Empagliflozin in Black Versus White Patients with Heart Failure: Analysis of EMPEROR-Pooled.

HomeCirculationVol. 147, No. 1Empagliflozin in Black Versus White Patients With Heart Failure: Analysis of EMPEROR-Pooled Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEmpagliflozin in Black Versus White Patients With Heart Failure: Analysis of EMPEROR-Pooled Subodh Verma, Nitish K. Dhingra, Javed Butler, Stefan D. Anker, João Pedro Ferreira, Gerasimos Filippatos, James L. Januzzi, Carolyn S.P. Lam, Naveed Sattar, Egon Pfarr, Matias Nordaby, Martina Brueckmann, Stuart J. Pocock, Faiez Zannad, Milton Packer and on behalf of the EMPEROR-Pooled Trial Committees and Investigators Subodh VermaSubodh Verma Correspondence to: Subodh Verma, MD, PhD, Professor and Cardiac Surgeon, St Michael’s Hospital, University of Toronto, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4018-8533 Division of Cardiac Surgery, St Michael’s Hospital, University of Toronto, Canada (S.V., N.K.D.). Search for more papers by this author , Nitish K. DhingraNitish K. Dhingra Division of Cardiac Surgery, St Michael’s Hospital, University of Toronto, Canada (S.V., N.K.D.). Search for more papers by this author , Javed ButlerJaved Butler https://orcid.org/0000-0001-7683-4720 Baylor Scott and White Research Institute, Dallas, TX (J.B.). Department of Medicine, University of Mississippi School of Medicine, Jackson (J.B.). Search for more papers by this author , Stefan D. AnkerStefan D. Anker https://orcid.org/0000-0002-0805-8683 Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Germany (S.D.A.). Search for more papers by this author , João Pedro FerreiraJoão Pedro Ferreira https://orcid.org/0000-0002-2304-6138 Université de Lorraine, Inserm, Centre d’Investigations Cliniques, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., F.Z.). Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.). Search for more papers by this author , Gerasimos FilippatosGerasimos Filippatos https://orcid.org/0000-0002-5640-0332 National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Greece (G.F.). Search for more papers by this author , James L. JanuzziJames L. Januzzi https://orcid.org/0000-0002-8338-1798 Division of Cardiology, Harvard Medical School and Massachusetts General Hospital, Boston (J.L.J.). Search for more papers by this author , Carolyn S.P. LamCarolyn S.P. Lam https://orcid.org/0000-0003-1903-0018 National Heart Centre Singapore, Duke-NUS Medical School (C.S.P.L.). Search for more papers by this author , Naveed SattarNaveed Sattar https://orcid.org/0000-0002-1604-2593 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland, UK (N.S.). Search for more papers by this author , Egon PfarrEgon Pfarr https://orcid.org/0000-0002-7799-1733 Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany (E.P.). Search for more papers by this author , Matias NordabyMatias Nordaby Boehringer Ingelheim International GmbH, Ingelheim, Germany (M.N., M.B.). Search for more papers by this author , Martina BrueckmannMartina Brueckmann https://orcid.org/0000-0003-1215-0746 Boehringer Ingelheim International GmbH, Ingelheim, Germany (M.N., M.B.). First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Germany (M.B.). Search for more papers by this author , Stuart J. PocockStuart J. Pocock Department of Medical Statistics, London School of Hygiene and Tropical Medicine, United Kingdom (S.J.P.). Search for more papers by this author , Faiez ZannadFaiez Zannad https://orcid.org/0000-0001-7456-1570 Université de Lorraine, Inserm, Centre d’Investigations Cliniques, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., F.Z.). Search for more papers by this author , Milton PackerMilton Packer https://orcid.org/0000-0003-1828-2387 Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.). Imperial College, London, United Kingdom (M.P.). Search for more papers by this author and on behalf of the EMPEROR-Pooled Trial Committees and Investigators Search for more papers by this author Originally published7 Nov 2022https://doi.org/10.1161/CIRCULATIONAHA.122.062644Circulation. 2023;147:101–104Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 7, 2022: Ahead of Print There are disparities in both rates and outcomes of heart failure (HF) between Black patients and White patients, and important questions remain about the generalizability of conventional HF therapies, including angiotensin-converting enzyme inhibitors and β-blockers, to Black patients. Whereas analyses from DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) have demonstrated a consistent benefit of SGLT2 (sodium–glucose cotransporter 2) inhibitors in Black patients, these data were limited to heart failure with reduced ejection fraction (HFrEF) and included a small number of Black patients.1,2 We studied the safety and efficacy of empagliflozin according to Black versus White race in the Americas across the spectrum of ejection fraction in the pooled dataset from both EMPEROR trials (n=9718).Ethics approval was obtained by each trial center and informed consent was received from every participant. A total of 478 Black patients and 3024 White patients were included. Black patients were more likely to be female (45.0% versus 36.8%) and younger (64.4 ± 11.7 versus 69.0 ± 10.8 years). Compared with White patients, Black patients had a lower ejection fraction (39.0 ± 15.9 versus 42.9 ± 15.8%), higher rates of nonischemic HF pathogeneses (69.7% versus 58.9%), higher estimated glomerular filtration rate (68.0 ± 25.4 versus 60.4 ± 20.9 mL/min/1.73 m2), lower rates of atrial fibrillation (25.1% versus 37.6%), and similar rates of diabetes. Baseline New York Heart Association class and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels (median 1338 versus 1320 pg/mL) were comparable; Kansas City Cardiomyopathy Questionnaire clinical (64.12 ± 24.07 versus 67.14 ± 22.55) and overall (61.93 ± 24.04 versus 64.78 ± 22.87) summary scores were lower among Black patients at baseline. Black patients and White patients had similar durations of HF (5.7 ± 6.5 versus 5.4 ± 6.0 years) as well as rates of hospitalization for HF (HHF) in the preceding 12 months (22.6% versus 22.2%). Rates of concomitant hydralazine and nitrate use were higher in Black patients (8.4% versus 2.8%), as were rates of loop/high-ceiling diuretics (76.8% versus 71.1%) and renin-angiotensin-aldosterone system inhibitors (angiotensin-converting enzyme/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor; 87.9% versus 84.2%). Rates of β-blocker use (93.1% versus 90.3%) and mineralocorticoid receptor antagonist use (53.1% versus 51.3%) were comparable. A higher percentage of Black patients had an implantable cardioverter defibrillator (14.4% versus 9.4%).Black patients randomized to placebo had higher risk of the primary outcome (HR, 1.49 [95% CI, 1.14–1.94]; P=0.004; Figure) as well as time to first HHF (1.55 [1.14–2.10]; P=0.005); time to first event of the extended composite outcome of cardiovascular death, HHF equivalent event, or diuretic intensification (1.40 [1.13–1.74]; P=0.002); and total HHF (1.44 [1.01–2.06]; P=0.046) compared with White patients randomized to placebo.Download figureDownload PowerPointFigure. Summary of major findings of White and Black patients in the Americas. A, End point data in EMPEROR-Pooled (a prospectively designed combined analysis of EMPEROR-Reduced [Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction] and EMPEROR-Preserved [Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction]) according to White versus Black race and (B) cumulative incidence of the primary end point in both the placebo and empagliflozin groups by Black versus White race. A total of 9718 patients with heart failure (HF) were included in EMPEROR-Pooled. Patients were randomized to 10 mg empagliflozin or placebo in addition to existing background therapy. The primary outcome of the trials was time to first HF hospitalization (HHF) or cardiovascular (CV) death. The estimated glomerular filtration rate values presented are derived from the conventional CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration), which uses serum creatinine and corrects for age, sex, and race. Given that 92.8% (478/515) of Black patients were recruited from the Americas, we report results of EMPEROR-Pooled by Black versus White patients specifically within the Americas. Baseline characteristics were compared between Black patients and White patients using t tests for continuous variables and chi-square tests for categorical variables. Time to first event analyses were performed with a Cox proportional hazards model, adjusted for age, sex, region (North America, Latin America), diabetes status (diabetes, prediabetes, no diabetes), estimated glomerular filtration rate at baseline, left ventricular ejection fraction at baseline, and study. These analyses were performed according to the intention-to-treat principle for all randomized patients and included data up to the end of the planned treatment period. Event rates per 100 patient-years and adjusted hazard ratios (HRs) are reported. Total (first and recurrent) hospitalizations for HF were evaluated accordingly with a joint frailty model that accounted for cardiovascular death, adjusted for the same covariates as the Cox model. Continuous end points were analyzed with the same covariates in a mixed model with repeated measures. To assess the consistency of the treatment effects across Black and White subgroups, subgroup by treatment interaction terms were added to the models. Adverse events were analyzed descriptively on the basis of patients with events occurring during the on-treatment period (including 7 days after last drug consumption by the patient).In the pooled analysis, there was a concordant efficacy of empagliflozin on the primary outcome in Black patients versus White patients (0.56 [0.38–0.81] versus 0.80 [0.68–0.95]; Pinteraction=0.083; Figure). In the HFrEF population specifically, this difference reached statistical significance (0.44 [0.27–0.73] versus 0.84 [0.66–1.06]; Pinteraction=0.022). This trend was driven by a larger treatment benefit among Black patients on time to first HHF in EMPEROR-Pooled (0.44 [0.28–0.70] versus 0.73 [0.60–0.90]; Pinteraction=0.052), an effect modification that was again particularly noted in the HFrEF population (0.35 [0.20–0.63] versus 0.79 [0.60–1.05]; Pinteraction=0.014) but not in the HF with preserved ejection fraction population. This also extended to total HHF, specifically with HFrEF (Black 0.36 [0.18–0.75] versus White 0.87 [0.63–1.20]; Pinteraction=0.030). Black patients with HFrEF (but not HF with preserved ejection fraction) had an amplified benefit of empagliflozin on the extended composite outcome (0.49 [0.32–0.74] versus 0.86 [0.71–1.05]; Pinteraction=0.015) as well as on Kansas City Cardiomyopathy Questionnaire clinical summary scores at 52 weeks (versus placebo: 6.71 [1.47–11.96] versus 0.77 [−1.57 to 3.12]; Pinteraction=0.043) compared with White patients.A sensitivity analysis was conducted with covariates limited to only treatment and race. The results were comparable for the primary outcome (Black 0.54 [0.37–0.79] versus White 0.80 [0.68–0.94]; Pinteraction=0.063); time to first HHF (0.42 [0.27–0.67] versus 0.72 [0.59–0.89]; Pinteraction=0.037); total HHF (0.50 [0.29–0.88] versus 0.86 [0.68–1.10]; Pinteraction=0.084); and time to cardiovascular death (0.75 [0.42–1.32] versus 1.03 [0.81–1.30]; Pinteraction=0.305).Adverse events and serious adverse events were comparable for empagliflozin versus placebo in Black patients and White patients (adverse events: Black patients: placebo 88.3%, empagliflozin 85.4%; White patients: placebo 83.6%, empagliflozin 82.9%; serious adverse events: Black patients: placebo 61.5%, empagliflozin 53.1%; White patients: placebo 51.2%, empagliflozin 48.2%); however, the placebo incidence of adverse events was higher in Black patients. Empagliflozin’s safety profile with respect to rates of hypotension, symptomatic hypotension, volume depletion, genital infections, acute kidney injury, and hypoglycemia was also comparable between populations.Study data will be stored at the Vivli Center for Global Clinical Research Data and access pertinent to the development of publications may be requested after the necessary regulatory activities are complete and other criteria are met.In summary, Black patients were at higher risk of HF events than were White patients in EMPEROR-Pooled. However, the efficacy and safety profile of empagliflozin is similar in Black patients and White patients with HF when assessed irrespective of ejection fraction, with a suggestion of potential enhanced efficacy in Black versus White patients particularly with HFrEF. Black patients may be predisposed to greater fluid retention and hence may derive more benefit from empagliflozin’s decongestive properties.3,4 Our findings are limited by the relatively small number of Black patients and could be confounded by differences in baseline characteristics; therefore, this finding remains hypothesis-generating. Efforts to recruit more Black patients in future trials are needed.5Article InformationSources of FundingThe EMPEROR studies were sponsored by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.Nonstandard Abbreviations and AcronymsDAPA-HFDapagliflozin and Prevention of Adverse Outcomes in Heart FailureEMPEROR-ReducedEmpagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection FractionHFheart failureHFrEFheart failure with reduced ejection fractionHHFhospitalization for heart failureNT-proBNPN-terminal pro-B-type natriuretic peptideSGLT2sodium–glucose cotransporter 2Disclosures Dr Verma holds a tier 1 Canada Research Chair in cardiovascular surgery; reports receiving research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer and honoraria from Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial and served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials; and is President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organisation. N.K. Dhingra declares no competing interests. Dr Butler reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave, and Vifor outside the submitted work. Dr Anker reports grants and personal fees from Vifor International and Abbott Vascular; personal fees from Astra-Zeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International; and personal fees from Boehringer Ingelheim during the conduct of the study. Dr Ferreira reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from Boehringer Ingelheim outside the submitted work. Dr Filippatos reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from Medtronic, Vifor, Servier, Novartis, Bayer, Amgen, and Boehringer Ingelheim outside the submitted work. Dr Januzzi is a Trustee of the American College of Cardiology; a Board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics and consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical end point committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Lam served on the Scientific Excellence Committee of the EMPEROR Program; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as 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 cofounder and nonexecutive director of Us2.ai. Dr Sattar has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharmaceuticals, Novo Nordisk, Novartis, Sanofi, and Pfizer and received grant support from Boehringer Ingelheim. E. Pfarr and Drs Nordaby and Brueckmann are employees of Boehringer Ingelheim. Dr Pocock reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from Boehringer Ingelheim outside the submitted work. Dr Zannad reports personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera; and other from CVCT and Cardiorenal outside the submitted work. Dr Packer reports personal fees from Boehringer Ingelheim, during the conduct of the study, and personal fees from Abbvie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and NovoNordisk, outside the submitted work.FootnotesFor Sources of Funding and Disclosures, see page 104.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Subodh Verma, MD, PhD, Professor and Cardiac Surgeon, St Michael’s Hospital, University of Toronto, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada. Email subodh.[email protected].toReferences1. Docherty KF, Ogunniyi MO, Anand IS, Desai AS, Diez M, Howlett JG, Nicolau JC, O’Meara E, Verma S, Inzucchi SE, et al. Efficacy of dapagliflozin in black versus white patients with heart failure and reduced ejection fraction.JACC Heart Fail. 2022; 10:52–64. doi: 10.1016/j.jchf.2021.08.006CrossrefMedlineGoogle Scholar2. Lam CSP, Ferreira JP, Pfarr E, Sim D, Tsutsui H, Anker SD, Butler J, Filippatos G, Pocock SJ, Sattar N, et al. Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.Eur Heart J. 2021; 42:4442–4451. doi: 10.1093/eurheartj/ehab360CrossrefMedlineGoogle Scholar3. Morris AA, Testani JM, Butler J. Sodium-glucose cotransporter-2 inhibitors in heart failure: racial differences and a potential for reducing disparities.Circulation. 2021; 143:2329–2331. doi: 10.1161/CIRCULATIONAHA.120.052821LinkGoogle Scholar4. Vallon V, Verma S. Effects of SGLT2 inhibitors on kidney and cardiovascular function.Annu Rev Physiol. 2021; 83:503–528. doi: 10.1146/annurev-physiol-031620-095920CrossrefMedlineGoogle Scholar5. Yancy CW. The journey toward health equity: are we nearing an abyss or ascending a peak?Circulation. 2021; 143:2327–2328. doi: 10.1161/CIRCULATIONAHA.121.055157LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Pandey A, Dhingra N, Pandey A, Puar P, Ahmed S, Verma R, Mazer C, Butler J, Badiwala M, Yau T, Yanagawa B, Bhatt D and Verma S (2023) Efficacy of sodium–glucose cotransporter 2 inhibitors and angiotensin receptor–neprilysin inhibitors for heart failure in black patients: a systematic review and meta‐analysis of randomized controlled trials , European Journal of Heart Failure, 10.1002/ejhf.2825 January 3, 2023Vol 147, Issue 1 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.062644PMID: 36342827 Originally publishedNovember 7, 2022 Keywordsheart failureracial groupstherapeuticsPDF download Advertisement SubjectsHeart Failure