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Randomized Controlled Trial
. 2023 Jan 1;8(1):56-65.
doi: 10.1001/jamacardio.2022.4210.

Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial

Finnian R Mc Causland  1   2 , Brian L Claggett  2   3 , Muthiah Vaduganathan  2   3 , Akshay S Desai  2   3 , Pardeep Jhund  4 , Rudolf A de Boer  5 , Kieran Docherty  4 , James Fang  6 , Adrian F Hernandez  7 , Silvio E Inzucchi  8 , Mikhail N Kosiborod  9 , Carolyn S P Lam  10 , Felipe Martinez  11 , Jose F Kerr Saraiva  12 , Martina M McGrath  1   2 , Sanjiv J Shah  13 , Subodh Verma  14 , Anna Maria Langkilde  15 , Magnus Petersson  15 , John J V McMurray  4 , Scott D Solomon  2   3
Affiliations
Randomized Controlled Trial

Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial

Finnian R Mc Causland et al. JAMA Cardiol. .

Abstract

Importance: Sodium-glucose cotransporter 2 inhibitors are known to reduce heart failure events and slow progression of kidney disease among patients with heart failure and a reduced ejection fraction.

Objective: To determine the effect of dapagliflozin on cardiovascular and kidney outcomes and the influence of baseline kidney disease among patients with heart failure and a mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.

Design, setting, and participants: This was a prespecified analysis conducted from July 1 to September 18, 2022 of the DELIVER randomized clinical trial. This was an international, multicenter trial including patients with ejection fraction greater than 40% and estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m2 or higher.

Interventions: Dapagliflozin, 10 mg, per day or placebo.

Main outcomes and measures: Outcomes assessed were whether baseline kidney function modified the treatment effect on the primary outcome (cardiovascular death or worsening heart failure). Also examined was the treatment effect on the prespecified outcomes of eGFR slope and a post hoc composite kidney outcome (first ≥50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m2; end-stage kidney disease; death from kidney causes).

Results: A total of 6262 patients (mean [SD] age, 72 [10] years; 3516 male [56%]) had mean (SD) eGFR measurements available: 61 (19) mL/min/1.73 m2; 3070 patients (49%) had an eGFR less than 60 mL/min/1.73 m2. The effect of dapagliflozin on the primary outcome was not influenced by baseline eGFR category (eGFR ≥60 mL/min/1.73 m2: hazard ratio [HR], 0.84; 95% CI, 0.70-1.00; eGFR 45-<60 mL/min/1.73 m2: HR, 0.68; 95% CI, 0.54-0.87; eGFR <45 mL/min/1.73 m2: HR, 0.93; 95% CI, 0.76-1.14; P for interaction = .16). Over a median (IQR) follow-up of 2.3 (1.7-2.8) years, the overall incidence rate of the kidney composite outcome was low (1.1 events per 100 patient-years) and was not affected by treatment with dapagliflozin (HR, 1.08; 95% CI, 0.79-1.49). However, dapagliflozin attenuated the decline in eGFR from baseline (difference, 0.5; 95% CI, 0.1-0.9 mL/min/1.73 m2 per year; P = .01) and from month 1 to 36 (difference, 1.4; 95% CI, 1.0-1.8) mL/min/1.73 m2 per year; P < .001).

Conclusions and relevance: Results of this prespecified analysis showed that baseline kidney function did not modify the benefit of dapagliflozin in patients with heart failure and a mildly reduced or preserved ejection fraction. Dapagliflozin did not significantly reduce the frequency of the kidney composite outcome, although the overall event rate was low. However, dapagliflozin slowed the rate of decline in eGFR compared with placebo.

Trial registration: ClinicalTrials.gov Identifier: NCT03619213.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mc Causland reported receiving consulting fees from GlaxoSmithKline, Advanced Instruments, and Zydus Therapeutics and grants from Fifth Eye, the National Institute of Diabetes and Digestive and Kidney Diseases, Satellite Healthcare, and Advanced Medical outside the submitted work. Dr Claggett reported receiving consulting fees from Amgen, Cardurion, Corvia, and Novartis outside the submitted work. Dr Vaduganathan reported receiving personal fees from Amgen, AstraZeneca, Baxter HealthCare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Relypsa, American Regent, Novartis, Roche Diagnostics, Lexicon Pharmaceuticals, Galmed, Occlutech, Impulse Dynamics, and Tricog Health outside the submitted work. Dr Desai reported receiving grants from AstraZeneca, Abbott, Alnylam, Bayer, and Novartis, to Brigham and Women’s Hospital; consulting fees from AstraZeneca; and consulting fees from Abbott, Alnylam, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, Novartis, New Amsterdam Pharma, Parexel, Regeneron, Roche, and Verily outside the submitted work. Dr Jhund reported receiving grants and speaker/advisory fees from AstraZeneca during the conduct of the study; speaker/advisory fees from Novartis; grants and personal fees from Boehringer Ingelheim; clinical trial work from Bayer and NovoNordisk; grants from Analog Devices Inc; personal fees from ProAdwise, Alkem Metablomics, and Sun Pharmaceuticals outside the submitted work; and serving as director of Global Clinical Trial Partners. Dr Docherty reported institutional fees paid to University of Glasgow from AstraZeneca for work related to the DAPA-HF and DELIVER trials; receiving speakers fees from AstraZeneca; grants from AstraZeneca and Boehringer Ingelheim; and consulting fees from Us2.ai outside the submitted work. Dr Fang reported being a part of the steering committee of AstraZeneca and Amgen and the executive committee of Novartis and Abbott; being a member of the data safety monitoring board of Boerhinger Ingelheim/Lilly and Windtree; being on the board of directors of the Heart Failure Society of America; and receiving grants from the American Heart Association and the National Institutes of Health. Dr Hernandez reported receiving personal fees from AstraZeneca, Bayer, Merck, Boston Scientific, Cytokinetics, and Bristol Myers Squibb and grants from American Regent, Amgen, Boehringer Ingelheim, Verily, and Somologic outside the submitted work. Dr Inzucchi reported nonfinancial support from AstraZeneca as an executive committee member and through travel fees to meetings during the conduct of the study; nonfinancial support from AstraZeneca through consultant/speaker fees; nonfinancial support from Boehringer Ingelheim through consultant/speaker/travel fees; and consultant fees from Novo Nordisk, Merck/Pfizer, Lexicon, VTV Therapeutics, Abbott/Alere, Esperion, and Bayer outside the submitted work. Dr Kosiborod reported receiving personal fees (paid to institution) from Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Sanofi, Vifor Pharma; and grants from AstraZeneca and Boehringer Ingelheim outside the submitted work. Dr Lam reported receiving personal fees from AstraZeneca as an executive committee member of DELIVER during the conduct of the study; grants from Bayer and Roche Diagnostics; personal fees from Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics; serving as consultant or on the advisory board/steering committee/executive committee for Us2.ai; being a cofounder and nonexecutive director of Us2.ai; and having a patent for diagnosis and prognosis of chronic heart failure and a patent for automated clinical workflow that recognizes and analyses 2-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction and prognosis of heart disease. Dr Martinez reported receiving personal fees from AstraZeneca Modest during the conduct of the study. Dr Saraiva reported receiving personal fees from AstraZeneca outside the submitted work and advisory board fees from Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Lilly, Bayer, Janssen, Pfizer, and Novartis. Dr Shah reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Verma reported receiving grants from AstraZeneca and Boehringer Ingelheim and personal fees from Boehringer Ingelheim, Janssen, and AstraZeneca outside the submitted work. Dr Langkilde reported being a full-time employee of and a shareholder in AstraZeneca during the conduct of the study. Dr Petersson reported receiving personal fees from AstraZeneca, being a paid employee of AstraZeneca, and being a minor shareholder of AstraZeneca outside the submitted work. Dr McMurray reported fees paid to Glasgow University from AstraZeneca for time spent as principal investigator of DAPA-HF and co–principal investigator of DELIVER (trials using dapagliflozin) in heart failure and meetings related to trial; being executive committee member for DETERMINE and PRIORITIZE trials; being an advisory board member for the AZD9977 trial; receiving travel/accommodation fees from AstraZeneca; reported fees paid to Glasgow University from Bayer for time spent as steering committee member for the FINEARTS-HF trial; reported fees paid to Glasgow University from Amgen for time spent as steering committee member for GALACTIC-HF trial and meetings related to this trial; travel/accommodation fees from Amgen; reported fees paid to Glasgow University from Cytokinetics for time spent as steering committee member for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; travel/accommodation fees from Cytokinetics; reported fees paid to Glasgow University from Servier for time spent as steering committee member for the GALACTIC-HF trial; reported fees paid to Glasgow University from Theracos for time spent as principal investigator for the BEST trial and meetings related to this trial; travel/accommodation fees from Theracos; reported fees paid to Glasgow University from Dalcor for time spent as steering committee member for the Dal-GenE trial and meetings related to this trial; reported fees paid to Glasgow University from Pfizer for time spent as steering committee member for the ARRAY-797-301 and meetings related to this trial; reported fees paid to Glasgow University from GlaxoSmithKline (GSK) for time spent as co–principal investigator and steering committee member, respectively, for the Harmony-Outcomes trial (albiglutide) and 2 trials, ASCEND-D and ASCEND-ND, using daprodustat, and meetings related to these trials; travel/accommodation fees from GSK; reported fees paid to Glasgow University from Bristol Myers Squibb (BMS) for time spent as a steering committee member for the STAND-UP clinical trial (using an HNO donor) in heart failure and meetings related to this trial; reported fees paid to Glasgow University from Novartis for time spent executive committee member and then co–principal investigator of ATMOSPHERE, co–principal investigator of the PARADIGM-HF trial, and executive/steering committee member for PARACHUTE-HF, PARADISE-MI, and PERSPECTIVE trials (with sacubitril/valsartan) and meetings/presentations related to these trials and aliskiren and sacubitril/valsartan and for participation in a company advisory board that meets twice per year and covers the cardiometabolic field; personal fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus Personal Lecture Fees; reported fees paid to Glasgow University from Ionis Pharmaceuticals for time spent as consultant in services related to Ionis angiotensinogen program; travel/accommodation fees from Ionis; reported fees paid to Glasgow University from Cardurion for participation in a company advisory board about development of a PDE-9 inhibitor in heart failure; and receiving fees paid to Glasgow University from Boehringer Ingelheim for participation as a consultant for Empa Pragmatic Trial outside the submitted work. Dr Solomon reported receiving grants from AstraZeneca, Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, Us2.ai for grants to institutions and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health for consulting outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Treatment Effect On The Composite Cardiovascular Outcome According To Baseline Estimated Glomerular Filtration Rate (eGFR)
Figure 2.
Figure 2.. Change in Kidney Function Over Time (95% CIs)
Shown are the means for the estimated glomerular filtration rate (eGFR) over a period of 36 months. The whiskers indicate 95% CIs. The eGFR was calculated according to the creatinine formula developed by the Chronic Kidney Disease Epidemiology Collaboration study. Effect estimates are based on a mixed-model repeated-measures analysis in patients who had a baseline and postbaseline measurement. Dapa indicates dapagliflozin.
See this image and copyright information in PMC

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References

    1. Damman K, Valente MAE, Voors AA, O’Connor CM, van Veldhuisen DJ, Hillege HL. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J. 2014;35(7):455-469. doi:10.1093/eurheartj/eht386 - DOI - PubMed
    1. Hillege HL, Nitsch D, Pfeffer MA, et al. ; Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Investigators . Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113(5):671-678. doi:10.1161/CIRCULATIONAHA.105.580506 - DOI - PubMed
    1. Go AS, Yang J, Ackerson LM, et al. . Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation. 2006;113(23):2713-2723. doi:10.1161/CIRCULATIONAHA.105.577577 - DOI - PubMed
    1. Beldhuis IE, Lam CSP, Testani JM, et al. . Evidence-based medical therapy in patients with heart failure with reduced ejection fraction and chronic kidney disease. Circulation. 2022;145(9):693-712. doi:10.1161/CIRCULATIONAHA.121.052792 - DOI - PMC - PubMed
    1. Parving HH, Brenner BM, McMurray JJV, et al. ; ALTITUDE Investigators . Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-2213. doi:10.1056/NEJMoa1208799 - DOI - PubMed

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