Most studies and meta-analyses of ulcer hemorrhage outcomes combine both spurting and oozing bleeding into an “active ulcer bleeding” category. However, results from prospective trials suggest they should be viewed separately because the risk of further bleeding with spurting probably is substantially higher than the risk with oozing. In non-randomized cohorts of patients receiving only conservative therapy (without endoscopic therapy) in two studies, the rate of further bleeding requiring surgery was higher in those with spurting than those with oozing (7/10 (70%) vs. 7/24 (29%) and 5/8 (63%) vs. 7/35 (20%)) (50,51). In a study restricted to UGIB patients requiring intensive care unit admission, transfusion-requiring further bleeding occurred in 23/24 (88%) with spurting and 3/28 (11%) of those with oozing (52). Data from eight prospective trials including UGIB patients with oozing treated conservatively without endoscopic therapy reveal a pooled rate of further bleeding of 39% (range, 10–100%) (50,51,53,54,55,56,57,58) and further bleeding requiring emergency surgery in 26% (range, 20–38%) (50,51,55,56).
Marked differences can be seen across different reports in the relative proportions of SRH and may relate to several factors. One potential explanation is the timing of the endoscopy, as discussed above, with more high-risk SRH identified with earlier endoscopy. Another potential explanation is inter-observer disagreement among endoscopists. Considerable variability has been reported among endoscopists in classifying SRH from photographs or video clips (59,60). Improvements in agreement may be achieved with training (e.g., instruction with review of photographs or videos, atlases) (49,59,61). It is also possible that differing patient characteristics (e.g., severity of comorbidities) may influence the prevalence of SRH.
Another potential difference in reported proportions of SRH may relate to variability in irrigation of clots. Vigorous irrigation with a water pump device will wash away overlying clot and reveal underlying SRH in a substantial portion of patients. Syringe irrigation followed by only 10 s of water pump irrigation removed clots in 33% of patients in one study (62). In another study water pump irrigation for up to 5 min removed clots in 43% of patients, revealing high-risk stigmata mandating endoscopic therapy in 30% and low-risk stigmata in 13%; no therapy was provided to the 57% with adherent clots and the rebleeding rate was only 8% (63). Thus, vigorous irrigation of clots on an ulcer base is recommended to more accurately determine underlying SRH and more accurately assess the risk of rebleeding.
Who should receive endoscopic therapy?
13. Endoscopic therapy should be provided to patients with active spurting or oozing bleeding or a non-bleeding visible vessel (Strong recommendation, high-quality evidence) (Figure 1).
14. Endoscopic therapy may be considered for patients with an adherent clot resistant to vigorous irrigation. Benefit may be greater in patients with clinical features potentially associated with a higher risk of rebleeding (e.g., older age, concurrent illness, inpatient at time bleeding began) (Conditional recommendation, moderate-quality evidence).
15. Endoscopic therapy should not be provided to patients who have an ulcer with a clean base or a flat pigmented spot (Strong recommendation, high-quality evidence).
Summary of evidence. Meta-analysis of trials of endoscopic therapy vs. no endoscopic therapy for patients with an actively bleeding ulcer (spurting and oozing combined) shows a significant decrease in further bleeding (RR=0.29, 0.20–0.43) with an NNT of only 2 (64). The need for urgent intervention and surgery is also significantly decreased. Meta-analysis of patients with a non-bleeding visible vessel in an ulcer reveals a significant decrease in further bleeding (RR=0.49, 0.40–0.59; NNT=5) as well as urgent intervention and surgery (64).
Although spurting and oozing bleeding are combined in most randomized trials and meta-analyses, as discussed above the rate of further bleeding appears to be substantially lower with oozing. Nevertheless, the 39% pooled rate of rebleeding in patients who were treated conservatively does support performing endoscopic therapy for oozing. Better efficacy may be expected after endoscopic therapy in patients with oozing than in those with other high-risk stigmata. In a cohort of patients within the placebo arm of a randomized trial of high-dose PPI vs. placebo after endoscopic therapy, the rates of further bleeding at 72 h were lower with oozing (4.9%) than with spurting (22.5%), clots (17.7%), or non-bleeding visible vessels (11.3%) (65).
Meta-analysis of randomized trials in patients with an adherent clot does not show a significant benefit (RR=0.31, 0.06–1.77) (64). However, significant heterogeneity is present among the studies. Two US trials reported significant benefit of endoscopic hemostasis, with pooled rebleeding rates for endoscopic vs. medical therapy of 3 vs. 35% (61,66). The other studies, from Europe and Asia, showed no suggestion of any benefit. The one study using therapy matching current recommendations (vigorous irrigation; bolus and continuous infusion of PPI following endoscopy) reported no rebleeding in the 24 control patients with clots receiving only medical therapy (67). The reasons for the marked variation in results are uncertain but potential explanations might include differences in severity of comorbidities (US studies done primarily in tertiary care centers), etiology of the ulcer disease (H. pylori ulcers may be more common outside the US), and response to PPIs (greater in H. pylori-positive patients and in Asia).
Patients with clean-based ulcers or flat pigmented spots rarely have serious recurrent bleeding (45) and therefore would not derive significant benefit from endoscopic therapy.
What endoscopic therapies should be used?
16. Epinephrine therapy should not be used alone. If used, it should be combined with a second modality (Strong recommendation, high-quality evidence).
17. Thermal therapy with bipolar electrocoagulation or heater probe and injection of sclerosant (e.g., absolute alcohol) are recommended because they decrease further bleeding, need for surgery, and mortality (Strong recommendation, high-quality evidence).
18. Clips are recommended because they appear to decrease further bleeding and need for surgery. However, comparisons of clips vs. other therapies yield variable results and currently used clips have not been well studied (Conditional recommendation, low-to-moderate quality evidence).
19. For the subset of patients with actively bleeding ulcers, thermal therapy or epinephrine plus a second modality may be preferred over clips or sclerosant alone to achieve initial hemostasis (Conditional recommendation, low-to-moderate-quality evidence).
Summary of evidence. The primary end point recommended in trials of UGIB is prevention of further bleeding, which includes initial hemostasis in actively bleeding patients plus prevention of rebleeding in those with initial hemostasis and in those without active bleeding at presentation (68). Endoscopic therapies that have shown efficacy in randomized trials include thermal therapy (e.g., bipolar electrocoagulation, heater probe, monopolar electrocoagulation, argon plasma coagulation, and laser), injection (epinephrine, sclerosants (e.g., absolute ethanol, polidocanol, and ethanolamine), thrombin or fibrin glue (thrombin plus fibrinogen)), and clips (64).
Randomized trials indicate epinephrine injection is effective at achieving initial hemostasis in patients with active bleeding, with results not significantly different from other therapies (64). However, epinephrine monotherapy is less effective than other monotherapies in preventing further bleeding (RR=1.72, 1.08–2.78; NNT=9) and surgery based on meta-analysis of three trials employing bipolar electrocoagulation, clips, or fibrin glue as comparators (64). Furthermore, epinephrine plus a second modality (e.g., bipolar electrocoagulation, sclerosant, and clip) is significantly more effective than epinephrine alone in reducing further bleeding (RR=0.34, 0.23–0.50; NNT=5) and surgery (64). However, if a second-look endoscopy is performed and higher risk lesions are retreated, the benefit of combined therapy vs. epinephrine alone is not seen (64).
Thermal contact therapy with bipolar electrocoagulation or heater probe is significantly more effective than no endoscopic therapy in achieving initial hemostasis (RR=11.70, 5.15–26.56), reducing further bleeding (RR=0.44, 0.36–0.54; NNT=4), surgery, and mortality (RR=0.58, 0.34–0.98; NNT=33) in a meta-analysis of 15 randomized trials (64). No significant differences were seen in randomized trials comparing these two thermal modalities. The term “multipolar electrocoagulation” is used in some studies. The multipolar probe and other bipolar probes all deliver bipolar electrocoagulation; the difference in terms relates only to the configuration of the electrodes on the probe tip. Thus, meta-analyses combine multipolar and bipolar electrocoagulation trials.
Results of two small studies suggested benefit of epinephrine plus bipolar electrocoagulation vs. bipolar electrocoagulation alone, but results with thermal monotherapy were poorer in these trials than most other studies (69,70). A larger high-quality study found that injection of thrombin plus heater probe was not better than heater probe alone (71). Thus, although limited information suggests that epinephrine followed by thermal contact therapy may be more efficacious than thermal therapy alone, data are insufficient to recommend that thermal contact devices should not be used alone as monotherapy.
However, there may be practical reasons to pre-inject epinephrine before other therapies for specific SRH. Anecdotally, for active bleeding, injection of epinephrine may slow or stop bleeding allowing improved visualization for application of subsequent therapy. In addition, if clot removal is planned for adherent clots resistant to irrigation, pre-injection of epinephrine may reduce the rate of severe bleeding induced by clot removal.
Sclerosant injection also significantly reduces further bleeding (RR=0.56, 0.38–0.83; NNT=5) as well as surgery and mortality as compared with no endoscopic therapy based on meta-analysis of three randomized trials of absolute alcohol (64). Because the volume of sclerosants must be limited due to concern for tissue necrosis, sclerosant therapy alone may not be optimal for actively bleeding ulcers. Among actively bleeding patients in a randomized trial comparing absolute alcohol vs. no therapy, initial hemostasis was achieved in only 46% with alcohol vs. 8% in controls (64). Epinephrine injection before sclerosant therapy for actively bleeding ulcers seems reasonable although this has not been compared with sclerosant alone in randomized trials.
Trials comparing thermal therapy with sclerosant therapy show no significant difference in further bleeding, surgery, or mortality, although thermal therapy showed significantly fewer urgent interventions (surgery, repeat endoscopic therapy, or interventional radiology) and a trend to less further bleeding (RR=0.69, 0.47–1.01) (64).
Clips have not been compared with no endoscopic therapy but are more effective than injection of epinephrine or water in reducing further bleeding and surgery (64). On comparison with other standard therapies (thermal or sclerosant, with or without epinephrine), clips were less effective at initial hemostasis than thermal therapy (heater probe) (64), but not significantly different in other outcomes such as further bleeding. However, these studies were heterogeneous with one showing clips to be significantly better and two others indicating clips were significantly worse than the comparators in their effect on further bleeding. Thus, more data are needed on the role of clips alone in the acute management of UGIB. Variables to consider in assessing the heterogeneous study results include variation among different endoscopists and among different types of clips. Newer clips in current use are easier to apply and vary in size, rigidity, depth of attachment, and duration of retention (72,73); however, they have not been well studied in randomized trials. Clips also have the theoretical benefit of not inducing tissue injury, unlike thermal therapies and sclerosants—and therefore may be preferred in patients on antithrombotic therapy and those undergoing retreatment for rebleeding.
Despite showing efficacy in randomized trials, laser, monopolar electrocoagulation, argon plasma coagulation, and injection of thrombin or fibrin glue are not recommended as first-line therapies due to less robust evidence, potential for slightly higher risk of adverse effects, availability, ease of use, and/or cost (64).
Techniques for endoscopic hemostatic therapy. Endoscopic hemostatic modalities are generally applied to the bleeding site to halt bleeding and in the immediate area of the SRH in the ulcer base with the intent to close or obliterate the underlying vessel and prevent rebleeding. The technique used to treat adherent clots in the two studies reporting benefit of endoscopic therapy was epinephrine injection into all four quadrants of the ulcer followed by mechanical clot removal (e.g., snare; manipulation with forceps, probe, or tip of endoscope) and application of thermal therapy (61,66).
Dilute (1:10,000 or 1:20,000 in saline) epinephrine is generally injected in 0.5–2 ml aliquots in and around the stigmata of hemorrhage in the ulcer base. Although large volumes of epinephrine (e.g., 30–45 ml) are reported to be more effective as monotherapy (74,75,76), no studies have documented the optimal volume when used in combination with other modalities. We recommend injection until active bleeding slows or stops or, for non-bleeding stigmata, in all four quadrants next to the SRH in the ulcer base.
Absolute alcohol is generally administered in 0.1–0.2 ml aliquots with a limitation of 1–2 ml (77) due to the concern for tissue injury with higher volumes. Five percent ethanolamine is administered in 0.5–1.0 ml aliquots; widely variable total volumes of 0.5–14 ml have been reported in randomized trials for ulcer bleeding (78,79,80).
Bipolar electrocoagulation should be performed with the endoscope tip as close as possible to the bleeding ulcer; the large (3.2 mm) probe should be applied en face or at the least possible angulation with firm/maximal pressure (81,82). A setting of ∼15 W and 8–10 s applications are recommended (81,83,84). Multiple applications should be applied in the ulcer base on and around the SRH, until bleeding has stopped, the vessel is flattened, and the base is whitened. Recommendations for the heater probe are identical with a setting of 30 J being used.
Clips should be placed over the bleeding site and on either side of the SRH in an attempt to seal the underlying artery.
MEDICAL THERAPY AFTER ENDOSCOPY
20. After successful endoscopic hemostasis, intravenous PPI therapy with 80 mg bolus followed by 8 mg/h continuous infusion for 72 h should be given to patients who have an ulcer with active bleeding, a non-bleeding visible vessel, or an adherent clot (Strong recommendation, high-quality evidence) (Figure 1).
21. Patients with ulcers that have flat pigmented spots or clean bases can receive standard PPI therapy (e.g., oral PPI once-daily) (Strong recommendation, moderate-quality evidence).
Summary of evidence. Meta-analysis of randomized trials of intravenous PPI therapy (80 mg bolus followed by 8 mg/h continuous infusion) vs. placebo/no treatment for 72 h after endoscopic therapy of high-risk stigmata reveals a significant reduction in further bleeding (RR=0.40, 0.28–0.59; NNT=12), surgery (RR=0.43, 0.24–0.76; NNT=28), and mortality (RR=0.41, 0.20–0.84; NNT=45) (64).
In a recent large randomized trial of bolus followed by continuous infusion PPI vs. placebo after successful endoscopic hemostasis, subgroup analysis of patients with oozing bleeding showed a very low rebleeding rate with placebo (8/163 (4.9%)) (65). The results of this subgroup analysis suggest that intensive PPI therapy may not be needed for oozing bleeding without other SRH.
Meta-analysis of trials of intermittent oral or intravenous PPI vs. placebo/no therapy reveals a significant reduction in further bleeding (RR=0.53, 0.35–0.78), but no significant difference in surgery, urgent intervention, or mortality. Meta-analysis of five fully published randomized trials that compare bolus followed by continuous infusion PPI vs. intermittent PPI therapy after endoscopic therapy for high-risk stigmata reveals an absolute risk reduction in further bleeding with intermittent PPI of 1% (95% CI −3 to 5%) (85,86,87,88,89). Most of these trials were relatively small, methodologic concerns have been raised about the single large trial, and rates of rebleeding were very low in all arms of the studies (3–14%). For these reasons, it is difficult to conclude that the two treatments are “equivalent”. Nevertheless, these data do suggest that intermittent PPI therapy may suffice after endoscopic therapy for high-risk stigmata.
Rates of serious rebleeding with lower risk stigmata (clean base, flat pigmented spot) are low (45) and thus standard antisecretory therapy to heal the ulcer is all that is recommended in patients with these findings.
22. Routine second-look endoscopy, in which repeat endoscopy is performed 24 h after initial endoscopic hemostatic therapy, is not recommended (Conditional recommendation, moderate-quality evidence).
23. Repeat endoscopy should be performed in patients with clinical evidence of recurrent bleeding and hemostatic therapy should be applied in those with higher risk stigmata of hemorrhage (Strong recommendation, high-quality evidence).
24. If further bleeding occurs after a second endoscopic therapeutic session, surgery or interventional radiology with transcathether arterial embolization is generally employed (Conditional recommendation, low-quality evidence).
Summary of evidence. Second-look endoscopy is generally defined as routine repeat endoscopy within 24 h after initial endoscopy and hemostatic therapy. Repeat endoscopic hemostatic therapy is typically given to patients with higher risk SRH. A meta-analysis of randomized trials assessing second-look endoscopy reported a small but significant reduction in rebleeding in patients undergoing second-look endoscopy (absolute risk reduction=6.2% (1.3–11.1%; NNT=16)) with no significant benefit in reducing surgery or death (90). A subsequent meta-analysis found no significant benefit when hemostatic therapy was epinephrine injection or fibrin glue injection, but did identify a significant difference in rebleeding for the two randomized trials employing thermal therapy (RR=0.29, 0.11–0.73) (91).
However, these studies were done before the currently accepted practice of adding intensive PPI therapy after endoscopic therapy, which has been shown to reduce further bleeding. In a randomized trial of single endoscopy plus high-dose intravenous PPI vs. routine second-look endoscopy without PPI, rebleeding occurred in 8.2 vs. 8.7% (RR=1.1, 0.4–2.7) (91).
The expense of second-look endoscopy also must be considered. A large number of unnecessary endoscopies will be performed since most patients do not have recurrent bleeding. In addition, second-look endoscopies do not prevent further bleeding in all patients, and repeat endoscopic therapy is successful in most patients with rebleeding (92). An economic analysis suggests that intravenous PPI therapy would be the dominant strategy as compared with second-look endoscopy if the PPI therapy reduced rebleeding to 9% or if it cost $10 per day (93). Recent randomized trials report rebleeding rates <9% (49,91) in patients with high-risk ulcer bleeding treated with endoscopic and PPI therapy. Furthermore, intensive PPI therapy is considered as standard therapy after endoscopic therapy of high-risk SRH (as discussed above) and would be employed even if second-look endoscopy is done.
If a population at very high risk of recurrent bleeding after endoscopic hemostasis could be identified, this group potentially could derive benefit from second-look endoscopy. Although several characteristics are reported to be associated with an increased risk of bleeding after hemostatic therapy, no grading system has been validated to reliably identify a very high-risk population (44).
Repeat endoscopy with endoscopic therapy is appropriate in patients with clinical evidence of rebleeding. A randomized trial comparing endoscopic therapy vs. surgery for recurrent bleeding after endoscopic hemostatic therapy revealed that 73% of patients with recurrent bleeding can be successfully treated with repeat endoscopic therapy and avoid the need for surgery, with a lower rate of complications than those treated with surgery (92). If further bleeding occurs after the second endoscopic treatment, surgery or interventional radiology (transcatheter arterial embolization) is reported to be successful in achieving hemostasis. A recent review of case series of angiographic embolization in patients with UGIB failing endoscopic and medical therapy revealed a technical success rate >90% and a rebleeding rate of 33%, which was widely variable across studies (9–66%) (94).
HOSPITALIZATION FOR PATIENTS WITH UGIB
25. Patients with high-risk stigmata (active bleeding, visible vessels, clots) should generally be hospitalized for 3 days assuming no rebleeding and no other reason for hospitalization. They may be fed clear liquids soon after endoscopy (Conditional recommendation, low-quality evidence).
26. Patients with clean-based ulcers may receive a regular diet and be discharged after endoscopy assuming they are hemodynamically stable, their hemoglobin is stable, they have no other medical problems, and they have a residence where they can be observed by a responsible adult (Strong recommendation, moderate-quality evidence).
Summary of evidence. Clear liquid diet can be provided after endoscopic therapy. This recommendation is based on the fact that patients with recurrent bleeding may have to undergo urgent interventions such as endoscopy, interventional radiology, or surgery. Clear liquids allow sedation or anesthesia to be administered within 2 h after the last ingestion (95). Thus, we suggest clear liquid diet for ∼2 days in patients who are at higher risk for rebleeding. However, given the excellent results obtained with current endoscopic and medical therapy some investigators have raised the possibility of early refeeding in higher risk patients. A randomized trial of normal diet vs. nothing by mouth for 24 h after endoscopic therapy for oozing or non-bleeding visible vessels found no significant difference in rebleeding (2 vs. 6%) (96). This trial may not simulate standard practice; however, because second-look endoscopy with retreatment was performed at 24 h.
With a low risk of recurrent bleeding, regular diet may be instituted. A randomized trial of patients with lower risk lesions (e.g., Mallory-Weiss tears, ulcers with clean base or flat pigmented spots) revealed no significant differences in outcomes with immediate refeeding of regular diet vs. delayed refeeding (clear liquids at 36 h and regular diet at 48 h) (97). Although patients with flat spots in this trial had similar outcomes with immediate refeeding, the 8% rebleeding rate and 5% rate of urgent intervention may argue for clear liquid diet in these patients for 1–2 days. Data to guide the duration of hospitalization for patients with flat pigmented spots are lacking.
Several trials have demonstrated that patients with UGIB who have low-risk features may be discharged on the first hospital day (or worked up and discharged as an outpatient) without negative consequences (9,33,98). Criteria vary across studies but generally include low-risk clinical features (e.g., stable vital signs and hemoglobin, no serious comorbidities), low-risk endoscopic features (e.g., clean-based ulcer, erosive disease, Mallory-Weiss tear), and satisfactory home/social support.
Other patients with higher risk stigmata (active bleeding, visible vessel, and clot) generally remain in the hospital for 3 days assuming no rebleeding or other medical issues. This is based primarily on older studies suggesting that recurrent bleeding almost always (∼≥ 95%) occurred within 3 days (43,99,100,101). More recent results of randomized trials suggest that a substantial minority of patients may have recurrent bleeding after 3 days—most often occurring within 7 days (49,102,103). For example, in a recent large randomized trial of patients with higher risk bleeding ulcers treated with endoscopic therapy, 24% of the 82 patients with rebleeding in the 30-day study rebled beyond 3 days, with equal proportions in the group receiving continuous infusion PPI and those receiving placebo after endoscopic therapy (49). Six percent of rebleeding occurred after 7 days (49).
Although patients should be educated about symptoms of UGIB and the need to return to hospital if these symptoms develop, we do not recommend hospital stays be routinely extended beyond 3 days in patients without further bleeding or other medical problems.
LONG-TERM PREVENTION OF RECURRENT BLEEDING ULCERS
27. Patients with H. pylori-associated bleeding ulcers should receive H. pylori therapy. After documentation of eradication, maintenance antisecretory therapy is not needed unless the patient also requires non-steroidal anti-inflammatory drugs (NSAIDs) or antithrombotics (Strong recommendation, high-quality evidence) (Figure 2).
28. In patients with NSAID-associated bleeding ulcers, the need for NSAIDs should be carefully assessed and NSAIDs should not be resumed if possible. In patients who must resume NSAIDs, a COX-2-selective NSAID at the lowest effective dose plus daily PPI is recommended (Strong recommendation, high-quality evidence).
29. In patients with low-dose aspirin-associated bleeding ulcers, the need for aspirin should be assessed. If given for secondary prevention (i.e., established cardiovascular disease) then aspirin should be resumed as soon as possible after bleeding ceases in most patients: ideally within 1–3 days and certainly within 7 days. Long-term daily PPI therapy should also be provided. If given for primary prevention (i.e., no established cardiovascular disease), antiplatelet therapy likely should not be resumed in most patients (Conditional recommendation, moderate-quality evidence).
30. In patients with idiopathic (non-H. pylori, non-NSAID) ulcers, long-term antiulcer therapy (e.g., daily PPI) is recommended (Conditional recommendation, low-quality evidence).
Summary of evidence. Patients with bleeding ulcers have an unacceptably high rate of recurrent bleeding if no strategy is employed to reduce this risk. For example, in patients with duodenal ulcer bleeding (H. pylori not assessed, no NSAID use) followed in a double-blind trial after ulcer healing, bleeding recurred within 1 year in nearly 40% (104). In a systematic review of randomized trials of patients with H. pylori-associated bleeding ulcers (105), the rate of recurrent bleeding in studies with 12-month follow-up was 26% (106,107,108,109). In H. pylori-positive NSAID users with bleeding ulcers followed for 6 months after ulcer healing, recurrent bleeding ulcers occurred with resumption of NSAIDs in 19% of those given only H. pylori therapy (110), while in H. pylori-positive low-dose aspirin users who presented with ulcer complications and were followed for a median of 12 months after ulcer healing and H. pylori eradication, recurrent bleeding ulcers occurred with resumption of low-dose aspirin in 15% (111). Finally, in a prospective cohort of patients with idiopathic bleeding ulcers (H. pylori negative, no NSAID use) followed for 7 years, the incidence of recurrent ulcer bleeding was 42% (112).
Biopsy-based H. pylori testing is recommended by ACG H. pylori guidelines in patients presenting with a bleeding ulcer (113). Because some studies suggest sensitivity may be decreased with acute UGIB, confirmation of a negative test with a subsequent non-endoscopic test has also been recommended (113,114). However, if histological examination of the biopsy specimens shows no mucosal mononuclear cell infiltrate, the predictive value for absence of H. pylori approaches 100%, while a neutrophilic infiltrate has >95% positive predictive value for H. pylori infection (115).
A meta-analysis of randomized trials showed that H. pylori eradication therapy for prevention of recurrent ulcer bleeding is significantly more effective than short-term antisecretory therapy alone (rebleeding 4.5 vs. 23.7%; OR=0.18, 0.10–0.35) (105). Furthermore, H. pylori eradication was also more effective than long-term maintenance antisecretory therapy with PPI or histamine-2 receptor antagonist (H2RA) (although most patients received H2RA: 1.6 vs. 5.6%; OR=0.24, 0.09–0.67) (105). A systematic review of studies assessing rebleeding in patients with documented H. pylori eradication revealed a 1.3% incidence of rebleeding over mean follow-up periods of 11–53 months (105).
Because patients with H. pylori ulcers have such low rebleeding rates if they have eradication of the infection, it is important to document cure of the infection at ≥1 month following the end of H. pylori therapy. Endoscopic biopsy can be done if patients are undergoing repeat endoscopy for another reason (e.g., to document gastric ulcer healing), but a urea breath test or stool antigen test should be done if endoscopy is not needed (113). Antibody testing should not be employed since it remains positive in most patients after successful therapy (116). PPIs can cause falsely negative H. pylori testing in approximately one third of cases (117,118) so PPIs should be discontinued 2 weeks before testing to ensure optimal sensitivity (118). Some practitioners may use an H2RA during this period to decrease risk of recurrent ulcers in case H. pylori therapy was not successful.
Randomized trials in NSAID users show that co-therapy with misoprostol, PPIs, and double-dose H2RAs or use of COX-2-selective inhibitors decrease endoscopic ulcers in patients taking NSAIDs (119,120) and that misoprostol and COX-2-selective NSAIDs also decrease complicated ulcers in arthritis patients (120,121). Although these trials suggest that the agents studied may be beneficial in patients who presented with a bleeding ulcer, they do not specifically address management of these high-risk patients.
Several randomized trials from Hong Kong have studied prevention of recurrent bleeding in NSAID users who presented with bleeding ulcers. In patients who were restarted on NSAID after ulcer healing, maintenance PPI therapy had a significantly lower risk of recurrent ulcer bleeding at 6 months as compared with H. pylori therapy only (4.4 vs. 18.8%; NNT=7) (110). In a follow-up study, celecoxib was compared with diclofenac plus PPI after ulcer healing in patients who were H. pylori negative or had successful H. pylori therapy (122). The rates of recurrent ulcer bleeding at 6 months were 4.9% with celecoxib and 6.4% for diclofenac plus PPI; recurrent ulcers were seen at 6-month endoscopy in 19 and 26% of patients (123). Because rates of recurrent ulcer bleeding were relatively high with either protective strategy, a subsequent 12-month double-blind study of similar design compared celecoxib plus twice-daily PPI vs. celecoxib plus placebo (124). Recurrent ulcer bleeding occurred in 0 vs. 8.9% (NNT=12). Thus, patients with a bleeding ulcer while on NSAIDs who must remain on NSAIDs should receive a COX-2-selective NSAID at the lowest effective dose plus PPI therapy.
Low-dose aspirin ulcers
Randomized trials in low-dose aspirin users show that PPIs and standard dose H2RAs reduce endoscopic ulcers (125,126,127) and that PPIs reduce UGIB in patients taking low-dose aspirin plus clopidogrel (128).
In a study of H. pylori-positive low-dose aspirin users with bleeding ulcers, the rates of recurrent ulcer bleeding at 6 months after resuming low-dose aspirin were 0.9% with PPI and 1.9% with H. pylori therapy (110). Although no placebo group was included, this trial raised the possibility that H. pylori eradication alone may reduce recurrent ulcer bleeding with low-dose aspirin. A subsequent trial performed in H. pylori-positive low-dose aspirin users with ulcer complications showed that after H. pylori eradication and ulcer healing, PPI therapy had significantly less recurrent ulcer bleeding than placebo at a median of 12 months (1.6 vs. 14.8%; NNT=8) (111). Thus, in patients with bleeding ulcers who require continued antiplatelet therapy, once-daily PPI should be given.
The need for antiplatelet therapy should be reviewed in patients who have ulcer bleeding while taking low-dose aspirin. In patients taking aspirin for primary prophylaxis (no overt cardiovascular disease), the benefit of low-dose aspirin is relatively small: meta-analysis of randomized trials reveals an annual absolute risk reduction of 0.07% (NNT=1,429) (129). Primary prevention is recommended only in patients at higher risk for cardiovascular events, based on risk assessment tools. In patients hospitalized with ulcer bleeding, the risk of subsequent bleeding likely outweighs the cardiovascular benefit in many or most patients on primary prophylaxis.
In contrast, the benefit of low-dose aspirin for secondary prophylaxis in patients with established cardiovascular disease is much larger (annual absolute risk reduction of 1.49% (NNT=68)) (129) and failure to resume low-dose aspirin after ulcer bleeding is associated with an increased mortality (130). A randomized trial in low-dose aspirin users with established cardiovascular disease who presented with a bleeding ulcer showed that resumption of low-dose aspirin vs. placebo after endoscopic hemostasis and initiation of PPI therapy was associated with no significant increase in recurrent ulcer bleeding at 1 month (10.3 vs. 5.4%), but a significant decrease in mortality at 1 month and 2 months (1.3 vs. 12.9%) (130). Thus, it is important to resume antiplatelet therapy, along with PPI co-therapy, as early as possible in patients with established cardiovascular disease.
The timing of resumption of aspirin is not clear and data are primarily based on observational studies. A systematic review found that thrombotic events in patients with established cardiovascular disease occurred at a mean of 10.7 days after aspirin withdrawal (131), while another review of patients on secondary prevention stopping aspirin perioperatively reported the mean interval after discontinuation for acute cerebral events was 14.3 days and for acute coronary syndrome was 8.5 days (132). Recent joint consensus recommendations from US cardiology and GI organizations stated that “reintroduction of antiplatelet therapy in high-cardiovascular-risk patients is reasonable in those who remain free of rebleeding after 3–7 days” (133), while the study from Sung et al. (130) indicated a benefit of resumption of low-dose aspirin immediately after endoscopic hemostasis in patients with high-risk stigmata. Thus, the benefit-risk ratio of aspirin resumption must be carefully considered jointly by gastroenterologists, cardiologists, neurologists, and patients on a case-by-case basis. However, early resumption of antiplatelet therapy within 1–3 days after hemostasis, and certainly within 7 days, will be appropriate in most patients with established cardiovascular disease.
Idiopathic (non-H. pylori, non-NSAID) ulcers
Patients with idiopathic bleeding ulcers have a high rate of recurrence when followed without protective co-therapy (112). Surreptitious NSAID use undoubtedly accounts for some of these ulcers. Although no randomized trials have assessed the benefit of medical co-therapy in this population, antiulcer therapy seems likely to reduce recurrent idiopathic ulcers and will also be effective at reducing recurrent ulcers in those surreptitiously using NSAIDs.
Management of the patient presenting with overt bleeding proceeds in a step-wise manner. The first step is assessment of hemodynamic status and initiation of resuscitative measures as needed. Patients are risk stratified based on clinical features such as hemodynamic status, comorbidities, age, and initial laboratory tests. Most patients should receive an upper endoscopy within 24 h or less, and endoscopic features of the ulcer assist in directing further management. Those with high-risk findings of active bleeding or non-bleeding visible vessel should receive endoscopic therapy and those with an adherent clot may receive endoscopic therapy; these patients should then receive intravenous PPI therapy with a bolus followed by continuous infusion. Those with flat spots or clean-based ulcers do not require endoscopic therapy or intensive intravenous PPI therapy. Recurrent ulcer bleeding after endoscopic therapy should be treated with a second endoscopic treatment, but if bleeding still persists or recurs treatment with surgery or interventional radiology is undertaken.
Prevention of recurrent bleeding is based on the presumed etiology of the bleeding ulcer. H. pylori should be eradicated if present and after cure is documented, no further therapy is needed. NSAIDs should be stopped; if they must be continued a low-dose of a COX-2-selective NSAID plus a PPI should be used. Patients with established cardiovascular disease who require aspirin or other antiplatelet agents should start PPI therapy and generally have antiplatelet therapy reinstituted as soon as possible after bleeding ceases (ideally within 1–3 days and certainly within 7 days). Those with idiopathic ulcers should receive long-term antiulcer therapy.
CONFLICT OF INTEREST
Guarantor of the article: Loren Laine, MD.
Specific author contributions: L. Laine: planning and conducting review; analysis/interpretation of data; drafting and revision of the manuscript. He approved final draft submitted. D. Jensen: planning and conducting review; analysis/interpretation of data; critical review and revision of the manuscript. He approved final draft submitted.
Financial support: None.
Potential competing interests: L. Laine has served as a consultant for AstraZeneca, Eisai, Pfizer, Horizon, and Logical Therapeutics, and has served on Data Safety Monitoring Boards for Bayer, BMS, and Merck. D. Jensen is a consultant for AstraZeneca, Boston Scientific, Merck, and US Endoscopy. D. Jensen has received research grants from Boston Scientific, Pentax, Olympus, US Endoscopy, and Vascular Technology Inc.
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