Sustained benefit of SGLT2i in HFrEF by 28 days

Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction

Literature - Berg DD, Jhund PS, Docherty KF, et al., - JAMA Cardiology 2021, doi:10.1001/jamacardio.2020.7585

Introduction and methods

The SGLT2 inhibitor dapagliflozin lowered risk of worsening heart failure events and CV death compared to placebo in HFrEF patients, demonstrated in the_DAPA-HF_trial (SGLT2 inhibitor reduces CV death and worsening HF events in HFrEF patients - PACE-CME ( [1]. Clinical inertia, which may be due to many therapeutic options for HFrEF patients nowadays, may lead to delayed initiation of therapy. This study examined the timing of onset of clinical benefit with dapagliflozin to estimate potential lost opportunities.

Hospitalization for worsening HF has substantial consequences for patient quality of life [2,3], and identifies patients at high risk for disease progression, CV death and those who require advanced therapies. In the DAPA-HF trial, almost half of the patients had been previously hospitalized [1]. This study examined whether risk of clinical events and effect of dapagliflozin varied as a function of proximity to the last HF hospitalization.

The DAPA-HF trial enrolled 4744 patients with HFrEF, who were randomized to dapagliflozin or placebo. Median follow-up was 18.2 months. Patients were excluded if they were currently hospitalized for acute decompensated HF or had been hospitalized for HF within 4 weeks of trial enrollment. For this analysis, patients were categorized according to timing of most recent HF hospitalization relative to trial enrollment: within the last 12 months, more than 12 months, or never. Primary efficacy outcome of the main trial was the composite of an episode of worsening HF or CV death.

Main results

  • Statistical significance of benefit of dapagliflozin was sustained 28 days after randomization (HR at 28 days: 0.51, 95%CI: 0.28-0.94, P=0.03).
  • Similar pattern of early and consistent benefit with dapagliflozin was observed for the individual components (worsening HF: HR at 28 days 0.48, 95%CI:0.23-0.94 and CV death: HR at 28 days 0.87, 95%CI:0.31-2.41).
  • In patients receiving placebo, there was a stepwise gradient of risk for the primary outcome of worsening HF or CV death according to timing of the most recent HF hospitalization (adjusted HRs were 1.08, 95%CI: 0.90-1.29 and 1.30, 95%CI: 1.12-1.51 for those hospitalized >12 months ago and ≤12 months ago compared with patients never hospitalized for HF), which appeared to be driven by increased risk of worsening HF.
  • Dapagliflozin reduced risk of the primary outcome by 16% (HR 0.84, 95%CI: 0.69-1.01) in patients with no prior history of HF hospitalization, 27% (HR 0.73, 95%CI: 0.54-0.99) in those with an HF hospitalization >1 year prior to enrollment, and 36% (HR 0.64, 95%CI: 0.51-0.81) in those with an HF hospitalization ≤12 months.


Benefit of dapagliflozin in HFrEF patients in the DAPA-HF trial was rapidly apparent, with a sustained statistically significant benefit 28 days after randomization. Risk of primary outcome was higher in patients who were closer to a prior HF hospitalization, and relative (and absolute) risk reduction by dapagliflozin was higher in these patients.


1. McMurray JJV, Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381 (21):1995-2008. doi:10.1056/NEJMoa1911303

2. Solomon SD, Dobson J, Pocock S, et al; Candesartan in Heart failure: Assessment of in Mortality and morbidity (CHARM) Investigators. Influence of nonfatal hospitalization

for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116(13): 1482-1487. doi:10.1161/CIRCULATIONAHA.107.696906

3. Bello NA, Claggett B, Desai AS, et al. Influence of previous heart failure hospitalization on cardiovascular events in patients with reduced and preserved ejection fraction. Circ Heart Fail. 2014;7(4):590-595. doi:10.1161/CIRCHEARTFAILURE.113.001281

Find this article online at JAMA Cardiol

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