CV and kidney outcomes with ARNI in HFpEF independent of MRA background use
This subanalysis of PARAGON-HF showed that efficacy outcomes with sacubitril/valsartan compared to valsartan were independent of MRA use in patients with HFpEF.
Introduction and methods
Patients with HFpEF have limited options for evidence-based treatment and management focuses on comorbid conditions. Current guidelines recommend the consideration of mineralocorticoid receptor antagonists (MRAs) in addition to an ARB, such as valsartan, in selected HFpEF patients . Since resistant hypertension is common in patients with HFpEF, the MRA spironolactone is frequently used for blood pressure control [2,3].
The PARAGON-HF trial (Prospective Comparison of ARNI with ARB Global Outcomes in HF with preserved Ejection Fraction) compared the effects of sacubitril/valsartan with valsartan on CV and renal outcomes in patients with HFpEF. This trial just missed significance for the primary endpoint CV death and HF hospitalization, but a significant lowering of the prespecified renal composite endpoint was observed with sacubitril/valsartan compared with valsartan . The efficacy and safety of sacubitril/valsartan in combination with an MRA in patients with HFpEF has not been evaluated yet.
This prespecified subanalysis of the PARAGON-HF trial assessed CV and renal outcomes and safety of sacubitril/valsartan compared to valsartan in patients with HFpEF according to MRA background.
Patients (≥50 years) with symptomatic HF (New York Heart Association [NYHA] functional classes II-IV), LVEF ≥45%, structural heart disease, need for diuretics, and elevated natriuretic peptides in the presence (n=1,239) or absence (n=3,557) of an MRA were included in the PARAGON-HF study. The primary endpoint was a composite of total (first and recurrent) hospitalization for HF and CV death. Secondary outcomes included a renal composite outcome of ≥50% decrease in eGFR, development of end-stage renal disease, or renal death The cardiorenal composite outcome was defined as first hospitalization for HF, CV death, ≥50% decrease in eGFR, development of end-stage renal disease, or renal death. Additional analysis included the slope of the change in eGFR during treatment (till week 192). Hyperkalemia (potassium >5.5 mmol/L) and severe hyperkalemia (potassium >6.0 mmol/L) were assessed as safety outcomes. Patients in this study were stratified by MRA treatment at baseline and treatment effects of sacubitril/valsartan were compared to valsartan.
- 26% Of all randomized patients were using an MRA at baseline. 87.3% Of these patients were treated with spironolactone. MRA users had more advanced NYHA functional class, higher NT-proBNP levels, lower LVEF, and were more commonly hospitalized for HF compared to nonusers (all P<0.001). Baseline renal function was similar in both groups.
- There was no difference in treatment effect of sacubitril/valsartan compared to valsartan on the primary outcome in MRA users and nonusers (rate ratio: 0.73, 95% CI: 0.56-0.95 and rate ratio: 0.94, 95% CI: 0.79-1.11, respectively, P interaction=0.11).
- The treatment effect of sacubitril/valsartan compared to valsartan in the presence or absence of an MRA was not significantly different for total hospitalization due to HF (rate ratio: 0.68, 95% CI: 0.50-0.91 and rate ratio: 0.93, 95% CI: 0.76-1.13, respectively, P interaction=0.08) or for CV death (P interaction=0.94).
- The incidence rate of renal outcomes was significantly lower in patients treated with sacubitril/valsartan compared to those with valsartan in MRA users and nonusers (HR 0.31, 95% CI: 0.13-0.76 and HR 0.59, 95% CI: 0.36-0.95, respectively, P interaction=0.21).
- There was no difference in treatment effect of sacubitril/valsartan compared to valsartan on the cardiorenal composite endpoint between MRA users and nonusers (rate ratio: 0.77, 95% CI: 0.62-0.96 and rate ratio: 0.93, 95% CI: 0.81-1.07, respectively, P interaction=0.15).
- The attenuation of the slope of eGFR decline in patients with sacubitril/valsartan compared to valsartan was greater in MRA users than in nonusers with an adjusted mean difference of 1.2 mL/min/1.73 m²/year (95% CI: 0.6-1.7) in MRA users and 0.4 mL/min/1.73 m²/year (95% CI: 0.1-0.7) in nonusers (P interaction=0.01).
- The incidence rate of hyperkalemia was higher among patients with an MRA (7.1 per 100 patient-years) than nonusers (4.7 per 100 patient-years) during the follow-up (HR 1.51, 95% CI: 1.28-1.77). Incidence rate for severe hyperkalemia did not differ between MRA users and nonusers.
This subanalysis of the PARAGON-HF trial showed that the clinical efficacy of sacubitril/valsartan compared to valsartan for predefined CV and renal composite outcomes were independent of MRA background use in patients with HFpEF. Moreover, eGFR decline was more attenuated over time in patients with sacubitril/valsartan compared to valsartan. This renal treatment effect was most prominent among MRA users.
The authors suggest that a combination therapy with sacubitril/valsartan and MRA could add possible beneficial value to patients with HFpEF.