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Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis

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Abstract

Background

Sacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF).

Methods

We compared the treatment arms (sacubitril/valsartan, vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on vericiguat and the HFrEF subgroup of DECLARE-TIMI 58.

Results

There was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat.

Conclusions

Based on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to vericiguat.

Registration Number

PROSPERO ID 186351.

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Abbreviations

ACEi/ARB:

Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker

CI:

Confidence interval

CV:

Cardiovascular

HFrEF:

Heart failure with reduced ejection fraction

HR:

Hazard ratio

MRA:

Mineralocorticoid receptor antagonist

NMA:

Network meta-analysis

NP:

Natriuretic peptide

RCT:

Randomized controlled trial

SOC:

Standard-of-care

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Authors and Affiliations

  1. Institute of Life Sciences, Scuola Superiore Sant’Anna, Piazza Martiri della Libertà 33, 56124, Pisa, Italy

    Alberto Aimo, Claudio Passino & Michele Emdin

  2. Cardiology Division, University Hospital of Pisa, Piazza Martiri della Libertà 33, 56124, Pisa, Italy

    Alberto Aimo

  3. Department of Biostatistics and Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    Konstantinos Pateras

  4. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece

    Kimon Stamatelopoulos & Georgios Georgiopoulos

  5. Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain

    Antoni Bayes-Genis

  6. CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain

    Antoni Bayes-Genis

  7. Department of Medical and Surgical Specialties, Radiological Sciences, Public Health University and Civil Hospital, Brescia, Italy

    Carlo Mario Lombardi

  8. Cardiology Department, Fondazione Toscana Gabriele Monasterio, Pisa, Italy

    Claudio Passino & Michele Emdin

  9. School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK

    Georgios Georgiopoulos

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  1. Alberto Aimo
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Correspondence to Alberto Aimo.

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Conflict of Interest

M.E. is one of the 2 Italian national leaders of the VICTORIA trial; the other authors have no conflicts of interest to disclose.

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Aimo, A., Pateras, K., Stamatelopoulos, K. et al. Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis. Cardiovasc Drugs Ther 35, 1067–1076 (2021). https://doi.org/10.1007/s10557-020-07099-2

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