Study Summary

The mechanism underlying the clinical benefit derived from sacubitril-valsartan over enalapril in heart failure with reduced ejection fraction (<40%) remains unclear. The EVALUATE-HF trial was a randomized, double-blinded multicenter trial of 464 patients with heart failure with reduced ejection fraction ≤40% randomized to sacubitril-valsartan or enalapril for 12 weeks for the purposes of addressing this question. The primary outcome was change in aortic characteristic impedance (Zc), a measure of central aortic stiffness, with 9 secondary outcomes which included 1) change in N-terminal pro-B-type natriuretic peptide (NT-proBNP), 2) ejection fraction, 3) global longitudinal strain, 4) mitral annual relaxation velocity, 5) mitral E/e’ ratio, 6) left ventricular end-systolic and 7) end-diastolic volume indices (LVEDVI and LVESVI), 8) left atrial volume index, and 9) ventricular-vascular coupling ratio. A total of 427 subjects completed the study, with no statistically significant change between groups in the Zc at 12 weeks despite a trend toward decreased Zc in the sacubitril-valsartan group and increased Zc in the enalapril group. The sacubitril-valsartan group did sustain significant reductions in 5/9 prespecified secondary outcomes: NT-proBNP, left atrial volume index, LVEDVI, LVESVI, and mitral E/e’ ratio but not in the others. Patients in the sacubitril-valsartan group reported better quality of life as measured by the Kansas City Cardiomyopathy Questionnaire compared to the enalapril group. Adverse event rates including hypotension were similar in both groups.

Commentary

Study strengths: This study sought to shed light on the pathophysiologic mechanisms responsible for the impressive clinical benefit derived from angiotensin receptor-neprilysin inhibitors (ARNIs) in patients with heart failure with reduced ejection fraction compared to ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARB). The study selected endpoints to reflect the vasodilatory, antifibrotic, and antihypertrophic effects of neprilysin inhibition as manifested through central aortic impedance, which determines ventricular load and cardiac performance, as well as biomarkers such as NT-proBNP and echocardiographic changes which might represent changes in ventricular wall stress and cardiovascular structure and function. The study design effectively limited safety issues by excluding patients with baseline hypotension, ensuring baseline guideline directed medical therapy while avoiding major confounders by following an ACE-I washout and excluding prior ARNI use. Data was obtained at 84 US study sites and sent to core laboratory for evaluation allowing for proper standardization, and most patients had successful dose titration with very little dropout from the study facilitating more robust data analysis. Overall the results may suggest that sacubitril-valsartan likely leads to benefit in clinical outcomes and quality of life by reducing congestion and perhaps by reversing remodeling but not by than reduction in afterload or increase in contractility.

Study weaknesses: Though central aortic stiffness is a key contributor to pulsatile load and wall stress on the left ventricle, it is unclear whether this was the appropriate primary endpoint to select to best understand the underlying mechanism of clinical benefit derived from sacubitril valsartan in HfrEF. This population already had high levels of circulating NT-proBNP by virtue of being a HFRef population, and pretreatment with ACEi or ARB in >80% of the population likely rendered subjects with lower central aortic stiffness than expected to see a meaningful difference. Furthermore, the primary outcome in this study is calculated using the ratio of change in carotid pressure (derived from applanation tonometry waveform) and change in flow in proximal aorta (derived from Doppler echocardiography). The clinical significance of this is somewhat unclear, as this is not a readily available measure in most instances. Generalizability is also limited given inclusion of less symptomatic (NYHA Class 1, 2 and some 3) HF and exclusion of patients with atrial fibrillation. Additionally, while the authors made a notable effort to recruit racial and ethnic minorities, most patients were male and white. This study was not powered for assessment of secondary endpoints and thus reductions in LA volume, LVESI, LVEDI, and mitral E/e’ ratio as reflections of favorable changes in cardiac structure and function linked to the clinical benefit of sacubitril-valsartan cannot be considered confirmatory. Finally, the study was limited to 12 weeks for ethical reasons given the known benefit of ARNI, which may be insufficient to see significant changes in aortic stiffness.

Next Steps/Clinical Perspective: The clinical benefit derived from sacubitril-valsartan in HfrEF is clear – again demonstrated in this study by virtue of reduction in NT-proBNP and an improvement in quality of life as measured by the KCCQ. The underlying pathophysiologic mechanisms are likely multifactorial and still incompletely understood. The findings of this study suggest that the benefit derived may be more due to reduction in congestion and reverse remodeling as opposed to a reduction in pulsatile and after-load. Further biomarker analyses including norepinephrine, epinephrine, etc, longer duration of treatment, and perhaps invasive hemodynamic evaluations and inclusion of sicker patients who stand to derive more benefit may shed more light as to underlying mechanisms. The HFN-LIFE trial is currently enrolling patients with NYHA Class IV symptoms to assess the potential benefit of sacubitril-valsartan in sicker patients with lower blood pressures and may further our understanding of underlying pathophysiologic mechanisms.