Ulcer Bleeding Clinical Trial
Official title:
Second-look Endoscopy in High Risk Patients After Endoscopic Hemostasis to Their Bleeding Peptic Ulcers Improves Their Outcomes
Bleeding peptic ulcer is a common medical emergency. Endoscopic treatment stops bleeding in those actively bleeding from their peptic ulcers, reduces further bleeding, transfusion, surgery and deaths. After initial endoscopic control of bleeding, approximately 10% of them will develop recurrent bleeding. Mortality rate in this group of patients is at least 4 fold higher. In the few who need surgery, mortality approaches 30%. Prevention of further bleeding is therefore a major treatment objective. Currently the investigators use a high dose infusion of proton pump inhibitor (PPI) for 72 hours to render gastric pH neutral. In a previous randomized trial, the investigators showed that the rate of bleeding in 30 days was around 7% with such an approach. In a small subgroup of high risk patients defined by presentation with shock and ulcers > 2 cm in size, 1 in 6 would re-bleed. An alternate strategy is to select those at especially high risk of further bleeding and repeat endoscopic treatment the next morning. The investigators have shown that persistence of major bleeding stigmata, i.e. a visible vessel, during a second endoscopy predicts further bleeding. It is therefore logical that by repeating endoscopic treatment the next morning, the investigators can prevent further bleeding and possibly surgery and deaths. The current study proposes to develop a score to identify those at risk of further bleeding after endoscopy. The investigators used a historical cohort with carefully collected clinical data to derive a risk score. In this derivation phase of 939 patients, the investigators have developed a 9 point risk score which consists of the following parameters (Age>60, Male sex, ulcer>2cm, posterior bulbar in location, spurting or Forrest Ia bleeding and admission hemoglobin of < 8 g/dl). Using AUROC and Youden J statistics, a score of 5 or above has been shown to highly predictive of further bleeding. The score will then be validated in a prospective cohort of patients with bleeding peptic ulcers. In the final phase of this study, the investigators propose a randomized controlled trial to test the hypothesis that a second look endoscopy with treatment in selected high risk patients can further reduce bleeding and improve their outcomes. After endoscopic hemostasis to their bleeding peptic ulcers, patients are risk stratified based on the score. Those with a score of 5 or more are randomized to receive the standard treatment (a high dose PPI infusion) or a second look endoscopy with treatment in addition to PPI infusion. The primary outcome to the trial is further significant clinical bleeding.
Hospitalization for bleeding peptic ulcers has declined over past decades [1]. Bleeding from
peptic ulcers however remains the commonest diagnosis in those who present with acute upper
gastrointestinal bleeding (AUGIB). The incidence has been around 60-80/100,000 population.
Endoscopic hemostatic therapy is the first treatment to those with active bleeding and major
stigmata of bleeding. Endoscopic therapy stops bleeding and reduces rate of further bleeding,
requirement for surgery and importantly deaths [2]. Adjunctive intravenous infusion of a high
dose proton pump inhibitor (PPI) further reduces rebleeding. In a multicentre international
placebo controlled trial that involved 767 patients with bleeding peptic ulcers, a PPI
infusion reduced the rate of further bleeding (10.3 to 5.9% at 72 hour, P=0.026) In a
subgroup analysis of a Cochrane meta-analysis over use of PPI in bleeding peptic ulcers, the
adjunctive use of PPI in those who underwent endoscopic hemostatic treatment, when compared
to those without PPI therapy, was associated with a reduction in deaths (17/954 vs. 32/ 969;
OR 0.54; 95%CI 0.3-0.96) [ 4 ] . Despite of aggressive endoscopic therapy and maximal acid
suppression using a PPI infusion, further bleeding occurs in around 8% of patients. Further
bleeding is the single most important adverse prognostic factor and is associated with a 4
fold increase in mortality. From a National United Kingdom Audit on the management of
patients with AUGIB, those who needed surgery for further bleeding and failed endoscopic
control had a mortality of 28% [ 5 ]. In addition to initial control of bleeding with
endoscopic therapy, the prevention of further bleeding is an important objective.
The use of routine second look endoscopy with re-treatment has been evaluated in several
clinical trials. A recent meta-analysis [ 6 ] of these clinical trials concluded that the use
of routine second look endoscopy confers a modest reduction in rate of further bleeding. In
this pooled analysis of 8 trials and 938 patients, the absolute risk reduction was 6.8% (16.5
to 9.7%). The number to treat to prevent one episode of recurrent bleeding was 15. Only one
of these trials used high dose PPI infusion and epinephrine injection alone was used as
endoscopic treatment. The use of epinephrine injection is no longer considered an optimal
treatment. A second modality should be added to induce vessel thrombosis [ 7 ]. Clinical
practice in the reported trials was considered not contemporary. In the modern practice of
combination endoscopic treatment and maximal acid suppression, the use of routine second look
endoscopy cannot be recommended as the NNT to prevent further bleeding would likely be
higher. A policy of routine second look endoscopy is generally not recommended as suggested
by an International Consensus Group [ 8 ].
Second look endoscopy in those at high risk of further bleeding is however a logical
approach. The NNT to prevent further bleeding diminishes as risk of further bleeding
increases. For instance, an ulcer > 2 cm in size with Forrest I or Forrest II a bleeding
would be associated with a re-bleeding risk of 15-20% even with high dose PPI infusion. Saeed
et al. reported a study consisted of a small number of patients (n=40) and showed that
endoscopic re-treatment in selected high risk patients based on a Baylor College score led to
significant reduction in further bleeding (0 vs. 24%). This selective approach warrants
investigation and could represent a dominant strategy in addition to high dose PPI infusion
as a pre-emptive management of patients at high risk of further bleeding. A prerequisite to
this approach is a risk score that predicts further bleeding in patients after endoscopic
hemostasis and PPI infusion. This risk score needs to be derived from a large cohort of
patients after uniform endoscopic treatment and acid suppression. The score will have to be
validated in a prospective cohort of patients with bleeding peptic ulcers again after the
same aggressive treatment. Furthermore, a randomized controlled trial on the use of second
look endoscopy in high risk patients as identified by this risk score is required.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
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| Completed |
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