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What pathophysiologic mechanisms contribute to the clinical effects of sacubitril-valsartan compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF)?
In 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 dyne × s/cm5).
Treatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT02874794
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Corresponding Author: Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (email@example.com).
Accepted for Publication: August 6, 2019.
Published Online: September 2, 2019. doi:10.1001/jama.2019.12843
Author Contributions: Drs Desai and Claggett had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Desai, Solomon, Rocha, Mitchell.
Acquisition, analysis, or interpretation of data: Desai, Shah, Claggett, Fang, Izzo, McCague, Abbas, Mitchell.
Drafting of the manuscript: Desai, Claggett, Abbas.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Desai, Solomon, Claggett, McCague, Abbas.
Obtained funding: Solomon, Mitchell.
Administrative, technical, or material support: Abbas, Rocha, Mitchell.
Supervision: Desai, Solomon, Fang, Rocha, Mitchell.
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.
Funding/Support: This study was sponsored by Novartis.
Role of the Funder/Sponsor: The protocol, including the statistical analysis plan, was developed by the trial steering committee in collaboration with the sponsor. Data were collected, managed, and analyzed by the sponsor according to the predefined statistical analysis plan, and all analyses were verified by an independent academic statistician (Dr Claggett). The sponsor had the right to review the manuscript but did not have the right to veto publication or control the decision regarding to which journal the manuscript was submitted, and several individuals employed by the sponsor were coauthors of the manuscript who fulfilled authorship criteria. All decisions regarding publication of the study results were made by the academic steering committee and approved by all authors.
Group Information: EVALUATE-HF Investigators (listed in descending order according to number of patients randomized): Erie County Medical Center, Buffalo, New York: Joseph Izzo; Infinite Clinical Research, Doral, Florida: Melvin Martinez-Castrillon; Hi Tech and Global Research LLC, Coral Gables, Florida: Jorge Beato; Carolina Heart Specialists, Lancaster, South Carolina: Vipul Shah; Aventura Clinical Research, Aventura, Florida: Leonard Pianko; Elite Cardiac Research Center, Hialeah, Florida: Manuel Bouza; Research Associates of Jackson/Apex Cardiology, Jackson, Tennessee: Mohsin Alhaddad; Private Practice Leadership LLC, Houston, Texas: Amir Kashani; Clinical Trials of America, Minden, Louisiana: Gregory Sampognaro; Midwest Heart & Vascular Specialists LLC, Overland, Kansas: Lloyd Stahl; Medicoricium LLC, Fairview Heights, Illinois: John Lehman; Pharma Research International Inc, Naples, Florida: Steve Lebhar; Clinical Trials of America LA LLC, Monroe, Louisiana: Mark Napoli; Elite Clinical Research, Miami, Florida: Aurelio Torres Consuegra; Innovation Medical Research Center, Miami, Florida: Humberto Gonzalez; Cardiovascular Research Center of South Florida, Miami: Ramon Lloret; Valley Clinical Trials Inc, Northridge, California: Mehrdad Ariani, Masoud Azizad; Coastal Heart Medical Group, Santa Ana, California: Anil Shah; Cardiology Associates Research Co, Daytona Beach, Florida: David Henderson; Garden State Health Care, Manalapan, New Jersey: John Covalesky; PharmaTex Research, Amarillo, Texas: David Brabham; California Heart Specialists, Huntington Beach: Majed Chane; Cardiovascular & Vein Center of Florida, Bradenton: Eulogio Sanchez; Crystal Pharmacology Research, Miami, Florida: Ramses Vega; Cardiology Physicians PA, Newark, Delaware: Anthony Clay; Mid Michigan Heart and Vascular Center, Saginaw: John McClure; Georgia Arrhythmia Consultants, Macon, Georgia: Felix Sogade; SIMA Research Clinic, Miami, Florida: Luis Ortiz-Munoz; East Coast Institute for Research LLC, St Augustine, Florida: Todd Lewis; Celen Medical Group Corp, Miami, Florida: Argentina Gonzalez Zequeira; Bay Area Heart, Webster, Texas: Rakesh Shah; Westside Medical Associates of Los Angeles, Beverly Hills, California: Norman Lepor; Advance Research Center LLC, Miami, Florida: Marisela Gonzalez; River Birch Research Alliance LLC, Blue Ridge, Georgia: Raymond Tidman; Cardiology Associates of Fairfield County PC, Trumbull, Connecticut: Jeffrey Berman; Cardiology Associates of Fairfield County PC, Norwalk, Connecticut: David Lorenz; Cardiac Care & Vascular Medicine, Bronx, New York: Michele Nanna; East Coast Institute for Research, Jacksonville, Florida: Trevor Greene; Cardiology Associates of Fairfield County, Stamford, Connecticut: Edward Portnay; Louisiana Heart Center, Slidell: Marc Bernstein; Cordova Research Institute LLC, Miami, Florida: Guillermo Somodevilla; Detroit Clinical Research Center, Farmington Hills, Michigan: Robert Grodman; Gaffney Health Services, Charlotte, North Carolina: Mary Gaffney; Lakeland Cardiology Center PA, Mountain Lakes, New Jersey: Hyeun Park; Comprehensive Cardiovascular Care, Gurnee, Illinois: Isaac Dor; Northwest Houston Clinical Research PLLC, Tomball, Texas: Shamaila Aslam; Dominion Medical Associates Inc, Richmond, Virginia: Richard Jackson; BioMed Research Institute, Miami, Florida: Guido Perez; Universal Axon Clinical Research, Doral, Florida: Luis Martinez; Gandelman Cardiology, Greenwich, Connecticut: Glenn Gandelman; Clinical Trials of America–NC LLC, Lenoir, North Carolina: Johnny Dy; Endeavor Medical Research, Alpena, Michigan: Abraham Salacata; Nature Coast Clinical Research, Inverness, Florida: Rafik Abadier; Integrated Cardiology Group LLC dba Bryan Heart, Lincoln, Nebraska: John Steuter; M.A.R.C. Trials LLC, Little Rock, Arkansas: Sadeem Mahmood, Harold Betton; Research Integrity LLC, Owensboro, Kentucky: Kishor Vora; University of Alabama at Birmingham: Jose Tallaj; Atlantic Clinical Research Collaborative–Cardiology, Boynton Beach, Florida: Debra Weinstein; East Carolina Heart Institute, Greenville, North Carolina: Hassan Alhosaini; Kooental Heart Clinics, Coeur d’Alene, Illinois: John Everett; Heart and Vascular Center/Holy Family Memorial Inc, Manitowoc, Wisconsin: Michael Rosenberg; Augusta University, Clinical Trials Office, Augusta, Georgia: Stephanie Dunlap; Laurelton Heart Specialists PC, Rosedale, New York: Olakunle Akinboboy; NJ Heart, Linden, New Jersey: Jasjit Walia; Premier Cardiology Consultants, Lake Success, New York: Yuly Lyandres; Integrative Research Associates Inc, Fort Lauderdale, Florida: Barry Harris; CardioVoyage LLC, McKinney, Texas: Wael Abo-Auda; Horizon Research Group of Opelousas LLC, Eunice, Louisiana: Zebediah Stearns; Palm Research Center Inc, Las Vegas, Nevada: Navid Kazemi; Advanced Clinical Research Group, Stuart, Florida: Arden Bradley; Mid Columbia Research, Richland, Washington: Lucien Megna; CardioCare, Hillsborough, New Jersey: Jeff Taylor; The Heart & Vascular Clinic PA, Newark, Delaware: Anthony Innasimuthu; Kootenai Heart Clinics LLC, Spokane, Washington: L. Douglas Waggoner; Our Lady of the Lake Physician Group, Office of Research, Baton Rouge, Louisiana: Denzil Moraes; MedStar Heart and Vascular Institute, Baltimore, Maryland: Sandeep Jani; Cardiology Care Clinics, Eatonton, Georgia: Nicolas Chronos; Sherman Clinical Research, Sherman, Texas: Nikhil Joshi; Radin Cardiovascular Medical Associates, Newport Beach, California: Michael Radin; The Heartbeat Clinic PA, McKinney, Texas: Amer Suleman; Cardiology Consultants of Philadelphia, Yardley, Pennsylvania: Paul Grena; Athena Clinical Research LLC, Athens, Georgia: Subodh Agrawal; CHI Health Creighton University Medical Center–Bergan, Omaha, Nebraska: Mark Holmberg.
Meeting Presentation: This research was presented at the ESC Congress; September 2, 2019; Paris, France.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We acknowledge Jessica Kachadourian, PharmD, a Novartis employee, for her contributions to the design, implementation, and execution of the EVALUATE-HF trial.
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