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 (pace-cme.org)) (1)
Clinical inertia, which may be due to many therapeutic options for HFrEF patients nowadays, may lead to delayed initiation of therapy. This analysis of DAPA-HF examined the timing of onset of clinical benefit with dapagliflozin to estimate potential lost opportunities (2).
This analysis of DAPA-HF sought to answer the question:
- when does the clinical benefit of dapagliflozin emerge in patients with heart failure with reduced ejection fraction, and what is the magnitude as a function of proximity to prior heart failure hospitalization?
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
The study authors concluded (2)
- treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin
Commentary (3):
- "This analysis of the DAPA-HF data has revealed that evidence of benefit of the use of dapagliflozin 10mg versus placebo in HFrEF is rapidly evident, with a sustained statistically significant benefit 28 days after randomization. The reduction in risk of the primary outcome (a composite of an episode of worsening HF or CV death) seen in the dapagliflozin group (compared to placebo) was higher in patients who were closer to a prior HF hospitalization, i.e., the patients with most recent hospitalisation with heart failure showed the greatest benefit from dapagliflozin use. This study highlights that the benefit of dapagliflozin in patients with HFrEF is evident after 28 days of use. Also the closer to a prior hospitalisation that patients were, the greater the benefit of dapagliflozin use was (and this was apparent at 28 days post initiation)."
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