EXPERT OPINION ESC 2022 Highlights The DELIVER Trial: the Beginning of the End of Ejection Fraction Tyranny Antoni Bayes-Genis ,1,2 1. Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 2. Department of Medicine, Universitat Autònoma Barcelona, Barcelona, Spain Abstract It has been reported at the 2022 European Society of Cardiology Congress that the DELIVER trial has met its primary outcome – a relative reduction of 18% in a composite of worsening heart failure (HF) or cardiovascular death. These results, added to evidence from previously reported pivotal trials with sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with reduced and preserved heart failure (HF), provide compelling evidence of the benefit of SGLT2is across the HF spectrum, irrespective of ejection fraction. New diagnostic algorithms that are quick and easy to implement at the point of care are needed for quick diagnosis and implementation of these drugs. Ejection fraction may come later for proper phenotyping. Keywords Heart failure, dapagliflozin, ejection fraction, natriuretic peptides, diagnosis, sodium-glucose cotransporter-2 inhibitors Disclosure: The author has received honoraria for lectures and/or advisory boards from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Roche Diagnostics and Vifor. He is on the editorial board of European Cardiology Review and this did not influence the decision to publish. Received: 16 September 2022 Accepted: 16 September 2022 Citation: European Cardiology Review 2022;17:e30. DOI: https://doi.org/10.15420/ecr.2022.44 Correspondence: Antoni Bayes-Genis, Heart Institute, Hospital Universitari Germans Trias i Pujol, Department of Medicine, UAB, Carretera del Canyet s/n 08916, Badalona, Spain. E: abayesgenis@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. ‘The DELIVER trial has Delivered!’, declared consultant cardiologist many similarities. First, despite different components of the composite Theresa McDonagh when she discussed the trial findings at the European primary endpoint, the relative reduction achieved in primary outcomes Society of Cardiology Congress in Barcelona on 27 August, 2022 with were similar: 18% for DELIVER versus 21% for EMPEROR-Preserved. A principal investigator Scott Solomon when he presented the results. recent analysis of EMPEROR-Preserved found a 24% reduction in outcomes if an endpoint similar to that of DELIVER was used. Second, in The Dapagliflozin Evaluation to Improve the Lives of Patients with both trials, the principal effect was essentially on reduction of HF Preserved Ejection Fraction Heart Failure (DELIVER) trial was designed to hospitalisation, without a meaningful reduction on CV mortality. Third, the test the hypothesis that the sodium-glucose cotransporter-2 inhibitors population enrolled in both trials had identical age, mean LVEF and (SGLT2i) dapagliflozin would reduce the risk of worsening heart failure estimated glomerular filtration rate (eGFR) and had a similar proportion of (HF) or cardiovascular (CV) death among patients with a mildly reduced patients with LVEF >60%.3 The new information provided by DELIVER is its ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF). efficacy in patients with improved/recovered LVEF and the clear signal of benefit across LVEF categories including LVEF ≥60%. Last, DELIVER’s The primary outcome was a composite of worsening HF (which was safety data were of no concern, similar to all pivotal clinical trials of HF, defined as either an unplanned hospitalisation for HF or an urgent visit for without the need for titration nor close monitoring. HF) or cardiovascular (CV) death, as assessed in a time-to-event analysis. Over a median of 2.3 years, the primary outcome occurred in 512 patients These two trials provide compelling evidence of the benefit of using (16.4%) in the dapagliflozin group and in 610 patients (19.5%) in the SGLT2i in patients with HFmrEF and HFpEF and add to the already robust placebo group (HR 0.82; 95% CI [0.73–0.92]; p<0.001). The main benefit evidence in patients with reduced ejection fraction (HfrEF) found in the of dapagliflozin in this population was mainly in reducing worsening HF DAPA-HF and EMPEROR-Reduced trials. Clinical guidelines will have to with a non-significant effect on CV death. The benefit was consistent adapt soon to incorporate these new data, with a more than likely class IA across prespecified subgroups, including those defined according to left indication for SGLT2i in HFmrEF and HFpEF (it is already class IA for ventricular ejection fraction (LVEF), with no attenuation in the highest LVEF patients with HFrEF). group. Dapagliflozin was effective in patients with recent HF hospitalisation and in those with previously reduced LVEF that had improved to over SGLT2is have emerged as first-line medication (along with diuretics, if 40%.1 necessary) across the HF spectrum, irrespective of LVEF. In terms of clinical practice, this represents a major game changer, particularly in the DELIVER is the second positive trial using SGLT2is in patients with HFmrEF primary care setting, where echocardiography is not always available or and HFpEF, together with EMPEROR-Preserved.2 The two trials share has major delays. With the recent evidence from SGLT2i trials, patients © 2022 The Author(s). Published by Radcliffe Group Ltd. www.ECRjournal.com The DELIVER Trial: the Beginning of the End of Ejection Fraction Tyranny with signs and symptoms of HF plus positive natriuretic peptide levels empagliflozin) without delay.4 In summary, after DELIVER, it is clear that should receive an SGLT2i, even before echo data are available. It is the waiting to have an LVEF – which may take weeks or months – before right time to extend the use of natriuretic peptides in primary care (ideally initiating a disease-modifying medication in HF is unnecessary and may as point-of-care) and in-hospital, to start an SGLT2i (dapagliflozin or even be harmful. 1. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin 3. Bayes-Genis A, Aimo A, Lupón J. Empagliflozin in heart 4. Bayes-Genis A, Coats AJS. ‘Peptide for Life’ in primary care: in heart failure with mildly reduced or preserved ejection failure with preserved and mildly reduced ejection fraction: work in progress. Eur Heart J 2021:ehab829. fraction. N Engl J Med 2022;387:1089–98. https://doi. prognostic benefit confirmed with different endpoint https://doi.org/10.1093/eurheartj/ehab829; PMID: 34897424. org/10.1056/NEJMoa2206286; PMID: 36027570. definitions. Eur J Heart Fail 2022;24:1406–9. https://doi. 2. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart org/10.1002/ejhf.2597; PMID: 35781908. failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61. https://doi.org/10.1056/NEJMoa2107038; PMID: 34449189. EUROPEAN CARDIOLOGY REVIEW www.ECRjournal.com