Abstract
Introduction
The risk and benefit for patients on dialysis receiving anticoagulation (AC) therapy have not been clearly established. This study aimed to compare the rates of clinically significant thrombotic and bleeding events in patients on dialysis.
Methods
This is a retrospective cohort study conducted using Kaiser Permanente Northern California’s electronic medical record database from 2013 to 2021. Patients over 18 years old on dialysis who were prescribed warfarin or apixaban were included. Patients with mechanical valves were excluded. The outcomes were analyzed using Mann–Whitney tests for continuous variables, χ2 tests for categorical variables, and Kaplan–Meier method for time-to-event analysis.
Results
In the study period, 9832 patients were not on AC, and 2088 were taking apixaban or warfarin. The baseline demographics (age, Charlson Comorbidity Index, and sex) were comparable between apixaban and warfarin groups. Among the patients on anticoagulants, 181 were taking apixaban, while 1907 were taking only warfarin. The outcomes 1–3 years within the study period showed that the rates of clinically significant bleeding and thrombosis were comparable in both groups, with the exception of the rate of dialysis access thrombosis being lower in the apixaban group (7% vs 17%, P < .001).
Conclusion
In this diverse cohort, apixaban and warfarin showed no clinically significant differences in bleeding rates and lower rate of access thrombosis with apixaban. This study adds to the growing data of AC in the population with end-stage kidney disease, highlighting the need to enroll patients in an adequately powered randomized controlled trial to inform future practice.
Keywords: DOAC, VKA, ESKD, Dialysis, Bleeding, Cerebrovascular accident, Atrial fibrillation, Shared decision making
Introduction
Patients with end-stage kidney disease (ESKD) on kidney replacement therapy requiring anticoagulation are at high risk for both bleeding and thrombosis. 1 Limited data exist on the efficacy and complications of different anticoagulants in these patients. 2 Warfarin, a vitamin K antagonist (VKA), has been widely used since 1954, but direct oral anticoagulants (DOACs) have largely replaced it in many indications due to better safety, ease of use, and fewer dietary restrictions. 3,4 Despite their potential to reduce thromboembolic events, clinical trials often exclude dialysis patients, leaving a gap in data to guide clinicians. 5,6 Before the US Food and Drug Administration approved apixaban and rivaroxaban for dialysis patients in 2011 and 2012, warfarin was the only option for patients with ESKD due to a lack of clinical trials. 7–9 Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation (RENAL-AF), a randomized controlled trial (RCT) comparing VKA and DOACs in dialysis patients with atrial fibrillation (AF), was halted due to difficulties in enrollment. 10
This retrospective study aims to identify incidences of cerebrovascular accident, transient ischemic attack, death, major bleeds, and calciphylaxis in a cohort of dialysis patients. This was done by comparing outcomes in dialysis patients using VKA or apixaban, over 1, 2, and 3 years.
Methods
Study population
Kaiser Permanente Northern California is a community-based, integrated health care delivery system providing care to approximately 4.6 million members in the greater San Francisco Bay Area and Central Valley. The demographic characteristics of Kaiser Permanente Northern California members are similar to the general population within each of the Kaiser Permanente Regions. 11 The authors identified an incident cohort of all adult dialysis patients with acute kidney injury (AKI) or ESKD who underwent dialysis treatment between January 1, 2013, and December 31, 2021, within the Kaiser Permanente Northern California electronic medical record system.
Inclusion criteria
Patients were included if they were a member of a Kaiser Permanente Northern California Health Plan during the study period, aged 18 years or older, and were on dialysis (peritoneal dialysis or hemodialysis) with more than a year of pharmacy records as proof of anticoagulation use. Patients with both AKI and ESKD were included in the dataset.
Exclusion Criteria
Patients were excluded if they did not have 12 months of continuous Kaiser Permanente Northern California membership following their initiation of dialysis for reasons other than death. Patients with mechanical valves were excluded. Additionally, patients with pregnancy in the 12 months following initiation of dialysis were excluded.
Data Collection
The Kaiser Permanente Northern California institutional review board approved the study with a waiver of informed consent. Study participants were electronically identified by their use of anticoagulants and types of anticoagulants (warfarin, apixaban) using international classification of diseases diagnosis codes and pharmacy records (Supplemental Material). Baseline clinical and demographic characteristics (age, sex, race and ethnicity, hypertension, coronary artery disease, peripheral vascular disease, diabetes, dialysis modality, use of aspirin, and use of clopidogrel) at time of dialysis initiation, and outcomes (death, cerebrovascular accident, transient ischemic attack, major bleeding, and calciphylaxis) were identified within 1 year, 2 years, and 3 years of initiation of anticoagulation using diagnosis codes and pharmacy records (Tables 1–3). Use of oral anticoagulants was identified using the medication order and pharmacy fill records in the Kaiser Permanente Northern California electronic medical record. Patients were considered to use anticoagulants if they used them in the 12 months following the start of dialysis. For the analysis comparing types of anticoagulants, the index date was the date of initiating anticoagulants.
Table 1:
Outcomes in year 1 after initiating oral anticoagulant treatment
| Outcome | Apixaban (N = 181), n (%) | Warfarin (N = 1907), n (%) | P value a |
|---|---|---|---|
| Death | 56 (31) | 521 (27) | .298 |
| Pulmonary embolism | 8 (4) | 113 (6) | .506 |
| Cerebrovascular accident | 19 (11) | 229 (12) | .631 |
| Transient ischemic attack | 6 (3) | 86 (5) | .571 |
| Bleeding | 24 (13) | 326 (17) | .212 |
| Packed red blood cell transfusion | 30 (17) | 305 (16) | .832 |
| Arteriovenous fistula ligation | 7 (4) | 43 (2) | .196 |
| Access thrombosis | 13 (7) | 331 (17) | < .001 |
| Catheter placement | 13 (7) | 166 (9) | .579 |
| Prothrombin complex concentrate | 1 (1) | 1 (0) | .166 |
| Vitamin K deficiency | 0 (0) | 1 (0) | 1 |
| Tranexamic acid | 8 (4) | 40 (2) | .063 |
| Calciphylaxis | 1 (1) | 29 (2) | .51 |
P values from Fisher’s exact test.
Table 2:
Outcomes in 2 years after initiating oral anticoagulant treatment
| Outcome | Apixaban (N = 91), n (%) | Warfarin (N = 1339), n (%) | P value a |
|---|---|---|---|
| Death | 26 (29) | 263 (20) | .059 |
| Pulmonary embolism | 5 (5) | 93 (7) | .676 |
| Cerebrovascular accident | 11 (12) | 217 (16) | .375 |
| Transient ischemic attack | 4 (4) | 96 (7) | .399 |
| Bleeding | 14 (15) | 315 (24) | .093 |
| Packed red blood cell transfusion | 24 (26) | 304 (23) | .444 |
| Arteriovenous fistula ligation | 5 (5) | 54 (4) | .427 |
| Access thrombosis | 7 (8) | 331 (25) | < .001 |
| Catheter placement | 8 (9) | 164 (12) | .406 |
| Prothrombin complex concentrate | 0 (0) | 2 (0) | 1 |
| Vitamin K deficiency | 0 (0) | 2 (0) | 1 |
| Tranexamic acid | 3 (3) | 56 (4) | 1 |
| Calciphylaxis | 0 (0) | 47 (4) | .069 |
P values from Fisher’s exact test.
Table 3:
Outcomes in 3 years after initiating oral anticoagulant treatment
| Outcome | Apixaban (N = 33), n (%) | Warfarin (N = 980), n (%) | P value a |
|---|---|---|---|
| Death | 10 (30) | 223 (23) | .299 |
| Pulmonary embolism | 2 (6) | 70 (7) | 1 |
| Cerebrovascular accident | 6 (18) | 196 (20) | 1 |
| Transient ischemic attack | 2 (6) | 82 (8) | 1 |
| Intracerebral hemorrhage | 1 (3) | 28 (3) | 1 |
| Bleeding | 5 (15) | 288 (29) | .081 |
| Arteriovenous fistula ligation | 2 (6) | 46 (5) | .667 |
| Access thrombosis | 3 (9) | 297 (30) | .006 |
| Catheter placement | 2 (6) | 137 (14) | .3 |
| Prothrombin complex concentrate | 0 (0) | 5 (1) | 1 |
| Vitamin K deficiency | 0 (0) | 1 (0) | 1 |
| Tranexamic acid | 1 (3) | 63 (6) | .717 |
| Calciphylaxis | 0 (0) | 40 (4) | .637 |
P values from Fisher’s exact test.
Statistical Analysis
Descriptive statistics were provided for baseline patient characteristics. The frequencies and proportions of patients who underwent each type of anticoagulation (apixaban only, warfarin only, warfarin to apixaban, apixaban to warfarin) within each year between 2013 and 2021 were calculated.
The association between anticoagulant use and type of anticoagulant and baseline clinical and demographic factors was analyzed among patients, excluding patients who used more than 1 type of anticoagulant. For each clinical and demographic factor and 1-year, 2-year, and 3-year study outcomes, the means and standard deviations for continuous variables frequencies and proportions for categorical factors were reported, stratified by use of anticoagulants and type of anticoagulant.
The authors observed the frequencies between each exposure (use of anticoagulant, type of anticoagulant) category, and each clinical and demographic factor was assessed using Mann–Whitney tests for continuous factors and χ2 tests for categorical factors. In addition, the associations between each exposure category and 1-year, 2-year, and 3-year outcomes were assessed using χ2 tests.
Additionally, the Kaplan–Meier method was used to perform time-to-event analysis to compare the incidence of the study outcomes in the apixaban-only and warfarin-only groups and calculated log rank statistics were used for the association of the type of anticoagulant treatment with each time-to-event outcome. P values were reported for each test and were considered significant at a < .05 level. All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc) for Windows.
Results
A total of 12,026 patients on dialysis between 2013 and 2021 were identified. Among them, 9832 did not use anticoagulation, and 2194 used anticoagulation: 1907 warfarin, 181 apixaban, and 106 both. After excluding the 106 patients who were on both warfarin and apixaban, a total of 2088 patients were included in this study (Figure 1). Baseline demographics, comorbidities, and medication usage were similar among patients on apixaban vs warfarin (Table 4).
Figure 1:
Cohort assembling flow diagram.
Table 4:
Demographic and clinical characteristics by anticoagulant drug used
| Category | Apixaban/warfarin only (N = 2088) | No anticoagulant (N = 9832) |
P value a | Apixaban only (N = 181) |
Warfarin only (N = 1907) |
P value a |
|---|---|---|---|---|---|---|
| Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | |||
| Age, y | 69.7 (12.3) | 63.9 (14.5) | < .001 | 70.1 (12.7) | 69.7 (12.3) | .400 |
| Charlson comorbidity index | 6.19 (2.44) | 5.22 (2.34) | < .001 | 6.20 (2.52) | 6.19 (2.44) | .662 |
| Category | No. (%) | No. (%) | P value a | No. (%) | No. (%) | P value a |
| Sex | .636 | .946 | ||||
| Female | 838 (40) | 4001 (41) | 73 (40) | 765 (40) | ||
| Male | 1250 (60) | 5831 (59) | 108 (60) | 1142 (60) | ||
| Race and ethnicity | < .001 | .349 | ||||
| White | 940 (45) | 3023 (31) | 78 (43) | 862 (45) | ||
| Asian/Pacific Islander | 393 (19) | 2562 (26) | 43 (24) | 351 (18) | ||
| Hispanic | 355 (17) | 2205 (22) | 24 (13) | 330 (17) | ||
| Black | 284 (14) | 1544 (16) | 26 (14) | 258 (14) | ||
| Other | 116 (6) | 498 (5) | 10 (6) | 106 (6) | ||
| Hypertension | 2016 (97) | 9328 (95) | .001 | 174 (96) | 1842 (97) | .746 |
| Coronary artery disease | 1024 (49) | 2889 (29) | < .001 | 94 (52) | 930 (49) | .416 |
| Peripheral vascular disease | 248 (12) | 708 (7) | < .001 | 28 (15) | 220 (12) | .118 |
| Diabetes | 1448 (69) | 6692 (68) | .252 | 128 (71) | 1320 (69) | .676 |
| Dialysis modality | < .001 | .640 | ||||
| Hemodialysis | 1751 (84) | 7242 (74) | 154 (85) | 1597 (84) | ||
| Peritoneal dialysis | 337 (16) | 2590 (26) | 27 (15) | 310 (16) | ||
| Aspirin | 917 (44) | 4817 (49) | < .001 | 83 (46) | 834 (44) | .582 |
| Clopidogrel | 251 (12) | 1014 (10) | .021 | 28 (15) | 223 (12) | .136 |
P values calculated for continuous variables using Mann–Whitney tests and for categorical variables using χ2 tests.
Over the study period, patients were exclusively on warfarin during the early years of the study; however, during 2017–2018, the use of apixaban began to increase as warfarin use began to decline (Figure 2).
Figure 2:
Temporal trend of anticoagulant usage in dialysis patients; the denominator is 12,026 dialysis patients. Points start to diverge about 2017. Top line is all anticoagulated dialysis patients. The warfarin line is second from the top of the chart. The apixaban line is third from the top of the chart. The warfarin to apixaban line is fourth from the top of the chart. The apixaban to warfarin line is fifth from top of the chart. ESKD = end-stage kidney disease.
For the 2088 total patients included in this analysis, indications for anticoagulation are listed in Figure 3, which demonstrated 2% for pulmonary embolism, 8% for deep vein thrombosis, 17% for unknown reason, and 60% for AF.
Figure 3:
Indications for anticoagulation. Atrial fibrillation = 60%; unknown = 17%; > 1 indication = 12%; deep vein thrombosis = 8%; and pulmonary embolism = 2%.
The outcomes within 1–3 years after anticoagulation initiation showed that overall, the rates of clinically significant bleeding and thrombosis were similar between patients on apixaban and warfarin groups. There is lower dialysis access thrombosis rate in the apixaban group, and the difference lasted throughout all 3 years after initiation of anticoagulation. The relatively rare but serious diagnosis of calciphylaxis occurred solely in the warfarin group, 1% to 4% per year (Tables 1–3). The 3-year Kaplan–Meier all-cause survival remains the same between these 2 cohorts (Figure 4).
Figure 4:
Kaplan–Meier all-cause survival estimates. Warfarin is represented by the top line. Apixaban is represented by the bottom line.
Discussion
In this study of 2088 dialysis patients on anticoagulants within Kaiser Permanente Northern California, there were no major differences in major bleeding and thrombosis rates, except access thrombosis, between warfarin vs apixaban groups. The gradual transition from warfarin in the early study period to apixaban in the later study period is not surprising, given the US Food and Drug Administration approval of apixaban in 2011. Despite no RCT to demonstrate the superiority of apixaban to warfarin, most practitioners chose apixaban, likely due to its ease of usage and concerns of warfarin-associated calciphylaxis.
Since the approval of apixaban and rivaroxaban, several RCTs have studied the use of anticoagulation, including apixaban, warfarin, and rivaroxaban, in patients dependent on dialysis. 10,12–14 However, enrollment issues and conflicting results make these findings difficult to interpret definitively. 15 According to the 2018 Kidney Disease Improving Global Outcomes (KDIGO) guidance statement on anticoagulation in dialysis patients, there was insufficient evidence to recommend warfarin for stroke prevention, while apixaban 2.5 mg and rivaroxaban 15 mg could be considered. 16 The 2023 American College of Cardiology/American Heart Association/American College of Clinical Pharmacy/Heart Rhythm Society guidelines give a 2b/B-NR recommendation in favor of DOACs in dialysis patients but emphasize that dosage decisions should be made via a multidisciplinary approach, considering factors such as residual renal function, weight in kg (< 60 kg), patient age (> 80 years), dialysis modality, and indication for anticoagulation. 17
A retrospective study by Siontis et al reported that among 25,523 Medicare patients in the United States Renal Data System between 2010 and 2015, apixaban use may be associated with a lower chance of major bleeding compared with warfarin. 7 The authors’ study did not find a difference in major bleeding events, possibly due to population differences and the inclusion of other indications for anticoagulation besides AF.
It remains unclear whether dialysis patients with AF will benefit from anticoagulation due to competing possibility of death in dialysis patients in general. This study and others have observed an increase in mortality of up to 20%, while Hsieh et al demonstrated AF was associated with a hazard ratio of 4.1. 18,19 The competing outcomes of bleeding or death might outweigh the possibility of cerebral vascular accident prevention. This also highlights a need to consider all options and partner with patients regarding anticoagulation, emphasizing the importance of shared decision-making in patients with advanced kidney disease. 20–22 Due to the high mortality rates observed, the authors emphasize shared decision-making and the importance of care delivery discussions with patients and other specialties. 23–25
The authors’ finding of an increased possibility of calciphylaxis in warfarin-treated patients (1–4%) is consistent with previously documented rates in dialysis patients (0.04%–4%). 26–28 This is one advantage of using DOAC over warfarin for dialysis patients.
The authors’ finding of a lower thrombosis rate from apixaban use compared with warfarin use is a surprise and, to their current knowledge, there is no study comparing the effect of DOAC vs warfarin in access patency. This result needs further study.
This study had several strengths. It included a large diverse group of patients making results more generalizable to the US population and beyond. The study accessed data up to December 31, 2021, which is more recent than prior studies given trends toward more doctors prescribing apixaban to patients dependent on dialysis since 2013. 7 This study exclusively included patients requiring dialysis (due to AKI and ESKD), whereas other studies included varying stages of chronic kidney disease and dialysis patients. 29–31
This study had limitations. Observational design can lead to confounding factors. To minimize confounding factors, study investigators compared groups with similar baseline characteristics. However, the decision to initiate anticoagulation or choose a specific anticoagulant cannot be fully adjusted in observational studies. Exclusion of patients due to loss of Kaiser Permanente insurance would likely introduce bias; however, the authors were unable to overcome this due to not being able to assess these patients’ outcomes after they lost Kaiser Permanente membership. Univariate analysis was performed due to a lack of data in smaller subgroups which did not allow the authors to perform multivariate analysis. Regardless, conclusions drawn from observational studies must be interpreted cautiously.
Conclusion
In this diverse northern California cohort of dialysis patients, apixaban was comparable to warfarin in terms of rates of cerebral vascular accidents and clinically significant bleeding events. These study data add to the growing body of literature exploring outcomes in dialysis patients with indications for anticoagulation. Furthermore, these data highlight the notion that the best anticoagulant for a patient on dialysis is the one that is most individualized to the patient, supporting informed consent, patient-centered, multidisciplinary care, and shared decision-making approaches. Future RCTs evaluating this question should be performed to aid specific dosing and best practices.
Supplementary Material
online supplementary file 1:
Acknowledgments
Kaiser Permanente group and its members, Kaiser Division of Research, Kaiser San Francisco Graduate Medical Education, and the entire study team. We gratefully acknowledge the invaluable contributions of the patients, including those from the electronic health record.
Disclosure.
Part of the data in this paper was previously presented in abstract format at the following conferences: Journal of the American Society of Nephrology 34(11S):p 160, November 2023. | https://doi.org/10.1681/ASN.20233411S1160c. American Journal of Kidney Diseases, Volume 83, Issue 4, Supplement 2, 2024, Page S89, ISSN 0272-6386, https://doi.org/10.1053/j.ajkd.2024.01.294
Footnotes
Author Contributions: Tariq Shaheed, DO, initiated the development of the study design and assisted in interpretation of the data, drafting the manuscript, and revising the manuscript. Douglas Stram, MS, did the data analysis and assisted in data interpretation, drafting the data interpretation section, and revising manuscript content. Aida Shirazi, PhD assisted in data interpretation and revising manuscript content. Sumie Iwasaki, MD, assisted in data interpretation and revising manuscript content. Cynthia Davila, MD, assisted in revising manuscript content. Sijie Zheng, MD, PhD, assisted in developing the study design, interpretation of the data, drafting the manuscript, and revising the manuscript.
Conflicts of Interest: Dr Zheng serves on the scientific advisory board of Calliditas.
Funding: None declared
Data-Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to the privacy of research participants; costs or use agreements may apply.
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Supplementary Materials
online supplementary file 1: