Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients With Heart Failure and Reduced Ejection Fraction PARADIGM-HF

Background: The contemporary prognostic value of the physical examination- beyond traditional risk factors including natriuretic peptides, risk scores, and symptoms-in heart failure (HF) with reduced ejection fraction is unknown. We aimed to determine the association between physical signs of congestion at baseline and during study follow-up with quality of life and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and third heart sound) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up and whether improvement in congestion is related to changes in clinical outcomes and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores. Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2% of patients, respectively. Patients with baseline congestion were older, more often female, had higher MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure) and lower Kansas City Cardiomyopathy Questionnaire overall summary scores (P<0.05). After adjusting for baseline natriuretic peptides, time-updated Meta-Analysis Global Group in Chronic Heart Failure score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (P<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (P=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than did enalapril (P=0.011). Each 1-sign reduction was independently associated with a 5.1 (95% CI, 4.7-5.5) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (P<0.001). Conclusions: In HF with reduced ejection fraction, the physical exam continues to provide significant independent prognostic value even beyond symptoms, natriuretic peptides, and Meta-Analysis Global Group in Chronic Heart Failure risk score. Sacubitril/valsartan improved congestion to a greater extent than did enalapril. Reducing congestion in the outpatient setting is independently associated with improved quality of life and reduced cardiovascular events, including mortality.