This article summarizes and appraises the evidence from randomized controlled trials (RCT) and meta-analyses of RCTs on the role of proton pump inhibitors (PPIs) in non-variceal upper gastrointestinal bleeding, with a specific emphasis on peptic ulcer bleeding. PPIs have an established role in the management of endoscopically documented peptic ulcer bleeding. PPIs, compared with H 2 -receptor antagonists or placebo, consistently reduce re-bleeding rates. All-cause mortality is reduced in patients with high risk endoscopic signs and in Asian populations. The optimal dose and route of PPI administration in peptic ulcer bleeding has not yet been defined. The role of PPIs prior to endoscopy in patients presenting with non-variceal upper gastrointestinal bleeding is still somewhat controversial; PPIs reduce the proportion of patients with high risk endoscopic signs and may reduce the requirement for endoscopic hemostatic therapy at index endoscopy, but there is no demonstrable effect on mortality, re-bleeding or surgical interventions.
Acute upper gastrointestinal (GI) bleeding is a common emergency, associated with substantial morbidity, mortality, and health care cost. Patients with portal hypertension who bleed from esophageal or gastric varices comprise a small proportion of bleeders, but have worse prognosis and require a different therapeutic approach than patients with nonvariceal bleeding. Peptic ulcer bleeding is the principal cause of nonvariceal upper GI bleeding.
Prompt resuscitation and fluid replacement are of major importance especially in severe bleeding. Concurrent major diseases should be carefully monitored and treated; there may be further decompensation following the bleeding episode, and comorbidity is the major cause of mortality. Endoscopic hemostatic treatment is of established efficacy in patients with nonvariceal upper GI bleeding. Proton pump inhibitor (PPI) treatment is widely used as pharmacotherapy in nonvariceal upper GI bleeding, but its effect on mortality is not clear and is difficult to interpret.
This article will summarize and critically evaluate the evidence from randomized controlled trials (RCTs) and meta-analyses of RCTs on the role of PPIs in nonvariceal upper GI bleeding, with specific emphasis on peptic ulcer bleeding.
Rationale for acid suppression pharmacotherapy
Endoscopic hemostatic therapy reduces but does not eliminate the risk for adverse outcomes in patients with nonvariceal upper GI bleeding. Thus, there is room for further improvement in outcomes. Pharmacotherapy is a good candidate for adjuvant therapy, because it does not require any technical skills or specialty training to administer.
Furthermore, there is a biologically plausible underlying principle with regard to acid suppression therapy in this situation. Hemostasis in the stomach and duodenum is antagonized by gastric acid, which inhibits clot formation and promotes clot lysis. In vitro studies have shown that plasma coagulation and platelet aggregation are compromised by 50% in the presence of gastric juice at pH 6.4. At pH 6.0, previously formed platelet aggregates disaggregate; at pH 5.4, plasma coagulation and platelet aggregation are practically abolished; and at pH 4.0, previously formed fibrin clots are dissolved. Pepsin can further inhibit coagulation by promotion of clot lysis in an acidic environment, since its proteolytic activity is maximal at pH 2 and negligible at pH above 5. Such findings provided the rationale for rigorous acid suppression treatment attempting to maintain intragastric pH above 6 during the first 1–3 days following a bleeding episode. It is plausible that hydrochloric acid and pepsin can also provoke further bleeding from an ulcer by inducing ongoing tissue damage. However, this mechanism can be easily addressed even with standard doses of histamine H 2 -receptor antagonists (H 2 RAs) or PPIs; for healing of duodenal and gastric ulcers, maintaining the intragastric pH above 3 and 4 respectively, is adequate.
Several RCTs have assessed the efficacy of acid suppression therapy at more than standard doses in nonvariceal upper GI bleeding. These studies had included patients with peptic ulcer bleeding either exclusively or predominantly.
H 2 -Receptor Antagonists in peptic ulcer bleeding
H 2 RAs were the first class of acid suppression medications to be tested in this patient population. In 1985 Collins and Langman published a seminal meta-analysis of 27 RCTs that had compared either cimetidine (Tagamet) or ranitidine (Zantac) with placebo in a total of 2670 patients with nonvariceal upper GI bleeding. There were marginally significant reductions in mortality and surgical intervention rates in the H 2 RA group, but no evidence of an effect on rebleeding rates. When the analysis was restricted to studies that reported outcomes separately for patients who had bled from gastric and duodenal ulcers, the beneficial effect of H 2 RAs was confined to patients with gastric ulcers; H 2 RAs significantly reduced mortality, rebleeding and surgical intervention rates in patients with gastric ulcer bleeding, but there was no evidence of an effect on clinical outcomes in patients with duodenal ulcer bleeding. 14 That meta-analysis was updated in 2002 by Levine and colleagues, who pooled 30 RCTs that had compared intravenous cimetidine, ranitidine, or famotidine (Pepcid) with placebo in patients with peptic ulcer bleeding. The meta-analysis found no evidence of an effect of intravenous H 2 RAs on mortality (odds ratio [OR] 0.81; 95% confidence intervals [CI] 0.62–1.06), rebleeding (OR 0.86; 95% CI 0.74–1.00), or surgical intervention rates (OR 0.83; 95% CI 0.68–1.00), even though there were trends toward significance in rebleeding and surgical intervention rates. Subgroup analysis showed that H 2 RAs significantly reduced rebleeding and surgical interventions in patients with gastric ulcer bleeding, but had no verifiable effect on mortality. As in the previous meta-analysis, H 2 RAs did not significantly affect any clinical outcome in patients with duodenal ulcer bleeding.
A planned subgroup analysis of 17 RCTs from a recent Cochrane meta-analysis showed that PPIs compared with H 2 RAs significantly reduced rebleeding rates in patients with peptic ulcer bleeding (OR 0.61; 95% CI 0.48–0.78; number needed to treat [NNT] 20; 95% CI 13–34). There was no verifiable difference in mortality and surgical intervention rates.
Therefore, there is insufficient evidence to recommend H 2 RA treatment for peptic ulcer bleeding. This was also the conclusion of a consensus meeting that recommended against the use of H 2 RAs in the management of nonvariceal upper GI bleeding.
H 2 -Receptor Antagonists in peptic ulcer bleeding
H 2 RAs were the first class of acid suppression medications to be tested in this patient population. In 1985 Collins and Langman published a seminal meta-analysis of 27 RCTs that had compared either cimetidine (Tagamet) or ranitidine (Zantac) with placebo in a total of 2670 patients with nonvariceal upper GI bleeding. There were marginally significant reductions in mortality and surgical intervention rates in the H 2 RA group, but no evidence of an effect on rebleeding rates. When the analysis was restricted to studies that reported outcomes separately for patients who had bled from gastric and duodenal ulcers, the beneficial effect of H 2 RAs was confined to patients with gastric ulcers; H 2 RAs significantly reduced mortality, rebleeding and surgical intervention rates in patients with gastric ulcer bleeding, but there was no evidence of an effect on clinical outcomes in patients with duodenal ulcer bleeding. 14 That meta-analysis was updated in 2002 by Levine and colleagues, who pooled 30 RCTs that had compared intravenous cimetidine, ranitidine, or famotidine (Pepcid) with placebo in patients with peptic ulcer bleeding. The meta-analysis found no evidence of an effect of intravenous H 2 RAs on mortality (odds ratio [OR] 0.81; 95% confidence intervals [CI] 0.62–1.06), rebleeding (OR 0.86; 95% CI 0.74–1.00), or surgical intervention rates (OR 0.83; 95% CI 0.68–1.00), even though there were trends toward significance in rebleeding and surgical intervention rates. Subgroup analysis showed that H 2 RAs significantly reduced rebleeding and surgical interventions in patients with gastric ulcer bleeding, but had no verifiable effect on mortality. As in the previous meta-analysis, H 2 RAs did not significantly affect any clinical outcome in patients with duodenal ulcer bleeding.
A planned subgroup analysis of 17 RCTs from a recent Cochrane meta-analysis showed that PPIs compared with H 2 RAs significantly reduced rebleeding rates in patients with peptic ulcer bleeding (OR 0.61; 95% CI 0.48–0.78; number needed to treat [NNT] 20; 95% CI 13–34). There was no verifiable difference in mortality and surgical intervention rates.
Therefore, there is insufficient evidence to recommend H 2 RA treatment for peptic ulcer bleeding. This was also the conclusion of a consensus meeting that recommended against the use of H 2 RAs in the management of nonvariceal upper GI bleeding.
Proton Pump Inhibitors in peptic ulcer bleeding
Effects of PPIs on Clinical Outcomes: Evidence From Meta-analyses of Randomized Controlled Trials
A recent Cochrane meta-analysis aimed to evaluate the efficacy of PPIs in treating peptic ulcer bleeding, using evidence from RCTs that had compared PPIs with either H 2 RAs or placebo and had been published in November 2004. Twenty-four RCTs comprising 4373 patients were included.
The meta-analysis revealed a highly significant and robust reduction in rebleeding rates with PPI treatment. PPIs significantly reduced 30-day rebleeding rates compared with control treatment; unweighted pooled rates were 10.6% and 17.3%, respectively (OR 0.49, 95% CI 0.37–0.65; NNT 13, 95% CI 10–25) ( Fig. 1 ). Three-day rebleeding rates were also significantly reduced by PPI treatment (8.3%) compared with control (14.2%); OR 0.39; 95% CI 0.19–0.80; NNT 13, 95% CI 8–34. The reduction of 30-day rebleeding rates remained statistically significant in all predetermined subgroup analyses. That is, PPIs significantly reduced rebleeding independent of methodological quality of the trials, severity of baseline endoscopic signs of recent hemorrhage, type of control treatment (placebo or H 2 RA), geographic location of the trials (conducted in Asia or elsewhere), mode of PPI administration (oral or intravenous), dose of PPI (high-dose defined as at least 80 mg bolus followed by an intravenous infusion of 8 mg/h for 72 hours; low-dose defined as any lesser dose intravenous or oral), and whether or not endoscopic hemostatic treatment was given.
Nevertheless, there was statistically significant heterogeneity among trials for rebleeding ( P = .04) and this had to be explained. The abovementioned subgroup analyses provided clues about the effect of population and study characteristics. Two of the subgroup analyses, according to route of administration of PPI and geographic location of trials, resulted in groups of trials that were statistically homogeneous for rebleeding. Moreover, when the influence of predefined study characteristics on the effect of treatment on rebleeding was assessed by metaregression, only the geographic location of the studies had a significant influence: PPIs produced quantitatively greater reductions in rebleeding among RCTs that had been conducted in Asia compared with RCTs that had been conducted elsewhere. The findings of the subgroup analysis and the metaregression not only explained the heterogeneity for the outcome of rebleeding, but also provided indirect evidence of increased efficacy of PPIs for peptic ulcer bleeding in Asian trials.
The trials were nonheterogeneous for the other outcomes that were assessed. Surgical interventions were significantly less common with PPI treatment (6.1%) than with control treatment (9.3%); OR 0.61, 95% CI 0.48–0.78; NNT 34, 95% CI 20–50. Further endoscopic hemostatic treatment (after randomization) was also reduced with PPIs (5.6%) compared with control treatment (15.7%); OR 0.32, 95% CI 0.20–0.51; NNT 10, 95% CI 8–17.
Despite the beneficial effect of PPI treatment on the above outcomes, there was no evidence of an effect on all-cause mortality rates (OR 1.01, 95% CI 0.74–1.40; Fig. 2 ). Unweighted pooled rates were 3.9% for PPI treatment and 3.8% for control treatment. It is plausible that any beneficial or detrimental effect of PPIs on mortality could have been diluted by the inclusion of patients with low-risk in the studies. A planned subgroup analysis was restricted to patients with high-risk endoscopic findings of active bleeding or a nonbleeding visible vessel—the patient population that clinicians are mainly concerned about. In this population PPIs significantly reduced mortality; OR 0.53, 95% CI 0.31–0.91, NNT 50, 95% CI 34–100. Among such patients, the reduction of mortality by PPI treatment remained significant when the analysis was confined to the RCTs that consistently used initial endoscopic hemostatic treatment, which is the accepted standard of care for such patients (OR 0.54, 95% CI 0.30–0.96; NNT 50, 95% CI 34–100), but was not significant among trials that did not consistently do so.
Separating the trials according to geographic location was the only other subgroup analysis that showed a statistically significant effect of PPI treatment on mortality. PPIs significantly reduced mortality among trials that had been conducted in Asia (OR 0.35, 95% CI 0.16–0.74; NNT 34, 95% CI 20–100), but had no verifiable effect among trials that had been conducted elsewhere (OR 1.36, 95% CI 0.94–1.96). Similarly to the outcome of rebleeding, a higher treatment effect of PPIs in Asian trials was confirmed by metaregression.
Funnel plots for mortality, rebleeding and surgical interventions were visually asymmetric, suggesting the presence of publication bias because of some missing small trials with negative results. However, this was only confirmed statistically for the outcome of surgical interventions.
There have been three other published meta-analyses of RCTs that have assessed the role of PPIs in peptic ulcer bleeding. The most consistent finding of these meta-analyses, which is also in agreement with the Cochrane meta-analysis, is that PPIs compared with H 2 RAs or placebo significantly reduce rebleeding rates in patients with peptic ulcer bleeding.
Khuroo and colleagues pooled RCTs on acute nonvariceal upper GI bleeding that had been published till 2002. They found no evidence that PPI treatment compared with H 2 RAs or placebo affected all-cause mortality. PPI treatment significantly reduced rebleeding and surgical intervention rates. However, a predetermined subgroup analysis showed that these beneficial effects of PPIs were restricted to trials on patients who had bled from peptic ulcers with active bleeding, nonbleeding visible vessels, or adherent clots. There was no verifiable effect of PPI treatment on rebleeding or surgical intervention rates among trials that had included patients with all causes of nonvariceal upper GI bleeding.
Khuroo and colleagues also reported that all-cause mortality in nonvariceal upper GI bleeding was significantly increased with intravenous PPI treatment, although it was significantly reduced with oral PPI treatment. They also reported that PPI treatment significantly reduced deaths directly caused by bleeding, while it significantly increased deaths caused by associated diseases or of unknown etiology. However, the validity of these analyses on mortality was undermined by several factors: some eligible RCTs were missed, noneligible trials were inadvertently included, and there were mistakes in the data extraction process. When the authors re-extracted raw data and repooled the trials, it was found that PPI treatment marginally reduced “bleeding related” deaths and had no effect on “non–bleeding related” deaths. The fact that the vast majority of published trials did not provide sufficient data to allow for a reliable differentiation of causes of deaths renders even this “corrected” analysis unreliable. It would be very useful if future studies were prospectively designed to categorize causes of death in patients with nonvariceal upper GI bleeding in a systematic way (as only one of the published studies did ), but until then it would be premature to draw conclusions regarding any differential effect of PPIs on different causes of death.
Andriulli and colleagues conducted a series of meta-analyses of RCTs published till August 2003 on PPI treatment for peptic ulcer bleeding. It was concluded that PPI treatment, compared with H 2 RA or placebo, significantly reduced rebleeding but not surgical intervention or all-cause mortality rates.
The meta-analysis by Bardou and colleagues included RCTs published up to April 2003 that compared PPIs with H 2 RAs or placebo in patients with peptic ulcers with active bleeding, non-bleeding visible vessels, or adherent clots. The trials were divided into three groups according to the dose of PPI treatment: high-dose intravenous PPI (40–80 mg bolus followed by intravenous infusion of at least 6 mg/h), high-dose oral PPI (at least twice the standard dosage), and non-high-dose PPI (any other dose of PPI). In each group, trials were further subgrouped according to the control treatment used. PPI treatment significantly reduced rebleeding rates in all comparisons apart from that of high-dose intravenous PPI versus H 2 RA. The effect of PPIs on surgical intervention rates was less consistent. Mortality was significantly reduced in the analyses of high-dose intravenous versus placebo and non-high-dose PPI versus placebo. The authors have expressed concerns about the exclusion of two studies from the former analysis and the misclassification of another study in the latter analysis. Nevertheless, this was the first meta-analysis that showed that PPIs significantly reduced mortality in a subgroup of patients with high-risk endoscopic stigmata.
Effects of Proton Pump Inhibitors on Clinical Outcomes: Evidence From Recent Randomized Controlled Trials
Since the completion of the most recent of the above meta-analyses, two RCTs that had been included in the meta-analysis as abstracts were published in full. Furthermore, eight new RCTs that assessed the efficacy of PPI treatment in peptic ulcer bleeding have been published. The characteristics and main results of these trials are shown in Table 1 . PPI treatment produced statistically significant reductions in rebleeding rates in all but 1 trial, did not have a verifiable effect on mortality in any trial, and significantly reduced surgical interventions in one trial. Since these results are consistent with the results of the Cochrane meta-analysis, it is unlikely that the inclusion of the above trials will significantly affect the update of the meta-analysis scheduled for 2009. The trial by Sung and colleagues is of particular importance. It had great methodological quality (in fact the protocol had been registered in ClinicalTrials.gov and prospectively published ), was adequately powered, and was the first trial to use high-dose intravenous esomeprazole (Nexium). Among the 18 RCTs that had compared PPI treatment with H 2 RAs or placebo in predominantly Caucasian populations, it is the only trial that has shown a highly significant reduction of rebleeding rates with PPI treatment; 3-day rebleeding rates were 5.9% and 10.3% ( P = .03) and 30-day rebleeding rates were 7.7% and 13.6% ( P = .01), respectively. The results of a predetermined analysis confined to Caucasian patients (87% of total population) were very similar to the results from the total study population, which also included Asians, blacks, and others. The only other trial on Caucasian patients that reported that PPIs significantly reduced rebleeding rates is a small trial by Naumovski-Mihalic and colleagues, but the statistical significance of this finding is dependent on the statistical test used, and is marginal at best.
Related posts:
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Predicting Poor Outcome from Acute Upper Gastrointestinal Hemorrhage
Stress-Induced Ulcer Bleed ing in Critically Ill Patients
Helicobacter pylori -Negative Nonsteroidal Anti-Inflammatory Drug-Negative Ulcer
Differences in Peptic Ulcer Between the East and the West
Balancing Risks and Benefits of Cyclooxygenase-2 Selective Nonsteroidal Anti-Inflammatory Drugs
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