Meta-analysis: predictors of rebleeding after endoscopic treatment for bleeding peptic ulcer

Meta-analysis: predictors of rebleeding after endoscopictreatment for bleeding peptic ulcerP. Garcıa-Iglesias*, A. Villoria*, D. Suarez�, E. Brullet*,�, M. Gallach*, F. Feu�,§, J. P. Gisbert�,–, A. Barkun** & X. Calvet*,�

*Digestive Diseases Department, Hos-pital de Sabadell, Institut UniversitariParc Taulı, Departament de Medicina,Universitat Autonoma de Barcelona,Spain.�Unitat d’Epidemiologia i Avaluacio,Fundacio Parc Taulı, UniversitatAutonoma de Barcelona, Spain.�Centro de Investigacion Biomedicaen Red de Enfermedades Hepaticas yDigestivas (CIBEREHD), Instituto deSalud Carlos III, Madrid, Espana.§Servei de Gastroenterologia, Institutde Malalties Digestives, HospitalClınic de Barcelona, Spain.–Servicio de Aparato Digestivo,Instituto de Investigacion SanitariaPrincesa (IP), Hospital de la Princesa,Madrid, Spain.**Division of Gastroenterology, McGillUniversity Health Center and Depart-ment of Clinical Epidemiology, McGillUniversity, Montreal, Quebec, Canada.

Correspondence to:Dr X. Calvet, Unitat de MalaltiesDigestives, Hospital de Sabadell,Institut Universitari ParcTaulı,Universitat Autonoma de Barcelona,CIBEREHD – Instituto de Salud CarlosIII, Parc Taulı, 1, 08208 Sabadell,Barcelona, Spain.E-mail: [email protected]

Publication dataSubmitted 23 May 2011First decision 15 June 2011Resubmitted 3 August 2011Accepted 5 August 2011EV Pub Online 7 September 2011

SUMMARY

BackgroundDetermining the risk of rebleeding after endoscopic therapy for peptic ulcerbleeding (PUB) may be useful for establishing additional haemostatic mea-sures in very high-risk patients.

AimTo identify predictors of rebleeding after endoscopic therapy.

MethodsBibliographic database searches were performed to identify studies assessingrebleeding after endoscopic therapy for PUB. All searches and data abstrac-tion were performed in duplicate. A parameter was considered to be anindependent predictor of rebleeding when it was detected as prognostic bymultivariate analyses in ‡2 studies. Pooled odds ratios (pOR) were calcu-lated for prognostic variables.

ResultsFourteen studies met the prespecified inclusion criteria. Pre-endoscopic pre-dictors of rebleeding were: (i) Haemodynamic instability: significant in 9 of13 studies evaluating the variable (pOR: 3.30, 95% CI: 2.57–4.24); (ii) Hae-moglobin value: significant in 2 of 10 (pOR: 1.73, 95% CI: 1.14–2.62) and(iii) Transfusion: significant in two of six (pOR not calculable). Endoscopicpredictors of rebleeding were: (i) Active bleeding: significant in 6 of 12studies (pOR: 1.70, 95% CI: 1.31–2.22); (ii) Large ulcer size: significant in 8of 12 studies (pOR: 2.81, 95% CI: 1.98–4.00); (iii) Posterior duodenal ulcerlocation: significant in four of eight studies (pOR: 3.83, 95% CI: 1.38–10.66)and (iv) High lesser gastric curvature ulcer location: significant in three ofeight studies (pOR: 2.86; 95% CI: 1.69–4.86).

ConclusionsMajor predictors for rebleeding in patients receiving endoscopic therapy arehaemodynamic instability, active bleeding at endoscopy, large ulcer size, ulcerlocation, haemoglobin value and the need for transfusion. These risk factorsmay be useful for guiding clinical management in patients with PUB.

Aliment Pharmacol Ther 2011; 34: 888–900

888 ª 2011 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2011.04830.x

Alimentary Pharmacology and Therapeutics

INTRODUCTIONPeptic ulcer bleeding (PUB) is a major cause of acutenonvariceal gastrointestinal bleeding. It is a common rea-son for emergency hospital admission and a major causeof mortality, morbidity and health care expenditure.1, 2

In recent years, improvements in the treatment ofPUB have reduced the risk of rebleeding and death. Mostsevere bleeding is associated with high-risk endoscopicstigmata. In these patients, the combination of aggressivevolume repletion and rapid correction of hypotension,3

endoscopic therapy and intravenous proton-pump inhib-itors (PPI) improve outcomes.4–10

Recurrent haemorrhage is one of the most significantpredictive factors for mortality.11, 12 The risk of reblee-ding in patients with clean ulcers is insignificant andrecurrence occurs mainly after endoscopic therapy ofulcers showing high-risk stigmata.5, 13 Identifyingpatients at very high risk for rebleeding within this pop-ulation may allow targeting additional haemostatic mea-sures in a cost-effective way. For example, routine use ofsecond-look endoscopy in all endoscopically treatedpatients is not cost-effective 6 but becomes so when per-formed in those at very high risk.14 At the other end ofthe scale, identifying patients with the lowest risk of reb-leeding after therapy may also be useful: A previousstudy by our group showed that highly selected patientscould be safely discharged after endoscopic therapy.15

Even if not discharged immediately, patients at low riskof rebleeding after therapeutic endoscopy are likely tobenefit from an early switch to oral PPI and dischargeinstead of maintaining the costly and uncomfortable hos-pitalisation for a 72-h PPI perfusion that is currently rec-ommended in all patients after endoscopic therapy.6

The scores currently available were not designed topredict rebleeding after endoscopic therapy, and may notwork well in this setting16: Most have been developed incohorts that included different causes of haemorrhageand patients not receiving endoscopic treatment. In addi-tion, many were designed on the basis of a single studyand their reproducibility has never been satisfactory.17–20

Finally, most scores were designed to predict mortalityor a combination of mortality and rebleeding instead ofonly rebleeding. Predictors of ulcer rebleeding differ fromthose for mortality: they are related more to the severityof haemorrhage and the ulcer characteristics, whereaspredictors for mortality are mainly comorbidity andrebleeding.11, 12, 21

In consequence, it is important from a clinical pointof view to develop a specific score for predicting reblee-ding after endoscopic therapy. The first step in develop-

ing an accurate score is to identify the most importantpredictive variables. To ensure general applicability, weaimed to determine which variables have been found tobe prognostic in a range of populations, instead ofderiving them from a single study. For this reason, thepresent study performed a systematic review and ameta-analysis to identify the most consistent predictorsof recurrent haemorrhage in patients after endoscopictherapy.

In addition, little attention has been paid to the heter-ogeneity in the definition of the different prognostic vari-ables. A secondary aim of the study was to address thisissue and to evaluate whether the definition or the cut-off value used could influence a variable’s prognosticvalue. Therefore we set out to determine how these vari-ables are described in the different studies and to estab-lish whether a reliable cut-off value for predictingrebleeding can be established.

METHODS

Search StrategyA systematic review of the evidence was performed cov-ering the period from January 1990 to June 2010. Rele-vant papers were identified by searching PubMed, the ISIWeb of Knowledge and the Abstracts from the DigestiveDisease Week (DDW) from 1990 to 2010 and the UnitedEuropean Gastroenterology Week (UEGW) from 1995 to2009. The search was restricted to human studies inadults published in English, Spanish or French. Multiplesearch strategies were used. Search strings for each data-base were:

Pubmed (ulcer AND rebleeding AND factors (160cites), ulcer AND bleeding AND failure AND endoscopy(52 cites), ulcer AND rebleeding AND endoscopy (366cites), ulcer AND rebleeding AND endoscopy ANDtreatment (345 cites), ulcer AND rebleeding AND risk(245 cites), (Ulcer*[ti] OR nonvariceal[ti]) AND(Bleed*[ti] OR rebleed*[ti] OR failure[ti]) AND endo-scop*[ti] (365 cites).

ISI web of Knowledge: ulcer AND rebleeding ANDfactors (123 cites), ulcer and bleeding AND failure ANDendoscopy (33 cites), ulcer AND rebleeding AND endos-copy (181 cites), ulcer AND rebleeding AND endoscopyAND treatment (107 cites), ulcer AND rebleeding ANDrisk (216 cites).

In addition, a fully recursive search of the referencesof the original studies and significant reviews in the per-sonal databases of the authors was performed to findstudies not identified by the previous searches. Abstracts

MMeettaa--aannaallyyssiiss:: pprreeddiiccttoorrss ooff rreebblleeeeddiinngg aafftteerr eennddoossccooppiicc ttrreeaattmmeenntt

Aliment Pharmacol Ther 2011; 34: 888–900 889

ª 2011 Blackwell Publishing Ltd

of the articles selected in the search were reviewed sepa-rately by two of the authors (PG and AV) and the arti-cles that met the inclusion criteria were selected forfurther analysis. Discrepancies regarding the eligibility ofa given study were solved by repeated review and discus-sion with a third author (XC).

Inclusion and Exclusion CriteriaThe selection criteria were: (i) Inclusion of patients withpeptic ulcer bleeding who presented high-risk stigmatafor rebleeding (Forrest Ia, Ib, IIa and IIb) and who hadreceived successful endoscopic treatment. (ii) Evaluationusing multivariate analysis of predictors of rebleeding inpatients who received endoscopic therapy. (iii) Studies inhumans, (iv) Studies published in English, Spanish orFrench. (v) Data not duplicated in another manuscript.

Dual publications were excluded; when multiple publi-cations of the same patients’ group were retrieved, onlythe more recent or complete version was included.Therefore, abstracts previous to published articles werenot evaluated. Pharmaco-dynamic studies, studies oftreatment in upper gastrointestinal bleeding (UGIB) ofunspecified causes or from aetiologies other than pepticulcer disease, were also excluded.

Data AbstractionThe following data were abstracted for each of the stud-ies: (i) date and setting of the trial, (ii) demographics ofthe study population, (iii) definition of UGIB, (iv) defini-tion of rebleeding Including follow-up duration, (v)patient selection criteria, (vi) type of associated pharma-cotherapy, (vii) modality of endoscopic haemostatic ther-apy, (viii) definition of the outcome measure, (ix)number and proportion of patients achieving initial hae-mostasis, (x) number and proportion of patients experi-encing rebleeding, (xi) predictors of rebleeding in theunivariate analysis, (xii) predictors of rebleeding in themultivariate analysis, (xiii) OR for each individual riskfactor.

Validity AssessmentTwo investigators assessed the quality of the studiesindependently, and a third researcher was consulted incase of disagreement. Studies were graded using six qual-ity criteria, defined a priori, and adapted to observationalstudies from those described by Cook et al.8, 22 for clini-cal trials. Each component of the scoring system wasgraded ‘1’ if the study met the quality criterion and ‘0’ ifit did not. The methodological quality of each studyincluded was also assessed using the criteria used by the

Third U.S. Preventive Services Task Force for cohortstudies.23 These criteria rate the internal validity of astudy as ‘good’ (all criteria met), ‘fair’ (not all criteriamet, but no fatal flaws), or ‘poor’ (fatal flaw in at leastone of the criteria).

Statistical MethodsAlthough the PRISMA criteria24 were primarily designedto evaluate meta-analyses of randomised trials, these rec-ommendations were followed whenever applicable.

Pooled odds ratios (pOR) and their associated 95%confidence intervals (95%CI) were obtained for all vari-ables selected as significant by at least two multivariateanalyses. pOR were calculated by including the raw dataand the results of all the studies regardless of whetherthe variable was significant. The analyses were performedusing RevMan 5.2 (The Nordic Cochrane Centre, TheCochrane Collaboration, Copenhagen, Denmark). Theodds ratio (OR) was estimated using the Mantel–Haens-zel method with a random effects model. Evidence forheterogeneity between studies in these meta-analyses wasassessed by computing I-squared statistics.25 We consid-ered an I2 of <0.25 as small-scale heterogeneity, 0.25 to0.5 as moderate, and >0.5 as large-scale.

A previous meta-analysis26 used a different statisticalapproach and calculated a summary odds ratios (sOR)combining the OR obtained in the multivariate analysisonly for the significant variables. As it excludes negativestudies, this approach may carry the risk of overestimat-ing the prognostic value of the variable. We also per-formed calculations with this method to evaluate bothwhether our results correlate with the previous reportand whether the two methods for determining pOR ⁄ sORwere comparable. For this second analysis we performedrandom effects meta-analyses27 for each predictor thatwas significant in two or more studies to obtain sOR. Insome cases, ORs and confidence intervals were recon-structed from other values such as log-OR, standarderrors or P-values. Analyses were conducted in STATA

version 10 software (StataCorp LP, Texas, USA). Thesecombined as ORs from significant studies were labelledsORs in contrast to the OR obtained using raw data ofall studies that were labelled as pOR.

RESULTS

Results of the Search: Studies ExcludedThe search identified 2193 citations. After reviewing theabstracts and additional searches, 33 articles suitable foranalysis were detected. Nineteen of them were excluded,

PP.. GGaarrccııaa--IIgglleessiiaass eett aall..

890 Aliment Pharmacol Ther 2011; 34: 888–900


for a variety of reasons. Ten articles included (either inaddition or exclusively) patients without endoscopictreatment.2, 28–36 Five did not perform or did not reportthe results of multivariate analysis.37–41 One study deter-mined risk factors exclusively for mortality,12 andanother included a large proportion of patients withbleeding from aetiologies other than peptic ulcer.42

Finally, one study determined the predictors of reblee-ding after a second-look endoscopy,43 and one used ascore combining different prognostic variables but didnot give values for individual prognostic variables ineither the univariate or the multivariate analysis.44 ThePRISMA flow-diagram of the study is shown in Figure 1.

Studies IncludedFourteen studies (12 full articles and two abstracts)including 3609 patients which evaluated the predictors ofrecurrent haemorrhage after endoscopic haemostatictherapy for PUB were finally included in the meta-analy-sis.45–58 Detailed characteristics of the studies are shownin Table 1. Three of the studies included a small propor-tion (<10%) of endoscopically treated oesophagealulcers.54–56 Even in the improbable case that prognosticfactors in oesophageal ulcers were very different from

those for peptic ulcer, the number of cases was smalland was unlikely to have affected the analysis. Inconsequence, these studies were included in the meta-analysis. Data regarding quality assessment are shown inTable 2.

The design of the studies varied widely. Data regard-ing whether a second elective endoscopy was performedare also shown in Table 2. Finally, the systematic reviewaccepted the definition of rebleeding of each individualstudy. Criteria for further bleeding were relatively homo-geneous and are described in Table 2. Furthermore,bleeding was confirmed by either endoscopy or surgeryin all studies.

Independent Factors Predicting RebleedingThe risk factors that independently predicted rebleedingafter endoscopic therapy based on the multivariate analy-sis are shown in Figure 2. Variables selected in at leasttwo multivariate analyses were further evaluated in detail.Factors that fulfilled these criteria were haemodynamicinstability, active bleeding at endoscopy, ulcer size, bleed-ing from an ulcer situated in the duodenal posterior wallor gastric high lesser curvature, transfusion and haemo-globin lower than 10 g ⁄ L.

Haemodynamic instability. Haemodynamic instabilitywas analysed in 13 of 14 studies, with a total of 3537patients. The variable was significant in 9 of 13 studies.Haemodynamic instability was evaluated at admission inall the studies. Definition of haemodynamic instabilitywas quite homogeneous across the different studies,allowing a pooled analysis of the OR. Most studies useda definition of shock ⁄ haemodynamic instability ⁄ compro-mise that included a systolic blood pressure<100 mmHg,35, 37–53, 55, 56 generally associated to tachy-cardia >100 b.p.m. and peripheral signs of shock. Onestudy did not define this topic,58 another used only pulserate54 and another used a slightly different definition forshock (systolic blood pressure <90 mmHg, pulse>110 b.p.m.).56 Despite this relative homogeneity in thecriteria for shock, the populations of the different studiesand the methods for assessing shock were heterogeneous,as the rate of patients with haemodynamic instabilityranged from 10% to 74% depending on the study.Excluding the few studies with extreme values, however,the range of haemodynamic instability was more reason-able, between 15% and 40%.

Data were available from 11 of 13 studies, including3088 patients. Heterogeneity was low (I2: 12%). pOR was3.30, 95% CI 2.57–4.24 (Figure 3).

2193 citations from multiple searches

PUBMED 1553, ISI web of Knowledge 660

33 articles evaluating prognostic factors

10 no endoscopic therapy inall or part of patiens

5 did not performedmultivariate analysis

1 evaluated only prognostic

1 evaluated patients after

factors for mortality

1 Included bleeding sourcesother than peptic ulcer

second-look endoscopy

1 did not allowed dataextraction

14 studies included

Figure 1 | PRISMA flow-diagram of the systematicreview.




Seven studies reported a significant OR from the mul-tivariate analysis for calculating the sOR. Low heteroge-neity was observed (I2: 7.2%). sOR was 3.05, 95% CI:2.18–4.26 (Figure 4).

Active bleeding at endoscopy. Active bleeding was anal-ysed in 12 studies including 3220 patients. Oneabstract did not specify whether active bleeding wasanalysed 58 and one study included only patients withnonbleeding visible vessel.45 The variable was signifi-cant in the multivariate analysis in 6 of 12 studiesincluding 2091 patients. In this case, the definitionof the variables was clearly heterogeneous: somestudies 52, 53 evaluated patients with spurting haemor-rhage separately, while others analysed spurting andoozing bleeding together.

Meta-analysis of spurting bleeding alone included fourstudies with a total of 745 patients. The degree of hetero-geneity was significant (I2: 64%). pOR was 3.30 (95% CI

1.55–7.03). Eleven studies analysed spurting and oozingbleeding together. Heterogeneity was moderate (I2: 31%)and the prognostic value of the variable decreased: pOR:1.70, 95% CI: 1.31–2.22 (Figures 5 and 6).

Regarding sOR, the respective values were: no signifi-cant heterogeneity (I2 = 0.0%) and an sOR of 5.33, 95%CI: 3.00–9.44 for spurting bleeding (two studies), andmoderate heterogeneity (I2 = 24.1%), and an sOR of2.28, 95% CI: 1.42–3.67 for any active bleeding(Figure 4).

Large ulcer size. Large ulcer size was analysed in 12 of14 studies including 2937 patients, and proved significantin the multivariate analysis in 8 of 12 studies. The defini-tion of large ulcer varied, with ulcers larger than 1 cm.being included in four studies46, 50, 53, 56 and ulcers lar-ger than 2 cm. being included in five.47–49, 51, 52 Onestudy used size as a continuous variable54 and two othersused cut-off values of 1.5 cm.57 and 3 cm.58 respectively.

Table 1 | Characteristics of the studies

Author CountryStudydesign N

Gastric ⁄Duodenal

Age(mean)

Women(n ⁄%)

Drugtherapy

Endoscopictreatment

Initial Hemosthasis (n ⁄%)

Re-Bleeding(n ⁄%)

Villanueva1993

Spain N ⁄ S 233 103 ⁄ 130 64.9 79 ⁄ 33.9 H2-B iv M ⁄D(E, E + Po; E + T)

217 ⁄93.1 57 ⁄24.5

Park 1994 UK N ⁄ S 135 52 ⁄63 64 53 ⁄ 39.3 H2-B iv M (E) 127 ⁄94.1 25 ⁄ 18.5Brullet gast1996

Spain R 178 178 ⁄0 65 57 ⁄ 32.0 H2-B iv D (E + Po) 155 ⁄87.1 23 ⁄ 12.9

Brullet duod1996

Spain R 120 0 ⁄ 120 61 23 ⁄ 19.2 H2-B iv D (E + Po) 88 ⁄73.3 18 ⁄ 15.0

Lin 1998 Taiwan R 100 N ⁄ S N ⁄ S N ⁄ S PPI ⁄H2-B iv

M (MPE) 97 ⁄97.0 17 ⁄ 17.0

Thomopoulos2001

Greece P 427 162 ⁄ 319 58.6 84 ⁄ 19.7 H2-B iv M (E) 389 ⁄91.1 86 ⁄20.1

Chung 2001 Korea N ⁄ S 143 94 ⁄49 55.2 19 ⁄ 13.3 H2-B iv M ⁄D(C, ES; C + ES)

139 ⁄97.2 36 ⁄ 25.2

Huang 2002 Taiwan P 1251 59 ⁄64 N ⁄ S 8 ⁄6.4 H2-B iv M (E) 115 ⁄92.0 22 ⁄ 17.6Wong 2002 China P 1144 478 ⁄666 62.5 348 ⁄ 30.4 PPI oral D (E+HP) 1128 ⁄98.6 110 ⁄9.6

G Sanchez2003

Spain R 208 208 ⁄0 65 72 ⁄ 34.6 PPI ⁄H2-B iv

M ⁄D(E; TC, E + TC)

181 ⁄87.0 13 ⁄6.3

Lopez 2003 Spain R 336 0 ⁄ 336 60 65 ⁄ 19.4 PPI ⁄H2-B iv

M ⁄D(E; TC, E + TC)

297 ⁄88.4 39 ⁄ 11.6

Thomopoulos2004

Greece N ⁄ S 191 79 ⁄ 112 58.3 36 ⁄ 18.9 PPI iv M (E) 154 ⁄80.6 37 ⁄ 19.4

Majid 2007 Pakistan N ⁄ S 74 0 ⁄74 53 15 ⁄20.3 N ⁄ S D(E + APC) 74 ⁄ 100.0 16 ⁄ 21.6

Toki 2008 N ⁄ S N ⁄ S 200 N ⁄ S Elderly N ⁄ S N ⁄ S M ⁄D (C + others) N ⁄ S 31 ⁄ 15.5

APC, argon plasma coagulation; C, hemoclip; D, dual therapy; E, epinephrine; ES, epinephrine + hypertonic saline; HP, heaterprobe; H2-B, H2-blocker; M, Monotherapy; MPE, multipolar electrocoagulation; N ⁄ S, not specified; P, prospective; Po, polydocanol;R, retrospective; T, thrombin; TC, thermocoagulation.




Raw data analysis was possible for four studies using acut-off of 1 cm, and for five studies using a cut-off of2 cm. pOR was 2.31, 95%CI 1.09–4.94 with significantheterogeneity (I2:58%) for the former studies; for the lat-ter, pOR was 2.81, 95% CI: 1.98–4.00 with lower hetero-geneity (I2: 33%) (Figure 7).

SOR could only be calculated for ulcers larger than2 cm. Heterogeneity was low - I2 = 17%- and the sORwas 2.31, 95% CI: 1.56–3.41 (Figure 4).

Posterior duodenal wall ulcer. Posterior duodenal ulcerwas analysed in eight of the 14 studies, including 2449

patients, and was significant in the multivariate analysisin four. Six studies (including 1178 patients) presentedenough data for the meta-analysis. The analysis showedsignificant heterogeneity (I2: 77%) and the pOR was 3.83,95%CI: 1.38–10.66 (Figure 8).

OR for calculating an sOR were available only fromtwo studies. No heterogeneity was observed (I2 = 0.0%)and sOR was 6.15, 95%CI: 2.77–13.68 (Figure 4).

High lesser gastric curvature ulcer. This variable was sig-nificant in three of eight studies, including 2705 patients.Raw data were available from six studies including 953

Table 2 | Quality criteria and definition of rebleeding

Author

US preventivetask forcecriteria

Cook’smodifiedcriteria Second-look Criteria for rebleeding�

Villanueva 1993 Fair 5 Yes* Active bleeding at endoscopy or fresh blood in vomitingor aspirate plus either evidence of hypovolaemia or�haemoglobin requiring transfusion

Park 1994 Fair 4 No Hematemesis + tachycardia or hypotension ortransfusion of at least 6 BU.

Brullet gastric 1996 Fair 5 No Fresh blood in vomiting or aspirate + hypovolaemia(� SBP >15 mmHg) after 6 h or transfusion of >4 BU

Brulletduod. 1996 Fair 5 No Similar to Brullet, gastric ulcer 1996

Lin 1998 Fair 5 Fresh blood in vomiting or aspirate + hypovolaemia(SBP <100 mmHg, or drop in SBP >30 mmHg or DBP>15 mmHg after standing) or bloody stools

Thomopoulos 2001 Fair 5 No Tranfusion >5 BU in 24 h or 12 BU in 48 h andrecurrence of bleeding with shock (SBP<100 mmHg ,pulse rate >100 ⁄min)

Chung 2001 Fair 4 Yes Fresh blood in vomiting or aspirate or bloody stools ,instability of vital signs, or �Hb 2 mg ⁄ dL in 24 h

Huang 2002 Fair 6 No Similar to Lin 1998

Wong 2002 Fair 5 No Fresh hematemesis, hypotension( SBP < 90 mmHg) + tachycardia(pulse rate < 110 ⁄min), melena, transfusion of>4 BU in 72 h.

G Sanchez 2003 Fair 5 No Hematemesis or melena + �Hematocrit >5 points in24 h or hypovolaemia (>1000 mL ⁄ h or 3000 mL ⁄ 12 h)

Lopez 2003 Fair 4 No Similar to G Sanchez 2003

Thomopoulos 2004 Fair 3 No Fresh blood in vomiting and ⁄ or melena + shock(SBP < 100 mmHg , pulse rate >100 ⁄min) or �Hb2 mg ⁄ dL in 24 h

Majid 2007 – 2 – Abstract. Not described

Toki 2008 – 2 – Abstract. Not described

BU, blood unit; HB, haemoglobin; Hto, haematocrit; SBP, systolic blood pressure.

* In 105 of 233 patients.

� In all cases rebleeding was confirmed by endoscopy or surgery.




patients. Low heterogeneity was found (I2: 15%) and thepOR was 2.86; 95% CI: 1.69–4.86; (Figure 9).

ORs for calculating a sOR were available from twostudies, with no heterogeneity (I2:0.0%) and an sORof2.92, 95%CI: 1.37–6.21 (Figure 4).

Haemoglobin value & transfusion. Transfusion wasselected as significant in two of the six studies analysingthis variable. Three studies recorded the need for trans-fusion after the diagnostic endoscopy and the remainingthree considered only the period before endoscopy. In

addition, one evaluated transfusion of any amount andtwo the need for transfusion of 500 mL or more. Valuesfor this variable were not pooled because (i) in moststudies the need for transfusion was recorded 1–2 daysafter the diagnostic endoscopy, which limits its applica-bility as a prognostic variable for deciding early addi-tional measures, (ii) the criteria for evaluation oftransfusion were very heterogeneous.

Haemoglobin value was significant in two of 10 multi-variable analyses. This variable was selected only whentransfusion was not evaluated. Haemoglobin was

Duodenal posterior wallHigh lesser curvature

TransfusionHb < 10ComorbidityRed blood vomitingDuodental vs. gastricAge

SexNSAID

Blood in stomachAnticoagulant use

Ulcer size

Active bleeding

Haemodinamaic instabilityReference

Significant in the univariate analysisSignificant in the multivariate analysis

Not evaluatedNot significant

No data

Villanu.

1993

19943

1996

1996

1998

Park

Brullet

Brullet

Lin

2001

2001

2002

2002

2003

2003

2004

2007

2008

Chung

Thom

op.

Wong

Huang

García

López

Thom

op.

Majid

Toki

Figure 2 | Variables analysedand found significant in thedifferent studies.

Study or subgroupShock No shock

Events EventsTotal Total Weight (%)Odds ratio Odds ratio

M-H, random, 95% Cl M-H, random, 95% Cl

Brullet Gastric (1996)Brullet Duodenal (1996)

Chung (2001)Garcia (2003)Huang (2002)Lin (1998)López (2003)

Thomopoulos (2004)Thomopoulos (2001)

Villanueva (1993)Wong (2002)

8103019156

2724139

35

2539

10779303582513223

182

1013

69

17111262244675

8113936

1299562

154376159210962

5.16.86.17.87.24.99.8

13.88.27.1

23.1

3.85 (1.68–8.81)4.50 (2.44–8.32)

0.96 (0.32–2.87)

4.22 (1.80–9.89)

3.34 (1.15–9.74)3.34 (1.33–8.37)1.95 (0.74–5.15)

4.59 (1.89–11.14)

5.81 (2.75–12.27)

2.29 (0.93–5.63)2.82 (1.82– 4.36)

Total (95% Cl) 685 2403 100.0 3.30 (2.57–4.24)

0.02 0.1 1 10 50Increases risk Decreases risk

Test for overall effect: Z = 9.32 (P < 0.00001)Heterogeneity: τ2 = 0.02; χ2 = 11.33, df = 10 (P = 0.33); I2 = 12%Total events 285196

Figure 3 | Meta-analysis of the studies evaluating hemodynamic instability.




analysed as a continuous variable in four stud-ies.45, 48, 49, 52 When a cut-off was selected, it was8.9 g ⁄ L in one study and 10 g ⁄ L in five. Data from thesefive studies using the 10 g ⁄ L cut-off, and including 1810

patients, were pooled in a meta-analysis. The heterogene-ity was moderate (I2: 32%) and the pOR of 1.73, 95% CI:1.14–2.62 (Figure 10).

As an OR was available in only one study, the sORcould not be calculated.

DISCUSSIONThis systematic review identifies the presence of haemo-dynamic instability at admission, active bleeding atendoscopy, and ulcer size and location as the most con-sistent prognostic variables for rebleeding in patientswho received endoscopic treatment. These variables areshown to be prognostic despite the fact that the studiesincluded have a relatively heterogeneous design and oftenuse different definitions and cut-off points. Our findingssuggest that their prognostic values are not due to theparticular design or population used in the individualstudies.

A second point highlighted by the study is that mostof the cut-offs used in the different studies were estab-lished empirically or, at best, were taken from empiri-cally established standards (such as the blood pressureand pulse cut-offs for haemodynamic instability or thesize of large vs. small ulcers). Whether cut-offs specifi-cally calculated for determining the rebleeding risk couldhave better discriminative capacity remains to be deter-mined.

The analysis also suggests that the cut-off used forhaemoglobin (10 g ⁄ L) may be inadequate. Although thepooled analysis found borderline significant differencesfor haemoglobin, transfusion seemed to achieve betterdiscrimination, despite the fact that the criteria for

Prognostic variable

Haemodynamic instabilityPooled OR: 3.30 (2.57–4.24)

Pooled OR: 1.7 (1.31–2.22)

Pooled OR: 3.30 (1.55–7.03)

Pooled OR: 2.81 (1.98–4.00)

Pooled OR: 3.83 (1.38–10.66)

Pooled OR: 2.86 (1.69–4.86)

sOR: 3.05 (2.18–4.26)

Active bleeding (spurting)

Active bleeding (spurting + oozing)

sOR: 5.33 (3.00–9.44)

sOR: 2.28 (1.42–3.67)

sOR: 2.31 (1.56–3.41)

sOR: 6.15 (2.77–13.7)

sOR: 2.92 (1.37–6.21)

Ulcer > 2 cm.

Posterior duodenal ulcer

High lesser curvature

OR

0 1 2 4 6

Figure 4 | Comparative OR using conventional pOR andsOR of positive multivariable analysis.

0.02 0.1 1 10 50

Odds ratioM-H, random, 95% Cl

Odds ratioM-H, random, 95% Cl YearStudy or subgroup

Heterogeneity: τ2 = 0.06; χ2 = 14.46, df = 10 (P = 0.15); I2 = 31%Test for overall effect: Z = 3.97 (P < 0.0001)

InactiveActiveEvents EventsTotal Total Weight (%)

Favours experimental Favours control

19931994199619961998200120012002200220032003

200272Total (95% Cl)Total events

221913127

512620719

22

356

106

10351112391917

15539

1285353

1726569

557150194

7888505344

2547856

58758

125

11.45.66.75.15.1

15.38.07.6

17.87.2

10.2

1471 1635 100.0 1.70 (1.31–2.22)

2.45 (1.10–5.47)

4.15 (1.68–10.23)

1.35 (0.72–2.51)1.51 (0.55–4.15)

2.29 (0.79–6.66)0.81 (0.28–2.35)0.98 (0.61–1.59)

2.64 (1.15–6.04)1.83 (1.21–2.75)1.27 (0.54–2.99)2.22 (1.13–4.38)

Garcia (2003)Wong (2002)Huang (2002)Chung (2001)Thomopoulos (2001)Lin (1998)Brullet Duodenal (1996)Brullet Gastric (1996)Park (1994)Villanueva (1993)

López (2003)

Figure 5 | Meta-analysis evaluating active bleeding (both spurting and oozing) vs. no active bleeding.




evaluating transfusion varied widely between the differ-ent studies. Transfusion is probably a surrogate markerfor haemoglobin values lower than 10 g ⁄ L, as it is usu-ally indicated with haemoglobin values below 7 g ⁄ L to9 g ⁄ L. This suggests that it might be more appropriate toapply a lower cut-off for haemoglobin. It would be inter-esting to see whether assessing haemoglobin either as acontinuous variable or with a cut-off value lower thanthe currently accepted level of 10 g ⁄ L would be moreuseful for predicting rebleeding. In addition, the presentdata do not establish whether the haemoglobin value

adds any significant prognostic capacity to the five vari-ables mentioned above. We did not attempt to perform ameta-regression to ascertain this last point because thenumber of studies included in the meta-analysis wasinsufficient.

The findings of our study confirm and complete thoseof the recent systematic review by Elmunzer et al.26 Thatreview included 10 studies and 3524 patients and foundhaemodynamic instability, active bleeding at endoscopy,large ulcer size, posterior duodenal ulcer and lessergastric curvature ulcer and co-morbid illness to be

Study or subgroup Events Total Events Total Weight %

Odds ratio Odds ratio

M-H, random, 95% Cl Year M-H, random, 95% Cl

InactiveSpurting

Thomopoulos (2001)Chung (2001)Lin (1998)Park (1994)

4696

61411

94

46

1826

2840

3371

125332

21.921.323.233.5 7.00 (4.15–11.79)

3.46 (1.26– 9.56)1.64 (0.54–5.00)1.97 (0.67–5.83) 1994

199820012001

Total events

Total (95% Cl)

75 85

184 561 100.0 3.30 (1.55–7.03)

Heterogeneity: τ2 = 0.37; χ2 = 8.42, df = 3 (P = 0.04); I 2 = 64%Test for overall effect: Z = 3.10 (P = 0.002)

0.10.02 1 5010ControlSpurting

Figure 6 | Meta-analysis of the studies evaluating spurting bleeding vs. no active bleeding.

Study or subgroupOdds ratio

M-H, random, 95% ClOdds ratio

M-H, random, 95% Cl YearEvents EventsTotal Total Weight(%)

Small ulcerLarge ulcer

Total events

5.1.1 1 cmVillanueva (1993)Lin (1998)Garcia (2003)Thomopoulos (2004)Subtotal (95% Cl)

34

52

666

23

69

114

31

8134

25161

21

1526352

166433

15.77.85.38.9

37.6 2.31 (1.09–4.94)1.38 (0.51–3.73)

4.80 (1.19–19.30)1.01 (0.34–3.03)4.06 (2.17–7.59)

2004200319981993

Heterogeneity: τ2 = 0.34; χ2 = 7.10, df = 3 (P = 0.07); I2 = 58%Test for overall effect: Z = 2.17 (P = 0.03)

Total events

5.1.2 2 cm

Subtotal (95% Cl)

Chung (2001)Wong (2002)López (2003)

Brullet Duodenal (1996)Brullet Gastric (1996) 16

288

3613

101

672284

24443

460 1447

7109

7426

126

1118459

900293

9.57.8

11.221.312.662.4 3.01 (2.00–4.54)

4.45 (2.07–9.57)1.93 (1.26–2.96)2.78 (1.20–6.45)

4.23 (1.42–12.59)4.66 (1.80–12.04)

20032002200119961996

Heterogeneity: τ2 = 0.10; χ2 = 13.05, df = 8 (P = 0.11); I2 = 39%

Heterogeneity: τ2 = 0.07; χ2 = 5.93, df = 4 (P = 0.20); I2 = 33%

Test for subgroup differences: not applicableTest for overall effect: Z = 5.74 (P < 0.00001)

Test for overall effect: Z = 5.25 (P < 0.00001)

Total (95% Cl)Total events

621195153

1880 100.0 2.81 (1.98–4.00)

0.02 0.1 1 10 50Large ulcerSmall ulcer

Figure 7 | Meta-analysis of the studies evaluating ulcer size.




significant prognostic factors for ulcer rebleeding. Ourreview of 14 studies confirmed the prognostic value ofall of the above except co-morbidity. Finally, our datasuggest that haemoglobin level may also be an indepen-dent predictor of rebleeding and may add prognosticvalue to the above variables.

The discrepancies between our study and the reviewby Elmunzer et al. 26 may be due in part to the slightly

different inclusion and exclusion criteria used. We alsoincluded one study 52 which was not selected by Elmun-zer et al., and excluded two additional studies that didnot fulfil our inclusion criteria: one that included a largeproportion of patients with low risk lesions who werenot receiving endoscopic treatment 31 and anotherbecause multivariate analysis was not effectively per-formed.32

Study or subgroup

Odds ratio

M-H, random, 95% Cl

0.10.02 1 5010Posterior duodenal ulcerOther duodenal

Villanueva (1993)Park (1994)Brullet Duodenal (1996)Wong (2002)Huang (2002)Thomopoulos (2004)

2011543

23

352519491138

174

1351144

1083887

6175378

18.715.916.717.414.916.5


Total (95% Cl)Total events

17766 103

981 100.0

Events EventsTotal Total Weight(%)

Odds ratio

M-H, random, 95% Cl Year

200220022004

199619941993

3.83 (1.38–10.66)

7.14 (3.06–16.64)6.68 (1.82–24.57)2.03 (0.63–6.61)0.99 (0.34–2.85)1.04 (0.24–4.50)

28.37 (8.56–94.00)

Posterior duodenal ulcer Other duodenal

Figure 8 | Meta-analysis of the studies evaluating posterior duodenal ulcer location.

Study or subgroup Events EventsTotal Total Weight(%)

Odds ratio


Odds ratio

M-H, random, 95% Cl

Other gastric locationsHigh lesser curvature

Park (1994)Brullet Gastric (1996)Huang (2002)Wong (2002)Garcia (2003)Thomopoulos (2001)

7162

2

919

2070

6

11

6188

07

12

5

347

24108

53

51

355106

3.124.1

7.9

8.1

31.525.3

19941996

20022003

2002

2004

27.22 (1.44–514.31)4.28 (1.66–11.03)1.71 (0.28–10.49)

1.63 (0.74–3.60)3.89 (1.55–9.77)

2.04 (0.34–12.23)

Heterogeneity: τ2 = 0.07; χ2 = 5.91, df = 5 (P = 0.32); I2 = 15%Test for overall effect: Z = 3.90 (P < 0.0001)

Total (95% Cl)

Total events

25655 65

697 100.0 2.86 (1.69–4.86)

0.02 0.1 1 10 50Control High lesser curvature

Figure 9 | Meta-analysis of the studies evaluating high gastric lesser curvature ulcer location.

Study or subgroup Events EventsTotal Total Weight(%)

Odds ratio


Odds ratio

M-H, random, 95% Cl

Hb > 10 g/LHb < 10 g/L

Lin (1998)Wong (2002)Huang (2002)Garcia (2003)López (2003)

11

1880

525

65

56645

56152

63014

147

3249969

18452

11.737.018.59.9

22.9

0.88 (0.29–2.65)2.21 (1.43–3.43)1.86 (0.83–4.19)0.63 (0.19–2.13)2.39 (1.19–4.78)

1998

20032003

20022002


Total (95% Cl)

Total events 139 71

974 836 100.0 1.73 (1.14–2.62)

0.02 0.1 1 10 50Hb < 10 g/LHb > 10 g/L

Figure 10 | Meta-analysis of the studies evaluating haemoglobin value.




Pooling only the significant values in the multivariateanalysis, as Elmunzer et al. did in their study,26 could bemisleading; taking only positive studies carries a risk ofoverestimating the prognostic value of the selected vari-ables. In consequence, the reliability of this approach forcalculating pORs is uncertain. To avoid this problem weperformed the meta-analysis using a more classicalapproach, examining the raw data from the univariateanalysis of each study and including all studies, whetheror not the variable was selected in the multivariate analy-sis to obtain a pOR. This approach does not take intoaccount the adjustment of independent predictors forconfounding that multivariate analysis provides, butallows the inclusion of both positive and negative studies.To compare the two methods, we also calculated thesOR as Elmunzer et al.26 had done, and found that it didnot generally overestimate the risk: however, overestima-tion might have occurred when data were pooled from asmall number of studies as, for example, in the case ofposterior duodenal ulcer. In this case, the estimates ofthe sOR were far larger than those of the raw data meta-analysis.

Also, pooling the variables regardless of their defini-tion may miss important information and decrease theprecision of the risk estimates. For this reason, wecarefully evaluated the definitions for each variable,pooling only studies using similar definitions for agiven variable. This approach leads us to suggest thatthe cut-off for ulcer size may be important and thatlarger ulcer size probably leads to a higher risk of reb-leeding. Our study also suggests that spurting and ooz-ing bleeding may have different prognostic values.Neither of these points were raised in the previousanalysis.

Many potential limitations of our meta-analysis haveto be discussed. The first is that the review included pro-spective and retrospective studies, an approach that mayhave limited the quality of data. There were two reasonsfor not including prospective studies alone. First, veryfew studies (see Table 1) were truly prospective, and byexcluding retrospective ones we would have missedimportant data. Furthermore, most of the prognosticvariables were ‘hard’ variables that are routinely collectedfor clinical reasons in emergency wards and endoscopicunits. In addition, no differences were found in the vari-ables selected as prognostic variables according towhether the study was prospective or retrospective(Table 1 and Figure 1).

A second important point is that the precision ofendoscopic evaluation both for measuring ulcer size and

for establishing the ulcer position in the duodenum islimited.59, 60 In our case, the study confirms that thesevariables have prognostic value even with the currentmeasuring methods, which are relatively imprecise. Anadditional drawback in assessing ulcer site is the risk ofa biassed assessment. In case of doubt about the positionof a duodenal ulcer during a difficult endoscopy, theendoscopist would suspect that profuse duodenal bleed-ing would come from the gastroduodenal artery and,therefore, would be located in the posterior wall. Itwould be interesting to establish whether the prognosticvalue of these variables improves as new methods forprecise positioning and measurement of endoscopiclesions become available.

Finally, a major reason for performing a meta-analysisis to avoid the problem of the power limitations of indi-vidual studies. As nonsignificant variables were not eval-uated, we could have missed some potentially prognosticvariables. However, since the objective of the analysiswas to determine the most consistent and reliable vari-ables to predict rebleeding, we were interested in vari-ables that were strong predictors of rebleedingindependently of patient population, supportive therapyand medical treatment, and even if the criteria for defin-ing the variables differed between the studies. In addi-tion, as shown in Figure 2, few other variables are likelyto have significant prognostic value. The most promising,the presence of haematemesis, was not selected in any ofthe multivariate analyses, probably because it is a surro-gate marker for haemodynamic instability. Additionally,many of the variables detected in the present review werealso prognostic in the studies that we excluded becausethey did not use endoscopic treatment or because theyincluded patients bleeding from lesions other than pepticulcer.2, 28–33, 37, 42

Since the literature review was finished, two additionalarticles evaluating the prognostic factors for rebleedinghave been published.61, 62 The study by Hu et al.61

included 175 patients and found older age >60 years,haemoglobin <8 g ⁄ dL, haematemesis or haematocheziaand injection dose >12 mL as prognostic variables. Thesecond study62 included an indeterminate number ofpatients without high risk stigmata and was not suitablefor inclusion in the review.

Future areas for research include determining the bestmethod of measuring and combining these prognosticvariables to develop a reliable score for predicting reblee-ding after endoscopic treatment, and to validate the scorein the setting of appropriately treated patients. Validatedscores would allow the evaluation of the efficacy and




cost-effectiveness of different procedures according to therisk of rebleeding of individual patients.

In conclusion, the major clinical parameters for pre-dicting rebleeding after receiving endoscopic treatmentare haemodynamic instability at admission and haemo-globin value. Major endoscopic parameters are activebleeding, large ulcer size and high-risk location. The useof these variables for stratifying risk in PUB patientsmay well improve the detection and management ofpatients at high risk for rebleeding.

ACKNOWLEDGEMENTSWe thank Michael Maudsley for his help with theEnglish. Declaration of personal interests: Xavier Calvet is

a speaker for AstraZeneca y Almirall-Prodesfarma. He isalso a consultant and has received research support fromAstraZeneca y Janssen-Cilag. Faust Feu is a speaker forAstraZeneca. He is also a consultant from AstraZeneca.Alan N. Barkun is a speaker for Olympus Corporation.He is also a consultant and has received research supportfrom Olympus Corporation and AstraZeneca. P. GarcıaIglesias, A. Villoria, D. Suarez, E. Brullet, M. Gallach andJP. Gisbert have no conflicts of interest. Declaration offunding interests: CIBERehd was funded by the Institutode Salud Carlos III. This study was funded in part byresearch grants from the Societat Catalana de Digestolo-gia and the Institutional Research Committee of the Hos-pital Parc Tauli (Sabadell).

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Meta-analysis: predictors of rebleeding after endoscopic treatment for bleeding peptic ulcer

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