title: Epinephrine injection versus epinephrine injection and a second endoscopic method in high-risk bleeding ulcers.
abstract: BACKGROUND
  Endoscopic therapy reduces the rebleeding rate and the need for surgery in patients with bleeding peptic ulcers.
  
  
  OBJECTIVE
  To determine whether a second procedure improves haemostatic efficacy or patient outcomes or both after epinephrine injection in adults with high-risk bleeding ulcers.
  
  
  METHODS
  For our update in 2014, we searched the following versions of these databases, limited from June 2009 to May 2014: Ovid MEDLINE(R) 1946 to May Week 2 2014; Ovid MEDLINE(R) Daily Update May 22, 2014; Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations May 22, 2014 (Appendix 1); Evidence-Based Medicine (EBM) Reviews-the Cochrane Central Register of Controlled Trials (CENTRAL) April 2014 (Appendix 2); and EMBASE 1980 to Week 20 2014 (Appendix 3).
  
  
  METHODS
  We included randomised controlled trials (RCTs) comparing epinephrine alone versus epinephrine plus a second method. Populations consisted of patients with high-risk bleeding peptic ulcers, that is, patients with haemorrhage from peptic ulcer disease (gastric or duodenal) with major stigmata of bleeding as defined by Forrest classification Ia (spurting haemorrhage), Ib (oozing haemorrhage), IIa (non-bleeding visible vessel) and IIb (adherent clot) (Forrest Ia-Ib-IIa-IIb).
  
  
  METHODS
  We used standard methodological procedures as expected by The Cochrane Collaboration. Meta-analysis was undertaken using a random-effects model; risk ratios (RRs) with 95% confidence intervals (CIs) are presented for dichotomous data.
  
  
  RESULTS
  Nineteen studies of 2033 initially randomly assigned participants were included, of which 11 used a second injected agent, five used a mechanical method (haemoclips) and three employed thermal methods.The risk of further bleeding after initial haemostasis was lower in the combination therapy groups than in the epinephrine alone group, regardless of which second procedure was applied (RR 0.53, 95% CI 0.35 to 0.81). Adding any second procedure significantly reduced the overall bleeding rate (persistent and recurrent bleeding) (RR 0.57, 95% CI 0.43 to 0.76) and the need for emergency surgery (RR 0.68, 95% CI 0.50 to 0.93). Mortality rates were not significantly different when either method was applied.Rebleeding in the 10 studies that scheduled a reendoscopy showed no difference between epinephrine and combined therapy; without second-look endoscopy, a statistically significant difference was observed between epinephrine and epinephrine and any second endoscopic method, with fewer participants rebleeding in the combined therapy group (nine studies) (RR 0.32, 95% CI 0.21 to 0.48).For ulcers of the Forrest Ia or Ib type (oozing or spurting), the addition of a second therapy significantly reduced the rebleeding rate (RR 0.66, 95% CI 0.49 to 0.88); this difference was not seen for type IIa (visible vessel) or type IIb (adherent clot) ulcers. Few procedure-related adverse effects were reported, and this finding was not statistically significantly different between groups. Few adverse events occurred, and no statistically significant difference was noted between groups.The addition of a second injected method reduced recurrent and persistent rebleeding rates and surgery rates in the combination therapy group, but these findings were not statistically significantly different. Significantly fewer participants died in the combined therapy group (RR 0.50, 95% CI 0.25 to 1.00).Epinephrine and a second mechanical method decreased recurrent and persistent bleeding (RR 0.31, 95% CI 0.18 to 0.54) and the need for emergency surgery (RR 0.20, 95% CI 0.06 to 0.62) but did not affect mortality rates.Epinephrine plus thermal methods decreased the rebleeding rate (RR 0.49, 95% CI 0.30 to 0.78) and the surgery rate (RR 0.20, 95% CI 0.06 to 0.62) but did not affect the mortality rate.Our risk of bias estimates show that risk of bias was low, as, although the type of study did not allow a double-blind trial, rebleeding, surgery and mortality were not dependent on subjective observation. Although some studies had limitations in their design or implementation, most were clear about important quality criteria, including randomisation and allocation concealment, sequence generation and blinding.
  
  
  CONCLUSIONS
  Additional endoscopic treatment after epinephrine injection reduces further bleeding and the need for surgery in patients with high-risk bleeding peptic ulcer. The main adverse events include risk of perforation and gastric wall necrosis, the rates of which were low in our included studies and favoured neither epinephrine therapy nor combination therapy. The main conclusion is that combined therapy seems to work better than epinephrine alone. However, we cannot conclude that a particular form of treatment is equal or superior to another.
authors.affiliation: Servei de Malalties Digestives, Hospital de Sabadell & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Parc Tauli s/n, Sabadell, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Vergara
authors.forename: Cathy
authors.initials: C
authors.lastname: Bennett
authors.forename: Xavier
authors.initials: X
authors.lastname: Calvet
authors.forename: Javier P
authors.initials: JP
authors.lastname: Gisbert
mesh_terms: D000328:Adult; D003131:Combined Modality Therapy / Q000379:methods; D004837:Epinephrine / Q000008:administration & dosage*; D016558:Hemostasis, Endoscopic / Q000379:methods*; D006801:Humans; D010438:Peptic Ulcer Hemorrhage / Q000401:mortality / Q000517:prevention & control / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic; D055502:Secondary Prevention / Q000379:methods; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*
chemical_list: D014662:Vasoconstrictor Agents; D004837:Epinephrine