Endoscopic Therapy
Recommendation 6: Early endoscopy (within the first 24 hours) with risk classification by clinical and endoscopic criteria allows for safe and prompt discharge of patients classified as low risk (Recommendation: A [vote: a, 92%; b, 8%]; Evidence: I); improves patient outcomes for patients classified as high risk (Recommendation: C [vote: a, 64%; b, 36%]; Evidence: II-2); and reduces resource utilization for patients classified as either low or high risk (Recommendation: A [vote: a, 88%; b, 12%]; Evidence: I).
The definition of early endoscopy varies widely among studies, from 2 to 24 hours after presentation to the emergency department (41, 73-77). In the RUGBE cohort, first endoscopy in "real life" was performed within 24 hours of presentation in 76% of patients (mean [+SD], 23 + 38 hours) (4). This was similar to the rate of 78% reported in a survey in the Amsterdam area (42). The consensus panel agreed to define early as within the first 24 hours.
Several observational studies (65, 67, 76, 78-80) and a systematic review (81) support the use of early endoscopic stratification for all risk groups. Studies in low-risk patients have shown no major complications in those triaged to outpatient care with early endoscopy (65, 67, 73, 75, 78, 79, 82, 83). A retrospective cohort trial found reductions in both length of hospital stay and need for surgery with early endoscopy in unselected patients (76).
In a randomized, controlled trial, early endoscopy and endoscopic therapy reduced transfusion requirements and length of hospital stay in patients with bloody nasogastric tube aspirate but not in those with clear or "coffee-grounds" aspirate (74). Studies in patients at low risk (66, 73, 75), patients at high risk (74), and unselected patients (69, 76, 82) have demonstrated statistically significant reductions in length of hospital stay. In patients at low risk, 2 randomized, controlled trials have demonstrated cost reductions of 43% to 91% with the use of early endoscopy (73, 75).
Recommendation 7: A finding of low-risk endoscopic stigmata (a clean-based ulcer or a nonprotuberant pigmented dot in an ulcer bed) is not an indication for endoscopic hemostatic therapy (Recommendation: A [vote: a, 100%]; Evidence: I). A finding of a clot in an ulcer bed warrants targeted irrigation in an attempt at dislodgment, with appropriate treatment of the underlying lesion (Recommendation: A [vote: a, 72%; b, 28%]; Evidence: I). A finding of high-risk endoscopic stigmata (active bleeding or a visible vessel in an ulcer bed) is an indication for immediate endoscopic hemostatic therapy (Recommendation: A [vote: a, 100%]; Evidence: I).
On the basis of the favorable natural history discussed in recommendation 5, the 1989 National Institutes of Health Consensus Conference did not recommend any endoscopic treatment for patients with low-risk endoscopic stigmata (a clean-based ulcer or a nonprotuberant pigmented spot in an ulcer bed) (11). Furthermore, the 2 meta-analyses that have demonstrated the benefits of endoscopic therapy mainly examined patients with high-risk rather than low-risk stigmata, with resultant statistically significant decreases in rates of further bleeding, surgery, and mortality (84, 85). Modern endoscopic hemostasis techniques were reviewed more recently in meta-analyses of 56 studies. Bardou and colleagues (13, 14) showed that, compared with drug or placebo treatment, endoscopic treatment was associated with statistically significant absolute decreases in rates of rebleeding, surgery, and mortality.
The optimal management of adherent clots has long been controversial, since this finding obscures underlying stigmata that may be at high or low risk for rebleeding. The risk for rebleeding with clots that remained adherent after washing has been reported as only 8% in 1 study (86) but as high as 25% to 29% in others (47, 87). Two recent studies found that endoscopic therapy for adherent clots statistically significantly reduced the rate of rebleeding compared with medical therapy alone (23, 24).
Recommendation 8: No single solution for endoscopic injection therapy is superior to another for hemostasis. Recommendation: A (vote: a, 92%; b, 8%); Evidence: I
The meta-analyses by Bardou and colleagues (13, 14), which included 38 relevant studies (52, 88-124), demonstrated no statistically significant benefits of 1 solution over another for endoscopic injection. In individual trials, no statistically significant differences were seen for epinephrine alone versus distilled water (52), cyanoacrylate (107), epinephrine in combination with ethanolamine or polidocanol (94, 123), thrombin (89, 104), sodium tetradecyl sulfate (96), or ethanol (97, 109). Ethanol injection was superior to sprayed epinephrine plus thrombin (103) and epinephrine plus polidocanol (121). In 1 study, no statistically significant differences were seen in treatment with normal saline, hypertonic saline (3% NaCl), 50% glucose-water solution, or pure alcohol (108). Some data suggested that injection of fibrin glue was the same as or better than polidocanol (90, 120).
Recommendation 9: No single method of endoscopic thermal coaptive therapy is superior to another. Recommendation: A (vote: a, 100%); Evidence: I
The McGill University meta-analyses by Bardou and colleagues (13, 14) included 20 studies relevant to this question (93, 95, 100, 105, 106, 110-112, 116, 122, 124-133) and demonstrated no statistically significant benefit of one coaptive endoscopic technique over another. Most individual randomized studies have shown no differences in rates of rebleeding, surgery, and mortality among coaptive therapy with heater probe thermocoagulation, multipolar electrocoagulation, or neodymium yttrium-aluminium-garnet laser when compared with injection therapy, although some studies have shown differences in rates of hemostasis (93, 95, 110, 112, 116, 122, 132). Laser therapy is no longer commonly used for acute management of high-risk patients because of high costs and poor portability of the equipment (134).
Argon plasma coagulation is a noncoaptive method of electrocoagulation in which current is applied to tissues by means of ionized argon gas (plasma) (135). Early uncontrolled experience found it was safe, effective, and easy to perform, with advantages over standard electrocoagulation (135). In a prospective study comparing argon plasma coagulation with heater probe in 41 patients with bleeding peptic ulcers, rates of hemostasis, recurrent bleeding, mortality, and surgery were comparable in both groups, with argon plasma coagulation providing faster hemostasis (126). However, the statistical power of the study was insufficient to conclude equivalence. A larger study, published since the consensus conference was held, suggested no difference between injection plus heater probe and injection plus argon plasma coagulation in 185 patients with high-risk lesions (136).
Recommendation 10: Monotherapy, with injection or thermal coagulation, is an effective endoscopic hemostatic technique for high-risk stigmata; however, the combination is superior to either treatment alone. Recommendation: B (vote: a, 48%; b, 48%; c, 4%); Evidence: I
Previous meta-analyses of injection or thermal endoscopic hemostatic therapies reported statistically significant relative decreases in rebleeding rates (odds ratio, 0.27 to 0.31) and mortality (odds ratio, 0.55 to 0.7) compared with standard therapy (84, 85). The more recent McGill University meta-analyses by Bardou and colleagues found statistically significant reductions in the absolute rates of rebleeding and mortality with endoscopic treatment compared with placebo or pharmacotherapy (see previously discussed recommendations) (13, 14). Combination therapy with both injection and coaptive therapy has shown superiority over medical therapy (23, 24, 137). How combination therapy compares with endoscopic monotherapy and whether combination therapy should be the initial approach remains controversial. Bardou and colleagues (13, 14) investigated combinations of 2 endoscopic methods in 8 studies: epinephrine injection plus thermal treatment in 5 studies (23, 24, 98, 111, 137), epinephrine injection plus laser treatment in 2 studies (102, 113), and epinephrine injection plus clips in 1 study (99). Combination treatment was associated with statistically significant reductions in absolute rates of rebleeding compared with injection alone, thermal treatment alone, or pharmacotherapy. Similar reductions in rebleeding were not observed when the combination was compared with hemoclip therapy alone, despite statistically significant reductions in surgery rates. In an analysis of the 5 studies combining thermal methods with injection (23, 24, 98, 111, 137), combination treatment was associated with statistically significant reductions in absolute rates of rebleeding compared with pharmacologic, injection, or thermal treatment alone. The absolute mortality rates were statistically significantly lower with combination therapy than with pharmacologic or injection therapy. Stratification by endoscopic stigmata yielded insufficient data to compare the combination of injection plus nonlaser thermal therapy with single treatment methods for lesions other than actively spurting lesions (98) and adherent clots (23, 24). Combined injection and laser therapy has shown no substantial advantage over use of injection alone (102, 113).
Recommendation 11: The placement of clips is a promising endoscopic hemostatic therapy for high-risk stigmata. Recommendation: B (vote: a, 44%; b, 52%; c, 4%); Evidence: I
Several randomized, controlled trials have investigated the use of endoscopic clips, alone (99, 127, 138) or in combination (99, 138, 139), for endoscopic hemostasis. Endoscopic clips have shown superiority over heater probe (127) or injection therapy (99) in 2 trials but higher failure rates compared with injection therapy (138) in another. Studies of the combination of injection plus endoscopic clips have demonstrated no statistically significant benefit over injection alone (138, 139) or clips alone (99). The finding of increased rebleeding with the combination of injection and clips compared with clips alone (99, 138) requires further study.
The variable success of endoscopic clips may reflect difficulty with their placement. Some studies report outcomes only of patients in whom clips were successfully placed, rather than performing an intention-to-treat analysis. It is likely that further improvement in the clips and their ease of placement will lead to more widespread use. It was suggested that as the choice of endoscopic therapeutic method evolves, it may, in the future, be tailored to the nature of the underlying high-risk lesion.
Recommendation 12: Routine second-look endoscopy is not recommended. Recommendation: E (vote: a, 92%; b, 8%); Evidence: I
Four randomized, controlled trials have specifically examined the utility of scheduled (programmed) repeated endoscopy after endoscopic hemostatic therapy. Messmann and coworkers (140) found that scheduled repeated endoscopies after initial successful treatment did not improve outcomes compared with second endoscopy performed only at recurrent hemorrhage. In a study of patients with high-risk stigmata, Villanueva and colleagues (141) noted a statistically nonsignificant trend toward better outcomes in the group that received routine second-look endoscopy within 24 hours. A study by Saeed and associates (142) in highly selected patients who had undergone initial endoscopic therapy for persistent high-risk lesions showed benefits for those randomly assigned to repeated hemostatic treatment compared with no retreatment. Rutgeerts and coworkers (120) did not find superiority of repeated sessions versus a single session of fibrin glue injection in patients with high-risk stigmata but did find that the former was superior to polidocanol injection. The variability in patient samples and interventions limits any attempt to pool these data quantitatively. Second-look endoscopy may therefore be of statistical benefit in select high-risk patients, but data are conflicting regarding its routine use. A second endoscopy is ultimately needed in patients whose initial endoscopic examination is incomplete because of technical reasons (such as excessive blood).
Recommendation 13: In cases of rebleeding, a second attempt at endoscopic therapy is generally recommended. Recommendation: A (vote: a, 100%); Evidence: I
In the only randomized comparison, immediate endoscopic retreatment in patients with rebleeding after endoscopic hemostasis reduced the need for surgery without increasing the risk for death and was associated with fewer complications than surgery (143). However, these surgical procedures performed in Hong Kong were somewhat more complex and had greater attendant morbidity than those usually performed in North America. This limits the generalizability of the results. Endoscopic therapy should be tailored according to available expertise.
Recommendation 14: Surgical consultation should be sought for patients who have failed endoscopic therapy. Recommendation: B (vote: a, 100%); Evidence: II-2
In the RUGBE cohort, continued bleeding or rebleeding was noted in 14.1% of patients, and 6.5% required surgery (4). Similar proportions, after differing patient population characteristics are taken into account, have been reported in other large cohorts (34, 42, 49, 56, 81, 144-147). In the study by Lau and colleagues of patients at high risk (143), 27% of those with rebleeding after endoscopic treatment required salvage surgery. Thus, early surgical consultation may be particularly beneficial in patients at high risk for failed endoscopic retreatment.
