Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial

Key PointsQuestionWhat pathophysiologic mechanisms contribute to the clinical effects of sacubitril-valsartan compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF)? FindingsIn this randomized clinical trial of 464 participants with HFrEF, there was no significant difference in the change in aortic characteristic impedance (a measure of central aortic stiffness) at 12 weeks among patients treated with sacubitril-valsartan vs enalapril (-2.9 vs -0.7 dynexs/cm(5)). MeaningTreatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness. ImportanceCompared with enalapril, sacubitril-valsartan reduces cardiovascular mortality and heart failure hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). These benefits may be related to effects on hemodynamics and cardiac remodeling. ObjectiveTo determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril. Design, Setting, and ParticipantsRandomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of 40% or less enrolled across 85 US sites between August 17, 2016, and June 28, 2018. Follow-up was completed on January 26, 2019. InterventionsRandomization (1:1) to sacubitril-valsartan (n=231; target dosage, 97/103 mg twice daily) vs enalapril (n=233; target dosage, 10 mg twice daily) for 12 weeks. Main Outcomes and MeasuresThe primary outcome was change from baseline to week 12 in aortic characteristic impedance (Zc), a measure of central aortic stiffness. Prespecified secondary outcomes included change from baseline to week 12 in N-terminal pro-B-type natriuretic peptide, ejection fraction, global longitudinal strain, mitral annular relaxation velocity, mitral E/e ratio, left ventricular end-systolic and end-diastolic volume indexes (LVESVI and LVEDVI), left atrial volume index, and ventricular-vascular coupling ratio. ResultsOf 464 validly randomized participants (mean age, 67.3 [SD, 9.1] years; 23.5% women), 427 completed the study. At 12 weeks, Zc decreased from 223.8 to 218.9 dyne x s/cm(5) in the sacubitril-valsartan group and increased from 213.2 to 214.4 dyne x s/cm(5) in the enalapril group (treatment difference, -2.2 [95% CI, -17.6 to 13.2] dyne x s/cm(5); P=.78). Of 9 prespecified secondary end points, no significant between-group difference in change from baseline was seen in 4, including left ventricular ejection fraction (34%-36% with sacubitril-valsartan vs 33 to 35% with enalapril; treatment difference, 0.6% [95% CI, -0.4% to 1.7%]; P=.24). However, greater reductions from baseline were seen with sacubitril-valsartan than with enalapril in all others, including left atrial volume (from 30.4 mL/m(2) to 28.2 mL/m(2) vs from 29.8 mL/m(2) to 30.5 mL/m(2); treatment difference, -2.8 mL/m(2) [95% CI, -4.0 to -1.6 mL/m(2)]; P<.001), LVEDVI (from 75.1 mL/m(2) to 70.3 mL/m(2) vs from 79.1 mL/m(2) to 75.6 mL/m(2); treatment difference, -2.0 mL/m(2) [95% CI, -3.7 to 0.3 mL/m(2)]; P=.02), LVESVI (from 50.8 mL/m(2) to 46.3 mL/m(2) vs from 54.1 to 50.6 mL/m(2); treatment difference, -1.6 mL/m(2) [95% CI, -3.1 to -0.03 mL/m(2)]; P=.045), and mitral E/e ratio (from 13.8 to 12.3 vs from 13.4 to 13.8; treatment difference, -1.8 [95% CI, -2.8 to -0.8]; P=.001). Rates of adverse events including hypotension (1.7% vs 3.9%) were similar in both groups. Conclusions and RelevanceTreatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness. The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in HFrEF. Trial RegistrationClinicalTrials.gov Identifier: NCT02874794 This randomized trial compares the effects of sacubitril-valsartan vs enalapril on central aortic stiffness and other physiologic indexes in patients with heart failure and reduced ejection fraction.