Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF

Objectives: This study sought to evaluate the efficacy and safety of sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF) according to background mineralocorticoid receptor antagonist (MRA) therapy.

Background: Current guidelines recommend consideration of MRAs in selected patients with HFpEF. This study assessed cardiovascular outcomes, renal outcomes, and safety of sacubitril/valsartan compared with valsartan in patients with HFpEF according to background MRA treatment.

Methods: PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. In a pre-specified subgroup analysis, the effect of sacubitril/valsartan versus valsartan was evaluated according to baseline MRA use on the primary study composite of total heart failure hospitalizations and cardiovascular death using semiparametric proportional rates methods, as well as the renal composite of ≥50% decrease in estimated glomerular filtration rate, development of end-stage renal disease, or death from renal causes using Cox proportional hazards regression models. Annual decline in estimated glomerular filtration rate was analyzed with repeated-measures mixed-effect models. Key safety outcomes included incidence of hypotension, hyperkalemia, and elevations in serum creatinine above predefined thresholds.

Results: Patients treated with MRAs at baseline (n = 1,239, 26%), compared with MRA nonusers (n = 3,557, 74%), were younger (72 vs. 73 years), more often male (52% vs. 47%), had lower left ventricular ejection fraction (57% vs. 58%), and a higher proportion of prior HF hospitalization (59% vs. 44%) (all p < 0.001). Efficacy of sacubitril/valsartan compared with valsartan with regard to the primary cardiovascular (for MRA users: rate ratio: 0.73; 95% confidence interval [CI]: 0.56 to 0.95; vs. for MRA nonusers: rate ratio: 0.94; 95% CI: 0.79 to 1.11; p_interaction = 0.11) and renal endpoints (for MRA users: hazard ratio: 0.31; 95% CI: 0.13 to 0.76; vs. for MRA non-users: HR: 0.59; 95% CI: 0.36 to 0.95; p_interaction = 0.21) did not significantly vary by baseline MRA use. The incidence of key safety outcomes including hypotension and severe hyperkalemia (K > 6.0 mmol/l) did not vary by baseline MRA use. However, annual decline in estimated glomerular filtration rate was less with the combination of MRA and sacubitril/valsartan (for MRA users: absolute difference favoring sacubitril/valsartan: +1.2 ml/min/1.73 m² per year; 95% CI: 0.6 to 1.7; vs. for MRA nonusers: +0.4; 95% CI: 0.1 to 0.7; p_interaction = 0.01).

Conclusions: Clinical efficacy of sacubitril/valsartan compared with valsartan with regard to predefined cardiorenal composite outcomes in PARAGON-HF was consistent in patients treated and not treated with MRA at baseline. Addition of sacubitril/valsartan rather than valsartan alone to MRA appears to be associated with a lesser decline in renal function and no increase in severe hyperkalemia. These data support possible added value of combination treatment with sacubitril/valsartan and MRA in patients with HFpEF. (Prospective Comparison of ARNI [angiotensin receptor -neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).