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.
This cohort study evaluates candidacy for initiation of dapagliflozin based on the US Food and Drug Administration label among contemporary US patients with heart failure with reduced ejection fraction and describes potential barriers to therapeutic optimizations.
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.1,2,3 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.6,7,8 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).
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.
eGFR indicates estimated glomerular filtration rate; and LVEF, left ventricular ejection fraction.
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).
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.
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).
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).
Table. Clinical Profiles in the DAPA-HF Trial and GWTG-HF Registry.
| Characteristic | Patients, No. (%) | ||
|---|---|---|---|
| DAPA-HF trial population (n = 4744) | GWTG-HF registry | ||
| DAPA-HF trial eligible (n = 68 383) | FDA label candidates (n = 125 497) | ||
| Enrollment period | 2017-2018 | 2014-2019 | 2014-2019 |
| Sites | 410 Sites, 20 countries | 406 Sites across US | 406 Sites across US |
| Demographic characteristics | |||
| Age, mean (SD), y | 66 (11) | 69 (15) | 68 (15) |
| Women | 1109 (23.4) | 24 611 (36.0) | 42 016 (33.5) |
| Race/ethnicity | |||
| White | 3333 (70.3) | 42 076 (61.5) | 76 575 (61.0) |
| Black | 226 (4.8) | 17 586 (25.7) | 33 356 (26.6) |
| Asian | 1116 (23.5) | 930 (1.4) | 1616 (1.3) |
| Other | 69 (1.5) | 7791 (11.4) | 13 950 (11.1) |
| North America | 677 (14.3) | 68 383 (100) | 125 497 (100) |
| Medical history | |||
| Current smokinga | 693 (14.6) | 15 514 (22.7) | 30 022 (23.9) |
| Atrial fibrillation | 1818 (38.3) | 23 085 (33.8) | 43 894 (35.0) |
| Hypertension | 3523 (74.3) | 55 181 (80.7) | 100 645 (80.2) |
| Diabetesb | 2139 (45.1) | 28 471 (41.6) | 51 609 (41.1) |
| COPD or asthmac | 585 (12.3) | 21 321 (31.2) | 39 888 (31.8) |
| History | |||
| Myocardial infarction | 2092 (44.1) | 16 085 (23.5) | 31 059 (24.7) |
| Stroke or transient ischemic attackd | 466 (9.8) | 10 132 (14.8) | 18 729 (14.9) |
| PCI | 1624 (34.2) | 13 181 (19.3) | 26 033 (20.7) |
| CABG | 799 (16.8) | 12 939 (18.9) | 24 622 (19.6) |
| Other clinical characteristicse | |||
| Ischemic HF etiology | 2674 (56.4) | 36 554 (53.5) | 69 450 (55.3) |
| Left ventricular ejection fraction, mean (SD), % | 31 (7) | 27 (9) | 26 (9) |
| BMI, mean (SD) | 28 (6) | 29 (8) | 29 (8) |
| Systolic blood pressure, mean (SD), mm Hg | 122 (16) | 121 (18) | 118 (191) |
| Heart rate, mean (SD), beats/min | 72 (12) | 80 (16) | 80 (15) |
| eGFR, median (IQR), mL/min/1.73 m2 | 66 (20)f | 59 (45-77) | 59 (45-77) |
| Potassium, mean (SD), mEq/L | 4.5 (0.5) | 4.1 (0.5) | 4.1 (0.5) |
| Background therapiesg | |||
| ARNI | 508 (10.7) | 3793 (5.5) | 7818 (6.2) |
| ACEi or ARB | 3934 (82.9) | 44 870 (65.6) | 81 094 (64.6) |
| β-Blocker | 4558 (96.1) | 60 568 (88.6) | 110 625 (88.1) |
| MRA | 3370 (71.0) | 22 224 (32.5) | 45 039 (35.9) |
| Digoxin | 887 (18.7) | 4571 (6.7) | 10 244 (8.2) |
| Isosorbide dinitrate and hydralazine | NA | 7290 (10.7) | 13 697 (10.9) |
| Implantable cardioverter-defibrillatorh | 953 (20.1) | 14 877 (21.8) | 35 873 (28.6) |
| In-hospital outcomes and dispositioni | |||
| Hospital length of stay, median (IQR) | NA | 4 (3-6) | 4 (3-6) |
| Disposition | |||
| Death | NA | 1685 (2.5) | 2291 (1.8) |
| Hospice | NA | 967 (1.4) | 2917 (2.3) |
| Other health care facility | NA | 9704 (14.2) | 17 189 (13.7) |
| Home | NA | 55 958 (81.8) | 102 986 (82.1) |
| Missing | NA | 69 (0.1) | 114 (0.1) |
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin-receptor neprilysin inhibitor; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; GWTG-HF, Get With the Guidelines–Heart Failure; HF, heart failure; IQR, interquartile range; MRA, mineralocorticoid receptor antagonist; PCI, percutaneous coronary intervention.
SI conversion factor: To convert potassium to millimoles per liter, multiply by 1.0.
In GWTG-HF, this variable reflects recent history (within 12 months) or current cigarette smoking.
In both populations, this variable includes incident cases identified at screening or during hospitalization.
In DAPA-HF, this variable includes COPD alone.
In DAPA-HF, this variable includes stroke alone.
Vital signs and laboratory parameters were assessed at discharge. If not available, the closest value to discharge was considered.
Data reported as mean (SD).
Data were missing in 52 651 of 154 714 patients (34.0%) for ARNI use, 4539 of 154 714 patients (2.9%) for ACEi or ARB use, 4459 of 154 714 patients (2.9%) for β-blocker use, and 5774 of 154 714 patients (3.7%) for MRA use.
In GWTG-HF, this variable includes cardiac resynchronization therapy with defibrillator.
In-hospital outcomes and disposition were not relevant to the DAPA-HF trial population given enrollment of patients with chronic HFrEF.
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.
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.
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%),29,30,31,32,33 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.
eTable 1. FDA Label for Dapagliflozin and DAPA-HF Trial Eligibility Criteria
eTable 2. Demographic and Clinical Characteristics of GWTG-HF Participants With and Without Available eGFR and SBP
eTable 3. Characteristics of Sites With ≥ vs<10 Hospitalizations
eTable 4. Flow Chart Displaying Selection of FDA Treatment Candidate Cohort and DAPA-HF Trial Eligible Cohort
eTable 5. Comprehensive Clinical Profiles of GWTG-HF Participants With HFrEF
eFigure. Temporal Trends in In-Hospital Mortality by Admission Year
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. FDA Label for Dapagliflozin and DAPA-HF Trial Eligibility Criteria
eTable 2. Demographic and Clinical Characteristics of GWTG-HF Participants With and Without Available eGFR and SBP
eTable 3. Characteristics of Sites With ≥ vs<10 Hospitalizations
eTable 4. Flow Chart Displaying Selection of FDA Treatment Candidate Cohort and DAPA-HF Trial Eligible Cohort
eTable 5. Comprehensive Clinical Profiles of GWTG-HF Participants With HFrEF
eFigure. Temporal Trends in In-Hospital Mortality by Admission Year