Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Dec;22(12):2393-2398.
doi: 10.1002/ejhf.2065. Epub 2020 Dec 14.

Design of a prospective patient-level pooled analysis of two parallel trials of empagliflozin in patients with established heart failure

Milton Packer  1   2 , Javed Butler  3 , Gerasimos Filippatos  4 , Faiez Zannad  5 , Joao Pedro Ferreira  5 , Cordula Zeller  6 , Martina Brueckmann  7 , Waheed Jamal  8 , Stuart J Pocock  9 , Stefan D Anker  10 ; EMPEROR Trial Committees and Investigators
Affiliations

Design of a prospective patient-level pooled analysis of two parallel trials of empagliflozin in patients with established heart failure

Milton Packer et al. Eur J Heart Fail. 2020 Dec.

Abstract

Aim: The EMPEROR-Reduced trial demonstrated that empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with a reduced ejection fraction, and the EMPEROR-Preserved trial is currently evaluating the effect of the drug on the same endpoint in patients with an ejection fraction >40%. However, neither the trial was designed to have adequate statistical power to evaluate the effects of empagliflozin and dapagliflozin on major adverse renal outcomes or on mortality. Herein we describe the design of a prospective individual patient-level pooled analysis of two large-scale trials with empagliflozin (EMPEROR-Reduced and EMPEROR-Preserved) in patients with heart failure across the spectrum of ejection fraction.

Methods: The trials were carried out in parallel using the same administrative structure and committees, randomization procedure, schedule of study visits and adjudication criteria and similar groups of investigators and case report forms. The two component trials specified the same primary and key secondary endpoints and used an identical hierarchical testing procedure, which included a pooled analysis of the two trials as a key component of the hierarchy. Consequently, the pooled analysis has been prospectively assigned a false positive error rate, which is conditional on one or both trials first achieving success on their primary and one or both key secondary endpoints. The pooled analysis has its own statistical plan with its own endpoints, and this plan was finalized before either trial had begun recruitment of patients into either study. The primary endpoint of the pooled analysis is a composite of serious adverse renal outcomes, defined by chronic dialysis, renal transplantation and a profound or sustained decrease in glomerular filtration rate. All-cause and cardiovascular mortality are specified as secondary endpoints.

Conclusion: The planned pooled analysis has an unusually high degree of statistical rigour that will allow it to address important questions that cannot be fully addressed by the individual trials.

Keywords: Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Renal outcomes; Sodium-glucose co-transporter 2 inhibitors.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Diagram of the stepwise evaluation of endpoints in the EMPEROR‐Reduced and EMPEROR‐Preserved trials. The figure shows planned alpha for each analysis. The final alpha is determined by an alpha‐spending function that depends on number of events at time of the interim analysis of each trial.
See this image and copyright information in PMC

References

    1. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RH, Bhatt DL, Leiter LA, McGuire DK, Wilding JP, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta‐analysis of cardiovascular outcome trials. Lancet 2019;393:31–39. - PubMed
    1. Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, Mahaffey KW, Charytan DM, Wheeler DC, Arnott C, Bompoint S, Levin A, Jardine MJ. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta‐analysis. Lancet Diabetes Endocrinol 2019;7:845–854. - PubMed
    1. McMurray JJ, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CE, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA‐HF Trial Committees and Investigators . Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. - PubMed
    1. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner‐La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR‐Reduced Trial Investigators . Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–1424. - PubMed
    1. Jhund PS, Solomon SD, Docherty KF, Heerspink HJ, Anand IS, Böhm M, Chopra V, de Boer RA, Desai AS, Ge J, Kitakaze M, Merkely B, O'Meara E, Schou M, Tereshchenko S, Verma S, Vinh PN, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Bengtsson O, Langkilde AM, Sjöstrand M, McMurray JJ. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA‐HF. Circulation 2020. Oct 12. 10.1161/CIRCULATIONAHA.120.050391 [Epub ahead of print]. - DOI - PMC - PubMed

MeSH terms