This subanalysis of PARAGON-HF showed that efficacy outcomes with sacubitril/valsartan compared to valsartan were independent of MRA use in patients with HFpEF.

Literature - Jering KS, Zannad F, Claggett B, et al. - JACC Heart Fail. 2021;9:13-24. doi: 10.1016/j.jchf.2020.08.014.

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 [1]. 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 [4]. 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.

Main results

• 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.

Conclusion

References

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