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Limited influence of ARNI on loop diuretic use in symptomatic HFpEF

onlinelibrary.wiley.com
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

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”.

References

1. Vardeny O, Claggett B, Kachadourian J, et al. Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail. 2019;21:337-41.

2. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022;24:4-131.

3. Solomon SD, McMurray JJV, Anand IS, et al.; PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381:1609-20.

Find this article online at Eur J Heart Fail.

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Schedule28 May 2024