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Efficacy and safety of sacubitril/allisartan for the treatment of primary hypertension: a phase 2 randomized, double-blind study

Hypertension Research volume 46, pages 2024–2032 (2023)Cite this article

Abstract

This randomized, double-blind phase 2 study assessed the efficacy and safety of sacubitril/allisartan, an angiotensin receptor neprilysin inhibitor, compared with placebo in Chinese patients with mild to moderate hypertension. Eligible patients aged 18–75 years (n = 235) with mild to moderate hypertension were randomized to receive sacubitril/allisartan 120 mg (n = 52), sacubitril/allisartan 240 mg (n = 52), sacubitril/allisartan 480 mg (n = 52), placebo (n = 26) or olmesartan 20 mg (n = 53) once daily for 8 weeks. The primary end point was a reduction in clinic systolic blood pressure from baseline with different doses of sacubitril/allisartan versus placebo at 8 weeks. Secondary efficacy variables included clinic diastolic blood pressure and 24-h ambulatory blood pressure for the comparison between sacubitril/allisartan and placebo at 8 weeks. Safety assessments included all adverse events and serious adverse events. Sacubitril/allisartan 480 mg/day provided a significantly greater reduction in clinic systolic blood pressure than placebo at 8 weeks (between-treatment difference: −9.1 mmHg [95% confidence interval −1.6 to −16.6 mmHg], P = 0.02). There were also significant reductions in 24-h, daytime and nighttime systolic and diastolic blood pressure for sacubitril/allisartan 480 mg/day compared with placebo (P ≤ 0.03). Similarly, a greater reduction in daytime systolic blood pressure was observed for sacubitril/allisartan 240 mg/day compared with placebo (between-treatment difference: −7.3 mmHg [95% confidence interval −0.5 to −14.0 mmHg], P = 0.04). Sacubitril/allisartan was well tolerated, and no cases of angioedema were reported. Sacubitril/allisartan is effective for the treatment of hypertension in Chinese patients and is well tolerated.

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References

  1. Zhou B, Perel P, Mensah GA, Ezzati M. Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nat Rev Cardiol. 2021;18:785–802.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wang Z, Chen Z, Zhang L, Wang X, Hao G, Zhang ZG, et al. China Hypertension Survey Investigators. Status of hypertension in China: Results from the China Hypertension Survey, 2012-2015. Circulation. 2018;137:2344–56.

    Article  PubMed  Google Scholar 

  3. Chen X, Xu SK, Guo QH, Hu Z, Wang HY, Yu J, et al. Barriers to blood pressure control in China in a large opportunistic screening. J Clin Hypertens. 2020;22:835–41.

    Article  CAS  Google Scholar 

  4. Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind placebo-controlled, active comparator study. Lancet. 2010;375:1255–66.

    Article  CAS  PubMed  Google Scholar 

  5. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.

    Article  PubMed  Google Scholar 

  6. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, 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.

    Article  CAS  PubMed  Google Scholar 

  7. Wang TD, Chiang CE, Chao TH, Cheng HM, Wu YW, Wu YJ, et al. 2022 guidelines of the Taiwan Society of Cardiology and the Taiwan Hypertension Society for the management of hypertension. Acta Cardiol Sin. 2022;38:225–325.

    PubMed  PubMed Central  Google Scholar 

  8. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee of clinical practice guidelines. Circulation. 2022;145:e895–1032.

    PubMed  Google Scholar 

  9. Li Y, Li XH, Huang ZJ, Yang GP, Zhang GG, Zhao SP, et al. A randomized, double blind, placebo-controlled, multicenter phase II trial of Allisartan Isoproxil in essential hypertensive population at low-medium risk. PLoS One. 2015;10:e0117560.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sun JC, Xu WJ, Hua HJ, Xiao Y, Chen XY, Gao ZW, et al. Pharmacodynamic and pharmacokinetic effects of S086, a novel angiotensin receptor neprilysin inhibitor. Biomed Pharmacother. 2020;19:110410.

    Article  Google Scholar 

  11. Hu Y, Zhang H, Li XJ, Mai JJ, Yang LZ, Yan J, et al. A randomized, double-blind, placebo-controlled, single, and multiple dose-escalation Phase I clinical trial to investigate the safety, pharmacokinetic, and pharmacodynamic profiles of oral S086, a novel angiotensin receptor-neprilysin inhibitor, in healthy Chinese volunteers. Expert Opin Investig Drugs. 2022;31:977–85.

    Article  CAS  PubMed  Google Scholar 

  12. Huo Y, Li WM, Webb R, Zhao L, Wang Q, Guo WN. Efficacy and safety of sacubitril/valsartan compared with olmesartan in Asian patients with essential hypertension: A randomized, double-blind, 8-week study. J Clin Hypertens (Greenwich). 2019;21:67–76.

    CAS  PubMed  Google Scholar 

  13. Rakugi H, Kario K, Yamaguchi M, Sasajima T, Gotou H, Zhang J. Efficacy of sacubitril/valsartan versus olmesartan in Japanese patients with essential hypertension: A randomized, double-blind, multicenter study. Hypertens Res. 2022;45:824–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang JG, Yukisada K, Sibulo A Jr, Hafeez K, Jia Y, Zhang J. Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy. J Hypertens. 2017;35:877–85.

    Article  CAS  PubMed  Google Scholar 

  15. Mangiafico S, Costello-Boerrigter LC, Andersen IA, Cataliotti A, Burnett JC Jr. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J. 2013;34:886–93c.

    Article  CAS  PubMed  Google Scholar 

  16. Campese VM, Lasseter KC, Ferrario CM, Smith WB, Ruddy MC, Grim CE, et al. Omapatrilat versus lisinopril: efficacy and neurohormonal profile in salt-sensitive hypertensive patients. Hypertension. 2001;38:1342–8.

    Article  CAS  PubMed  Google Scholar 

  17. Hubers SA, Brown NJ. Combined angiotensin receptor antagonism and neprilysin inhibition. Circulation. 2016;133:1115–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A. 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. 2014;63:698–705.

    Article  CAS  PubMed  Google Scholar 

  19. Yano Y, Tanner RM, Sakhuja S, Jaeger BC, Booth JN 3rd, Abdalla M, et al. Association of daytime and nighttime blood pressure with cardiovascular disease events among African American individuals. JAMA Cadiol. 2019;4:910–7.

    Article  Google Scholar 

  20. Kario K, Hoshide S, Mizuno H, Kabutoya T, Nishizawa M, Yoshida T, et al. Nighttime blood pressure phenotype and cardiovascular prognosis: Practitioner-based nationwide JAMP study. Circulation. 2020;142:1810–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li Y, Wang JG. Isolated nocturnal hypertension: a disease masked in the dark. Hypertension. 2013;61:278–83.

    Article  CAS  PubMed  Google Scholar 

  22. Sun NL, Jiang YN, Wang HY, Yuan YF, Cheng WL, Han QH, et al. Survey on sodium and potassium intake in patients with hypertension in China. J Clin Hypertens (Greenwich). 2021;23:1957–64.

    Article  CAS  PubMed  Google Scholar 

  23. Du SF, Wang HJ, Zhang B, Popkin BM. Dietary potassium intake remains low and sodium intake remains high, and most sodium is derived from home food preparation for Chinese adults, 1991-2015 trends. J Nutr. 2020;150:1230–9.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gardner DG, Chen S, Glenn DJ, Grigsby CL. Molecular biology of the natriuretic peptide system: implications for physiology and hypertension. Hypertension. 2007;49:419–26.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge all investigators at the participating centers and all patients for their commitment to the study.

Funding

The study was funded by Salubris Pharma (Shenzhen, Guangdong Province, China). The study investigators were also financially supported by grants from the National Natural Science Foundation of China (91639203 and 82070435), and Ministry of Science and Technology (grants 2018YFC1704902 and 2022YFC3601302), Beijing, China, from the Shanghai Municipal Commissions of Science and Technology (grant 19DZ2340200), and Health (a special grant for “leading academics”), and The Three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWV-10.1-XK05) Big Data and Artificial Intelligence Application, Shanghai, China, and from The Clinical Research Program, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (grant 2018CR010), Shanghai, China.

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Author notes

  1. These authors contributed equally: Jin Zhang, Wei Zhang, Jie Yan

Authors and Affiliations

  1. Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jin Zhang, Wei Zhang, Qian Ge, Xiao-Hong Lu, Shao-Xing Chen & Ji-Guang Wang

  2. Shenzhen Salubris Pharmaceuticals Co., Ltd, Shenzhen, Guangdong, China

    Jie Yan, Wen-Jie Xu, Ying Li, Jin-Feng Li & Shi-Ying He

  3. National Research Centre for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Ji-Guang Wang

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Correspondence to Ji-Guang Wang.

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JGW reports receiving lecture and consulting fees from Novartis, Omron, Servier, and Viatris; The other authors declared no conflicts of interest.

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Zhang, J., Zhang, W., Yan, J. et al. Efficacy and safety of sacubitril/allisartan for the treatment of primary hypertension: a phase 2 randomized, double-blind study. Hypertens Res 46, 2024–2032 (2023). https://doi.org/10.1038/s41440-023-01326-7

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