Proton pump inhibitors are widely used for patients with ulcer bleeding of varying severity,9-12
though it has not been specifically approved for that indication. Given the morbidity, mortality, and healthcare costs associated with bleeding peptic ulcer, it is important to establish definitively whether early treatment with proton pump inhibitors is associated with any meaningful clinical benefit. We deliberately focused on the use of proton pump inhibitors in patients with a proved diagnosis of ulcer bleeding and cannot, therefore, make any conclusions about use for managing other causes of upper gastrointestinal tract bleeding. Although one trial included patients with non-ulcer bleeding,14
we excluded those patients from our analysis. The other trials we included were confined to patients with a proved diagnosis. While we cannot exclude the possibility of some publication bias (see ), our search was rigorous and we did not identify any other trials through contact with pharmaceutical companies.
We used odds ratios rather than absolute risk reduction as our pooled summary statistic. Though absolute risk reduction would have allowed the simple calculation of numbers needed to treat, a pooled number needed to treat derived from a meta-analysis of absolute risk differences can be misleading as baseline risk often varies considerably among included trials.34
We have, however, reported pooled number needed to treat for clinical applicability.
Overall, we found no evidence that treatment with proton pump inhibitors reduces mortality after ulcer bleeding. There were, however, significant reductions in rates of rebleeding and surgery. Much of the mortality after an episode of ulcer bleeding may be unrelated to continued or recurrent bleeding but to comorbid disease.35
Alternatively, there may have been too few patients in our pooled analysis of mortality data to enable us to detect a difference. The data are also compatible with treatment causing a small excess of deaths, which we consider unlikely on clinical grounds. In most trials, we could not determine whether deaths were attributable to comorbid conditions.
Some trials compared proton pump inhibitor therapy with placebo and others with an H2
receptor antagonist, though this is unlikely to have made any substantive difference in results. A meta-analysis by Collins and Langman,36
and its update by Levine and colleagues,37
found no benefit of intravenous H2
receptor antagonist over intravenous placebo in clinically important outcomes of bleeding duodenal ulcer and, at best, only small benefits in bleeding gastric ulcer.
This meta-analysis included randomised controlled trials of oral or intravenous proton pump inhibitor therapy; both methods of administration were associated with reduced rebleeding (). Oral treatment is widely available and has the obvious advantage of costing less than intravenous administration. In areas of the world where intravenous treatment is unavailable or particularly expensive, oral treatment would be appropriate. Furthermore, it would be less costly for any patient with recent ulcer bleeding who did not require endoscopic haemostatic therapy.
Some trials of intravenous proton pump inhibitor treatment gave intermittent bolus injections, while others used a continuous infusion after a single intravenous bolus (). These high dose regimens have been shown to maintain intragastric pH around 6.0.7,8
The continuous administration of proton pump inhibitor is not associated with the development of pharmacological tolerance, unlike continuous H2
receptor antagonist administration.38
Our predetermined subgroup analysis examining only those trials that had used such high doses found no significant reduction in mortality, but significant reductions in rebleeding and rates of surgery ().
It was important to determine whether the addition of intravenous proton pump inhibitor therapy to appropriate endoscopic haemostatic therapy had any added benefit for those patients at the greatest risk. In our subgroup analysis of the trials that used endoscopic haemostatic therapy before randomisation we found no evidence for any effect on mortality, though there was a significant reduction in rebleeding. Of the trials that provided specific outcome data for patients with active arterial bleeding, oozing of blood, or a non-bleeding visible vessel, only five routinely incorporated some form of endoscopic haemostatic therapy before randomisation. In the five trials that did not routinely use endoscopic haemostatic therapy, proton pump inhibitor treatment was associated with significant reductions in rebleeding and surgical intervention but not in mortality. Failure to use endoscopic haemostatic therapy for such patients, however, would be considered as outside standard care. Proton pump inhibitor therapy is not an alternative to appropriate endoscopic haemostatic therapy, as shown in a trial from Hong Kong that randomised patients with bleeding ulcer and adherent clot or non-bleeding visible vessel to high dose intravenous omeprazole alone or to the combination of endoscopic haemostatic therapy and high dose intravenous omeprazole.39
Treatment with high dose intravenous omeprazole alone was associated with a significantly higher rate of rebleeding and a longer duration of hospital stay than combination therapy.
In summary, proton pump inhibitor treatment does not reduce mortality after ulcer bleeding, though it does reduce rates of rebleeding and, in general, the need for surgical intervention. This may be associated with important cost savings, which should be further evaluated in formal cost effectiveness studies.
What is already known on this topic
Proton pump inhibitors are effective for healing non-bleeding ulcers
Their role in the management of patients with bleeding ulcers is unclear
What this study adds
This systematic review and meta-analysis found that proton pump inhibitor treatment reduces the risk of ulcer rebleeding but does not influence overall mortality from ulcer bleeding
Requirement for surgery to manage ulcer bleeding is also likely to be reduced with early proton pump inhibitor treatment