Endoscopic therapy for acute nonvariceal upper gastrointestinal hemorrhage: A meta-analysis

GASTROENTEROLOGY

1992:102:139-148

Endoscopic Therapy for Acute Nonvariceal Upper Gastrointestinal Hemorrhage: A Meta-Analysis DEBORAH J, COOK, GORDON and LOREN A. LAINE

H. GUYATT,

BRUNO

J. SALENA,

Divisions of Critical Care and Gastroenterology, Department of Medicine, and Department and Biostatistics, McMaster University Medical Center, Hamilton, Ontario, Canada; and Division of Gastroenterology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, California

Endoscopic hemostatic therapy for upper gastrointestinal bleeding is gaining widespread acceptance despite often conflicting results of randomized controlled trials. To examine the effect of endoscopic therapy in acute nonvariceal upper gastrointestinal hemorrhage, a meta-analysis was performed using a computerized search of the English-language literature and a bibliographic review. The methodology, population, intervention, and outcomes of each relevant trial were evaluated by duplicate independent review. Thirty randomized controlled trials evaluating hemostatic endoscopic treatment were identified. Endoscopic therapy significantly reduced rates of further bleeding (odds ratio, 0.38; 95% confidence interval, 0.32-0.45), surgery (odds ratio, 0.36; 95% confidence interval, 0.28-0.45), and mortality (odds ratio, 0.55; 95% confidence interval, 0.40-0.78). When analyzed separately, thermal-contact devices (monopolar and bipolar electrocoagulation and heater probe), laser treatment, and injection therapy al1 significantly decreased further bleeding and surgery rates. The reductions in mortality were comparable for al1 three forms of therapy, but the decrease reached statistical significante only for laser therapy. Further examination of subgroups indicated that endoscopic treatment decreased rates of further bloeding, surgery, and mortality in patients with high-risk endoscopic features of active bleeding or nonbleeding visible vessels. Rebleeding was not reduced by endoscopic therapy in patients with ulcers containing flat pigmented spots or adherent clots. Endoscopic hemostatic therapy provides a clinically important reduction in morbidity and mortality in patients with acute nonvariceal upper gastrointestinal hemorrhage. Ithough endoscopy has prove? to be an excellent diagnostic tool in patients with upper gastrointestinal bleeding, the use of early diagnostic endoscopy has not been shown to significantly alter

A

of Epidemiology

patient outcome.‘-3 A variety of endoscopic methods for the treatment of upper gastrointestinal hemorrhage has come into use since prospective studies evaluating the impact of early endoscopy were performed.4 The extent to which therapeutic endoscopy may decrease further bleeding, the need for surgical intervention, and mortality have been addressed by several randomized, controlled clinical trials. The results often have been inconclusive or conflicting, possibly because of smal1 sample sizes, variable entry criteria, and differences in patient characteristics and trial methodology. In addition, endoscopic therapy has rarely been shown to decrease the rate of mortality in these individual trials. We performed a meta-analysis of the results of 30 randomized clinical trials evaluating hemostatic endoscopic treatment to determine whether the use of endoscopic therapy benefits patients with nonvariceal upper gastrointestinal hemorrhage. An attempt has been made recently to synthesize the data from these studies in a forma1 quantitative manner.5 However, in our analysis, additional studies and unpublished data were included, primary authors actively participated in the overview, and the reasons for heterogeneity in study results were explored. Materials and Methods Locating Research Medline (National Library of Medicine, Bethesda, MD) and EMBASE(Elsevier, New York, NY) were searched from 1966onward to locate published research in the area of nonvariceal upper gastrointestinal hemorrhage and endoscopic therapy. MeSH terms used for key and text word

searching included hemorrhage (gastrointestinal), endoscopy, and clinical trials. Frequently cited references were 0 1992 by the American

Gastroenterological 0018-5085/92/$3.00

Association

140 COOK ET AL.

identified, and SCISEARCH (Institute for Scientific Information, Philadelphia, PA; (Science Citation Index on-line) was used to locate additional studies that cited these articles. Reference lists of al1 articles obtained were scanned to identify additional research not found in the computerized bibliographic data base searching. Strategies to obtain unpublished material included searching Federal Research in Progress (National Technical Information Service, Springfield, VA), NTIS (National Technical Information Service, Springfield, VA), Conference Papers Index (Cambridge Scientific Abstracts, Bethesda, MD), and BIOSIS Previews (Biosciences Information Service, Philadelphia, PA). We also communicated with experts in this field, the National Institutes of Health, and the Medical Research Council of Canada to obtain information on other unpublished or published studies. The titles and abstracts of al1 printouts were reviewed by two of the authors (D.J.C. and B.J.S.). Al1 potentially relevant articles that met the inclusion criteria below were retrieved.

Selecting Research The following inclusion criteria were applied independently by two of the authors (D.J.C. and B.J.S.) to select studies for the overview: (a) design [randomized or quasirandomized (by identification no. or date) controlled clinical trials comparing one or more endoscopic therapies with a control group]; (b) target population (patients with acute nonvariceal upper gastrointestinal bleeding); and (c) outcome measure (mortality, surgery, and/or further rebleeding). Validity

Assessment

The criteria used to assess the validity of the primary articles are listed in Table 1. Each study received a score based on specification of the population, intervention, and outcome. For studies evaluating two different modalities, the higher of the two endoscopic treatment validity scores was considered to be the validity score for the paper. Total validity scores were then used to rank studies.

Data Collection Duplicate independent data abstraction was performed by two of the authors (D.J.C. and L.A.L.). Missing or ambiguous data were solicited from authors. The corresponding author of each article received a copy of the completed validity and data-abstraction forms and was then requested to correct erroneous assessments and provide missing information when necessary. Authors of articles published in abstract form were contacted to request full manuscripts and data sets. In abstracting data from the articles, the endoscopic appearance of the lesions was categorized as either active hemorrhage, nonbleeding visible vessel [also recently referred to as “pigmented protruberance”4], adherent clot, flat spot, or stigmata of recent hemorrhage. In this analysis, we define “further bleeding” as either persistent bleeding or recurrent bleeding. Persistent bleeding may occur in patients with actively bleeding lesions at initial endoscopy. Recurrent bleeding may occur in patients not ac-

GASTROENTEROLOGY Vol. 102, No. 1

Table 1. Therapeutic Assessment

Endoscopy:

Methodological

Quaiity

Population Patient selection 2 Consecutive eligible consenting patients/random series 1 Attempt made to enroll consecutive eligible patients 0 Selected patients/not described Patient characteristics 2 Comparable with respect to 5 or more characteristics 1 Comparable with respect to 3-4 characteristics 0 Comparable with respect to 2 or fewer characteristics Intervention Randomization 2 Nonmanipulable 1 Potentially manipulable or no description 0 Quasirandomization Blinding 2 Attending physician blinded to endoscopic treatment and blinded assessment of rebleeding 1 Blinding in one instance 0 Unblinded or can’t tel1 Endoscopic treatment Monopolar/multipolar/heater probe/laser articles 2 Settings, no. of pulses, and duration of pulses described 1 Two of the above stated 0 One or none of the above stated Injection therapy 2 Volume, concentration of injectate, and number of applications stated 1 Two of the above stated 0 One or none of the above stated Outcome Rebleeding definition Objective direct evidente of upper GI bleeding with unstable vita1 signs or decrease in hemoglobin concentration of 20 g/L per day or endoscopic evidente of active rebleeding Objective indirect evidente of upper GI bleeding without unstable vita1 signs or decrease in hemoglobin concentration of 20 g/L per day Subjective evidente or criteria not explicitly stated ^ Indications tor surgery 2 Criteria stated explicitly 1 Reference to the use of “clinical judgment” 0 Not stated GI, gastrointestinal.

tively bleeding at initial endoscopy, hemostasis was initially achieved.

or in patients

in whom

Data Analysis Agreement between ceders for research selection and validity assessment was measured using the K statistic with quadratic weights. The measure of association used in this meta-analysis was the odds ratio (OR). The Breslow-Day method was used to test for homogeneity under the nul1 hypothesis that the ORs were consistent across studies, and the corrected Mantel-Haenszel xZ test (1 df, two-tailed) was used to test whether the ORs differed systematically from a value of 1. To avoid the problems of biased and/or unstable estimators when data are sparse, a modification of the Mantel-Haenszel technique (adding

METAANALYSIS

January 1992

one half to each cell) was used to estimate the common OR. The 95% confidence interval (CI) was calculated using the Cornfield method. The different forms of endoscopic therapy were separated into three groups based on their mode of action. Separate analyses were performed on the results of trials that evaluated laser treatment, thermal-contact devices (monopolar, multipolar, and heater probe), and injection therapy compared with no endoscopic treatment. The three contact thermal devices were grouped together because al1 involve tamponade of a bleeding lesion in combination with the application of heat. Results Of 298 references identified by the literature search, 30 randomized controlled trials involving 2412 patients met the inclusion criteria (Table 2).635 Twenty were published fully in peer-reviewed journals 6,8,9,11-18~20,21,23,24,28-32 1 was a symposium,33

2

were

inckded in a book chapter,34v35 and 7 were published in abstract form.7*‘o*‘g*22*25-27 None of the trials included in the analysis were from unpublished

OF ENDOSCOPIC HEMOSTASIS

141

sources. Agreement between reviewers for the selection of relevant articles was 100%. Chance-corrected agreement for the validity assessment yielded K values of 0.79-0.92. Of the selected trials, 13 compared contact thermal modalities with no endoscopic treat13 compared laser tberapy ment, 7.15,16,19,21-25,28,31-33 witb no active treatment,6~3~10-13~17~21~26~29.30.34~35 and 7 compared injection therapy with no active treatment.6~g~14~18~20~22*27 Twenty-four of 30 authors (80%) participated in the assimilation of data by providing corroborative, corrective, or missing information when requested. To evaluate the role of endoscopic therapy in acute nonvariceal upper gastrointestinal hemorrhage, we first examined further bleeding rates in patients receiving endoscopic treatment compared with control groups. The common OR for further bleeding was 0.38 (95% CI, 0.32-0.45), indicating a significant benefit from endoscopic treatment. We then grouped trials according to whether they com-

Table 2. Randomized Controiled Trials of Endoscopic Hemostasis Author

n

Ihre et al.’ Buset”’ ’ Krejs et al.” Swain et al.” MacLeod et a1.13 Rutgeerts et al.” Escourrou35 ’ Vallon et aLZ Swain et a1.30 Jensen et al.” ’ Lebodic et a1.34’ Matthewson et aLZ Rutgeerts et al.” Jensen et al.’ a Laine” Laine16 Goudie et a1.19a Kernohan et aLZ Brearly et aLZ Fullarton et a1.25’ O’Brien et al.” Moreto et aL31 Freitas et aL3’ Papps3 Averginos et al.** Chung et a1.14 Pascu et al.*’ Balanzo et al9 Panes et al.” Chiozzini et aLZ o

42

88 173 138 45 120 61 136 76 12 25 143 140 62 44 75 46 45 41 43 204 37 78 32 49 68 143 72 113 53

Proportion active bleeding

Proportion with peptic ulcer

-

0.95

0.00 0.18 0.27 0.67 1.00 0.21 0.25 1.00 1.00 0.10 0.43 0.40 1.00 0.00 0.00 0.29 0.91 0.30 0.32 0.27 0.00 1.00 1.00 0.49 0.29 0.28

1.00 1.00 1.00 0.96 0.83 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.55 1.00 1.00 0.89 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00

Modalities evaluation YAG, control YAG, control YAG, control YAG, control YAG, control YAG, control YAG, control Argon, control Argon, control Argon, control Argon, control YAG, HP, control A, A + P, A + YAG, control MPEC, HP, control MPEC, control MPEC, control MPEC, control MPEC, control MPEC, control HP, control MPEC, control Monopolar, control Monopolar, control Monopolar, control HP, A, control A, control A, control A + P, control A + P, control E, A, control

adrenaline injection; P, polidocanol injection; E, ethanol injection; MPEC, multipolar electrocoagulation; Monopolar, monopolar electrocoagulation;HP, heater probe; YAG, neodymium:yttrium-aluminum-garnet laser photocoagulation; argon, argon laser photoco-

A,

agulation. ’ Published

in abstract form or as book chapter.

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COOK ET AL.

GASTROENTEROLOGY Vol. 102, No. 1

pared thermal-contact modalities (heater probe or bipolar or monopolar electrocoagulation), laser treatment (argon or neodymium:yttrium-aluminum-garnet laser) or injection therapy (epinephrine, alcohol, or polidocanol) with control groups. Results are given in Table 3 and Figure 1. When patients receiving thermal-contact therapy were compared with those in control groups, the common OR for further bleeding was 0.32 (95% CI, 0.22-0.41), indicating a significant reduction in further bleeding following thermal-contact treatment. Similarly, for studies evaluating laser therapy (OR, 0.58; 95% CI, 0.38-0.69) and injection therapy (OR, 0.23; 95% CI, 0.12-0.45), the common ORs were significantly different from 1 (P < 0.05; an OR of unity indicating no treatment effect). However, the statistical test for homogeneity suggests that there may be systematic differences between results of these trials that cal1 into question the validity of aggregating these data. This is true for al1 modalities combined, but not for injection therapy, in which the test for homogeneity indicated that the differences between ORs in these studies were consistent with random variation alone (P = 0.73). Pooled results evaluating the need for surgical intervention to control bleeding show that individually and in aggregate each of these three treatment modalities significantly reduced surgery rates (Table 3 and Figure 2). The mortality rate was significantly decreased in patients receiving endoscopic treatment (OR, 0.55; 95% CI, 0.40-0.76); Table 3 and Figure 3). When specific modalities were evaluated, the ORs for mortality rates were similar across al1 treatment groups. However, the reduction in the rate of mortality between treatment and control therapies reached conventional levels of statistical significante only for laser therapy (OR, 0.49; 95% CI, 0.30-0.81), which was evaluated in 12 trials.6,8,11-13.17.21,26,29,30,34,35

Table 3. Results of Rcmdomized Therapy Thermal contact’ ORb (95% CI) No. of trials (n) Laser ORb (95% CI) No. of trials (n) Injection ORb (95% CI) No. of trials (n) Al1 therapies ORb (95% CI) No. of trials (n) ’ Heater probe and monopolar b Treatment vs. control. ’ Statistical heterogeneity.

Trials of Therapeutic

Study quality varied among the articles in this analysis. Attempts to enroll consecutive patients How_ were made in 79% of t~i~l~.6~6~9~11-'6~ZO~Z5~27~30-32 ever, only 50% of studies scored highly with respect to comparability of five or more important patient characteristics 9~11~12~14~16~18~21~25~2626~32.33 In only 11 of 30 studies (36%) were both the attending physician and the clinician assessing rebleeding blinded to the treatment group.“-‘3~‘7~21~22’25~z*~31 Although the definition of rebleeding was objective in 58% of trials 9~11~13~15~18,20,21,23-25,27,30~33 the indications for surgery were explicitly defined in only 9 of 30 articles (30%).

6,9,10,14,17,16.20,24,30

We examined studies in detail to try to explain the heterogeneity. The OR did not differ systematically across studies according to any of the following variables: methodologie quality, patient characteristics, characteristics of the intervention, duration of follow-up, and definition of outcome. Because studies with greater potential for bias may show greater heterogeneity,36 we also tested to see whether there was less variability in results among higher-quality studies. An analysis restricted to trials with an overall validity score of 10 or greater that also scored in the middle category (score of 1) or highest category (score of 2) for comparability of patient characteristics, randomization, and blinding was performed. Results are shown in Table 4. The test of homogeneity in al1 cases was nonsignificant, indicating that the differences between ORs in these studies were consistent with random variation. Evaluation of the trials to which higher validity scores were assigned yields similar results to those in the overall analysis; al1 forms of endoscopic therapy appear to reduce further bleeding, surgery, and mortality rates. The homogeneity of these study results was confirmed by deriving the standard deviation of the ORs of trials evaluating each treatment modality against a control

Endoscopy

Further bleeding

Surgery

Mortality

0.32’ (0.22-0.41) 13 (866)

0.31C (0.19-0.43) 13 (870)

0.67 (0.39-1.14) 12 (739)

0.58’ (0.38-0.69) 11 (1018)

0.58 (0.40-0.80) 13 (1072)

0.49 (0.30-0.81) 12 (984)

0.23 (0.12-0.45) 4 (312)

0.18 (0.11-0.32) 7 (517)

0.50 (0.22-1.12) 6 (549)

0.38’ (0.32-0.45) 25 (2139)

0.36’ (0.28-0.45) 30 (2534)

0.55 (0.40-0.76) 30 (2366)

and bipolar electrocoagulation.

METAANALYSIS

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Log Odds Ratios Laser Therapy (n=ll)

.Ol 4

.5

.l

1

-

2

10

100

(6) _(lV

-Vz)_

(13)

-(17)

-

(21) (26) (36)

A-

-W’A)

(34A) (36A)

Typical odds ratio

Log Odds Ratios Contact Thermal Devices .ol 4 (n=13) +

.5

.l =

1

2

10

100 b

(15)

1 a

(16) (21) .(22)

=

-

(23)

(26) (3ij

4’--t

(32) -(7A)

_

t

;

Typical odds ratio

(25A)

(16A)

I

A

Log Odds Ratios Injection Therapy (n=4)

.l .5 -

1

2

(6) (9)

-UW - (22)

Figure 1. Further bleeding in trials evaluating laser therapy, thermal-contact devices, and injection therapy. A, abstracts or studies published in book chapters.

Typical odds ratio

group with respect to further bleeding, surgery, and mortality rates. The standard deviations of the ORs in the highest-quality studies were lower than those in the remaining studies, confirming less variability in the ORs in the higher-quality trials. On the assumption that endoscopic diagnosis may affect the response to endoscopic therapy, we evaluated the results of the 20 trials in which data were extractable on patients who were bleeding because Althou& a of peptic ulcers .8.9-12,18.18,19,21.22,24-31,33-35 proportion of assessable patients in some of the remaining trials also had peptic ulcers identified as the cause of bleeding,8~‘3~14*‘5~1’~23~32 information on this specific subset was not extractable. An analysis of patients with bleeding due to peptic ulcer disease is shown in Table 5; results are similar to those of the overall analysis.

Patients with active bleeding and nonbleedingvisible vessels have a high rate of further bleeding with an attendant increase in morbidity and mortality rates.‘e~37-3g We hypothesized that patients at high risk for further bleeding are most likely to derive benefit from treatment, whereas patients at low risk for further bleeding may not benefit from therapy because they do wel1 in any event. We therefore separately analyzed patients with high-risk endoscopic features (active bleeding or nonbleeding visible vessels) (Table 6) and those with lower-risk characteristics (other stigmata of recent hemorrhage including flat pigmented spots and clots). Endoscopic hemostatic therapy in patients with active bleeding or nonbleeding visible vessels reduced rates of further bleeding (OR, 0.23; 95% CI, 0.15-0.27), surgery (OR, 0.26; 95% CI, 0.17-0.32), and mortality (OR, 0.62;

144

COOK ET AL.

GASTROENTEROLOGYVol.102,No.l

Log Odds Ratios Laser Therapy (n=13)

.Oi 4

.5 1

2

10

,(6,

(6)

-

(11)

(264

4 4

-

Typical odds ratio

Contact Thermal Devices (n=13)

100 b

ti

(34A)

(35A)

-

Log Odds Ratios, .l 4

2

.5

10

100 b

. (15) -(21/12, -(23) -i;J - (32) (7A) (25A)

(19A)

Typical odds ratio

Injection Therapy (n=7)

4

Log Odds Ratios .5 1

4

2

10

WN

Figure 2. Urgent surgery in trials evaluating laser therapy, tbermal-contact devices, and injection therapy. A, abstracts or studies published in book chapters.

Typical odds ratio

95% CI, 0.38-0.98). Only information on the outcome of rebleeding was extractable for patients with spots or clots in ulcer bases12~13~2*~2g~30~32; rebleeding was not reduced by endoscopic therapy in this group (OR, 1.00;95% CI,0.45-2.23). Data regarding transfusion requirements were provided in 16 of the trials evaluated. A significant differente favoring endoscopic therapy was reported in 7 of the 16 articles. To evaluate the risk of therapeutic endoscopy, we examined the complication rates in trials reporting this outcome. The incidences of bleeding induced during endoscopic therapy that required surgery were 0.40% [95% CI, -0.14%-0.87% (2/542 patients)] for laser therapy, 0.39% [95% CI, -0.14%0.92% (2/513patients)] for contact thermal devices, and 0.4% [95% CI, -0.35%-1.07% (1/275patients)]

100 *

for injection therapy. The reported incidences of perforation were 0.9% [95% CI, O.ll%-1.60%(5/586patients], 0.7% [95% CI, 0.02%-1.48% (4/568 patients)], and 0% (0/316), respectively, with these three treatment modalities. However, these figures may be subject to reporting bias and may not reflect the risk of endoscopic hemostasis in al1 centers. Discussion The results of this meta-analysis indicate that endoscopic hemostatic therapy provides a clinically important reduction in rates of morbidity and mortality in patients with acute nonvariceal upper gastrointestinal hemorrhage. This benefit is evident in patients with endoscopic features associated with the highest risk of further bleeding (active bleeding and nonbleeding visible vessels). Patients known to have

METAANALYSIS

January 1992

OF ENDOSCOPIC

HEMOSTASIS

145

Log Odds Ratios Laser Theraw (n=12) .

.Ol

.5

.l

1

2

10

100

4

.

* (12)

I

(21) (17)

.

:

113)

-“ri”’

*

I

I

.’

(26A)

_

(34A)

I -

1 Typical odds ratio

(3-1

-1

Log Odds Ratios Contact Thermal Devices (n=12)

.Ol M

.5

.l

1

100 *

10

2 (21) (15)

4

CW (32)

4 N

ti *

(16) (24)

w b

(25~) UW

(23) (33)

(31) * 4 (7A)

I

Typical odds ratio

Log Odds Ratios

,

l

Injection Therapy (n=6)

Figure 3. Mortality in trials evaluating laser therapy, thermal-contact devices, and injection therapy. A, abstracts or studies reported in book chapters.

.Ol

.l

.5

A

10

2

100

(16)

4’

I

1

(274

Typical odds ratio

low morbidity and mortality with medical treatment (those with spots or clots in an ulcer base)40 do not appear to benefit from endoscopic treatment. Therefore, this metaanalysis supports the National Institutes of Health Consensus Conference statement on therapeutic endoscopy in bleeding ulcers, which stated that endoscopic hemostasis is indicated for the treatment of bleeding ulcers but should only be used in patients at high risk for persistent or recurrent bleeding. Although the common OR in metaanalysis provides an overall estimate of a treatment’s impact, in the presence of statistical heterogeneity caution in interpretation is warranted. There was no such statistical heterogeneity of the results of trials evaluating the effect of endoscopic therapy on mortality. However, the results for further bleeding and the

-7

need for surgery showed variation beyond the degree that would be expected if the true effect size were the same in each study. In trying to explain the heterogeneity, we found no differences in patient population, intervention, or specific ways of defining the outcomes systematically related to the magnitude of treatment effect. Heterogeneity may also be explained by the fact that the treatment impact may actually be uniform, and differences in the effect of treatment may be due to variations in measurement. Consistent with this explanation is the fact that no heterogeneity is present when mortality is evaluated. Mortality can be measured objectively and without bias. In contrast, an explicit definition of rebleeding and precise criteria for surgical intervention were not usually provided for these studies. Therefore, differences in the more

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COOK ET AL.

TabJe 4. ResuJts of Trials

GASTROENTEROLOGY

With Highest

Therapy Thermal contact OR” (95% CI) No. of trials (n] Laser OR” (95% CI) No. of trials (n) Injection OR” (95% CI) No. of trials (n) Al1 therapies OR” (95% CI) No. of trials (n) a Treatment

MethocJoJogicaJ

Vol. 102, No. 1

QuaJity

Further bleeding

Surgery

Mortality

0.24 (0.14-0.40) 5 (282)

0.11 (0.04-0.23) 4 (199)

0.78 (0.30-1.99) 5 (298)

0.22 (0.13-0.38) 3 (360)

0.22 (0.19-0.49) 2 (267)

0.47 (0.20-1.00) 3 (353)

0.20 (0.07-0.57) 1 (113)

0.11 (0.02-0.43)

0.81 (0.27-2.45) 1 (113)

0.22 (0.16-0.31) 9 (729)

0.15 (0.09-0.25) 7 (574)

1 (37)

0.56 (0.32-0.98) 9 (780)

vs. control.

subjective outcome criteria of rebleeding and need for surgery may contribute to the nonuniformity of results. Moreover, physicians assessing clinical outcomes in these trials were generally not blinded to the treatment group, raising the possibility of an expectation bias.** Heterogeneity may also be explained by variations in methodology among the trials. A sensitivity analysis restricted to trials of the highest methodological quality, determined after objectively grading the studies with respect to a number of important methodological criteria (Table l), showed greater uniformity of trial results than was found across al1 studies (Table 3). Endoscopic therapy in these homogeneous trials of highest quality was found to be significantly better than no treatment with respect to further bleeding, the need for surgery, and mortality. Variations in technique may also explain some heterogeneity in trial results. For example, factors such as probe size, application pressure, generator setting, and duration of treatment al1 influence the efficacy of thermal-contact devices such as bipolar electrocoagulation and heater probes. Recent studies42*43

TabJe 5. ResuJts of Trials Evaluating Therapy Thermal contact ORb (95% CI) No. of trials (n) Laser ORb (95% CI) No. of trials (n) Injection ORb (95% CI) No. of trials (n)

Al1 therapy ORb (95% CI) No. of trials (n) ’ Statistical heterogeneity. b Treatment vs. control.

Patients

With Peptic

have outlined improvements in technique that may explain some of the differences in results between early and more recent trials. In addition, studies of injection therapy have used a wide variety of agents for combinations of agents injected in varying doses. A potential limitation of metaanalysis, as in any type of review, is the problem of publication bias. Our sensitivity analysis restricted to fully published trials (data not shown) correlated closely with the overall results, making a significant publication bias unlikely in this analysis. The reported rates of serious complications resulting from endoscopic therapy are very low in these studies. The incidences of perforation and bleeding requiring surgery induced by each endoscopic method are similar. However, the extent to which patient characteristics and endoscopic technique determine success and complication rates remains uncertain. In conclusion, endoscopic hemostatic therapy is safe and effective in reducing rates of morbidity and mortality in patients with acute nonvariceal gastrointestinal hemorrhage. This effect appears to be lim-

UJcers Surgery

Mortality

0.80 (0.44-1.45) 10 (711)

0.28’ (0.15-0.42) 11 (756)

0.32” (0.22-0.44) 9 (754)

0.40 (0.21-0.75) 9 (850)

0.55 (0.36-0.80) 10 (856)

0.57’ (0.40-0.79) 9 (764)

0.56 (0.18-1.73) 4 (312)

0.22 (0.11-0.41) 5 (379)

0.24 (0.13-0.42) 4 (339)

0.57 (0.39-0.85) 20 (1920)

0.37” (0.27-0.46) 22 (2039)

0.40” (0.31-0.48) 22 (1764)

Further

Bleeding

METAANALYSIS

January 1992

Table 6. Results

for Actively

Therapy Thermal contact ORb (95% CI) No. of trials (n) Laser ORb (95% CI) No. of trials (n) Injection ORb (95% CI) No. of trials (n) Al1 therapy ORb (95% CI) No. of trials (n)

BJeeding

or Nonbleeding

Visible

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Vessels Surgery

Mortality

0.18 (0.11-0.26) 9 (515)

o.20° (0.11-0.31) 7 (344)

0.66 (0.27-1.52) 7 (377)

0.36a (0.21-0.51) 8 (521)

0.58 (0.33-0.95) 8 (427)

0.75 (0.35-1.59) 6 (350)

0.13” (0.04-0.24) 2 (163)

0.13 (0.06-0.26) 7 (457)

0.43 (0.16-1.07) 6 (428)

0.23” (0.15-0.27) 19 (999)

0.26” (0.17-0.32) 21 (1281)

0.62 (0.38-0.98) 16 (1092)

Further

Bleeding

’Statistical heterogeneity. b Treatment vs. control.

ited to patients with endoscopic features predictive of a high risk of persistent or recurrent bleeding (those with active bleeding and nonbleeding visible vessels). The relative effectiveness of each of the treatments has not been addressed in this review. Further comparative trials and analysis are necessary to adequately evaluate their differential impact on patients with acute upper gastrointestina1 bleeding.

References 1.

2.

3.

4. 5.

6.

7.

8.

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Received March 13, 1991. Accepted June 7, 1991. Address requests for reprints to: Loren A. Laine, M.D., Division of Gastroenterology and Liver Diseases, Department of Medicine, USC School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. The authors thank the contributors of the primary studies for their interest and support in this project and for providing additional information when possible.