Eligibility of patients with heart failure with preserved ejection fraction for sacubitril/valsartan according to the PARAGON-HF trial

Abstract

Aims: In the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON-HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios.

Methods and results: Eligibility was assessed in the Karolinska-Rennes study (acute HFpEF, LVEF ≥ 45%, and N-terminal pro-B-type natriuretic peptide ≥300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (<54% in women and <52% in men); and (iv) LVEF below mean of normal range (<64% in women and <62% in men). Among 425 patients [age 78 (72-83) years, 57% women, 28% LVEF ≤ 57% (median in PARAGON-HF), the trial scenario, identified 34% as eligible. Left atrial enlargement and/or left ventricular hypertrophy were present in 99%. Inclusion criteria not met were diuretic treatment and New York Heart Association class. Important exclusion criteria were estimated glomerular filtration rate <30 mL/min/1.73 m2 , haemoglobin <10 g/day, and cancer. In the pragmatic scenario, 63% were eligible. In LVEF below lower limit of normal range, 5.4% were eligible, and in LVEF below mean of normal range, 41% were eligible. In patients with LVEF ≤ 57%, eligibility was 42%, 69%, 21%, and 91% according to the trial scenario, pragmatic scenario, LVEF below lower limit of normal range, and LVEF below mean of normal range, respectively.

Conclusions: In real-world HFpEF (LVEF ≥ 45%) with N-terminal pro-B-type natriuretic peptide and cardiac structure/function assessed, eligibility for sacubitril/valsartan was according to PARAGON-HF complete criteria 34%, pragmatic criteria 63%, LVEF below lower limit of normal range 5.4%, and LVEF below mean of normal range 41%. Cardiac structural impairment was almost ubiquitous. Ineligibility was more due to exclusion criteria than failing to meet inclusion criteria.

Trial registration: ClinicalTrials.gov NCT00774709.

Keywords: Echocardiography; Eligibility; Heart failure with borderline ejection fraction; Heart failure with mid-range ejection fraction; Heart failure with mildly reduced ejection fraction; Heart failure with preserved ejection fraction; PARAGON-HF; Sacubitril/valsartan; Structural heart disease; Trial design.

Conflict of interest statement

C.H. reports consulting fees from Novartis and Roche Diagnostics and speaker and honoraria from MSD, supported by the Swedish Research Council (Grant 20180899). C.L. reports research grants, speaker honoraria, and consulting fees from Medtronic, Abbot, Impulse Dynamics, Novartis, Bayer, Vifor, MicroPort, Boston Scientific, AstraZeneca, and Orion Pharma. G.S. reports financial support from Novartis for the current research; grants and personal fees from Vifor and AstraZeneca; grants and non‐financial support from Boehringer Ingelheim; personal fees from Società Prodotti Antibiotici, Roche, Servier, GENESIS, Cytokinetics, and Medtronic; and grants from Boston Scientific, outside the submitted work. L.H.L. reports personal fees from Sanofi and Lexicon, during the conduct of the study; personal fees from Merck, Bayer, Pharmacosmos, Abbott, Medscape, and Myokardia; grants and personal fees from Vifor Fresenius, AstraZeneca, Relypsa, Boehringer Ingelheim, and Novartis, outside the submitted work; and grants from Boston Scientific. E.D. reports echocardiographic core lab for Abbott and consulting fees for GE Healthcare, Abbott, AstraZeneca, Novartis, and Pfizer. A.L. is employed by Novartis Sweden.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1

Inclusion criteria met and exclusion criteria not met in men (blue), women (pink), left ventricular ejection fraction (LVEF) ≤57% (yellow), and the whole KaRen cohort (purple). Inclusion criteria: age: ≥50 years; diuretic treatment: required for heart failure ≥30 days prior to enrolment; New York Heart Association (NYHA) Class: II–IV; structural heart disease: left atrial volume index ≥29 mL/m2 or septal thickness or posterior wall thickness ≥1.1 cm; N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP): >300 pg/mL for patients in sinus rhythm or >600 pg/mL for patients in atrial fibrillation. Exclusion criteria: acute coronary syndrome (ACS) within 3 months; haemoglobin (Hb): <10 g/dL; body mass index (BMI): >40 kg/m2; systolic blood pressure (SBP): >150 and <180 mmHg unless receiving three or more antihypertensive drugs; estimated glomerular filtration rate (eGFR): <30 mL/min/1.73 m2; malignancy: within the past 5 years (except localized basal or squamous cell carcinoma of the skin or localized prostate cancer).

Figure 2

(A) Adjusted associations between baseline characteristics and left ventricular ejection fraction (LVEF) below lower limit of normal range (