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)

Background—Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or 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 PARADIGM-HF. Methods and Results—Outpatient intensification of HF therapy (IT) was added to an expanded composite outcome with ED visits, HF hospitalizations (HFh) and cardiovascular deaths. Examining first non-fatal events, 361/8399 patients (4.3%) had IT without a subsequent event (i.e. ED visit/HFh) within 30 days; 78/8399 (1.0%) had an ED visit without prior IT or a subsequent event within 30 days; and 1107/8399 (13.2%) had HFh without a preceding event. The risk of death (compared with "no event" patients) was similar after each manifestation of worsening - IT: HR=4.8(95%CI 3.9-5.9); ED visit: 4.5(3.0-6.7); HFh: 5.9(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 (HR 0.79, 0.73-0.86) and was consistent across the components of the latter. Conclusions—Focusing only on HFh 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 HFh, 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 endpoints in an event-driven trial