Applicability of US Food and Drug Administration Labeling for Dapagliflozin to Patients With Heart Failure With Reduced Ejection Fraction in US Clinical Practice: The Get With the Guidelines–Heart Failure (GWTG-HF) Registry | Cardiology | JAMA Cardiology | JAMA Network
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Figure 1.  Identifying the Proportion of Treatment Candidates With Heart Failure With Reduced Ejection Fraction (HFrEF) for Initiation of Dapagliflozin Under the US Food and Drug Administration (FDA) Label in the Get With the Guidelines–Heart Failure (GWTG-HF) Registry
Identifying the Proportion of Treatment Candidates With Heart Failure With Reduced Ejection Fraction (HFrEF) for Initiation of Dapagliflozin Under the US Food and Drug Administration (FDA) Label in the Get With the Guidelines–Heart Failure (GWTG-HF) Registry

eGFR indicates estimated glomerular filtration rate; and LVEF, left ventricular ejection fraction.

Figure 2.  Proportion of Patients With Heart Failure With Reduced Ejection Fraction (HFrEF) at Each Get With the Guidelines–Heart Failure (GWTG-HF) Site Meeting US Food and Drug Administration (FDA) Label Criteria for Dapagliflozin
Proportion of Patients With Heart Failure With Reduced Ejection Fraction (HFrEF) at Each Get With the Guidelines–Heart Failure (GWTG-HF) Site Meeting US Food and Drug Administration (FDA) Label Criteria for Dapagliflozin

Ordered histogram displaying the proportion of patients meeting FDA label criteria for dapagliflozin of all eligible patients with HFrEF at each participating site in GWTG-HF. We included only hospitals with at least 10 eligible hospitalizations for HFrEF during the study period (355 sites, 154 522 patients). There was a median of 81.1% treatment candidates per site (interquartile range, 77.8%-84.6%) (range, 56.0%-100%). The x-axis indicates the distribution of sites (ordered from lowest to highest).

Figure 3.  Background Medical Therapies in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) Trial and Get With the Guidelines–Heart Failure (GWTG-HF) Registry
Background Medical Therapies in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) Trial and Get With the Guidelines–Heart Failure (GWTG-HF) Registry

GWTG-HF medical therapies were assessed at the time of discharge. Data were missing in 52 651 of 154 714 patients (34.0%) for ARNI use, 4539 of 154 714 patients (2.9%) for angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use, 4459 of 154 714 patients (2.9%) for β-blocker use, and 5774 of 154 714 patients (3.7%) for mineralocorticoid receptor antagonist (MRA) use. FDA indicates US Food and Drug Administration.

Table.  Clinical Profiles in the DAPA-HF Trial and GWTG-HF Registry
Clinical Profiles in the DAPA-HF Trial and GWTG-HF Registry
1.
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Jackson  SL, Tong  X, King  RJ, Loustalot  F, Hong  Y, Ritchey  MD.  National burden of heart failure events in the United States, 2006 to 2014.   Circ Heart Fail. 2018;11(12):e004873. doi:10.1161/CIRCHEARTFAILURE.117.004873 PubMedGoogle Scholar
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Petrie  MC, Verma  S, Docherty  KF,  et al.  Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes.   JAMA. 2020;323(14):1353-1368. doi:10.1001/jama.2020.1906 PubMedGoogle ScholarCrossref
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Vaduganathan  M, Butler  J.  SGLT-2 inhibitors in heart failure: a new therapeutic avenue.   Nat Med. 2019;25(11):1653-1654. doi:10.1038/s41591-019-0647-4 PubMedGoogle ScholarCrossref
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Zannad  F, Ferreira  JP, Pocock  SJ,  et al.  SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.   Lancet. 2020;396(10254):819-829. doi:10.1016/S0140-6736(20)31824-9 PubMedGoogle ScholarCrossref
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Boehringer Ingelheim. U.S. FDA grants fast track designation to empagliflozin for the treatment of chronic heart failure. Published June 26, 2019. Accessed October 2, 2020. https://www.boehringer-ingelheim.us/press-release/us-fda-grants-fast-track-designation-empagliflozin-treatment-chronic-heart-failure
11.
O’Meara  E, McDonald  M, Chan  M,  et al.  CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis.   Can J Cardiol. 2020;36(2):159-169. doi:10.1016/j.cjca.2019.11.036 PubMedGoogle ScholarCrossref
12.
Vaduganathan  M, Claggett  BL, Jhund  PS,  et al.  Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.   Lancet. 2020;396(10244):121-128. doi:10.1016/S0140-6736(20)30748-0 PubMedGoogle ScholarCrossref
13.
Greene  SJ, Fonarow  GC, DeVore  AD,  et al.  Titration of medical therapy for heart failure with reduced ejection fraction.   J Am Coll Cardiol. 2019;73(19):2365-2383. doi:10.1016/j.jacc.2019.02.015 PubMedGoogle ScholarCrossref
14.
Greene  SJ, Butler  J, Albert  NM,  et al.  Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry.   J Am Coll Cardiol. 2018;72(4):351-366. doi:10.1016/j.jacc.2018.04.070 PubMedGoogle ScholarCrossref
15.
Hong  Y, LaBresh  KA.  Overview of the American Heart Association “Get With the Guidelines” programs: coronary heart disease, stroke, and heart failure.   Crit Pathw Cardiol. 2006;5(4):179-186. doi:10.1097/01.hpc.0000243588.00012.79 PubMedGoogle ScholarCrossref
16.
Docherty  KF, Jhund  PS, Inzucchi  SE,  et al.  Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.   Eur Heart J. 2020;41(25):2379-2392. doi:10.1093/eurheartj/ehaa183 PubMedGoogle ScholarCrossref
17.
Bassi  NS, Ziaeian  B, Yancy  CW, Fonarow  GC.  Association of optimal implementation of sodium-glucose cotransporter 2 inhibitor therapy with outcome for patients with heart failure.   JAMA Cardiol. 2020;5(8):1-5. doi:10.1001/jamacardio.2020.0898 PubMedGoogle ScholarCrossref
18.
Heerspink  HJL, Stefánsson  BV, Correa-Rotter  R,  et al; DAPA-CKD Trial Committees and Investigators.  Dapagliflozin in patients with chronic kidney disease.   N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816 PubMedGoogle ScholarCrossref
19.
Bhagat  AA, Greene  SJ, Vaduganathan  M, Fonarow  GC, Butler  J.  Initiation, continuation, switching, and withdrawal of heart failure medical therapies during hospitalization.   JACC Heart Fail. 2019;7(1):1-12. doi:10.1016/j.jchf.2018.06.011 PubMedGoogle ScholarCrossref
20.
Sabatine  MS, DeMets  DL, Inzucchi  SE,  et al. Timing of onset of clinical benefit with dapagliflozin in patients with heart failure: an analysis from the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF). Presented at the American Heart Association Scientific Sessions; November 17, 2019; Philadelphia, Pennsylvania.
21.
Damman  K, Beusekamp  JC, Boorsma  EM,  et al.  Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF).   Eur J Heart Fail. 2020;22(4):713-722. doi:10.1002/ejhf.1713 PubMedGoogle ScholarCrossref
22.
Tromp  J, Bamadhaj  S, Cleland  JGF,  et al.  Post-discharge prognosis of patients admitted to hospital for heart failure by world region, and national level of income and income disparity (REPORT-HF): a cohort study.   Lancet Glob Health. 2020;8(3):e411-e422. doi:10.1016/S2214-109X(20)30004-8 PubMedGoogle ScholarCrossref
23.
Yancy  CW, Jessup  M, Bozkurt  B,  et al.  2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an 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.   J Am Coll Cardiol. 2016;68(13):1476-1488. doi:10.1016/j.jacc.2016.05.011 PubMedGoogle ScholarCrossref
24.
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.   J Am Coll Cardiol. 2017;70(6):776-803. doi:10.1016/j.jacc.2017.04.025 PubMedGoogle ScholarCrossref
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Heart Failure Society of America. ACC seeks comments on updated expert consensus decision pathway for HF treatment optimization. Accessed October 22, 2020. https://hfsa.org/acc-seeks-comments-updated-expert-consensus-decision-pathway-hf-treatment-optimization
26.
Tahhan  AS, Vaduganathan  M, Greene  SJ,  et al.  Enrollment of older patients, women, and racial and ethnic minorities in contemporary heart failure clinical trials: a systematic review.   JAMA Cardiol. 2018;3(10):1011-1019. doi:10.1001/jamacardio.2018.2559 PubMedGoogle ScholarCrossref
27.
Greene  SJ, DeVore  AD, Sheng  S,  et al.  Representativeness of a heart failure trial by race and sex: results from ASCEND-HF and GWTG-HF.   JACC Heart Fail. 2019;7(11):980-992. doi:10.1016/j.jchf.2019.07.011 PubMedGoogle ScholarCrossref
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Das  D, Savarese  G, Dahlström  U,  et al.  Ivabradine in heart failure: the representativeness of SHIFT (Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial) in a broad population of patients with chronic heart failure.   Circ Heart Fail. 2017;10(9):e004112. doi:10.1161/CIRCHEARTFAILURE.117.004112 PubMedGoogle Scholar
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Parikh  KS, Lippmann  SJ, Greiner  M,  et al.  Scope of sacubitril/valsartan eligibility after heart failure hospitalization: findings from the GWTG-HF registry (Get With The Guidelines-Heart Failure).   Circulation. 2017;135(21):2077-2080. doi:10.1161/CIRCULATIONAHA.117.027773 PubMedGoogle ScholarCrossref
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Oh  J, Lee  CJ, Park  JJ,  et al  Real-world eligibility for sacubitril/valsartan in heart failure with reduced ejection fraction patients in Korea: data from the Korean Acute Heart Failure (KorAHF) registry.   Int J Heart Fail. 2019;1(1):57-68. doi:10.36628/ijhf.2019.0007 Google ScholarCrossref
31.
Perez  AL, Kittipibul  V, Tang  WHW, Starling  RC.  Patients not meeting PARADIGM-HF enrollment criteria are eligible for sacubitril/valsartan on the basis of FDA approval: the need to close the gap.   JACC Heart Fail. 2017;5(6):460-463. doi:10.1016/j.jchf.2017.03.007 PubMedGoogle ScholarCrossref
32.
Inzucchi  SE, Fitchett  D, Jurišić-Eržen  D,  et al; EMPA-REG OUTCOME Investigators.  Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy?   Diabetes Obes Metab. 2020;22(4):631-639. doi:10.1111/dom.13938 PubMedGoogle ScholarCrossref
33.
Fudim  M, Sayeed  S, Xu  H,  et al.  Representativeness of the PIONEER-HF clinical trial population in patients hospitalized with heart failure and reduced ejection fraction.   Circ Heart Fail. 2020;13(4):e006645. doi:10.1161/CIRCHEARTFAILURE.119.006645 PubMedGoogle Scholar
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35.
Vaduganathan  M, Fonarow  GC, Greene  SJ,  et al.  Contemporary treatment patterns and clinical outcomes of comorbid diabetes mellitus and HFrEF: the CHAMP-HF registry.   JACC Heart Fail. 2020;8(6):469-480. doi:10.1016/j.jchf.2019.12.015 PubMedGoogle ScholarCrossref
Original Investigation
November 13, 2020

Applicability of US Food and Drug Administration Labeling for Dapagliflozin to Patients With Heart Failure With Reduced Ejection Fraction in US Clinical Practice: The Get With the Guidelines–Heart Failure (GWTG-HF) Registry

Author Affiliations
  • 1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Duke Clinical Research Institute and Division of Cardiology, Duke University School of Medicine, Durham, North Carolina
  • 3Department of Medicine, University of Mississippi Medical Center, Jackson
  • 4Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California
  • 5AstraZeneca, Wilmington, Delaware
  • 6Department of Cardiology, Smidt Heart Institute, Cedars-Sinai, Los Angeles, California
  • 7Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St Louis, Missouri
  • 8Heart and Vascular Center, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia
  • 9Department of Medicine, Denver Health Medical Center, Denver, Colorado
  • 10Center for Care Delivery and Outcomes Research, Minneapolis Veterans Affairs Health Care System and University of Minnesota, Minneapolis
  • 11Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 12Deputy Editor, JAMA Cardiology
  • 13Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, Los Angeles
  • 14Associate Editor for Health Care Quality and Guidelines, JAMA Cardiology
JAMA Cardiol. 2021;6(3):267-275. doi:10.1001/jamacardio.2020.5864
Key Points

Question  What proportion of the contemporary patients with heart failure with reduced ejection fraction (HFrEF) in the US would be potentially eligible for initiation of dapagliflozin based on the US Food and Drug Administration label?

Findings  This cohort study found that, among 154 714 patients hospitalized with HFrEF in the Get With The Guidelines–Heart Failure registry, 125 497 (81%) would be candidates for dapagliflozin, a proportion that was higher among those without type 2 diabetes than those with type 2 diabetes (86% vs 76%). Across 355 sites with patients with 10 or more hospitalizations, the median proportion of patients who were candidates for dapagliflozin was 81%.

Meaning  This study suggests that 4 of 5 patients with HFrEF (with or without type 2 diabetes) would be candidates for initiation of dapagliflozin, supporting its broad generalizability to US clinical practice.

Abstract

Importance  In May 2020, dapagliflozin was approved by the US Food and Drug Administration (FDA) as the first sodium-glucose cotransporter 2 inhibitor for heart failure with reduced ejection fraction (HFrEF), based on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. Limited data are available characterizing the generalizability of dapagliflozin to US clinical practice.

Objective  To evaluate candidacy for initiation of dapagliflozin based on the FDA label among contemporary patients with HFrEF in the US.

Design, Setting, and Participants  This cohort study included 154 714 patients with HFrEF (left ventricular ejection fraction ≤40%) hospitalized at 406 sites in the Get With the Guidelines–Heart Failure (GWTG-HF) registry admitted between January 1, 2014, and September 30, 2019. Patients who left against medical advice, transferred to an acute care facility or to hospice, or had missing data were excluded. The FDA label (which excluded patients with an estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2, those undergoing dialysis, and those with type 1 diabetes) was applied to the GWTG-HF registry sample. Data analyses were conducted from April 1 to June 30, 2020.

Main Outcomes and Measures  The proportion of patients hospitalized with HFrEF who would be candidates for dapagliflozin under the FDA label.

Results  Among 154 714 patients hospitalized with HFrEF, 125 497 (81.1%; 83 481 men [66.5%]; mean [SD] age, 68 [15] years) would be candidates for dapagliflozin according to the FDA label. Across 355 sites with patients with 10 or more hospitalizations, the median proportion of candidates for dapagliflozin according to the FDA label was 81.1% (interquartile range, 77.8%-84.6%) at each site. This proportion was similar across all study years (interquartile range, 80.4%-81.7%) and was higher among those without type 2 diabetes than with type 2 diabetes (85.5% vs 75.6%). Among GWTG-HF participants, the most frequent reason for not meeting the FDA label criteria was eGFR less than 30 mL/min/1.73 m2 at discharge (18.5%). Among 75 654 patients with available paired admission and discharge data, 14.2% had an eGFR less than 30 mL/min/1.73 m2 at both time points, while 3.8% developed an eGFR less than 30 mL/min/1.73 m2 by discharge. Although there were more older adults, women, and Black patients in the GWTG-HF registry than in the DAPA-HF trial, most clinical characteristics were qualitatively similar between the 2 groups. Compared with the DAPA-HF trial cohort, there was lower use of evidence-based HF therapies among patients in GWTG-HF.

Conclusions and Relevance  These data from a large, contemporary US registry of patients hospitalized with heart failure suggest that 4 of 5 patients with HFrEF (with or without type 2 diabetes) would be candidates for initiation of dapagliflozin, supporting its broad generalizability to US clinical practice.

Introduction

Despite accelerating progress in identifying new therapeutic options for heart failure with reduced ejection fraction (HFrEF), affected patients continue to face high residual risks of premature mortality, frequent hospitalizations, poor health status, and high health care costs.1-3 The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial demonstrated that dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, reduced mortality and worsening heart failure (HF) events and improved health-related quality of life in patients with HFrEF.4 Empagliflozin, another SGLT-2 inhibitor, was recently shown to reduce risk of cardiovascular death or hospitalization for HF in the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial.5 Although these therapies were initially developed for the management of type 2 diabetes, they now represent a new therapeutic avenue for the treatment of HFrEF, irrespective of diabetes status.6-8 In May 2020, the US Food and Drug Administration (FDA) approved dapagliflozin as the first SGLT-2 inhibitor for use in HFrEF to reduce the risk of cardiovascular death and hospitalization for HF.9 Empagliflozin is currently undergoing regulatory review by the US FDA under fast track designation.10 Dapagliflozin is now supported for use in HFrEF in the Canadian Cardiovascular Society HF practice guidelines.11

Optimal implementation of SGLT-2 inhibitors alongside other effective disease-modifying therapies could meaningfully extend patient survival.12 However, prior data have revealed large gaps in translating clinical trial findings to practice, such that evidence-based therapies are slowly and infrequently adopted.13,14 Limited data are available examining whether the findings of the DAPA-HF trial and the new treatment indication of dapagliflozin are applicable in routine HFrEF care in the US. Therefore, in a large, contemporary hospital-based registry, we aimed to estimate the proportion of patients who may be candidates for initiation of dapagliflozin, evaluate their in-hospital course and background therapies, and describe potential barriers to therapeutic optimization. As DAPA-HF evaluated a population of patients with chronic HFrEF, we focused on treatment eligibility based on discharge parameters during the transition to ambulatory care.

Methods
Get With the Guidelines–Heart Failure Registry

The design and objectives of the American Heart Association Get With the Guidelines–Heart Failure (GWTG-HF) registry have been previously described.15 In brief, GWTG-HF is a hospital-based quality improvement registry that prospectively collects data from patients hospitalized for HF or who develop HF during hospitalization at participating centers across the US. Data are abstracted by trained personnel on standardized case report forms that encompass demographics, comorbid conditions, vital signs and laboratory data, in-hospital treatments, left ventricular ejection fraction (LVEF), hospital characteristics, in-hospital outcomes (length of stay and death), and patient disposition. In compliance with the Joint Commission and Centers for Medicare & Medicaid Services standards, data are then collated using the American Heart Association’s web-based Patient Management Tool (IQVIA Inc). Duke Clinical Research Institute aggregates all deidentified data on an ongoing basis and independently monitors data for quality assurance. Given that the primary purpose of the registry is for quality improvement, a waiver for patient informed consent is granted under the Common Rule. The institutional review boards at each participating site have approved the GWTG-HF protocol. Analyses of deidentified data from GWTG-HF for research purposes were approved by the Duke Clinical Research Institute Institutional Review Board.

Study Population

We identified adults aged 18 years or older admitted between January 1, 2014, and September 30, 2019, from 529 sites participating in the GWTG-HF registry. Patients whose most recent LVEF was 40% or less were included. We excluded patients with missing LVEF or LVEF greater than 40%, who left against medical advice, who transferred to an acute care facility or to hospice, or had missing critical data (those without any measure of estimated glomerular filtration rate [eGFR] or vital signs during hospitalization) (Figure 1).

Study Cohorts

The FDA label was applied to identify potential candidates for treatment among the GWTG-HF study population, by excluding those with an eGFR less than 30 mL/min/1.73 m2 at discharge (or based on the closest value to discharge if the discharge value was missing), those undergoing dialysis (either a history of chronic dialysis or if required during hospitalization), or those with type 1 diabetes. Although dapagliflozin is contraindicated when used for glycemic control among patients without established cardiovascular disease or cardiovascular risk factors when the starting eGFR is less than 30 mL/min/1.73 m2, its use is not specifically contraindicated among patients with an eGFR in this range when it is used for the treatment of HFrEF. However, insufficient data are available to support dosing recommendations as DAPA-HF excluded this cohort.4 For comparative purposes, we additionally identified patients who would have been eligible for DAPA-HF by applying the strict trial inclusion and exclusion criteria such as systolic blood pressure less than 95 mm Hg, in-hospital or planned cardiovascular implantable electronic device implantation, or limited estimated life expectancy (eTable 1 in the Supplement). As all participants were hospitalized for HF, New York Heart Association functional class II to IV symptoms were assumed as specified in FDA labeling and DAPA-HF eligibility criteria.

Statistical Analysis

Statistical analysis was conducted from April 1 to June 30, 2020. We first assessed candidacy for initiation of dapagliflozin under the FDA label overall and stratified by admission year. In addition, we separately evaluated candidacy among patients with and without a reported history of or new diagnosis of diabetes.

To evaluate if treatment candidacy was broadly generalizable or concentrated in specific hospital centers, we examined the proportion of the treatment candidates under the FDA label at each participating site. We included only hospitals with at least 10 eligible patients hospitalized for HFrEF during the study period, and visualized variation with an ordered histogram. To assess potential barriers to initiation, we further explored variation in eGFR and systolic blood pressure at both admission and discharge, if data were available. We assessed the proportion of all patients with HFrEF in GWTG-HF with eGFR less than 30 mL/min/1.73 m2 at admission and/or discharge, as well as the proportion of patients with systolic blood pressure less than 95 mm Hg at admission and/or discharge (a hemodynamic exclusion criterion in the DAPA-HF trial).4

We then compared the clinical profiles and HF medical therapies among candidates meeting the FDA label criteria and those meeting more stringent criteria for DAPA-HF eligibility. We juxtaposed published data detailing patient characteristics and medication use from the DAPA-HF trial for reference.4,16 Temporal trends in hospital length of stay and in-hospital mortality by admission year were assessed. All analyses were performed in SAS version 9.4 (SAS Institute Inc). Two-tailed statistical testing was performed, with P < .05 considered statistically significant.

Results
Patient Selection

Between January 1, 2014, and September 30, 2019, 586 580 patients were hospitalized for HF across 529 sites in GWTG-HF, of whom 238 936 were adults aged 18 years or older with HFrEF (LVEF≤40%) who did not leave against medical advice and who were not discharged to another acute care facility. Of this cohort, 84 222 patients had missing discharge data on eGFR or vital signs; these excluded patients had characteristics comparable with those who had available data (eTable 2 in the Supplement). The remaining 154 714 patients hospitalized with HFrEF at 406 sites made up the primary study cohort (Figure 1).

Candidates for Dapagliflozin Initiation Under the FDA Label

Among patients with HFrEF in GWTG-HF with available data, 125 497 (81.1%) would be candidates for initiation of dapagliflozin under the FDA label (Figure 1). This proportion was similar across all study years (range, 80.4%-81.7%). In the subset of 68 249 patients with a history of or new diagnosis of diabetes, 51 610 patients (75.6%) would be candidates for dapagliflozin. Among 86 465 patients without diabetes, 73 887 (85.5%) would be candidates for dapagliflozin treatment. Across 355 sites with patients with 10 or more hospitalizations (enrolling 154 522 patients), the median proportion of candidates for dapagliflozin according to the FDA label was 81.1% (interquartile range, 77.8%-84.6%) (Figure 2). The 51 with fewer than 10 hospitalizations in which we could not evaluate site-based variation were smaller, less likely to be teaching hospitals, and more likely to be located in rural settings compared with the 355 sites included in this analysis (eTable 3 in the Supplement).

Key Reasons for Not Meeting the FDA Label Criteria

Among GWTG-HF participants with HFrEF, the most frequent reason for not meeting the FDA label criteria was eGFR less than 30 mL/min/1.73 m2 as calculated by the Modification in Diet in Renal Disease equation at discharge (n = 28 608 [18.5%]). This exclusion criterion was met more frequently in patients with a history of or new diagnosis of diabetes (n = 16 278 of 68 249 [23.9%]) than in patients without diabetes (n = 12 327 of 86 465 [14.3%]). Overall, other reasons for ineligibility were less frequent: chronic dialysis (n = 4969 [3.2%]), in-hospital dialysis (n = 3319 [2.1%]), and type 1 diabetes (n = 32 [0.02%]).

eGFR and Systolic Blood Pressure Patterns

Among 75 654 patients with available paired admission and discharge eGFR data (48.9% of the study cohort), 4.3% had eGFR less than 30 mL/min/1.73 m2 at admission alone and 3.8% at discharge alone, and 14.2% had low eGFR at both time points. Among 147 134 patients with paired blood pressure data (95.1% of the study cohort), systolic blood pressure was less than 95 mm Hg at admission in 2.8% of patients, at discharge in 6.3% of patients, and at both admission and discharge in 1.1% of patients.

Clinical Profiles and Therapies of Participants in the DAPA-HF Trial and GWTG-HF Registry
DAPA-HF Trial Participants vs FDA Label Candidates in GWTG-HF

Participants in the GWTG-HF registry who would be FDA label candidates for dapagliflozin were older (mean [SD] age, 68 [15] years vs 66 [11] years), more likely to be women (42 016 of 125 497 [33.5%] vs 1109 of 4744 [23.4%]), and more likely to be Black (33 356 of 125 497 [26.6%] vs 226 of 4744 [4.8%]) compared with DAPA-HF trial participants (Table). In addition, mean (SD) LVEF was lower in participants in the GWTG-HF registry compared with those in the DAPA-HF trial (26% [9%] vs 31% [7%]). History of myocardial infarction and percutaneous coronary intervention were more common in DAPA-HF participants than GWTG-HF participants (myocardial infarction, 2092 of 4744 [44.1%] vs 31 059 of 125 497 [24.7%]; and percutaneous coronary intervention, 1624 of 4744 [34.2%] vs 26 033 of 125 497 [20.7%]), while chronic obstructive pulmonary disease and stroke were higher in GWTG-HF participants than DAPA-HF participants (chronic obstructive pulmonary disease, 39 888 of 125 497 [31.8%] vs 585 of 4744 [12.3%]; and stroke, 18 729 of 125 497 [14.9%] vs 466 of 4744 [9.8%]). Other clinical comorbidities and vital signs were qualitatively similar between DAPA-HF and GWTG-HF participants. In all GWTG-HF registry participants with HFrEF, preadmission history of diabetes was 43.7%; diabetes was newly diagnosed during hospitalization in 578 participants, raising the overall prevalence of diabetes to 44.1% (compared with 45.1% observed in the DAPA-HF trial population). Compared with the DAPA-HF trial cohort, there was lower use of evidence-based HF medical therapies but higher use of implantable cardioverter defibrillators among GWTG-HF patients (Figure 3).

FDA Label Candidates vs DAPA-HF–Eligible Participants in GWTG-HF

After additionally applying inclusion and exclusion criteria (eTable 4 in the Supplement), 68 383 of all HFrEF participants in GWTG-HF (44.2%) would have been eligible for the DAPA-HF trial. Among GWTG-HF registry participants, demographic and clinical characteristics and background medications were qualitatively similar when comparing treatment candidates based on the FDA label criteria and those meeting more stringent eligibility criteria for DAPA-HF (Table).

Detailed characteristics of GWTG-HF registry participants are provided in eTable 5 in the Supplement. Among candidates for the initiation of dapagliflozin, 6.8% were uninsured, while 46.0% were Medicare beneficiaries and 19.7% were Medicaid beneficiaries. Median household income of the hospital area of treatment candidates was $56 580 (interquartile range, $50 450-$63 700). Median number of cardiometabolic medications at discharge among treatment candidates was 5 (interquartile range, 3-6). Insurance coverage, local household income, and number of cardiometabolic therapies were qualitatively similar between FDA label candidates and DAPA-HF–eligible participants.

Median length of stay was 4 days (interquartile range, 3-6 days) across all years in the study period, and was similar in FDA label candidate and DAPA-HF trial–eligible cohorts. Across the study period, observed in-hospital mortality was 1.8% among treatment candidates by the FDA label criteria and 2.5% among DAPA-HF–eligible participants. These in-hospital death rates did not substantially vary across calendar years (eFigure in the Supplement).

Discussion

Leveraging data from more than 150 000 patients hospitalized for HFrEF at more than 400 hospital centers across the US from 2014 to 2019, this study has several important findings: (1) 81.1% of patients were candidates for the initiation of dapagliflozin based on the FDA label criteria, a proportion that was higher among those without type 2 diabetes (85.5%) than with type 2 diabetes (75.6%); (2) eGFR less than 30 mL/min/1.73 m2 was the most common reason for not being a candidate for dapagliflozin treatment, and candidacy is anticipated to dynamically fluctuate during hospitalization for HF; and (3) treatment candidates based on the FDA label criteria and patients who would have met more stringent eligibility criteria for the DAPA-HF trial shared demographic and clinical characteristics. These data support the broad generalizability of dapagliflozin in the treatment of HFrEF in current US clinical practice.

A recent decision analytical model based on published figures from the American Heart Association Heart Disease and Stroke Statistics 2019 Update estimated that 69% of patients with HFrEF may be eligible for SGLT-2 inhibitor therapy, and its optimal implementation across the US was projected to prevent or postpone 34 125 deaths per year.17 Our study, which was based on detailed clinical and laboratory information, suggests a potentially larger eligible population for SGLT-2 inhibitor treatment. We further examined hospital variation in candidacy and found that nearly all hospitals sites cared for a proportion of patients who meet criteria under the FDA label as potential candidates for dapagliflozin treatment. The finding of potentially greater eligibility among patients with HF without diabetes reinforces the need for clear communication to treating clinicians that the benefits associated with dapagliflozin extend beyond diabetes.6 Taken together, effective and appropriate implementation of SGLT-2 inhibitors is poised to affect a large at-risk population across a broad range of US health systems.

The substantial estimated proportion of potential treatment candidates is striking given the high-risk setting of evaluation. As anticipated, patients’ kidney function and hemodynamics dynamically changed during hospitalization for HF, such that some patients may become ineligible for treatment with dapagliflozin by the time of discharge in GWTG-HF. Conversely, some patients who developed kidney injury during hospitalization may be expected to have recovery of kidney function in follow-up, and may become eligible for SGLT-2 inhibitor treatment in the ambulatory setting, reinforcing the need for serial assessment for treatment candidacy. Recent compelling data from the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial,18 which evaluated patients with albuminuric chronic kidney disease with eGFR as low as 25 mL/min/1.73 m2, and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction),5 which evaluated patients with HFrEF with eGFR as low as 20 mL/min/1.73 m2, will further extend SGLT-2 inhibitor treatment indications to patients with more severe chronic kidney disease. Although greater eligibility for treatment may have been observed in an outpatient registry cohort, even accounting for these in-hospital changes, a large proportion of patients remain eligible for treatment optimization with dapagliflozin at hospital discharge. In-hospital implementation of evidence-based medical therapies represents a potential strategy to disrupt typical therapeutic inertia encountered in ambulatory care.19 DAPA-HF and EMPEROR-Reduced demonstrated the safety and efficacy of SGLT-2 inhibitors in patients with stable chronic HFrEF. Although recent secondary analyses of hospitalized patients in DAPA-HF20 and an initial pilot study21 appear favorable, this therapeutic strategy of the use of SGLT-2 inhibitors among hospitalized patients with HF is actively being evaluated in dedicated clinical trials (NCT04363697, NCT04298229, and NCT04157751).

In contrast with the use of background HFrEF therapies in the DAPA-HF trial population, these data from GWTG-HF highlight major gaps in even well-established components of guideline-directed medical therapy by the time of hospital discharge in clinical practice. For instance, in GWTG-HF, only one-third of participants were treated with mineralocorticoid receptor antagonists. Several reasons may underlie these therapeutic differences in this contemporary trial and registry. First, some of these treatment gaps (such as the discrepancy in mineralocorticoid receptor antagonist use) may reflect DAPA-HF being an international trial with much lower mineralocorticoid receptor antagonist use in North America than in other regions of the world.22 Higher relative use of implantable cardioverter-defibrillators in the US compared with other global settings may similarly explain higher use in GWTG-HF. Second, higher rates of electrolyte abnormalities and kidney dysfunction may preclude optimization prior to hospital discharge, which may have affected the use of renin-angiotensin-aldosterone system inhibitors. Finally, lower use of sacubitril-valsartan may in part be associated with its more recent integration in focused US clinical practice guidelines in 2016 and 2017.23,24 Regardless, these data reinforce the need to reduce or remove barriers to therapeutic optimization and expand access and affordability of multiple components of guideline-directed medical therapies. Despite underuse of effective therapies, on average, patients with HFrEF in GWTG-HF are discharged on 5 cardiometabolic therapies. Active deprescription of non–evidence-based therapies in HF has the potential to lessen polypharmacy and improve adherence.

These GWTG-HF data suggest that potential implementation of SGLT-2 inhibitors would be anticipated to be on a background of varying, less-complete medical regimens in clinical practice. The therapeutic benefits associated with SGLT-2 inhibitors have been shown to be consistent irrespective of background therapy.8,16 These data are in keeping with distinct posited mechanisms of action of multidrug regimens, supporting their complementary and additive roles in contemporary HFrEF care. Structured pathways such as the updated American College of Cardiology Expert Consensus Decision Pathway for HF25 are anticipated to guide early introduction of combination medical therapies in patients with HFrEF.

The underrepresentation of older adults, women, racial/ethnic minority groups, and patients with multiple comorbidities in clinical trials relative to reference usual-care populations has been well recognized across medical disciplines26,27: patients in DAPA-HF were younger, less often women, and less often Black compared with participants in GWTG-HF. Although the racial/ethnic distribution in DAPA-HF may partially reflect the global nature of the trial population compared with the US-based GWTG-HF cohort, further research is needed regarding the effectiveness of dapagliflozin in diverse populations in the US. Initial uptake patterns and associations with subsequent outcomes in registries such as GWTG-HF should be carefully evaluated for those not well represented in clinical trials.

We estimate that 44.1% of patients in GWTG-HF would have met the strict eligibility criteria of the DAPA-HF trial. This trial eligibility for dapagliflozin was higher than prior estimates of eligibility for trials evaluating ivabradine (14%)28 and sacubitril/valsartan (12%-38%),29-33 suggesting broader representativeness of DAPA-HF. It is additionally reassuring that despite multiple inclusion and exclusion criteria in the DAPA-HF trial, baseline demographics and clinical characteristics of patients in GWTG-HF were well balanced between the patients eligible for dapagliflozin based on the FDA label criteria and the DAPA-HF trial. Although these data from GWTG-HF support the broader and more practical eligibility criteria put forth by the FDA, dapagliflozin may not be appropriate in all covered clinical scenarios, such as established nonadherence or mechanical circulatory support requirement.

Limitations

This study is subject to certain limitations. The GWTG-HF registry is voluntary; the patients and hospitals that participate in the program may differ from those that do not. However, a prior study found that patients who participated in the GWTG-HF registry were nationally representative.34 Although both dapagliflozin and empagliflozin have been demonstrated to be safe and effective in patients with HFrEF, we evaluated treatment candidacy for dapagliflozin alone as it is currently the only SGLT-2 inhibitor with a specific FDA label for use in HFrEF. Although eligibility for dapagliflozin was assessed at hospital discharge in GWTG-HF, we recognize that the putative benefits in this higher-risk cohort (than studied in the DAPA-HF trial) cannot be directly inferred and is the subject of ongoing study. We were unable to assess eligibility in a proportion of patients (<15%) with missing eGFR or vital signs; however, the characteristics of these patients did not systematically vary from those with available data. Owing to the deidentified nature of the GWTG-HF registry, these data reflect unique hospitalization episodes rather than unique patients; some patients may be represented more than once during the 2014-2019 study period. However, because each hospitalization represents an opportunity to optimize therapeutic care, we believe that determining treatment candidacy across hospitalization episodes is still informative. Data regarding newer antihyperglycemic therapies were collected only during more recent study years and thus were subject to high missingness. As such, we were unable to examine current use patterns of SGLT-2 inhibitors or prior intolerance or serious hypersensitivity reaction to dapagliflozin or this class of therapies. However, previous examinations of large, US-based registries have estimated that recent use of SGLT-2 inhibitors among patients with HFrEF and diabetes is 2% or less.35 Glycated hemoglobin levels were not captured in a protocolized manner; this limited availability and few number of patients with newly detected diabetes during hospitalization reflect infrequent assessment of glycemic measures in routine HF care and potential missed opportunities at screening. Although data were available regarding the use of evidence-based HF therapies, dosing was not rigorously captured in GWTG-HF. Similarly, data regarding postdischarge laboratory data or use of therapies were not available. Despite these limitations, this study uniquely assessed eligibility, representativeness, and barriers to implementation of the newest addition to the HFrEF armamentarium, dapagliflozin, in a well-characterized HF registry in the US.

Conclusions

These data from a large, contemporary US registry of patients hospitalized with HF suggest that 4 of 5 patients with HFrEF (with or without type 2 diabetes) would be candidates for initiation of dapagliflozin, supporting its broad generalizability to US clinical practice.

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Article Information

Accepted for Publication: October 7, 2020.

Published Online: November 13, 2020. doi:10.1001/jamacardio.2020.5864

Corresponding Author: Gregg C. Fonarow, MD, Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan UCLA Medical Center, University of California, Los Angeles, 10833 LeConte Ave, Room 47-123 CHS, Los Angeles, CA 90095 (gfonarow@mednet.ucla.edu).

Author Contributions: Drs Vaduganathan and Fonarow had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Vaduganathan, Butler, Huang, Kittleson, McDermott, Peterson, Solomon, Vardeny, Yancy, Fonarow.

Acquisition, analysis, or interpretation of data: Vaduganathan, Greene, Zhang, Grau-Sepulveda, DeVore, Butler, Heidenreich, Joynt Maddox, Owens, Fonarow.

Drafting of the manuscript: Vaduganathan, Butler, Heidenreich, Huang, McDermott.

Critical revision of the manuscript for important intellectual content: Vaduganathan, Greene, Zhang, Grau-Sepulveda, DeVore, Butler, Huang, Kittleson, Joynt Maddox, Owens, Peterson, Solomon, Vardeny, Yancy, Fonarow.

Statistical analysis: Zhang, Grau-Sepulveda.

Obtained funding: Huang, McDermott, Fonarow.

Administrative, technical, or material support: Greene, Fonarow.

Supervision: Greene, Butler, Huang, Owens, Solomon, Yancy, Fonarow.

Conflict of Interest Disclosures: Dr Vaduganathan reported being supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health (NIH)/National Center for Advancing Translational Sciences Award UL 1TR002541); receiving research grant support from Amgen; serving on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa; and participating on clinical end point committees for studies sponsored by Galmed, Novartis, and the NIH. Dr Greene reported receiving a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; receiving research support from Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis; serving on advisory boards for Amgen and Cytokinetics; and serving as a consultant for Amgen and Merck. Dr DeVore reported received research funding through the Duke Clinical Research Institute from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent Inc, the National Heart, Lung, and Blood Institute (NHLBI), Novartis, and Patient-Centered Outcomes Research Institute (PCORI); serving as a consultant for AstraZeneca; receiving nonfinancial support from Amgen, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, Story Health, and Zoll; and receiving nonfinancial support from Abbott for educational activities outside the submitted work. Dr Butler reported receiving research support from the NIH, PCORI, and the European Union; and serving as a consultant for Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Innolife, Janssen, LivaNova, American Regent, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, StealthPeptide, SC Pharma, V-Wave Ltd, Vifor, and ZS Pharma. Dr Joynt Maddox reported receivng grants from NIH/NHLBI, NIH/National Institute on Aging, and Commonwealth Fund; and other from US Department of Health and Human Services for prior contract work outside the submitted work. Dr Owens reported serving as a consultant for MyoKardia and Cytokinetics outside the submitted work. Dr Peterson reported receiving grant funding from the National Heart, Lung, and Blood Institute (grant R33HL143324-02) and personal fees from American Heart Association outside the submitted work. Dr Solomon reported receiving research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Respicardia, Sanofi Pasteur, and Theracos; and serving as a consultant for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, and Moderna. Dr Vardeny reported being the US National Lead Investigator for trials of an SGLT-2 inhibitor in heart failure, sponsored by AstraZeneca, receiving funding from the NIH and the US Food and Drug Administration, and receiving personal fees from the American Heart Association. Dr Yancy reported that his spouse is employed by Abbott Labs Inc. Dr Fonarow reported receiving research funding from the NIH and serving as a consultant for Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Medtronic, Merck, and Novartis. No other disclosures were reported.

Funding/Support: The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association and sponsored, in part, by Novartis, Boehringer Ingelheim and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. This analysis, as a part of the TRANSLATE-HF research series, was supported by AstraZeneca.

Role of the Funder/Sponsor: TRANSLATE-HF is an industry-academic collaboration overseen by an independent voluntary steering group and supported by AstraZeneca. All statistical analyses were conducted independently at Duke Clinical Research Institute. The manuscript was drafted by the first author and revised based on input from all coauthors.

Disclaimer: Dr Yancy is a Deputy Editor and Dr Fonarow is the Associate Editor for Health Care Quality and Guidelines of JAMA Cardiology, but they were not involved in any of the decisions regarding review of the manuscript or its acceptance.

Meeting Presentation: This paper was presented at the American Heart Association Scientific Sessions; November 13, 2020; virtual conference.

Additional Information: Drs Huang and McDermott are employees of AstraZeneca and participated similar to other TRANSLATE-HF investigators in the interpretation of data and critical revision of the manuscript for important intellectual content, but did not play a direct role in collection, management, or analysis of the data, or drafting of the manuscript.

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