Effect of dapagliflozin on outpatient worsening heart failure in patients with mildly reduced or preserved ejection fraction: the DELIVER trial

Abstract

Abstract Background Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing decompensation are hospitalized. Outpatient intensification of diuretics is common in response to worsening symptoms suggestive of HF, yet its prognostic and clinical relevance is less certain. Purpose To evaluate the prognostic importance of outpatient oral diuretic intensification and assess the treatment effect of dapagliflozin across the spectrum of worsening HF events. Methods DELIVER was a global, randomized clinical trial of dapagliflozin vs. placebo in 6,263 participants with HF with mildly reduced or preserved ejection fraction. In this prespecified landmark analysis, we assessed the association between various non-fatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. Diuretic intensification was defined as new initiation (among those not on diuretics at baseline) or dose uptitration sustained for at least 30 days (among those on diuretics at baseline). We also examined the treatment effect of dapagliflozin on an expanded composite endpoint of CV death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification. Results In DELIVER, 4,532 (72%) patients experienced no worsening HF event, while 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had a HF hospitalization, and 271 (4%) died of CV causes as a first manifestation of worsening HF. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10 per 100py) than those without a worsening HF event (4 per 100py) but similar to rates of subsequent death following urgent HF visit (10 per 100py). Patients with a HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35 per 100py); Figure 1. The addition of outpatient diuretic intensification to the adjudicated DELIVER primary endpoint (CV death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1,122 to 1,731. Dapagliflozin reduced the need for outpatient diuretic intensification alone (HR 0.72; 95% CI: 0.64-0.82; P<0.001) and when analyzed as a part of an expanded composite endpoint of worsening HF (HR 0.76; 95% CI: 0.69-0.84; P<0.001); Figure 2. Conclusions Even in patients with HF with mildly reduced or preserved ejection fraction, hospitalization as a first presentation of worsening HF is associated with significant subsequent mortality. Moreover, oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin.Figure 1Figure 2