Epinephrine injection versus epinephrine injection and a second endoscopic method in high-risk bleeding ulcers

Background

Peptic ulcers develop when the usual protective mechanism of the body breaks down and digestive juices produced in the stomach, intestines and digestive glands damage the lining of the stomach or duodenum. Non-steroidal anti-inflammatory drugs and a bacterium called Helicobacter pylori are common causes of ulcers.

When ulcers in the stomach and small intestine (duodenum) start to bleed extensively (haemorrhage), the bleeding can be life threatening and requires emergency treatment.

Patients undergo an endoscopy so clinicians can locate the source of bleeding. Active bleeding or non-bleeding visible blood vessels at endoscopy are deemed 'high risk,' in that further bleeding may occur even if the initial haemorrhage can be stopped. Once the source of bleeding has been identified, endoscopic therapy reduces rebleeding rate, need for surgery and deaths. Endoscopic therapy consists of an agent to stop the bleeding, which is injected into the bleeding area; epinephrine (adrenaline) is the most popular agent. Experts disagree on the need for a second procedure such as bipolar electrocoagulation, heater probe, sclerosant or clips immediately after epinephrine; although it seems to reduce further bleeding, the effects of a second procedure on continuing illness (morbidity), surgery rates and death remain unclear.

Review question

In bleeding peptic ulcers, does a second endoscopic method reduce further bleeding, the need for emergency surgery and death rates?

Study characteristics

We performed an extensive search for randomised trials comparing epinephrine alone versus epinephrine plus a second method. We found 19 clinical trials involving 2033 randomly assigned participants

Key results

We found that adding a second procedure reduced the further bleeding rate and the need for emergency surgery, but the effect of this approach on death rates has not been proven. In conclusion, additional endoscopic treatment after epinephrine injection reduces further bleeding and the need for surgery in patients with high-risk bleeding peptic ulcer.

Quality of the evidence

Our risk of bias estimates show that the overall quality of the included studies was moderate or high. 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. We rated the quality of evidence as moderate for most outcomes. Further research is likely to have an impact on our confidence in the estimate of effect and may change the conclusions of this review.

Authors' 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.

Read the full abstract...
Background: 

Endoscopic therapy reduces the rebleeding rate and the need for surgery in patients with bleeding peptic ulcers.

Objectives: 

To determine whether a second procedure improves haemostatic efficacy or patient outcomes or both after epinephrine injection in adults with high-risk bleeding ulcers.

Search strategy: 

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).

Selection criteria: 

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).

Data collection and analysis: 

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.

Main 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.

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