DEFINE-HF: Dapagliflozin improves HF-related health regardless of diabetes status
PHILADELPHIA — In patients with HF with reduced ejection fraction with or without diabetes, the SGLT2 inhibitor dapagliflozin was associated with clinically meaningful improvements in HF-related health status or N-terminal pro-B type natriuretic peptide at 12 weeks, according to results of the DEFINE-HF trial presented at the Heart Failure Society of America Scientific Meeting.
While dapagliflozin (Farxiga, AstraZeneca) met its co-primary endpoint of meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, it did not meet its other co-primary endpoint of improvement in mean NT-proBNP at an average of 6 and 12 weeks, Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine said during a presentation here.
In related news, AstraZeneca announced that the FDA has granted fast-track status for development of dapagliflozin to reduce CV death or HF worsening in patients with HF with reduced or preserved ejection fraction. The program accelerates the development and review of new medicines for which there is an unmet need, according to a company press release.
As Healio previously reported, in the DAPA-HF trial presented at the European Society of Cardiology Congress, dapagliflozin reduced risk for CV death or HF worsening when added to standard therapy in patients with HFrEF with or without diabetes.
For the new, investigator-initiated DEFINE-HF trial, researchers randomly assigned 263 patients with HF with ejection fraction of 40% or less, NYHA class II or III status, estimated glomerular filtration rate at least 30 mL/min/1.73m2 and elevated natriuretic peptide to receive dapagliflozin 10 mg daily or placebo for 12 weeks. Most patients were on optimal medical therapy.
“No prior trials have focused specifically on the early effects of SGLT2 inhibitors on health status and natriuretic peptides,” Kosiborod said. “The DEFINE-HF trial was specifically designed to address this knowledge gap.”
The first primary endpoint was mean NT-proBNP at an average of 6 weeks and 12 weeks. The second primary endpoint was percentage of patients with at least a 5-point increase in HF-specific health status on the KCCQ overall summary score or at least a 20% decrease in NT-proBNP at 12 weeks. The findings were simultaneously published in Circulation.
Mean NT-proBNP at an average of 6 weeks and 12 weeks was 1,133 pg/nL in the dapagliflozin group and 1,191 pg/nL in the placebo group (P = .43), according to the researchers.
However, 61.5% of patients in the dapagliflozin group met the second primary endpoint compared with 50.4% of the placebo group (adjusted OR = 1.8; 95% CI, 1.03-3.06; number needed to treat = 10), Kosiborod said during the presentation.
The results of the second primary endpoint did not differ between patients with and without diabetes (P for interaction = .304), nor by renin-angiotensin-aldosterone inhibitor used, sex, age, race, history of atrial fibrillation, NT-proBNP level (above vs. below median), LVEF, KCCQ overall summary score, loop diuretic dose, ischemic vs. nonischemic HF type and estimated glomerular filtration rate, according to the researchers.
Three domains of the KCCQ score — total symptoms, physical limitations and quality of life — showed greater improvement at 12 weeks in the dapagliflozin group than in the placebo group, while the fourth domain, social limitations score, did not, according to the researchers.
In a time-to-first-event analysis, there was no difference between the groups in adjudicated HF events (HR = 0.84; 95% CI, 0.35-1.97).
Adverse events were similar between the groups, Kosiborod said.
“Collectively, we find these results [of DEFINE-HF and DAPA-HF] support the use of dapagliflozin as a treatment option in patients with HFrEF, regardless of diabetes status,” Kosiborod said during his presentation. “We believe these results have important implications for clinical practice.” – by Erik Swain
Kosiborod M, et al. Late-Breaking Clinical Trials. Presented at: Heart Failure Society of America Scientific Meeting; Sept. 13-16, 2019; Philadelphia.
Disclosures: The trial was initiated by the investigators and funded by AstraZeneca. Kosiborod reports he received grant/research support from AstraZeneca and Boehringer Ingelheim, honoraria from AstraZeneca, Boehringer Ingelheim and Novo Nordisk, and consultant fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk and Sanofi Aventis. Please see the study for the other authors’ relevant financial disclosures.