CHEST

Original Research CARDIOVASCULAR DISEASE

A Prospective Study of Estimated Glomerular Filtration Rate and Outcomes in Patients With Atrial Fibrillation The Loire Valley Atrial Fibrillation Project Amitava Banerjee, MPH, DPhil; Laurent Fauchier, MD, PhD; Patrick Vourc’h, PhD; Christian R. Andres, MD, PhD; Sophie Taillandier, MD; Jean Michel Halimi, MD, PhD; and Gregory Y. H. Lip, MD

Background: Atrial fibrillation (AF) is more likely to develop in patients with chronic kidney disease (CKD) than in individuals with normal renal function, and patients with CKD are more likely to suffer ischemic stroke (IS)/thromboembolism (TE). To our knowledge, no prior study has considered the impact of estimated glomerular filtration rate (eGFR) on bleeding. We investigated the relationship of eGFR to IS/TE, mortality, and bleeding in an AF population unrestricted by age or comorbidity. Methods: Patients with nonvalvular AF (NVAF) were stratified into five categories according to eGFR (ⱖ 90, 60-89, 30-59, 15-29, and , 15 mL/min/1.73 m2), analyzing risk factors, all-cause mortality, bleeding, and IS/TE. Of 8,962 eligible individuals, 5,912 had NVAF and available serum creatinine data, with 14,499 patient-years of follow-up. Results: The incidence rates of IS/TE were 7.4 and 7.2 per 1,000 person-years in individuals not receiving and receiving anticoagulation therapy, respectively. Rates of all-cause mortality were 13.4 and 9.4 per 1,000 person-years, respectively, and of major bleeding, 6.2 and 9.0 per 1,000 person-years, respectively. Rates increased with decreasing eGFR, with IS/TE rates being lower in individuals receiving oral anticoagulation (OAC) therapy. eGFR was not an independent predictor of IS/TE on multivariate analyses. When the benefit of IS reduction is balanced against the increased risk of hemorrhagic stroke, the net clinical benefit (NCB) was clearly positive in favor of OAC use. Conclusions: Incidence rates of IS/TE, mortality, and bleeding increased with reducing eGFR across the whole range of renal function. OAC use was associated with a lower incidence of IS/TE and mortality at 1 year compared with individuals not receiving anticoagulants in all categories of renal function as measured by eGFR. The NCB balancing IS against serious bleeding was positive in favor of OAC use among patients with renal impairment. CHEST 2014; 145(6):1370–1382 Abbreviations: AF 5 atrial fibrillation; ATRIA 5 Anticoagulation and Risk Factors in Atrial Fibrillation; CHADS2 5 congestive heart failure, hypertension, age ⱖ 75 years, diabetes, prior stroke or transient ischemic attack; CHA2DS2-VASc 5 congestive heart failure, hypertension, age ⱖ 75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, and sex category; CKD 5 chronic kidney disease; eGFR 5 estimated glomerular filtration rate; HAS-BLED 5 hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; ICH 5 intracerebral hemorrhage; IS 5 ischemic stroke; MDRD 5 Modification of Diet in Renal Disease; NCB 5 net clinical benefit; NVAF 5 nonvalvular atrial fibrillation; OAC 5 oral anticoagulation; TE 5 thromboembolism; VKA 5 vitamin K antagonist

impairment of renal function and atrial fibrilBoth lation (AF) are independently associated with poor

cardiovascular outcomes and all-cause mortality, presenting a growing global burden of disease.1-12 Moreover, AF and chronic kidney disease (CKD) share

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several risk factors, including age, hypertension, history of vascular disease, and diabetes mellitus. Thus, improved understanding of the associations between renal function and AF may lead to new approaches in risk stratification, management, and prevention. Original Research

AF, ischemic stroke (IS), and thromboembolism (TE)13 are more likely to develop in individuals with CKD14,15 than in those with normal renal function. In a large prospective study of 132,372 Danish individuals with AF of whom 3,587 had CKD, the latter was associated with an increased risk of IS/TE and bleeding,16 thus, confirming observations of previous smaller studies.17-21 However, the study by Olesen et al16 was of a nationwide registry cohort that only categorized patients as having no renal disease, non-end-stage CKD, and renal replacement therapy. In clinical practice, renal function is quantified by urinary creatinine clearance or by the estimated glomerular filtration rate (eGFR).22-24 To our knowledge, only two previous studies have considered the association between eGFR and stroke/TE,13,25 including only time off oral anticoagulation (OAC). No epidemiologic studies have considered the impact of eGFR on major bleeding and all long-term outcomes concurrently or included individuals with AF regardless of OAC use.2-4,16,26 Therefore, the balance between risk of IS/TE and bleeding has not been quantified by eGFR in a large real-world population of individuals with AF. Of note, renal failure is included as a dichotomous variable in risk prediction tools for bleeding but is rarely included in guideline-recommended risk prediction tools for IS/TE,21,25,27-30 which is supported by a recent analysis in our cohort that proved that renal impairment and eGFR do not improve risk prediction of IS/TE.31 However, this analysis also showed that renal impairment was associated with higher rates of IS/TE compared with normal renal function. A better understanding of the impact of renal function and eGFR on clinical outcomes in AF is required. In a population of individuals with AF unrestricted by age or comorbidity, we conducted the first, to our Manuscript received September 5, 2013; revision accepted November 19, 2013; originally published Online First December 19, 2013. Affiliations: From the University of Birmingham Centre for Cardiovascular Sciences (Drs Banerjee and Lip), City Hospital, Birmingham, England; Service de Cardiologie, Pôle Coeur Thorax Vasculaire (Drs Fauchier and Taillandier), Centre Hospitalier, Universitaire Trousseau et Faculté de Médecine, Université François Rabelais, Tours, France; Laboratoire de Biochimie et Biologie moléculaire (Drs Vourc’h and Andres), Hôpital Bretonneau, Centre Hospitalier régional et Universitaire de Tours, Tours, France; and Service de Nephrologie-Immunologie Clinique (Dr Halimi), Hôpital Bretonneau and Université François Rabelais, Tours, France. Drs Halimi and Lip are joint senior authors. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Rd, Birmingham, B18 7QH, England; e-mail: g.y.h.lip@ bham.ac.uk © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2103 journal.publications.chestnet.org

knowledge, prospective study of renal function, as measured by eGFR, on IS/TE, mortality, and bleeding. Among patients with renal impairment receiving OAC therapy, we also assessed the net clinical benefit (NCB) of IS reduction balanced against the increased risk of hemorrhagic stroke. Materials and Methods The methods of the Loire Valley Atrial Fibrillation Project have been previously reported.31,32 An extended description of the methods for the present article are shown in e-Appendix 1. Patients with nonvalvular atrial fibrillation (NVAF) or atrial flutter as diagnosed by the cardiology department between 2000 and 2010 were identified (Fig 1). The CHADS228 (congestive heart failure, hypertension, age ⱖ 75 years, diabetes, prior stroke or transient ischemic attack) and CHA2DS2-VASc29 (congestive heart failure, hypertension, age ⱖ 75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, and sex category) scores were calculated after the first diagnosis of AF during hospital admission, as was the HAS-BLED21 (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score. During follow-up, information on outcomes of TE, stroke (ischemic or hemorrhagic), major bleeding, and all-cause mortality were recorded by active surveillance of hospital administrative data. The study was approved by the Review Board of the Pole Coeur Thorax Vaisseaux from the Trousseau University Hospital in 2010 (December 7, 2010). Assessment of Renal Function Renal failure was defined as reported history of renal failure or baseline serum creatinine level of . 133 mmol/L in men and . 115 mmol/L in women.33 To convert serum creatinine from micromoles per liter to milligrams per deciliter, the former was divided by a conversion factor of 88.4. Current consensus guidelines state that prediction equations have greater consistency and accuracy than serum creatinine level in the assessment of glomerular filtration rate.22-24,34-36 In addition, prediction equations were equivalent or better than 24-h urine creatinine clearance in all but one study.22-24,37 In adults, the most widely used and validated method for estimating glomerular filtration rate from serum creatinine level is the isotope dilution mass spectrometry-traceable Modification of Diet in Renal Disease (MDRD) study equation.22-24 The laboratory tests where biochemical analysis of creatinine levels was conducted were calibrated to be isotope dilution mass spectrometry traceable. The MDRD equation was preferred to the more recently validated CKD-Epi equation38 because there were very few patients aged ⱖ 75 years in cohorts used to validate this equation, whereas the current study population was unrestricted by age: eGFR 5 175 3 (Scr) 2 1.154 3 (age) 2 0.203 3 (0.742 if female) 3 (1.212 if black), where eGFR is in mL/min/1.73 m2, and Scr is serum creatinine level in mg/dL. The black population in the study was , 1%; therefore, no correction factor for ethnicity was required in the MDRD calculation of eGFR. Statistical Analysis The study population was stratified into five categories according to eGFR, corresponding to the stages of CKD (ⱖ 90, 60-89, 30-59, 15-29, and , 15 mL/min/1.73 m2) (Fig 1).22-24 Because data regarding proteinuria were not available, stage of renal impairment could not be defined. Baseline characteristics were determined separately for the five eGFR strata, and differences were CHEST / 145 / 6 / JUNE 2014

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Figure 1. Study population by stage of renal impairment. eGFR 5 estimated glomerular filtration rate; VKA 5 vitamin K antagonist. investigated by x2 test for categorical covariates and Kruskal-Wallis test for continuous covariates. Age adjustment was performed by including age as a covariate in a logistic regression model. Cumulative incidence rates of IS/TE, bleeding, and all-cause mortality were calculated for all patients by eGFR category, stratifying by presence or absence of vitamin K antagonist (VKA) therapy. Because VKA therapy was the only form of OAC used during the study period, the terms VKA and OAC are used interchangeably in the analyses. Because of low numbers of patients and outcomes in the eGFR ⱖ 90 and , 15 mL/min/1.73 m2 categories, rates were calculated for the eGFR ⱖ 60, 30-59, and , 30 mL/min/1.73 m2 categories. Hemorrhagic strokes were excluded from analyses of stroke or stroke/TE. Event rates were also calculated by age and sex categories. In each eGFR category, Cox proportional hazards analyses were performed to calculate 1-year survival for IS/TE, bleeding, and all-cause mortality. Bivariate analyses of event rates in different subgroups were used to calculate hazard ratios associated with renal impairment and eGFR category. Cox proportional hazard regression models were constructed to investigate whether renal impairment and eGFR were independent predictors of IS/TE. The risks associated with renal impairment and eGFR were estimated in a univariate analysis as well as in a sex- and age-adjusted analysis, an analysis adjusted for the risk factors included in the CHADS2 score, and a multivariate analysis adjusted for all baseline characteristics shown in Table 1. All analyses were repeated by eGFR category and by combined stratification by renal impairment and eGFR. Furthermore, to test whether the results were influenced by patients initiating VKA treatment, we performed additional analyses excluding patients at the initiation of such treatment. Finally, the NCB was calculated, as originally proposed by Singer et al,39 using the following equation: NCB 5 (IS rate on no treatment 2 IS rate on anticoagulant) 2 1.5(ICH rate on no treatment 2 ICH rate on anticoagulant), where ICH is intracerebral hemorrhage, which is the most serious form of bleeding associated with OAC use. A modified equation with the term “hemorrhagic stroke” instead of “ICH” was used to calculate NCB for the different eGFR categories. The NCB is used by clinicians and researchers as a validated method of balancing risk of IS against ICH. A two-sided P , .05 was considered statistically significant.

Results Of 8,962 eligible individuals, 5,912 (66.0%) had NVAF and available serum creatinine data, allowing 1372

the eGFR to be calculated (Fig 1). Thus, 14,499 patientyears of follow-up were included in the analysis, with a mean (SD) follow-up of 2.45 (3.56) years. We focused on the 1-year outcomes in the current analyses. Baseline characteristics are shown in Table 1. Individuals with eGFR , 15 mL/min/1.73 m2 were older and more likely to be women and have paroxysmal AF than individuals with eGFR . 90 mL/min/1.73 m2. After age adjustment, individuals with an eGFR , 15 mL/min/1.73 m2 were more likely to have hypertension (P , .001), heart failure (P , .001), diabetes mellitus (P 5 .001), liver impairment (P 5 .005), a pacemaker or implantable cardioverter defibrillator (P 5 .004), smoking history (P 5 .04), diuretic therapy (P , .001), and higher CHADS2, CHA2DS2-VASc, and HAS-BLED scores (P , .001) compared with those with an eGFR . 90 mL/min/1.73 m2, but there were no significant differences in rates of OAC or antithrombotic therapies. Rates of the composite of stroke and all-cause mortality were lower in individuals receiving OAC compared with those not receiving OAC therapy. Rates of IS/TE were 7.4 (95% CI, 6.3-8.6) and 7.2 (95% CI, 6.3-8.2) per 1,000 person-years for individuals not receiving and receiving anticoagulation therapy, respectively. Incidence rates (per 1,000 person-years) of allcause mortality were 13.4 (95% CI, 12.0-15.0) and 9.4 (95% CI, 8.3-10.5), respectively, and of major bleeding, 6.2 (95% CI, 5.2-7.3) and 9.0 (95% CI, 8.0-10.1), respectively. Rates of all events increased with decreasing eGFR regardless of OAC therapy (Table 2). Bleeding rates were higher in individuals receiving OAC therapy than in those not receiving OAC. VKA treatment was associated with an approximately 50% relative risk reduction for stroke/TE/all-cause mortality and all-cause mortality in all eGFR categories (Table 2). There was a trend toward relative risk reduction for stroke and IS/TE with VKA treatment, but Original Research

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Table 1—Characteristics of Patients With AF in Relation to Degree of Renal Impairment eGFR, mL/min/1.73 m2 Characteristic

CHEST / 145 / 6 / JUNE 2014

Age, y Female sex Follow-up, y Type of AF Paroxysmal Permanent Persistent Comorbidities Hypertension Diabetes Previous stroke Coronary artery disease Any vascular disease Heart failure Renal impairment Liver impairment Dyslipidemia Smoking Pacemaker/ICD Bleeding risk factors Previous bleeding Labile INR Anemia NSAIDs Drugs Cancer Excessive risk of falls Thrombocytopenia Antithrombotic agents Vitamin K antagonist Antiplatelet Any antithrombotic

ⱖ 90 (n 5 284)

60-89 (n 5 2,646)

30-59 (n 5 2,641)

15-29 (n 5 287)

, 15 (n 5 54)

P Value

Age-Adjusted P Valuea

52.8 ⫾ 21.2 53 (18.7) 3.0 ⫾ 2.9

65.1 ⫾ 15.2 741 (28.0) 2.5 ⫾ 3.3

75.9 ⫾ 10.5 1,217 (46.1) 2.4 ⫾ 3.8

79.9 ⫾ 9.1 158 (55.1) 2.1 ⫾ 2.0

76.4 ⫾ 11.5 27 (50.0) 1.6 ⫾ 1.4

, .001 , .001 … , .001

… , .001 … .87

188 (66.2) 85 (29.9) 11 (3.9)

1,604 (60.6) 897 (33.9) 145 (5.5)

1,426 (54.0) 1,060 (40.1) 155 (5.9)

146 (50.9) 127 (44.3) 17 (4.9)

31 (57.4) 20 (37.0) 3 (5.6)

75 (26.4) 42 (14.8) 24 (8.5) 48 (16.9) 57 (20.1) 101 (35.6) 0 (0.0) 5 (1.8) 40 (14.1) 52 (18.3) 34 (12.0)

979 (37.0) 377 (14.2) 173 (6.5) 728 (27.5) 797 (30.1) 1,164 (44.0) 2 (0.1) 8 (0.3) 506 (19.1) 385 (14.6) 395 (14.9)

1,274 (48.2) 454 (17.2) 212 (8.0) 942 (35.7) 1,031 (39.0) 1,578 (59.8) 1,194 (45.2) 4 (0.2) 529 (20.0) 259 (9.8) 537 (20.3)

175 (61.0) 81 (28.2) 30 (10.5) 112 (39.0) 129 (44.9) 212 (73.9) 287 (100.0) 1 (0.3) 61 (21.3) 40 (13.9) 60 (20.9)

34 (63.0) 14 (25.9) 9 (16.7) 16 (29.6) 20 (37.0) 43 (79.6) 54 (100.0) 0 (0.0) 12 (22.2) 8 (14.8) 12 (22.2)

, .001 , .001 .005 , .001 , .001 , .001 , .001 , .001 .15 , .001 , .001

, .001 .001 .29 .17 .07 , .001 , .001 .005 .11 .004 .04

21 (7.4) 7 (2.5) 0 (0.0) 0 (0.0) 31 (10.9) 4 (1.4) 3 (1.1) 0 (0.0)

109 (4.1) 45 (1.7) 13 (0.5) 2 (0.1) 416 (15.7) 39 (1.5) 16 (0.6) 2 (0.1)

126 (4.8) 43 (1.6) 19 (0.7) 6 (0.2) 560 (21.2) 51 (1.9) 36 (1.4) 3 (0.1)

20 (7.0) 7 (2.4) 5 (1.7) 0 (0.0) 64 (22.3) 8 (2.8) 5 (1.7) 0 (0.0)

7 (13.0) 2 (3.7) 0 (0.0) 0 (0.0) 11 (20.4) 2 (3.7) 3 (5.6) 0 (0.0)

.001 .54 .06 .53 , .001 .30 .001 .94

.47 .82 .04 .59 .44 .76 .44 .88

116 (40.8) 81 (28.5) 175 (61.6)

1,425 (53.9) 779 (29.5) 1,965 (74.3)

1,408 (53.3) 897 (34.0) 1,990 (75.4)

129 (44.9) 95 (33.1) 205 (71.4)

13 (24.1) 22 (40.7) 30 (55.6)

, .001 , .001 , .001

.32 .83 .83 (Continued)

1373

1374

Table 1—Continued eGFR, mL/min/1.73 m2 Characteristic Other therapies ACEI b-Blocker Digoxin Diuretic Antiarrhythmic agent Calcium channel blocker CHADS2 Low (score 5 0) Intermediate (score 5 1) High (score ⱖ 2) CHA2DS2-VASc Low (score 5 0) Intermediate (score 5 1) High (score ⱖ 2) HAS-BLED Low (score 5 0) Moderate (score 5 1-2) High (score ⱖ 3)

ⱖ 90 (n 5 284)

60-89 (n 5 2,646)

30-59 (n 5 2,641)

15-29 (n 5 287)

, 15 (n 5 54)

P Value

Age-Adjusted P Valuea

36 (12.7) 46 (16.2) 34 (12.0) 38 (13.4) 66 (23.2) 8 (2.8)

477 (18.0) 602 (22.8) 322 (12.2) 438 (16.6) 739 (28.0) 89 (3.4)

549 (20.8) 677 (25.6) 373 (14.1) 679 (25.7) 764 (28.9) 112 (4.2)

58 (20.2) 70 (24.4) 35 (12.2) 96 (33.4) 82 (28.6) 14 (4.9)

9 (16.7) 11 (20.4) 5 (9.3) 23 (42.6) 14 (25.9) 4 (7.4)

.27 .10 .14 , .001 .74 .02

.26 .93 .06 , .001 .53 .30

128 (45.1) 64 (22.5) 92 (32.4)

788 (29.8) 712 (26.9) 1,144 (43.3)

290 (11.0) 661 (25.0) 1,690 (64.0)

3 (1.0) 52 (18.1) 232 (80.8)

2 (3.7) 3 (5.6) 49 (90.7)

, .001 , .001 , .001

, .001 , .001 , .001

85 (29.9) 68 (23.9) 131 (46.1)

379 (14.3) 514 (19.4) 1,751 (66.2)

48 (1.8) 186 (7.0) 2,407 (91.1)

0 (0.0) 4 (1.4) 283 (98.6)

1 (1.9) 1 (1.9) 52 (96.2)

, .001 , .001 , .001

, .001 , .001 , .001

132 (46.5) 134 (47.2) 18 (6.3)

796 (30.1) 1,708 (64.5) 142 (5.4)

197 (7.5) 2,130 (80.7) 314 (11.8)

6 (2.1) 173 (60.3) 108 (37.6)

0 (0.0) 26 (48.2) 28 (52.0)

, .001 , .001 , .001

, .001 , .001 , .001

Data are presented as No. (%) or mean ⫾ SD. ACEI 5 angiotensin-converting enzyme inhibitor; AF 5 atrial fibrillation; CHADS2 5 congestive heart failure, hypertension, age ⱖ 75 years, diabetes (1 point each), prior stroke or transient ischemic attack (or thromboembolism) (2 points); CHA2DS2-VASc 5 congestive heart failure, hypertension, age ⱖ 75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, and sex category (1 point each for heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years, and female sex; 2 points for previous stroke [or thromboembolism] and age ⱖ 75 years); eGFR 5 estimated glomerular filtration rate; HAS-BLED 5 hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; ICD 5 implantable cardioverter defibrillator; INR 5 international normalized ratio; NSAID 5 nonsteroidal antiinflammatory drug. aAge adjustment was performed by including age as a covariate in a logistic regression model.

Original Research

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Table 2—Event Rates Per 1,000 Person-Y in Patients With AF by Renal Function eGFR, mL/min/1.73 m2 ⱖ 60 (n 5 2,930) Event

30-59 (n 5 2,641)

, 30 (n 5 341)

No.

Rate (95% CI)

No.

Rate (95% CI)

No.

Rate (95% CI)

P Valuea

108 49 59 …

4.0 (3.3-4.8) 4.1 (3.1-5.4) 3.8 (2.9-4.9) 0.92 (0.63-1.36)

151 73 78 …

6.3 (5.4-7.4) 7.5 (5.9-9.4) 5.5 (4.4-6.9) 0.72 (0.52-1.01)

20 13 6 …

6.6 (4.0-10.2) 8.1 (4.3-13.8) 4.2 (1.6-9.2) 0.50 (0.19-1.36)

.004 .007 .23 …

169 71 98 …

6.2 (5.3-7.2) 6.0 (4.7-7.6) 6.4 (5.2-7.8) 1.06 (0.78-1.46)

231 117 114 …

9.7 (8.5-11.0) 12.0 (9.9-14.4) 8.1 (6.7-9.7) 0.65 (0.49-0.85)

34 23 11 …

11.2 (7.8-15.7) 14.3 (9.1-21.4) 7.8 (3.9-13.9) 0.50 (0.24-1.07)

, .001 , .001 .17 …

341 176 165 …

12.5 (11.2-13.9) 11.9 (10.2-13.8) 10.7 (9.1-12.5) 0.69 (0.55-0.86)

518 287 231 …

21.7 (19.9-23.7) 29.4 (26.1-33.0) 16.4 (14.4-18.7) 0.47 (0.39-0.57)

107 61 36 …

35.3 (28.9-42.7) 37.9 (29.0-48.7) 25.4 (17.8-35.1) 0.55 (0.34-0.91)

, .001 , .001 , .001 …

35 10 23 …

1.19 (0.83-1.66) 0.84 (0.41-1.55) 1.49 (0.95-2.24) 1.78 (0.84-3.75)

43 17 24 …

1.63 (1.18-2.19) 1.74 (1.02-2.79) 1.70 (1.09-2.54) 0.98 (0.52-1.83)

3 3 0 …

0.88 (0.18-2.57) 1.86 (0.38-5.45) … …

.28 .15 .28 …

194 65 129 …

7.1 (6.2-8.2) 4.4 (3.4-5.6) 8.4 (7.0-10.0) 1.57 (1.16-2.14)

221 95 126 …

9.3 (8.1-10.6) 9.7 (7.9-11.9) 9.0 (7.5-10.7) 0.91 (0.69-1.20)

57 24 23 …

18.8 (14.3-24.4) 14.9 (9.6-22.2) 16.2 (10.3-24.3) 1.10 (0.59-2.06)

, .001 , .001 .03 …

225 130 95 …

8.3 (7.2-9.4) 8.8 (7.3-10.4) 6.2 (5.0-7.5) 0.53 (0.40-0.70)

373 210 163 …

15.7 (14.1-17.3) 21.5 (18.7-24.7) 11.6 (9.9-13.5) 0.48 (0.38-0.60)

90 58 32 …

29.7 (23.9-36.5) 36.0 (27.4-46.6) 22.5 (15.4-31.8) 0.52 (0.31-0.86)

, .001 , .001 , .001 …

IS

CHEST / 145 / 6 / JUNE 2014

Total No VKA VKA Relative risk (VKA vs no VKA) IS/TE Total No VKA VKA Relative risk (VKA vs No VKA) ISTE/mortality Total No VKA VKA Relative risk (VKA vs no VKA) Hemorrhagic stroke Total No VKA VKA Relative risk (VKA vs no VKA) Major bleeding Total No VKA VKA Relative risk (VKA vs no VKA) All-cause mortality Total No VKA VKA Relative risk (VKA vs no VKA)

IS 5 ischemic stroke; TE 5 thromboembolism; VKA 5 vitamin K antagonist. See Table 1 legend for expansion of other abbreviations. P value for two-sided x2 test.

a

1375

this was not statistically significant. In individuals with an eGFR ⱖ 60 mL/min/1.73 m2, VKA treatment was associated with a higher risk of bleeding (risk ratio, 1.57; 95% CI, 1.16-2.14), but there was no statistically significant increase in bleeding risk in other eGFR categories (Table 2). After stratification by age and sex, the reduction in eGFR was associated with increased rates of all-cause mortality, IS/TE, and bleeding in men and women and in all age groups (Fig 2). Table 3 shows the results from the Cox regression analyses. Neither renal impairment nor eGFR were independent predictors of IS/TE in AF at 1-year follow-up in univariate or multivariate analyses after adjustment for age, sex, CHADS2 risk factors, or baseline characteristics. Table 4 shows analogous results from Cox regression analyses after excluding patients receiving VKA treatment at baseline (n 5 3,592 [60.8%]). As a categorical variable, eGFR was an independent predictor for IS/TE on univariate analysis (hazard ratio, 1.80; 95% CI, 1.27-2.55) but not after adjustment for age, sex, CHADS2 risk factors, or baseline characteristics at 1-year follow-up. When the benefit of IS reduction was balanced against the increased risk of hemorrhagic stroke among individuals with renal impairment, the NCB was clearly positive in favor of VKA use; for example, in individuals with an eGFR of 30 to 59 mL/min/1.73 m2, NCB

was 2.06 (95% CI, 1.40-2.88), and in those with an eGFR , 30 mL/min/1.73 m2, NCB was 6.69 (95% CI, 3.27-12.78). Renal Failure vs Normal Renal Function In the presence of VKA treatment, rates of IS/TE were 6.2% and 3.9% at 1 year in individuals with renal failure and with normal renal function, respectively. The corresponding rates at 1 year of all-cause mortality were 10.8% and 3.4%, and those of bleeding were 9.3% and 4.5% (Fig 3). In individuals with renal failure and normal renal function not receiving anticoagulation therapy at 1 year, rates of IS/TE, all-cause mortality, and bleeding were 5.8% and 5.1%, 18.9% and 9.6%, and 9.4% and 3.9%, respectively (Fig 3). Individuals With an eGFR ⱖ 60 mL/min/1.73 m2 Compared With an eGFR , 30 mL/min/1.73 m2 Rates of IS/TE were 3.3% and 7.0% at 1 year in individuals with an eGFR ⱖ 60 mL/min/1.73 m2 and , 30 mL/min/1.73 m2, respectively. At 1 year, the corresponding rates of all-cause mortality were 4.2% and 17.6%, and those of bleeding were 3.8% and 10.0% (Fig 3). VKA treatment was associated with a reduced hazard of mortality, an increased hazard of bleeding, and

Figure 2. Event rates for stroke/thromboembolism, major bleeding, and all-cause mortality by age and sex. 1376

Original Research

Table 3—Renal Impairment and Risk of IS/TE: Results From Cox Regression Analyses Analysis Univariate analysis Renal impairment eGFR (categorical variable) Adjusted for sex and age Renal impairment eGFR (categorical variable) Female sex Age per 5-y increase Adjusted for CHADS2 risk factors Renal impairment eGFR (categorical variable) Heart failure Hypertension Age ⱖ 75 y Diabetes mellitus Previous stroke/thromboembolism Adjusted for baseline characteristicsa Renal impairment eGFR (categorical variable)

Hazard Ratio (95% CI) 1.05 (0.76-1.46) 1.15 (0.90-1.47) 1.03 (0.73-1.43) 1.07 (0.82-1.40) 1.16 (0.84-1.61) 1.04 (0.99-1.02) 1.06 (0.75-1.49) 1.09 (0.84-1.41) 0.91 (0.65-1.27) 1.22 (0.88-1.68) 1.25 (0.77-2.02) 1.22 (0.82-1.80) 0.88 (0.62-1.26) 1.09 (0.77-1.55) 1.08 (0.83-1.41)

See Table 1 and 2 legends for expansion of abbreviations. aAdjusted for Table 1 risk factors and including age as a continuous covariate; the result is only displayed for renal impairment.

a trend toward reduced risk of IS/TE, regardless of renal function (Fig 3). Incidence rates of IS/TE, mortality, and bleeding increased with reducing eGFR in individuals receiving and not receiving anticoagulation therapy. In individuals with renal failure not receiving anticoagulation therapy, the risk of mortality was fourfold greater than in individuals with normal Table 4—Renal Impairment and Risk of IS/TE: Results From Cox Regression Analyses Excluding Patients on Vitamin K Antagonist Therapy at Baseline Analysis Univariate analysis Renal impairment eGFR (categorical variable) Adjusted for sex and age Renal impairment eGFR (categorical variable) Female sex Age per 5-y increase Adjusted for CHADS2 risk factors Renal impairment eGFR (categorical variable) Heart failure Hypertension Age ⱖ 75 y Diabetes mellitus Previous stroke/thromboembolism Adjusted for baseline characteristicsa Renal impairment eGFR (categorical variable)

Hazard Ratio (95% CI) 1.51 (0.93-2.44) 1.80 (1.27-2.55) 1.16 (0.71-1.90) 1.34 (0.90-2.00) 1.15 (0.91-1.45) 1.15 (1.05-1.25) 1.20 (0.73-1.96) 1.47 (1.00-2.15) 1.00 (0.61-1.64) 1.37 (0.83-2.27) 1.84 (1.01-3.33) 1.13 (0.61-2.08) 1.99 (1.09-3.63) 0.87 (0.46-1.65) 1.40 (0.84-2.35)

See Table 1 and 2 legends for expansion of abbreviations. aAdjusted for Table 1 risk factors and including age as a continuous covariate; the result is only displayed for renal impairment. journal.publications.chestnet.org

renal function receiving anticoagulation therapy (hazard ratio, 3.65; 95% CI, 2.86-4.66) (Fig 4).

Discussion To our knowledge, this is the first prospective study of the impact of renal function, as measured by eGFR, on IS/TE, mortality, and bleeding in the same population of individuals with AF, with four major findings. First, in patients with AF, renal failure and reduced eGFR were associated with a more severe risk factor profile, higher rates of permanent AF, higher risk of IS/TE and bleeding as measured by validated risk stratification schemes, and worse outcomes. Second, individuals receiving OAC therapy had a lower incidence of IS/TE and mortality than those not receiving anticoagulation in all categories of renal function measured by eGFR. Indeed, the NCB balancing IS reduction against the increased risk of hemorrhagic stroke was clearly positive in favor of OAC use among individuals with renal impairment. Third, rates of IS/TE, mortality, and bleeding increased with reducing eGFR, regardless of sex, age, or OAC therapy. Fourth, renal impairment, whether as a dichotomous variable or measured by eGFR, was not a significant predictor of IS/TE at 1 year after adjustment for baseline characteristics. The 1-year risks for stroke/TE and mortality were significantly increased by renal failure and absence of OAC. When eGFR was , 30 mL/min/1.73 m2, 1-year mortality was 17.6%. The present data confirm that in addition to its growing global burden,8-10 AF outcomes are at least as severe as contemporary data support for atherosclerotic vascular diseases.40 The rates of IS/TE in individuals not receiving anticoagulation in this population (12.0 and 14.3 per 1,000 person-years with eGFR 5 30-59 and , 30 mL/min/1.73 m2, respectively) were lower than in the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study (4.2 per 100 person-years in patients with an eGFR , 45 mL/min/1.73 m2).13 Although the ATRIA cohort and the present study population have similar comorbidities and similar rates of OAC use, the older age of patients in the ATRIA study may explain the higher IS/TE rates. The present data suggest that the association between low eGFR and IS/TE is explained by confounding because there was no independent association after adjustment for baseline characteristics; moreover, we show that eGFR does not add incremental value to risk prediction in IS/TE. Indeed, renal impairment is commonly associated with many of the individual components of the CHADS2 and CHA2DS2-VASc scores, and, thus, the observation that neither renal impairment nor eGFR are independent predictors of IS/TE in AF is CHEST / 145 / 6 / JUNE 2014

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Figure 3. All-cause mortality, stroke/thromboembolism, and major bleeding by renal failure, oral anticoagulation, and stage of renal impairment. See Figure 1 legend for expansion of abbreviations.

perhaps unsurprising. Two recent analyses found that renal function (as measured by eGFR) was independently predictive of IS/TE.25,41 However, the present study is in a contemporary real-world population, whereas the ATRIA cohort stopped recruiting in 2003 and, therefore, may not represent contemporary clinical practice in AF populations. In this study, individuals with AF and renal failure as measured by eGFR were less likely to be receiving OAC therapy than individuals with normal renal function (Table 1). Current consensus guidelines do not recommend routine OAC use in patients receiving hemodialysis (which may explain the low rates of OAC therapy in patients with renal impairment in the present population), although limited data already suggest 1378

a reduction in stroke/TE with OAC therapy in patients with CKD.42-45 The present observations illustrate the high bleeding risk associated with increasing renal impairment in a series of patients with one of the longest follow-up periods in the literature to date. Indeed, the latter may have implications for future risk stratification schemes for major bleeding, which currently classify renal failure as a dichotomous variable.21 Trials of OAC therapy (including novel anticoagulants) are urgently required in patients with renal impairment to establish the balance of efficacy vs safety of OAC in this patient group, especially because the majority of AF trials have excluded patients with CKD, and most have not analyzed the effect of renal function.22,45-50 However, the Original Research

Figure 4. Hazard ratios for stroke/TE, major bleeding, and all-cause mortality. TE 5 thromboembolism. See Figure 1 legend for expansion of other abbreviations.

moderate to high renal clearance of most novel anticoagulants probably limits their use in moderate and severe renal impairment, although the oral factor Xa inhibitor betrixaban is minimally renally cleared and is the only novel agent that could be studied in individuals with severe renal impairment.51 In the present NCB analysis balancing IS reduction against the increased risk of hemorrhagic stroke among patients with renal impairment, there was a positive NCB in favor of OAC use. The original NCB analysis for warfarin by Singer et al39 in patients with AF showed the greatest benefit in patients with the highest untreated risk for stroke. The NCB of warfarin may be greatest in patients with the highest bleeding risk who also have high stroke risk (as measured by validated risk stratification scoring systems),52 and extrapolation of available clinical trial data suggests the same trends for novel anticoagulants.53 In the present study, we clearly show for the first time to our knowledge that warfarin may have the greatest NCB when balancing IS against hemorrhagic stroke in individuals with AF and renal failure. Study Limitations This study is based on a real-world registry with inherent limitations of diagnostic coding and case ascertainment, as previously reported.31,32 Despite stratification and adjustment for several risk factors, the nonrandomized design leaves a risk for residual confounding factors, but as already stated, the majority of randomized trials to date in patients with AF excluded analyses of the effect of renal function. If a resident moved away from the area, died, or had a stroke diagnosed elsewhere, information on the event was not available. However, the relatively high number of deaths in the present study suggests a high proportion of ascertainment of events. The study population was hospital based and, therefore, may not be representative of all patients with AF, many of whom are not hospitalized for arrhythmia. The study was not ethnically journal.publications.chestnet.org

diverse, and the findings may not be generalizable to other populations. In the randomized trials, anticoagulation therapy reduces stroke (by 64%) and all-cause mortality (by 26%).54 In the present study, although VKA treatment was associated with a relative risk reduction in stroke/ TE/mortality and all-cause mortality, there was not a statistically significant relative risk reduction for IS, despite lower event rates in patients receiving vs patients not receiving VKA treatment. A possible explanation may be that in such real-world registries, some recorded deaths may be due to stroke because not all patients had routine postmortem studies or detailed cerebral imaging, therefore, leading to the present findings of a higher-than-predicted risk reduction for all-cause mortality and a nonstatistically significant risk reduction for IS compared with clinical trials. The data regarding OAC use are only from baseline therapy and do not reflect any changes in prescribed therapy or adherence to therapy. Additionally, data regarding the time in therapeutic range are not available for this study population. The study was a prospective cohort design and not a randomized clinical trial; therefore, confounding by indication is a possibility.55 However, the effect of this confounding is likely to be minimal because the individuals at highest risk of study outcomes (based on risk prediction scores) were least likely to be receiving OAC therapy. Only baseline creatinine measurements and eGFR calculations are available; therefore, we are unable to comment on change or progression of renal impairment or on the need for renal replacement therapy. We used a categorical eGFR variable analysis because this would be more useful in terms of incorporating eGFR into a risk prediction score; there was no appreciable difference with eGFR analyzed as a continuous variable. However, eGFR is probably the most important indicator of renal function to take into account because OAC doses are usually lower in patients with CKD than in those without CKD and changes are more often necessary in this situation.56 Finally, the number of CHEST / 145 / 6 / JUNE 2014

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individuals with an eGFR , 30 mL/min/1.73 m2 in the study population was small (as was the number receiving dialysis); therefore, the statistical power of the analysis in this subgroup may be limited. Conclusions Renal impairment is associated with poor outcomes at 1 year in individuals with NVAF across the whole range of renal function as measured by eGFR. OAC use was associated with a lower incidence of IS/TE and mortality compared with nonanticoagulation use in all categories of renal function as measured by eGFR. Indeed, the NCB balancing IS against major bleeding was positive in favor of OAC use among patients with renal impairment, suggesting that bleeding risk is not the most important variable in stroke prevention treatment decisions in these individuals. Therefore, full anticoagulation therapy is recommended in patients with at least moderate renal impairment, with improved attention to good-quality international normalized ratio control (as reflected by a high time in therapeutic range, which is associated with lower event rates57). Although eGFR was not an independent predictor of IS/TE in individuals with AF, these patients are still at high risk, and regular checks on eGFR would be recommended, especially because normal or mild renal impairment at baseline does not preclude some patients from deteriorating to severe renal impairment.58 These observations have implications for future risk prediction tools of outcomes in NVAF as well as for future clinical trials. Acknowledgments Author contributions: Dr Fauchier had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Banerjee: contributed to the study concept and design, analyses, interpretation of results, drafting of the manuscript, revising the manuscript critically for important intellectual content, and approval of the final manuscript. Dr Fauchier: contributed to the study concept and design, data collection, interpretation of results, revising the manuscript critically for important intellectual content, and approval of the final manuscript. Dr Vourc’h: contributed to the data collection, interpretation of results, revising the manuscript critically for important intellectual content, and approval of the final manuscript. Dr Andres: contributed to the interpretation of results, revising the manuscript critically for important intellectual content, and approval of the final manuscript. Dr Taillandier: contributed to the data collection, interpretation of results, revising the manuscript critically for important intellectual content, and approval of the final manuscript. Dr Halimi: contributed to the data collection, interpretation of results, revising the manuscript critically for important intellectual content, and approval of the final manuscript. Dr Lip: contributed to the study concept and design, interpretation of results, revising the manuscript critically for important intellectual content, and approval of the final manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Lip has served 1380

as a consultant for Bayer; Astellas Pharma; Merck & Co; Sanofi; Bristol-Myers Squibb/Pfizer Inc; Daiichi-Sankyo, Inc; BIOTRONIK; Medtronic; Portola Pharmaceuticals, Inc; and Boehringer Ingelheim GmbH and has been on the speakers’ bureau for Bayer, BristolMyers Squibb/Pfizer Inc, Boehringer Ingelheim GmbH, DaiichiSankyo Inc, Medtronic, and Sanofi-Aventis. Drs Banerjee, Fauchier, Vourc’h, Andres, Taillandier, and Halimi report no conflicts exist with any companies/organizations whose products or services may be discussed in this article. Additional information: The e-Appendix can be found in the “Supplemental Materials” area of the online article.

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Original Research