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EMPEROR-Preserved: A promise fulfilled

2021; Cell Press; Volume: 33; Issue: 11 Linguagem: Inglês

10.1016/j.cmet.2021.10.011

1932-7420

Deepak L. Bhatt, Subodh Verma, Bertram Pitt,

Heart Failure Treatment and Management

Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest unmet needs in medicine. In the EMPEROR-Preserved trial, recently reported in the NEJM, the SGLT2 inhibitor empagliflozin reduced the primary outcome of heart failure hospitalizations and cardiovascular death by 21% in patients with HFpEF. This represents an important breakthrough in the war against heart failure. Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest unmet needs in medicine. In the EMPEROR-Preserved trial, recently reported in the NEJM, the SGLT2 inhibitor empagliflozin reduced the primary outcome of heart failure hospitalizations and cardiovascular death by 21% in patients with HFpEF. This represents an important breakthrough in the war against heart failure. Heart failure has been generally classified based on systolic ejection fraction (EF) into heart failure with a reduced EF (HFrEF; EF ≤ 40%) and heart failure with a preserved EF (HFpEF; EF ≥ 50%)—with the global burden shared relatively equally among these two phenotypes. Although there are differences in the pathophysiology and clinical characteristics of each type of heart failure (Figure 1A), they both negatively affect quality of life, lead to frequent hospitalizations, and carry poor prognoses, often worse than many types of cancers. Notably, in the war against HFrEF we have made some significant gains (Braunwald, 2015Braunwald E. The war against heart failure: the Lancet lecture.Lancet. 2015; 385: 812-824Abstract Full Text Full Text PDF PubMed Scopus (532) Google Scholar). Carefully conducted clinical trials have yielded four complementary and disease-modifying therapies for HFrEF. These therapies, namely the renin-angiotensin-aldosterone system inhibitors (RAASis; angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], or angiotensin receptor blocker neprilysin inhibitors [ARNIs]), β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose transport protein 2 inhibitors (SGLT2is), have now been recommended in practice guidelines as the core foundational therapies to reduce HFrEF-associated symptoms, hospitalizations, and mortality. Unlike HFrEF, unfortunately the story with HFpEF therapies has been less encouraging. Trials with ACEis, ARBs, MRAs, digoxin, and sacubitril/valsartan have not demonstrated superiority for their primary efficacy endpoints. While subsequent analyses of some of these trials revealed benefit in the subgroup of patients within the lower EF range of 45%–55% and have led to the United States FDA approval in certain cases, these data have not been widely endorsed by international guidelines. The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) investigated the efficacy and safety of an SGLT2i, empagliflozin, in patients with HFpEF (Anker et al., 2021Anker S.D. Butler J. Filippatos G. Ferreira J.P. Bocchi E. Böhm M. Brunner-La Rocca H.P. Choi D.J. Chopra V. Chuquiure-Valenzuela E. et al.EMPEROR-Preserved Trial InvestigatorsEmpagliflozin in heart failure with a preserved ejection fraction.N. Engl. J. Med. 2021; 385: 1451-1461Crossref PubMed Scopus (832) Google Scholar). Leading up to this trial, SGLT2is had been shown to prevent heart failure events in people with type 2 diabetes and reduce heart failure hospitalizations and cardiovascular death among individuals with chronic HFrEF in the ambulatory setting (Bhatt et al., 2021bBhatt D.L. Szarek M. Steg P.G. Cannon C.P. Leiter L.A. McGuire D.K. Lewis J.B. Riddle M.C. Voors A.A. Metra M. et al.SOLOIST-WHF Trial InvestigatorsSotagliflozin in patients with diabetes and recent worsening heart failure.N. Engl. J. Med. 2021; 384: 117-128Crossref PubMed Scopus (603) Google Scholar; Connelly et al., 2018Connelly K.A. Bhatt D.L. Verma S. Can we DECLARE a victory against cardio-renal disease in diabetes?.Cell Metab. 2018; 28: 813-815Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar; McMurray et al., 2019McMurray J.J.V. Solomon S.D. Inzucchi S.E. Køber L. Kosiborod M.N. Martinez F.A. Ponikowski P. Sabatine M.S. Anand I.S. Bělohlávek J. et al.DAPA-HF Trial Committees and InvestigatorsDapagliflozin in patients with heart failure and reduced ejection fraction.N. Engl. J. Med. 2019; 381: 1995-2008Crossref PubMed Scopus (2622) Google Scholar; Packer et al., 2020Packer M. Anker S.D. Butler J. Filippatos G. Pocock S.J. Carson P. Januzzi J. Verma S. Tsutsui H. Brueckmann M. et al.EMPEROR-Reduced Trial InvestigatorsCardiovascular and renal outcomes with empagliflozin in heart failure.N. Engl. J. Med. 2020; 383: 1413-1424Crossref PubMed Scopus (1567) Google Scholar; Zinman et al., 2015Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. Mattheus M. Devins T. Johansen O.E. Woerle H.J. et al.EMPA-REG OUTCOME InvestigatorsEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N. Engl. J. Med. 2015; 373: 2117-2128Crossref PubMed Scopus (6986) Google Scholar). While there was efficacy of SGLT2/1 inhibition in patients with diabetes in the prespecified subgroup of HFpEF with sotagliflozin in the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) and Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trials (Bhatt et al., 2021aBhatt D.L. Szarek M. Pitt B. Cannon C.P. Leiter L.A. McGuire D.K. Lewis J.B. Riddle M.C. Inzucchi S.E. Kosiborod M.N. et al.SCORED InvestigatorsSotagliflozin in patients with diabetes and chronic kidney disease.N. Engl. J. Med. 2021; 384: 129-139Crossref PubMed Scopus (366) Google Scholar, Bhatt et al., 2021bBhatt D.L. Szarek M. Steg P.G. Cannon C.P. Leiter L.A. McGuire D.K. Lewis J.B. Riddle M.C. Voors A.A. Metra M. et al.SOLOIST-WHF Trial InvestigatorsSotagliflozin in patients with diabetes and recent worsening heart failure.N. Engl. J. Med. 2021; 384: 117-128Crossref PubMed Scopus (603) Google Scholar), EMPEROR-Preserved was the first to test an SGLT2i in a dedicated HFpEF population not only with diabetes, but also without diabetes. The trial randomized ∼6,000 patients with symptomatic HFpEF (defined as an EF ≥ 40%, with an elevation in natriuretic peptides, and evidence of structural heart disease) to receive 10 mg empagliflozin daily versus placebo. Patients were enrolled with an estimated glomerular filtration rate (eGFR) of ≥20 mL/min/1.73 m2. The baseline demographics were reflective of HFpEF in that the mean age of the population was ∼71 years, approximately 45% were women, the mean body mass index was ∼30 kg/m2, and 90% had a history of hypertension. One-half had a history of diabetes, chronic kidney disease, and atrial fibrillation. Over a follow-up of 26 months, the primary endpoint of time to first hospitalization for heart failure or cardiovascular death was reduced by 21% (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.69 to 0.90; p < 0.001). Total (first and recurrent) heart failure hospitalizations were reduced by 27% (HR, 0.73; 95% CI, 0.61 to 0.88; p < 0.001). There was a numerical (but not statistically significant) reduction in cardiovascular death (HR, 0.91; 95% CI, 0.76 to 1.09). Empagliflozin was well tolerated with fewer overall side effects compared with placebo and no excess in diabetic ketoacidosis or serious volume-related side effects or hypoglycemia. There was a small excess in genitourinary tract infections. Many noteworthy observations and clinical implications merit discussion. At the outset, this is the first positive HFpEF trial in patients with or without diabetes, providing an unequivocal demonstration of a clinically significant and persuasive result. The benefit of empagliflozin emerged soon after initiation of therapy, with statistical significance by day 18 post-randomization (Packer et al., 2021Packer M. Butler J. Zannad F. Filippatos G. Ferreira J.P. Pocock S.J. Carson P. Anand I. Doehner W. Haass M. et al.EMPEROR-Preserved Trial Study GroupEffect of empagliflozin on worsening heart failure events in patients with heart failure and a preserved ejection fraction: the EMPEROR-Preserved Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (114) Google Scholar). The absolute risk reductions were meaningful and yielded a number needed to treat of only 31 over the trial duration. Additionally, the benefits were observed on a background of intensive pharmacotherapy including β-blockers, RAASis, and MRAs in 86%, 81%, and 37% of patients, respectively. There was remarkable consistency in the overall result across baseline demographics including age, sex, race, body mass index, heart failure history, NT-proBNP, diabetes status, eGFR, and background therapy. Furthermore, empagliflozin was associated with a reduction in serious heart failure events (i.e., those requiring ICU/CCU admission, inotropic or vasodilator support, or intensification of diuretics for worsening heart failure) (Packer et al., 2021Packer M. Butler J. Zannad F. Filippatos G. Ferreira J.P. Pocock S.J. Carson P. Anand I. Doehner W. Haass M. et al.EMPEROR-Preserved Trial Study GroupEffect of empagliflozin on worsening heart failure events in patients with heart failure and a preserved ejection fraction: the EMPEROR-Preserved Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (114) Google Scholar). The treatment also improved patient-reported quality of life and objective measures of New York Heart Association class. The exact EF that denotes HFpEF is a topic of intense controversy. In EMPEROR-Preserved, an EF cut-point of ≥40% was employed, with an equal representation of patients within the pre-specified EF categories of 40%–50%, 50%–60%, and >60%, respectively. Interestingly, for total heart failure hospitalizations, heterogeneity was observed in patients with a baseline EF ≥ 60% where the HR was 1.06 versus 0.57 and 0.66 in those with EFs >40% to <50% and 50% to <60%, respectively (p trend = 0.008) (Packer, 2021Packer, M. (2021). EMPEROR-Pooled: effect of empagliflozin on serious adverse renal outcomes in chronic heart failure – a prospective alpha-protected, individual patient-level pooled analysis. In ESC Congress 2021 (Virtual).Google Scholar). Pooled analyses of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) and EMPEROR-Preserved trials demonstrated a consistent 30% relative risk reduction of empagliflozin on the primary and secondary outcomes across a broad range of EFs from <25% to 64%, but also noted a neutral result in those with an EF ≥ 65% (Packer, 2021Packer, M. (2021). EMPEROR-Pooled: effect of empagliflozin on serious adverse renal outcomes in chronic heart failure – a prospective alpha-protected, individual patient-level pooled analysis. In ESC Congress 2021 (Virtual).Google Scholar). The EMPEROR-Preserved trial should be viewed as a trial of patients with both HFpEF and heart failure with mildly reduced ejection fraction (HFmrEF). This latter category, previously called mid-range EF, is now endorsed in the guidelines and identifies patients with an EF of 41% to 49%. The change in nomenclature is reflective of the pathophysiological similarities between HFrEF and HFmrEF and the consistency of benefit of therapies across this EF range. Accordingly, SGLT2is are now the first class of medications to have benefits across HFrEF, HFmrEF, and HFpEF. Although several direct and systemic effects of SGLT2i have been proposed, the unifying mechanisms that explain the benefit of SGLT2is irrespective of the etiology of heart failure or the baseline EF are unclear (Figure 1B). What is evident is that the benefits are independent of glycemic status or meaningful changes in conventional risk factors (such as blood pressure or weight). There are still unanswered questions. The important population of patients with improved EF was excluded. These are patients who might have started with an EF below 40% and over time recovered their EF to above 40%. This crucial question will be answered in the ongoing Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial. We are also reminded that much work needs to be done to understand the group of patients with heart failure and an EF of ≥60%–65%, where to date the response to various treatments except for sotagliflozin seems to be consistently blunted. Some studies have suggested that the additional inhibition of SGLT1 with sotagliflozin may confer unique benefits in HFpEF, though further mechanistic work is needed. (Pitt and Bhatt, 2021Pitt B. Bhatt D.L. Does SGLT1 inhibition add benefit to SGLT2 inhibition in type 2 diabetes?.Circulation. 2021; 144: 4-6Crossref PubMed Scopus (8) Google Scholar). EMPEROR-Preserved marks the beginning of new era in HFpEF. The reliance on EF may have been an oversimplification of the complexities of heart failure, though now we have a therapeutic approach with SGLT2 inhibition whose benefit does not appear dependent on it (Anker et al., 2021Anker S.D. Butler J. Filippatos G. Ferreira J.P. Bocchi E. Böhm M. Brunner-La Rocca H.P. Choi D.J. Chopra V. Chuquiure-Valenzuela E. et al.EMPEROR-Preserved Trial InvestigatorsEmpagliflozin in heart failure with a preserved ejection fraction.N. Engl. J. Med. 2021; 385: 1451-1461Crossref PubMed Scopus (832) Google Scholar; Bhatt et al., 2019Bhatt D.L. Verma S. Braunwald E. The DAPA-HF Trial: a momentous victory in the war against heart failure.Cell Metab. 2019; 30: 847-849Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar; Verma et al., 2020Verma S. Anker S.D. Butler J. Bhatt D.L. Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST-WHF in perspective.ESC Heart Fail. 2020; 7: 3261-3267Crossref Scopus (16) Google Scholar) (Figures 2A and 2B ). S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery. D.L.B. reports the following relationships: Advisory Board, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors, Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; Chair, Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Novartis, and Population Health Research Institute; honoraria, American College of Cardiology (Senior Associate Editor, Clinical Trials and News, https://www.acc.org/; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor and Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); other, Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); research funding, Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon (including for his role as Chair of SOLOIST and SCORED), Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, and 89Bio; royalties, Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); site co-investigator, Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, and Svelte; Trustee, American College of Cardiology; unfunded research, FlowCo, Merck, and Takeda. S.V. served as a Canadian National Coordinator for the EMPEROR-Preserved and EMPEROR-Reduced trials and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. B.P. reports that he received consulting fees from Sanofi/Lexicon, Bayer, Astra Zeneca, Boehringer Ingelheim/Lilly, and Phasebio, and consulting fees and stock options from SCPharmaceuticals, SQinnovations, G3pharmaceuticals, Relypsa/Vifor, Cereno Scientific, KBP Pharmaceuticals, Sarfez, Tricida, Proton Intel, and Brainstorm Medical. B.P. is chairman of the steering committee for the National Heart, Lung, and Blood Institute's TRANSFORM (Torsemide Comparison with Furosemide for Management of Heart Failure) trial and co-chair of SPIRRIT (Spironolactone Initiation Registry Randomized Interventional Trial; from the National Heart, Lung, and Blood Institute–Swedish Heart Foundation). He holds US Patent no. 9931412 on site-specific delivery of eplerenone to the myocardium and has a pending US Patent (63/045,784) on histone acetylation-modulating agents for the treatment and protection of organ damage.