Fewer Outpatient Heart-Failure Med Adjustments on Dapagliflozin: DAPA-HF

June 26, 2020

The scope of sodium-glucose cotransporter 2 (SGLT2) inhibition's clinical benefits in DAPA-HF may be greater than already appreciated, suggests a prespecified secondary analysis of the heart failure with reduced ejection fraction (HFrEF) trial.

DAPA-HF is already renowned for showing a highly significant 26% drop in clinical events (< .001) in HFrEF patients who received dapagliflozin (Farxiga, AstraZeneca), compared with placebo, regardless of glycosylated hemoglobin levels. The number needed to treat (NNT) to prevent one such event was only 21 in the trial, which had a median 18 months follow-up.

The new analysis adds "outpatient intensification of heart failure (HF) therapy" to the trial's composite primary end point of cardiovascular (CV) death, HF hospitalization, and urgent HF visit.

The resulting "expanded composite outcome" more inclusively accounts for a broader range of clinically dire "worsening HF events," according to DAPA-HF researchers.

Outpatient intensification of therapy was defined as a diuretic dosage increase — accounting for three-fourths of instances — or new addition of an evidence-based HF medication, like a renin-angiotensin-system inhibitor or mineralocorticoid receptor antagonist, reported Kieran Docherty, MBChB, University of Glasgow, United Kingdom, in his presentation June 19 in a Late-Breaking Science Session during HFA Discoveries.

For context, 8.6% of patients in the trial overall had such outpatient intensification of HF therapy, which itself predicted a two- to threefold increased mortality risk in adjusted analysis. An "urgent HF visit," seen in only 0.4% of patients in the trial, still tripled the mortality risk. An "HF hospitalization," in about 10% of patients, multiplied the risk six times, observed Docherty at his presentation.

The online HFA Discoveries conference substituted for the traditional annual scientific meeting of the Heart Failure Association (HFA) of the European Society of Cardiology, which was cancelled this year due to the COVID-19 pandemic.

Mortality Hazard Ratios* for Individual Nonfatal Worsening Heart Failure Events vs No Event in DAPA-HF
End Point HR (95% CI)
HF hospitalization 6.21 (5.07–7.62)
Urgent HF visit 3.00 (1.39–6.48)
Outpatient intensification of HF therapy 2.67 (2.03–3.52)
*Adjusted for randomization group, demographics, NYHA class, LVEF, body mass index, pulse rate, systolic BP, serum creatinine and natriuretic peptide levels, history of HF hospitalization, AF, stroke, MI, and hypertension, and cardiac implantable electronic rhythm device use.

One in eight patients in the trial, overall, experienced at least one of the worsening HF events, Docherty said. "These events were prognostically important, with an approximately threefold higher risk of death following [such] an event compared to patients with no worsening heart failure event."

But, he noted, "dapagliflozin reduced the risk of worsening heart failure events, including outpatient worsening events, and cardiovascular death, compared with placebo."

The dapagliflozin group showed a 16.5 per 100 patient-years rate for the expanded composite outcome; the placebo group's rate was 22.6 per 100 patient-years. The risk reduction for patients on dapagliflozin reached 27%; the NNT fell to 16.

The risk declined significantly, as well, for each of the expanded end point's four components, Docherty observed.

Hazard Ratios for the Expanded Composite Outcome and its Components, Dapagliflozin vs Placebo, in DAPA-HF
End Point HR (95% CI)
Expanded composite outcome 0.73 (0.65–0.82)
CV death 0.82 (0.69–0.98)
HF hospitalization 0.70 (0.59–0.85)
Urgent HF visit 0.43 (0.20–0.90)
Outpatient intensification of HF therapy 0.74 (0.63–0.87)

Unsurprisingly, patients with a worsening HF event had entered the trial sicker than other patients, Docherty noted. They had been in a higher NYHA functional class, with greater natriuretic peptide levels, lower systolic blood pressure, and more left ventricular dysfunction, atrial fibrillation, and diabetes.

"Based on the results of this study, we may claim that such episodes of worsening heart failure are common; moreover, these events are associated with a higher risk of mortality compared to patients with no worsening heart failure events," said Yuri M. Lopatin, MD, PhD, Volgograd State Medical University, Russian Federation, as the invited discussant after the study presentation.

Patients in DAPA-HF were overwhelmingly treated with guideline-directed medical therapy at baseline, Lopatin observed, so it would be expected that those with features indicating more advanced HF would require "more frequent optimization of heart failure therapy."

DAPA-HF is sponsored by AstraZeneca. Docherty discloses that he is an employee of the University of Glasgow, which is paid by AstraZeneca for his participation in the trial. Lopatin had no disclosures.

HFA Discoveries 2020 from the Heart Failure Association (HFA) of the European Society of Cardiology: Late Breaking Science Session 6. Presented June 19, 2020.

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