Literature - Chatur S, Claggett BL, Vardeny O, et al. - Eur J Heart Fail. 2022 Oct 1. doi: 10.1002/ejhf.2703.

Introduction and methods

Background

In patients with HFrEF, treatment with sacubitril/valsartan resulted in a lower loop diuretic requirement, compared with enalapril [1]. Consequently, the ESC guidelines state that in patients with HFrEF, the use of sacubitril/valsartan may allow a reduction in loop diuretic requirement [2], but data in patients with HFpEF are lacking. Previously, the PARAGON-HF study showed that in patients with symptomatic HFpEF, treatment with sacubitril/valsartan leads to a non-statistically significant lower incidence of the primary composite outcome of CV death or total hospitalizations for HF, compared with valsartan [3]. However, it is unclear how treatment with sacubitril/valsartan affects longitudinal patterns in loop diuretic use and to what extent the efficacy and safety of sacubitril/valsartan is affected by background diuretic therapy in patients with symptomatic HFpEF.

Aim of the study

This post hoc analysis of data from the PARAGON-HF study examined the influence of treatment with sacubitril/valsartan on longitudinal patterns in loop diuretic use and the extent to which the efficacy and safety of sacubitril/valsartan is affected by background diuretic therapy in patients with symptomatic HFpEF.

Methods

The researchers conducted a post hoc analysis of data from the PARAGON-HF study. In this multicenter, double-blind phase 3 study, 4822 adults ≥50 years with symptomatic HFpEF were randomized to twice-daily sacubitril/ valsartan (97 mg sacubitril and 103 mg valsartan) or valsartan (target dose of 160 mg). Participants had a NYHA class II-IV, elevated natriuretic peptide levels and evidence of structural heart disease. In this post hoc analysis, 4796 patients for whom data were available on diuretic therapy at baseline were divided into 3 groups: patients on no diuretic (n=341), a non-loop diuretic (n=698), or a loop diuretic (n=3757). The dose of loop diuretics was converted to an equivalent dose for furosemide (FED) and categorized as <40 (n=1255), 40 (n=1589) or >40 mg (n=913). Patients treated with a mineralocorticoid receptor antagonist alone were considered as if they were on no diuretic. Patients on multiple diuretics (n=330) were assigned to a group based on the most potent diuretic (e.g., patients treated with a non-loop diuretic and a loop diuretic were assigned to the group of patients on a loop diuretic).

Outcomes

The primary outcome was a composite of CV death and total hospitalizations for HF. Safety outcomes included the occurrence of hypotension (SBD <100 mmHg), elevated serum creatinine levels (≥2.0, ≥2.5 and ≥3.0 mg/dL) and drug discontinuation. The researchers were also interested in changes in loop diuretic use over time.

Main results

Efficacy

• The cumulative incidence of the primary composite outcome was lowest in the subgroup of patients on no diuretic at baseline and highest in the subgroup of patients on FED >40 mg (P<0.0001 )

.

• Background diuretic therapy had no statistically significant impact on the effect of sacubitril/valsartan on the primary composite outcome (P-interaction=0.65).

Safety

• Background diuretic therapy had no statistically significant impact on the effect of sacubitril/valsartan on the occurrence of hypotension, serum creatinine concentration ≥2.0, ≥2.5 and ≥3.0 mg/dl and drug discontinuation.

Changes in loop diuretic use over time

• During follow-up, the mean FED did not differ between the sacubitril/valsartan and valsartan groups.
• In a subgroup of patients on no loop diuretic at baseline (n=1083), treatment with sacubitril/valsartan resulted in a non-statistically significant lower risk of new loop diuretic initiations, compared with valsartan (HR: 0.83; 95%CI: 0.68-1.00; P=0.055).
• In baseline diuretic users, there was no difference on new diuretic discontinuations or treatment disruptions over the course of the trial.

Conclusion

References

Find this article online at Eur J Heart Fail.