Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials
2021; Lippincott Williams & Wilkins; Volume: 144; Issue: 15 Linguagem: Inglês
10.1161/circulationaha.121.056657
ISSN1524-4539
AutoresMilton Packer, Faı̈ez Zannad, Stefan D. Anker,
Tópico(s)Cardiac pacing and defibrillation studies
ResumoHomeCirculationVol. 144, No. 15Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessArticle CommentaryPDF/EPUBHeart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials Milton Packer, MD, Faiez Zannad, MD, PhD and Stefan D. Anker, MD, PhD Milton PackerMilton Packer Correspondence to: Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N Hall St, Dallas, TX 75226. Email E-mail Address: [email protected] https://orcid.org/0000-0003-1828-2387 Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.). Imperial College, London, UK (M.P.). , Faiez ZannadFaiez Zannad https://orcid.org/0000-0001-7456-1570 Université de Lorraine, Inserm INI-CRCT, CHRU, Nancy, France (F.Z.). and Stefan D. AnkerStefan D. Anker https://orcid.org/0000-0002-0805-8683 Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Germany (S.D.A.). Originally published29 Aug 2021https://doi.org/10.1161/CIRCULATIONAHA.121.056657Circulation. 2021;144:1193–1195Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 11, 2021: Previous Version of Record October 8, 2021: Ahead of Print August 29, 2021: Ahead of Print Heart failure and a preserved ejection fraction (HFpEF) is characterized in many patients by the coexistence of a systemic metabolic or inflammatory disorder that causes coronary endothelial dysfunction, microvascular rarefaction, and cardiac fibrosis, leading to impaired left ventricular distensibility. Neurohormonal antagonists that are effective in patients with heart failure and a reduced ejection fraction have generally not been useful in patients with HFpEF. Until recently, large-scale trials of patients with HFpEF have reported no benefit or only a modest reduction in the risk of heart failure outcomes, with borderline levels of statistical significance.1,2 The trials have also noted meaningful subgroup interactions, which have further complicated interpretation of the results.The EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) investigators recently reported the effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin in patients with heart failure and an ejection fraction >40%.3 Empagliflozin reduced the risk of the composite of cardiovascular death or hospitalization for heart failure by 21% (hazard ratio, 0.79 [95% CI, 0.69–0.90]; P 40% in EMPEROR-Preserved. Both trials specified that patients had evidence of structural heart disease (typically left atrial enlargement) and increased levels of natriuretic peptides, using the same threshold for NT-proBNP (N-terminal pro-B-type natriuretic peptide; ie, >300 pg/mL). The baseline characteristics were similar in the 2 trials for most variables, including renal function and prevalence of diabetes. Because of differences in ejection fraction eligibility, compared with EMPEROR-Preserved, patients in the PARAGON-HF trial had higher ejection fractions (57.5±8.0% versus 54.3±8.8%). Compared with PARAGON-HF, patients in the EMPEROR-Preserved trial were somewhat more likely to be treated with β-blockers (85.9% versus 79.5%) and mineralocorticoid receptor antagonists (37.6% versus 27.1%).Although PARAGON-HF is often referred to as an active control trial, the study compared sacubitril/valsartan with valsartan, thus allowing an unconfounded comparison of neprilysin inhibition in 1 group with no neprilysin inhibition in the other. Similarly, EMPEROR-Preserved compared patients receiving empagliflozin in 1 group with patients receiving no sodium-glucose cotransporter 2 inhibitor in the other.The PARAGON-HF trial randomized 4796 patients who were followed up for a median of 35 months, whereas the EMPEROR-Preserved trial randomized 5988 patients who were followed up for a median of 26 months. For the composite of cardiovascular death and total hospitalizations for heart failure, the incidence rates for the control groups were comparable, that is, 14.6 versus 12.5 per 100 patient-years of follow-up in PARAGON-HF and EMPEROR-Preserved, respectively. However, because of its longer follow-up, more of these events were recorded in PARAGON-HF than in EMPEROR-Preserved. The PARAGON-HF trial recorded more total (first and recurrent) hospitalizations for heart failure than EMPEROR-Preserved (1487 versus 948) and more deaths (691 versus 463), thus providing PARAGON-HF with more statistical power to discern a treatment effect. In PARAGON-HF, the addition of neprilysin inhibition reduced the rate ratio for the composite of cardiovascular death and total hospitalizations for heart failure by 13% (rate ratio, 0.87 [95% CI, 0.75–1.01]; P=0.059).2 In contrast, in EMPEROR-Preserved, the addition of empagliflozin reduced the rate ratio for the same end point by 21% (rate ratio, 0.79 [95% CI, 0.68–0.92]; P=0.003). For the primary end point of time to cardiovascular death or hospitalization for heart failure, the effect size for empagliflozin was identical (hazard ratio, 0.79 [95% CI, 0.69–0.90]; P 42.5% to ≤52.5% (n=1427), >52.5% to ≤62.5% (n=2166), and >62.5% (n=1202); for EMPEROR-Preserved, >42.5% to ≤52.5% (n=2340), >52.5% to ≤62.5% (n=2130), and >62.5% (n=1106).Neither sacubitril/valsartan nor empagliflozin exerted a significant effect on cardiovascular death. Nevertheless, for all outcomes that included hospitalization for heart failure, the effect size was larger for empagliflozin than for sacubitril/valsartan in most ejection fraction subgroups (Figure). Of particular note, with respect to time to first hospitalization for heart failure, for patients with an ejection fraction of >42.5% to ≤52.5%, the hazard ratios were 0.83 (95% CI, 0.65–1.06) for PARAGON-HF and 0.65 (95% CI, 0.50–0.85) for EMPEROR-Preserved. For this same end point, for patients with an ejection fraction of >52.5% to ≤62.5%, the hazard ratios were 0.87 (95% CI, 0.71–1.07) for PARAGON-HF and 0.68 (95% CI, 0.51–0.89) for EMPEROR-Preserved.ConclusionsA side-by-side examination of the pattern of effects in 2 large-scale outcomes trials in patients with HFpEF affords an opportunity to evaluate the benefits of neprilysin inhibition and sodium-glucose cotransporter 2 inhibition using the same end points in the same ejection fraction subgroups in comparable patient populations. The magnitude of the reduction in the risk of serious heart failure outcomes appears to be greater with sodium-glucose cotransporter 2 inhibition than with neprilysin inhibition for most patients with HFpEF.Sources of FundingThe PARAGON-HF trial was funded by Novartis, and the EMPEROR-Preserved trial was funded by Boehringer Ingelheim and Eli Lilly and Co.Disclosures Dr Packer reports consulting fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Lilly, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance, outside the submitted work. He was a member of the Executive Committee of the PARAGON-HF and EMPEROR-Preserved trials. DrZannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. He was a member of the Executive Committee of the PARAGON-HF and EMPEROR-Preserved trials.Dr Anker reports grants and personal fees from Vifor International and Abbott Vascular, as well as personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circThe podcast and transcript are available as a Data Supplement at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.121.056657.This work was presented in a Late-Breaking Clinical Trial session at the European Society of Cardiology Congress, August 27, 2021 to August 30, 2021.For Sources of Funding and Disclosures, see page 1195.Correspondence to: Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N Hall St, Dallas, TX 75226. Email milton.[email protected]eduReferences1. 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