Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure.

Autor:	Packer M; Baylor University Medical Center, Dallas, TX (M.P.).; Imperial College, London, United Kingdom (M.P.)., Butler J; Baylor Scott and White Research Institute, Dallas, TX (J.B.).; Department of Medicine, University of Mississippi School of Medicine, Jackson, MS (J.B.)., Zeller C; Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, Germany (C.Z.)., Pocock SJ; Department of Medical Statistics, London School of Hygiene & Tropical Medicine, United Kingdom (S.J.P.)., Brueckmann M; Boehringer Ingelheim International GmbH, Ingelheim, Germany (M.B.).; First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Germany (M.B.)., Ferreira JP; Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Portugal (J.P.F.).; Centre d'Investigations Cliniques Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, Nancy, France (J.P.F., F.Z.)., Filippatos G; National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece (G.F.)., Usman MS; Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (M.S.U.)., Zannad F; Centre d'Investigations Cliniques Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, Nancy, France (J.P.F., F.Z.)., Anker SD; Department of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin Berlin (S.D.A.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2023 Sep 26; Vol. 148 (13), pp. 1011-1022. Date of Electronic Publication: 2023 Aug 24.
DOI:	10.1161/CIRCULATIONAHA.123.065748
Abstrakt:	Background: It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy. Methods: In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment. Results: From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P =0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P =0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo ( P <0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P <0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients. Conclusions: These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug. Registration: URL: https://www. Clinicaltrials: gov; Unique identifiers: NCT03057977 and NCT03057951. Competing Interests: Disclosures Dr Butler reports consulting fees from Abbott Fund, American Regent, Amgen, Applied Therapeutics, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiac Dimensions, Cardior, CVRx, Inc, Cytokinetics, Edwards Lifesciences, Element Sciences, Eli Lilly & Company, Impulse Dynamics, Imbria, Inventiva, Innolife, Janssen Global, Lexicon Pharmaceuticals, Liva Nova USA, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Novo Nordisk, Pharmacosmos, Roche Diagnostics, Occlutech, Relypsa, SQ Innovation, Sequana, Stelthpeptide, Vifor Pharma. Dr Zannad reports consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cellprothera, Merck, Novartis, Novo Nordisk, Owkin, Pfizer, Servier Affaires Medicale, Vifor Fresenius. Dr Ferreira reports consulting fees from Boehringer Ingelheim. Dr Packer reports consulting fees from 89bio, Abbvie, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Reata, Relypsa, Salamandra. Dr Anker reports consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cardior, Cordio, CVRx, Inc., Edwards Lifesciences, GlaxoSmithKline, Impulse Dynamics (USA) Inc., Novartis, Pfizer, Servier, V-Wave, Vectorious, Vifor International. Dr Pocock reports consulting fees from Boehringer Ingelheim. Drs Brueckmann and Zeller are employees of Boehringer Ingelheim. Dr Usman reports no conflicts.
Databáze:	MEDLINE
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