Treatment effects of ARNI in HF independent of eGFR decline during run-in phase

Introduction and methods

Background

Some patients with HF may experience a transient decline in eGFR of up to 15-20% after initiation of sacubitril/valsartan [1]. It is unknown whether eGFR decline has an effect on treatment outcome.

Aim of the study

This post hoc analysis of data from the PARADIGM-HF and PARAGON-HF study examined the frequency of eGFR decline after initiation of sacubitril/valsartan, and the extent to which eGFR decline affects the treatment effects of sacubitril/valsartan in HF patients.

Methods

The researchers performed a post hoc analysis of data from the PARADIGM-HF and PARAGON-HF study [2,3]. In these multicenter, double-blind phase 3 studies, patients were randomized between sacubitril/valsartan or enalapril (PARADIGM-HF) or valsartan (PARAGON-HF). In the prematurely terminated PARADIGM-HF study, 8442 patients ≥18 years of age with an LVEF ≤40% and NYHA class II-IV symptoms who additionally had elevated natriuretic peptides levels or had been hospitalized for HF in the past 12 months participated. The PARAGON-HF study enrolled patients ≥50 years of age with symptomatic HF, an LVEF ≥45%, NYHA class II-IV symptoms, elevated natriuretic peptides levels and evidence of structural heart disease. During sequential run-in periods, enalapril was titrated to 10 mg b.d. and then sacubitril/valsartan to 97/103 mg b.d. (PARADIGM-HF), or valsartan was titrated to 80 mg b.d. and then sacubitril/valsartan to 49/51 mg b.d. (PARAGON-HF). eGFR decline was defined as a deterioration in eGFR >15% during the run-in period.

Outcomes

The researchers were interested in: the frequency of eGFR decline after initiation of sacubitril/valsartan; and the extent to which such eGFR decline affects the treatment effects of sacubitril/valsartan on the primary outcome and safety outcomes. The primary outcome was a composite of CV death and first hospitalization for HF (PARADIGM-HF) or total hospitalizations for HF (PARAGON-HF). Safety outcomes were the frequency of hypotension (PARADIGM-HF: SBP <90 mmHg; PARAGON-HF: SBP <100 mmHg), elevated serum creatinine levels (≥2.0, ≥2.5 and ≥3.0 mg/dL), hyperkalemia, and drug discontinuation.

Main results

• During the sacubitril/valsartan run-in period, eGFR decline >15% occurred in 919 (11%) patients in the PARADIGM-HF study and in 461 (10%) of patients in the PARAGON-HF study; during the RAS inhibitor run-in period, eGFR decline occurred in 13% of patients in both studies.
• The median percent recovery from the lowest point to week 16 in patients who had experienced a decline in eGFR during the run-in phase was 49.7% in the sacubitril/valsartan group and 52.9% in the enalapril group of the PARADIGM-HF study (P=0.55), and 45.9% in the sacubitril/valsartan group and 43.9% in the valsartan group of the PARAGON-HF study (P=0.76).
• eGFR decline during the sacubitril/valsartan run-in period was not related to the primary outcome, in both the PARADIGM-HF study (HR: 1.01; 95%-CI: 0.87-1.16) and the PARAGON-HF study (RR: 1.26; 95%-CI: 0.98-1.61).
• The treatment effect of sacubitril/valsartan versus a RAS inhibitor on the primary outcome was independent of eGFR decline during the sacubitril/valsartan run-in period, both in the PARADIGM-HF study (eGFR decline: HR: 0.69; 95%-CI: 0.53-0.90; no eGFR decline: HR: 0.80; 95%-CI: 0.73-0.88; P-interaction=0.32) and in the PARAGON-HF study (eGFR decline: RR: 0.84; 95%-CI: 0.52-1.36; no eGFR decline: RR: 0.87; 95%-CI: 0.75-1.02; P-interaction=0.92); this was also true for eGFR decline during the RAS inhibitor run-in period.
• In both studies, the treatment effect of sacubitril/valsartan versus a RAS inhibitor on the safety outcomes was independent of eGFR decline during the sacubitril/valsartan run-in period.

Conclusion

References

Find this article online at J Am Coll Cardiol. Watch a video on this study