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Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis
  1. Emil Eik Nielsen1,2,
  2. Joshua Buron Feinberg1,2,
  3. Fan-Long Bu3,
  4. Michael Hecht Olsen1,2,4,
  5. Ilan Raymond1,
  6. Frank Steensgaard-Hansen1 and
  7. Janus Christian Jakobsen2,5
  1. 1Department of Internal Medicine – Cardiology Section, Holbaek Hospital, Holbaek, Denmark
  2. 2Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
  3. 3Beijing Children's Hospital, Capital Medical University, Beijing, China
  4. 4Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, University of Southern Denmark, Odense, Denmark
  5. 5Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  1. Correspondence to Dr Emil Eik Nielsen; Emil.eik.nielsen{at}


Current guidelines recommend angiotensin receptor blocker neprilysin inhibitors (ARNI) (sacubitril/valsartan) as a replacement for angiotensin-converting-enzymeinhibitor (ACE-I) in heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy. The effects of ARNIs have not previously been assessed in a systematic review. We searched for relevant trials until October 2019 in CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, CNKI, VIP, WanFang and CBM. Our primary outcomes were all-cause mortality and serious adverse events. We systematically assessed the risks of random errors and systematic errors. PROSPERO registration: CRD42019129336. 48 trials randomising 19 086 participants were included. The ARNI assessed in all trials was sacubitril/valsartan. ACE-I or ARB were used as control interventions. Trials randomising HFrEF participants (27 trials) and heart failure with preserved ejection fraction (HFpEF) participants (four trials) were analysed separately. In HFrEF participants, meta-analyses and Trial Sequential Analyses showed evidence of a beneficial effect of sacubitril/valsartan when assessing all-cause mortality (risk ratio (RR), 0.86; 95% CI, 0.79 to 0.94) and serious adverse events (RR, 0.89; 95% CI, 0.86 to 0.93); and the results did not differ between the guideline recommended target population and HFrEF participants in general. We found no evidence of an effect of sacubitril/valsartan in HFpEF participants. Sacubitril/valsartan compared with either ACE-I or ARB seems to have a beneficial effect in patients with HFrEF. Our results indicate that sacubitril/valsartan might be beneficial in a wider population of patients with heart failure than the guideline recommended target population. Sacubitril/valsartan does not seem to show evidence of a difference compared with valsartan in patients with HFpEF.

  • heart failure
  • heart failure treatment
  • renin-angiotensin system

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  • Contributors EEN conceived the systematic review, conducted the literature search, data extraction, data analysis, data interpretation and wrote the article. JF conducted the literature search, data extraction, aided in data interpretation and amended the article. F-LB conducted the literature search, data extraction and amended the article. MHO, IR, and FS-H helped conceive the systematic review, provided invaluable comments and amended the article. JCJ conceived the systematic review, aided in data interpretation and amended the article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Disclaimer No ethics approval was obtained, as all data is anonymised and all data used is obtained from clinical trials in which informed consent has already been obtained by trial investigators.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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