Chatur Safia, Claggett Brian L, McCausland Finnian R, Rouleau Jean, Zile Michael R, Packer Milton, Pfeffer Marc A, Lefkowitz Martin, McMurray John J V, Solomon Scott D, Vaduganathan Muthiah
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: https://twitter.com/safchat.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Am Coll Cardiol. 2023 Apr 18;81(15):1443-1455. doi: 10.1016/j.jacc.2023.02.009. Epub 2023 Feb 20.
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.
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.
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).
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 = 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 = 0.92). The treatment effect of sacubitril/valsartan remained consistent across a range of eGFR declines.
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).
一些心力衰竭患者在转换为沙库巴曲缬沙坦治疗时可能会出现肾功能的短暂变化。这种变化是否预示不良结局或影响继续使用沙库巴曲缬沙坦的长期治疗获益尚不清楚。
本研究旨在评估在PARADIGM-HF和PARAGON-HF研究中，初始使用沙库巴曲缬沙坦后出现中度估算肾小球滤过率（eGFR）下降（>15%）与后续心血管结局及其治疗获益之间的关联。
在序贯导入期，患者先滴定至依那普利每日2次、每次10 mg，然后滴定至沙库巴曲缬沙坦每日2次、每次97 mg/103 mg（PARADIGM-HF研究），或先滴定至缬沙坦每日2次、每次80 mg，然后滴定至沙库巴曲缬沙坦每日2次、每次49 mg/51 mg（PARAGON-HF研究）。
在随机分组的参与者中，PARADIGM-HF研究中有11%、PARAGON-HF研究中有10%的患者在沙库巴曲缬沙坦导入期出现eGFR下降（>15%）。无论随机分组后继续使用沙库巴曲缬沙坦还是换用肾素-血管紧张素系统抑制剂（RASi），eGFR均有部分恢复（从最低点至随机分组后第16周）。在两项试验中，初始eGFR下降均未始终如一地与临床结局相关。在PARADIGM-HF研究中（eGFR下降，HR：0.69；95%CI：0.53-0.90；未出现eGFR下降，HR：0.80；95%CI：0.73-0.88；P=0.32）以及PARAGON-HF研究中（eGFR下降，率比[RR]：0.84；95%CI：0.52-1.36；未出现eGFR下降，RR：0.87；95%CI：0.75-1.02，P=0.92），与RASi相比，沙库巴曲缬沙坦对主要结局的治疗获益相似。无论导入期eGFR下降情况如何，沙库巴曲缬沙坦的治疗效果在一系列eGFR下降范围内均保持一致。
从RASi转换为沙库巴曲缬沙坦时出现的中度eGFR下降并非始终与不良结局相关，并且在广泛的eGFR下降范围内，其对心力衰竭的长期获益得以保留。早期eGFR变化不应妨碍继续使用沙库巴曲缬沙坦或阻止剂量递增。（射血分数保留的心力衰竭患者中LCZ696与缬沙坦相比对发病率和死亡率的疗效和安全性[PARAGON-HF]；NCT01920711；血管紧张素受体脑啡肽酶抑制剂与血管紧张素转换酶抑制剂对心力衰竭全球死亡率和发病率影响的前瞻性比较[PARADIGM-HF]；NCT01035255）
