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Individual NSAIDs and UpperGastrointestinal ComplicationsA Systematic Review and Meta-Analysis of ObservationalStudies (the SOS Project)

Jordi Castellsague,1 Nuria Riera-Guardia,1 Brian Calingaert,2 Cristina Varas-Lorenzo,1

Annie Fourrier-Reglat,3Federica Nicotra,4Miriam Sturkenboom5 andSusana Perez-Gutthann1,

on behalf of the investigators of the Safety of Non-Steroidal Anti-InflammatoryDrugs (SOS) Project

1 RTI Health Solutions, Barcelona, Spain

2 RTI Health Solutions, Research Triangle Park, NC, USA

3 Universite V. Segalen, Bordeaux, France

4 University Milan-Bicocca, Milan, Italy

5 Erasmus University Medical Center, Rotterdam, the Netherlands

Abstract Background:The risk of upper gastrointestinal (GI) complications associatedwith the use of NSAIDs is a serious public health concern. The risk variesbetween individual NSAIDs; however, there is little information on the risk

associated with some NSAIDs and on the impact of risk factors. These data

are necessary to evaluate the benefit-risk of individual NSAIDs for clinical

and health policy decision making. Within the European Communitys Seventh

Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs

(NSAIDs) [SOS] project aims to develop decision models for regulatory and

clinical use of individual NSAIDs according to their GI and cardiovascular

safety.

Objective:The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of

upper GI complications (UGIC) associated with the use of individual

NSAIDs, including selective cyclooxygenase-2 inhibitors.

Methods:We used the MEDLINE database to identify cohort and case-control

studies published between 1 January 1980 and 31 May 2011, providing adjusted

effect estimates for UGIC comparing individual NSAIDs with non-use of

NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual

NSAIDs overall and by dose using fixed- and random-effects methods. Sub-

group analyses were conducted to evaluate methodological and clinical

heterogeneity between studies.Results:A total of 2984 articles were identified and 59 were selected for data

abstraction. After review of the abstracted information, 28 studies met the

SYSTEMATIC REVIEW Drug Saf 2012; 35 (12): 1127-1146

0114-5916/12/0012-1127

Adis 2012 Castellsague et al., publisher and licensee Springer International Publishing AG.This is an open access article published under the terms of the Creative Commons License

Attribution-NonCommercial-NoDerivative 3.0 (http://creativecommons.org/licenses/by-nc-nd/3.0/)which permits non-commercial use, distribution, and reproduction,

provided the original work is properly cited and not altered.

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meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95%CI 0.65,

3.15) for aceclofenac to 18.45 (95%

CI 10.99, 30.97) for azapropazone. RRwas less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and

ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR

2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac

(RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), ni-

mesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70,

5.69); 45 for tenoxicam (RR 4.10; 95%CI 2.16, 7.79), naproxen (RR 4.10;

95%CI 3.22, 5.23), indometacin (RR 4.14; 95%CI 2.91, 5.90) and diflunisal

(RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43;

95%CI 5.19, 10.63), ketorolac (RR 11.50; 95%CI 5.56, 23.78) and azapro-

pazone. RRs for the use of high daily doses of NSAIDs versus non-use were23 times higher than those associated with low daily doses.

Conclusions:We confirmed variability in the risk of UGIC among individual

NSAIDs as used in clinical practice. Factors influencing findings across

studies (e.g. definition and validation of UGIC, exposure assessment, anal-

ysis of new vs prevalent users) and the scarce data on the effect of dose and

duration of use of NSAIDs and on concurrent use of other medications need

to be addressed in future studies, including SOS.

1. Background

NSAIDs are widely used for the symptomatictreatment of acute pain and chronic inflammatoryand degenerative joint diseases. However, their useis restricted by the occurrence of upper gastro-intestinal (GI) complications (UGIC) such as pep-tic ulcer perforations, obstructions and bleeding.The use of NSAIDs has been associated with a 3- to5-fold increase in the risk of UGIC.[1,2] Clinicaltrials and observational studies have shown that

the use of selective cyclooxygenase (COX)-2 inhibi-tors is associated with a lower risk of UGIC;[3-5]

however, they have been also associated withan increased risk of serious cardiovascular (CV)events.[6] Further data are necessary to quantify therisk of UGIC associated with many individualNSAIDs, including selective COX-2 inhibitors, andto evaluate the benefit-risk balance of the NSAIDsmost often used in regular clinical practice, takinginto account dose, duration and effect of other riskfactors. These data can help clinicians select

treatments for individual patients and help healthpolicy regulators assess the public health impactof therapy.

Within the European Communitys SeventhFramework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (SOS) colla-borative project started in 2008 with the goal ofdeveloping statistical and decision models to fa-cilitate regulatory and treatment decisions basedon the GI and CV safety of individual NSAIDs.One of the initial tasks of the SOS project was tosummarize the data available on the risk of GIand CV events from observational studies. In thiscontext, we conducted a systematic review and

meta-analysis of published observational studiesto provide pooled relative risks (RR) for UGICassociated with the use of individual NSAIDsversus non-use of NSAIDs. We followed theMOOSE guidelines for reporting meta-analysesof observational studies (http://www.equator-network.org/resource-centre/).

2. Materials and Methods

We performed a literature search in PubMedusing medical subject headings (MeSH) and free-text terms for individual NSAIDs and selective

1128 Castellsague et al.

Adis 2012 Castellsague et al., publ ish er and l icensee Springer In tern ationa l Publ ish ing AG. Drug Saf 2012; 35 (12)

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COX-2 inhibitors, GI disease, case-control stud-ies and cohort studies. The search was restrictedto observational studies published in the Englishlanguage between 1 January 1980 and 31 May 2011.Details of the search strategy are available inthe supplemental digital content (SDC; http://links.adisonline.com/DSZ/A78). Studies had to be(i) cohort, case-control or nested case-controlstudies; (ii) provide odds ratios or RRs of UGICcomparing individual NSAIDs with non-use ofNSAIDs; and (iii) provide effect estimates ad-

justed at least for age and sex. All titles and/or

abstracts of the articles identified were reviewedto select those potentially meeting the inclusioncriteria. Data from these articles were abstractedin a standardized database that included informa-tion on source population, inclusion and exclusioncriteria, study design, case definition and valida-tion, selection of controls, exposure definition,confounding factors and statistical analysis. Theaccuracy of the abstracted data was reviewedindependently by two of the authors (NR-G,JC). References from relevant studies and prior

meta-analyses were also reviewed. Study authorswere contacted when additional information wasneeded.[7]

The methodological quality of each study wasevaluated using the Newcastle-Ottawa Scale(NOS).[8] The NOS involves a score system inwhich the study design is evaluated on threebroad categories: (i) selection of the study groups;(ii) comparability between the study groups; and(iii) exposure/outcome ascertainment. For eachstudy, the NOS was evaluated independently by

two of the authors (NR-G and JC), and any dif-ferences were resolved by consensus.

We estimated pooled RRs for those individualNSAIDs that had effect estimates reported in atleast three different studies. Pooled RRs and 95%CIs were estimated using both the inverse-varianceLagrange fixed-effects method and the DerSimonianand Laird random-effects method.[9] We gener-ated forest plots from the random-effects models.Heterogeneity between studies was assessed bygraphical inspections of the forest plots and by

Cochrans Chi-squared (w2

) test of homogeneity,and subgroup analyses evaluating methodologicaland clinical heterogeneity between studies. Sub-

group analyses included stratification by studydesign, prior history of UGIC, bleeding complica-tions, study period and dose of NSAIDs. Pooledestimates for dose were calculated according tothe dose categorization used in each study. In thesubgroup analyses, pooled RRs were also calcu-lated for those NSAIDs with only two effect es-timates available. The Higgins inconsistency I2

statistic was used to describe the percentage of thevariability in effect estimates that is due toheterogeneity rather than chance.[10] The meta-analysis was conducted using Review Manager

(RevMan), Version 5.0.22 (The Nordic CochraneCentre, The Cochrane Collaboration, Copenhagen,Denmark, 2009).

3. Results

A total of 2984 articles on NSAIDs and GIcomplications were identified. Of these, 2974 ar-ticles were identified in the PubMed search andten additional articles were identified through thereferences of relevant studies (figure 1). The re-

view of titles and abstracts of these studies led toselect 59 articles for full data abstraction. Afterreview of the abstracted information, 28 stud-ies on the use of individual NSAIDs and the riskof UGIC met the inclusion criteria and were in-cluded in the meta-analysis.[7,11-35] The remaining31 articles were excluded for the following reasons:the reference group was other than non-use ofNSAIDs in nine studies;[36-44] the outcome wasoverall upper and lower GI complications in threestudies;[45-47] the outcome was uncomplicated upper

GI events in two studies;[48,49]

the study populationwas restricted to users of specific drugs or to patientswith specific diseases in three studies;[50-52] the studypopulation and the study period overlapped in fourstudies;[53-56] and the study design did not meet theinclusion criteria in ten studies (i.e. different typeof study or measures of association and exposureassessment).[57-66]

Selected characteristics of the 28 studies includedin the meta-analysis are summarized in table I; 3studies were cohort studies,[20,24,26] 10 were nested

case-control studies,[7,11,17-19,23,25,33,35,67] and 15were case-control studies.[12-16,21,22,27-32,34,68] Twelvestudies, all case-control studies, were field studies

Individual NSAIDs and Upper GI Complications (SOS Project) 1129


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collecting individual information by standardized

questionnaires. The 16 remaining studies usedinformation recorded in healthcare databases.Cases were defined as hospitalization or re-

ferral to a specialist for upper GI bleeding in13 studies,[12,15,16,19-22,27-30,33,34] and for bleedingand/or perforation in 15 other studies; four studiesalso included cases of uncomplicated pepticulcer.[14,17,33,68] The site of complication was de-fined as gastric and/or duodenal in all studies,and two included oesophageal complica-tions.[12,32] Most studies, both field and database

studies, required information from endoscopy orother diagnostic procedures to confirm UGIC.Six studies conducted in healthcare databases didnot conduct any validation of the cases identi-fied.[14,17-20,68] Sixteen studies reported aggregateresults for patients with and without a history ofUGIC,[7,12-14,16,20-23,28,31-34,67,68] and 12 provid-ed results for patients without a history ofUGIC;[11,15,17-19,24-27,29,30,35] the remaining studywas a case-crossover study.[14] Most studies ex-cluded subjects with a history of a known cause of

UGIC, including the use of gastrotoxic medicationsand life-threatening diseases (table II). Four stud-ies did not have any exclusion criteria.[20,22,28,34]

Among the 14 case-control studies, seven included

hospital controls;[12,13,16,21,29-31]

five included bothhospital and community controls;[22,27,28,32,34] oneincluded community controls;[15] and two werecase-crossover studies.[14,68] All case-control stud-ies were matched on age, sex (except one study[16]),hospital or geographic area, and index date. Threeof the case-control studies with hospital and com-munity controls estimated separate results for eachset of controls;[22,28,34] as results between the twosets were similar, we included in the meta-analysisresults reported using hospital controls. In cohort

studies, current use of NSAIDs was defined asthe time covered by each prescription,[20,24] andone study extended the coverage by 15 days. [26]

Most case-control studies defined current use ofNSAIDs as any use ending at the index date orwithin 7 days before the index date. A few case-control studies considered current use as thatending up to 30 days[11,13,17,19,28,35] or 90 days[18]

before the index date. Two cohort studies focusedon new users of NSAIDs,[20,26] and one nestedcase-control study provided results for both new

users and all users (incident and prevalent) ofNSAIDs.[17] In addition to age and sex, the mostfrequent confounders considered were a history

Articles identified with

PubMed search strategy

on GI events(n =2974)

Articles retrievedthrough

cross-referencing(n =10)

Articles screened

(n =2984)

Articles excluded after reviewing

titles and abstracts

(n =2925)

Articles excluded (n =31)

Other reference category (n =9) Upper and lower GI complications combined (n =3)

Uncomplicated upper GI events (n =2)

Specific populations (n =3) Same population, overlapping period (n =4) Different type of study (n =10)

Articles included in qualitative synthesis

(n =59)

Articles included in the meta-analysis(n =28)

Fig. 1. Flow diagram for identification of studies on upper gastrointestinal complications and individual NSAIDs. GI =gastrointestinal.



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Table

I.

Descriptionofobservationalstudiesontheriskofuppergastrointestinalcomplica

tionsassociatedwiththeuseofindividua

lNSAIDs

Study,y

Source

population;

studyperiod

Study

popula

tion

(N);ag

e(y)

Study

design

Typeof

endpoint

Studyen

dpoint

Case

validation

Dose

assessment

Exposure

assessment

Definitionof

curren

tusea

Mamdanietal.,

2002[20]

Ontario,

Canada;

20001

14396

9;

>65

Cohort

All

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer,upperGIb

No

No

Dispensed

prescriptions

Prescription

covera

ge

Menniti-Ippolitoetal.,

1998[24]

Umbria,Italy;

19934

20135

7;

3584

Cohort

Incident

Bleeding

,perforation

Site:gas

tric,duodenal


Review

medical

records

No

Dispensed

prescriptions

Estima

ted

prescription

covera

ge

McMahonetal.,

1997[26]

Tayside,

Scotland;

1989

15639

8;

All

Cohort

Incident

Bleeding

,perforation

Site:gas

tric,duodenal

Lesion:upperGIb

Review

medical

records

No

Dispensed

prescriptions

Prescription

covera

ge

plus15days

Helin-Salmivaara

etal.,2007[17]

Finland;

20004

50971

;

All

Nested

case-

control

Incident

Bleeding

,perforation,ulcer

Site:gas

tric,duodenal

Lesion:pepticulcer

No

No

Dispensed

prescriptions

030d

ays

Hippisley

-Coxetal.,

2005[18]

QResearch,

UK;

20004

98274

;

25+

Nested

case-

control

Incident

Bleeding

,perforation

Site:gas

tric,duodenal


No

No

Electronic

prescriptions

090d

ays

Nrgardetal.,

2004[19]

NorthJutland,

Denmark;

20002

3686;

1890

Nested

case-

control

Incident

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer,gastritis,

upperGIb

No

No

Dispensed

prescriptions

030d

ays

Castellsa

gueetal.,

2009[67]

Saskatchewan,

Canada;

19992001

20728

;

2089

Nested

case-

control

All

Bleeding

,perforation

Site:gas

tric,duodenal


Review

medical

records

Yes

Electronic

prescriptions

07da

ys

GarcaRodrguez

andBarreales,

2007[7]

THIN,UK;

20005

11561

;

4085

Nested

case-

control

All

Bleeding

,perforation

Site:gas

tric,duodenal

Lesion:pepticulcer,erosions,

inflammation

Review

computerized

information

andfreetext,

andrandom

sample

medical

records

Yes

Electronic

prescriptions

07da

ys

GarcaRodrguez

andHern

andez-Daz,

2001[23]

GPRD,UK;

19938

13605

;

4079

Nested

case-

control

All

Bleeding

,perforation

Site:gas

tric,duodenal


Review

medical

records

No

Electronic

prescriptions

06da

ys

GarcaRodrguez

etal.,1998[25]

FriuliVenezia

Giulia,Italy;

19915

21505

;

2589

Nested

case-

control

Incident

Bleeding

,perforation

Site:gas

tric,duodenal


Review

medical

records

Yes

Dispensed

prescriptions

0days

(on

dateof

event)

Continuednext

page



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TableI.C

ontd

Study,y

Source

population;

studyperiod

Study

popula

tion

(N);ag

e(y)

Study

design

Typeof

endpoint

Studyen

dpoint

Case

validation

Dose

assessment

Exposure

assessment

Definitionof

curren

tusea

GarcaRodrguez

andJick,

1994[11]

GPRD,UK;

19903

9879;

2577

Nested

case-

control

Incident

Bleeding

,perforation

Site:gas

tric,duodenal


Review

random

sample

medical

records

Yes

Electronic

prescriptions

030d

ays

Griffinet

al.,1991[33]

Tennessee

Medicaid,US;

19846

8478;

65+

Nested

case-

control

All

Bleeding

,ulcer

Site:gas

tric,duodenal,


Review

medical

records

Yes

Dispensed

prescriptions

0days

(on

dateof

event)

Perez-Gu

tthann

etal.,1997[35]

Saskatchewan,

Canada;

19826

11377

;

All

Nested

case-

control

Incident

Bleeding

,perforation

Site:gas

tric,duodenal


Review

medical

records

Yes

Dispensed

prescriptions

030d

ays

Changet

al.,2011[68]

Taiwan;2006

23million;

20+

Case-

crossover

All

Bleeding

,perforation,ulcer

Site:gas

tric,duodenal


duodenitis,upperGIb

No

Yes

Electronic

prescriptions

Prescription

covera

ge

Sakamotoetal.,

2006[15]

Selected

hospitalsin

Japan;

20024

522;

40+

Case-

control

Incident

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer,gastritis

Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Lanaset

al.,2006[16]

Selected

hospitalsin

Spain;

20014

3353;

2085

Case-

control

All

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer

Fieldstudy.

Endoscopy

required

Yes

Questionnaire

07da

ys

Laportee

tal.,

2004[21]

Selected

hospitalsin

SpainandItaly;

19982001

10006

;

>18

Case-

control

All

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer,acute

lesionso

fthegastricmucosa,

erosiveduodenitis,mixed

lesions

Fieldstudy.

Endoscopy

required

Yes

Questionnaire

07da

ys

Biskupiaketal.,

2006[14]

Outpatient

database,US;

19962004

60212

;

All

Case-

crossover

All

Bleeding

,perforation,ulcer

Site:gas

tric,duodenal


No

Lowdose

Electronic

prescriptions

90day

s

following

prescription

date

Continuednext

page



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TableI.C

ontd

Study,y

Source

population;

studyperiod

Study

popula

tion

(N);ag

e(y)

Study

design

Typeof

endpoint

Studyen

dpoint

Case

validation

Dose

assessment

Exposure

assessment

Definitionof

curren

tusea

Lanaset

al.,2003[22]

Selected

hospitalsin

Spain;

19958

8309;

All

Case-

control

All

Bleeding

Site:gas

tric,duodenal


acutelesionsofthegastric

mucosa

Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Matikaine

nand

Kangas,1996[12]

Twohospitalsin

Finland;

19923

204;

All

Case-

control

All

Bleeding

Site:oes

ophageal,gastric,

duodena

l

Lesion:oesophagitis,peptic

ulcer,erosions

Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Morideand

Abenhaim

,1994[13]

Selected

hospitalsin

Montreal,

Canada;

198890

859;

68+

Case-

control

All

Bleeding

,perforation

Site:gas

tric,duodenal


duodenitis,upperGIb

Review

medical

records

No

Dispensed

prescriptions

030d

ays

Kaufman

etal.,

1993[27]

US,

Sweden,

Hungary;

198792

1733;

1879

Case-

control

Incident

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer,gastritis

Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Langman

etal.,

1994[28]

Selected

hospitalsinthe

UK;

198791

3259;

60+

Case-

control

All

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer

Fieldstudy.

Endoscopy

required

No

Questionnaire

030d

ays

Nobilietal.,1992[29]

Hospitalin

NorthernItaly;

19878

1764;

All

Case-

control

Incident

Bleeding

Site:gas

tric,duodenal


Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Laportee

tal.,

1991[30]

Selected

hospitalsin

Spain;

19878

3557;

All

Case-

control

Incident

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer,acute

lesionso

fthegastricmucosa,

erosiveduodenitis

Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Savagee

tal.,

1993[31]

Selected

hospitalsin

Christchurch,

NewZealand;

1986

1466

All

Case-

control

All

Bleeding

,perforation

Site:gas

tric,duodenal

Lesion:pepticulcer

Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Continuednext

page



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of peptic ulcer (21 studies),[7,11,15-31,35,67] smoking(13 studies),[7,11,15,18,20,21,23,27-32] alcohol use (9 stud-ies),[7,15,19,21,27,28,30-32]use of proton-pump inhibitorsand anti-ulcer medications (11 studies),[16-23,30,67,68]

and concurrent use of medications increasing the riskof UGIC (16 studies).[7,11,15,16,19-21,23,27,29-31,33,35,67,68]

The quality of the studies measured with the NOSwas, in general, very good: for the selection com-ponent, 12 studies had the maximum score of4[7,11,15,22-25,32,33,35,67,68] and 13 studies had thenext highest score of 3;[13,14,16-19,21,26,28,29,30,32,34]

for comparability, 24 studies had the maximum

score of 2;[7,11,14-19,21-33,35,67,68]

and for the exposure/

outcome component, 14 studies had the maximumscore of 3[7,11,13,17-19,23-26,33,35,67,68] and 10 studieshad the next highest score of 2.[12,14,16,20,21,28-30,32,34]

The studies included in the meta-analysis al-lowed us to estimate pooled RRs for the current useof 16 different NSAIDs (table III and figure 2).Forest plots for each individual NSAID are avail-able in the SDC. Using random-effects models,pooled RRs ranged from 1.43 (95%CI 0.65, 3.15)for aceclofenac to 18.45 (95%CI 10.99, 30.97) for

azapropazone. Pooled RR was less than 2 for ace-clofenac, celecoxib and ibuprofen; between 2 andless than 4 for rofecoxib, sulindac, diclofenac, me-loxicam, nimesulide and ketoprofen; between 4 andless than 5 for tenoxicam, naproxen, indometacinand diflunisal; and greater than 5 for piroxicam,ketorolac and azapropazone. Pooled RRs fromstudies providing results for patients without ahistory of UGIC were similar to those from theoverall analysis except for naproxen (more than10% change), 3.10 (95% CI 2.45, 3.91) and diclo-

fenac, 3.76 (95% CI 2.71, 5.21). Data in patientswith a history of peptic ulcer disease were availableonly for celecoxib (two studies) and rofecoxib (onestudy).[67,68] The pooled RR for celecoxib in thispopulation was 1.50 (95%CI 1.16, 1.94).

Pooled RRs from case-control studies werehigher than those from cohort studies for allNSAIDs except ibuprofen, ketorolac and sulindac.In general, pooled RRs from fixed-effects modelswere slightly lower than those from random-effects models. In general, there was significant

heterogeneity between studies, which decreasedin the subsequent subgroup analysis exploringmethodological and clinical diversity.Ta

bleI.C

ontd

Study,y

Source

population;

studyperiod

Study

popula

tion

(N);ag

e(y)

Study

design

Typeof

endpoint

Studyen

dpoint

Case

validation

Dose

assessment

Exposure

assessment

Definitionof

curren

tusea

Henryet

al.,1993[32]

Selected

hospitalsin

Newcastle,

Australia;

19859

1912;

All

Case-

control

All

Bleeding

,perforation

Site:oes

ophageal,gastric,

duodena

l


inflammation,upperGIb

Fieldstudy.

Endoscopy

required

No

Questionnaire

07da

ys

Somervilleetal.,

1986[34]

Nottingham

Universityand

CityHospitals,

UK;

19835

667;

60+

Case-

control

All

Bleeding

Site:gas

tric,duodenal

Lesion:pepticulcer

Fieldstudy.

Endoscopy

required

No

Questionnaire

0days

(on

dateof

event)

a

Numb

erofdaysbeforetheindexdateifnotde

finedotherwise.

b

Uppe

rGIreferstodiagnosisofmelena,haem

atemesisorhaemorrhageoftheintestinaltractunspecified.

GI=gastrointestinal;GPRD=GeneralPracticeRe

searchDatabase;THIN=TheHealthImprovementNetwork.



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Table

II.

Exclusionsappliedinobservationalstud

iesontheriskofuppergastrointestinalc

omplicationsa

Study,y

Priorpeptic

ulcerdisease

Malignancy

Oesophageal

varices

Mallory-

Weiss

syndrome

Alcohol-

related

disorders

Liver

diseases

Coagulopathies

Useof

anticoagulants

Nursing

home

residence

O

ther

Mamdanietal.,2002[20]

Menniti-Ippolitoetal.,

1998[24]

Excl.

Exc

l.

Excl.

Excl.

Excl.

McMahonetal.,1997[26]

Excl.

E

xcl.b

Helin-Salmivaaraetal.,

2007[17]

Excl.

Exc

l.

Excl.

Excl.

Hippisley

-Coxetal.,

2005[18]

Excl.

Nrgardetal.,2004[19]

Excl.

Castellsa

gueetal.,2011[67]

Exc

l.

Excl.

Excl.

Excl.

Excl.

Excl.

E

xcl.c

GarcaRodrguezand

Barreales,2007[7]

Exc

l.

Excl.

Excl.

Excl.

Excl.

Excl.

GarcaRodrguezand

Hernandez-Daz,2001[23]

Exc

l.

Excl.

Excl.

Excl.

Excl.

Excl.

GarcaRodrguezetal.,

1998[25]

Excl.

Exc

l.

Excl.

Excl.

Excl.

Excl.

Excl.

E

xcl.d

GarcaRodrguezandJick,

1994[11]

Excl.

Exc

l.

Excl.

Excl.

Excl.

Excl.

Excl.

Griffinet

al.,1991[33]

Exc

l.e

Excl.e

Perez-Gu

tthannetal.,

1997[35]

Excl.

Exc

l.

Excl.

Excl.

Excl.

Excl.

Excl.

Changet

al.,2011[68]

Exc

l.

Excl.

Sakamotoetal.,2006[15]

Excl.

Exc

l.

Excl.

Excl.

Excl.

Lanaset

al.,2006[16]

Exc

l.

Excl.

Excl.

Laportee

tal.,2004[21]

Exc

l.

Excl.

Excl.

Excl.

Excl.

Biskupiaketal.,2006[14]

Exc

l.

Excl.

E

xcl.f

Lanaset

al.,2003[22]

Matikaine

nandKangas,

1996[12]

Exc

l.

Excl.

Excl.

E

xcl.g

MorideandAbenhaim,

1994[13]

Exc

l.

Excl.

Excl.

Kaufman

etal.,1993[27]

Excl.

Excl.

Excl.

Excl.

Excl.

Langman

etal.,1994[28]

Nobilietal.,1992[29]

Excl.

Exc

l.

Excl.

Excl.

Excl.

Excl.

Excl.

Continuednext

page



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Pooled RRs for the effect of daily dose wereestimated for eight different NSAIDs. Cut-offvalues used in each study to define the daily doseof each NSAID are presented in table IV. Varia-tions in cut-off values were, in general, small ex-cept for those used for ibuprofen (200 mg) andnaproxen (220 mg) in one study,[14] and for ibu-profen (

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TableIII.

Contd

Study,y

NSAID

Ibuprofen

Naproxen

Diclofenac

Indometacin

Piroxicam

Ketoprofen

PooledR

R

Random

effects

1.60(1.09

,2.33)

4.73(2.92,7.68)

3.37(2.55,

4.46)

4.24(2.42,7.45)

8.32(4.32,16.03)

4.25(2.06,8.76)

Fixedeffects

1.74(1.60

,1.88)

2.87(2.54,3.25)

2.36(2.23,

2.50)

2.27(1.94,2.66)

3.62(3.21,4.07)

2.35(1.97,2.79)

Heteroge

neity(w2

p-value)

art%3A10.1007%2FBF03261999

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