Abstract 4140034: Orthostatic Pulse Pressure, A Novel Indicator of Preload Insufficiency, May Predict Clinical Response to SGLT2 Inhibition in HFpEF: Findings from the PRESERVED-HF Trial

Introduction: Preload insufficiency can mimic HFpEF or complicate its treatment, and SGLT2 inhibitors may worsen preload insufficiency by reducing stressed blood volume. A drop in pulse pressure (PP) when going from supine to standing (i.e., orthostatic PP) may indicate an inability to vasoconstrict the splanchnic circulation, leading to preload insufficiency. We, therefore, sought to determine baseline characteristics associated with orthostatic PP and whether the effects of dapagliflozin vary by baseline orthostatic PP in patients with HFpEF. Hypothesis: In patients with HFpEF, the magnitude of treatment response to dapagliflozin – in terms of efficacy and safety - may be associated with orthostatic PP at baseline. Methods: We measured orthostatic PP (standing PP – supine PP) at baseline in 321 of the 324 patients with HFpEF randomized in the PRESERVED-HF trial. We categorized patients into tertiles of orthostatic PP and compared baseline characteristics. We examined the interaction between baseline orthostatic PP, treatment, and the following outcomes during 12 weeks of follow-up: (1) Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); (2) 6-minute walk distance (6MWD); (3) volume depletion events. Results: At baseline, the median orthostatic PP was 0 mmHg (25 th -75 th percentile, -8.0, +5.3 mmHg). Patients with lower orthostatic PP had higher supine SBP and lower standing SBP. There were no differences in age, comorbidities, laboratory studies, KCCQ, and 6MWD among tertiles of orthostatic PP. Dapagliflozin improved KCCQ-CSS and 6MWD across the range of orthostatic PP; participants with the highest (vs lowest) orthostatic PP appeared to have numerically greater improvements with dapagliflozin, but these differences were not statistically significant (Table). Overall, 18 (5.6%) experienced volume depletion events (dapagliflozin 11 [6.8%], placebo 7 [4.3%]). In tertile 1 (lowest orthostatic PP), there were numerically more volume depletion events with dapagliflozin than placebo (8 [14.3%] vs 3 [5.0%] events); whereas the numbers of such events were similar in tertiles 2 and 3 (Table). Conclusions: In patients with HFpEF, dapagliflozin improved KCCQ and 6MWD across the range of orthostatic PP, although those with the highest (vs lowest) orthostatic PP appeared to have numerically greater improvements. Very low orthostatic PP may identify patients who could be at increased risk of volume depletion events with SGLT2 inhibitors.