September 4, 2019 – Novartis announced results from two new clinical trials evaluating improvement in heart structure and function and long-term safety of Entresto (sacubitril/valsartan) in patients with heart failure with reduced ejection fraction (HFrEF). Results suggest that Entresto not only positively impacts a biomarker shown to be associated with prognosis of clinical outcomes in HFrEF, but also that the effect is associated with significant improvement in the structural and functional changes, known as cardiac remodeling, that occur with this disease.1-11 Safety and tolerability were similar to that in previously reported studies.1,2,3
Cardiac remodeling impairs the heart's ability to pump blood to the body and leads to poor prognosis.9 Therefore, a positive impact on cardiac remodeling may be important in the treatment of HFrEF as it may result in reversed damage to the heart, which can lead to improved clinical outcomes.9,12 These data are the first to demonstrate that Entresto improved heart structure and function, indicative of reversal of cardiac remodeling, and that this improvement is correlated with positive changes in a biomarker.1,2 These results, which further support Entresto as a first-choice treatment for HFrEF, were presented as late-breakers at the European Society of Cardiology (ESC) Congress 2019, and published in Journal of the American Medical Association.1-5,8
The Phase IV, 52-week, single-arm, open-label PROVE-HF trial showed that treatment with Entresto significantly improved levels of an important biomarker shown to be associated with prognosis of clinical outcomes in HFrEF, N-terminal pro–B-type natriuretic peptide (NT-proBNP), which was linked for the first time to significant improvements in left ventricular remodeling and echocardiographic measures of cardiac structure and function.1,10,11 Importantly, the study demonstrated this association between improvement in this biomarker and these positive changes indicative of reversal of cardiac remodeling at six months and one year.1 The study found Entresto's safety and tolerability to be largely consistent with that seen in the pivotal PARADIGM-HF trial with the exception of dizziness, which was reported more frequently in PROVE-HF.1,3
Novartis also conducted the Phase IV, multicenter, randomized, double-blind, active-controlled EVALUATE-HF trial to examine Entresto's effect on remodeling of the blood vessels of the heart and ventricular-vascular coupling – a measure of the mechanical efficiency of the heart – compared with enalapril.2 The study, also presented at ESC Congress 2019, showed that neither Entresto nor enalapril improved the primary endpoint of change in aortic impedance (a measure of vascular stiffness).2 It is possible that the short length of the study, as well as the specific patient population, which may already have experienced a degree of improved aortic impedance, may have contributed to this outcome.2 However, consistent with the findings in PROVE-HF, the study showed that Entresto improved the structure and function of the left ventricle – the chamber that pumps blood to the rest of the body – compared to enalapril, and safety was comparable to that seen in PARADIGM-HF.1,2,3
Entresto is indicated for the treatment of patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.13
For more information: www.escardio.org
- Januzzi J., Prescott M., Butler J., et al. Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction. JAMA. 2019. doi:10.1001/jama.2019.12821.
- Desai A, Solomon S, Shah A, et al. Effect of Sacubitril-Valsartan Versus Enalapril on Aortic Stiffness in Patients with Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2019;322(11). doi:10.1001/jama.2019.12843.
- McMurray J, Packer M, Desai A, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004. doi: 10.1056/NEJMoa1409077.
- Ponikowski P, Voors A, Anker S, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37:2129-2200. doi:10.1093/eurheartj/ehw128.
- Seferovic P, Ponikowski P, Anker S, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of The Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019. doi: 10.1002/ejhf.1531.
- Velazquez E, Morrow D, DeVore, A, et al., Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2018. doi: 10.1056/NEJMoa1812851.
- Chandra A, Lewis E, Claggertt B, et al. The Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Heart Failure Patients: The PARADIGM-HF Trial. JAMA Cardiol. 2018;3(6):498-505. doi: 10.1001/jamacardio.2018.0398.
- Yancy C, Jessup M, Butler J, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137-161. doi: 10.1161/CIR.0000000000000509.
- Poelzl G, Frick M, Lackner B, et al. Chronic heart failure is associated with vascular remodeling of the brachial artery. Eur J Heart. 2005;7(1):43-48.
- Ndumele C, Matsushita K, Sang Y, et al. NT-proBNP and Heart Failure Risk Among Individuals With and Without Obesity: The ARIC Study. Circulation. 2016;133:631-638.
- Chow S, Maisel A, Anand I, et al. Role of biomarkers for the prevention, assessment, and management of heart failure: A scientific statement from the American Heart Association. Circulation. 2017;135:e1054-e1091.
- Almufleh A, Marbach J, Chih S, et al. Ejection fraction improvement and reverse remodeling achieved with Sacubitril/Valsartan in heart failure with reduced ejection fraction patients. Am J Cardiovasc Dis. 2017;7(6):108-113.
- ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; November 2018.