Cardio/Kidney Composite End Points: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial

Abstract

Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.

Keywords: cardio/kidney composite end points; cardio‐renal; empagliflozin; hazard ratio; win ratio.

Conflict of interest statement

Dr Ferreira receives modest consulting fees from Boehringer Ingelheim. Dr Kraus has received grant support from the IZKF Würzburg (Interdisziplinäres Zentrum für Klinische Forschung, project ZZ‐13) and honoraria from Boehringer Ingelheim. Drs Zwiener, Koitka‐Weber, George, and Ofstad are employees of Boehringer Ingelheim. Dr Fitchett has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck & Co., and Sanofi. Dr Zinman has received grant support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi‐Aventis. Dr Lauer has received consulting fees from Hoffmann La Roche and Boehringer Ingelheim. Dr Wanner has received honoraria for consultancy and lecturing from AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Janssen, Protalix, Sanofi Genzyme, and Shire. Dr Zannad has recently received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius.

Figures

Figure 1. End point hierarchy from highest to lowest priority of ordered cardio/kidney composite end point definition.

A: Cardiac (excluding fatal stroke) or kidney death; B: KF; C: HHF; D1: sustained eGFR decline of ≥40%; D2: doubling of serum creatinine; E: sustained progression to macroalbuminuria. aNumber of kidney deaths=3. bKF=sustained eGFR <15 mL/min per 1.73 m2 or sustained continuous kidney replacement therapy (including transplantation). eGFR indicates estimated glomerular filtration rate, equation developed by the Chronic Kidney Disease Epidemiology Collaboration; HHF, hospitalization for heart failure; and KF, kidney failure.

Figure 2. Unmatched win ratio analysis.

End point hierarchy from highest to lowest priority of ordered cardio/kidney composite end point definition. A: Cardiac (excluding fatal stroke) or kidney death; B: KF; C: HHF; D1: sustained eGFR decline of ≥40%; D2: doubling of serum creatinine; E: sustained progression to macroalbuminuria. Number (percent) of pairs winning for placebo (gray bar) or empagliflozin (red bar). Number of pairs in analysis: 10 934 771. Number of patient pairs (empagliflozin, placebo) for which no decision on winning can be made (ie, for all end points, either both patients are censored or 1 patient is censored before the other patient having an event: Composite 1: 8 683 755 (79.4%); Composite 2: 9 360 288 (85.6%); Composite 3: 9 603 349 (87.8%). Counting 1 event/participant and type. aNumber of kidney deaths=3. bKF=sustained eGFR <15 mL/min per 1.73 m2 or sustained continuous kidney replacement therapy (including transplantation). eGFR indicates estimated glomerular filtration rate, equation developed by Chronic Kidney Disease Epidemiology Collaboration; HHF, hospitalization for heart failure; HR, hazard ratio; and KF, kidney failure.