Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting: Evidence From the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF)

• Published in: Circulation (New York, N.Y.) Vol. 133; no. 23; pp. 2254 - 2262
• Main Authors: Okumura, Naoki, Jhund, Pardeep S, Gong, Jianjian, Lefkowitz, Martin P, Rizkala, Adel R, Rouleau, Jean L, Shi, Victor C, Swedberg, Karl, Zile, Michael R, Solomon, Scott D, Packer, Milton, McMurray, John J.V
• Format: Journal Article
• Language: English
• Published: United States by the American College of Cardiology Foundation and the American Heart Association, Inc 07-06-2016
• Subjects: Aged; Ambulatory Care; Aminobutyrates - adverse effects; Aminobutyrates - therapeutic use; Angiotensin II Type 1 Receptor Blockers - adverse effects; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Angiotensin-Converting Enzyme Inhibitors - adverse effects; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Cardiac and Cardiovascular Systems; Cardiovascular System & Cardiology; care; Disease Progression; Double-Blind Method; Drug Combinations; emergency service; emergency-department; enalapril; Enalapril - adverse effects; Enalapril - therapeutic use; Endpoint Determination; Female; heart failure; Heart Failure - diagnosis; Heart Failure - mortality; Heart Failure - physiopathology; Heart Failure - therapy; hospital; hospital readmission; Hospitalization; Humans; inpatient; Kardiologi; Male; Middle Aged; mortality; neprilysin; Neprilysin - antagonists & inhibitors; Neprilysin - metabolism; neprilysin inhibition; outcomes; Prospective Studies; Protease Inhibitors - adverse effects; Protease Inhibitors - therapeutic use; Research Design; risk; Risk Assessment; Risk Factors; sacubitril/valsartan; subsequent mortality; Tetrazoles - adverse effects; Tetrazoles - therapeutic use; therapy; Time Factors; Treatment Outcome; mortality; heart failure; hospitalization; neprilysin; emergency service, hospital; sacubitril/valsartan
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.115.020729

BACKGROUND—Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or temporary intravenous treatment in the community or emergency department (ED), without hospital admission. We studied the frequency and prognostic importance of these episodes of worsening 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 Trial (PARADIGM-HF).
METHODS AND RESULTS—Outpatient intensification of HF therapy was added to an expanded composite outcome with ED visits, HF hospitalizations, and cardiovascular deaths. In an examination of first nonfatal events, 361 of 8399 patients (4.3%) had outpatient intensification of HF therapy without a subsequent event (ie, ED visit/HF hospitalizations) within 30 days; 78 of 8399 (1.0%) had an ED visit without previous outpatient intensification of HF therapy or a subsequent event within 30 days; and 1107 of 8399 (13.2%) had HF hospitalizations without a preceding event. The risk of death (in comparison with no-event patients) was similar after each manifestation of worseningoutpatient intensification of HF therapy (hazard ratio, 4.8; 95% confidence interval, 3.9–5.9); ED visit (hazard ratio, 4.5; 95% confidence interval, 3.0–6.7); HF hospitalizations (hazard ratio, 5.9; 95% confidence interval, 5.2–6.6). The expanded composite added 14% more events and shortened time to accrual of a fixed number of events. The benefit of sacubitril/valsartan over enalapril was similar to the primary outcome for the expanded composite (hazard ratio, 0.79; 95% confidence interval, 0.73–0.86) and was consistent across the components of the latter.
CONCLUSIONS—Focusing only on HF hospitalizations underestimates the frequency of worsening and the serious implications of all manifestations of worsening. For clinical trials conducted in an era of heightened efforts to avoid HF hospitalizations, inclusion of episodes of outpatient treatment intensification (and ED visits) in a composite outcome adds an important number of events and shortens the time taken to accrue a target number of end points in an event-driven trial.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT01035255.