EMPEROR-Preserved clinical trial review

EMPEROR-Preserved clinical trial review

EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) evaluated the role of sodium-glucose cotransporter 2 inhibitor empagliflozin in heart failure with preserved ejection fraction [1]. It was a double blind randomized trial in 5988 patients who had class III-IV heart failure and ejection fraction above 40%. The comparison was between empagliflozin and placebo, in addition to usual therapy. Primary outcome measured was a composite of cardiovascular death or hospitalization for heart failure.

Primary outcome event occurred in 415 patients in empagliflozin group and 511 patients in the placebo group. This was statistically significant with a P<0.001. Main contributor to the benefit was a lower risk of hospitalization for heart failure in the empagliflozin group. Reduction in composite end point was 21% and that of hospitalization for heart failure 29%. Time to first hospitalization was also longer in empagliflozin group. The effect was consistent in patients with or without diabetes. Uncomplicated genital and urinary tract infections and hypotension were more frequent in the empagliflozin group.

Heart failure with preserved ejection fraction (HFpEF) was hitherto considered as difficult to treat group with lack of evidence based therapy which can significantly improve outcome. Previous trials with candesartan, spironolactone and sacubitril-valsartan had benefits of borderline statistical significance on cardiovascular death and hospitalization for heart failure in HFpEF. Subgroup analyses had suggested that any benefit may have been preferentially seen in patients with LVEF of 40 to 49%.

The cut off ejection fraction in EMPEROR-Preserved was 40%. According to the universal definition of heart failure, heart failure with preserved ejection fraction is heart failure with left ventricular ejection fraction of 50% or more. Heart failure with mildly reduced ejection fraction (HFmrEF) is heart failure with left ventricular ejection fraction from 41% to 49% [2]. Prespecified subgroup analysis in EMPEROR-Preserved had ejection fraction values of 50% and 60% as thresholds. Hazard ratios of less than 1 were documented in each of the ejection fraction subgroups.

Though treatment with empagliflozin reduced hospitalizations for heart failure, it did not appear to affect the number of deaths due to cardiovascular or other causes. Authors attribute it to the 23% discontinuation of medications for reasons other than death, though it was similar in the two treatment groups. 219 patients in the empagliflozin group died from cardiovascular causes and the corresponding figure in placebo group was 244.

Health-related quality of life in patients enrolled for EMPEROR-Preserved has been reported separately [3]. Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to assess health-related quality of life at baseline, 12, 32 and 52 weeks. The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ Clinical Summary Score tertiles. It was also noted that empagliflozin improved health-related quality of life. The effect on quality of life appeared early and was sustained for at least one year.

References

1. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Piña IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27. PMID: 34449189.
2. Bozkurt B, Coats AJ, Tsutsui H, Abdelhamid M, Adamopoulos S, Albert N, Anker SD, Atherton J, Böhm M, Butler J, Drazner MH, Felker GM, Filippatos G, Fonarow GC, Fiuzat M, Gomez-Mesa JE, Heidenreich P, Imamura T, Januzzi J, Jankowska EA, Khazanie P, Kinugawa K, Lam CSP, Matsue Y, Metra M, Ohtani T, Francesco Piepoli M, Ponikowski P, Rosano GMC, Sakata Y, SeferoviĆ P, Starling RC, Teerlink JR, Vardeny O, Yamamoto K, Yancy C, Zhang J, Zieroth S. Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail. 2021 Mar 1:S1071-9164(21)00050-6. doi: 10.1016/j.cardfail.2021.01.022. Epub ahead of print. PMID: 33663906.
3. Butler J, Filippatos G, Jamal Siddiqi T, Brueckmann M, Böhm M, Chopra VK, Pedro Ferreira J, Januzzi JL, Kaul S, Piña IL, Ponikowski P, Shah SJ, Senni M, Vedin O, Verma S, Peil B, Pocock SJ, Zannad F, Packer M, Anker SD. Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial. Circulation. 2022 Jan 18;145(3):184-193. doi: 10.1161/CIRCULATIONAHA.121.057812. Epub 2021 Nov 15. PMID: 34779658; PMCID: PMC8763045.