Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial

doi:10.1161/CIRCULATIONAHA.121.057812

Clinical Trial

. 2022 Jan 18;145(3):184-193.

doi: 10.1161/CIRCULATIONAHA.121.057812. Epub 2021 Nov 15.

Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial

Javed Butler¹, Gerasimos Filippatos², Tariq Jamal Siddiqi¹, Martina Brueckmann^{3

4}, Michael Böhm⁵, Vijay K Chopra⁶, João Pedro Ferreira^{7

8}, James L Januzzi⁹, Sanjay Kaul¹⁰, Ileana L Piña¹¹, Piotr Ponikowski¹², Sanjiv J Shah¹³, Michele Senni¹⁴, Ola Vedin¹⁵, Subodh Verma¹⁶, Barbara Peil¹⁷, Stuart J Pocock¹⁸, Faiez Zannad⁷, Milton Packer^{19

20}, Stefan D Anker^{21

22

23}

Affiliations

¹ Department of Medicine, University of Mississippi School of Medicine, Jackson (J.B., T.J.S.).
² National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Greece (G.F.).
³ Boehringer Ingelheim International GmbH, Ingelheim, Germany (M. Brueckmann).
⁴ Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany (M. Brueckmann).
⁵ Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Saarland University, Homburg/Saar, Germany (M. Böhm).
⁶ Max Superspeciality Hospital, Saket, New Delhi, India (V.K.C.).
⁷ Université de Lorraine, Inserm, Centre d'Investigations Cliniques, Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., F.Z.).
⁸ Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.).
⁹ Massachusetts General Hospital and Baim Institute for Clinical Research, Boston (J.L.J.).
¹⁰ Cedars-Sinai Medical Center, Los Angeles, CA (S.K.).
¹¹ Central Michigan University, Mount Pleasant (I.L.P.).
¹² Wroclaw Medical University, Poland (P.P.).
¹³ Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.).
¹⁴ Cardiovascular Department, Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo, Italy (M.S.).
¹⁵ Boehringer Ingelheim AB, Stockholm, Sweden (O.V.).
¹⁶ Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, ON, Canada (S.V.).
¹⁷ Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany (B.P.).
¹⁸ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, United Kingdom (S.J.P.).
¹⁹ Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
²⁰ Imperial College, London, United Kingdom (M.P.).
²¹ Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, Germany (S.D.A.).
²² German Centre for Cardiovascular Research partner site Berlin, Germany (S.D.A.).
²³ Charité Universitätsmedizin Berlin, Germany (S.D.A.).

PMID: 34779658
PMCID: PMC8763045
DOI: 10.1161/CIRCULATIONAHA.121.057812

Clinical Trial

Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial

Javed Butler et al. Circulation. 2022.

. 2022 Jan 18;145(3):184-193.

doi: 10.1161/CIRCULATIONAHA.121.057812. Epub 2021 Nov 15.

Authors

Affiliations

¹ Department of Medicine, University of Mississippi School of Medicine, Jackson (J.B., T.J.S.).
² National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Greece (G.F.).
³ Boehringer Ingelheim International GmbH, Ingelheim, Germany (M. Brueckmann).
⁴ Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany (M. Brueckmann).
⁵ Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Saarland University, Homburg/Saar, Germany (M. Böhm).
⁶ Max Superspeciality Hospital, Saket, New Delhi, India (V.K.C.).
⁷ Université de Lorraine, Inserm, Centre d'Investigations Cliniques, Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F., F.Z.).
⁸ Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.).
⁹ Massachusetts General Hospital and Baim Institute for Clinical Research, Boston (J.L.J.).
¹⁰ Cedars-Sinai Medical Center, Los Angeles, CA (S.K.).
¹¹ Central Michigan University, Mount Pleasant (I.L.P.).
¹² Wroclaw Medical University, Poland (P.P.).
¹³ Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.).
¹⁴ Cardiovascular Department, Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo, Italy (M.S.).
¹⁵ Boehringer Ingelheim AB, Stockholm, Sweden (O.V.).
¹⁶ Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, ON, Canada (S.V.).
¹⁷ Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany (B.P.).
¹⁸ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, United Kingdom (S.J.P.).
¹⁹ Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
²⁰ Imperial College, London, United Kingdom (M.P.).
²¹ Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, Germany (S.D.A.).
²² German Centre for Cardiovascular Research partner site Berlin, Germany (S.D.A.).
²³ Charité Universitätsmedizin Berlin, Germany (S.D.A.).

PMID: 34779658
PMCID: PMC8763045
DOI: 10.1161/CIRCULATIONAHA.121.057812

Abstract

Background: Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status.

Methods: Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin.

Results: The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69-1.00], 0.70 [95% CI, 0.55-0.88], and 0.82 [95% CI, 0.62-1.08] for scores <62.5, 62.5-83.3, and ≥83.3, respectively; P trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; P<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10-1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03-1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02-1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75-0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score.

Conclusions: In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.

Keywords: empagliflozin; health status; heart failure, diastolic; quality of life.

PubMed Disclaimer

Figures

**Figure 1.**
**Effect of empagliflozin on outcomes by baseline KCCQ tertiles.** CSS indicates Clinical Summary Score; KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, Overall Summary Score; and TSS, total symptom score. *P value from trend test assuming ordering of the KCCQ tertiles

**Figure 2.**
**Effects of empagliflozin versus placebo on mean KCCQ scores.** Changes in (A) Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score, (B) Total Symptom Score, and (C) Overall Summary Score from baseline to 12, 32, and 52 weeks for empagliflozin versus placebo. Adj. mean diff indicates adjusted mean difference.

**Figure 3.**
**Adjusted mean difference in KCCQ-CSS, TSS, OSS, and subdomains for empagliflozin versus placebo at 12, 32, and 52 weeks.** CSS indicates Clinical Summary Score; empa, empagliflozin; KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, Overall Summary Score; and TSS, Total Symptom Score.

**Figure 4.**
**Responder analysis for improvement and deterioration across the KCCQ domains.** CSS indicates Clinical Summary Score; empa, empagliflozin; KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, Overall Summary Score; and TSS, total symptom score

**Figure 5.**
**Responder analysis with proportion of responders at 12, 32, and 52 weeks with empagliflozin versus placebo.** CSS indicates Clinical Summary Score; OSS, Overall Summary Score; and TSS, Total Symptom Score.

See this image and copyright information in PMC

Comment in

Designing clinical trials in heart failure with preserved ejection fraction: quality over quantity?
Straw S, Gierula J, Witte KK. Straw S, et al. Eur J Heart Fail. 2022 May;24(5):851-854. doi: 10.1002/ejhf.2510. Epub 2022 May 5. Eur J Heart Fail. 2022. PMID: 35445788 No abstract available.

Cited by

Empagliflozin cost-effectiveness analysis in Japanese heart failure with mildly reduced and preserved ejection fraction.
Tsutsui H, Sakamaki H, Momomura SI, Sakata Y, Kotobuki Y, Linden S, Idehara K, Nitta D. Tsutsui H, et al. ESC Heart Fail. 2024 Feb;11(1):261-270. doi: 10.1002/ehf2.14565. Epub 2023 Nov 15. ESC Heart Fail. 2024. PMID: 37969049 Free PMC article.
Development and Challenges of Pre-Heart Failure with Preserved Ejection Fraction.
Dong G. Dong G. Rev Cardiovasc Med. 2023 Sep 25;24(9):274. doi: 10.31083/j.rcm2409274. eCollection 2023 Sep. Rev Cardiovasc Med. 2023. PMID: 39076392 Free PMC article. Review.
Targeting unfolded protein response reverts ER stress and ER Ca²⁺ homeostasis in cardiomyocytes expressing the pathogenic variant of Lamin A/C R321X.
Pietrafesa G, De Zio R, Scorza SI, Armentano MF, Pepe M, Forleo C, Procino G, Gerbino A, Svelto M, Carmosino M. Pietrafesa G, et al. J Transl Med. 2023 May 22;21(1):340. doi: 10.1186/s12967-023-04170-y. J Transl Med. 2023. PMID: 37217929 Free PMC article.
The effect of sodium-glucose co-transporter 2 inhibitors on clinical outcomes after acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.
Khan U, Amin AM, Mohamed Taha A, Khlidj Y, M AlBarakat M, Elewidi M, Abuelazm M, Turkmani M, Abdelazeem B, Laeeq R. Khan U, et al. Future Cardiol. 2025 Mar;21(3):177-190. doi: 10.1080/14796678.2025.2464449. Epub 2025 Feb 12. Future Cardiol. 2025. PMID: 39939290 Free PMC article.
Empagliflozin: A Review in Symptomatic Chronic Heart Failure.
Frampton JE. Frampton JE. Drugs. 2022 Nov;82(16):1591-1602. doi: 10.1007/s40265-022-01778-0. Epub 2022 Nov 14. Drugs. 2022. PMID: 36374374 Review.

See all "Cited by" articles

References

1. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, et al. ; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2021 update: a report from the American Heart Association. Circulation. 2021;143:e254–e743. doi: 10.1161/CIR.0000000000000950 - PubMed
1. Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, Devore AD, Yancy CW, Fonarow GC. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017;70:2476–2486. doi: 10.1016/j.jacc.2017.08.074 - PubMed
1. Lewis EF, Lamas GA, O’Meara E, Granger CB, Dunlap ME, McKelvie RS, Probstfield JL, Young JB, Michelson EL, Halling K, et al. ; CHARM Investigators. Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM. Eur J Heart Fail. 2007;9:83–91. doi: 10.1016/j.ejheart.2006.10.012 - PubMed
1. McMurray J, Ostergren J, Pfeffer M, Swedberg K, Granger C, Yusuf S, Held P, Michelson E, Olofsson B; CHARM Committees and Investigators. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur J Heart Fail. 2003;5:261–270. doi: 10.1016/s1388-9842(03)00052-7 - PubMed
1. Butler J, Anker SD, Filippatos G, Khan MS, Ferreira JP, Pocock SJ, Giannetti N, Januzzi JL, Piña IL, Lam CSP, et al. ; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021;42:1203–1212. doi: 10.1093/eurheartj/ehaa1007 - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
Medical
- ClinicalTrials.gov
- MedlinePlus Health Information

[1] Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, et al. ; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2021 update: a report from the American Heart Association. Circulation. 2021;143:e254–e743. doi: 10.1161/CIR.0000000000000950 - PubMed

[2] Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, et al. ; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2021 update: a report from the American Heart Association. Circulation. 2021;143:e254–e743. doi: 10.1161/CIR.0000000000000950 - PubMed

[3] Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, Devore AD, Yancy CW, Fonarow GC. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017;70:2476–2486. doi: 10.1016/j.jacc.2017.08.074 - PubMed

[4] Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, Devore AD, Yancy CW, Fonarow GC. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017;70:2476–2486. doi: 10.1016/j.jacc.2017.08.074 - PubMed

[5] Lewis EF, Lamas GA, O’Meara E, Granger CB, Dunlap ME, McKelvie RS, Probstfield JL, Young JB, Michelson EL, Halling K, et al. ; CHARM Investigators. Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM. Eur J Heart Fail. 2007;9:83–91. doi: 10.1016/j.ejheart.2006.10.012 - PubMed

[6] Lewis EF, Lamas GA, O’Meara E, Granger CB, Dunlap ME, McKelvie RS, Probstfield JL, Young JB, Michelson EL, Halling K, et al. ; CHARM Investigators. Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM. Eur J Heart Fail. 2007;9:83–91. doi: 10.1016/j.ejheart.2006.10.012 - PubMed

[7] McMurray J, Ostergren J, Pfeffer M, Swedberg K, Granger C, Yusuf S, Held P, Michelson E, Olofsson B; CHARM Committees and Investigators. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur J Heart Fail. 2003;5:261–270. doi: 10.1016/s1388-9842(03)00052-7 - PubMed

[8] McMurray J, Ostergren J, Pfeffer M, Swedberg K, Granger C, Yusuf S, Held P, Michelson E, Olofsson B; CHARM Committees and Investigators. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur J Heart Fail. 2003;5:261–270. doi: 10.1016/s1388-9842(03)00052-7 - PubMed

[9] Butler J, Anker SD, Filippatos G, Khan MS, Ferreira JP, Pocock SJ, Giannetti N, Januzzi JL, Piña IL, Lam CSP, et al. ; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021;42:1203–1212. doi: 10.1093/eurheartj/ehaa1007 - PMC - PubMed

[10] Butler J, Anker SD, Filippatos G, Khan MS, Ferreira JP, Pocock SJ, Giannetti N, Januzzi JL, Piña IL, Lam CSP, et al. ; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021;42:1203–1212. doi: 10.1093/eurheartj/ehaa1007 - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial

Affiliations

Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial

Authors

Affiliations

Abstract

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Abstract

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Associated data

Related information

LinkOut - more resources

Full Text Sources

Medical