Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials
- PMID: 39217458
- DOI: 10.1161/CIRCULATIONAHA.124.071110
Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: heart failure; kidney outcomes; medical therapies.
Conflict of interest statement
Dr Butt reports advisory board honoraria from AstraZeneca and Bayer; consultant honoraria from Novartis and AstraZeneca; and travel grants from AstraZeneca. Dr McMurray reports payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, and Novartis. Dr McMurray reports personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp, British Heart Foundation, National Institutes of Health–National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and Catalyze Group. Dr McMurray reports personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, Translational and Medicine Academy. Dr McMurray is a member of the data safety monitoring board for WIRB-Copernicus Group Clinical Inc. He is a director of Global Clinical Trial Partners Ltd. Dr Claggett has received consulting fees from Bristol Myers Squibb, Cardurion, Corvia, Cytokinetics, Intellia, Novartis, and Rocket. Dr Jhund reports speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices Inc; and is director of Global Clinical Trial Partners. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Neuen has received fees for advisory boards, scientific presentations, continuing education, steering committee roles, and travel from AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare, Cornerstone Medical Education, the Limbic, Medscape, and Travere Pharmaceuticals, with all honoraria paid to his institution. Dr McCausland reports research grants from NIDDK, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon paid directly to his institution; expert witness fees from Rubin-Anders Scientific; and consulting fees from GlaxoSmithKline and Zydus Therapeutics. Dr Desai reports institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal Roche, Veristat, Verily, and Zydus. Dr Lam is supported by a clinician scientist award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr Pitt has served as a consultant for Bayer, AstraZeneca, Bristol Meyers Squibb, Boehringer Ingelheim, Lexicon, Anacardia, and G3 Pharmaceuticals. He has served as a consultant and received stock options or stocks from Sea Star Medical, Vifor, scPharmaceuticals, SQ Innovation, KBP Biosciences, Sarfez, Cereno Scientific, Prointel, and Brainstorm Medical. He holds a US patent (9931412, “Site Specific Delivery of Eplerenone to the Myocardium”) and has a US patent pending (63/045,783, “Histone Modulating Agents for the Prevention and Treatment of Organ Damage”). Dr Pfeffer has received research grant support through his institution from Novartis; has been a consultant to Alnylam, AstraZeneca, Boehringer Ingelheim, Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, Lexicon, National Heart, Lung, and Blood Institute CONNECTs (Collaborating Network of Networks for Evaluating COVID‐19 and Therapeutic Strategies; Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. Dr Packer reports personal fees from AbbVie, Actavis, Altimmune, Amgen, Amarin, Ardelyx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Caladrius, Casana, CSL Behring, Cytokinetics, Eli Lilly, Johnson & Johnson, Imara, Moderna, Novartis, ParatusRx, Pfizer, Reata, Regeneron, Relypsa, Salamandra, Synthetic Biologics, and Theravance. Dr Beldhuis is supported by the junior clinical scientist grant from the Dutch Heart Foundation, and her employer is supported by an unrestricted medical grant from Novartis. Dr Voors has received consultancy fees or research support from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Zannad reports personal fees from Applied Therapeutics, Bayer, Boehringer, Bristol Myers Squibb, CVRx, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Merck, Novartis, Novo Nordisk, Owkin, Pfizer, and Servier; has stock options at G3 Pharmaceuticals and equities at Cereno Pharmaceutical, Cardiorenal, and Eshmoun Clinical Research; and is the founder of Cardiovascular Clinical Trialists. Dr Heerspink reports consultancy for AstraZeneca, Alexion, Bayer, Boehringer Ingelheim, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Merck, Novartis, Novo Nordisk, and Travere Pharmaceuticals and research support from AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi‐Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Bristol Myers Squibb, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored.
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