Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials

Kidney outcomes have been variably defined using nonstandardized composite end points in key heart failure trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists, the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan, and SGLT2 (sodium-glucose cotransporter-2) inhibitors on composite kidney end points using uniform definitions in 6 contemporary heart failure trials. Individual participant-level data from trials of steroidal mineralocorticoid receptor antagonists (EMPHASIS-HF [Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure], TOPCAT [Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist] Americas), angiotensin receptor-neprilysin inhibitor (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure], PARAGON-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in HF With Preserved Ejection Fraction]), and SGLT2 inhibitors (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure], DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]) were included. The standardized composite kidney end point was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%; end-stage kidney disease; or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Among 28 690 participants across the 6 trials (median age, 69 years [interquartile range, 62-76]; 9656 [33.7%] women), the proportion experiencing the composite kidney end point with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this end point with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% to 10.0%. The steroidal mineralocorticoid receptor antagonists doubled the risk of the composite kidney end point when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. Angiotensin receptor-neprilysin inhibitor appeared to consistently reduce the occurrence of the composite kidney end points irrespective of the specific eGFR threshold applied. The potential benefits of SGLT2 inhibitors on the composite kidney end points appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. When applying standardized stringent kidney end point definitions, steroidal mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitor, and SGLT2 inhibitors have either neutral or beneficial effects on kidney outcomes in heart failure. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.