Summary of main results

Nineteen studies including a total 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.

For the comparison of epinephrine versus any second agent, we produced meta‐analyses for eight outcomes. Few participants failed initial haemostasis, and analyses of epinephrine versus epinephrine plus any second method failed to show differences in achieving initial haemostasis between epinephrine alone and epinephrine with a second endoscopic method.

Adding any second procedure significantly reduced rebleeding rates in three analyses, that is, fewer participants in the combined therapies groups experienced recurrent bleeding after initial haemostasis (RR 0.53, 95% CI 0.35 to 0.81); fewer participants had persistent and recurrent bleeding (with or without second‐look endoscopy) (RR 0.57, 95% CI 0.43 to 0.76) and fewer had persistent or recurrent bleeding (without scheduled second‐look endoscopy) (RR 0.32, 95% CI 0.21 to 0.48). No difference in rebleeding rates was seen between groups in studies that did schedule second‐look endoscopy.

The numbers needing emergency surgery were significantly lower in the combined group (RR 0.68, 95% CI 0.50 to 0.93), but mortality rates were not significantly different with either method. Adverse events included perforations, mucosal injury and necrosis; these events were few, and no statistically significant difference between groups was noted.

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.

Our analyses therefore showed that the risk of further bleeding was lower in the combination therapy groups than in the epinephrine alone groups, regardless of which second procedure was applied. Failure of endoscopic therapy is the main predictor of the need for surgery and of morbidity and mortality in patients with bleeding peptic ulcer (Brullet 1996). Therefore, it seems highly likely that reduction of further bleeding rates decreased the need for surgery and improved survival.

We also compared epinephrine versus epinephrine plus injected agents, versus epinephrine plus a mechanical method and versus epinephrine plus thermal methods separately.

For the comparison of epinephrine versus epinephrine plus any injected method, we produced meta‐analyses for three outcomes. Fewer participants in the combination group experienced recurrent and persistent bleeding, but this finding was not statistically significant. Fewer participants in the combination therapy group died and this was statistically significant (RR 0.50, 95% CI 0.25 to 1.00), but no difference between groups was noted for the number needing emergency surgery.

For the comparison of epinephrine versus epinephrine plus a mechanical method such as haemoclips, results favoured the combination therapy group for recurrent or persistent bleeding (RR 0.31, 95% CI 0.18 to 0.55); fewer participants in the combination group needed surgery (RR 0.20, 95% CI 0.06 to 0.62), but no statistically significant difference was reported for mortality.

For the comparison of epinephrine versus epinephrine plus a thermal method, results favoured combined therapy for recurrent and persistent bleeding (RR 0.49, 95% CI 0.30 to 0.78) and for surgery (RR 0.92, 95% CI 0.37 to 2.26), but no statistically significant difference was reported for mortality.

Our updated review with new data confirms the results published in our previous review (Vergara 2007).

Overall completeness and applicability of evidence

One limitation of this review is that definitions for haemorrhage, surgery and death were not the same in the different studies (Characteristics of included studies). Marked heterogeneity observed in defining further bleeding among studies precluded the definition of a homogeneous, predetermined criterion for the primary endpoint. We therefore accepted the definition established for each study. Further bleeding definitions are shown in Characteristics of included studies. As the analysis includes only randomised, comparative studies, the criteria were similar for the two groups (epinephrine alone and combined therapy) in each study, thus allowing further comparison. Furthermore, endoscopic confirmation of bleeding was required for studies that reported second‐look endoscopy, thus reducing heterogeneity. Criteria for mortality rate were different between studies. Some studies used hospital mortality as a key, and others used 30‐day mortality or did not specify the mortality criteria applied. This makes it difficult to extract definitive conclusions about mortality rates in haemorrhage from those in ulcer disease. Moreover, characteristics of the co‐morbidities of participants were not included in the results of most of the studies.

Medical treatments were also different between studies or were not specified. However, the best treatment for bleeding from a peptic ulcer is the endoscopic treatment that we analysed in the present meta‐analysis.

One important point to state involves the dosage of epinephrine and the methodological process used in each study. The dosage of epinephrine used was detailed in Characteristics of included studies. Seven included studies did not specify the dosage (Balanzo 1990; Chung 1993; Chung 1996; Chung 1999; Garrido 2002; Park 2004; Villanueva 1996). Two studies used the same dosage of epinephrine for both groups independently of whether haemorrhage stopped (Choudari 1994; Loizou 1991). Another study (Lo 2006) injected epinephrine until haemostasis or to a maximum dose of 20 mL of epinephrine in both groups, independently of achieving haemostasis.

Comparisons of epinephrine versus epinephrine plus a specific second method also raise some unanswered questions. First, although one might consider that the efficacy of injecting a second agent is similar to that achieved with thermal and mechanical methods, this interpretation should be treated with extreme caution. The only conclusion that can be drawn from our meta‐analysis is that, whichever second treatment is used, 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. Indeed, an earlier meta‐analysis evaluating endoscopic therapy for bleeding peptic ulcers demonstrated that all methods of controlling bleeding in peptic ulcers (thermal devices, injectable agents such as sclerosants and thrombin/fibrin glue and haemoclips) were effective, with no single modality determined to be superior (Laine 2009). There are two main reasons for this. First, the subgroups (further injection, thermal methods or mechanical methods) include different procedures that may present heterogeneous activity. In fact, each endoscopic treatment presents different characteristics: Epinephrine produces vasoconstriction, vessel compression and platelet aggregation, but it does not seem to induce permanent thrombosis in blood vessels (Lin 2002). Sclerosant agents such as polidocanol or ethanol can produce thrombosis of vessels favouring haemostasis, although they may also induce significant tissue injury (Randall 1989; Ritgeers 1989). Whether human thrombin injection could reduce the risk of tissue damage remains unclear, and thrombin is more expensive than other additional treatments (Laine 2003). Thermal agents produce thrombosis of vessels and risk damaging tissue. Among them, laser photocoagulation seems to be associated with higher risks of perforation, optical hazard, high cost and imperfect haemostatic effect. Multi‐polar electrocoagulation and heater probe thermocoagulation have been reported to produce excellent results; they are also less expensive and are more easily portable than laser methods (Llach 1996). Mechanical methods close the vessel. They were also associated with few complications, but technical difficulty was associated with applying the haemoclip to the posterior wall of the proximal body and cardia of the stomach (Grgov 2012), and to the posterior wall of the duodenum, because of the requirement that the haemoclip meet the lesion at a right angle (Chung 1999; Simoens 2001). A meta‐analysis compared haemoclip versus other methods to investigate the possible benefits of haemoclips versus other endoscopic methods. The evidence showed no differences between them (Yuan 2008).

Even more important, the statistical treatments used in our meta‐analyses are not designed to compare additional treatments head to head. In fact, we lack randomised trials comparing different additional treatments after epinephrine injection, although some recent studies are available (e.g. Grgov 2013; Karaman 2011; Taghavi 2009), and we must await analysis of comparative studies to establish which is the best therapy when combined with epinephrine.

Our review did not determine whether combined therapy is better than sclerosants, thermal methods or mechanical methods alone. Little evidence in the literature suggests that this is the case. In a small study, Lin 1999 found that combined therapy seems better than bipolar electrocoagulation alone. Also, a recent meta‐analysis concluded that combined injection is superior to a sclerosant alone (Rollhauser 2000). In any event, the clinical relevance of this question may be minor.

One of the major fears associated with using combined therapy involves the possible risk of gastric wall necrosis or perforation or both. The present meta‐analysis shows that the risk of significant complications is very low. This review failed to find evidence of a difference in complication rates between groups. When the complications are examined in detail, it can be seen that induction of massive bleeding requiring surgery was more frequent in the epinephrine group, whereas gastric wall necrosis or perforation was more common in the combined therapy group. This possible small increase in the risk of perforation or necrosis is clearly compensated for by the benefits derived from reducing further bleeding, which result in a significant decrease in the need for surgery and in mortality; therefore this risk is not a reason for avoiding combined therapy.

Epinephrine injection is cheap, easy to perform and safe. In addition, according to our analysis, epinephrine seems as good as combined therapy for achieving initial haemostasis. By controlling active bleeding, it could allow a better endoscopic view and more accurate targeting of additional therapy. Therefore, medical or economic arguments against epinephrine injection are few.

Quality of the evidence

Of the 19 trials included in this review, some had limitations in design or implementation, but most were clear about important quality criteria including randomisation and allocation concealment, sequence generation and blinding. Our risk of bias estimates show that overall most studies were not at high risk of bias in any of the domains that we assessed. It should be noted that we did not rate performance bias because it is not possible to blind participants and personnel in studies of this nature. Although the type of study did not allow a double‐blind trial (Figure 2), rebleeding, surgery and mortality were not dependent on subjective observation.

The meta‐analysis involved a large number of well‐designed studies, but for most outcomes, the quality of the evidence was rated as moderate, and further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. We summarised the quality of the studies in Summary of findings table 1. When we downgraded the evidence to moderate quality, we did so because few events were reported; this was the case for the outcomes of surgery, mortality and adverse effects. The included studies involved relatively few participants, but larger populations are difficult to achieve in this type of trial. Some imprecision was noted (wide confidence intervals), and the results of some meta‐analyses showed low to moderate levels of statistical heterogeneity (inconsistency). One explanation for this may be the differences noted between trials (populations, definitions of outcomes such as in‐hospital or 30‐day mortality and definitions of rebleeding), as discussed above.

Potential biases in the review process

One limitation of our review is that despite exhaustive searching, it is difficult to be certain that every published and unpublished study was identified. We acknowledge that there is always a risk that some studies were not identified. However for the studies that we identified, the quality was rated as moderate for most outcomes, and because of the serious nature of this condition, incidences of adverse effects were reported in many trials.

Agreements and disagreements with other studies or reviews

The findings of our updated review are in agreement with the recommendations provided in three major clinical guidelines produced since the first published version of this review. Combined therapy of epinephrine plus a second endoscopic agent (e.g. bipolar electrocoagulation, heater probe, sclerosant, clips) for the treatment of patients with high‐risk bleeding peptic ulcers (Laine 2012; NICE 2012; Hwang 2012) is the main recommendation for active bleeding or non‐bleeding visible vessels.

As far as second‐look endoscopy is concerned, one meta‐analysis showed that although scheduled second‐look endoscopies reduced the rebleeding rate, they did not decrease the need for surgery nor mortality (Marmo 2003). It was also suggested that selective second‐look endoscopy for selected high‐risk patients could be a cost‐effective approach (Spiegel 2003). However, this strategy exposes patients to uncomfortable and somewhat risky procedures and increases the workload of the endoscopy unit. Results of the present study did not confirm that second‐look endoscopy diminished the risk of rebleeding. For all of these reasons, it remains unclear whether second‐look endoscopy offers any added benefit to combined therapy associated with proton pump inhibitor infusion. This finding is in agreement with current guidelines on the management of acute non‐variceal upper gastrointestinal bleeding. In the NICE 2012 guideline, the recommendation is to "consider a repeat endoscopy, with treatment as appropriate" (further endoscopic treatment or emergency surgery),"for all patients at high risk of re‐bleeding, particularly if there is doubt about initial haemostasis at the first endoscopy." The AGA guideline (Laine 2012) does not recommend routine second‐look endoscopy 24 hours after initial endoscopic haemostatic therapy but says that this should be offered for patients with clinical evidence of recurrent bleeding, and in these cases, haemostatic therapy should be applied for those with greater risk of stigmata of haemorrhage. Routine second‐look endoscopy, defined as a planned endoscopy performed within 24 hours of the initial endoscopy, in patients who have received adequate endoscopy is not recommended by the ASGE in its 2012 guideline (Chung 1999; Hwang 2012).