There are many clinical outcome measures for evaluation of the effectiveness of a pharmacologic agent in the management of upper gastrointestinal bleeding (UGIB). As a preemptive treatment, it should reduce the need for emergency endoscopy and endoscopic intervention, facilitate the efficient identification of the bleeding source and, hence, shorten procedure time and reduce the risk of procedure-related complications. As an effective adjunctive therapy after endoscopic hemostasis, it should reduce the incidence of recurrent bleeding and the need to repeat endoscopic hemostasis. This article provides an overview of different pharmacologic agents that have been used in the management of UGIB.
Despite major advances in endoscopic treatment, upper gastrointestinal bleeding (UGIB) is still associated with a significant risk of rebleeding, morbidity, and mortality. Pharmacologic agents have been extensively used in the management of acute UGIB because of the ease of administration, high accessibility, and independence of therapeutic endoscopy expertise in terms of efficacy. Various pharmacologic agents have been used as preemptive treatment before endoscopy or adjunctive therapy after endoscopic treatment.
There are many clinical outcome measures for evaluation of the effectiveness of a pharmacologic agent in the management of UGIB. First, as a preemptive treatment it should reduce the need for emergency endoscopy and endoscopic intervention, facilitate the efficient identification of the bleeding source and, hence, shorten procedure time and reduce the risk of procedure-related complications. As an effective adjunctive therapy after endoscopic hemostasis, it should reduce the incidence of recurrent bleeding and the need to repeat endoscopic hemostasis. Other common treatment targets for both preemptive and adjunctive therapy include reduction in transfusion needs, hospitalization, surgery, and even mortality. Cost-effectiveness is also an important factor that determines the applicability of pharmacologic treatment in the management of UGIB. This article provides an overview of different pharmacologic agents that have been used in the management of UGIB.
Role of acid suppression in UGIB
Due to their efficacy in ulcer healing, gastric acid suppressants have been extensively investigated as therapeutic agents in the treatment of acute UGIB. The purpose of gastric acid suppressant in acute UGIB is to control bleeding through enhancement of the hemostatic mechanisms, which include stabilization of platelet plugs and fibrin clots. Aggregation of platelets and the robustness of fibrin clots are highly pH-dependent and possible only at a gastric pH of above 6. Because most recurrent bleeding occurs in the first 72 hours, the treatment target of gastric aid suppression and stabilization of platelet aggregates and fibrin clots is to substantially raise and maintain the gastric pH to 6 or above within this short period of time.
Histamine 2 receptor antagonists
The results on the efficacy of histamine 2 (H2)-receptor antagonists in management of acute upper gastrointestinal (GI) bleeding have been conflicting. Earlier meta-analysis of 27 placebo-controlled trials with more than 2500 patients suggested that H2-receptor antagonist treatment might marginally reduce the rates of rebleeding, surgery, and death in patients with bleeding gastric ulcers but not duodenal ulcers. However, most of the trials included in this meta-analysis were underpowered. Another more recent meta-analysis that included 17 placebo-controlled trials with 3566 patients treated with H2-receptor antagonists showed a significant reduction in rebleeding (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.62–0.86; P <.001) and surgery rates (OR 0.707, 95% CI 0.582–0.859; P <.001) in patients with acute peptic ulcer bleeding. Mortality rates appear to be unaffected. On the other hand, another meta-analysis concluded that intravenous H2-receptor antagonists provided no additional benefit in bleeding duodenal ulcers when compared with placebo, but provided small but statistically significant reductions in rebleeding, surgery, and death in patients with bleeding gastric ulcer.
The major limitation of the use of H2-receptor antagonists in acute UGIB is tachyphylaxis and tolerance. It has been shown that omeprazole infusion consistently maintained gastric pH above 4 over a period of 72 hours with progressively lower doses, whereas significant tolerance to ranitidine infusion developed with significant reduction in antisecretory activity. The loss in antisecretory activity could not be overcome with further substantial increment in dosage.
Because of the superior efficacy of proton-pump inhibitors (PPIs) in both acid suppression and treatment of UGIB in the subsequent studies, and the inconsistent and at best marginal benefits of H2-receptor antagonists, the latter are no longer recommended as the first-line pharmacologic treatment for UGIB.
Histamine 2 receptor antagonists
The results on the efficacy of histamine 2 (H2)-receptor antagonists in management of acute upper gastrointestinal (GI) bleeding have been conflicting. Earlier meta-analysis of 27 placebo-controlled trials with more than 2500 patients suggested that H2-receptor antagonist treatment might marginally reduce the rates of rebleeding, surgery, and death in patients with bleeding gastric ulcers but not duodenal ulcers. However, most of the trials included in this meta-analysis were underpowered. Another more recent meta-analysis that included 17 placebo-controlled trials with 3566 patients treated with H2-receptor antagonists showed a significant reduction in rebleeding (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.62–0.86; P <.001) and surgery rates (OR 0.707, 95% CI 0.582–0.859; P <.001) in patients with acute peptic ulcer bleeding. Mortality rates appear to be unaffected. On the other hand, another meta-analysis concluded that intravenous H2-receptor antagonists provided no additional benefit in bleeding duodenal ulcers when compared with placebo, but provided small but statistically significant reductions in rebleeding, surgery, and death in patients with bleeding gastric ulcer.
The major limitation of the use of H2-receptor antagonists in acute UGIB is tachyphylaxis and tolerance. It has been shown that omeprazole infusion consistently maintained gastric pH above 4 over a period of 72 hours with progressively lower doses, whereas significant tolerance to ranitidine infusion developed with significant reduction in antisecretory activity. The loss in antisecretory activity could not be overcome with further substantial increment in dosage.
Because of the superior efficacy of proton-pump inhibitors (PPIs) in both acid suppression and treatment of UGIB in the subsequent studies, and the inconsistent and at best marginal benefits of H2-receptor antagonists, the latter are no longer recommended as the first-line pharmacologic treatment for UGIB.
Proton-pump inhibitors
There is substantial evidence supporting the superior efficacy of PPIs in acid-suppressing ability as well as ulcer healing rate. Unlike H2-receptor antagonists, PPIs do not have the limitation of tachyphylaxis and therefore the acid suppressive capacity is more durable. There is no ceiling effect for PPIs and, therefore, maximum acid suppression can be achieved with a high-dose regimen. PPIs are effective in suppressing both basal and postprandial gastric acid secretion.
Adjunctive Therapy After Endoscopic Hemostasis
There is strong evidence supporting the efficacy of PPIs as an adjunctive therapy for prevention of recurrent bleeding in patients with a high risk of bleeding peptic ulcers. There are several randomized trials assessing high-dose bolus and continuous-infusion PPI regimens, mainly in patients with high-risk stigmata following endoscopic therapy. Because most episodes of recurrent bleeding occur during the first 3 days, most of these trials evaluated the efficacy of a 72-hour regimen. These trials have shown decreased rebleeding and, in some studies, reduced need for surgery compared with H2-receptor antagonists or placebo. Both the rationale for the potent acid suppression and the existing evidence suggest that this is a class effect of PPIs.
In the most updated Cochrane meta-analysis that included 24 randomized controlled trials with 4373 patients, PPIs have been shown to significantly reduce rebleeding, with pooled rates of 10.6% with PPIs compared with 17.3% with control treatment (OR 0.49, 95% CI 0.37–0.65). PPI treatment also significantly reduced surgery (6.1% on PPI vs 9.3% on control, OR 0.61, 95% CI 0.48–0.78) compared with placebo, but there was no significant difference when compared with H2-receptor antagonists. Although there was no reduction in overall all-cause mortality rates (3.9% on PPI vs 3.8% on control, OR 1.01, 95% CI 0.74–1.40), patients with active bleeding or nonbleeding visible vessels were found to have reduced mortality with PPI treatment (OR 0.53, 95% CI 0.31–0.91). Of interest, PPI treatment appeared more efficacious in Asian patients, with significant reduction of all-cause mortality and greater reductions in rebleeding and surgery.
The use of high-dose intravenous PPI infusion also has a major impact on patients with high-risk aspirin-related peptic ulcer bleeding. In a randomized controlled trial of 156 patients with aspirin-related peptic ulcer bleeding who required endoscopic hemostasis, the clinical outcomes were compared between patients with immediate resumption of aspirin and those with aspirin withdrawn for 8 weeks with high-dose intravenous pantoprazole infusion for 72 hours. Early aspirin resumption led to a nonsignificant increase in 30-day recurrent bleeding risk (10.3% in the aspirin group vs 5.4% in the placebo group). However, patients who received aspirin had significantly lower all-cause mortality rates than patients who received placebo (1.3% vs 12.9%).
Despite the well-proven efficacy as an adjunctive therapy, intravenous high-dose PPI infusion cannot replace endoscopic treatment. In a randomized trial of patients with nonbleeding visible vessels and adherent clots, a combination of intravenous high-dose omeprazole infusion and endoscopic hemostasis was more effective than intravenous high-dose treatment alone in the prevention of recurrent bleeding.
Preemptive PPI Before Endoscopy
The treatment success of PPI as an adjunctive therapy after endoscopic treatment leads to the enthusiasm for evaluating the potential use of PPI treatment before endoscopy in unselected patients with acute UGIB. However, the results on the efficacy of preendoscopic (preemptive) PPI therapy are more conflicting.
The efficacy of preemptive PPI was supported initially in a retrospective review of 385 patients who were admitted to tertiary care centers for acute nonvariceal UGIB. Patients receiving preendoscopic PPI therapy were significantly less likely to develop adverse outcomes (25% vs 13%, P = .005) such as rebleeding, surgery, and mortality compared with those not given preendoscopic PPIs. Length of hospital stay was significantly shorter in patients receiving preendoscopic PPIs. However, these results were not supported by another randomized controlled trial by Daneshmend and colleagues, who reported improvement only in reduction of endoscopic stigmata. However, the dose of PPI used in this study (omeprazole 80 mg bolus plus 40 mg intravenously every 8 hours for 1 day, followed by 40 mg orally every 12 hours for 4 days) might be suboptimal.
The therapeutic value of preemptive high-dose intravenous PPI infusion was evaluated in a randomized controlled trial of 638 patients in Hong Kong. In this study, preemptive high-dose intravenous PPI infusion led to significantly fewer endoscopic treatments (19.1% vs 28.4%, P = .007) and shorter hospital stay (less than 3 days in 60.5% vs 49.2%, P = .005) compared with the placebo group. Fewer patients in the omeprazole group had actively bleeding ulcers (12 of 187, vs 28 of 190 in the placebo group; P = .01) and more omeprazole-treated patients had ulcers with clean bases (120 vs 90, P = .001). However, there was no significant difference in the transfusion requirement (mean transfusion amount: 1.54 and 1.88 units, respectively; P = .12), recurrent bleeding episodes (11 and 8, respectively; P = .49), emergency surgery (3 and 4, respectively; P = 1.00), and 30-day mortality (8 and 7, respectively; P = .78).
The lack of efficacy of preemptive PPI on major clinical outcomes of acute UGIB has been further proved by meta-analysis. The most updated Cochrane meta-analysis of 6 randomized controlled trials of 2223 hospitalized patients with unselected UGIB showed no significant difference in mortality, rebleeding, or surgery between preemptive PPI and control treatment. However, PPI treatment significantly reduced the proportion of patients with high-risk stigmata compared with the control group, with unweighted pooled rates of 37.2% and 46.5%, respectively (OR 0.67, 95% CI 0.54–0.84). Furthermore, PPI treatment also significantly reduced the need for endoscopic therapy compared with the control group, with unweighted pooled rates of 8.6% and 11.7%, respectively (OR 0.68, 95% CI 0.50–0.93).
In summary, the reduction of rebleeding is largely attributed to endoscopic treatment and adjunctive PPI therapy after endoscopy, whereas preemptive PPI therapy probably plays a minor role as determinant of major clinical outcomes, such as rebleeding, surgery, and mortality. Preemptive PPI therapy should not be used as replacement for emergency endoscopic intervention in severe cases of UGIB. The merit of preemptive PPI therapy is the reduction in endoscopic treatment through downstaging of the bleeding stigmata of the ulcers, which is important where therapeutic endoscopy expertise is lacking, expensive, or not readily accessible in the emergency setting. The therapeutic value and cost-effectiveness of preemptive PPI treatment in selected high-risk patients with UGIB needs further elucidation.
Controversial Issues
Is there any ethnic difference in the efficacy of intravenous PPI?
Current evidence suggests that PPIs seem to be more efficacious in Asian patients than in non-Asian patients for the management of acute UGIB. In a post hoc analysis of Cochrane Collaboration systematic review and meta-analysis of PPI therapy for ulcer bleeding, 16 European and North American randomized controlled trials were reanalyzed separately from the 7 trials conducted in Asia. Although there were significant reductions in rebleeding and surgery for both Asian and Western trials, the effect size was greater in Asian patients. Furthermore, reduced all-cause mortality was seen only in the Asian trials (OR 0.35, 95% CI 0.16–0.74; number needed to treat = 33) but not in Western studies (OR 1.36, 95% CI 0.94–1.96).
The observed ethnic difference in efficacy is probably attributed to the difference in the proportion of CYP2C19 polymorphism between the Asian and Western populations. In a study from Korea that compared the gastric acid suppressing effect of different intravenous pantoprazole regimens, it has been observed that once-daily regimen is associated with significant variations in acid inhibition correlating with CYP2C19 genotypes. The regimen of 40 mg twice daily of pantoprazole is sufficient to maintain pH greater than 6.0, except for patients with extensive metabolizing CYP2C19 genotypes. It has also been shown that concomitant PPI and H2-receptor antagonist infusion might be more useful in rapid metabolizers of CYP2C19.
What is the most optimum regimen of intravenous PPI?
Although there is no doubt that adjunct PPI therapy is useful in the management of acute peptic ulcer bleeding following endoscopic hemostasis, the most effective schedule of administration remains uncertain.
There have been controversies as to whether intravenous infusion can be replaced by regular injections to facilitate administration. In recent years, several randomized controlled trials have shown that high-dose intravenous infusion may not be superior to both low-dose and high-dose intravenous injection regimens. The common flaw of these trials is the small sample size, therefore they are underpowered in detecting small but clinically relevant difference in efficacy. In a meta-analysis of controlled trials by Laine and McQuaid, a significant therapeutic benefit in reduction of rebleeding (relative risk [RR] 0.40, 95% CI 0.28–0.59), surgery (RR 0.43, 95% CI 0.24–0.58), and mortality (RR 0.41, 95% CI, 0.20–0.84) was observed in high-dose intravenous PPI regimen after endoscopic therapy, whereas low-dose regimens were associated with significant benefits in rebleeding (RR 0.53, 95% CI 0.35–0.78) but not surgery or mortality, compared with placebo. Although the clear therapeutic advantage of high-dose intravenous PPI regimen over low-dose injection regimen has been questioned, current evidence favors the use of high-dose PPI infusion in view of the more robust therapeutic efficacies in various clinical outcomes.
Another topic of major interest is the relative merit of intravenous and oral PPI. The efficacy of oral PPI treatment in prevention of rebleeding was supported by 2 Asian studies that compared oral omeprazole 40 mg every 12 hours for 5 days, with either placebo (without endoscopic therapy) or endoscopic injection of alcohol for high-risk lesions. Both studies reported significant reduction in rebleeding rates. Current evidence from both retrospective studies and randomized controlled trials suggests that oral PPI may be equally effective compared with the intravenous counterparts of equivalent doses, although intravenous PPI may provide a more rapid increase in gastric pH.
The efficacy of various PPI regimens were compared in a meta-analysis of 18 randomized trials that consisted of 1855 patients with high-risk bleeding peptic ulcers. Three different regimens were assessed: high-dose intravenous PPI (40–80 mg and at least 6 mg/h), high-dose oral PPI (at least twice the standard dosage), and non–high-dose PPI. It has been shown that all 3 different PPI treatment strategies effectively improved clinical outcomes.
To date, most controlled trials comparing intravenous and oral PPI treatments have been underpowered. Furthermore, there is no direct comparison between high-dose intravenous and oral PPI regimens. Although high-dose intravenous PPI treatment may have the theoretical advantage of providing more rapid acid suppression, further studies are required to compare the clinical efficacy of high-dose intravenous and oral regimens.
Is intravenous PPI therapy cost-effective?
Although intravenous PPI has been shown to achieve better clinical outcomes with a high safety profile, its clinical effectiveness has been offset by the high cost of the drugs. The cost-effectiveness of intravenous PPI therapy in patients with high-risk peptic ulcer bleeding has been evaluated in several studies. High-dose intravenous esomeprazole after successful endoscopic hemostasis appears to improve outcomes at a modest increase in costs relative to a nonintravenous esomeprazole strategy in the United States and Sweden. However, this strategy appeared to be more cost-effective in Spain.
In another study, cost-effectiveness of 3 different postendoscopy adjunctive medical treatment strategies (oral PPI, intravenous PPI, and intravenous H2-receptor antagonist) in high-risk peptic ulcer bleeding was evaluated. Compared with the PPI strategies, the H2-receptor antagonist strategy was less cost-effective. However, the higher effectiveness of intravenous PPI therapy may not offset its increased costs compared with oral PPI therapy in acute peptic ulcer bleeding.
The cost-effectiveness of preemptive intravenous PPI in unselected patients with acute peptic ulcer bleeding is still unclear. Given the marginal cost-effectiveness of adjunctive intravenous PPI observed in the aforementioned studies and the lack of significant benefit on major clinical outcomes, preemptive PPI may be cost-effective only if it is restricted to high-risk patients in the setting where the cost of endoscopic intervention is very high.
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Epidemiology and Demographics of Upper Gastrointestinal Bleeding: Prevalence, Incidence, and Mortality
Radiologic Techniques and Effectiveness of Angiography to Diagnose and Treat Acute Upper Gastrointestinal Bleeding
Management of Nonvariceal Upper Gastrointestinal Bleeding
New Diagnostic Imaging Technologies in Nonvariceal Upper Gastrointestinal Bleeding
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