GASTROENTEROLOGY 2004;126:441– 450
Addition of a Second Endoscopic Treatment Following
Epinephrine Injection Improves Outcome in High-Risk
Bleeding Ulcers
XAVIER CALVET,* MERCEDES VERGARA,* ENRIC BRULLET,* JAVIER P. GISBERT,‡
and RAFEL CAMPO*
*Unitat de Malalties Digestives, Hospital de Sabadell/UDIAT, Institut Universitari Parc Taulı́, Universitat Autónoma de Barcelona, Barcelona;
and ‡Servicio de Aparato Digestivo Hospital de la Princesa, Madrid, Spain
Background & Aims: Endoscopic therapy reduces the rebleeding rate, the need for surgery, and the mortality in
patients with peptic ulcer and active bleeding or visible
vessel. Injection of epinephrine is the most popular therapeutic method. Guidelines disagree on the need for a
second hemostatic procedure immediately after epinephrine; although it seems to reduce further bleeding,
its effects on morbidity, surgery rates, and mortality
remain unclear. The aim of this study was to perform a
systematic review and meta-analysis to determine
whether the addition of a second procedure improves
hemostatic efficacy and/or patient outcomes after epinephrine injection. Methods: An extensive search for
randomized trials comparing epinephrine alone vs. epinephrine plus a second method was performed in MEDLINE and EMBASE and in the abstracts of the AGA
Congresses between 1990 and 2002. Selected articles
were included in a meta-analysis. Results: Sixteen studies including 1673 patients met inclusion criteria. Adding a second procedure reduced the further bleeding
rate from 18.4% to 10.6% (Peto odds ratio 0.53, 95% CI:
0.40 – 0.69) and emergency surgery from 11.3% to 7.6%
(OR: 0.64, 95% CI: 0.46 – 0.90). Mortality fell from 5.1%
to 2.6% (OR: 0.51, 95% CI: 0.31– 0.84). Subanalysis
showed that the risk of further bleeding decreased regardless of which second procedure was applied. In
addition, the risk was reduced in all subgroups, although
reduction was more evident in high-risk patients and
when no scheduled follow-up endoscopies were performed. Conclusions: Additional endoscopic treatment
after epinephrine injection reduces further bleeding,
need for surgery, and mortality in patients with bleeding
peptic ulcer.
ndoscopic therapy reduces the rebleeding rate, the
need for surgery, and the morbidity and mortality of
patients bleeding from a peptic ulcer.1 Many different
endoscopic hemostatic techniques have been developed
and studied over the last 25 years. Methods are based on
the injection of vasoconstrictor substances (epinephrine),
E
sclerosant substances (polidocanol, absolute alcohol),
clotting factors (thrombin, fibrin glue), or adhesives (cyanoacrylate). Thermal therapies include laser, monopolar
electrocoagulation, argon plasma coagulation, bipolar
probes, and heater probe. More recently, the use of
mechanical devices to clip the bleeding vessel (hemoclip)
has been incorporated. Epinephrine injection—alone or
in combination with another technique— has become
the most popular endoscopic method for emergency endoscopic hemostasis because of its safety, low cost, and
easy application.2
Although some randomized studies have established
that epinephrine in combination with a second hemostatic technique is better than epinephrine alone, the
guidelines do not make clear recommendations on this
point.3,4 The addition of a second endoscopic technique
can increase the cost and the risk of complication of the
procedure, and it remains unclear whether the reduction
of further bleeding actually offsets these drawbacks.
The aim of the present study was to perform a metaanalysis of the studies comparing the safety and efficacy
of endoscopic injection of epinephrine alone vs. epinephrine plus a second hemostatic method in the treatment of
patients with a bleeding peptic ulcer.
Materials and Methods
Literature Search and Identification of
Primary Studies
A literature search was performed in September 2002
using the MEDLINE and EMBASE databases and the
Cochrane Controlled Trials Register. The strategy included the
words “(peptic ulcer OR gastric ulcer OR duodenal ulcer)
AND (bleeding OR haemorrhage OR hemorrhage) AND
(sclerotherapy OR sclerosis OR injection).” We also conducted
Abbreviation used in this paper: OR, odds ratio.
© 2004 by the American Gastroenterological Association
0016-5085/04/$30.00
doi:10.1053/j.gastro.2003.11.006
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CALVET ET AL.
GASTROENTEROLOGY Vol. 126, No. 2
Table 1. Criteria for Further Bleeding and Mortality
Study
19
Balanzo et al.
Choudari and Palmer20
Chung et al.21
Chung et al.22
Chung et al.23
Chung et al.24
Garrido et al.25
Kubba et al.26
Lee et al.27
Lin et al.28
Lin et al.29
Loizou and Brown30
Pescatore et al.31
Sollano et al.32
Villanueva et al.33
Villanueva et al.34
Criteria for clinical further bleeding
Not specified
Fresh hematemesis or melena ⫹ shock or fall in hemoglobin ⬎2 g/dL
Fresh hematemesis or melena ⫹ shock or fall in hemoglobin ⬎2 g/dL
Not specified
Not specified
Fresh hematemesis or melena ⫹ shock or transfusion ⬎8 U
Hematemesis or fresh melena
Fresh hematemesis or melena ⫹ shock or fall in hemoglobin ⬎2 g/dL
Not specified
Unstable vital signs or continued bloody stools or hematemesis
Unstable vital signs or continued bloody stools or hematemesis
Fresh hematemesis or melena ⫹ shock or fall in hemoglobin despite transfusion
Fresh hematemesis or melena ⫹ shock or fall in hemoglobin despite transfusion
Recurrence of hematemesis, melena, or anemia
Fresh hematemesis or melena ⫹ hypovolemia or fall of hemoglobin requiring transfusion
Not specified
a manual search of abstracts submitted to the Digestive Diseases Week between 1990 and 2002. The search was primarily
planned to include articles in English, French, or Spanish.
Articles selected in the search were reviewed separately by 2
of the authors, and those fulfilling the inclusion criteria were
selected for further analysis. In addition, a fully recursive
search of reference lists of the original studies was performed to
find studies not identified by the previous searches. Papers
recorded in the personal databases of the authors were also
reviewed and included when appropriate.
Studies Selection
Studies designed to compare the efficacy of different
endoscopic methods to achieve definitive hemostasis in peptic
ulcer patients were evaluated separately by 2 of the authors.
The inclusion criteria were as follows: (1) Articles or abstracts
should report the results of comparative, randomized trials. (2)
Studies must include patients with hemorrhage from peptic
ulcer disease (gastric or duodenal) with major stigmata of
bleeding as defined by groups Ia (spurting hemorrhage), Ib
(oozing hemorrhage), IIa (nonbleeding visible vessel), and IIb
(adherent clot) of the Forrest classification.5 (3) Studies had to
include at least 2 branches of endoscopic treatment: epinephrine alone vs. epinephrine associated with a second hemostatic
method. (4) The data on the baseline characteristics of the
patients (number, age, sex, and others), inclusion and exclusion
criteria, and results should allow adequate evaluation.
Further clinically significant bleeding was defined according
to the criteria established in each study (Table 1). Bleeding had
to be confirmed by endoscopy.
Criteria Used for the End Points of the
Study
Primary end point: further bleeding. In most of the
studies, the primary end point was defined as endoscopic
therapy failure, i.e., a combination of persistent hemorrhage
and recurrence during follow-up. Here, for the sake of simplicity, this primary end point is referred to throughout the
Mortality
Not specified
30-Day mortality
Hospital mortality
Hospital mortality
Hospital mortality
Hospital mortality
Not specified
30-Day mortality
Not specified
Hospital mortality
Hospital mortality
Hospital mortality
30-Day mortality
Not specified
Hospital mortality
Not specified
text as further bleeding—a more usual term and one that gives
a clearer image. Clinical criteria used for presuming further
bleeding differed between the studies and are shown in Table
1. Bleeding was confirmed by endoscopy in all the studies.
Clinically silent bleeding observed at scheduled endoscopies
was not considered for the analysis. A subanalysis comparing
data separately for persistent hemorrhage and recurrence during follow-up was also performed.
Surgery and mortality. Criteria for emergency surgery were not specified in the majority of the studies, and few
gave the criteria for mortality; 30-day mortality or in-hospital
mortality were the most often used (Table 1).
Data Extraction
Data were extracted separately by 2 of the authors and
reviewed by a third. If results were discordant, papers were
jointly reviewed until the differences were resolved.
Quality Assessment
The quality of the studies included was assessed using
the criteria proposed by Chalmers et al.6 This method evaluates the design, implementation, and analysis of randomized
controlled trials. The overall index of trial quality was
weighted as follows: trial design and protocol (0.60), statistical
analysis (0.30), and presentation of results (0.10). Final quality
score ranged from 0 to 1, with maximum quality studies rating 1.
Statistical Analysis
Main comparisons contrasted epinephrine injection vs.
epinephrine injection plus another hemostatic method. The
primary outcome variable was further bleeding, defined as
persistence or recurrence of bleeding during follow-up. Emergency surgery during hospitalization, morbidity, and mortality rate were also analyzed. Subanalysis for further bleeding
was performed to examine the efficacy of the different techniques (sclerosant agents, mechanical hemostasis, or thermal
devices) associated to epinephrine injection vs. epinephrine
alone. Subanalysis was also performed depending on the type of
February 2004
ENDOSCOPIC TREATMENT IN BLEEDING PEPTIC ULCERS
Table 2. Reasons for Excluding Articles
Study
Results
Reasons for exclusion
Pescatore et al.8
Male et al.9
Gevers et al.10
De Goede et al.11
Chung et al.12
Chung et al.13
Chung et al.14
Chua et al.15
Buffoli et al.16
Dedeu et al.17
Ell18
443
Included and Excluded Studies
Preliminary results of Pescatore et al.31
Preliminary results of Lin et al.29
Combines epinephrine plus polidocanol plus
hemoclip
Preliminary results of Givers et al.10
Preliminary results of Chung et al.22
Preliminary results of Chung et al.23
Preliminary results of Chung et al.21
Not randomized
Not randomized
Does not specify number of patients in
each group
Does not specify number of patients in
each group
peptic ulcer hemorrhage: active spurting or oozing (Forrest Ia
or Ib), nonbleeding visible vessel (Forrest IIa), or adherent clot
(Forrest IIb). Also, further bleeding rates were divided into
failure to achieve initial hemostasis and recurrence during
follow-up and analyzed separately. Finally, to ascertain the
influence of second-look endoscopy on the results, studies that
performed this procedure were also analyzed separately.
Peto odds ratios and 95% confidence intervals were used for
comparisons. Prior to meta-analysis, the heterogeneity of results was assessed by means of a Q test. Because of the low
power of the test, a cutoff P value of 0.20 was established as a
threshold for homogeneity. In case of lower values indicating
heterogeneity, a random-effect model was used for the analysis.
If no heterogeneity was observed, odds ratios for all studies
were pooled in a global odds ratio by means of a fixed-effects
model.
All results were obtained using the freeware program Review Manager 4.1.3. The statistical tests and formula implemented in RevMan are described in the RevMan User Guide.7
The preliminary search identified 27 studies (26
in English, 1 in Spanish, and none in French).8 –34 A
wider search including articles in other languages did not
find any additional papers suitable for inclusion. Eleven
studies were excluded from further analysis.8 –18 Reasons
for exclusion are outlined in Table 2. Sixteen studies
were included in the meta-analysis.19 –34 Characteristics
of the studies are shown in Tables 1, 3, and 4.
Quality Assessment
The articles included ranged in quality from 0.38
to 0.88. Individual assessment of quality is shown in
Table 3. Most of the studies were published as full papers
and were rated high in the quality scores.
Epinephrine vs. Epinephrine and a Second
Endoscopic Method
Sixteen articles compared epinephrine injection
vs. epinephrine plus other endoscopic methods for the
endoscopic treatment of peptic ulcers. A total of 1673
patients were included. The further bleeding rate in the
epinephrine group was 155 of 840 (18.4%) vs. 88 of 833
(10.6%) patients in the combined therapy group. Peto
odds ratio was 0.53 (95% CI: 0.40 – 0.69) (Figure 1). The
need for emergency surgery was evaluated in 15 studies
with a total of 1588 patients. In the epinephrine group,
90 of 795 (11.3%) patients needed surgical intervention
and 60 of 793 (7.6%) in the combined therapy. Peto
odds ratio was 0.64 (95% CI: 0.46 – 0.90) (Figure 2). The
mortality rate was evaluated in 15 studies and 1588
Table 3. Characteristics of the Studies Included in the Meta-analysis
Study
19
Balanzo et al.
Choudari and Palmer20
Chung et al.21
Chung et al.22
Chung et al.23
Chung et al.24
Garrido et al.25
Kubba et al.26
Lee et al.27
Lin et al.28
Lin et al.29
Loizou and Brown30
Pescatore et al.31
Sollano et al.32
Villanueva et al.33
Villanueva et al.34
IV, intravenously; PO, per os.
Patients (N)
Quality
Additional treatment
Second look
Medical treatment
64
107
83
196
160
270
85
140
60
64
64
42
135
61
63
79
0.73
0.79
0.82
0.77
0.75
0.88
0.59
0.83
Abstract
0.74
0.64
0.70
0.76
0.38
0.86
Abstract
Thrombin injection
Ethanolamine injection
Hemoclip
Sodium tetradecyl sulfate
Ethanol injection
Heat probe
Polidocanol injection
Thrombin injection
Ethanol injection
Ethanol injection
Bipolar electrocoagulation
NYAG laser
Fibrin glue injection
Polidocanol injection
Polidocanol injection
Hemoclip
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Yes
No
Yes
Yes
Yes
No
Not specified
H2 antagonists
Ranitidine 50 mg/6 h IV
Anti-H2
Ranitidine
Not specified
Not specified
Not specified
Not specified
Ranitidine or cimetidine
Omeprazole 40 mg/6 h IV
Ranitidine 300 mg/12 h PO
Not specified
Not specified
Ranitidine
Not specified
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CALVET ET AL.
GASTROENTEROLOGY Vol. 126, No. 2
Table 4. Volume of Injected Epinephrine and Complications and Blood Transfusion Requirements
Study
al.19
Balanzo et
Choudari and Palmer20
Chung et al.21
Chung et al.22
Chung et al.23
Chung et al.24
Garrido et al.25
Kubba et al.26
Lee et al.27
Lin et al.28
Lin et al.29
Loizou and Brown30
Pescatore et al.31
Sollano et al.32
Villanueva et al.33
Villanueva et al.34
Epinephrine volume
Complications
Transfusion
Not specified
7.5 mL in both groups
Not specified
Not specified
A: 9.5 ⫾ 5.5 mL, B: 10.1 ⫾ 6.2 mL
Not specified
Not specified
A: 10 mL, B: 7 mL
A: 17.6 mL, B: 14.5 mL
A: 6 mL, B: 5.5 mL
A: 7.1 mL, B: 6.8 mL
10–30 mL (both groups)
A: 10.3 ⫾ 1.8 mL, B: 7.5 ⫾ 3.5 mL
A: 8.6 mL, B: 11 mL
A: 12 ⫾ 3.5 mL, B: 15.2 ⫾ 6.2 mL
Not specified
Not specified
Not specified
A: 1 bleeding, 2 sub mucosal hematoma. B: None
A: None, B: Necrosis of lesser curvature
Not specified
A: None, B: 2 perforations
Not specified
No complications
Not specified
No complications
No complications
A: Spurting hemorrhage, B: None
A: 1 hemorrhage, B: 1 perforation
A: 1 mucosal necrosis, B: 1 mucosal necrosis
A: None, B: Pneumoperitoneum
Not specified
A: 3.9 U, B: 3.14 U
Not specified
A: 9.1 U, B: 8.9 U
A: 3 U (0–41), B: 3 U (0–19)
A: 3 U (0–20), B: 2 U (0–23)
A: 2 U (0–18), B: 3 U (0–29)
Not specified
A: 297 (total U), B: 219 (total U)
Not specified
A: 1.2 L ⫾ 1.1 L, B: 1.2 L ⫾ 1.6 L
A: 0.7 (0.5–1) L, B: 0.6 (0.3–0.8) L
A: 5.8 ⫾ 4.3 U, B: 5.1 ⫾ 3.2 U
A: 2 U (2–4), B: 2 U (2–4)
Not specified
A: 2.03 ⫾ 2.04 U, B: 1.9 ⫾ 2.5 U
A: 2.6 ⫾ 2.1 U, B: 1.6 ⫾ 2.4 U
A, Epinephrine alone; B, combined therapy; N (n-n), median (range); N ⫾ n, mean ⫾ SD; U, blood units.
patients, with a total of 41 of 795 (5.1%) patients in the
epinephrine group and 21 of 793 (2.6%) in the combined therapy group. Peto odds ratio was 0.51 (95% CI:
0.31– 0.84) (Figure 3). In addition, 10 studies, including
1118 patients, reported data about complications of en-
doscopic therapy. The number and type of complications
in each group are detailed in Table 4. Significant complications were found in 6 of 560 (1.1%) patients in the
epinephrine group and in 6 of 558 patients (1.1%) in the
combined therapy group. Peto odds ratio was 1.01 (95%
Figure 1. Further bleeding rates for endoscopic treatment with epinephrine injection vs. combined therapy.
February 2004
ENDOSCOPIC TREATMENT IN BLEEDING PEPTIC ULCERS
445
Figure 2. Surgical rates for endoscopic treatment with epinephrine injection vs. combined therapy.
CI: 0.32–3.16). No significant heterogeneity was found
in any of the analyses.
Epinephrine vs. Epinephrine and a Second
Injected Agent
All articles that compared substances administered by endoscopic injection (sclerosants such as ethanol, polidocanol, ethanolamine, or tetradecyl sulfate; adhesive agents such as cyanoacrylate, and thrombotic
substances such as a fibrin glue or thrombin) were analyzed together. Eleven studies with 1135 patients were
included.19,20,22,23,25–28,31–33 The further bleeding rate
was 108 of 575 (18.8%) patients in the epinephrine
group and 68 of 560 (12.1%) in the combined therapy
group. Peto odds ratio was 0.60 (95% CI: 0.43– 0.82).
The need for surgery was evaluated in 10 studies with a
total of 1050 patients. Fifty-nine of 530 (11.1%) patients
in the epinephrine group and 49 of 520 (9.4%) in the
combined therapy group needed surgical intervention;
Peto odds ratio was 0.82 (95% CI: 0.55–1.22). Mortality
rate was evaluated in 10 studies with a total of 1050
patients. In the epinephrine group, 28 of 530 patients
died (5.3%) vs. 11 of 520 (2.1%) in the combined group,
Peto odds ratio was 0.41 (95% CI: 0.21– 0.77).
Epinephrine vs. Epinephrine and
Mechanical Endoscopic Methods
Two studies analyzed the efficacy of adding a
mechanical hemoclip to achieve hemostasis in bleeding
peptic ulcers.21,34 A total of 162 patients were evaluated.
The further bleeding rate was 15 of 78 (19.2%) in the
epinephrine group and 7 of 84 (8.3%) in the combined
therapy group. The Peto odds ratio was 0.40 (95% CI
0.16 – 0.98). Both studies evaluated the need for surgery.
Nine of 78 (11.5%) patients in the epinephrine group
and 2 of 84 (2.4%) in the combined therapy group
required surgical intervention. Peto odds ratio was 0.24
(95% CI: 0.07– 0.82). Mortality rate was 3 of 78 (3.8%)
patients in the epinephrine group compared with 1 of 84
(1.2%) in the combined therapy group. Peto odds ratio
was 0.34 (95% CI: 0.05–2.42).
Epinephrine vs. Epinephrine and Thermal
Methods
Three studies compared epinephrine alone with
epinephrine combined with thermal hemostatic methods
(contact heat probe, N-YAG laser or bipolar electrocoagulation).24,29,30 A total of 376 patients were evaluated.
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CALVET ET AL.
GASTROENTEROLOGY Vol. 126, No. 2
Figure 3. Mortality rates for endoscopic treatment with epinephrine injection vs. combined therapy.
The further bleeding rate was 32 of 187 (17.1%) patients
in the epinephrine group vs. 13 of 189 (6.9%) in the
combined therapy group. Peto odds ratio was 0.37 (95%
CI: 0.19 – 0.69). The surgery rate was analyzed in 376
patients, being required in 22 of 187 (11.8%) patients in
the epinephrine group and in 9 of 189 (4.8%) in the
combined therapy group. Peto odds ratio was 0.40 (95%
CI: 0.19 – 0.83). The mortality rate was also analyzed in
376 patients. It was 10 of 187 (5.3%) patients in the
epinephrine group and 9 of 189 (4.8%) in the combined
therapy group. Peto odds ratio was 0.88 (95% CI: 0.35–
2.23).
Further Bleeding Rates in Patients With
Active Hemorrhage (Forrest Ia or Ib) or
Nonbleeding Visible Vessel (Forrest IIa) or
Adherent Clot (Forrest IIb)
Eleven studies with a total of 913 patients analyzed
further bleeding rates when peptic ulcers were actively
bleeding (spurting or oozing, Forrest Ia or Ib).19 –26,28,30,33
Eighty-nine of 453 (19.6%) patients further bled in the
epinephrine alone group vs. 54 of 460 (11.7%) in the
combined therapy group. Peto odds ratio was 0.55 (95%
CI: 0.38 – 0.79).
Seven studies with a total of 353 patients gave data on
peptic ulcers with nonbleeding visible vessel (Forrest
IIa).19 –21,25,26,30,33 Twenty-three of 182 (12.6%) patients
in the epinephrine alone group presented further bleeding vs. 14 of 171 (8.2%) in the combined therapy group.
Peto odds ratio was 0.62 (95% CI: 0.31–1.22). Only 1
study25 included patients with adherent clot (Forrest
IIb), and, therefore, a meta-analysis could not be performed.
Initial Failure of Hemostasis vs. Recurrence
During Follow-up
Thirteen studies gave separate data on the patients who did not achieve initial hemostasis.19,21–24,26 –33
A total of 1402 patients were evaluated. Of these, 20 of
703 (2.8%) patients in the epinephrine group and 17 of
699 (2.4%) in the combined therapy group presented
initial failure of hemostasis, Peto odds ratio 0.84 (95%
CI: 0.44 –1.62).
In the 1365 patients with initial hemostasis, the rate
of recurrence of bleeding during follow-up was 108 of
683 (15.8%) in the epinephrine group and 61 of 682
(8.9%) in the combined therapy group. Peto odds ratio
was 0.53 (95% CI: 0.38 – 0.73).
February 2004
Role of Second Look Endoscopy
Ten studies performed one or more second look
endoscopies 24 to 72 hours after the initial technique.19 –24,29,31–33 When active bleeding or persistent
high-risk stigmata were observed, a second therapeutic procedure was performed. A total of 1202 patients
were included in these studies. The further bleeding
rate was 95 of 605 (15.7%) patients in the epinephrine
group and 68 of 597 (11.4%) in the combined therapy
group. Peto odds ratio was 0.69 (95% CI: 0.49 – 0.96).
Six studies with a total of 470 patients did not schedule a second-look endoscopy.25–28,30,34 Sixty of 235
(25.5%) patients in the epinephrine group further bled
after the first endoscopic procedure compared with 20 of
235 (8.5%) in the combined therapy group. Peto odds
ratio was 0.27 (95% CI: 0.15– 0.46).
Discussion
Guidelines agree that there is no clear evidence
that any technique is superior to injection of epinephrine
alone for the endoscopic treatment of high-risk bleeding
peptic ulcers.3,4 However, a few individual studies have
shown a significant reduction in the further bleeding
rates with the addition of a second endoscopic treatment24 –26,29 (Figure 1). Advancing further in this direction, the results of the present meta-analysis clearly
suggest that combined therapy is the treatment of choice
for high-risk bleeding peptic ulcers. Although the absolute improvements in hemostatic efficacy are relatively
small (from 5% to 10%), they represent a 30% to 50%
reduction in the relative risk of a recurrent hemorrhage.
Failure of endoscopic therapy is the main predictor of the
need for surgery and morbidity and mortality in bleeding
peptic ulcer patients.35 Therefore, it is no surprise that
reduction of further bleeding rates decreased the need for
surgery and improved survival.
One of the major fears about using combined therapy
is the possible risk of gastric wall necrosis and/or perforation. The present meta-analysis shows that the risk of
significant complications is very low (1.1% in the epinephrine group and 1.1% in the combined therapy
group) and that there were no differences between
groups. Looking at the complications in detail, induction
of massive bleeding requiring surgery was the most
frequent in the group of adrenaline alone; gastric wall
necrosis appeared in 3 patients (2 in the combined therapy group and 1 in the adrenaline alone group), and
perforation (4 patients) was observed only in the combined therapy group. These complications appeared with
ENDOSCOPIC TREATMENT IN BLEEDING PEPTIC ULCERS
447
both further injection and thermal methods. Thus, it
would seem that perforation or necrosis was slightly
more frequent in the combined therapy group (6/558
patients) than in the adrenaline alone group (1/560 patients), although this difference did not achieve statistical significance. In any case, this possible small increase
in the risk of perforation or necrosis is clearly compensated for by the benefits in reducing further bleeding,
which result in a significant decrease in the need for
surgery and mortality; it is therefore not a reason for
avoiding combined therapy.
The subanalysis shows many interesting data: first,
that the improvement in prognosis seems to be more
evident in higher risk patients—that is, those with Forrest I bleeding ulcers— or when no second-look endoscopy is performed. However, because the basal risk of
further bleeding is much lower in Forrest II patients or
when repeated endoscopy is performed, the sample size
needed to demonstrate a significant reduction in further
bleeding may be larger than those available for the subanalysis. Second, that beneficial effects of combined therapy
seem to derive from the reduction of recurrent bleeding
during follow-up rates, and the ability to achieve initial
hemostasis seems very similar in the 2 groups.
The subanalysis also raises many unanswered questions. First, although it could be taken to suggest that
the efficacy of the injection of a second agent is similar to
that achieved with thermal and mechanical methods, this
interpretation should be treated with extreme care. The
only conclusion that can be drawn from the study is that,
whichever second treatment is used, combined therapy
seems to work better than adrenaline alone. By contrast,
it cannot be concluded that a particular form of treatment is equal to another. There are 2 main reasons for
this. First, the subgroups (further injection, thermal, or
mechanical methods) include different procedures, which
may present heterogeneous activity. In fact, each endoscopic treatment had different characteristics: epinephrine produces vasoconstriction, vessel compression, and
platelet aggregation but seems not to induce permanent
thrombosis in blood vessels.36 Sclerosant agents such as
polidocanol or ethanol can produce thrombosis of vessels
favoring hemostasis, although they may also induce significant tissue injury.37,38 Whether human thrombin injection could reduce the risk of tissue damage remains
unclear, and thrombin is more expensive than other
additional treatments.39 Thermal agents also produce
thrombosis of vessels and also risk, therefore, of damaging tissue. Among them, laser photocoagulation seems to
be associated with higher risks of perforation, optical
hazard, high cost, and imperfect hemostatic effect. Mul-
448
CALVET ET AL.
tipolar electrocoagulation and heater probe thermocoagulation have been reported to produce excellent results;
they are also less expensive and more easily portable than
a laser.40 Mechanical methods also closed the vessel. They
were also associated with few complications, but there
was a certain amount of technical difficulty in applying
the hemoclip on the posterior wall of the proximal body
and cardia of the stomach and on the posterior wall of the
duodenum because of the requirement that the hemoclip
meet the lesion at a right angle.21,41
Even more important, the statistical treatment of the
study is not designed to compare additional treatments
head to head. In fact, we lack randomized trials comparing different additional treatments after epinephrine injection and must await future comparative studies to
establish which is the best therapy to add to adrenaline.
Nor did our study determine whether combined therapy is better than sclerosants or thermal or mechanical
methods alone. The evidence in the literature to suggest
so is scarce. In a small study Lin et al. found that
combined therapy seems better than bipolar electrocoagulation alone.29 Also, a recent meta-analysis concluded
that combined injection is superior to a sclerosant
alone.42 In any event, the clinical relevance of this question may be minor. Adrenaline injection is cheap, easy to
perform, and safe. In addition, according to our analysis,
epinephrine is as good as combined therapy for achieving
initial hemostasis. Therefore, by controlling active bleeding, it could allow a better endoscopic view and a more
accurate targeting of the additional therapy. Therefore,
there are few medical or economic arguments against
adrenaline injection.
An important methodologic point about the study was
the definition of the primary end point. The marked
heterogeneity in defining further bleeding among the
studies precluded the definition of a homogeneous, predetermined criteria for the primary end point. We therefore accepted the definition established for each study.
Further bleeding definitions are shown in Table 1. Because the analysis includes only randomized, comparative
studies, the criteria were similar for the 2 groups (adrenaline alone and combined therapy) in each study, thus
allowing further comparison. Furthermore, endoscopic
confirmation of bleeding was required, thus reducing
heterogeneity. Finally, results on further bleeding are
consistent with those of variables with a lower degree of
subjectivity in their evaluation, such as the need for
surgery or mortality. This indirectly confirms that the
assessment of further bleeding was adequate.
An interesting question is how other therapeutic approaches—such as the use of high-dose PPI or second-
GASTROENTEROLOGY Vol. 126, No. 2
look endoscopy— could influence the efficacy of combined therapy. The use of high-dose proton pump inhibitors in bleeding peptic ulcer patients is gaining acceptance. The evidence clearly suggests that these drugs
reduce the risk of rebleeding.43 However, many points
remain unclear, such as the cost effectiveness of this
approach, the ideal drug dosage, and whether this strategy should be reserved for patients at high risk of rebleeding. Both combined therapy and proton pump inhibitor infusion are safe and comfortable for the patient.
Furthermore, there is no reason to suspect that associating high-dose proton pump inhibitors and combined
endoscopic therapy will show ill effects or decrease efficacy. Therefore, although the extent of the benefit of
combining the 2 approaches remains uncertain, it seems
reasonable to do so until more evidence becomes available.
As far as second-look endoscopy is concerned, a recent
meta-analysis showed that, although scheduled secondlook endoscopies reduced the rebleeding rate, they did
not decrease the need for surgery or mortality.44 Recently, it has been suggested that selective second-look
endoscopy for selected high-risk patients could be a
cost-effective approach.45 However, this strategy exposes
patients to uncomfortable and somewhat risky procedures and increases the workload of the endoscopy unit.
The results of the present study indirectly suggest that
the effect of associating a second hemostatic procedure
after epinephrine injection is similar to that obtained
using second-look endoscopy. For all these reasons, it
remains unclear whether second-look endoscopy offers
any added benefit to combined therapy associated with
proton pump inhibitor infusion.
In conclusion, the present study shows that adding a
second endoscopic procedure after adrenaline injection
reduces the rates of recurrence in high-risk bleeding
peptic ulcer patients, thus reducing the need for surgery
and mortality. Currently, there is no justification for
preferring a specific second hemostatic method after
adrenaline injection. In view of the evidence—and while
we await the results of further studies— combined therapy should be considered as the standard procedure.
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Received May 29, 2003. Accepted October 23, 2003.
Address requests for reprints to: Xavier Calvet, M.D., Unitat de
Malalties Digestives, Hospital de Sabadell, Institut Universitari Parc
Tauli, UAB, Parc Tauli, s/n, 08208 Sabadell (Barcelona), Spain. e-mail:
[email protected]; fax: (34) 937160646.
Supported in part by a grant from the Instituto de Salud Carlos III
(C03/02).
The authors thank the group that elaborated on the Catalan Guidelines for nonvariceal upper gastrointestinal bleeding, which were of
invaluable help to determine the gaps in knowledge on the bleeding
peptic ulcer treatment. We are indebted to all participants, especially
Dr. Faust Feu as their coordinator. We thank Michael Maudsley for his
help with the English.