Cardiovascular and Bleeding Outcomes with Anticoagulants Across Kidney Disease Stages: Analysis of a National US Cohort

Abstract

Background:

While Direct Oral Anticoagulants (DOACs) are considered safe among patients without chronic kidney disease (CKD), the evidence is conflicting as to whether they are also safe in the CKD and end-stage kidney disease (ESKD) population. In this observational cohort study, we examined whether DOACs are a safe alternative to warfarin across CKD stages for a variety of anticoagulation indications.

Methods:

Individuals on DOACs or warfarin were identified from OptumLabs^® Data Warehouse, a longitudinal dataset with de-identified administrative claims, from 2010–2017. Cox models with sensitivity analyses were used to assess risk of cardiovascular disease and bleeding outcomes stratified by CKD stage.

Results:

Among 351,407 patients on anticoagulation, 45% were on DOACs. CKD stage 3–5 and ESKD patients comprised approximately 12% of the cohort. The most common indications for anticoagulation were atrial fibrillation (44%) and venous thromboembolism (23%). DOACs was associated with a 22% decrease in risk of cardiovascular outcomes (HR 0.78, 95% CI: 0.77 – 0.80, p<0.001) and a 10% decrease in risk of bleeding outcomes (HR 0.90, 95% CI: 0.88 – 0.92, p<0.001) compared to warfarin after adjustment. On stratified analyses, DOACs maintained a superior safety profile across CKD stages. Patients with atrial fibrillation on DOACs had a consistently lower risk of cardiovascular and bleeding events compared to warfarin patients, while among other indications (venous thromboembolism, peripheral vascular disease, arterial embolism) the risk of cardiovascular and bleeding events was the same among DOAC and warfarin users.

Conclusion:

DOACs may be a safer alternative to warfarin even among CKD and ESKD patients.

INTRODUCTION

Direct oral anticoagulant (DOAC) medications have transformed the treatment of venous thromboembolism (VTE) and have also been shown to decrease stroke risk with superior side effect profiles compared to warfarin in patients with atrial fibrillation (AF) since their first approval by the Food and Drug Administration (FDA) in 2010 [1–7]. In the absence of chronic kidney disease (CKD), DOAC therapy is preferred over warfarin as it eliminates the need for continuous international normalized ratio (INR) monitoring, reduces dietary restrictions on patients with regards to oral vitamin K intake, and most importantly, is a safe and effective alternative to warfarin [8,9]. Moreover, DOAC therapy combined with aspirin has been shown to reduce the risk of cardiovascular events [10]. Unsurprisingly, DOACs have become cornerstones for treatment of AF and VTE in DOAC-eligible patients based upon most recent guidelines [11,12].

In CKD patients, DOACs theoretically confer another advantage over warfarin because they do not inhibit the vitamin K–dependent g-carboxylation activation of matrix Gla proteins, important inhibitors of vascular calcification [13,14]. However, DOAC randomized clinical trials excluded patients with advanced CKD and only apixaban, with its lower degree of renal clearance, has been approved for use in dialysis patients based upon a single dose pharmacokinetic study involving eight hemodialysis patients [15]. Currently, the other three DOACs approved for use in the United States (rivaroxaban, edoxaban, and dabigatran) are not recommended in dialysis patients given the lack of evidence from clinical trials [11]. Furthermore, findings regarding safety and efficacy of DOACs from large retrospective non-dialysis CKD and dialysis cohorts of patients have been conflicting [16–18].

To better understand the risks of anticoagulation in the CKD population, we conducted a comparative analysis and examined cardiovascular and major bleeding outcomes with warfarin vs DOAC therapy in non-CKD, pre-dialysis CKD, and ESKD patients on dialysis across a range of anticoagulation indications not limited to AF.

METHODS

Study Population and Data Source

This study used de-identified administrative claims data from the OptumLabs^® Data Warehouse (OLDW), which includes medical and pharmacy claims, laboratory results, and enrollment records for commercial and Medicare Advantage (MA) enrollees. The database contains longitudinal health information on over 200 million enrollees and patients, representing a diverse mix of ages, ethnicities and geographical regions across the United States [19,20]. New users of anticoagulant medication (either DOACs or warfarin) between October 1, 2010 to September 30, 2017 were identified via pharmacy claims with the first prescription date defined as the index anticoagulant date. DOACs included apixaban (30%), rivaroxaban (59%), edoxaban (0.1%), and dabigatran (10%). Betrixaban, which was FDA-approved in 2017, was excluded from this study. New users had to have been continuously enrolled in their healthcare plan without an enrollment gap longer than 45 days and be free of any anticoagulant prescriptions for at least one year prior to the index anticoagulant prescription date (Supplemental Figure S1).

We excluded patients who had ambiguous birth dates or gender, were younger than 18 years, had anticoagulation treatment before October 1, 2010, or were reported to be on both DOAC and warfarin on the index treatment date (Supplemental Figure S2).

As this study involved analysis of preexisting, de-identified data, it was exempt from institutional review board approval at the University of California, Irvine Medical Center and the Tibor Rubin Veterans Affairs Medical Center.

Demographic and Clinical Data Ascertainment

Patient characteristics (including age, sex, and race) were obtained from OLDW. Comorbidities (acute kidney disease (AKI), diabetes, myocardial infarction (MI), congestive heart failure (CHF), ischemic stroke, hemorrhagic stroke, liver disease, substance or alcohol use), indications for anticoagulation (AF, pulmonary embolism/infarction, deep venous thrombosis, arterial embolism/thrombosis, peripheral vascular disease, or hypercoagulable states), and presence and stage of kidney disease were identified according to presence of the respective International Classification of Disease, 9^th Revision (ICD-9) codes in a physician or facility claim within the year prior to the index date [21]. We categorized CKD stages 1 and 2 as non-CKD. CHA₂DS₂-VASC and HAS-BLED scores to assess risk of stroke and bleeding outcomes respectively were calculated for patients with pre-existing AF [22,23]. Comorbidities to calculate the CHA₂DS₂-VASC and HAS-BLED scores were also ascertained from ICD-9 codes; however, labile international normalized ratio (INR) was not included, and renal disease was defined as having CKD 3–5 and ESKD in the HAS-BLED score. Use of antiplatelet medication was coded according to whether the patient had a prescription for the medication in the year prior to the index date.

Outcome Assessment

The main outcomes of interest were a composite cardiovascular disease (CVD) endpoint (combination of MI and ischemic stroke) and a composite bleeding endpoint (Supplemental Table S1). These outcomes were ascertained from validated ICD-9 codes in facility and physician claims from patients’ index date until end of follow-up [22]. Patients were followed from their respective index date until date of first event, end of continuous enrollment, end of prescription supply, or date of final follow-up for all patients (September 30, 2017), whichever came first. Mortality information was not available for analysis.

Statistical Analysis

Patient demographic and clinical characteristics were ascertained for the total cohort and stratified by patient’s anticoagulation treatment medication (DOAC vs warfarin). Student’s t-test and chi-squared tests for continuous and categorical variables, respectively, were used to test for statistically significant differences in patient characteristics between exposure groups.

We utilized a Cox model to perform a time-varying as-treated analysis (with time-updated information on anticoagulation medication type), where patients were considered at risk on the medication type until medication switch or end of last prescription date (prescription date plus number of supplied days). Outcomes were attributed to the last anticoagulation prescription available and patients were administratively censored at the end of the last prescription date, the end of continuous enrollment, or the end of the study period.

We performed three sequential levels of adjustment for hazard ratios. Model 1: unadjusted (anticoagulation medication type only with DOAC as reference) Model 2: adjusted for demographics (age, gender, and race) and year of the index anticoagulation prescription date, Model 3: adjusted for Model 2 plus comorbidities (diabetes, MI, CHF, ischemic stroke, and hemorrhagic stroke), antiplatelet medication use, and CKD stage. We defined Model 3 as the primary model of interest to prevent over-adjustment. A fourth model (Model 4) was used for sensitivity analyses and included adjustment for variables in model 3 plus other comorbidities including the anticoagulation indication (acute kidney disease, hypertension, atrial fibrillation, pulmonary embolism infarction, deep venous thrombosis, arterial embolism/thrombosis, peripheral vascular disease, hypercoagulable states). There were no missing data on patient characteristics, anticoagulation medication prescription date, and comorbidities.

Association of anticoagulation treatments with the composite of CVD and the composite of bleeding outcomes were also examined across CKD stage strata (non-CKD, CKD stage 3, CKD stage 4 and 5, and ESKD on dialysis). We also performed a sub-group analysis examining a composite of CVD and composite of bleeding outcomes stratified by indication for anticoagulation (AF, deep venous thrombosis, pulmonary embolism, peripheral vascular disease, and arterial embolism).

To account for treatment indication bias in the primary analysis, we performed a coarsened exact matching (CEM) as-treated analysis to improve the estimation of anticoagulation treatment effects on outcomes by stratifying patients by CKD stage and then matching them by anticoagulation treatment according to patient’s demographics (age, gender, race), year of the index date, comorbidities (diabetes, MI, CHF, ischemic stroke, hemorrhagic stroke), and antiplatelet medication use. CEM models were also evaluated across covariate model adjustments as previously described. Patients were censored at the time of anticoagulation change or when there was a gap larger than 90 days from the end of the last prescription treatment date (prescription date plus day supply) to next subsequent prescription (suggesting medication discontinuation or non-adherence to treatment).

The proportionality assumption was checked for all statistical models. SAS (SAS Institute, Cary, NC) was used for all statistical analysis. P<0.05 was considered statistically significant.

RESULTS

Baseline demographic and clinical characteristics

The analytical cohort included 351,407 patients from the OptumLabs^® Data Warehouse (OLDW) who met inclusion criteria. 158,732 (45%) were treated with DOAC and 192,675 (55%) were treated with warfarin as their index anticoagulant prescription. Patients were on average 67 ± 14 years old (mean ± SD) and our cohort consisted of 49% females, 79% non-Hispanic whites, and 11% African-American (Table 1). Thirty percent of patients had type 2 diabetes mellitus. Compared to warfarin treated patients, patients initiating DOACs were slightly younger, less likely to be female or African-American, more likely to be Hispanic, less likely to have any comorbidities, and more likely to have AF as the indication for anticoagulation. After CKD stage stratification, there was no significant difference in age or gender between warfarin and DOAC treated patients; however, patients started on DOACs were more likely to be Hispanic, less likely to have any comorbidities, but more likely to have AF.

Table 1.

Baseline Characteristics of Individuals in OLDW.

	Total Cohort		Non-CKD		CKD3		CKD4&5		ESRD
Variables	DOAC	Warfarin	DOAC	Warfarin	DOAC	Warfarin	DOAC	Warfarin	DOAC	Warfarin
Total number of patients	158732 (45)	192675 (55)	140823 (46)	162682 (54)	10938 (43)	14565 (57)	2064 (32)	4350 (68)	1038 (20)	4254 (80)
Age	66±13	67±13	65±13	66±14	75±10	74±10	76±9	75±10	68±12	67±12
Female	76557 (48)	96357 (50)	67911 (48)	82201 (51)	5349 (49)	6997 (48)	1113 (54)	2193 (50)	449 (43)	1867 (44)
Race
White	125026 (79)	152697 (79)	111906 (79)	130645 (80)	8151 (75)	11222 (77)	1424 (69)	3188 (73)	603 (58)	2572 (60)
Black	15965 (10)	21259 (11)	13210 (9.38)	16318 (10.03)	1564 (14)	2058 (14)	366 (18)	713 (16)	274 (26)	1069 (25)
Hispanic	9595 (6)	9990 (5)	8497 (6)	8325 (5)	621 (6)	683 (5)	171 (8)	257 (6)	105 (10)	370 (9)
Asian	2862 (1.8)	2864 (1.5)	2526 (1.8)	2387 (1.5)	216 (2)	199 (1.4)	42 (2)	72 (1.7)	26 (2.5)	124 (2.9)
Unknown	5284 (3)	5865 (3)	4684 (3)	5007 (3)	386 (4)	386 (3)	61 (3)	120 (3)	30 (3)	119 (3)
Comorbidity
Acute kidney disease	13442 (8)	22899 (12)	7201 (5)	10918 (7)	3527 (32)	5060 (35)	1016 (49)	2225 (51)	506 (49)	2294 (54)
Congestive heart failure	53181 (34)	77315 (40)	42160 (30)	57366 (35)	6452 (60)	8976 (62)	1520 (74)	3216 (74)	782 (75)	3431 (81)
Diabetes	45692 (29)	60559 (31)	36351 (26)	44227 (27)	5570 (51)	7446 (51)	1272 (62)	2617 (60)	713 (69)	3008 (71)
Hypertension	62554 (39)	80514 (42)	49676 (35)	58712 (36)	7778 (71)	10199 (70)	1693 (82)	3454 (79)	851 (82)	3567 (84)
Myocardial infarction	7628 (5)	13312 (7)	5720 (4)	9218 (6)	1064 (10)	1701 (12)	277 (13)	684 (16)	175 (17)	830 (20)
Hemostroke	294 (0.2)	742 (0.4)	241 (0.2)	615 (0.4)	30 (0.3)	65 (0.5)	*	*	*	*
Ischemic stroke	19485 (12)	31993 (17)	15748 (11)	24243 (15)	2213 (20)	3626 (25)	502 (24)	1109 (25)	244 (24)	1235 (29)
Indications
Atrial fibrillation	83178 (52)	73594 (38)	71334 (51)	57286 (35)	7255 (66)	7900 (54)	1479 (72)	2543 (58)	636 (61)	2424 (57)
Pulmonary Embolism	15684 (10)	29860 (16)	13752 (10)	25317 (16)	1165 (11)	2265 (16)	192 (9)	578 (13)	120 (12)	527 (12)
Deep venous thrombosis	28215 (18)	52031 (27)	24466 (17)	42589 (26)	2118 (19)	4152 (29)	448 (22)	1448 (33)	355 (34)	1641 (39)
Arterial Embolism	2354 (1)	5873 (3)	1876 (1)	4470 (3)	267 (2)	587 (4)	53 (3)	189 (4)	56 (5)	332 (8)
Peripheral Vasc. Dis.	12386 (8)	19397 (10)	9209 (7)	13152 (8)	1844 (17)	2763 (19)	423 (20)	1011 (23)	270 (26)	1172 (28)
Hypercoagulable states	2562 (2)	4986 (3)	2298 (2)	4383 (3)	155 (1)	260 (2)	30 (1)	85 (2)	20 (2)	140 (3)
Medications
Antiplatelets	16799 (11)	20707 (11)	13293 (9)	15035 (9)	2094 (19)	2511 (17)	483 (23)	955 (22)	251 (24)	1021 (24)

Abbreviations: CKD, chronic kidney disease; Dis, disease; ESKD, end-stage kidney disease; OLDW, OptumLabs Data Warehouse; Vasc, Vascular.

Data presented as mean ± standard deviation or proportion where appropriate.

NB: 2% of DOAC and 4% of warfarin patients from the total cohort were missing CKD information

^*Values for cells with <20 patients are suppressed

Among patients with AF as the indication for anticoagulation, warfarin-treated patients had a higher median CHA₂DS₂-VASC score in non-CKD and CKD stage 3 compared to DOAC-treated patients (Supplemental Table S2); however, there was no difference among CKD stages 4, 5 and ESKD patients. There was also no difference in median HAS-BLED scores between DOAC and warfarin patients across all CKD strata.

Time-Varying As-treated Analysis

In the time-varying as-treated analysis, 50,272 patients had at least one combined CVD outcome during a median follow-up time of 90 days (interquartile range, IQR: 30 – 279 days). Of the 17,836 patients taking DOACs, 4,269 developed a myocardial infarction and 13,567 developed a stroke. Of the 32,436 patients taking warfarin, 8,388 developed a myocardial infarction and 24,048 developed a stroke. The crude rate of combined CVD outcomes in DOAC treated patients was 17.9 events per 100 person-years (95% CI 17.6 – 18.1) while the crude rate of combined CVD outcomes in warfarin treated patients was 25.4 events per 100 person-years (95% CI 25.2 – 25.7) (Supplemental Table S3A). A lower combined CVD outcome risk was observed across all models of adjustment in DOAC treated patients compared to warfarin treated patients. Compared to warfarin treated patients, those treated with DOAC had a 33% lower risk of combined CVD outcomes (HR: 0.67, 95% CI: 1.47 – 1.52) in the unadjusted model and a 22% lower risk of combined CVD outcomes (HR: 0.78, 95% CI: 0.77 – 0.80) after model 3 adjustment (Supplemental Table S3A). In our sensitivity analysis with adjustment for additional variables (model 4), there was no significant change in our findings.

We further assessed association of anticoagulation treatments with CVD combined outcomes across CKD stage. After Model 3 adjustment, DOAC compared to warfarin use was associated a 21% lower risk of combined CVD outcomes in the non-CKD strata (HR: 0.79, 95% CI: 0.77 – 0.81). CKD stage 3 patients also had a 21% lower risk of CVD outcomes (HR: 0.79, 95% CI: 0.74 – 0.84), CKD stage 4 and 5 patients had a 28% lower risk of CVD outcomes (HR: 0.72, 95% CI: 0.63 – 0.81), and ESKD patients had a 25% lower risk of CVD outcomes (HR: 0.75, 95% CI: 0.64 – 0.89) (Figure 1A & Supplemental Table S3B). These results remained consistent after model 4 adjustment.

Figure 1:

Risk of time-varying cardiovascular and bleeding outcomes stratified by CKD stage (as-treated analysis). Hazard ratios are shown for the association between warfarin vs direct oral anticoagulants (DOACs) therapy with (a) combined CVD and (b) bleeding outcomes in a cohort of 351,407 individuals from the OptumLabs^® Data Warehouse (warfarin as reference group). CKD: chronic kidney disease; CVD: cardiovascular disease; ESKD: end-stage kidney disease on dialysis.

Note: Model 1: unadjusted; Model 2: adjusted for demographics (age, gender, and race) and year of the index anticoagulation prescription date; Model 3: adjusted for model 2 plus comorbidities and medications (diabetes, MI, CHF, ischemic stroke, hemorrhagic stroke, and antiplatelet medication use), and CKD stage; Model 4 (sensitivity analysis): adjusted for model 3 plus other comorbidities (acute kidney disease, hypertension, atrial fibrillation, pulmonary embolism infarction, deep venous thrombosis, arterial embolism/thrombosis, peripheral vascular disease, hypercoagulable state).

Furthermore, in our analysis, 48,684 patients (18,311 on DOACs and 30,373 on warfarin) had at least one bleeding outcome with a crude rate of 20.6 events per 100 person-years (95% CI: 20.4 – 20.8) (Supplemental Table S4A). The median follow-up time for the bleeding outcome in the total cohort was 105 days (IQR: 30 – 299 days). We also found that DOAC patients had a 23% lower risk of bleeding in our unadjusted model (HR: 0.77, 95% CI: 0.76 – 0.78) compared to patients treated with warfarin, and an 10% and 6% lower bleeding risk (HR: 0.90, 95% CI: 0.88 – 0.92; HR: 0.94, 95% CI: 0.92 – 0.96) after model 3 adjustment and in sensitivity analysis (model 4), respectively (Supplemental Table S4A).

In our CKD sub-group analysis, DOAC compared to warfarin was associated with a 8% lower risk of bleeding in non-CKD patients (HR: 0.92, 95% CI: 0.90 – 0.94), 10% lower risk of bleeding in CKD stage 3 patients (HR: 0.90, 95% CI: 0.84 – 0.96), 22% lower risk of bleeding in CKD stage 4 and 5 patients (HR: 0.78, 95% CI: 0.69 – 0.89), and 19% lower risk of bleeding in ESKD patients (HR: 0.81, 95% CI: 0.69 – 0.96) (Figure 1B & Supplemental Table S4B). Adjustment with additional variables (model 4) did not significantly change our findings. All models met the proportionality assumption.

Subgroup Analysis by Anticoagulation Indication

In subgroup analysis by anticoagulation indication of all patients in our total cohort, DOAC-treated patients had a lower risk of composite CVD outcomes compared to warfarin-treated patients in all indication subgroups (Figure 2A). For AF indication, DOAC patients had a lower composite CVD risk compared to warfarin patients across all stages of CKD. For the deep venous thrombosis and peripheral vascular disease indications, DOAC-treated patients also had a lower composite CVD risk in non-CKD and CKD stages 3 to 5. Among ESKD patients, DOAC-treated patients trended towards a lower risk of composite CVD outcomes. For patients with pulmonary embolism, DOAC use was associated with lower composite CVD risk in both non-CKD and CKD stage 4/5, but not in CKD stage 3 and ESKD. Patients with arterial embolism only had a significantly lower composite CVD risk among DOAC-treated patients in the non-CKD group.

Figure 2:

Risk of time-varying cardiovascular and bleeding outcomes stratified by CKD stage and anticoagulation indication after Model 3 adjustment. Hazard ratios are shown for subgroup analyses stratified by indication for anticoagulation, examining the association of warfarin vs direct oral anticoagulants (DOACs) therapy with (a) combined CVD and (b) bleeding outcomes in a cohort of 351,407 individuals from the OptumLabs^® Data Warehouse (warfarin as reference group, Model 3 adjustment). CKD: chronic kidney disease; CVD: cardiovascular disease; ESKD: end-stage kidney disease on dialysis.

With respect to our bleeding outcomes, DOAC use was associated with a lower risk of bleeding compared to warfarin for patients with AF. Patients with deep venous thrombosis and peripheral vascular disease on DOACs trended towards lower bleeding risk compared to warfarin for patients in our total cohort (Figure 2B). For arterial embolism and pulmonary embolism, there did not appear to be a significant difference in bleeding risk among those treated with DOAC vs warfarin. No interaction was found between CKD stage and indication for anticoagulation. All models met the proportionality assumption.

Coarsened Exact Matching Analysis

In our CEM analysis, we found both bleeding and CVD risk decreased as CKD stage worsening in patients with DOAC treatment compared to warfarin patients. Furthermore, across all CKD strata, both risk of bleeding and CVD outcomes were lower among DOAC users compared to warfarin users, similar to our previous analyses (Table S5 & Figure 3).

Figure 3:

Hazard ratios for the association of anticoagulation treatments with (a) cardiovascular combined and (b) bleeding outcome after matching DOAC patients with warfarin patients using coarsened exact matching in 299,171 non-CKD, 23,012 CKD Stage 3, 4,696 CKD Stage 4–5, and 2,884 ESRD patients (reference: warfarin patients).

Note: Patients were matched on variables in Model 3. Model 3: demographics (age, gender, and race), year of the index anticoagulation prescription date, comorbidities and medications (diabetes, MI, CHF, ischemic stroke, hemorrhagic stroke, and antiplatelet medication use), and CKD stage.

DISCUSSION

In a large and nationally representative US de-identified administrative claims database we observed equal or reduced risk of composite CVD and composite bleeding outcomes with DOAC therapy compared to warfarin across CKD stages. When assessing individual anticoagulation indications, AF was the only indication showing consistently lower risk of combined bleeding and CVD outcomes among DOAC users compared to warfarin users across non-CKD, CKD and ESKD strata.

In non-CKD patients, our study is consistent with prior reports showing superior safety profiles of DOACs and is in line with guidelines recommending DOACs as first line therapy for most anticoagulation indications [11,12]. Our study adds to the prior report by Graham et al. who observed a lower risk of thromboembolic stroke and intracranial bleeding with DOACs in a cohort of approximately 450,000 Medicare beneficiaries (of which 8.5–13.5% were non-dialysis CKD patients) [24]. Our study also adds to the recent COMPASS trial showing a decrease risk of cardiovascular outcomes (cardiovascular death, stroke, or myocardial infarction) among patients receiving rivaroxaban and aspirin vs aspirin alone or rivaroxaban alone [10]. While the COMPASS trial did not enroll patients with GFR < 15 ml/min, our data suggests that the cardioprotective effect of DOACs may extend to other DOACs and potentially to more severe stages of CKD.

In contrast to non-CKD patients, findings regarding safety and efficacy of DOACs from large retrospective non-dialysis CKD and dialysis cohorts of patients have been conflicting. Data from a study investigating CKD stages 3–5 patients with AF reported similar ischemic stroke event rates with warfarin vs DOACs (apixaban, rivaroxaban, dabigatran); however, there was a slightly higher risk of bleeding with DOACs [16]. Data from the Geisinger Health System also showed higher bleeding risks associated with DOACs compared to warfarin. This study utilized a smaller cohort of 6,412 AF patients of which 4% had eGFR values less than 30 mL/min/1.73m² and 0.4% – 0.5% were dialysis patients, potentially limiting generalizability to advanced CKD and ESKD populations [16]. In contrast, a recent meta-analysis comprising a subset of 78,053 patients among 15 studies showed that DOAC (vs warfarin) use for any indication was associated with reduced risk of intracerebral hemorrhage, stroke, systemic embolism, mortality and major bleeding among CKD patients [18].

In the dialysis population specifically, Siontis, et al. assessed 25,523 AF patients on dialysis and showed equivalent risks of stroke but lower risk of major bleeding with apixaban [25]. In contrast, Chan et al. analyzed the Fresenius Medical Care North America (FMCNA) ESKD database and noted that dabigatran and rivaroxaban were associated with a higher risk of adverse outcomes especially bleeding risk [26]. In this study published in 2015, only 525 patients on DOACs were assessed and newer DOACs such as apixaban were not included, potentially limiting generalizability. A recent meta-analysis suggests that DOACs are associated with a reduced risk of thromboembolism in patients with AF on long term dialysis, though findings were dominated Siontis’ large single study comparing apixaban with warfarin [27].

Given these disparate findings, the relative safety profile of DOACs as an alternative to warfarin in the CKD and ESKD populations remains unclear. Nor is it clear if these studies done on AF patients are generalizable to patients who are on anticoagulation for other indications. Nonetheless, the results of our study provide further evidence that DOACs may be safer compared to warfarin in CKD and ESKD patients, though it remains unclear if DOACs are safer for other anticoagulation indications aside from AF.

The strengths of our study include a large cohort with a relatively long follow up period of up to 7 years, with comprehensive claims data. However, our large dataset containing commercial insurance coverage and Medicare Advantage enrollees, while representing a large swath of the American population, may under-represent those among lower socioeconomic status (especially those who are unable to obtain or decline to obtain insurance coverage). There are other inherent limitations of retrospective database analysis with the potential for confounding by indication and selection bias. In addition, we utilized time-varying models in an attempt to overcome the limitation that some patients may have been switched from one anticoagulant to another which may have introduced bias to our results. There may still be residual confounding by indication as the guidelines for using anticoagulation in ESKD patients remain controversial despite expert opinion and a recent comprehensive systematic review on this topic [28–30]. In an attempt to assess residual confounding, we performed a coarsened exact matching analysis which did not show any major differences to our analysis. We also acknowledge the lack of mortality data is a limitation to our paper. The sources of mortality data available in the OLDW are incomplete; this is a known and inherent limitation to administrative claims databases in general [31]. However, as previous studies have shown a higher mortality with warfarin compared to DOACs, we do not believe that fewer events in the DOAC groups is due to a higher competing risk of death [32,33].

While our cohort was constructed from 2010 onwards, treatment guidelines for both VTE and AF have changed dramatically with the approval of new DOACs between 2010 through 2015. It is unlikely that we will be able to fully account for temporal changes in treatment strategies despite sensitivity analysis our models. We also acknowledge potential inaccuracy with determining the stage of CKD as well as CVD and bleeding outcomes as we relied on ICD-9 codes [34]. Furthermore, some medications such as non-steroidal anti-inflammatory medications, serotonin reuptake inhibitors, proton pump inhibitors, H2-blockers, and other anticoagulants such as heparin products can potentially alter bleeding risks that we were unable to account for in our analysis.

Our study was not able to address anticoagulation treatment efficacy, especially since there is heterogeneity across various anticoagulation indications in terms of treatment duration and stroke risk. We were also not able to construct a referent no-treatment group, which is particularly relevant in the setting of AF in ESKD where clinical equipoise exists and the risk of bleeding with any anticoagulant may outweigh potential benefits [35,36]. We note the recent meta-analysis by Kuno and colleagues which suggests that there may not be a reduction in stroke risk with the addition of anticoagulation among dialysis patients with atrial fibrillation [27]. Further, a recent retrospective cohort study using 2012–2015 US Renal Data System data reported that apixaban did not impact stroke risk but was associated with a higher incidence of intracranial bleeding, compared to maintenance dialysis patients not on any anticoagulation matched via a propensity score [37]. Randomized, placebo-controlled trials are needed to better define safe and effective treatment strategies for advanced CKD patients with VTE and AF.

While there are limitations with this investigation, we believe that our robust analysis provides insight into the safety profile of DOACs especially in advanced CKD, a population that has traditionally been excluded from or has been difficult to study in clinical trials. The RENAL-AF trial, which compared apixaban to warfarin in U.S. ESKD patients, was stopped early due to lack of funding after 155 of a planned 760 patients were enrolled and produced inconclusive results [38]. Outcomes data from large cohorts such as ours provide real-world evidence to guide clinical decision-making while prescribers await results from an ongoing German randomized trial in ESKD patients that directly compare apixaban and warfarin (the AXADIA trial) [39]. Overall, our data suggests an equivalent or superior safety profile with DOACs as compared to warfarin, across anticoagulation indications, which may factor into decision-making when providers are prescribing anticoagulation in the advanced CKD population.