	1.96	0.98	0.89	0.83	0.12	0.82	0.12	0.82	0.12
				(0.78 – 1.24)		(0.65 – 1.05)		(0.64 – 1.05)		(0.64 – 1.05)
All-cause death	Warfarin user
	915	73	1.93	ref		ref		ref		ref
	NOAC user
	970	141	2.12	0.59	<0.001	0.42	<0.001	0.12	<0.001	0.41	<0.001
				(0.45 – 0.70)		(0.31 – 0.56)		(0.31 – 0.57)		(0.30 – 0.56)

^*Model 1: adjusted for age, sex, dialysis dependency, and CCI; ^**Model 2: adjusted for model 1 + baseline use of medications; ^***Model 3: adjusted for model 3 + CHA₂DS₂-VASc score + modified HAS-BLED score. HR, hazard ratio; CI, confidence interval; CCI, Charlson comorbidity index

Table 3. Primary safety outcomes

Outcome	Group	Events	Person-year	Unadjusted		Adjusted^*		Adjusted^**		Adjusted^***
	(n)	(n)	(per 1,000)	HR	P value	HR	P value	HR	P value	HR	P value
				(95% CI)		(95% CI)		(95% CI)		(95% CI)
Intracranial	Warfarin user
hemorrhage	915	32	2.12	ref		ref		ref		ref
	NOAC user
	970	13	1.92	0.45	0.02	0.48	0.03	0.49	0.04	0.48	0.04
				(0.23 – 0.85)		(0.24 – 0.94)		(0.25 – 0.97)		(0.24 – 0.96)
Gastrointestinal	Warfarin user
bleeding	915	154	1.93	ref		ref		ref		ref
	NOAC user
	970	104	1.82	0.73	0.02	0.64	0.001	0.64	0.001	0.65	0.002
				(0.57 – 0.94)		(0.49 – 0.84)		(0.49 – 0.84)		(0.50 – 0.85)
Extracranial	Warfarin user
or unclassified	915	107	1.99	ref		ref		ref		ref
Major bleeding	NOAC user
	970	73	1.84	0.73	0.04	0.75	0.07	0.75		0.78	0.12
				(0.57 – 0.94)		(0.54 – 1.02)		(0.56 – 1.04)	0.08	(0.56 – 1.07)

No competing interests reported.

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Non-Vitamin K Antagonist Anticoagulants versus Warfarin in newly diagnosed Atrial Fibrillation and CKD: the Korean National Health Insurance Data

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