Sacubitril/valsartan was compared to enalapril in The Prospective Comparison of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) with ACEI (Angiotensin-Converting-Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure (HF) Trial (PARADIGM-HF) trial, which was stopped early after an observed 20% reduction in the composite endpoint of cardiovascular death or HF hospitalization.1 The United States Food and Drug Administration (FDA) approved sacubitril/valsartan for patients with HF with reduced ejection fraction (HFrEF) in July 2015. However, FDA labeling is broader than trial entry criteria, and the scope of potential sacubitril/valsartan use in HFrEF is not well understood. We used the Get With The Guidelines-Heart Failure (GWTG-HF) registry to characterize patients’ eligibility and potential barriers for sacubitril/valsartan initiation, according to criteria set forth in FDA labeling and PARADIGM-HF. The GWTG-HF registry was started in 2005 by the American Heart Association to improve adherence to quality of care guidelines for patients hospitalized for HF. Briefly, patients were eligible for inclusion in the registry if they were admitted for worsening HF or developed significant HF symptoms during a hospitalization.2 We included GWTG-HF registry participants ≥18 years hospitalized with HFrEF (EF≤40%) between January 1, 2011 to December 31, 2013. Patients were excluded if they had in-hospital death or any missing information for variables needed to determine PARADIGM-HF eligibility. To assess post-discharge clinical outcomes, included participants who were ≥65 years with fee-for-service Medicare coverage were linked to Medicare denominator and inpatient claims files.
We divided patients into three groups: FDA-excluded (not meeting FDA labeling), PARADIGM-HF-excluded (meeting FDA but not PARADIGM-HF criteria), and PARADIGM-HF-like (meeting PARADIGM-HF criteria). FDA labeling requires HFrEF, potassium ≤5.2 mmol/L, and no contraindication or intolerance to ACEI/angiotensin-receptor blocker (ARB). To incorporate real-world considerations, we also required patients to have discharge SBP ≥90 mmHg due to concern for hypotension with sacubitril/valsartan. The PARADIGM-HF-like group met the following additional criteria: EF ≤35%; BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL (or if hospitalized for HF within 6 months BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL); on ACEI/ARB and beta-blocker at discharge; discharge SBP≥100 mmHg; estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. PARADIGM-HF criteria were modified based on GWTG-HF data availability in 2 instances: 1) natriuretic peptide cutoffs were determined with a 12-month window of prior HF hospitalizations in PARADIGM-HF; 2) a 2-week run-in period with enalapril 20mg daily in PARADIGM-HF (no ACEI discharge dose in GWTG-HF). For the primary analysis, we made group comparisons for baseline, in-hospital, and discharge characteristics; for the CMS-linked analysis, we compared survival and HF hospitalization outcomes at 30 days and 1 year post-discharge. The Institutional Review Board of the Duke University Health System approved this study.
Among 28,932 hospitalizations of HFrEF patients, 20,083 (69%) were for patients meeting FDA labeling (Table 1). The stricter PARADIGM-HF criteria limited eligibility to 11,018/20,083 (55%) of the cohort meeting FDA labeling, or 11,018/28,932 (38%) of the overall HFrEF cohort. The most common reason to be in the FDA-excluded group was an existing contraindication to ACEI/ARB (89%); low discharge SBP excluded only 11% of patients. Among those in the PARADIGM-HF-excluded group, 34% of patients had EF of 35–40%, and 29% had discharge SBP<100 mmHg. Using the original EF ≤40% PARADIGM-HF criterion3 would have shifted 1780 patients to the PARADIGM-HF-like group; similarly, relaxing the SBP criterion to the post-run in value (≥95 mmHg) would have shifted 1051. Only 13% of the PARADIGM-HF-excluded patients were not receiving ACEI/ARB therapy. Once discharged, the PARADIGM-HF-like group had the best survival and HF hospitalization rate of all 3 groups (Table 1).
Table 1.
Characteristics and Outcomes by Sacubitril/Valsartan Eligibility
| FDA-Excluded | PARADIGM-HF-Excluded | PARADIGM-HF-Like | P Valueb | |
|---|---|---|---|---|
| Characteristic | ||||
| Na | 8849 | 9065 | 11,018 | |
| Age, mean ± SD, y | 71.8 ± 14.2 | 69.3 ± 15.1 | 66.8 ± 15.4 | <.001 |
| Men, No. (%) | 5631 (64%) | 5406 (60%) | 7040 (64%) | <.001 |
| Race, No. (%) | <.001 | |||
| Asian/Pacific Islander | 129 (2%) | 131 (1%) | 179 (2%) | |
| Black | 1472 (17%) | 1556 (17%) | 2209 (20%_ | |
| Native American | 34 (0%) | 58 (1%) | 56 (0%) | |
| White | 4971 (56%) | 4994 (55%) | 5357 (49%) | |
| Unknown | 2243 (25%) | 2326 (26%) | 3217 (29%) | |
| Medical History, No. (%) | ||||
| Anemia | 2321 (26%) | 1910 (21%) | 1350 (12%) | <.001 |
| Atrial fibrillation | 3420 (39%) | 2960 (33%) | 3032 (28%) | <.001 |
| Atrial flutter | 407 (5%) | 350 (4%) | 341 (3%) | <.001 |
| Coronary artery disease | 5266 (60%) | 4922 (54%) | 5360 (49%) | <.001 |
| Chronic renal insufficiency | 3451 (39%) | 1874 (21%) | 967 (9%) | <.001 |
| Dialysis (chronic) | 364 (4%) | 469 (5%) | 30 (0%) | <.001 |
| COPD | 2993 (34%) | 3060 (34%) | 3332 (30%) | <.001 |
| Stroke/TIA | 1592 (18%) | 1394 (15%) | 1522 (14%) | <.001 |
| Diabetes | 4139 (47%) | 4158 (46%) | 4756 (43%) | <.001 |
| Depression | 1145 (13%) | 1065 (12%) | 1259 (11%) | .003 |
| Hyperlipidemia | 5069 (57%) | 4953 (55%) | 5630 (51%) | <.001 |
| Hypertension | 6887 (78%) | 7238 (80%) | 8967 (81%) | <.001 |
| Prior CABG | 3905 (44%) | 3525 (39%) | 3741 (34%) | <.001 |
| Prior myocardial infarction | 2706 (31%) | 2533 (28%) | 2783 (25%) | <.001 |
| Peripheral vascular disease | 1426 (16%) | 1205 (13%) | 1212 (11%) | <.001 |
| Smoker in past year | 1531 (17%) | 1972 (22%) | 2834 (26%) | <.001 |
| Valvular heart disease | 2151 (24%) | 1876 (21%) | 1723 (16%) | <.001 |
| Devices | ||||
| CRT-D or CRT-P | 1493 (17%) | 997 (11%) | 1232 (11%) | <.001 |
| ICD | 1759 (20%) | 1428 (16%) | 1835 (17%) | <.001 |
| Pacemaker | 1357 (15%) | 1314 (15%) | 1357 (12%) | <.001 |
| In-Hospital | ||||
| BMI at admission, mean ± SD, kg/m2 | 28 ± 8 | 29 ± 9 | 29 ± 8 | <.001 |
| Ejection fraction, mean ± SD, % | 25.9 ± 8.7 | 29.0 ± 9.5 | 23.9 ± 7.3 | <.001 |
| Length of stay, median (IQR), d | 6 (4, 9) | 5 (4, 7) | 5 (3, 7) | <.001 |
| SBP at admission, mean ± SD, mmHg | 130 ± 29 | 139 ± 30 | 141 ± 28 | <.001 |
| Discharge | ||||
| BNP and NT-proBNP | ||||
| BNP, median (Q1, Q3), pg/mL | 1349 (668, 2532) | 939 (361, 1969) | 1110 (616, 1995) | <.001 |
| NT-proBNP, median (Q1, Q3), pg/mL | 11,002 (5045, 22,570) | 6382 (2836, 14,301) | 5,539 (2784, 11,105) | <.001 |
| SBP, mean ± SD, mmHg | 114.5 ± 20.2 | 116.2 ± 20.0 | 121.7 ± 16.0 | <.001 |
| Heart rate, mean ± SD, bpm | 77.2 ± 13.7 | 76.3 ± 13.3 | 76.9 ± 13.3 | <.001 |
| Potassium, mean ± SD, mEq/L | 4.2 ± .6 | 4.0 ± .6 | 4.0 ± .5 | <.001 |
| Creatinine, mean ± SD, mg/dL | 2.0 ± 1.2 | 1.7 ± 1.3 | 1.2 ± .4 | <.001 |
| HF Medications | ||||
| Renin-angiotensin inhibition | ||||
| ACEI or ARB | 931 (11%) | 7919 (87%) | 11018 (100%) | <.001 |
| ACEI | 744 (8%) | 6183 (68%) | 9067 (82%) | <.001 |
| ARB | 199 (2%) | 1815 (20%) | 2079 (19%) | <.001 |
| ß-blocker | 7285 (82%) | 7474 (82%) | 11018 (100%) | <.001 |
| Aldosterone antagonist | 2170 (25%) | 2804 (31%) | 4492 (41%) | <.001 |
| Outcome, CMS subgroupc | ||||
| N | 2802 | 2803 | 2986 | |
| Mortality | ||||
| 30 days | 310 (11%) | 161 (6%) | 112 (4%) | < .001 |
| 1 year | 1396 (51%) | 1000 (36%) | 860 (29%) | < .001 |
| Heart Failure Hospitalization | ||||
| 30 days | 417 (15%) | 257 (9%) | 263 (9%) | < .001 |
| 1 year | 1163 (42%) | 958 (35%) | 964 (33%) | < .001 |
Abbreviations: BMI, body mass index; BNP, B-type natriuretic peptide; CRT-D, cardiac resynchronization therapy with defibrillator; CRT-P, cardiac resynchronization therapy with pacemaker; ICD, implantable cardioverter-defibrillator; NT-proBNP, N-terminal pro B-type natriuretic peptide; SBP, systolic blood pressure.
N’s for the baseline characteristics represent unique hospitalizations; data may be correlated to the extent that patients have multiple hospitalizations during the study period.
P-values for baseline characteristics were derived from Wilcoxon rank-sum tests for continuous variables and Chi-square and Fisher’s exact tests for categorical variables.
Time-to-event analysis was performed using Kaplan-Meier methods for all-cause mortality outcomes; hospitalization was evaluated using the cumulative incidence function, treating death as a competing risk. P-values for outcomes were derived from log-ranks tests (mortality) and Gray’s tests (hospitalizations).
Discharge from an acute HF hospitalization represents an important opportunity to re-evaluate medications, including potentially switching from ACEI/ARB, or starting sacubitril/valsartan de novo. In a post-hoc analysis of PARADIGM-HF, although most subjects reported NYHA II symptoms, sacubitril/valsartan had similar benefit regardless of risk stratification.4 Further, if a hospitalization occurred in the follow-up period, subjects taking sacubitril/valsartan had reduced 30-day and 60-day HF re-hospitalization (odds ratio: 0.62).5 Importantly, sacubitril/valsartan is currently approved and recommended for chronic, ambulatory HFrEF patients only, and our GWTG-HF analysis includes post-acute HF patients at discharge. The ongoing PIONEER-HF trial will provide safety/efficacy data on in-hospital initiation. Concerns for sacubitril/valsartan initiation include worsening hypotension, generalizability of trial results, and potential need to have achieved ACEI/ARB target doses prior to initation. Our assessment of candidacy for sacubitril/valsartan was based on objective criteria that governed PARADIGM-HF and supported the FDA label indications. We recognize however that physicians are the final arbiters of treatment decisions and that varying thresholds of equipoise may be operative in the decision analysis. We also acknowledge the insurance exigencies in practice and recognize that additional points of inertia may be again operative in access to therapy. Thus, the overall assessment of the potential adaptation of newer HF therapies may be impacted by factors beyond both trial and FDA criteria.
Acknowledgments
Funding Source: The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association. GWTG-HF is sponsored, in part, by Amgen Cardiovascular and has been funded in the past through support from Medtronic, GlaxoSmithKline, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable. This project was supported in part by grant number U19HS021092 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. Preparation of the manuscript was supported by grant 5T32GM086330-05 from the NIH (KSP).
Footnotes
Disclaimer: Dr Fonarow reported consulting for Amgen, Medtronic, Novartis, and St Jude. Dr Hernandez reported receiving honoraria from Amgen, Gilead, Janssen, Merck & Co, and Novartis; and receiving research funding from Amgen, AstraZeneca, BMS, GlaxoSmithKline, Janssen, Novartis, and Portola.
Disclosures: Damon M. Seils, MA, Duke University, assisted with manuscript preparation. Mr Seils did not receive compensation for his assistance apart from his employment at the institution where the study was conducted.
Additional Contributions: Damon M. Seils, MA, Duke University, assisted with manuscript preparation. Mr Seils did not receive compensation for his assistance apart from his employment at the institution where the study was conducted.
References
- 1.McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, Investigators P-H and Committees Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. doi: 10.1056/NEJMoa1409077. [DOI] [PubMed] [Google Scholar]
- 2.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;5:179–86. doi: 10.1097/01.hpc.0000243588.00012.79. [DOI] [PubMed] [Google Scholar]
- 3.Solomon SD, Claggett B, Desai AS, Packer M, Zile M, Swedberg K, Rouleau JL, Shi VC, Starling RC, Kozan O, Dukat A, Lefkowitz MP, McMurray JJ. Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial. Circ Heart Fail. 2016;9:e002744. doi: 10.1161/CIRCHEARTFAILURE.115.002744. [DOI] [PubMed] [Google Scholar]
- 4.Simpson J, Jhund PS, Silva Cardoso J, Martinez F, Mosterd A, Ramires F, Rizkala AR, Senni M, Squire I, Gong J, Lefkowitz MP, Shi VC, Desai AS, Rouleau JL, Swedberg K, Zile MR, McMurray JJ, Packer M, Solomon SD, Investigators P-H and Committees Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF. J Am Coll Cardiol. 2015;66:2059–71. doi: 10.1016/j.jacc.2015.08.878. [DOI] [PubMed] [Google Scholar]
- 5.Desai AS, Claggett BL, Packer M, Zile MR, Rouleau JL, Swedberg K, Shi V, Lefkowitz M, Starling R, Teerlink J, McMurray JJ, Solomon SD, Investigators P-H Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. J Am Coll Cardiol. 2016;68:241–8. doi: 10.1016/j.jacc.2016.04.047. [DOI] [PubMed] [Google Scholar]