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Meta-Analysis
. 2022 Sep;28(9):1956-1964.
doi: 10.1038/s41591-022-01971-4. Epub 2022 Aug 27.

Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER

Pardeep S Jhund  1 , Toru Kondo  1 , Jawad H Butt  1 , Kieran F Docherty  1 , Brian L Claggett  2 , Akshay S Desai  2 , Muthiah Vaduganathan  2 , Samvel B Gasparyan  3 , Olof Bengtsson  3 , Daniel Lindholm  3 , Magnus Petersson  3 , Anna Maria Langkilde  3 , Rudolf A de Boer  4 , David DeMets  5 , Adrian F Hernandez  6 , Silvio E Inzucchi  7 , Mikhail N Kosiborod  8 , Lars Køber  9 , Carolyn S P Lam  10 , Felipe A Martinez  11 , Marc S Sabatine  12 , Sanjiv J Shah  13 , Scott D Solomon  2 , John J V McMurray  14
Affiliations
Meta-Analysis

Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER

Pardeep S Jhund et al. Nat Med. 2022 Sep.

Abstract

Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and >40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76-0.97; P = 0.01), death from any cause (HR 0.90, 95% CI 0.82-0.99; P = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65-0.78; P < 0.001) and MACEs (HR 0.90, 95% CI 0.81-1.00; P = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient-level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524).

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Conflict of interest statement

P.S.J.’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials and by Bayer and Novo Nordisk for work on clinical trials; he has received speakers and consulting fees from Novartis and Boehringer Ingelheim, and grants from AstraZeneca and Boehringer Ingelheim. T.K. received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol Myers Squibb and Abiomed. J.B. reports advisory board honoraria from Bayer. K.F.D reports receiving honoraria from AstraZeneca and a research grant to his institution from Boehringer Ingelheim. B.L.C has received consulting fees from Boehringer Ingelheim. A.S.D has received grants and personal fees from AstraZeneca during the conduct of the study; and personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. M.V. has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi and Tricog Health; speaker engagements with AstraZeneca, Novartis and Roche Diagnostics and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech and Impulse Dynamics. S.B.G., O.B., D.L., M.P. and A.L. are employees and shareholders of AstraZeneca. R.A.deB.’s institution, the University Medical Center Groningen, has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk and Roche. He has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis and Roche (outside the submitted work). D.D. has received consulting fees from Frontier Science, Actelion, Bristol Myers Squibb, Medtronic, Boston Scientific, GlaxoSmithKline and Merck; and has received consulting fees and is the owner of DL DeMets Consulting. A.H. has received research support from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Myokardia, Merck, Novartis and Vifor. S.I. has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. M.K. has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi and Vifor Pharma; has received other research support from AstraZeneca; and has received an honorarium from AstraZeneca, Boehringer Ingelheim and Novo Nordisk. L.K. has received research support from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi and WebMD Global LLC; and serves as the co-founder and nonexecutive director of Us2.ai. F.M. has received personal fees from AstraZeneca. M.S. has received grants and personal fees from AstraZeneca during the conduct of the study; has received grants and personal fees from Amgen, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck and Novartis; has received personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics and Ionis; has received grants from Daiichi-Sankyo, Bayer, Pfizer, Poxel, Eisai, GlaxoSmithKline, Quark Pharmaceuticals and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche and Zora Biosciences. S.S. has received either personal or institutional research support for DELIVER from AstraZeneca. S.D.S. 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, Blood, and Lung Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer 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, CellPro-Thera, Moderna, American Regent and Sarepta. J.J.V.M. has received payments through Glasgow University for work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, DalCor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer and Theracos; and personal lecture fees from: the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier, Director, Global Clinical Trial Partners.

Figures

Fig. 1
Fig. 1. Effect of dapagliflozin on key clinical outcomes in pooled DAPA-HF and DELIVER dataset.
a–f, Incidence of: death from CV causes (a); death from all causes (b); the total number of hospital admissions for HF (c); time to first hospital admission for HF (d); death from CV causes, MI or stroke (e); and death from CV causes or hospital admission for HF (f), according to randomized therapy. Participants randomized to dapagliflozin are shown in blue and those randomized to placebo in red. All figures are Kaplan–Meier curves with an HR and 95% CI estimated from Cox’s model with two-sided P values except for the total number of hospital admissions for HF, which was plotted using the Gosh and Lin method accounting for death from CV causes (the RR is estimated from the joint frailty model with a two-sided P value). No adjustment for multiple comparisons was made. NNT indicates the number of patients who need to be treated over the median duration of follow-up to prevent one event (of the type in each panel). An NNT could not be calculated for the total number of hospital admissions for HF because this was an episode-based rather than a patient-based analysis (that is, patients may have had more than one hospital admission). ARRs and NNTs are shown with a 95% CI.
Fig. 2
Fig. 2. Effect of dapagliflozin on clinical outcomes across the range of ejection fraction.
a–f, Effect of dapagliflozin on: death from CV causes (a); death from all causes (b); the total number of hospital admissions for HF (c); time to first hospital admission for HF (d); death from CV causes, MI or stroke (e); and death from CV causes or hospital admission for HF (f), according to baseline LVEF. The horizontal blue line shows the continuous HR across the range of LVEF and the shaded area around this line represents the 95% CI from Cox’s model. The overall effect of treatment in the pooled population is shown in each panel as an HR (95% CI) with the two-sided P value from Cox’s model for Wald’s test of interaction between treatment and LVEF. No adjustment for multiple comparisons was made. aRestricted cubic spline and interaction P value derived from LWYY model for total HF hospitalization.
Fig. 3
Fig. 3. Effect of randomized treatment on CV death according to the pre-specified subgroups.
Estimates are HRs with error bars representing 95% CIs from Cox’s model and a two-sided P value for interaction from Wald’s test of Cox’s model. No adjustment for multiple comparisons was made. aNot a pre-specified subgroup.
Fig. 4
Fig. 4. Effect of dapagliflozin on clinical outcomes across the range of NT-proBNP.
a–f, Effect of dapagliflozin on: death from CV causes (a); death from all causes (b); the total number of hospital admissions for HF (c); time to first hospital admission for HF (d); death from CV causes, MI or stroke (e); and death from CV causes or hospital admission for HF (f), according to baseline NT-proBNP level. The horizontal blue line shows the continuous HR across the range of NT-proBNP levels at baseline and the shaded area around this line represents the 95% CI from Cox’s model. The overall effect of treatment in the pooled population is shown in each panel as an HR (95% CI) with the two-sided P value for Wald’s test of interaction between treatment and NT-proBNP level from Cox’s model. No adjustment for multiple comparisons was made. aRestricted cubic spline and interaction P value derived from LWYY model for total HF hospitalization.
Extended Data Fig. 1
Extended Data Fig. 1. Distribution of LVEF in pooled DAPA-HF and DELIVER dataset complete.
Distribution of left ventricular ejection fraction (LVEF) in the total population in DAPA-HF and DELIVER.
Extended Data Fig. 2
Extended Data Fig. 2. Effect of dapagliflozin on clinical outcomes across the range of NT-proBNP.
Effect of dapagliflozin on death from cardiovascular causes (CV death) and CV death or hospitalisation for heart failure (HF hospitalisation) where the definition of CV death used excluded undetermined deaths from the definition of CV death (top two panels) and according to the original trial definitions (that is, including undetermined deaths in DAPA-HF and excluding undetermined deaths in DELIVER) (bottom two panels). The horizontal blue line shows the continuous hazard ratio (HR) across the range of left ventricular ejection fraction (LVEF) and the shaded area around this line represents the 95% confidence interval (95%CI) estimated from a Cox model. The overall effect of treatment in the pooled population is shown in each panel as a HR (95%CI) with the two-sided p-value estimated from a Cox model for the Wald test of interaction between treatment and LVEF. No adjustment for multiple comparisons was made.
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