Aliment Pharmacol Ther 2002; 16: 11371142.

Meta-analysis: the efficacy of intravenous H2-receptor antagonists in

bleeding peptic ulcer
J. E. LEVINE*, G . I. LEON TIAD IS, V. K. SHA RMA & C. W. HOWDEN
*Department of Medicine, Evanston Hospital, Evanston, IL, USA; Endoscopy Department, General Hospital
of Alexandroupolis, Greece; Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ, USA; Division of Gastroenterology
and Hepatology, Northwestern University Medical School, Chicago, IL, USA
Accepted for publication 20 February 2002

SUMMARY

Background: Although a previous meta-analysis found

that intravenous H2-receptor antagonists were only
weakly beneficial in bleeding gastric ulcer and of no
benefit in bleeding duodenal ulcer, patients with ulcer
bleeding continue to receive such treatment.
Aim: To re-evaluate the efficacy of intravenous H2receptor antagonists in ulcer re-bleeding, surgery and
mortality by updating the previous meta-analysis.
Methods: After two independent literature searches,
randomized, placebo-controlled trials of intravenous
H2-receptor antagonists in bleeding ulcer published
between 1984 and 2000 were added to those from the
initial meta-analysis. Pooled rates of re-bleeding,
surgery and death were re-calculated, together with
the relative risk reduction, absolute risk reduction,

INTRODUCTION

The treatment of actively bleeding peptic ulcers remains

a challenge. The possible benefit of the intravenous
administration of H2-receptor antagonists (H2RA) has
stimulated interest for some time. In a 1985 metaanalysis, Collins & Langman studied randomized
controlled trials that had compared intravenous H2RA
with placebo in bleeding duodenal ulcer and gastric
Correspondence to: Dr C. W. Howden, Division of Gastroenterology and
Hepatology, Northwestern University Medical School, 676 N. St. Clair
Avenue, Suite 880, Chicago, IL 60611, USA.
E-mail: c.howden@northwestern.edu

2002 Blackwell Science Ltd

number needed to treat and MantelHaenszel odds

ratio.
Results: Intravenous H2-receptor antagonists did not
significantly reduce re-bleeding, surgery or death in
bleeding duodenal ulcer. There were small but significant reductions in re-bleeding, surgery and death in
bleeding gastric ulcer; the absolute risk reductions were
7.2%, 6.7% and 3.2%, respectively.
Conclusions: Intravenous H2-receptor antagonists are of
no value in bleeding duodenal ulcer, although they may
be mildly beneficial in bleeding gastric ulcer. Because
proton pump inhibitors have a greater inhibitory effect
on gastric acid secretion than H2-receptor antagonists,
they may be more effective in ulcer bleeding and should
be further evaluated for that indication.

ulcer.1 The clinical end-points assessed were

re-bleeding, surgical intervention and mortality. They
were unable to demonstrate any statistically significant
benefit for intravenous H2RA over placebo for any of
these end-points in bleeding duodenal ulcer. However,
they found small, but statistically significant, benefits in
bleeding gastric ulcer. Since the publication of that
meta-analysis, further randomized controlled trials have
compared intravenous H2RA with placebo in patients
with bleeding ulcers. These have included a large,
multicentre, randomized controlled trial from the UK
and Ireland2 which used a high dose of intravenous
famotidine that had previously been shown to elevate
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J. E. LEVINE et al.

intragastric pH to > 6 for up to 24 h in patients with

actively bleeding ulcers.3 However, the randomized
controlled trial failed to demonstrate significant reductions in any of the end-points studied.2
Despite the apparently weak level of supportive evidence, patients with undiagnosed upper gastrointestinal
bleeding and those with known bleeding from peptic
ulcer disease are likely to receive intravenous H2RA
treatment. With the inclusion of more recent randomized controlled trials into the database originally compiled by Collins & Langman,1 we aimed to re-evaluate
the evidence for intravenous H2RA in ulcer bleeding.
MATERIALS AND METHODS

Using the MEDLINE and PREMEDLINE databases, two of

the authors (JEL, GIL) performed independent, fully
recursive literature searches for randomized controlled
trials comparing intravenous H2RA with placebo in
actively bleeding peptic ulcers. The search was confined
to the period 19842000 and any relevant randomized
controlled trials identified were added to those that had
been included by Collins & Langman.1 The search
strategy employed is described in the Appendix. We also
searched for abstracts presented at major meetings.
For a trial to be included in the meta-analysis, adequate
information had to be extractable concerning the
numbers of patients randomized to intravenous H2RA
and placebo, and the rates of re-bleeding andor surgical
intervention andor mortality in both the treatment and
control groups. Dual publications were excluded; if more
than one publication of the same data was retrieved,
only the more recent version was included. Pharmacodynamic studies of H2RAs, uncontrolled studies of
H2RAs in bleeding ulcer and studies of H2RAs in upper
gastrointestinal tract bleeding from unspecified sources
or sources other than ulcer disease were also excluded.
Each author reviewed all trials independently to assess
their suitability for inclusion in the meta-analysis; any
differences were resolved by consensus.
We assessed trial homogeneity according to the
BreslowDay method.4 For each of the three predetermined end-points re-bleeding, surgical intervention and mortality the rate on intravenous H2RA
was defined as the experimental event rate (EER) and
the rate on placebo was defined as the control event
rate (CER).5 The relative risk reduction (RRR) was
calculated as (CER ) EER)CER, the absolute risk reduction (ARR) was calculated as CER ) EER, and the

number needed to treat (NNT) was calculated as the

inverse of ARR.6 The 95% confidence interval (CI) for
the ARR was calculated for each randomized controlled
trial and for the pooled data. The upper and lower limits
of the 95% CI for the NNT were defined, respectively, as
the inverse of the lower and upper limits of the 95% CI
of the ARR. When the 95% CI of the ARR encompassed
zero, indicating a statistically non-significant result, no
NNT value was computed. As an overall summary
statistic of the treatment effect, the pooled Mantel
Haenszel odds ratio (ORMH) was determined for each
outcome of interest using MA 2 2 statistical software
(Department of Clinical Epidemiology and Biostatistics,
McMaster University, Canada).
RESULTS

Following our literature searches, we were only able to

identify five randomized controlled trials2, 710 that had
not been included in the initial meta-analysis of Collins
& Langman.1 The study of Walt et al., which used highdose intravenous famotidine, reported re-bleeding and
surgical intervention rates for peptic ulcer at all sites,
but listed mortality rates individually for duodenal ulcer
and gastric ulcer.2 A small Hungarian study of cimetidine only reported re-bleeding rates, but did not
subdivide these for duodenal ulcer and gastric ulcer.7
An Italian study randomized patients to placebo,
ranitidine or somatostatin and reported rates of rebleeding, surgical intervention and death, but not
according to ulcer site.8 An Australian study of
intravenous ranitidine reported rates of re-bleeding,
surgical intervention and mortality separately for
duodenal ulcer and gastric ulcer.9 Another Italian
study randomized patients to intravenous ranitidine,
somatostatin or placebo, but only reported re-bleeding
rates that were not subdivided according to ulcer site.10
Bleeding peptic ulcer (duodenal and gastric ulcer combined)
Thirty randomized controlled trials reported re-bleeding
rates on intravenous H2RA and placebo. There was
significant heterogeneity among these randomized controlled trials (P 0.001) due presumably to the
different proportions of duodenal ulcer and gastric ulcer
included. This makes their pooling for meta-analysis
questionable. There were, however, 1901 patients
randomized to intravenous H2RA and 1885 to placebo.
Pooled rates of re-bleeding were 21.4% on intravenous

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 11371142

H 2 -RECEPTOR ANTAGONISTS FOR BLEEDING ULCER

H2RA and 24.0% on placebo. The RRR was 11% and

ARR was 2.6% (95% CI, 0.05.3%). The pooled ORMH
was 0.86 (95% CI, 0.741.00; P 0.053).
Twenty-five randomized controlled trials reported rates
of surgical intervention on intravenous H2RA treatment
and placebo. There was no significant heterogeneity
among these randomized controlled trials (P 0.34).
There were 1694 patients randomized to intravenous
H2RA treatment and 1706 to placebo. Pooled rates of
surgical intervention were 13.4% on intravenous H2RA
and 15.8% on placebo. The RRR was 15%, ARR was
2.4% (95% CI, 0.14.8%) and NNT was 41 (95% CI,
211880). The pooled ORMH was 0.83 (95% CI, 0.68
1.00; P 0.057).
Twenty-seven randomized controlled trials reported
mortality rates on intravenous H2RA and placebo.
There was no significant heterogeneity among these
randomized controlled trials (P 0.57). There were
1865 patients randomized to intravenous H2RA treatment and 1857 to placebo. Pooled mortality rates were
5.6% and 6.8%, respectively. The RRR was 18% and
ARR was 1.2% (95% CI, ) 0.32.8%). The pooled ORMH
was 0.81 (95% CI, 0.621.06; P 0.15).
Figure 1 depicts the pooled ORMH and 95% CI for each of
the three pre-determined end-points of interest in bleeding
ulcer (duodenal ulcer and gastric ulcer combined).
Bleeding duodenal ulcer
Twenty-three randomized controlled trials reported
duodenal ulcer re-bleeding rates on intravenous H2RA
and placebo. There was no significant heterogeneity

1139

among these randomized controlled trials (P 0.25).

There were 469 patients randomized to intravenous
H2RA and 446 to placebo. Pooled rates of re-bleeding
were 23.9% on intravenous H2RA and 25.3% on
placebo. The RRR was 6% and ARR was 1.5% (95%
CI, ) 4.17.0%). The pooled ORMH was 0.90 (95% CI,
0.661.22; P 0.48).
Eighteen randomized controlled trials reported rates of
surgical intervention between intravenous H2RA and
placebo in bleeding duodenal ulcer. There was no
significant heterogeneity among these randomized controlled trials (P 0.82). There were 392 patients
randomized to intravenous H2RA treatment and 378 to
placebo. Pooled rates of surgical intervention were
15.8% for intravenous H2RA and 19.8% for placebo.
The RRR was 20.0% and ARR was 4.0% (95% CI,
) 1.49.4%). The pooled ORMH for surgical intervention in bleeding duodenal ulcer with intravenous H2RA
was 0.76 (95% CI, 0.521.11; P 0.16).
Twenty-one randomized controlled trials reported rates
of mortality in bleeding duodenal ulcer managed by
intravenous H2RA or placebo. There was no significant
heterogeneity among these randomized controlled trials
(P 0.92). There were 727 patients randomized to
intravenous H2RA and 717 to placebo. Pooled mortality
rates were 5.0% for intravenous H2RA treatment and
4.3% for placebo. The RRR was ) 15.0% and ARR was
) 0.6% (95% CI, ) 2.81.5%). The pooled ORMH for
mortality in bleeding duodenal ulcer with intravenous
H2RA was 1.15 (95% CI, 0.721.82; P 0.57).
Figure 2 depicts the pooled ORMH and 95% CI for each
of the three pre-determined end-points of interest in
bleeding duodenal ulcer.
Bleeding gastric ulcer

Figure 1. Pooled MantelHaenszel odds ratio (ORMH) and 95%

confidence interval (CI) for re-bleeding, surgical intervention and
mortality from a meta-analysis of randomized controlled trials
comparing intravenous H2-receptor antagonists with placebo in
bleeding ulcer (duodenal and gastric ulcer combined).

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 11371142

Twenty-four randomized controlled trials reported

re-bleeding rates from bleeding gastric ulcer treated
with intravenous H2RA or placebo. There was no
significant heterogeneity among these randomized controlled trials (P 0.77). There were 313 patients
randomized to intravenous H2RA treatment and 347 to
placebo. Pooled re-bleeding rates were 20.4% for
intravenous H2RA and 27.7% for placebo. The RRR
was 26%, ARR was 7.2% (95% CI, 0.713.7%) and
NNT was 14 (95% CI, 7137). The pooled ORMH was
0.66 (95% CI, 0.460.95; P 0.02).
Twenty randomized controlled trials reported rates of
surgical intervention for bleeding gastric ulcer treated

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J. E. LEVINE et al.

Figure 2. Pooled MantelHaenszel odds ratio (ORMH) and 95%

confidence interval (CI) for re-bleeding, surgical intervention and
mortality from a meta-analysis of randomized controlled trials
comparing intravenous H2-receptor antagonists with placebo in
bleeding duodenal ulcer.

with intravenous H2RA or placebo. There was no

significant heterogeneity among these randomized controlled trials (P 0.47). There were 291 patients
randomized to intravenous H2RA and 312 to placebo.
Pooled rates of surgical intervention were 14.1% for
intravenous H2RA and 20.8% for placebo. The RRR
was 32%, ARR was 6.7% (95% CI, 0.712.8%) and
NNT was 15 (95% CI, 8139). The pooled ORMH for
surgical intervention in bleeding gastric ulcer managed
with intravenous H2RA was 0.61 (95% CI, 0.390.93;
P 0.02).
Twenty-two randomized controlled trials reported
mortality rates for bleeding gastric ulcer managed by
either intravenous H2RA or placebo. There was no
significant heterogeneity among these randomized controlled trials (P 1.00). There were 516 patients
randomized to intravenous H2RA treatment and 546 to
placebo. Pooled mortality rates were 5.8% for intravenous H2RA and 9.0% for placebo. The RRR was 35%,
ARR was 3.2% (95% CI, 0.06.3%) and NNT was 32
(95% CI, 163844). The pooled ORMH for mortality
from bleeding gastric ulcer managed with intravenous
H2RA was 0.68 (95% CI, 0.431.06; P 0.09).
Figure 3 depicts the pooled ORMH and 95% CI for each
of the three pre-determined end-points of interest in
bleeding gastric ulcer.
DISCUSSION

The management of patients with bleeding peptic

ulcer remains a challenge and, in some respects,

Figure 3. Pooled MantelHaenszel odds ratio (ORMH) and 95%

confidence interval (CI) for re-bleeding, surgical intervention and
mortality from a meta-analysis of randomized controlled trials
comparing intravenous H2-receptor antagonists with placebo in
bleeding gastric ulcer.

controversial. Intravenous H2RA treatment is widely

used for patients presenting with upper gastrointestinal
haemorrhage before diagnostic endoscopy has demonstrated the site or cause of bleeding. Whether this
contributes anything to the overall management is
unclear and cannot be addressed by this meta-analysis,
which focuses on randomized controlled trials among
patients known to be bleeding from peptic ulcer.
What is clear from the results of this meta-analysis is
that intravenous H2RA treatment provides no additional
benefit for patients found to be bleeding from duodenal
ulcer. Such patients should receive appropriate endoscopic treatment whenever it is clinically indicated. The
remainder can be safely started on oral proton pump
inhibitor treatment as soon as it is considered to be
clinically appropriate. At least two randomized controlled trials have demonstrated the safety and efficacy of
oral proton pump inhibitor treatment in this context.11, 12 Patients who require endoscopic treatment of
bleeding duodenal ulcer might benefit from intravenous
proton pump inhibitor treatment for up to 72 h, as has
been demonstrated in a large randomized controlled trial
from Hong Kong.13 Proton pump inhibitors can maintain intragastric pH > 6 for prolonged periods if given in
an adequate dose.14, 15 Although a high-dose intravenous infusion of famotidine has been shown to maintain
intragastric pH > 6 in patients with actively bleeding
ulcers,3 this effect was only observed for up to 24 h. After
this period, it is likely that the antisecretory effect would
lessen because of the development of pharmacological
tolerance as has previously been shown for ranitidine
when given by high-dose intravenous infusion.16

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 11371142

H 2 -RECEPTOR ANTAGONISTS FOR BLEEDING ULCER

However, tolerance does not develop to proton pump

inhibitors during a few days of continuous intravenous
infusion,1417 supporting their potential usefulness in
bleeding peptic ulcer. At present, pantoprazole is the only
proton pump inhibitor available in the USA as an
intravenous formulation. To date, there are limited data
available concerning the efficacy of intravenous pantoprazole in bleeding peptic ulcer,18, 19 although further
trials are being conducted.
There may, however, be a useful but limited role for
intravenous H2RA treatment in patients found to be
bleeding from gastric ulcer. We found that the pooled
OR for re-bleeding was 0.66, suggesting a 34%
reduction attributable to intravenous H2RA treatment.
This is very close to the original estimate of Collins &
Langman of 0.68, or a 32% reduction in risk.1
Whether or not intravenous H2RA treatment has
any significant effect on mortality from bleeding gastric
ulcer is less clear. Collins & Langman reported a pooled
OR of 0.53 (95% CI, 0.300.96), suggesting that
intravenous H2RA treatment might reduce mortality
from bleeding gastric ulcer by around 47%. Our
revised estimate is 0.68, suggesting a reduction of
around 32%. However, the 95% CI on that OR
encompassed unity (0.431.06) and was therefore
not statistically significant (P 0.09). The results of
the large randomized controlled trial by Walt et al.,2
which failed to show any benefit of high-dose intravenous famotidine on mortality from bleeding gastric
ulcer (or duodenal ulcer), were largely responsible for
the non-significant result in our analysis. However,
reduced rates of re-bleeding and surgery among
patients with bleeding gastric ulcer would still be
important clinical benefits even without any reduction
in mortality.
In conclusion, we found no evidence to support
the continued use of intravenous H2RA treatment for
patients with bleeding duodenal ulcer, but moderate
evidence for patients with bleeding gastric ulcer.
Further study of proton pump inhibitors in bleeding
ulcer seems logical and appropriate because of their
greater antisecretory effect and because, unlike H2RAs,
there is no development of pharmacological tolerance to
their use as an intravenous infusion.
ACKNOWLEDGEMENTS

This work was not financially supported by any outside

agency or pharmaceutical company.

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 11371142

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18 Fried R, Beglinger C, Stumpf J, et al. Comparison of intravenous pantoprazole with intravenous ranitidine in peptic
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APPENDIX

The search string we used was (Peptic Ulcer Hemorrhage[MESH] OR peptic ulcer hemorrhage OR peptic
ulcer haemorrhage OR bleeding peptic ulcer OR

bleeding duodenal ulcer OR bleeding gastric ulcer

OR upper gastrointestinal bleeding OR ((bleeding OR
hemorrhage OR haemorrhage OR haemorrhagic
OR hemorrhagic) and (upper gastrointestinal OR
gastroduodenal OR duodenal OR gastric OR peptic
ulcer OR duodenal ulcer OR gastric ulcer))) and
(Histamine H2 Antagonists[MESH] OR histamine H2
antagonists OR histamine H2 antagonist OR H2RAs
OR H2RA OR Cimetidine[MESH] OR cimetidine OR
Famotidine[MESH] OR famotidine OR Ranitidine[MESH]
OR ranitidine OR Nizatidine[MESH] OR nizatidine).

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 11371142