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Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding

Alan Barkun, MD, MSc; Marc Bardou, MD, PhD; and John K. Marshall, MD, MSc
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From McGill University, Montreal, Quebec H3G 1A4, Canada; Faculté de Médecine, 21079 Dijon Cedex, France; and McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

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Ann Intern Med. 2004;141(1):80-81. doi:10.7326/0003-4819-141-1-200407060-00030
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Managing patients with nonvariceal upper gastrointestinal bleeding
Posted on August 1, 2004
Mohammad S Khuroo
King Faisal Specialist Hospital and Research Centre, Riyadh 11211 Saudi Arabia
Conflict of Interest: None Declared

TO THE EDITOR: We thank the members of the Nonvariceal Upper GI Bleeding Consensus Conference Group for response to our letter.1 They commented that issue of increased deaths with intravenous proton pumps inhibitors (PPI) is often a source of confusion. We disagree and believe that it is a matter of concern if the published data on intravenous PPI are critically analyzed. Twenty-six randomized trials have been published on PPI in acute nonvariceal gastrointestinal bleeding.2 PPI were administered orally in 7 trails (mean dose/day, 70±15 mg; range, 40 to 80 mg), intermittent intravenous doses in 15 trials (mean dose/day 145±42 mg; range 80 t0 230 mg) and large intravenous bolus followed by continuous infusion in 4 trials (mean dose/day, 274±4.0 mg; range 272 to 280 mg). Of the latter 4 trials, 3 were conducted in Europe and one in Hong Kong. All the 3 European trails included patients with high percentage of co- morbidities. 3-5 None of the trials using oral or intermittent low doses of proton pump inhibitors have reported higher deaths in treated group versus controls. All the 3 trials done in Europe with large intravenous bolus followed by continuous infusion had higher deaths in treated than in control group. Danshmend et al enrolled 1147 patients (PPI group 578 and control group 569) and reported higher death rates in the PPI group [40 vs. 30].3 The deaths caused by ulcer complications were similar in the two groups (12 vs. 11) and the higher deaths in the PPI group were exclusively due to medical causes (non-ulcer deaths) (29 vs.18). The postoperative death rates were significantly higher in the PPI group (20/62 vs. 6/63; 32.3% vs. 9.6%). Hasselgren et al 1997 enrolled 322 patients (PPI group 159 and control group 163) and reported higher death rates in the PPI group (11 vs. 1).4 The mortality in the control group was exceptionally low. However, ulcer deaths in the two groups were similar (1/157 vs. 1/163) while non-ulcer deaths were higher in the PPI group (10/157 vs. 0/163). Schaffalizky et al 1997 enrolled 265 patients (130 in the PPI group and 135 in the control group) and an independent statistician monitoring the deaths reported higher death rates in the PPI group to the steering committee when approximately 80% of the patients had been enrolled in the study.5 The steering committee had decided to discontinue recruitment of patients, but allowed patients already included to continue in the study. In the published report, reported death rates in the PPI and control group were similar (7 vs. 8). The data submitted by the independent statistician to the steering committee were not disclosed. An independent external safety group had stopped two of the 3 trials. 4,5 The baseline characteristics of patients in the PPI and the control groups in all the 3 trials were comparable. No explicit explanation was given for the higher death rates in the treatment group in any of the trials. These data were significant, as two of the three trials had shown a significant reduction in the rate of further bleeding and need for surgery in the PPI group and higher death rates in the treatment group could not be the result of ulcer complications. 4,5

In our meta-analysis, a subgroup analysis was carried out to determine the influence of route of PPI administration on outcome measures in UGI bleeding.2 Both oral and intravenous PPI were equally effective in reducing rates of further bleeding [OR with 95% CI, 0.39 (0.25-0.60) vs. 0.36 (0.25-0.51) respectively ]and surgery [OR with 95% CI, 0.71 (0.55- 0.91) vs. 0.31 (0.18-0.53) respectively ]. However, all cause mortality was significantly higher in trials using intravenous PPI [OR with 955 CI, 1.15 (1.01-1.57)]. In contrast all cause mortality was significantly lower in trials using oral PPI [OR with 95% CI, 0.43 (0.17-0.91)]. On the basis of these data, we question the recommendations of the Consensus group who stressed the use of intravenous bolus followed by continuous infusion of PPI for decreasing rebleeding.

Mohammad Sultan Khuroo, MD, DM, FRCP (Edin), MACP King Faisal Specialist Hospital and Research Centre Riyadh 11211, Saudi Arabia

Mehnaaz Sultan Khuroo, MD Sri-Ramachandra Medical College and Research Institute Porur Chennai, India.


1. Barkun A, Bardou M, Marshall JK. Managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2004;141:80. 2. Khuroo MS, Khuroo MS, Farahat KLC, Kagevi IE. Treatment with proton pump inhibitors in acute non-variceal upper gastrointestinal bleeding: A meta-analysis. Journal Gastroenterol Hepatol in print (DOI:10.111/j.1400- 1746.2004.03441.x) 3. Daneshmend TK, Hawkey CJ, Langman MJ, Logan RF, Long RG, Walt RP. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomized double blind controlled trial. BMJ 1992; 304: 143"“7. 4. Hasserlgren G, Lind T, Lundell L et al. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicenter study. Scand. J. Gastroenterol. 1997; 32: 328"“33. 5. Schaffalitzky de Muckadell OB, Havelund T, Harling H et al. Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomized double-blind placebo controlled multicentre study. Scand. J. Gastroenterol. 1997; 32: 320"“7.

Conflict of Interest:

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