Top Trials in Gastroenterology & Hepatology, 2nd Edition

By Mayur Brahmania

The Top Trials in Gastroenterology and Hepatology (2nd Edition) is a selection of 28 “hot” trials that have been influential in clinical practice. These trials have been critically appraised and summarized. Topics include:
- Luminal Gastroenterology
- Inflammatory Bowel Disease
- Nutrition
- Motility
- Hepatology
- Therapeutic Endoscopy

A perspective on each trial gives context and significance to the summaries, and a list of further reading identifies other influential papers.
- Mayur Brahmania, MD FRCPC, co-author
- Dustin Loomes, MD FRCPC, co-author
- Rahul Bhindi, MD, co-author
- Dana Moffatt, MD FRCPC, co-author

• Language: English
• Publisher: Mayur Brahmania
• Release date: May 24, 2016
• ISBN: 9781927799253

Mayur Brahmania

Dr. Mayur Brahmania is currently a Gastroenterologist/Hepatologist at the Toronto Western Hospital Liver Centre. Aside from clinical practice, Dr. Brahmania is involved in medical education both at the undergraduate and post-graduate level while also peer reviewing and publishing for many leading gastroenterology and hepatology journals. Dr. Brahmania’s research interests include quality improvement initiatives to advance and standardize quality of care in patients living with liver disease.

Book preview

1. Gastrointestinal Bleeding

Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers

Lau JY et al. The New England Journal of Medicine. 2000; 343(5):310–316.

Question

In patients treated endoscopically for bleeding peptic ulcers, does high-dose IV proton pump inhibitor therapy reduce the frequency of recurrent bleeding when compared to placebo?

Methods

Design: Randomized controlled

Blinding: Double-blind

Follow-up Period: 30 days post randomization

Setting: Single centre (Hong Kong)

Funding: Public

Participants

Inclusion criteria:

16 years old or greater

Successful endoscopic treatment (i.e, hemostasis) of actively bleeding ulcers or ulcers with non-bleeding visible vessels

Exclusion criteria:

Unsuccessful endoscopic treatment

Intervention

240 patients enrolled, with 120 randomly assigned to each group

After hemostasis achieved (endoscopic epinephrine and thermocoagulation) patients were given omeprazole 80 mg IV bolus, followed by 8 mg/hr infusion for 72 hours, followed by 20 mg PO daily for 2 weeks thereafter.

Control arm consisted of a placebo bolus and infusion for 72 hours, followed by omeprazole 20 mg PO daily x 2 weeks.

All patients with positive rapid urease test received a 1-week course of omeprazole 20 mg BID, clarithromycin 500 mg BID, amoxicillin 1 g BID and an additional 7 weeks of omeprazole 20mg PO.

Outcomes

Primary endpoint:

Recurrent bleeding within 30 days after endoscopy

Secondary endpoints:

Transfusion requirements

Hospital stay

Mortality rate

Rates of surgical intervention

Results

Primary endpoint:

There was less rebleeding (8/120, 6.7%) in treatment group compared with the placebo group (27/120, 22.5%; HR=3.9).

Most rebleeding occurred during the infusion period (first 3 days), with rebleeding in 5 patients (4.2%) in treatment group vs 24 patients (20.0%; p<0.001) in placebo group.

Secondary endpoints:

Smaller mean number of blood units transfused in treatment group (2.7 vs 3.5 units; p=0.04)

Shorter duration of hospital stay in treatment group for those admitted with a GI bleed (4 days in treatment group vs 5 days in placebo group; p=0.02)

Trend towards fewer deaths within 30 days of endoscopy in treatment group (5/120, 4.2%) vs placebo group (12/120, 10.0%; p=0.13)

No significant difference in surgical interventions between the two groups

Conclusion

After endoscopic treatment of bleeding peptic ulcers, high-dose IV omeprazole bolus followed by infusion for 72 hours reduced the rate of recurrent bleeding, the need for endoscopic retreatment, the need for blood transfusions, and shortened the length of hospitalization. There was no significant effect on mortality.

Perspective

In vitro studies have suggested that an increased pH (>6) helps to stabilize platelet aggregation and clot formation, as well as decrease clot breakdown by inhibition of pepsin. This trial was pivotal in demonstrating the benefit of IV PPI in decreasing rebleeding rates, transfusions, and length of stay; however, a clear mortality benefit was not shown.

There are still many unanswered questions: Are high dose PPIs better than low dose? Is IV better than PO administration? Are there geographic differences in Asian versus non-Asian populations? An attempt to answer some of these questions in a Cochrane review of 22 RCTs did not show a statistical difference in PPI brand (1). Additionally recent analysis comparing intermittent vs. continuous IV PPI has failed to show a difference in rebleeding or mortality rates (2). Nevertheless, 72 hours of PPI post-endoscopic hemostasis for high-risk lesions (Forrest Ia, Ib, IIa, and IIb) is now part of routine clinical practice and is still recommended by most major societal guidelines.

Further reading

Neumann I et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding.Cochrane database of systematic reviews. 2013; 6:CD007999.

Sachar H et al. Intermittent vs. continuous proton pump inhibitor therapy for high-risk bleeding ulcers. A systematic review and meta-analysis. Jama Intern Med 2014 Nov, 174 (11).

Omeprazole before endoscopy in patients with gastrointestinal bleeding

Lau JY et al. The New England Journal of Medicine. 2007; 356(16): 1631–1640.

Question

Does giving omeprazole before endoscopy have any effect on the need for endoscopic therapy or improve clinical outcomes?

Methods

Design: Randomized controlled

Blinding: Double-blind

Follow-up: Day 30 post randomization

Setting: Single centre (Hong Kong)

Funding: Public

Participants

Inclusion criteria:

Consecutive patients with overt signs of upper gastrointestinal bleeding

Exclusion criteria:

Hypotensive shock refractory to resuscitation

Age <18

Unable to consent

Pregnant

Allergy to proton pump inhibitors

Long-term ASA use

Intervention

Patients were randomized to omeprazole (n=314) or placebo (n=317) and were given 80 mg IV bolus followed by IV infusion of 8 mg/hr of omeprazole or placebo, respectively, until endoscopy.

Ulcers with spurting hemorrhage, oozing hemorrhage, or non-bleeding visible vessels were injected with epinephrine (dilution 1:10,000, aliquots of 0.5 to 1 mL) followed by coaptive thermocoagulation.

Bleeding esophageal and gastric varices were treated by band ligation and injection of cyanoacrylate, respectively, plus vasoactive drugs and IV antibiotics.

Omeprazole 8 mg/hr IV infusion continued for 72 hours after endoscopy in patients who required ulcer hemostasis.

Patients with recurrent bleeding underwent urgent endoscopy; if the bleeding could not be controlled by endoscopic method or second recurrence, surgical intervention was requested.

Post 72-hour infusion of omeprazole, patients were given 40 mg of omeprazole orally for 8 weeks; patients with positive urease test or H. pylori received 1 week of eradication therapy followed by 7 weeks of 40 mg omeprazole orally.

Outcomes

Primary endpoint:

Need for endoscopic treatment at the first endoscopic examination

Secondary endpoints:

Need for transfusion

Need for emergency surgery to achieve hemostasis

Duration of hospital stay

Rates of recurrent bleeding within 30 days after randomization

Mortality rate within 30 days after randomization

Results

Primary endpoint:

Less endoscopic treatment was required in the omeprazole group (60/314, 19.1%) compared with the placebo group (90/317, 28.4%; p=0.007).

Among patients with peptic ulcer bleeding, there were less actively bleeding peptic ulcers (12/187, 6.4%) and more clean based ulcers (120/187, 64.2% vs 90/190, 47.4%; p=0.001, respectively) in omeprazole group vs the placebo group (28/190, 14.7%; p=0.01).

Secondary endpoints:

Blood transfusions were not significantly different in the omeprazole group (1.54 units) vs the placebo group (1.88 units; p=0.12).

Surgery occurred equally as often in the omeprazole group (1.6%) vs the placebo group (2.1%).

Length of stay was significantly shorter in omeprazole group compared to placebo (p=0.003).

Rebleeding rates within 30 days of initial endoscopy was similar between the omeprazole group (3.5%) and the placebo group (2.5%; p=0.49).

Mortality rates were equal in the omeprazole group (8/314, 2.5%) vs the placebo group (7/317; 2.2%; p=0.78) within 30 days after randomization.

Conclusion

High-dose omeprazole before endoscopy down-staged peptic ulcers and decreased the need for endoscopic therapy.

Perspective

Building on results of the Lau NEJM paper in 2000 showing benefit of IV PPI post-endoscopy, this paper showed benefit of IV PPI pre-endoscopy. The mean time before endoscopy was 14.7 hours; it is unclear if this longer mean duration of PPI therapy had an effect on the positive results of the trial. Mortality and blood transfusion requirements were not different in this study, but the decreased need for endoscopic intervention and the decreased length of stay lead to cost-effectiveness analyses supporting pre-endoscopy PPI. For patients in the ER suspected of having an upper GI bleed, clinical and laboratory evaluation (1,2) will help to further define those who require IV PPI and endoscopy versus those who can safely be