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The efficacy and safety of sacubitril/valsartan in chronic kidney disease: a systematic review and meta-analysis

  • Nephrology - Original Paper
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Abstract

Background

Sacubitril/valsartan, a new pharmacological class of angiotensin receptor neprilysin inhibitor, is beneficial to heart failure through blocking the degradation of natriuretic peptides and inhibiting renin–angiotensin–aldosterone system (RAAS) activation which also relate to the pathophysiologic mechanisms of chronic kidney disease (CKD). However, its effects on CKD remain unclear. To assess the efficacy and safety of sacubitril/valsartan for patients with CKD, we performed this meta-analysis.

Methods

The Embase, PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sacubitril/valsartan with ACEI/ARBs in patients with CKD whose estimated glomerular filtration rate (eGFR) was below 60 mL/min/1.73 m2. We adopted the Cochrane Collaboration tool for assessing the risk of bias. The effect size was estimated using the odds ratio (OR) with 95% confidence interval (CI).

Results

Six trials with a total of 6217 patients with CKD were included. In terms of cardiovascular events, sacubitril/valsartan attenuated the risk of cardiovascular death or heart failure hospitalization (OR: 0.68, 95% CI 0.61–0.76, P < 0.00001, I2 = 43%). With respect to renal function, sacubitril/valsartan prevented the incidence of serum creatinine (Scr) elevation among patients with CKD (OR: 0.79, 95% CI 0.67–0.95, P = 0.01, I2 = 0%). Subgroup analysis about eGFR demonstrated that with long follow-up, sacubitril/valsartan significantly decreased the number of patients with more than 50% reduction in eGFR compared with ACEI/ARBs (OR: 0.52, 95% CI 0.32–0.84, P = 0.008, I2 = 9%). In patients with CKD, the incidence of end-stage renal disease (ESRD) was reduced with sacubitril/valsartan treatment, despite no statistically significant difference between the two groups (OR: 0.59, 95% CI 0.29–1.20, P = 0.14, I2 = 0%). As for the safety, we found that sacubitril/valsartan was associated with the occurrence of hypotension (OR: 1.71, 95% CI 1.15–2.56, P = 0.008, I2 = 51%). However, there was no trend towards increasing the risk of hyperkalemia in patients who received sacubitril/valsartan (OR: 1.09, 95% CI 0.75–1.60, P = 0.64, I2 = 64%).

Conclusion

This meta-analysis indicated that sacubitril/valsartan improved renal function and conferred effective cardiovascular benefits in patients with CKD, without serious safety issues being observed. Thus, sacubitril/valsartan may be a promising option for patients with CKD. Certainly, further large-scale randomized controlled trials are needed to confirm these conclusions.

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References

  1. Kuang H, Huang X, Zhou Z, Cheng X, Xu G (2021) Sacubitril/valsartan in chronic kidney disease: from pharmacological mechanism to clinical application. Eur J Pharmacol 907:174288. https://doi.org/10.1016/j.ejphar.2021.174288

    Article  CAS  PubMed  Google Scholar 

  2. Global, Regional, and National Burden of Chronic Kidney Disease, 1990–2017: a systematic analysis for the global burden of disease study 2017 (2020). Lancet (London, England) 395(10225):709–733. https://doi.org/10.1016/s0140-6736(20)30045-3

  3. Li N, Lv D, Zhu X, Wei P, Gui Y, Liu S, Zhou E, Zheng M, Zhou D, Zhang L (2021) Effects of SGLT2 inhibitors on renal outcomes in patients with chronic kidney disease: a meta-analysis. Front Med 8:728089. https://doi.org/10.3389/fmed.2021.728089

    Article  Google Scholar 

  4. Jankowski J, Floege J, Fliser D, Böhm M, Marx N (2021) Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143(11):1157–1172. https://doi.org/10.1161/circulationaha.120.050686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kang H, Zhang J, Zhang X, Qin G, Wang K, Deng Z, Fang Y, Chen G (2020) Effects of sacubitril/valsartan in patients with heart failure and chronic kidney disease: a meta-analysis. Eur J Pharmacol 884:173444. https://doi.org/10.1016/j.ejphar.2020.173444

    Article  CAS  PubMed  Google Scholar 

  6. Xu Y, Chen Y, Zhao JW, Li C, Wang AY (2021) Effect of angiotensin–neprilysin versus renin–angiotensin system inhibition on renal outcomes: a systematic review and meta-analysis. Front Pharmacol 12:604017. https://doi.org/10.3389/fphar.2021.604017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, Senni M, Gori M, Jhund PS, McGrath MM, Packer M, Shi V, Van Veldhuisen DJ, Zannad F, Comin-Colet J, Pfeffer MA, McMurray JJV, Solomon SD (2020) Angiotensin–neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction. Circulation 142(13):1236–1245. https://doi.org/10.1161/circulationaha.120.047643

    Article  CAS  PubMed  Google Scholar 

  8. Voors AA, Gori M, Liu LC, Claggett B, Zile MR, Pieske B, McMurray JJ, Packer M, Shi V, Lefkowitz MP, Solomon SD (2015) Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 17(5):510–517. https://doi.org/10.1002/ejhf.232

    Article  CAS  PubMed  Google Scholar 

  9. Damman K, Gori M, Claggett B, Jhund PS, Senni M, Lefkowitz MP, Prescott MF, Shi VC, Rouleau JL, Swedberg K, Zile MR, Packer M, Desai AS, Solomon SD, McMurray JJV (2018) Renal effects and associated outcomes during angiotensin–neprilysin inhibition in heart failure. JACC Heart Fail 6(6):489–498. https://doi.org/10.1016/j.jchf.2018.02.004

    Article  PubMed  Google Scholar 

  10. Quiroga B, de Santos A, Sapiencia D, Saharaui Y, Álvarez-Chiva V (2019) Sacubitril/valsartan in chronic kidney disease, the nephrologist point of view. Nefrologia 39(6):646–652. https://doi.org/10.1016/j.nefro.2019.01.005

    Article  PubMed  Google Scholar 

  11. Haynes R, Judge PK, Staplin N, Herrington WG, Storey BC, Bethel A, Bowman L, Brunskill N, Cockwell P, Hill M, Kalra PA, McMurray JJV, Taal M, Wheeler DC, Landray MJ, Baigent C (2018) Effects of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease. Circulation 138(15):1505–1514. https://doi.org/10.1161/circulationaha.118.034818

    Article  CAS  PubMed  Google Scholar 

  12. Cho IJ, Kang SM (2021) Angiotensin receptor–neprilysin inhibitor in patients with heart failure and chronic kidney disease. Kidney Res Clin Pract 40(4):555–565. https://doi.org/10.23876/j.krcp.21.900

    Article  PubMed  PubMed Central  Google Scholar 

  13. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ (2012) The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet (London) 380(9851):1387–1395. https://doi.org/10.1016/s0140-6736(12)61227-6

    Article  CAS  Google Scholar 

  14. Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E (2019) Angiotensin–neprilysin inhibition in acute decompensated heart failure. N Engl J Med 380(6):539–548. https://doi.org/10.1056/NEJMoa1812851

    Article  CAS  PubMed  Google Scholar 

  15. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Düngen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP (2019) Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 381(17):1609–1620. https://doi.org/10.1056/NEJMoa1908655

    Article  CAS  PubMed  Google Scholar 

  16. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (2014) Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371(11):993–1004. https://doi.org/10.1056/NEJMoa1409077

    Article  CAS  PubMed  Google Scholar 

  17. Tsutsui H, Momomura SI, Saito Y, Ito H, Yamamoto K, Sakata Y, Desai AS, Ohishi T, Iimori T, Kitamura T, Guo W (2021) Efficacy and safety of sacubitril/valsartan in japanese patients with chronic heart failure and reduced ejection fraction—results from the PARALLEL-HF study. Circ J 85(5):584–594. https://doi.org/10.1253/circj.CJ-20-0854

    Article  CAS  PubMed  Google Scholar 

  18. Berg DD, Samsky MD, Velazquez EJ, Duffy CI, Gurmu Y, Braunwald E, Morrow DA, DeVore AD (2021) Efficacy and safety of sacubitril/valsartan in high-risk patients in the PIONEER-HF trial. Circ Heart Fail 14(2):e007034. https://doi.org/10.1161/circheartfailure.120.007034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C (2017) 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 136(6):e137–e161. https://doi.org/10.1161/cir.0000000000000509

    Article  PubMed  Google Scholar 

  20. Chen X, Jin C, Xie L, Xiang M (2020) LCZ696 and preservation of renal function in heart failure: a meta-analysis of 6 randomized trials. Rev Cardiovasc Med 21(1):113–118. https://doi.org/10.31083/j.rcm.2020.01.2

    Article  PubMed  Google Scholar 

  21. Imamah NF, Lin HR (2021) Palliative care in patients with end-stage renal disease: a meta synthesis. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph182010651

    Article  PubMed  PubMed Central  Google Scholar 

  22. Li Q, Li L, Wang F, Zhang W, Guo Y, Wang F, Liu Y, Jia J, Lin S (2019) Effect and safety of LCZ696 in the treatment of hypertension: a meta-analysis of 9 RCT studies. Medicine 98(28):e16093. https://doi.org/10.1097/md.0000000000016093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhao Y, Yu H, Zhao X, Ma R, Li N, Yu J (2017) The effects of LCZ696 in patients with hypertension compared with angiotensin receptor blockers: a meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol Ther 22(5):447–457. https://doi.org/10.1177/1074248417693379

    Article  CAS  PubMed  Google Scholar 

  24. Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, Zhang Y, Gotou H, Lefkowitz M, Zhang J (2014) Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension (Dallas, Tex, 1979) 63(4):698–705. https://doi.org/10.1161/hypertensionaha.113.02002

    Article  CAS  PubMed  Google Scholar 

  25. Niu CY, Yang SF, Ou SM, Wu CH, Huang PH, Hung CL, Lin CC, Li SY (2022) Sacubitril/valsartan in patients with heart failure and concomitant end-stage kidney disease. J Am Heart Assoc 11(18):e026407. https://doi.org/10.1161/jaha.122.026407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gan L, Lyu X, Yang X, Zhao Z, Tang Y, Chen Y, Yao Y, Hong F, Xu Z, Chen J, Gu L, Mao H, Liu Y, Sun J, Zhou Z, Du X, Jiang H, Li Y, Sun N, Liang X, Zuo L (2022) Application of angiotensin receptor–neprilysin inhibitor in chronic kidney disease patients: Chinese expert consensus. Front Med 9:877237. https://doi.org/10.3389/fmed.2022.877237

    Article  Google Scholar 

  27. Ito S, Satoh M, Tamaki Y, Gotou H, Charney A, Okino N, Akahori M, Zhang J (2015) Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Hypertens Res off J Jpn Soc Hypertens 38(4):269–275. https://doi.org/10.1038/hr.2015.1

    Article  CAS  Google Scholar 

  28. Feng Y, Yin Y, Deng R, Li H (2020) Renal safety and efficacy of angiotensin receptor–neprilysin inhibitor: a meta-analysis of randomized controlled trials. J Clin Pharm Ther 45(6):1235–1243. https://doi.org/10.1111/jcpt.13243

    Article  CAS  PubMed  Google Scholar 

  29. Vollmer Barbosa C, Lang H, Melk A, Schmidt BMW (2022) Renal events in patients receiving neprilysin inhibitors: a systematic review and meta-analysis. Nephrol Dial Transpl Off Publ Eur Dial Transpl Assoc Eur Renal Assoc 37(12):2418–2428. https://doi.org/10.1093/ndt/gfac001

    Article  CAS  Google Scholar 

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Funding

This work was supported by the Hebei Provincial Specialty Capacity Building and Specialty Leader Training Project [(2018)674], the Hebei Provincial Excellent Talents in Clinical Medicine Training Project [(2019)139], the Hebei province medical technology tracking project (GZ2020013), the Hebei Clinical Medical Research Centre Project (20577701D), and the project of the Hebei Provincial Excellent Health Talents and High-Quality Development of Public Hospitals [(2022)180].

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Author notes

  1. Wei Zhou and Xinyue Yang have contributed to this work equally.

Authors and Affiliations

  1. Departments of Nephrology, The Fourth Hospital of Hebei Medical University, Hebei Key Laboratory of Vascular Calcification in Kidney Disease, Hebei Clinical Research Center for Chronic Kidney Disease, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of China

    Wei Zhou, Xinyue Yang, JingJing Jin, Meijuan Cheng, Yajing Li, Yaling Bai & Jinsheng Xu

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  1. Wei Zhou
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Correspondence to Yaling Bai or Jinsheng Xu.

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Zhou, W., Yang, X., Jin, J. et al. The efficacy and safety of sacubitril/valsartan in chronic kidney disease: a systematic review and meta-analysis. Int Urol Nephrol 56, 181–190 (2024). https://doi.org/10.1007/s11255-023-03599-w

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