The PARADIGM-HF trial demonstrated that the angiotensin receptor–neprilysin inhibitor sacubitril–valsartan improves outcomes compared with the angiotensin-converting enzyme (ACE) inhibitor enalapril in patients with heart failure with reduced ejection fraction (HFrEF), but how the drug exerts its benefits remained unclear. Now, two studies presented at the ESC Congress 2019 reveal new details of the mechanisms, suggesting that sacubitril–valsartan induces reverse cardiac remodelling but has no effect on central aortic stiffness.

In the PARADIGM-HF trial, sacubitril–valsartan treatment resulted in a reduction of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and this reduction was associated with better prognosis. Given that NT-proBNP levels have been related to cardiac structure and function status, Januzzi and colleagues conducted the prospective PROVE-HF trial, which included 794 patients with HFrEF, to assess whether the reduction of NT-proBNP levels with sacubitril–valsartan treatment reflected improved cardiac performance. At 1 year, NT-proBNP levels had decreased by 37% from baseline, and this reduction weakly but significantly correlated with improvements in markers of cardiac volume and function, including left ventricular (LV) ejection fraction (with a 9.4% improvement from baseline), LV and left atrial volumes and the ratio of early diastolic filling to early diastolic annular velocity (E/e′). “The improvements in cardiac remodelling were comparable with, if not greater than, those seen with many other heart failure drugs,” says Januzzi. Similar improvements were observed in prespecified subgroups, including patient populations not represented in PARADIGM-HF, such as patients not taking an ACE inhibitor or angiotensin-receptor blocker and those with new-onset HFrEF. The research team is now examining the effect of sacubitril–valsartan on symptoms and quality of life in the study population, and plans to study a broad range of mechanistic biomarkers.

The EVALUATE-HF trial, which included 464 patients with HFrEF, assessed the effect of sacubitril–valsartan on central aortic stiffness and cardiac remodelling compared with enalapril. At 12 weeks, no significant between-group differences were found in the change in central aortic stiffness, as assessed by aortic characteristic impedance. Patients receiving sacubitril–valsartan had greater reductions in LV and left atrial volumes and mitral E/e′ ratio, but no significant differences were found for other secondary end points including LV ejection fraction.

“These results provide important information on how this drug exerts its benefit, suggesting that the benefit of sacubitril–valsartan in the PARADIGM-HF trial was related to improvement in cardiac structure and function,” says Januzzi.