Adoption of Sacubitril/Valsartan Among Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The Get With The Guidelines-Heart Failure Registry

HomeCirculation: Heart FailureVol. 16, No. 1Adoption of Sacubitril/Valsartan Among Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The Get With The Guidelines-Heart Failure Registry Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBAdoption of Sacubitril/Valsartan Among Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The Get With The Guidelines-Heart Failure Registry Jacob B. Pierce, Zhen Li, Melissa A. Greiner, Steven J. Lippmann, N. Chantelle Hardy, Xian Shen, Mark Stampehl, Robert J. Mentz, Larry A. Allen, Pamela N. Peterson, Gregg C. Fonarow, Emily C. O’Brien and Stephen J. Greene Jacob B. PierceJacob B. Pierce Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Zhen LiZhen Li Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Melissa A. GreinerMelissa A. Greiner https://orcid.org/0000-0002-3614-5602 Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Steven J. LippmannSteven J. Lippmann Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , N. Chantelle HardyN. Chantelle Hardy Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Xian ShenXian Shen Novartis Pharmaceuticals Corporation, East Hanover, NJ (X.S., M.S.). Search for more papers by this author , Mark StampehlMark Stampehl https://orcid.org/0000-0001-5001-9613 Novartis Pharmaceuticals Corporation, East Hanover, NJ (X.S., M.S.). Search for more papers by this author , Robert J. MentzRobert J. Mentz https://orcid.org/0000-0002-3222-1719 Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (R.J.M., E.C.O., S.J.G.). Search for more papers by this author , Larry A. AllenLarry A. Allen https://orcid.org/0000-0003-2540-3095 Palliative and Advanced Illness Research, Center and Department of Medicine, Pennsylvania Perelman School of Medicine, Philadelphia (L.A.A.). Search for more papers by this author , Pamela N. PetersonPamela N. Peterson https://orcid.org/0000-0001-6864-2016 Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora (P.N.P.). Division of Cardiology, Denver Health Hospital, CO (P.N.P.). Search for more papers by this author , Gregg C. FonarowGregg C. Fonarow https://orcid.org/0000-0002-3192-8093 Department of Medicine, University of California Los Angeles (G.C.F.). Search for more papers by this author , Emily C. O’BrienEmily C. O’Brien https://orcid.org/0000-0002-8257-7561 Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (R.J.M., E.C.O., S.J.G.). Search for more papers by this author and Stephen J. GreeneStephen J. Greene Correspondence to: Stephen J. Greene, MD, Duke Clinical Research Institute, 300 West Morgan St, Durham, NC 27701. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6912-7374 Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (R.J.M., E.C.O., S.J.G.). Search for more papers by this author Originally published31 Oct 2022https://doi.org/10.1161/CIRCHEARTFAILURE.122.010176Circulation: Heart Failure. 2023;16Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 31, 2022: Ahead of Print In February 2021, the US Food and Drug Administration (FDA) expanded the indication for the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan beyond heart failure (HF) with reduced ejection fraction (EF) to newly include HF with mildly reduced (HFmrEF) or with preserved ejection fraction (HFpEF) based on results from the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor/Neprilysin Inhibitor [ARNI] With ARB Global Outcomes in HF With Preserved Ejection Fraction).1 The indication noted “benefits are most clearly evident among patients with left ventricular ejection fraction below normal,” phrasing that could be reasonably interpreted as EF ≤60%.2 However, nationwide trends in use of sacubitril/valsartan among patients with HFmrEF and HFpEF and the impact of FDA label expansion on adoption of sacubitril/valsartan remain unknown. In this study, we leveraged the American Heart Association’s Get With The Guidelines-Heart Failure registry to investigate temporal trends and patient characteristics associated with discharge prescription of sacubitril/valsartan among patients hospitalized for HF with EF 41% to 60% before and after FDA label expansion.We identified US patients hospitalized for HF in the Get With The Guidelines-Heart Failure registry with an EF 41% to 60% who were discharged alive between January 2016 and December 2021. EF was recorded quantitatively in the Get With The Guidelines-Heart Failure case report form, and represented the most recent value (ie, during index admission or prior). Patients were excluded if missing data on sacubitril/valsartan prescription at discharge, left against medical advice, transferred to an acute care facility, discharged to hospice, or had a history of heart transplantation, left ventricular assist device, or dialysis.We compared patient characteristics between those who were and were not prescribed sacubitril/valsartan at discharge using χ2 and Wilcoxon rank sum tests, as appropriate. We also calculated the percentage of patients prescribed sacubitril/valsartan for each quarter of the study period and tested for differences in the rate of sacubitril/valsartan prescription before and after FDA label expansion (landmark set as March 1, 2021 after FDA announcement February 2021). Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc). P<0.05 was considered statistically significant. The Duke University Health System Institutional Review Board approved this study.Among 148 762 hospitalizations for patients with EF 41% to 60% across 406 hospitals, 3001 (2.0%) included a prescription for sacubitril/valsartan at discharge. After FDA label expansion, discharge prescription of sacubitril/valsartan among patients with EF 41% to 60% more than doubled compared with earlier years (4.3% versus 1.6%; P<0.001), but absolute rates remained low (Figure [A]). Higher discharge prescription was concentrated at select hospitals, and 20.8% of hospitals had 0 prescriptions (Figure [B]).Download figureDownload PowerPointFigure. Discharge prescription of sacubitril/valsartan, among patients hospitalized for heart failure with ejection fraction 41% to 60% in the Get With The Guidelines-Heart Failure (GWTG-HF) registry (January 2016–December 2021). A, The quarterly rates of sacubitril/valsartan prescription among eligible HF patients. Publication of the PARAGON-HF trial is denoted by the red line (Quarter 4, 2019), and US Food and Drug Administration (FDA) label expansion is denoted by the blue line (Quarter 1, 2021). B, Details of the hospital-level variation in discharge prescription of sacubitril/valsartan among eligible hospital discharges. Data reflect only those hospitals contributing ≥10 eligible discharges, which was 371 (91.4%) of the 406 total hospitals in this analysis. C, Characteristics of eligible patients discharged with vs without prescriptions for sacubitril/valsartan. Data on discharge prescription of SGLT2i were missing for 68.9% and 86.2% of patients discharged with and without sacubitril/valsartan prescriptions, respectively. HFmrEF indicates heart failure with mildly reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; PARAGON-HF, Prospective Comparison of Angiotensin Receptor/Neprilysin Inhibitor (ARNI) With ARB Global Outcomes in HF With Preserved Ejection Fraction; and SGLT2i, sodium-glucose cotransporter-2 inhibitors.Patients prescribed sacubitril/valsartan were more likely to be younger (median 72 versus 76 years; P<0.001) and privately insured, and less likely to be female and of White race (Figure [C]). Median EF was lower among patients prescribed sacubitril/valsartan (48% versus 55%; P<0.001), and the proportion of patients with HFmrEF (EF 41–49%) was higher (53.0% versus 24.3%; P<0.001). Those prescribed sacubitril/valsartan had lower systolic blood pressure (median 123 versus 127 mm Hg; P<0.001), lower serum creatinine (median 1.2 versus 1.3 mg/dL; P<0.001), and higher rates of ischemic HF etiology (31.6% versus 27.2%; P<0.001) and diabetes (53.8% versus 49.4%; P<0.001). Concurrent prescription of mineralocorticoid receptor antagonist (31.8% versus 15.4%; P<0.001), and sodium/glucose cotransporter-2 inhibitor (19.7% versus 6.3%; P<0.001) therapies were also higher among patients prescribed sacubitril/valsartan. Among patients not prescribed sacubitril/valsartan, 40.3% were prescribed an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Patients prescribed sacubitril/valsartan before (n=2030) versus after FDA label expansion (n=971) were similar, with exception of patients prescribed after label expansion being younger (median 72 versus 73 years; P=0.04), less likely to be White (61.5% versus 69.6%; P<0.001), and more likely to have private insurance (88.2% versus 47.6%; P<0.001).Among US patients hospitalized for HF with EF 41% to 60%, patients prescribed sacubitril/valsartan had a distinct clinical profile and were more likely to have HFmrEF than HFpEF. Although the rate of sacubitril/valsartan prescription significantly increased following FDA label expansion, overall adoption of sacubitril/valsartan among patients with EF 41% to 60% remains low and concentrated at select hospitals.Limitations of this study should be noted. Admission medication data were limited, precluding assessment of in-hospital initiation versus in-hospital continuation of sacubitril/valsartan. Likewise, serial EF data were unavailable, and the degree to which these patterns of use include continuation of sacubitril/valsartan among patients with formerly reduced (and now recovered) EF is unknown.When considering EF ≤60% as below normal, a prior analysis estimated that expanded FDA labeling would increase the US population potentially eligible for sacubitril/valsartan by 1.8 million individuals.2 Likewise, compared with valsartan, complete implementation of sacubitril/valsartan among US patients with EF 41% to 60% would be projected to incrementally prevent or postpone >180 000 worsening HF events.2 Despite these potential benefits, our findings demonstrate slow early adoption of sacubitril/valsartan among patients with HFmrEF and HFpEF. Similar delays in implementation of sacubitril/valsartan were previously observed after initial FDA approval for patients with HFrEF.3 Given that patients with HFmrEF and HFpEF continue to face substantial risk of worsening HF and associated morbidity, continued efforts are needed to improve use and access to sacubitril/valsartan in this population.Article InformationSources of FundingThis study was funded by Novartis Pharmaceuticals Corporation (East Hanover, NJ). The Get With The Guidelines-Heart Failure program is provided by the American Heart Association and sponsored, in part, by Novartis, the Boehringer Ingelheim and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer.Disclosures Drs Shen and Stempehl are employees of Novartis Pharmaceuticals Corporation (East Hanover, NJ). Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Medtronic, Merck, Novartis, Roche, Sanofi, and Vifor. Dr Allen has received grant funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Agency for Healthcare Research and Quality, and the American Heart Association; and consultant fees from ACI Clinical, Boston Scientific, Cytokinetics, and Novartis. Dr Peterson reports research support from the National Heart, Lung, and Blood Insititute. Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, the American Heart Association (929502), the National Heart, Lung, and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck & Co Inc, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Corteria Pharmaceuticals, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim and Cytokinetics. All other authors report no disclosures.FootnotesThis work was presented as an abstract at the American Heart Association Scientific Sessions, November 5–7, 2022, Chicago, IL.This article was sent to Prof John J.V. McMurray, MB, ChB, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 107.Correspondence to: Stephen J. Greene, MD, Duke Clinical Research Institute, 300 West Morgan St, Durham, NC 27701. Email stephen.[email protected].eduReferences1. Solomon SD, McMurray JJ, Anand IS, Ge J, Lam CS, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.N Engl J Med. 2019; 381:1609–1620. doi: 10.1056/NEJMoa1908655CrossrefMedlineGoogle Scholar2. Vaduganathan M, Claggett BL, Greene SJ, Aggarwal R, Bhatt AS, McMurray JJV, Fonarow GC, Solomon SD. Potential implications of expanded US Food and Drug Administration labeling for sacubitril/valsartan in the US.JAMA Cardiol. 2021; 6:1415–1423. doi: 10.1001/jamacardio.2021.3651CrossrefMedlineGoogle Scholar3. Luo N, Fonarow GC, Lippmann SJ, Mi X, Heidenreich PA, Yancy CW, Greiner MA, Hammill BG, Hardy NC, Turner SJ, et al. Early adoption of sacubitril/valsartan for patients with heart failure with reduced ejection fraction: insights from Get With the Guidelines–Heart Failure (GWTG-HF).J Am Coll Cardiol HF. 2017; 5:305–309. doi: 10.1016/j.jchf.2016.12.018CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 2023Vol 16, Issue 1 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.122.010176PMID: 36314141 Originally publishedOctober 31, 2022 Keywordsheart failuresacubitril/valsartanejection fractionPDF download Advertisement SubjectsCardiomyopathyQuality and Outcomes