title: Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: a meta-analysis with trial sequential analysis of randomized controlled trials.
abstract: BACKGROUND
  Regional citrate or heparin is often prescribed as an anticoagulant for continuous renal replacement therapy (CRRT). However, their efficacy and safety remain controversial. Therefore, we performed this meta-analysis to compare these two agents and to determine whether the currently available evidence is sufficient and conclusive by using trial sequential analysis (TSA).
  
  
  METHODS
  We searched for relevant studies in PubMed, Embase, the Cochrane Library databases and the China National Knowledge Infrastructure (CNKI) Database from database inception until September 2015. We selected randomized controlled trials comparing regional citrate with heparin in adult patients with acute kidney injury (AKI) who were prescribed CRRT.
  
  
  RESULTS
  Fourteen trials (n = 1134) met the inclusion criteria. Pooled analyses showed that there was no difference in mortality between the regional citrate and heparin groups (relative risk (RR) 0.97, 95 % confidence interval (CI) 0.84, 1.13, P > 0.05), which was confirmed by TSA. Compared with heparin, regional citrate significantly prolonged the circuit life span in the continuous venovenous haemofiltration (CVVH) subgroup (mean difference (MD) 8.18, 95 % CI 3.86, 12.51, P < 0.01) and pre-dilution subgroup (MD 17.51, 95 % CI 9.85, 25.17, P < 0.01) but not in the continuous venovenous haemodiafiltration (CVVHDF) subgroup (MD 28.60, 95 % CI -3.52, 60.73, P > 0.05) or post-dilution subgroup (MD 13.06, 95 % CI -2.36, 28.48, P > 0.05). However, the results were not confirmed by TSA. A reduced risk of bleeding was found in the regional citrate compared with the systemic heparin group (RR 0.31, 95 % CI 0.19, 0.51, P < 0.01) and TSA provided conclusive evidence. Fewer episodes of heparin-induced thrombocytopoenia (HIT) (RR 0.41, 95 % CI 0.19, 0.87, P = 0.02) and a greater number of episodes of hypocalcaemia (RR 3.96, 95 % CI 1.50, 10.43, P < 0.01) were found in the regional citrate group. However, TSA did not provide conclusive evidence.
  
  
  CONCLUSIONS
  In adult patients with AKI, there is no difference in mortality between the regional citrate and heparin treated groups. However, regional citrate is more efficacious in prolonging circuit life span and reducing the risk of bleeding and should be recommended as the priority anticoagulant for critically ill patients who require CRRT.
authors.affiliation: Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, 28 Fu-Xing Road, Beijing, 100853, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, 28 Fu-Xing Road, Beijing, 100853, People's Republic of China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, 28 Fu-Xing Road, Beijing, 100853, People's Republic of China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, 28 Fu-Xing Road, Beijing, 100853, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, 28 Fu-Xing Road, Beijing, 100853, People's Republic of China. feihuzhou301@126.com.
authors.forename: Feihu
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D002681:China; D019343:Citric Acid / Q000494:pharmacology / Q000627:therapeutic use*; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D017582:Renal Replacement Therapy / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D019343:Citric Acid; D006493:Heparin
keywords: Anticoagulation; Continuous renal replacement therapy; Heparin; Meta-analysis; Regional citrate; Trial sequential analysis