Limited influence of ARNI on loop diuretic use in symptomatic HFpEF
Sacubitril/valsartan and loop diuretic requirement in heart failure with preserved ejection fraction in the PARAGON-HF trial
Introduction and methods
In patients with HFrEF, treatment with sacubitril/valsartan resulted in a lower loop diuretic requirement, compared with enalapril . Consequently, the ESC guidelines state that in patients with HFrEF, the use of sacubitril/valsartan may allow a reduction in loop diuretic requirement , 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 . 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.
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).
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.
- 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).
- 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.
This post hoc analysis of data from the PARAGON-HF study shows that in patients with symptomatic HFpEF, the influence of sacubitril/valsartan on longitudinal patterns in loop diuretic use is limited. Background diuretic therapy does not affect the efficacy and safety of sacubitril/valsartan, compared with valsartan.
In their summary, the investigator noted that “in contrast to HFreF, routine diuretic dose reduction on sacubitril/valsartan initiation in HFpEF may be less warranted”.