Association of Different Estimates of Renal Function With Cardiovascular Mortality and Bleeding in Atrial Fibrillation

Abstract

Background We compared different methods of estimated glomerular filtration rate (eGFR) and their association with cardiovascular death and major bleeding in 14 980 patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods and Results eGFR was calculated using equations based on creatinine (Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and/or cystatin C (CKD-EPICysC and CKD-EPICysC+Creatinine). These 5 eGFR equations, as well as the individual variables that are used in these equations, were assessed for correlation and discriminatory ability for cardiovascular death and major bleeding. The median age was 70.0 years, and 35.6% were women. The median eGFR was highest with Cockcroft-Gault (74.1 mL/min) and CKD-EPICysC (74.2 mL/min), and lowest with Modification of Diet in Renal Disease (66.5 mL/min). Correlation between methods ranged from 0.49 (Cockroft-Gault and CKD-EPICysC) to 0.99 (Modification of Diet in Renal Disease and CKD-EPI). Among the eGFR equations, those based on cystatin C yielded the highest C indices for cardiovascular death and major bleeding: 0.628 (CKD-EPICysC) and 0.612 (CKD-EPICysC+Creatinine), respectively. A model based on the variables within the different eGFR equations (age, sex, weight, creatinine, and cystatin C) yielded the highest discriminatory value for both outcomes, with a C index of 0.673 and 0.656, respectively. Conclusions In patients with atrial fibrillation on anticoagulation, correlation between eGFR calculated using different methods varied substantially. Cystatin C-based eGFRs seem to provide the most robust information for predicting death and bleeding. A model based on the individual variables within the eGFR equations, however, provided the highest discriminatory value. Our findings may help refine risk stratification in patients with atrial fibrillation and define how renal function should be determined in future atrial fibrillation studies. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00412984.

Keywords: atrial fibrillation; bleeding; outcome; renal function.

Conflict of interest statement

Z.H. reports lecture fees from Boehringer Ingelheim, Bristol‐Myers Squibb, Pfizer, and Roche Diagnostics; consulting fees from Boehringer Ingelheim, Bristol‐Myers Squibb, Meda, Merck Sharp & Dohme, Pfizer, and Roche Diagnostics; and research grants from the Swedish Society for Medical Research [S17‐0133] and the Swedish Heart‐Lung Foundation [20170718]. C.B.G. reports research grants and consulting/speaker fees from Boehringer Ingelheim, Bristol‐Myers Squibb, Janssen Pharmaceuticals, Pfizer, AstraZeneca, and Novartis; research grants from Daichii‐Sankyo, AKROS, Apple, GlaxoSmithKline, and the US Food & Drug Administration; and consulting/speaker fees from Bayer Corp, Boston Scientific Corp, Abbvie, Espero BioPharma, Medscape, Merck, National Institutes of Health, NovoNordisk, Roche Diagnostics, Rho Diagnostics, Sirtex, and Verseon. S.H.H. reports research grants, consulting fees, and lecture fees from Sanofi and St Jude Medical; consulting and lecture fees from Bristol Myers Squibb, Pfizer, Bayer Healthcare, Boehringer Ingelheim, Daichii‐Sankyo, and Medtronic; and consulting fees from Boston Scientific, Cardiome, Gilead, Johnson & Johnson, Portola, Servier, and Zoll. J.W. reports institutional research grants from Bristol‐Myers Squibb/Pfizer. J.L. reports institutional research grants from Bristol‐Myers Squibb/Pfizer. J.H.A. reports institutional research grants and consulting fees/honoraria from Bristol‐Myers Squibb and CSL Behring; institutional research grants from AstraZeneca, CryoLife, the US Food & Drug Administration, National Institutes of Health, Sanofi, VoluMetrix, and Boehringer Ingelheim; and consulting fees/honoraria from Pfizer, AbbVie Pharmaceuticals, NovoNordisk, Portola Pharmaceuticals, Quantum Genetics, Teikoku Pharmaceuticals, VA Cooperative Studies Program, and Zafgen. M.K. has nothing to report. A.P. reports grants and personal fees from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi. J.L.L. reports personal fees from Boehringer Ingelheim; grants from Bayer, GlaxoSmithKline; grants and personal fees from Novartis, Servier, Menarini, Pfizer and Sanofi. R.D.L. reports institutional research grants and consulting fees from Bristol‐Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC, and Sanofi; and consulting fees from Amgen, Bayer, and Boehringer Ingelheim. A.S. reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics; consulting fees from Olink Proteomics. L.W. reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co, Roche Diagnostics; and consulting fees from Abbott.

Figures

Figure 1. Distributions of estimated renal function by different equations.

Empirical cumulative distribution function plot of estimated renal function according to 5 different equations. CKD‐EPI indicates Chronic Kidney Disease Epidemiology Collaboration; CysC, cystatin C; eGFR, estimated glomerular filtration rate; and MDRD, Modification of Diet in Renal Disease.

Figure 2. Correlation between estimated glomerular filtration rate (eGFR) methods.

Above‐diagonal panels show the Spearman correlation coefficients between pairwise eGFR methods. Below‐diagonal panels show scatterplots of pairwise eGFR methods––the solid diagonal line is the 1:1 relationship. The dashed vertical lines show eGFR of 45 and 60 mL/min. CKD‐EPI indicates Chronic Kidney Disease Epidemiology Collaboration; CysC, cystatin C; and MDRD, Modification of Diet in Renal Disease.

Figure 3. Agreement between estimated glomerular filtration rate (eGFR) methods, mean differences, and Bland‐Altman plots.

Above‐diagonal panels show the mean difference and the limit of agreement (±1.96 SD). Below‐diagonal panels show Bland‐Altman plots of the difference vs the mean of pairwise methods. CKD‐EPI indicates Chronic Kidney Disease Epidemiology Collaboration; CysC, cystatin C; and MDRD, Modification of Diet in Renal Disease.

Figure 4. Associations between continuous estimated glomerular filtration rate (eGFR) estimates and cardiovascular death (left panel) and major bleeding (right panel).

The reference point for each eGFR method is 60 mL/min, the relative hazard is shown on the y axis according to the different values of renal function on the x axis. Each line represents a different method of eGFR. The bottom of the figure shows the distribution for each eGFR method. CKD‐EPI indicates Chronic Kidney Disease Epidemiology Collaboration; CysC, cystatin C; and MDRD, Modification of Diet in Renal Disease.