Dabigatran and warfarin were taken by 7,702 and 7,885 NVAF patients without a history of ... Dabigatran was associated with a lower risk of AKI than warfarin.
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 68, NO. 21, 2016
ª 2016 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
ISSN 0735-1097 http://dx.doi.org/10.1016/j.jacc.2016.08.063
THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Acute Kidney Injury in Asians With Atrial Fibrillation Treated With Dabigatran or Warfarin Yi-Hsin Chan, MD,a,b Yung-Hsin Yeh, MD,a,b Lai-Chu See, PHD,c,d,e Chun-Li Wang, MD,a,b Shang-Hung Chang, MD, PHD,a,b Hsin-Fu Lee, MD,a,b Lung-Sheng Wu, MD,a,b Hui-Tzu Tu, MS,c Chi-Tai Kuo, MDa,b
ABSTRACT BACKGROUND Whether dabigatran is associated with a lower risk of acute kidney injury (AKI) in patients with nonvalvular atrial fibrillation (NVAF) remains unknown. OBJECTIVES The authors compared the risk of AKI in Asians with NVAF who were prescribed dabigatran versus warfarin. METHODS The authors analyzed patients enrolled in the Taiwan nationwide retrospective cohort study from June 1, 2012, to December 31, 2013. Dabigatran and warfarin were taken by 7,702 and 7,885 NVAF patients without a history of chronic kidney disease (CKD) and 2,256 and 2,089 NVAF patients with a history of CKD, respectively. A propensity-score weighted method was used to balance covariates across study groups. RESULTS A total of 6,762 (88%) and 940 (12%) CKD-free patients and 2,025 (90%) and 231 (10%) CKD patients took dabigatran 110 mg and 150 mg twice daily, respectively. Dabigatran was associated with a lower risk of AKI than warfarin for either the CKD-free (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.49 to 0.77; p < 0.001) or CKD (HR: 0.56; 95% CI: 0.46 to 0.69; p < 0.001) cohort. As the increment in CHA2DS2-VASc score (a risk score based on congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, aged 65 to 74 years, and female sex) increased from 0/1 to 6þ points, the incidence of AKI for the dabigatran group was relatively stable (1.87% to 2.91% per year for the CKD-free cohort; 7.31% to 13.15% per year for the CKD cohort) but increased obviously for patients taking warfarin for either CKD-free (2.00% to 6.16% per year) or CKD cohorts (6.82 to 26.03% per year). The warfarin group had a significantly higher annual risk of AKI than the dabigatran group for those with a high CHA2DS2-VASc score ($4 for the CKD-free cohort and $3 for the CKD cohort). Subgroup analysis revealed that among dabigatran users, those taking either low-dose or standard-dose dabigatran, those with a warfarin-naïve or warfarin-experienced history, those with or without diabetes, and those with CHA2DS2VASc $4 or HAS-BLED $3 (risk score based on hypertension, abnormal renal and liver function, stroke, prior major bleeding, labile international normalized ratios, age 65 years or older, drugs or alcohol usage history) all had a lower risk of AKI than those taking warfarin. CONCLUSIONS Among Asians with NVAF, dabigatran is associated with a lower risk of AKI than warfarin. (J Am Coll Cardiol 2016;68:2272–83) © 2016 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Listen to this manuscript’s
From the aCardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; bCollege of Medicine, Chang
audio summary by
Gung University, Taoyuan, Taiwan; cDepartment of Public Health, College of Medicine, Chang Gung University, Taoyuan, Taiwan;
JACC Editor-in-Chief
d
Dr. Valentin Fuster.
of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan,
Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; and the eDivision
Taiwan. This study was supported by grants 102-2628-B-182-011-MY3, 102-2314-B-182A-053-MY3, and 105-2628-B-182A-003-MY3 from the Ministry of Science and Technology and CMRPG3B0991-3, CMRPG3E1681, CMRPG3F0041, CMRPG3D1631, CMRPD1F0251, CMRPG3F0041 and CMRPG3E0291 from the Chang Gung Memorial Hospital, Linkou, Taiwan. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 7, 2016; revised manuscript received August 23, 2016, accepted August 31, 2016.
Chan et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2272–83
O
2273
Acute Kidney Injury and Oral Anticoagulants
like
23.74 million Taiwanese. Because the original
ABBREVIATIONS
vitamin K antagonists (e.g., warfarin),
NHIRD identification number belonging to
AND ACRONYMS
ral
anticoagulant
drugs
(OACs),
have been shown to decrease the risk of
each patient is encrypted and de-identified to
thromboembolic events and all-cause mortality in
protect their privacy, informed consent was
patients with atrial fibrillation (AF) (1). OACs can
waived for this study. The claims for each
also increase the risk of hemorrhage caused by coa-
individual
gulopathy. Although warfarin has been commonly
continuously
used for more than 60 years, its harmful effects on
consistent data encryption process used. Di-
renal function (so-called warfarin-related nephropa-
agnoses were coded according to the Inter-
75 years or older, diabetes
thy [WRN]) have only recently been recognized
national
mellitus, previous stroke/
(2,3). It is estimated that as many as 20.5% of all
Revision-Clinical Modification (ICD-9-CM).
patients taking warfarin have experienced at least
The study protocol was approved by the
years, female
1 episode of WRN during their treatment course,
Institutional Review Board of Chang Gung
CKD = chronic kidney disease
with most cases occurring within 1 year after the initi-
Memorial Hospital, Taiwan.
patient
could
followed
Classification
be
linked
because
of
of
and the
Diseases-Ninth
ation of treatment (3,4). Dabigatran, a competitive
AF = atrial fibrillation AKI = acute kidney injury ASMD = absolute standardized mean difference
CHA2DS2-VASc = congestive heart failure, hypertension, age
transient ischemic attack, vascular disease, age 65 to 74
GFR = glomerular filtration rate
direct thrombin inhibitor, is increasingly used for
STUDY DESIGN AND OUTCOME. A cohort
HAS-BLED = hypertension,
the prevention of ischemic stroke and systemic embo-
with 2 study groups (dabigatran and warfarin)
abnormal renal and liver
lism in patients with nonvalvular AF as a safer alter-
was used in this study. A flowchart of the
function, stroke, prior major
native to warfarin with a lower risk of intracranial
study cohort enrollment is shown in Figure 1. A
years or older, drugs or alcohol
hemorrhage and other causes of major bleeding (5).
total of 304,252 new AF patients (ICD-9-CM
usage history
SEE PAGE 2284
Dabigatran is excreted primarily from the kidney; however, little is known about its effects on kidney function. In animal models, dabigatran has been
code 427.31) were identified from January 1, 1996, to December 31, 2013. Among these 304,252 patients, 89,705 had at least 1 prescription filled for dabigatran or warfarin after AF was diagnosed. The approval date for
bleeding, labile INRs, aged 65
ICD-9-CM = International Classification of Diseases-Ninth Revision-Clinical Modification
INR = international normalized ratio
NHIRD = National Health
dabigatran in Taiwan was June 1, 2012. The
Insurance Registry Database
maturia, similar to warfarin (6). Although the inci-
index date was defined as the first date
NOAC = non–vitamin K
dence of AKI was not significantly different between
of prescribing dabigatran or warfarin after
antagonist oral anticoagulant
dabigatran and warfarin in the RE-LY (Randomized
June 1, 2012. Patients were excluded if
OAC = oral anticoagulant
shown to produce acute kidney injury (AKI) and he-
Evaluation of Long-Term Anticoagulation Therapy) trial, there have been some case reports of AKI occurring with dabigatran use (7,8). Interestingly, the post hoc analysis of RE-LY indicated that patients with AF receiving dabigatran exhibited a slower decline in renal function than those taking warfarin, and the decline of renal function was amplified by previous warfarin use and the presence of diabetes mellitus (9). The magnitude of AKI risk associated with dabigatran and warfarin as administered to AF patients remains unknown in the real-world clinical setting. The objective of this study was to compare the risk of AKI associated with dabigatran versus warfarin among patients with nonvalvular AF.
they had pulmonary embolism or deep vein
WRN = warfarin-related
thrombosis within 6 months before AF diag-
nephropathy
nosis (n ¼ 1,618), received joint replacement or valvular surgery within 6 months before AF diagnosis (n ¼ 2,747), had end-stage renal disease before the index date (n ¼ 9,651), were
