Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial

Abstract

Background: Frailty is increasing in prevalence and because frail patients are often perceived to have a less favorable benefit/risk profile, they may be less likely to receive new pharmacological treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure and mildly reduced and preserved ejection fraction randomized in DELIVER. Methods: Frailty was measured using the Rockwood cumulative deficit approach. The primary endpoint was time to a first worsening heart failure event or cardiovascular death. Results: Of the 6263 patients randomized, a Frailty Index (FI) was calculable in 6258. In total, 2,354 (37.6%) patients had class 1 frailty (FI <0.210, i.e., not frail), 2,413 (38.6%) were in class 2 (FI 0.211-0.310, i.e., more frail), and 1,491 (23.8%) had class 3 frailty (FI >0.311, i.e., most frail). Greater frailty was associated with a higher rate of the primary endpoint (per 100 person years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7), P<0.001. The effect of dapagliflozin (as a hazard ratio) on the primary endpoint from FI class 1 to 3 was: 0.85 (95% CI, 0.68-1.06); 0.89 (0.74-1.08); and 0.74 (0.61-0.91), respectively (P interaction =0.40). Although frailer patients had worse KCCQ scores at baseline, the improvement with dapagliflozin was greater than in less frail patients: placebo-corrected improvement in KCCQ-OSS at 4 months FI class 1, 0.3 (95% CI -0.9 to 1.4); class 2, 1.5 (0.3-2.7); and class 3, 3.4 (1.7-5.1) [P interaction =0.021]. Adverse reactions and treatment discontinuation, while more frequent in frailer patients, were not more common with dapagliflozin than placebo, irrespective of frailty class. Conclusions: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with greater frailty.

Sodium–glucose cotransporter 2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: time to deliver implementation

“…This is indeed supported by the current analysis from DELIVER, where the magnitude of KCCQ‐TSS improvement was largest among those with most severe NYHA class. A similar theme has emerged in analyses of patients with worse symptoms, obesity, and frailty, each a patient subset where efforts to improve patient quality of life may be a particularly important driver of healthcare decisions 6,10,11 . The amplified benefits on symptoms and quality of life in these more debilitated patients are coupled with consistently strong safety and tolerability.…”

“…The amplified benefits on symptoms and quality of life in these more debilitated patients are coupled with consistently strong safety and tolerability. For example, even in patients with severe NYHA class, active/recent hospitalization, obesity, older age, or substantial frailty, rates of adverse reactions and treatment discontinuation with SGLT2i are no different than placebo, thus further solidifying the net clinical benefit of initiating therapy in these patients who arguably need it the most 10–13 . Nevertheless, it should be noted that only 18 (0.3%) of patients enrolled in DELIVER were NYHA class IV at baseline and only 18 patients (0.3%) were NYHA class IV in EMPEROR‐Preserved 1,2 .…”

“…For example, even in patients with severe NYHA class, active/recent hospitalization, obesity, older age, or substantial frailty, rates of adverse reactions and treatment discontinuation with SGLT2i are no different than placebo, thus further solidifying the net clinical benefit of initiating therapy in these patients who arguably need it the most. [10][11][12][13] Nevertheless, it should be noted that only 18 (0.3%) of patients enrolled in DELIVER were NYHA class IV at baseline and only 18 patients (0.3%) were NYHA class IV in EMPEROR-Preserved. Whether the benefits and safety of SGLT2i can be generalized to NYHA class IV patients will require further study.…”

“…A similar theme has emerged in analyses of patients with worse symptoms, obesity, and frailty, each a patient subset where efforts to improve patient quality of life may be a particularly important driver of healthcare decisions. 6,10,11 The amplified benefits on symptoms and quality of life in these more debilitated patients are coupled with consistently strong safety and tolerability. For example, even in patients with severe NYHA class, active/recent hospitalization, obesity, older age, or substantial frailty, rates of adverse reactions and treatment discontinuation with SGLT2i are no different than placebo, thus further solidifying the net clinical benefit of initiating therapy in these patients who arguably need it the most.…”

Does the Measurement of Ejection Fraction Still Make Sense in the HFpEF Framework? What Recent Trials Suggest

“…Demographic characteristics showed 44% were female, the mean LVEF was 54%, the mean age 71 years, the mean NT-proBNP was 1011 pg/mL and 18% had improved LVEF. The established primary end point was combination of CV death and worsening HF [ 32 ]. During the follow up (mean of 2.3 years), dapaglifozin demonstrated an 18% relative risk reduction (HR 0.82; CI: 0.73–0.92), along with a non-statistical significance in overall CV mortality reduction (HR 0.88; CI 0.74–1.05).…”