Patients With HFrEF, HFpEF See Different Functional Capacity Benefits With Dapagliflozin

For patients with heart failure with reduced ejection fraction (HFrEF), dapagliflozin was shown to improve the Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS) but not the KCCQ Physical Limitation Scale (PLS) or the 6-minute walk distance (6MWD), according to new research published in the American Heart Association’s Circulation.

For patients with HF with preserved ejection fraction (HFpEF), dapagliflozin did not improve any of these outcomes. In a post hoc analysis with all patients across the full spectrum of HF ejection fraction, dapagliflozin had an overall benefit on KCCQ-TSS and KCCQ-PLS, but not 6MWD.

These findings are based on the DETERMINE double-blind, placebo-controlled, multicenter trials, which included 313 patients with HFrEF in the DETERMINE-Reduced trial and 504 patients with HFpEF in the DETERMINE-Preserved trials. All patients had New York Heart Association class II or III symptoms as well as elevated natriuretic peptide levels, and outcomes were based on 16 weeks of treatment with dapagliflozin.

Patient and caretaker | Image credit: Rido – stock.adobe.com

“The results from the DETERMINE trials add to the body of evidence supporting the benefits of dapagliflozin in improving patient-reported symptom burden and functional limitations as assessed by the Kansas City Cardiomyopathy Questionnaire,” the authors said when pointing out the clinical implications of their study. “The neutral effect of dapagliflozin on 6-minute walk distance, along with the results of additional trials with sodium-glucose cotransporter 2 inhibitors and other heart failure treatments showing no benefit on 6-minute walk distance despite beneficial effects on patient-reported outcomes, raises questions as to its value as a measure of functional capacity in heart failure.”

Among those with HFrEF, the median difference in KCCQ-TSS between baseline and 16 weeks was 4.23 (95% CI, 0.96-8.22; P = .022) in favor of dapagliflozin when adjusted for placebo, and the median placebo-corrected difference in KCCQ-PLS was 4.2 (95% CI, 0.00-8.3; P = .058). Meanwhile, the median adjusted difference in 6MWD was 3.2 m (95% CI, –6.5 to 13.0; P = .69). For those with HFpEF, the median adjusted 16-week differences in KCCQ-TSS and KCCQ-PLS were 3.2 (95% CI, 0.4-6.0; P = .079) and 3.1 (–0.1 to 5.4; P = .23), respectively, and the median difference in 6MWD was 1.6 m (95% CI, –5.9 to 9.0; P = .67). In DETERMINE-Pooled, an exploratory post hoc analysis combining both trials, the median 16-week adjusted difference was 3.7 (1.5-5.9; P = .005) for KCCQ-TSS, 4.0 (0.3-4.9; P = .036) for KCCQ-PLS, and 2.5 m (–3.5 to 8.4; P = .50) for 6MWD.

A responder analysis also showed the proportion of patients in each group that demonstrated improvement, stability, deterioration, or death. In both DETERMINE-Reduced and DETERMINED-Preserved, a higher proportion of patients on dapagliflozin saw improved KCCQ-TSS, whereas a higher proportion of patients on placebo saw a deterioration in score.

For KCCQ-PLS, again, a higher percentage of patients on dapagliflozin saw improvements across both trials. However, more patients remained stable in this score in the placebo groups than treatment groups, and whereas deterioration was higher for patients with HFrEF on placebo, slightly more patients with HFpEF on dapagliflozin deteriorated in their score compared with patients on placebo.

For 6MWD, the ratios were much more similar, so it was harder to notice a clear benefit of dapagliflozin in this area.

“Given that these trials were adequately powered to detect a meaningful change in 6MWD, and rigorously designed and conducted, the question is whether the treatments do not improve functional capacity or whether the 6-minute walk test is not a good measure of functional capacity,” the authors mentioned.

In DETERMINE-Reduced, 12.2% of patients in the dapagliflozin group experienced a serious adverse event (AE) compared with 14.6% in the placebo group, and AEs leading to discontinuation of the study drug were observed in 5.8% of patients taking dapagliflozin and 7.6% of patients taking placebo. Meanwhile, in DETERMINE-Preserved, 10.3% of patients in the dapagliflozin group experienced a serious AE compared with 7.6% in the placebo group, and AEs leading to discontinuation of the study drug occurred in 3.6% and 2.4% of patients taking dapagliflozin and placebo, respectively.

Due to the differing timelines of the DETERMINE trials, the COVID-19 pandemic did not significantly impact DETERMINE-Reduced but did affect DETERMINE-Preserved, where some in-person follow-up visits became impractical. It’s important to note that in DETERMINE-Preserved, 7.1% of patients assigned to dapagliflozin and 9.6% assigned to placebo did not have a final visit—which could skew some results—with 4.7% and 4.8%, respectively, conducting their final visit remotely.

Reference

McMurray JJV, Docherty KF, de Boer RA, et al. Effect of dapagliflozin versus placebo on symptoms and 6-minute walk distance in patients with heart failure: the DETERMINE randomized clinical trials. Circulation. Published online December 7, 2023. doi:10.1161/CIRCULATIONAHA.123.065061