Variation in Renal Function Following Transition to Sacubitril/Valsartan in Patients With Heart Failure

Background: Some patients with heart failure may experience transient changes in kidney function upon transition to sacubitril/valsartan. Whether such changes portend adverse outcomes or influence long-term treatment benefits with sacubitril/valsartan continuation is unknown.

Objectives: This investigation aimed to evaluate the association between the occurrence of moderate estimated glomerular filtration rate (eGFR) decline (>15%) after initial exposure to sacubitril/valsartan and subsequent cardiovascular outcomes and its treatment benefits in PARADIGM-HF and PARAGON-HF.

Methods: In sequential run-in phases, patients were titrated to enalapril 10 mg twice daily and then sacubitril/valsartan 97 mg/103 mg twice daily (in PARADIGM-HF) or valsartan 80 mg twice daily and then sacubitril/valsartan 49 mg/51 mg twice daily (in PARAGON-HF).

Results: Among randomized participants, 11% in PARADIGM-HF and 10% in PARAGON-HF experienced eGFR decline (>15%) during sacubitril/valsartan run-in. eGFR partially recovered (from nadir to postrandomization week 16) regardless of sacubitril/valsartan continuation or switch to renin-angiotensin system inhibitor (RASi) postrandomization. Initial eGFR decline was not consistently associated with clinical outcomes in either trial. Treatment benefits of sacubitril/valsartan vs RASi on primary outcomes were similar irrespective of run-in eGFR decline in PARADIGM-HF (eGFR decline, HR: 0.69; 95% CI: 0.53-0.90; and no eGFR decline, HR: 0.80; 95% CI: 0.73-0.88; P_interaction = 0.32) and PARAGON-HF (eGFR decline, rate ratio [RR]: 0.84; 95% CI: 0.52-1.36 and no eGFR decline, RR: 0.87; 95% CI: 0.75-1.02, P_interaction = 0.92). The treatment effect of sacubitril/valsartan remained consistent across a range of eGFR declines.

Conclusions: Moderate eGFR decline when transitioning from RASi to sacubitril/valsartan is not consistently associated with adverse outcomes, and its long-term benefits are retained in heart failure across a broad range of eGFR declines. Early eGFR changes should not deter continuation of sacubitril/valsartan or stall uptitration. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711; Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitors with Angiotensin-Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).