Adding spironolactone or sacubitril/valsartan to empagliflozin suggested for a wide spectrum of symptomatic HFpEF
27 May 2022
bySarah Cheung
Spironolactone and sacubitril/valsartan are potential add-on therapies to empagliflozin for a wide spectrum of symptomatic heart failure with preserved ejection fraction (HFpEF), according to an evidence-based treatment algorithm presented at the 26th HKMF.
“Spironolactone or sacubitril/valsartan can be considered in [empagliflozin-treated] HFpEF patients with different clinical conditions. Spironolactone can be added to those with comorbidities, including obesity and diabetes, whereas sacubitril/valsartan can be added in females with lower left ventricular ejection fraction [LVEF],” suggested Dr Jo Jo Hai of the Department of Medicine, the University of Hong Kong.
To date, empagliflozin is the only US FDA–approved agent that significantly lowers the risk of a composite endpoint of cardiovascular (CV) mortality or heart failure (HF) hospitalization vs placebo in HFpEF patients with LVEF >40 percent (hazard ratio [HR], 0.79; 95 percent confidence interval [CI], 0.69 to 0.90; p<0.001). [N Engl J Med 2021;385:1451-1461] “In contrast, results were not significant in multiple large-scale clinical trials of other medications, including spironolactone and sacubitril/valsartan,” Hai said. [Nat Rev Cardiol 2020;17:559-573; N Engl J Med 2014;370:1383-1392; N Engl J Med 2019;381:1609-1620]
“Despite neutral effects in the overall study populations, spironolactone or sacubitril/valsartan may provide clinical benefits to some HFpEF patient cohorts,” she highlighted. [JACC Heart Fail 2020;8:172-184; N Engl J Med 2019;381:1609-1620; Circulation 2020;141:352-361]
A post hoc analysis of the phase III TOPCAT study showed that spironolactone significantly lowered the risk of the composite of CV mortality and HF hospitalization in 899 HFpEF patients with comorbidities, such as obesity, diabetes and high renin levels, vs placebo (HR, 0.75; 95 percent CI, 0.59 to 0.95; p=0.016). “[Despite worse overall prognosis,] patients with metabolic dysregulations achieved preferential responses to spironolactone [vs placebo],” stated Hai. [JACC Heart Fail 2020;8:172-184]
“Likewise, sacubitril/valsartan is preferred in some HFpEF subpopulations,” she continued. In a subgroup analysis of the phase III PARAGON-HF trial, sacubitril/valsartan significantly lowered HF hospitalization and CV mortality vs valsartan alone in both female patients (n=2,479) (HR, 0.73; 95 percent CI, 0.59 to 0.90) and patients with median LVEF ≤57 percent (n=2,495) (HR, 0.78; 95 percent CI, 0.64 to 0.95). A subsequent pooled analysis (n=13,195) further demonstrated benefits from sacubitril/valsartan in males and females with LVEF ≤45 percent and ≤65 percent, respectively. [N Engl J Med 2019;381:1609-1620; Circulation 2020;141:352-361]
“However, spironolactone and valsartan should be used sequentially to prevent hyperkalaemia,” Hai reminded. “Patients with LVEF ≥65 percent may have underlying factors that require cautious use of empagliflozin.”
