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

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

Akshay S Desai et al. JAMA. 2019.

Abstract

Importance: Compared 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.

Objective: To determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril.

Design, setting, and participants: Randomized, 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.

Interventions: Randomization (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 measures: The 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.

Results: Of 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 × s/cm5 in the sacubitril-valsartan group and increased from 213.2 to 214.4 dyne × s/cm5 in the enalapril group (treatment difference, -2.2 [95% CI, -17.6 to 13.2] dyne × s/cm5; 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/m2 to 28.2 mL/m2 vs from 29.8 mL/m2 to 30.5 mL/m2; treatment difference, -2.8 mL/m2 [95% CI, -4.0 to -1.6 mL/m2]; P < .001), LVEDVI (from 75.1 mL/m2 to 70.3 mL/m2 vs from 79.1 mL/m2 to 75.6 mL/m2; treatment difference, -2.0 mL/m2 [95% CI, -3.7 to 0.3 mL/m2]; P = .02), LVESVI (from 50.8 mL/m2 to 46.3 mL/m2 vs from 54.1 to 50.6 mL/m2; treatment difference, -1.6 mL/m2 [95% CI, -3.1 to -0.03 mL/m2]; 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 relevance: Treatment 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 registration: ClinicalTrials.gov Identifier: NCT02874794.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Desai reported receipt of research support from Alnylam, AstraZeneca, and Novartis and consulting fees from AstraZeneca, Abbott, Alnylam, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma, Novartis, and Regeneron. Dr Solomon reported receipt of research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos and consulting for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AOBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr Shah reported receipt of research support from Novartis, Gilead, and Actelion and consulting fees from Myocardia. Dr Claggett reported receipt of consulting fees from Gilead, MyoKardia, Corvia, AOBiome, and Boehringer Ingelheim. Dr Fang reported receipt of consulting fees from Amgen and Novartis. Dr Izzo reported receipt of research support from Novartis. Mr McCague, Dr Abbas, and Dr Rocha are employees of Novartis. Dr Mitchell is the president of Cardiovascular Engineering Inc, a company that designs and manufactures devices that measure vascular stiffness, and reported serving as a consultant to and receiving honoraria and grant support from Novartis, Servier, Merck, and the National Institutes of Health.

Figures

Figure.

Figure.. Participant Flow in the EVALUATE-HF Randomized Clinical Trial

aA patient whom the site intended to report as a screening failure was inadvertently entered into the computerized randomization system. This patient was excluded from the full analysis set.

Comment in

References

    1. McMurray JJ, Packer M, Desai AS, et al. ; PARADIGM-HF Investigators and Committees . Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi: 10.1056/NEJMoa1409077 - DOI - PubMed
    1. Böhm M, Young R, Jhund PS, et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J. 2017;38(15):1132-1143. doi: 10.1093/eurheartj/ehw570 - DOI - PMC - PubMed
    1. Yancy CW, Jessup M, Bozkurt B, 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(6):e137-e161. doi: 10.1161/CIR.0000000000000509 - DOI - PubMed
    1. Mitchell GF, Izzo JL Jr, Lacourcière Y, et al. Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the Conduit Hemodynamics of Omapatrilat International Research Study. Circulation. 2002;105(25):2955-2961. doi: 10.1161/01.CIR.0000020500.77568.3C - DOI - PubMed
    1. Williams B, Cockcroft JR, Kario K, et al. Effects of sacubitril/valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension: the PARAMETER study. Hypertension. 2017;69(3):411-420. doi: 10.1161/HYPERTENSIONAHA.116.08556 - DOI - PubMed

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