Physicians' Academy for Cardiovascular Education

Outpatient worsening HF in HFrEF patients reduced by SGLT2 inhibition

Effect of Dapagliflozin on Outpatient Worsening of Patients with Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF

Literature - Docherty KF, Jhund PS, Anand I, et al. - Circulation. 2020 Sep 4. doi: 10.1161/CIRCULATIONAHA.120.047480.

Introduction and methods

One of the most commonly used clinical outcome in trials with heart failure with reduced ejection fraction (HFrEF) patients is CV death or hospitalization due to worsening of HF. Worsening of symptoms and signs leading to hospitalization is a marker of increased risk of readmission and death [1,2]. For this reason, HF hospitalization has been considered an important end-point in clinical trials, including episodes of worsening HF that requires intravenous (IV) treatment [3-5]. However, many more patients are treated for worsening symptoms in an outpatient manner by intensified oral therapy [6-8]. Thus, focusing only on HF hospitalization might underestimate the frequency of clinical worsening in HFrEF patients and mask the possible prognostic importance of other HF events.

This Dapagliflozin And Prevention of Adverse Outcome in Heart Failure (DAPA-HF) substudy evaluated the frequency of episodes of outpatient worsening HF, the treatment for these episodes, the prognostic importance of these events and the effect of 10 mg dapagliflozin once daily on episodes of worsening HF.

The DAPA-HF trial was a prospective, randomized, double-blind, placebo-controlled trial in patients with HFrEF, that assessed the efficacy and safety of the SGLT2 inhibitor dapagliflozin (10 mg once daily) added to the patient’s standard treatment. HF patients (n=4744 and ≥18 years) with a New York Heart Association (NYHA) functional class II-IV and LVEF ≤40% and optimally treated with pharmacological and device therapy, as well as a NT-proBNP level of ≥600 pg/mL (≥400 pg/mL when hospitalized for HF within the previous 12 months, or ≥900 pg/mL when experiencing atrial fibrillation/atrial flutter). The primary outcome was a composite of CV death or an episode of worsening HF defined as unexpected hospitalization due to HF or an urgent visit resulting in IV-therapy for HF. The secondary outcomes included the composite of CV death or HF hospitalization. For this analysis, the prespecified exploratory endpoint was a wider composite reflecting worsening HF including: 1) worsening HF leading to initiation of new oral treatment or intensification of oral therapy, 2) hospitalization for HF, 3) urgent HF hospital visit, 4) time to first occurrence of CV death. At study visits information on outpatient intensification of HF therapy was collected and completed on a specific case report form page. Median follow-up was 18.2 months.

Main results


Episode of worsening HF in HFrEF patients in an outpatient setting and treated with intensive oral therapy was by far more common than patients hospitalized and treated with IV-therapy. Outpatient worsening HF was a prognostic marker of mortality and manifestations were reduced by 10 mg dapagliflozin treatment, daily, compared to placebo.

Outcome definition guidelines only include outpatient HF worsening events treated with IV-therapy However, the authors argue that because outpatient HF worsening events treated with oral therapy were more common than those treated with IV-therapy, and these events have the same prognostic outcome, outpatient worsening HF events should be considered for inclusion in the primary outcome of a future clinical trial.


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Find this article online at Circulation

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