Burden of Heart Failure Signs and Symptoms, Prognosis, and Response to Therapy: The PARAGON-HF Trial.

Objectives: This study investigated the prognostic importance of heart failure (HF) signs and symptoms in patients with heart failure and preserved ejection fraction (HFpEF), and the effect of sacubitril/valsartan on HF signs and symptoms.
Background: In patients with HFpEF, worsening of HF symptoms, as a marker of cardiac decompensation, is frequently the reason for hospitalization. In this heterogenous disease entity, the prognostic value of HF signs and symptoms with regard to cardiovascular (CV) outcomes is poorly defined.
Methods: The authors examined the association between baseline HF signs and symptoms (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, and third heart sound) as well as burden of these HF signs and symptoms (classified as ≤2 and ≥3 HF signs and symptoms) and the primary composite of total HF hospitalizations and CV death, its components, and all-cause death in 4,725 patients enrolled in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HFpEF) with available signs and symptoms at randomization. Response to sacubitril/valsartan on the basis of the presence of signs and symptoms was evaluated. Effects of sacubitril/valsartan on signs and symptoms over time were assessed using binary repeated-measures logistic regression.
Results: Patients with high (≥3) burden of HF signs and symptoms (n = 1,772 [38%]) were more commonly women, had slightly lower left ventricular ejection fractions, higher body mass index, and more advanced New York Heart Association functional class compared with patients with low (≤2) burden (n = 2,953 [62%]) (p < 0.001 for all). Levels of N-terminal pro-B-type natriuretic peptide did not differ significantly between groups (p = 0.14). Greater burden of signs and symptoms was associated with higher risk for total HF hospitalizations and CV death (rate ratio [RR]: 1.50; 95% confidence interval [CI]: 1.30 to 1.74) and all-cause death (RR: 1.41; 95% CI: 1.21 to 1.65). Among individual signs and symptoms, orthopnea (RR: 1.29; 95% CI: 1.04 to 1.61) and rales (RR: 1.52; 95% CI: 1.10 to 2.10) were most predictive of the primary endpoint. Treatment response to sacubitril/valsartan was not significantly modified by burden of HF signs and symptoms (p for interaction = 0.08), though patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR: 0.67; 95% CI: 0.49 to 0.90) than those without orthopnea (RR: 0.97; 95% CI: 0.82 to 1.14; p for interaction = 0.04). Compared with valsartan, sacubitril/valsartan did not significantly decrease overall burden of HF signs and symptoms over time (odds ratio: 0.84; 95% CI: 0.67 to 1.07) but did reduce exertional dyspnea (odds ratio: 0.76; 95% CI: 0.63 to 0.93).
Conclusions: High burden of HF signs and symptoms, particularly the presence of orthopnea and rales, portends a higher risk for adverse CV events in patients with HF with preserved ejection fraction. Sacubitril/valsartan did not significantly decrease the burden of HF signs and symptoms over time but did reduce exertional dyspnea relative to valsartan. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
Competing Interests: Funding Support and Author Disclosures PARAGON-HF was funded by Novartis. Dr. Jering is supported by the National Institutes of Health (training grant 5-T32 HL007604). Dr. Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, and Novartis. Dr. Redfield has served as an unpaid consultant for Novartis. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapies, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr. Anand has received fees for serving as U.S. national leader of a trial for AstraZeneca; receives fees for serving on steering committees for ARCA Biopharma, Amgen, LivaNova, and Novartis; has received fees for serving on an endpoint committee for Boehringer Ingelheim; has received fees for serving as chair of a data and safety monitoring board for Boston Scientific; and has received advisory board fees from Zensun. Dr. Martinez has received personal fees from AstraZeneca, Novartis, and Boehringer Ingelheim as honoraria. Drs. Sabarwal and Lefkowitz are salaried employees of Novartis. Dr. Seferović has received honoraria for lectures for Medtronic, Abbott, Servier, AstraZeneca, and Respicardia; has consultancy agreements with and has received honoraria for lectures from Boehringer Ingelheim and Novartis; and has a consultancy agreement with Vifor Pharma. Dr. Saraiva has received lecture fees from Amgen, Merck Sharpe & Dohme, and Pfizer; has received lecture fees, fees for serving on advisory boards, consulting fees, and fees for serving as a national leader of clinical trials from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk; and has received lecture fees and fees for serving on advisory boards from Eli Lilly and Servier. Dr. Katova has received lecture fees, fees for serving on an advisory board, and travel support from Novartis; and receives lecture fees, consulting fees, and fees for serving on an advisory board from AstraZeneca. Dr. Pfeffer has received consulting fees from AstraZeneca, DalCor, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz, MyoKardia, Servier, Takeda, and Corvidia. Dr. McMurray’s employer, Glasgow University, has received funding for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardurion, Cytokinetics, DalCor, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from Abbott, Hickma Pharmaceuticals, Sun Pharmaceuticals, and Servier. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Respicardia, Sanofi-Pasteur, and Theracos; and has consulted 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. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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