Arrhythmia/Electrophysiology

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1 Arrhythmia/Electrophysiology Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis Ziad Hijazi, MD, PhD; Stefan H. Hohnloser, MD; Jonas Oldgren, MD, PhD; Ulrika Andersson, MSc; Stuart J. Connolly, MD; John W. Eikelboom, MD; Michael D. Ezekowitz, MB, ChB, PhD; Paul A. Reilly, PhD; Agneta Siegbahn, MD, PhD; Salim Yusuf, MD, PhD; Lars Wallentin, MD, PhD Background Renal impairment increases the risk of stroke and bleeding in patients with atrial fibrillation. In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, dabigatran, with 80% renal elimination, displayed superiority over warfarin for prevention of stroke and systemic embolism in the 150-mg dose and significantly less major bleeding in the 110-mg dose in patients with nonvalvular atrial fibrillation. This prespecified study investigated these outcomes in relation to renal function. Methods and Results Glomerular filtration rate was estimated with the Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Modification of Diet in Renal Disease (MDRD) equations in all randomized patients with available creatinine at baseline (n=17 951), and cystatin C based glomerular filtration rate was estimated in a subpopulation with measurements available (n=6190). A glomerular filtration rate 80, 50 to <80, and <50 ml/ min was estimated in 32.6%, 47.6%, and 19.8% and in 21.6%, 59.6%, and 18.8% of patients based on Cockcroft-Gault and CKD-EPI, respectively. Rates of stroke or systemic embolism, major bleeding, and all-cause mortality increased as renal function decreased. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily compared with warfarin, without significant heterogeneity in subgroups defined by renal function (interaction P>0.1 for all). For the outcome of major bleeding, there were significant interactions between treatment and renal function according to CKD-EPI and MDRD equations, respectively (P<0.05). The relative reduction in major bleeding with either dabigatran dose compared with warfarin was greater in patients with glomerular filtration rate 80 ml/min. Conclusions The efficacy of both dosages of dabigatran was consistent with the overall trial irrespective of renal function. However, with the CKD-EPI and MDRD equations, both dabigatran dosages displayed significantly lower rates of major bleeding in patients with glomerular filtration rate 80 ml/min. Clinical Trial Registration URL: Unique identifier: NCT (Circulation. 2014;129: ) Key Words: anticoagulants atrial fibrillation dabigatran hemorrhage renal insufficiency stroke warfarin Impaired renal function is associated with a higher prevalence of atrial fibrillation (AF) 1 3 and with an increased risk of thromboembolic events in patients with nonvalvular AF. 4 7 Current guidelines recommend treatment with oral anticoagulants for AF patients at risk for stroke 8 ; however, impaired renal function also confers a substantially increased risk of major bleeding 9 and often contributes to underutilization of oral anticoagulation therapy in AF populations. 10,11 Clinical Perspective on p 970 Received May 7, 2013; accepted November 14, From Uppsala Clinical Research Center (Z.H., J.O., U.A., A.S., L.W.), Department of Medical Sciences, Cardiology (Z.H., J.O., L.W.), and Department of Medical Sciences, Clinical Chemistry (A.S.), Uppsala University, Sweden; Department of Cardiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Population Health Research Institute, Hamilton, Ontario, Canada (S.J.C., J.W.E., S.Y.); Thomas Jefferson Medical College and the Heart Center, Wynnewood, PA (M.D.E.); and Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (P.A.R.). The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Ziad Hijazi, MD, PhD, Uppsala Clinical Research Center, Dag Hammarskjölds väg 14B, SE Uppsala, Sweden. ziad.hijazi@ucr.uu.se 2013 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 962 Circulation March 4, 2014 Dabigatran is a novel oral direct thrombin inhibitor with 80% renal elimination. 12 The Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial randomized patients with AF at risk of stroke to 2 different dosages (110 or 150 mg BID) of dabigatran etexilate or warfarin. 13 In the RE-LY trial, compared with warfarin, dabigatran 110 mg twice a day was associated with a similar risk of stroke and systemic embolism and a lower risk of major bleeding, and dabigatran 150 mg twice a day was associated with a lower risk of stroke and systemic embolism and a similar risk of major bleeding. The present prespecified analysis evaluated the efficacy and safety of dabigatran compared with warfarin in relation to renal function in patients with AF. Glomerular filtration rate (GFR) was estimated with 3 different equations: Cockcroft-Gault, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and according to cystatin C. Furthermore, the Modification of Diet in Renal Disease (MDRD) equation was used in sensitivity analyses. The CKD-EPI is a new equation for estimation of GFR that was developed specifically to estimate renal function more accurately than existing creatinine-based GFR estimates, such as the Cockcroft-Gault and MDRD formulas, with respect to true invasively measured GFR. 14 Methods Study Population and Trial Design The study organization, trial design, patient characteristics, and outcomes of the RE-LY study have been published previously. 13 Patients were recruited from 967 centers in 44 countries between November 2005 and December A total of patients with AF who had 1 additional risk factor for stroke were randomized in a 1:1:1 fashion to receive, in a blinded fashion, fixed doses of dabigatran (110 or 150 mg BID) or, in an unblinded fashion, adjusted-dose warfarin (target international normalized ratio ) for a median of 2 years. 12 Dabigatran etexilate 110- and 150-mg capsules were identical in appearance. The randomization code was kept by the Trial Coordinating Center. All personnel involved in the conduct of the trial were blinded to treatment assignments until database lock. All patients were randomized by a central randomization service through an interactive voice-response system located at the Coordinating Center at Population Health Research Institute in Hamilton, Ontario, Canada. Estimated GFR (egfr) <30 ml/min according to Cockcroft-Gault was an exclusion criteria in the RE-LY trial. The trial design randomly tested both dabigatran doses and warfarin in all predefined renal function subgroups without a predefined dose adjustment in any subgroups. The primary efficacy outcome was fatal and nonfatal stroke (ischemic, hemorrhagic, or unspecified) or systemic embolism. The main safety outcome was major bleeding. Major bleeding was defined as a reduction in hemoglobin level 20 g/l, transfusion of 2 U of blood, or symptomatic bleeding in a critical area or organ. Life-threatening bleeding was a subcategory of major bleeding that consisted of fatal bleeding, symptomatic intracranial bleeding, bleeding with a decrease in the hemoglobin level 50 g/l, or bleeding that required transfusion of 4 U of blood or inotropic agents or that necessitated surgery. Approval by the appropriate ethics committees was obtained at all sites. All patients provided written informed consent. Laboratory Methods Venous blood was drawn at randomization, before initiation of study treatment, with a 21/22-gauge needle into vacuumized tubes containing EDTA. The blood was centrifuged within 30 minutes at 2000g for 10 minutes. The tubes were thereafter frozen immediately at 20 C or colder. Aliquots were stored at 70 C to enable batch analysis. Plasma creatinine measurements were performed in a core laboratory with a Roche Modular analyzer with a kinetic colorimetric compensated Jaffe assay (Roche Modular, Meylan, France). Cystatin C was analyzed centrally in the Uppsala Clinical Research Center laboratory (Uppsala, Sweden) with the ARCHITECT system ci8200 (Abbott Laboratories, Abbott Park, IL) using the particle-enhanced turbidimetric immunoassay (PETIA) from Gentian (Moss, Norway). The total analytic imprecision of the method is 1.09% at 0.85 mg/l and 1.03% at 3.06 mg/l. 15 GFR Estimation GFR (in ml/min) can be estimated from serum creatinine (SCr). The following equations were used to estimate GFR: (1) Cockcroft-Gault equation: GFR=[(140 age) (weight in kg) (0.85 if female)]/ (72 SCr); (2) CKD-EPI 14 : GFR=141 min(scr/κ, 1) α max(scr/κ, 1) Age [if female] [if black], where κ is 0.7 for females and 0.9 for males, α is for females and for males, min indicates the minimum of SCr/κ or 1, max indicates the maximum of SCr/κ or 1, and SCr is serum creatinine (expressed in mg/dl); (3) cystatin C: GFR= cystatin C (mg/l) For sensitivity analysis, GFR was also estimated according to the MDRD equation 16 with the formula GFR=186 (SCr/0.95) age [if black] [if female]. Statistical Analyses Cockcroft-Gault and CKD-EPI were calculated with creatinine at randomization to estimate GFR in this prespecified RE-LY analysis. All randomized patients with available creatinine measurements were included in the statistical analysis (n=17 951). egfr according to cystatin C level was calculated in a subset of participants with cystatin C available (n=6190). Patients were classified according to prespecified values as follows: No impairment, egfr 80 ml/min; mild impairment, egfr 50 to <80 ml/min; and moderate to severe impairment, egfr <50 ml/min. Baseline characteristics of patients were examined by categories of renal function. Continuous variables are presented as means (SD), 25th and 75th quartiles, or minimum and maximum, with between-group comparisons tested by ANOVA. Categorical variables are presented as counts and percentages and were compared by χ 2 square tests. Weighted κ-statistic was calculated as a measure of agreement between egfr methods. Efficacy and safety analyses included all randomized patients with baseline serum creatinine levels available (intention to treat) and included first event from randomization. The risk of an event was reported as percentage per year, which was calculated by dividing the total number of patients with events by the total number of patient-years of follow-up. Hazard ratios (95% confidence intervals) comparing dabigatran to warfarin were derived from Cox proportional hazards models. Treatment effects were compared according to renal function, both as a categorical variable and as continuous measures, by adding interactions to the model. The treatment hazard ratios were reported at various levels of renal function, regardless of the significance of interaction. Restricted cubic splines were used to allow for nonlinearity in the relationship between continuous renal function and outcomes. Interactions with continuous renal function were illustrated by plotting the estimated probability of 1-year events according to the continuous level of renal function, with separate curves for each treatment group. A sensitivity analysis was performed that used the MDRD formula to estimate GFR and the study treatment interactions (results presented in the online-only Data Supplement). All analyses were performed separately for dabigatran 110 mg BID versus warfarin, for dabigatran 150 mg BID versus warfarin, and for dabigatran 150 mg BID versus 110 mg BID. Because the subgroup analyses in the present study were exploratory, the P values were not adjusted for multiple comparisons and should be interpreted with caution. All analyses were performed

3 Hijazi et al Dabigatran vs Warfarin in Renal Dysfunction 963 Table 1. CKD-EPI Demographics and Clinical Characteristics According to Renal Function Estimated With 80 ml/min (n=3880) 50 to <80 ml/min (n=10 697) <50 ml/min (n=3374) * Age, y <01 Mean (SD) 66.9 (9.7) 72.0 (8.0) 75.2 (7.2) Median (25th, 75th percentile) 68.0 (61.0, 74.0) 72.0 (67.0, 78.0) 76.0 (71.0, 80.0) Minimum, maximum 22, 89 32, , 95 Male sex, n (%) 2734 (70.5) 6877 (64.3) 1803 (53.4) <01 Weight, kg Mean (SD) 82.8 (21.9) 82.7 (19.0) 82.1 (18.1) Median (25th, 75th percentile) 80.0 (68.0, 95.0) 81.0 (70.0, 93.4) 80.0 (70.0, 91.6) Minimum, maximum 32.0, , , AF duration, n (%) <3 mo 1192 (30.7) 3367 (31.5) 1022 (30.3) 3 mo 2 y 865 (22.3) 2319 (21.7) 765 (22.7) >2 y 1821 (47.0) 5007 (46.8) 1586 (47.0) Type of AF, n (%) 09 Paroxysmal 1293 (33.3) 3336 (31.2) 1113 (33.0) Persistent 1272 (32.8) 3603 (33.7) 1021 (30.3) Permanent 1314 (33.9) 3755 (35.1) 1239 (36.7) CHADS 2 risk factors, n (%) Heart failure 1126 (29.0) 2632 (24.6) 1100 (32.6) <01 Hypertension 2827 (72.9) 8447 (79.0) 2889 (85.6) <01 Age 75 y 938 (24.2) 4266 (39.9) 1968 (58.3) <01 Diabetes mellitus 883 (22.8) 2315 (21.6) 982 (29.1) <01 Previous stroke or TIA 849 (21.9) 2075 (19.4) 677 (20.1) 42 CHADS 2 score, n (%) (37.1) 3654 (34.2) 633 (18.8) < (36.0) 3765 (35.2) 1233 (36.5) (26.9) 3278 (30.6) 1508 (44.7) Medications, n (%) Aspirin 1512 (39.0) 4190 (39.2) 1403 (41.6) Any anticoagulant 2468 (63.6) 7031 (65.7) 2202 (65.3) ACE inhibitor or ARB 2427 (62.6) 7001 (65.4) 2442 (72.4) <01 β-blocker 2343 (60.4) 6742 (63.0) 2212 (65.6) <01 Digoxin 1309 (33.7) 2992 (28.0) 936 (27.7) <01 Statin 1569 (40.4) 4809 (45.0) 1614 (47.8) <01 Proton pump inhibitor 451 (11.6) 1494 (14.0) 601 (17.8) <01 ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CHADS 2, clinical prediction rule for stroke risk assessment based on presence of congestive heart failure, hypertension, age 75 y, diabetes mellitus, and previous stroke or transient ischemic attack; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; and TIA, transient ischemic attack. *P value for comparison between groups, based on χ 2 test for categorical variables and ANOVA for continuous variables. with SAS software, version 9.3 (SAS Institute Inc, Cary, NC). A 2-sided P<0.05 was considered statistically significant. Results Baseline Characteristics Baseline characteristics by CKD-EPI are displayed in Table 1. The treatment groups were well balanced (Table I in the online-only Data Supplement). According to the Cockcroft-Gault equation, a total of 5844 patients (32.6%) were classified at baseline as having an egfr 80 ml/min, 8553 (47.6%) as having egfr 50 to <80 ml/min, and 3554 (19.8%) as having egfr <50 ml/min. According to the CKD-EPI equation, 3880 (21.6%), (59.6%), and 3374 (18.8%) patients were classified as having an egfr 80, 50 to <80, and <50 ml/min, respectively. With the cystatin C equation, 2804 (45.3%), 2457 (39.7%), and 929 (15.0%) patients were classified as having an egfr 80, 50 to <80, and

4 964 Circulation March 4, 2014 Table 2. Outcome Interaction Between Categorical Renal Function According to Cockcroft-Gault Formula and Treatment in a Cox Model for Outcome According to Renal Function Level (in ml/min) Dabigatran 110 mg BID Events/n (%/y) Events, n (%/y) Dabigatran 150 mg BID Events/n (%/y) Warfarin Events/n (%/y) <50 ml/min, respectively. Comparison of the level of agreement between the equations yielded a weighted κ-statistic of 0.48 between Cockcroft-Gault and CKD-EPI and 0.93 between MDRD and CKD-EPI. Efficacy Outcomes According to Renal Function There were a total of 516 cases of stroke or systemic embolism (the primary outcome) and 1362 cases of all-cause mortality, a secondary outcome, during the trial in the entire cohort. Annual rates for all outcomes increased as renal function decreased. According to the Cockcroft-Gault equation, patients with egfr 80 ml/min had annual stroke or systemic embolism rates of 0.88%, compared with 1.59% in patients with egfr 50 to <80 ml/min and 2.16% in patients with egfr <50 ml/min; rates for all-cause mortality were 2.25%, 3.67%, and 7.13%, respectively. The associations between decreased kidney function and increased incidence Dabigatran 110 mg BID vs Warfarin HR (95% CI) Dabigatran 150 mg BID vs Warfarin HR (95% CI) Dabigatran 150 vs Dabigatran 110 mg BID HR (95% CI) Stroke or systemic embolism 80 35/1958 (0.88) 28/1945 (0.71) 41/1941 (1.05) 0.84 ( ) ( ) ( ) 50 to <80 94/2803 (1.69) 70/2852 (1.25) 103/2898 (1.83) 0.93 ( ) 0.68 ( ) 0.73 ( ) <50 52/1196 (2.32) 36/1232 (1.53) 57/1126 (2.70) 0.85 ( ) 0.56 ( ) 0.66 ( ) All-cause mortality /1958 (2.24) 81/1945 (2.04) 97/1941 (2.48) 0.90 ( ) ( ) ( ) 50 to <80 175/2803 (3.15) 198/2852 (3.53) 244/2898 (4.32) 0.72 ( ) 0.81 ( ) 1.12 ( ) <50 176/1196 (7.86) 159/1232 (6.77) 143/1126 (6.77) 1.16 ( ) 1.00 ( ) 0.86 ( ) Major bleed /1958 (1.48) 81/1945 (2.04) 95/1941 (2.43) 0.61 ( ) ( ) ( ) 50 to <80 158/2803 (2.84) 188/2852 (3.35) 209/2898 (3.70) 0.76 ( ) 0.91 ( ) 1.19 ( ) <50 122/1196 (5.45) 129/1232 (5.50) 116/1126 (5.49) 0.99 ( ) 1.01 ( ) 1.02 ( ) Life-threatening bleed 80 17/1958 (0.43) 31/1945 (0.78) 50/1941 (1.28) 0.33 ( ) ( ) ( ) 50 to <80 74/2803 (1.33) 87/2852 (1.55) 107/2898 (1.90) 0.70 ( ) 0.82 ( ) 1.17 ( ) <50 56/1196 (2.50) 60/1232 (2.56) 61/1126 (2.89) 0.86 ( ) 0.88 ( ) 1.02 ( ) Intracranial bleed /1958 (0.05) 7/1945 (0.18) 15/1941 (0.38) 0.13 ( ) ( ) ( ) 50 to <80 14/2803 (0.25) 22/2852 (0.39) 49/2898 (0.87) 0.29 ( ) 0.45 ( ) 1.56 ( ) <50 11/1196 (0.49) 9/1232 (0.38) 26/1126 (1.23) 0.40 ( ) 0.31 ( ) 0.78 ( ) Net clinical benefit* /1958 (4.68) 182/1945 (4.59) 207/1941 (5.29) 0.88 ( ) ( ) ( ) to <80 376/2803 (6.77) 396/2852 (7.05) 453/2898 (8.03) 0.84 ( ) 0.88 ( ) 1.05 ( ) <50 291/1196 (12.99) 269/1232 (11.46) 260/1126 (12.31) 1.05 ( ) 0.93 ( ) 0.88 ( ) CI indicates confidence interval; HR, hazard ratio; and, P value for interaction. *Net clinical benefit: Composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major bleed. of cardiovascular events were consistent with all 3 methods of GFR estimation. Efficacy of Dabigatran Versus Warfarin in Patients With Renal Dysfunction The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily compared with those with warfarin, without significant heterogeneity in subgroups defined by renal function (Table 2; Figure 1). The treatment effects were also consistent, with no significant interactions for renal impairment with regard to ischemic strokes (P>0.69) or all-cause mortality (P<0.05 with Cockcroft-Gault, but not significant on the basis of continuous analysis or when the other egfr equations were used). The results for both dabigatran 110 mg and dabigatran 150 mg versus warfarin were consistent by all 3 methods of GFR estimation.

5 Hijazi et al Dabigatran vs Warfarin in Renal Dysfunction 965 A 0.08 Stroke/SEE p int= Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE110 Lower 95% CI DE110 DE110 Upper 95% CI B 0.08 Stroke/SEE p int= Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE110 Lower 95% CI DE110 DE110 Upper 95% CI Cockroft-Gault (ml/min) CKD-EPI (ml/min/1.73m2) 0.08 Stroke/SEE p int= Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE150 Lower 95% CI DE150 DE150 Upper 95% CI 0.08 Stroke/SEE p int= Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE150 Lower 95% CI DE150 DE150 Upper 95% CI Cockroft-Gault (ml/min) Safety Outcomes According to Renal Function There were 1157 major bleeds, 155 intracranial bleeds, and 543 life-threatening bleeds in total in the entire cohort. Based on the Cockcroft-Gault equation, patients with egfr 80 ml/min had annual major bleeding rates of 1.98% compared with 3.30% in patients with egfr 50 to <80 ml/min and 5.48% in patients with egfr <50 ml/min. Similarly, the incidence of intracranial bleeding increased substantially with worsening renal function (0.20%, 0.51%, and 0.69%, respectively). Life-threatening bleeds were 3.2 times higher in patients with egfr <50 ml/min than in subjects with egfr 80 ml/min (2.64% versus 0.83%, respectively). The associations between decreased renal function and increased incidence of major, intracranial, and life-threatening bleeds were consistent by all 3 methods of GFR estimation. Safety of Dabigatran Versus Warfarin in Patients With Renal Dysfunction Rates of major bleeding increased with decreasing renal function with dabigatran (both doses) and with warfarin (Figure 2). Based on Cockcroft-Gault egfr groups, dabigatran 110 mg was associated with fewer major bleeds across CKD-EPI (ml/min/1.73m2) Figure 1. A, Study treatment interaction for stroke or systemic embolism (SEE) according to renal function estimated by Cockcroft-Gault equation for dabigatran 110 mg (top) and 150 mg (bottom). B, Study treatment interaction for stroke or systemic embolism according to renal function estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for dabigatran 110 mg (top) and 150 mg (bottom). CI indicates confidence interval; DE, dabigatran; and p int, P value for interaction. the entire range of renal function (P for interaction=0.0607; Table 2). However, egfr groups according to the CKD- EPI equation displayed a significant interaction for renal function, with a significantly greater relative reduction in major bleeding with dabigatran 110 mg than with warfarin in patients with egfr 80 ml/min (hazard ratio, 0.41; 95% confidence interval, ; P for interaction=12; Table 3). This pattern was also evident in the continuous analysis of egfr when both renal function equations were used, although it was more pronounced with CKD-EPI (Figure 2). For dabigatran 150 mg compared with warfarin, there was no significant difference in major bleeds in egfr groups based on the Cockcroft-Gault equation (Table 2); however, by estimating egfr with the CKD-EPI equation, it was apparent that significantly fewer major bleeds occurred with dabigatran 150 mg than with warfarin in patients with egfr 80 ml/ min (hazard ratio, 0.59; 95% confidence interval, ; P for interaction=5; Table 3). In continuous analysis, egfr calculated with the Cockcroft-Gault formula revealed no significant difference in major bleeding rates between dabigatran 150 mg and warfarin-treated patients regardless of renal function (Figure 2A). The use of CKD-EPI estimated

6 966 Circulation March 4, 2014 A 0.15 Major bleed p int= Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE110 Lower 95% CI DE110 DE110 Upper 95% CI B 0.15 Major bleed p int=22 Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE110 Lower 95% CI DE110 DE110 Upper 95% CI Cockroft-Gault (ml/min) CKD-EPI (ml/min/1.73m2) 0.15 Major bleed p int= Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE150 Lower 95% CI DE150 DE150 Upper 95% CI 0.15 Major bleed p int= Warfarin Lower 95% CI Warfarin Warfarin Upper 95% CI DE150 Lower 95% CI DE150 DE150 Upper 95% CI Cockroft-Gault (ml/min) egfr revealed no significant differences between dabigatran 150 mg and warfarin at an egfr <80 ml/min but a significantly lower rate of major bleeding with dabigatran 150 mg at an egfr 80 ml/min (Figure 2B). With regard to life-threatening bleeding outcomes, the renal interaction on study treatment was similar to that for the major bleeding outcomes, with a significantly greater relative reduction with dabigatran 110 mg according to both the Cockcroft-Gault and CKD-EPI equations at egfr 80 ml/ min (P<0.02 for interaction for both equations) and with dabigatran 150 mg according to the CKD-EPI equation than with warfarin (P=40 for interaction). Cystatin C egfr did not display any significant interaction with the treatment effect with regard to major bleeding (P for interaction >0.1; Figure I in the online-only Data Supplement). A sensitivity analysis of study treatment interaction with regard to major bleeding and egfr according to the MDRD equation was performed, which yielded results similar to the CKD-EPI analysis (Figure II in the online-only Data Supplement). Net Clinical Benefit According to Renal Function There were a total of 2620 events of a net clinical benefit outcome, a predefined composite that consisted of stroke, CKD-EPI (ml/min/1.73m2) Figure 2. A, Study treatment interaction for major bleed according to renal function estimated by Cockcroft-Gault equation for dabigatran 110 mg (top) and 150 mg (bottom). B, Study treatment interaction for major bleed according to renal function estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for dabigatran 110 mg (top) and 150 mg (bottom). systemic embolism, pulmonary embolism, myocardial infarction, death, or major bleeding events. According to the Cockcroft-Gault equation, patients with egfr 80, 50 to <80, and <50 ml/min had annual rates of 4.85%, 7.29%, and 12.24%, respectively, for the composite outcome. The associations between decreased kidney function and increased incidence of cardiovascular events were consistent with all 3 methods of GFR estimation. Net Clinical Benefit of Dabigatran Versus Warfarin in Patients With Renal Dysfunction Irrespective of the degree of renal function, the effect of dabigatran 110 mg was similar relative to warfarin with regard to net clinical benefit (Tables 2 and 3) according to both the Cockcroft-Gault and CKD-EPI equations. According to the Cockcroft-Gault equation, dabigatran 150 mg was associated with fewer events across the range of egfr, with no significant interaction by renal function (Table 2). However, egfr groups according to the CKD- EPI equation displayed significant interaction with renal function, with a significantly greater relative reduction in net clinical benefit outcomes with dabigatran 150 mg than with warfarin in patients with egfr 80 ml/min (hazard ratio, 0.71; 95% confidence interval, ; P for

7 Hijazi et al Dabigatran vs Warfarin in Renal Dysfunction 967 Table 3. Outcome Interaction Between Categorical Renal Function According to CKD-EPI Equation and Treatment in a Cox Model for Outcome According to Renal Function Level (in ml/min) Dabigatran 110 mg BID Events, n (%/y) interaction=0.0371; Table 3). With cystatin C, dabigatran 150 mg was associated with fewer events across all ranges of egfr, but with no significant interaction with the treatment effect (P for interaction=0.65). Discussion The major findings from this prespecified RE-LY analysis were that dosages of 110 and 150 mg of dabigatran twice daily displayed an efficacy relative to warfarin that was consistent with the overall trial across the range of renal function with regard to the primary outcome of stroke or systemic embolism. With regard to the primary safety outcome of major bleeding, dabigatran 110 mg displayed a lower risk and dabigatran 150 mg a similar risk compared with warfarin, irrespective of renal function. However, when GFR was estimated with the CKD-EPI equation, a significantly greater relative reduction in major bleeding risk was displayed for both doses of dabigatran in patients with egfr 80 ml/min. Dabigatran 110 mg BID vs Warfarin Dabigatran 150 mg BID Warfarin HR (95% CI) Dabigatran 150 mg BID vs Warfarin HR (95% CI) Dabigatran 150 vs Dabigatran 110 mg BID HR (95% CI) Stroke or systemic embolism 80 28/1284 (1.09) 21/1296 (0.81) 32/1300 (1.25) 0.87 ( ) ( ) ( ) 50 to <80 116/3547 (1.65) 86/3576 (1.21) 124/3574 (1.76) 0.94 ( ) 0.69 ( ) 0.73 ( ) <50 37/1126 (1.71) 27/1157 (1.21) 45/1091 (2.17) 0.78 ( ) 0.55 ( ) 0.71 ( ) All-cause mortality /1284 (2.77) 61/1296 (2.36) 86/1300 (3.37) 0.82 ( ) ( ) ( ) 50 to <80 233/3547 (3.31) 229/3576 (3.22) 265/3574 (3.76) 0.88 ( ) 0.85 ( ) 0.97 ( ) <50 136/1126 (6.28) 148/1157 (6.64) 133/1091 (6.41) 0.97 ( ) 1.03 ( ) 1.06 ( ) Major bleed /1284 (1.25) 46/1296 (1.78) 77/1300 (3.01) 0.41 ( ) ( ) ( ) 50 to <80 196/3547 (2.78) 217/3576 (3.05) 238/3574 (3.38) 0.82 ( ) 0.90 ( ) 1.10 ( ) <50 111/1126 (5.13) 135/1157 (6.06) 105/1091 (5.06) 1.02 ( ) 1.22 ( ) 1.20 ( ) Life-threatening bleed /1284 (0.51) 20/1296 (0.77) 42/1300 (1.64) 0.30 ( ) ( ) ( ) 50 to <80 87/3547 (1.24) 89/3576 (1.25) 125/3574 (1.78) 0.69 ( ) 0.70 ( ) 1.01 ( ) <50 47/1126 (2.17) 69/1157 (3.10) 51/1091 (2.46) 0.88 ( ) 1.27 ( ) 1.44 ( ) Intracranial bleed /1284 (0.04) 5/1296 (0.19) 13/1300 (0.51) 0.08 ( ) ( ) ( ) 50 to <80 18/3547 (0.26) 26/3576 (0.37) 60/3574 (0.85) 0.30 ( ) 0.43 ( ) 1.43 ( ) <50 8/1126 (0.37) 7/1157 (0.31) 17/1091 (0.82) 0.45 ( ) 0.38 ( ) 0.85 ( ) Net clinical benefit* /1284 (4.76) 117/1296 (4.53) 161/1300 (6.30) 0.74 ( ) ( ) ( ) 50 to <80 489/3547 (6.94) 464/3576 (6.52) 519/3574 (7.37) 0.94 ( ) 0.89 ( ) 0.94 ( ) <50 242/1126 (11.18) 266/1157 (11.94) 240/1091 (11.57) 0.96 ( ) 1.04 ( ) 1.09 ( ) CI indicates confidence interval; HR, hazard ratio; and, P value for interaction. *Net clinical benefit: Composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major bleed. Renal Function and Treatment Interaction In the RE-LY trial, compared with warfarin, dabigatran 110 mg BID was associated with a similar risk of stroke/systemic embolism and a lower risk of major bleeding, and dabigatran 150 mg BID was associated with a lower risk of stroke/systemic embolism and a similar risk of major bleeding. 13 The results from this renal function analysis display substantially higher rates of stroke, all-cause death, and major bleeding with decreasing renal function, which is consistent with findings from recent clinical trials and outpatient registries. 4 7 In this prespecified analysis concerning efficacy and safety of dabigatran in relation to renal function, there were significant interactions primarily for the bleeding outcomes that were more pronounced when renal function was estimated with the new CKD-EPI equation. Despite the fact that dabigatran is 80% renally eliminated by glomerular filtration, both the 110- and 150-mg doses were safe with regard to major bleeding rates in states of renal impairment (egfr <80 ml/min) relative to warfarin, in accordance with previous results based solely

8 968 Circulation March 4, 2014 on Cockcroft-Gault estimation. 17 However, in patients with no renal impairment (egfr 80 ml/min) according to the CKD-EPI equation, both dosages of dabigatran yielded significantly lower rates of major bleeding than warfarin. A similar result was also achieved when the MDRD equation was used in the sensitivity analyses. Bleeding Risk in AF and Renal Impairment The rates of major bleeding increases as renal function deteriorates in patients taking warfarin or other oral anticoagulants despite a variable extent of renal elimination. 4,6 Bleeding risk in patients with impaired renal function has been attributed to several factors such as platelet and platelet vessel wall interaction dysfunction, coagulopathy, hypertension, and general frailty, apart from concomitant medications and comorbidities. 10,18,19 GFR-estimating equations are important tools in clinical practice to accurately assess renal function and identify individuals at higher risk for thromboembolic and major bleeding events, as well as for balanced dosing of medications eliminated by the kidneys. Apart from renal dysfunction, higher age is an established risk factor for major bleeding events in AF. 9,17,20 Age is incorporated in all creatinine-based egfr equations; however, even when cystatin C is used to estimate GFR, with no need to include age in the equation, the result concerning an increase in major bleeding with deteriorating renal function remains. An evaluation of both age and renal function appears reasonable when one assesses major bleeding risk in patients with AF who are undergoing oral anticoagulation. Estimating Renal Function GFR is an accepted index of renal function. Several equations exist to noninvasively estimate GFR from serum creatinine. The Cockcroft-Gault equation is at present the most widely used; however, it systematically overestimates GFR. 21 The CKD-EPI equation was developed to more accurately estimate GFR across all ranges of renal function. 14 The qualities of the different equations are evident in the differences regarding number of subjects classified with egfr 80 ml/min or egfr 50 to <80 ml/min between the Cockcroft-Gault and CKD-EPI equations. The majority of reclassification occurred in the group estimated as having normal renal function according to the Cockcroft-Gault equation. Approximately 50% of the participants, 3030 of 5844, estimated as having renal function 80 ml/min with the Cockcroft-Gault were classified as having GFR <80 ml/min with the CKD-EPI equation. The more accurate estimation of individuals renal function and reclassification achieved with the CKD-EPI equation appear to account for the more pronounced patterns and narrower confidence intervals in the renal function interaction analyses with regard to dabigatran relative to warfarin for the safety outcomes. Use of the cystatin C equation is not well described in elderly populations and was only available in a subset of patients (n=6190); consequently, the results need to be interpreted with some caution. However, similar patterns concerning egfr classification and treatment interactions have been described recently in a large AF population from the Apixaban for Reduction in Stroke and Other Thromboembolic Events (ARISTOTLE) trial. 6 On the basis of the present results, it appears that the CKD-EPI equation provides important and clinically useful information regarding the assessment of renal function and the tailoring of oral anticoagulation in AF. Renal Function and Anticoagulation in AF The present study shows that it is possible to achieve effective and safe oral anticoagulation with dabigatran in a randomized and fully powered dose comparison against warfarin without prespecified dose reductions as were assigned in the ROCKET-AF (Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ARISTOTLE trials. 22,23 For stroke prevention in AF, dabigatran 150 mg BID is generally recommended over dabigatran 110 mg BID because of the superiority in reduction of ischemic and hemorrhagic strokes relative to warfarin, as well as the superiority in net clinical benefit outcomes. 13 However, it appears feasible to use information regarding age and egfr to attain a dose tailoring of dabigatran in special situations, such as in patients with higher bleeding risk. Study Limitations A limitation of the present study is that egfr <30 ml/ min constituted an exclusion criteria for the RE-LY study. 12 However, dose-identification studies (confirmed and supported by the US Food and Drug Administration s clinical pharmacology division) that used pharmacokinetic modeling and simulation have been performed that showed that dabigatran 75 mg BID was a recommended dose in patients with severe renal dysfunction (egfr ml/min). 24 Because the present study was not dimensioned for subgroup analysis, statistical power was relatively low for testing interactions, and a nonsignificant result does not rule out the possibility of treatment heterogeneity. A total of 162 patients had missing creatinine samples, although annual event rates in participants with available measurements were almost identical to the main trial results. GFR was not measured invasively in the RE-LY trial, and therefore, no general assumptions may be made regarding the most accurate egfr method; however, on the basis of the present findings, estimation of renal function with the CKD-EPI equation may yield further improvements in tailoring oral anticoagulant treatment in AF patients. Conclusions Rates of stroke, mortality, and major bleeding increase as renal function deteriorates. Relative to warfarin, dabigatran 110 mg and dabigatran 150 mg displayed an efficacy consistent with the overall trial across the range of renal function with regard to the primary outcome of stroke or systemic embolism. When GFR was estimated with the newer CKD-EPI equation, a significantly greater relative reduction in major bleeding risk was displayed for both dosages of dabigatran in patients with egfr 80 ml/min.

9 Hijazi et al Dabigatran vs Warfarin in Renal Dysfunction 969 Sources of Funding The RE-LY trial was funded by Boehringer Ingelheim Pharmaceuticals. Disclosures Dr Hijazi reports receiving lecture fees and an institutional research grant from Boehringer-Ingelheim. Dr Hohnloser reports receiving consulting fees and lecture fees from Boehringer Ingelheim, St Jude Medical, and Sanofi Aventis and lecture fees from Cardiome. Dr Oldgren reports receiving consulting and lecture fees and grant support from Boehringer Ingelheim and consultant and lecture fees from Bayer and Bristol-Myers Squibb. Dr Connolly reports receiving consulting fees, lecture fees, and grant support from Boehringer Ingelheim. Dr Eikelboom has received grant support, honoraria, and consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Regado Biosciences, and Sanofi-Aventis. Dr Ezekowitz reports receiving consulting fees, lecture fees, and grant support from Boehringer Ingelheim and Aryx Therapeutics; consulting fees from Sanofi-Aventis; and lecture fees and grant support from Portola Pharmaceuticals. Dr Reilly is an employee of Boehringer Ingelheim. Dr Siegbahn reports receiving consulting fees, lecture fees, and grant support from Boehringer Ingelheim; lecture fees and grants from Eli Lilly; and grant support from AstraZeneca. Dr Yusuf reports receiving consulting fees, lecture fees, and grant support from Boehringer Ingelheim and consulting fees from AstraZeneca, Bristol-Myers Squibb, and Sanofi-Aventis. Dr Wallentin reports receiving consulting and lecture fees, honoraria, and research grants from Boehringer Ingelheim; research grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough; honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Schering-Plough; consultant fees from Athera Biotechnologies, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Regado Biotechnologies; and lecture fees from AstraZeneca and Eli Lilly. U. Andersson reports no conflicts. References 1. Ananthapanyasut W, Napan S, Rudolph EH, Harindhanavudhi T, Ayash H, Guglielmi KE, Lerma EV. Prevalence of atrial fibrillation and its predictors in nondialysis patients with chronic kidney disease. Clin J Am Soc Nephrol. 2010;5: Baber U, Howard VJ, Halperin JL, Soliman EZ, Zhang X, McClellan W, Warnock DG, Muntner P. Association of chronic kidney disease with atrial fibrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circ Arrhythm Electrophysiol. 2011;4: Deo R, Katz R, Kestenbaum B, Fried L, Sarnak MJ, Psaty BM, Siscovick DS, Shlipak MG. Impaired kidney function and atrial fibrillation in elderly subjects. J Card Fail. 2010;16: Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32: Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L, Singer DE; ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Circulation. 2009;119: Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M, Lanas F, Lopes RD, Lopez-Sendon J, Granger CB, Wallentin L. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33: Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, Patel MR, Mahaffey KW, Halperin JL, Breithardt G, Hankey GJ, Hacke W, Becker RC, Nessel CC, Fox KA, Califf RM. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: Validation of the r2chads2 index in the ROCKET AF (Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study cohorts. Circulation. 2013;127: Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey. Chest. 2010: Marinigh R, Lane DA, Lip GY. Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol. 2011;57: Piccini JP, Hernandez AF, Zhao X, Patel MR, Lewis WR, Peterson ED, Fonarow GC; Get With The Guidelines Steering Committee and Hospitals. Quality of care for atrial fibrillation among patients hospitalized for heart failure. J Am Coll Cardiol. 2009;54: Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E, Wallentin L, Yusuf S. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157: , 810.e Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150: Flodin M, Jonsson AS, Hansson LO, Danielsson LA, Larsson A. Evaluation of Gentian cystatin C reagent on Abbott Ci8200 and calculation of glomerular filtration rate expressed in ml/min/1.73 m 2 from the cystatin C values in mg/l. Scand J Clin Lab Invest. 2007;67: Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F; Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. 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10 970 Circulation March 4, Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365: Lehr T, Haertter S, Liesenfeld KH, Staab A, Clemens A, Reilly PA, Friedman J. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol. 2012;52: Clinical Perspective In patients with atrial fibrillation, impaired renal function is associated with a higher risk of thromboembolic events and major bleeding. Oral anticoagulation with vitamin K antagonists reduces thromboembolic events but raises the risk of bleeding. The new oral anticoagulant dabigatran has 80% renal elimination, and its efficacy and safety might, therefore, be related to renal function. In this prespecified analysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, outcomes with dabigatran versus warfarin were evaluated in relation to 4 estimates of renal function, that is, equations based on creatinine levels (Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and cystatin C. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily irrespective of renal function. Rates of major bleeding were lower with dabigatran 110 mg and similar with 150 mg twice daily across the entire range of renal function. However, when the CKD-EPI or MDRD equations were used, there was a significantly greater relative reduction in major bleeding with both doses of dabigatran than with warfarin in patients with estimated glomerular filtration rate 80 ml/min. These findings show that dabigatran can be used with the same efficacy and adequate safety in patients with a wide range of renal function and that a more accurate estimate of renal function might be useful for improved tailoring of anticoagulant treatment in patients with atrial fibrillation and an increased risk of stroke.