Papers
`
`5 Thelin A. Hip joint arthrosis: an occupational disorder amongst farmers.
`Am J Ind Med 1990;18:339›43.
`6 Croft P, Coggon D, Cruddas M, Cooper C. Osteoarthritis of the hip: an
`occupational disease in farmers. BMJ 1992;304:1269›72.
`7 O’Brien T, Moran R, McGoldrick F. The aetiology of degenerative disease
`of the hip. Ir J Med Sci 1989;158:63›6.
`8 Stecher RM. Heberden’s nodes. Hereditary in hypertrophic arthritis of
`the finger joints. Am J Med Sci 1941;201:801›9.
`9 Spector TD, Cicuttini FM, Baker J, Loughlin J, Hart DJ. Genetic influences
`on osteoarthritis in women: a twin study. BMJ 1996;312:940›4.
`10 Felson DT, Couropmitree N, Chaisson C, Hannan MT, Zhang Y,
`McAlindon TE, et al. Evidence for a Mendelian gene in a segregation
`analysis of generalised osteoarthritis. Arthritis Rheum 1998;41:1064›71.
`11 Hirsch R, Lethbridge›˙ejku M, Hanson R, Scott WW, Reichle R, Plato
`CC, et al. Familial aggregation of osteoarthritis. Data from the Baltimore
`longitudinal study on aging. Arthritis Rheum 1998;41:1227›32.
`12 Lindberg H. Prevalence of primary coxarthrosis in siblings of patients
`with primary coxarthrosis. Clin Orthop 1986;203:273›5.
`13 Chitnavis J, Sinsheimer J, Clipsham K, Loughlin J, Sykes B, Burge P, et al.
`Genetic influences in end›stage osteoarthritis. J Bone Joint Surg (Br)
`1997;79›B(4):660›4.
`14 Fox K, Hochberg MC, Resnik C, Kenzora J, Hebel R, Zimmerman S, et al.
`Severity of radiographic findings in hip osteoarthritis associated with
`total hip arthroplasty. J Rheumatol 1996;23:693›7.
`15 O’Reilly S, Doherty S, Johnson S, Muir K, Doherty M. Screening for hand
`osteoarthritis using a postal survey. Osteoarthritis Cartilage 1999;7:461›5.
`
`16 Altman RD, Hochberg MC, Murphy WA, Wolfe F. Atlas of individual
`osteoarthritis. Osteoarthritis Cartilage
`radiographic
`features
`in
`1995;3(suppl A):3›70.
`17 Croft P, Cooper C, Wickham C, Coggon D. Defining osteoarthritis of the
`hip for epidemiologic studies. Am J Epidemiol 1990;132:514›22.
`18 Cohen J. A coefficient of agreement for nominal scales. Educ Psychol Meas
`1960;20:37›46.
`19 Bland J, Altman DG. Statistical methods for assessing agreement between
`two methods of clinical assessment. Lancet 1986;i:307›10.
`20 Roach KE, Persky V, Miles T, Budiman›Mak E. Biomechanical aspects of
`occupation and osteoarthritis of the hip: a case›control study. J Rheumatol
`1994;21:2334›40.
`21 Tepper S, Hochberg MC. Factors associated with hip osteoarthritis: data
`from the first national health and nutrition examination survey
`(NHANES›I). Am J Epidemiol 1993;137:1081›8.
`22 Danielsson L. Incidence and prognosis of coxarthrosis. Acta Orthop Scand
`Suppl 1964;66:1›114.
`23 Jorring K. Osteoarthritis of the hip. Acta Orthop Scand 1980;51:523›30.
`24 Danielsson L, Lindberg H, Nilsson B. Prevalence of coxarthrosis. Clin
`Orthop 1984;191:110›5.
`25 Smith R, Egger P, Coggon D, Cawley MID, Cooper C. Osteoarthritis of
`the hip joint and acetabular dysplasia in women. Ann Rheum Dis
`1995;54:179›81.
`
`(Accepted 15 August 2000)
`
`Risk of gastrointestinal haemorrhage with long term use
`of aspirin: meta›analysis
`Sheena Derry, Yoon Kong Loke
`
`Abstract
`Objectives To assess the incidence of gastrointestinal
`haemorrhage associated with long term aspirin
`therapy and to determine the effect of dose reduction
`and formulation on the incidence of such
`haemorrhage.
`Design Meta›analysis of 24 randomised controlled
`trials (almost 66 000 participants).
`Intervention Aspirin compared with placebo or no
`treatment, for a minimum of one year.
`Main outcome measures Incidence of
`gastrointestinal haemorrhage.
`Results Gastrointestinal haemorrhage occurred in
`2.47% of patients taking aspirin compared with 1.42%
`taking placebo (odds ratio 1.68; 95% confidence
`interval 1.51 to 1.88); the number needed to harm
`was 106 (82 to 140) based on an average of 28
`months’ therapy. At doses below 163 mg/day,
`gastrointestinal haemorrhage occurred in 2.30% of
`patients taking aspirin compared with 1.45% taking
`placebo (1.59; 1.40 to 1.81). Meta›regression showed
`no relation between gastrointestinal haemorrhage
`and dose. For modified release formulations of aspirin
`the odds ratio was 1.93 (1.15 to 3.23).
`Conclusions Long term therapy with aspirin is
`associated with a significant increase in the incidence
`of gastrointestinal haemorrhage. No evidence exists
`that reducing the dose or using modified release
`formulations would reduce the incidence of
`gastrointestinal haemorrhage.
`
`Introduction
`The use of aspirin in the prevention of cardiovascular
`disease is now well established; an estimated 50 million
`Americans have started taking aspirin over the past
`
`BMJ VOLUME 321 11 NOVEMBER 2000 bmj.com
`
`two decades.1 However, aspirin causes haemorrhagic
`complications. A systematic review in 1993 showed
`that
`the risk of gastrointestinal haemorrhage was
`significantly increased by long term aspirin.2 Only four
`of the 21 trials included in that review, however, used
`doses below 300 mg a day. Since then, new data have
`become available from eight studies involving 24 964
`patients taking aspirin doses of 50›162.5 mg a day.
`Recent trends towards the use of lower doses have
`been driven by the belief that these offer a better safety
`profile while retaining equivalent therapeutic efficacy.
`Is there evidence that the risk of gastrointestinal haem›
`orrhage is substantially reduced at lower doses, and if
`so, by how much? Expensive “modified release” formu›
`lations have been developed in an attempt to reduce
`the likelihood of adverse gastrointestinal effects. What
`is the evidence that they do so?
`We reviewed the safety of aspirin, studying the
`effect of dose and formulation and incorporating the
`new data from the eight studies mentioned above.
`
`Methods
`The review was conducted using a defined protocol.
`
`Inclusion criteria
`Studies—We included reports if they were full jour›
`nal publications of randomised controlled trials of
`aspirin used as an antiplatelet agent. Trials were
`excluded if the term “randomised” was not specifically
`mentioned in the report or if the investigators clearly
`used non›random allocation, such as by date of birth.
`Abstracts, review articles, case reports, clinical observa›
`tions, and unpublished data were not included. Trials
`with fewer than 50 patients in each arm were not
`included in the analysis because they were unlikely to
`be able to detect uncommon or rare adverse effects.3
`
`Editorial by TramŁr
`
`Department of
`Clinical
`Pharmacology,
`University of
`Oxford, Radcliffe
`Infirmary, Oxford
`OX2 6HE
`Sheena Derry
`research assistant
`Yoon Kong Loke
`clinical lecturer in
`clinical pharmacology
`
`Correspondence to:
`Y K Loke
`yoon.loke@clinpharm.
`ox.ac.uk
`
`BMJ 2000;321:1183–7
`
`A further table and
`figure plus the
`references for the
`included studies
`appear on the
`BMJ’s website
`
`1183
`
`Page 1 of 5
`
`Patent Owner Ex. 2013
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`Papers
`
`We did not include studies designed to assess the
`effects of aspirin in special groups—such as pregnant
`women, children, and patients with pre›existing
`platelet disorders.
`Intervention—We included trials in which patients in
`one treatment arm were allocated to oral aspirin alone
`and patients in the control arm to either placebo or no
`treatment, provided that the scheduled duration of
`treatment was at least 12 months. Crossover studies
`and those in which aspirin was used in conjunction
`with other antiplatelet agents or anticoagulants were
`excluded. Trials that compared aspirin at different
`doses or with other antiplatelet agents or anticoagu›
`lants, without a placebo or “no treatment” control arm,
`were also excluded.
`Outcome measures—Only
`that provided
`trials
`numerical data on all gastrointestinal haemorrhages
`in both the treated and the control group were
`included. If specific terms were used to describe
`bleeding complications, we accepted data on patients
`with “haematemesis” or “melaena,” or with both of
`these, but not with “proctorrhagia.” We did not use
`data from trials that reported only on selected catego›
`ries of gastrointestinal haemorrhage—for example,
`major bleeds and patients needing admission to
`hospital or blood transfusion—as trials varied consid›
`erably in their definition and reporting of such
`categories.4
`
`Search strategy
`The search was performed separately by each author.
`Relevant trials were identified through a combination
`of electronic searching and manual checking of
`reference lists from previous review papers and
`retrieved trials. We applied no language restrictions.
`We concentrated specifically on selecting trials
`from a detailed list of over 200 antiplatelet studies
`
`Characteristics of studies included in meta›analysis
`
`identified in a systematic review that included trials
`published up to 1993.5 In view of the comprehensive
`search strategies used in that review, we chose not
`to repeat an electronic search for most of this period
`but carried out a search of Medline and Embase
`for 1990›9 to identify new trials and to provide a
`three year overlap. We found no discrepancy between
`the two lists of the trials identified in the overlap
`period.
`We used a sensitive search string for randomised
`controlled trials, based on that of
`the Cochrane
`Collaboration,6 in combination with the following free
`text terms: “aspirin” or “acetylsalicylic*” or “salicylic*”.
`This gave a yield of over 7000 hits on Medline and over
`10 000 hits on Embase for 1990›9. We made no
`attempt to limit the yield by introducing terms for
`adverse effects or haemorrhage as we knew that this
`strategy would lead to the loss of relevant trials.7
`
`Appraisal of study quality and data abstraction
`We did not anonymise the reports before assessment.
`All potentially relevant studies were checked inde›
`pendently by both reviewers to determine eligibility for
`inclusion and to extract data. A list of trials which were
`excluded is available from the authors.
`We sought information on participants, blinding,
`type of control, assessment of compliance, and
`duration of treatment and follow up, in addition to data
`on the numbers of participants with and without
`gastrointestinal haemorrhage. We also recorded the
`formulation of aspirin used—modified release or
`standard. Any discrepancies were resolved by discus›
`sion.
`
`Statistical analysis
`Pooled odds ratios and heterogeneity were analysed
`using the RevMan program, version 4.04, with Meta
`
`Average treatment
`Indication for aspirin therapy
`duration (months)
`Dose (mg/day)
`Aspirin formulation
`Year
`Study
`Diener et alw1 w2
`Transient ischaemic attack or stroke
`24
`50
`Unspecified
`1996
`Hansson et alw3
`Hypertension
`45
`75
`Standard
`1998
`Petersen et alw4
`Atrial fibrillation
`24
`75
`Unspecified
`1989
`SALTw5
`Transient ischaemic attack or stroke
`32
`75
`Standard
`1991
`TPTw6
`Cardiovascular risk factors
`81
`75
`Modified release
`1998
`Wallentinw7
`Unstable angina
`12
`75
`Unspecified
`1991
`Silagy et alw8
`Primary prevention
`12
`100
`Standard
`1993
`USPHSw9
`Primary prevention
`60
`162.5
`Standard
`1989
`EAFTw10
`Transient ischaemic attack or stroke
`28
`300
`Unspecified
`1993
`Elwood et alw11
`Myocardial infarction
`12
`300
`Standard
`1974
`UK›TIAw12
`Transient ischaemic attack
`48
`300, 1200
`Various
`1991
`Gavaghan et alw13
`Coronary artery bypass grafting
`12
`324
`Standard
`1991
`Olivotto et alw14
`Breast cancer
`12
`325
`Modified release
`1996
`Elwood et alw15
`Myocardial infarction
`12
`900
`Standard
`1979
`CDPAw16
`Myocardial infarction
`22
`972
`Unspecified
`1976
`PARISw17
`Myocardial infarction
`41
`972
`Unspecified
`1980
`Hess et alw18
`Peripheral vascular disease
`24
`990
`Unspecified
`1985
`AMISw19
`Myocardial infarction
`36
`1000
`Standard
`1980
`Breddin et alw20
`Myocardial infarction
`24
`1000
`Modified release
`1980
`CCSGw21
`Transient ischaemic attack
`26
`1300
`Standard
`1978
`Fields et alw22
`Transient ischaemic attack
`24
`1300
`Standard
`1977
`Fields et alw23
`Transient ischaemic attack
`24
`1300
`Standard
`1978
`Brittonw24
`Stroke
`24
`1500
`Modified release
`1987
`Ehresman et alw25
`Peripheral vascular disease
`12
`1500
`Modified release
`1977
`SALT=Swedish aspirin low dose trial; TPT=thrombosis prevention trial; USPHS=US physicians health study; EAFT=European atrial fibrillation trial; UK›TIA=UK
`transient ischaemic attack aspirin trial; CDPA=coronary drug project aspirin study; PARIS=persantine›aspirin reinfarction study; AMIS=aspirin myocardial infarction
`study; CCSG=Canadian Cooperative Study Group.
`
`1184
`
`BMJ VOLUME 321 11 NOVEMBER 2000 bmj.com
`
`Page 2 of 5
`
`Patent Owner Ex. 2013
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`Study
`
`Aspirin (50 – 162.5 mg/day)
`
`No of subjects/Total No in study
`Treatment
`Control
`
`Peto odds ratio
`(95% confidence interval, fixed)
`
`Weight (%)
`
`Peto odds ratio
`(95% confidence interval, fixed)
`
`Papers
`
`Diener et alw1 w2
`25/1649
`Hansson et alw3
`107/9399
`Petersen et alw4
`1/336
`SALTw5
`11/676
`TPTw6
`22/1268
`Wallentinw7
`0/399
`Silagy et alw8
`6/200
`USPHSw9
`402/11 037
`574/24 964
`Subtotal (95%CI)
`c 2=8.41 (df=6, P=0.21; Z=7.02, P<0.0001)
`
`Aspirin (162.5 – 1500 mg/day)
`
`EAFTw10
`10/404
`Elwood et alw11
`0/615
`UKTIAw12
`64/1621
`Gavaghan et alw13
`2/127
`Olivotto et alw14
`0/93
`Elwood et alw15
`8/832
`CDPAw16
`23/727
`PARISw17
`52/810
`Hess et alw18
`4/80
`AMISw19
`75/2267
`Breddin et alw20
`3/317
`CCSGw21
`0/144
`Fields et alw22
`1/88
`Fields et alw23
`2/65
`Brittonw24
`13/253
`Ehresman et alw25
`1/215
`258/8658
`Subtotal (95%CI)
`c 2=11.65 (df=13, P=0.56; Z=6.15, P<0.0001)
`
`19/1649
`55/9391
`0/336
`4/684
`10/1272
`0/397
`0/200
`274/11 034
`362/24 963
`
`6/378
`0/624
`9/814
`0/110
`0/93
`4/850
`13/727
`10/406
`1/80
`45/2257
`0/309
`2/139
`0/90
`0/60
`8/252
`2/213
`100/7402
`
`3.5
`12.9
`0.1
`1.2
`2.5
`0.0
`0.5
`52.6
`73.3
`
`1.3
`0.0
`5.1
`0.2
`0.0
`1.0
`2.8
`4.2
`0.4
`9.4
`0.2
`0.2
`0.1
`0.2
`1.6
`0.2
`26.7
`
`1.32 (0.73 to 2.39)
`1.91 (1.40 to 2.60)
`7.39 (0.15 to 372.41)
`2.60 (0.94 to 7.19)
`2.14 (1.07 to 4.30)
`Not estimable
`7.58 (1.51 to 37.93)
`1.48 (1.27 to 1.72)
`1.59 (1.40 to 1.81)
`
`1.56 (0.58 to 4.19)
`Not estimable
`2.66 (1.62 to 4.35)
`6.51 (0.40 to 105.53)
`Not estimable
`2.00 (0.64 to 6.22)
`1.77 (0.91 to 3.42)
`2.26 (1.32 to 3.89)
`3.42 (0.58 to 20.22)
`1.66 (1.16 to 2.39)
`7.25 (0.75 to 69.97)
`0.13 (0.01 to 2.08)
`7.56 (0.15 to 381.07)
`6.95 (0.43 to 112.62)
`1.64 (0.68 to 3.91)
`0.51 (0.05 to 4.90)
`1.96 (1.58 to 2.43)
`
`832/33 622
`Total (95%CI)
`c 2=22.73 (df=20, P=0.30; Z=9.18, P<0.0001)
`
`462/32 365
`
`100.0
`
`1.68 (1.51 to 1.88)
`
`5
`0.1
`0.2
`Favours control
`Favours treatment
`Fig 1 Peto odds ratio for gastrointestinal haemorrhage with aspirin. SALT=Swedish aspirin low dose trial; TPT=thrombosis prevention trial;
`USPHS=US physicians health study; EAFT=European atrial fibrillation trial; UK›TIA=UK transient ischaemic attack aspirin trial; CDPA=coronary
`drug project aspirin study; PARIS=persantine›aspirin reinfarction study; AMIS=aspirin myocardial infarction study; CCSG=Canadian Cooperative
`Study Group
`
`10
`
`1
`
`View 4.0 and MetaView 3.01. We used the Peto fixed
`effects model to calculate the pooled odds ratios as this
`is the most appropriate model for rare events.8 Closely
`similar results were obtained with the random effects
`model. Meta›regression is a technique used to assess
`statistically whether specific factors (covariates) influ›
`ence the magnitude of effect across studies. Random
`effects meta›regression was performed with the STATA
`“metareg” command.9
`The number needed to harm (with 95% confidence
`intervals) was calculated by applying the calculated
`odds ratio to the pooled control event rate. In our
`review the number needed to harm is the estimated
`number of patients who need to be treated with
`aspirin—rather than with placebo or no treatment—for
`one additional patient to be harmed by a gastro›
`intestinal haemorrhage.
`
`Results
`We identified 24 randomised controlled trials of
`aspirin that fulfilled our inclusion criteria (table). (A
`further table and the references for the 24 trialsw1›w25 are
`on the BMJ’s website.) The 65 987 participants were
`
`predominantly male (74%) and middle aged. Doses of
`aspirin used were 50›1500 mg/day for a mean
`duration of 28 months.
`Indications
`for aspirin
`extended from primary prevention in “healthy”
`individuals to secondary prophylaxis after stroke. In all
`trials patients were excluded if they had a history of
`peptic ulcer, previous gastrointestinal haemorrhage, or
`any other contraindication to aspirin.
`All 24 trials were double blind and placebo
`controlled. Fourteen trials had sufficient data to
`suggest that adequate concealment of allocation had
`taken place; in the other trials this was unclear. The
`number of patients lost to follow up was reported in 16
`trials, only one of which failed to achieve over 90% fol›
`low up.
`Figure 1 shows the results of our meta›analysis.
`Overall, gastrointestinal haemorrhage occurred in
`2.47% of the patients taking aspirin compared with
`1.42% of those taking placebo. The pooled odds ratio
`for gastrointestinal haemorrhage with aspirin was
`1.68 (95% confidence
`interval 1.51 to 1.88;
`P < 0.0001), and the number needed to harm based on
`an average of 28 months of aspirin was 106 (82 to
`
`BMJ VOLUME 321 11 NOVEMBER 2000 bmj.com
`
`1185
`
`Page 3 of 5
`
`Patent Owner Ex. 2013
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`10
`
`5
`
`2
`1
`0.2
`
`Odds ratio for gastrointestinal haemorrhage
`
`Papers
`
`75
`
`300
`
`1500
`Daily aspirin dose (mg)
`Fig 2 Meta›regression of Peto odds ratio for gastrointestinal
`haemorrhage against dose of aspirin (size of circle is proportional to
`size of trial)
`
`1000
`
`Two of the trialsw3 w9 were much larger than the
`others, and to be sure that neither unduly influenced
`the results, we performed a sensitivity analysis.
`Omitting either or both trials from the meta›analysis
`did not significantly change our findings. Only five
`trials, with 4298 participants, specifically stated that
`modified release formulations of aspirin were used
`with daily doses of 75›1500 mg.w6 w14 w20 w24 w25 The odds
`ratio for gastrointestinal haemorrhage in these five
`trials was 1.93 (1.15 to 3.23).
`
`Discussion
`Long term aspirin therapy, even at a low dose, carries a
`risk of gastrointestinal haemorrhage, with a number
`needed to harm per year of 248. Although it would be
`preferable, for the purposes of comparison, to have a
`number needed to harm and a number needed to treat
`from the same trial or review, this may not always be
`feasible. It is possible, however, to obtain some idea of
`the trade›off between benefit and harm when using
`aspirin in patients with different cardiovascular risk
`levels by weighing up the pooled estimate of the
`number needed to harm against the number needed to
`treat from individual trials.
`for
`stroke,
`In the secondary prevention of
`example, the number needed to treat per year with
`aspirin to prevent a further event was 106.w5 This
`means that if aspirin was used in patients with stroke
`who had similar baseline risks to those above, at least
`two recurrent strokes could be prevented at the cost of
`one gastrointestinal haemorrhage. The benefits of
`aspirin are less marked, however,
`in primary
`prevention of myocardial
`infarction—in the US
`physicians study, the number needed to treat per year
`was 555,w9 whereas the number needed to treat per
`year in hypertensive patients was 794.w3 Aspirin use
`in primary prevention could, depending on the base›
`line risks of
`the patients, cause two or
`three
`gastrointestinal haemorrhages for each myocardial
`infarction prevented.
`As there are relatively few deaths after gastro›
`intestinal haemorrhage (estimated death rate 12%10)
`compared with myocardial infarction, such a trade›off
`may be considered worth while. Doctors and patients
`involved in making decisions about aspirin therapy
`need to consider carefully whether the inconvenience
`of long term therapy and the associated risk of gastro›
`intestinal haemorrhage
`are outweighed by
`the
`potential cardiovascular benefits. This is particularly so
`for those at low absolute risk of cardiovascular events
`(with correspondingly high numbers needed to treat),
`in whom the likelihood of harm is greater than that of
`therapeutic benefit (as shown in the example above for
`hypertensive patients).
`Although doctors have hoped that changes in the
`dose or formulation of aspirin might reduce the prob›
`lem of gastrointestinal haemorrhage, the results of this
`meta›analysis do not suggest that either approach
`offers clear benefits. Our findings are supported by
`those of two recent case›control studies, in which aspi›
`rin increased the risk of gastrointestinal haemorrhage,
`despite the use of low dose or modified release formu›
`lations.11 12 The results of our meta›regression are com›
`patible with those of a large Dutch trial of transient
`ischaemic attack in which no significant difference in
`
`140). We found no evidence of significant heterogen›
`eity between the trials.
`Current clinical practice favours the use of lower
`doses of aspirin, and to increase the relevance of our
`findings we analysed separately the eight trials that
`used doses of 50›162.5 mg/day in 49 927 participants.
`Gastrointestinal haemorrhage occurred in 2.30% of
`those taking aspirin compared with 1.45% taking
`placebo. Even at
`these lower doses, aspirin was
`associated with a significantly increased rate of gastro›
`intestinal haemorrhage compared with placebo, with a
`pooled odds ratio of 1.59 (1.40 to 1.81; P < 0.0001).
`We performed meta›regression to test for a linear
`relation between daily dose of aspirin and risk of
`gastrointestinal haemorrhage (fig 2 ).The analysis gave
`a pooled odds ratio of 1.015 (0.984 to 1.047) per
`100 mg dose reduction, with an estimated relative
`reduction in the incidence of gastrointestinal haemor›
`rhage of 1.5% per 100 mg reduction of dose, but this
`was not significant (P = 0.3).
`
`What is already known on this topic
`
`Aspirin is widely used to prevent and treat
`cardiovascular disease but carries an increased risk
`of gastrointestinal haemorrhage
`
`Despite the lack of concrete evidence, lower doses
`and modified release formulations of aspirin have
`been used in the hope of reducing this risk
`
`Data from several trials of low dose aspirin have
`become available recently
`What this study adds
`
`About 1 in 100 patients taking aspirin over a
`28 month period will experience a gastrointestinal
`haemorrhage
`
`No evidence exists that dose reduction or the use
`of modified release formulations significantly
`lowers the risk of gastrointestinal haemorrhage
`
`Patients and doctors need to consider the trade›off
`between the benefits and harms of long term
`treatment with aspirin
`
`1186
`
`BMJ VOLUME 321 11 NOVEMBER 2000 bmj.com
`
`Page 4 of 5
`
`Patent Owner Ex. 2013
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`Papers
`
`the rate of gastrointestinal haemorrhage was found
`between two different doses of aspirin.13 In this study,
`aspirin was efficacious at a dose of 30 mg a day, but a
`threshold dose for either the therapeutic or adverse
`effects of aspirin has yet to be established, and further
`attempts at dosage reduction might compromise
`therapeutic efficacy before adverse effects are elimi›
`nated completely.
`Insufficient evidence exists to support the view that
`modified release formulations are safer, in terms of
`gastrointestinal haemorrhage, than standard formula›
`tions. Here we have studied the effect of dose and for›
`mulation on the incidence of gastrointestinal haemor›
`rhage only;
`it may be that other
`symptomatic
`gastrointestinal adverse effects, such as nausea and epi›
`gastric pain, can be significantly reduced.13
`The incidence of gastrointestinal haemorrhage
`with aspirin is relatively low, and to avoid factors that
`could have led us to underestimate the risk, we set
`inclusion and exclusion criteria such that only trials of
`a certain quality, with adequate numbers and follow up,
`would be selected. Although there is some asymmetry
`(see figure on BMJ’s website),
`in the funnel plot
`suggesting the possibility of selection bias, adjustment
`for the likely effect of bias using ‘‘trim and fill” gave a
`pooled odds ratio of 1.62, which is only a slight change
`from our estimate of 1.68.14 Our meta›analysis seems
`reasonably robust to the asymmetry observed in the
`funnel plot.
`the findings of our study are
`We believe that
`relevant to everyday practice. No significant heterogen›
`eity was found, even though the studies we analysed
`encompassed a broad selection of patients with varying
`clinical indications. All the trials excluded patients at
`increased risk of gastrointestinal haemorrhage or with
`aspirin intolerance, but this is consistent with current
`advice on the use of aspirin and does not invalidate the
`relevance of our findings. Nevertheless, aspirin is avail›
`able over the counter, and the risk of gastrointestinal
`haemorrhage could be higher in patients who take it
`without consulting a doctor.
`
`We thank Jon Deeks for encouragement and statistical support,
`particularly with the meta›regression; Alex Sutton for helping
`
`with the funnel plot; and Jeff Aronson for help with the manu›
`script.
`Contributors: YKL conceptualised the review, developed the
`protocol, provided clinical interpretation of the trials, abstracted
`data, and undertook most of the statistical analyses. SD contrib›
`uted to the development of the protocol, abstracted data, and
`prepared the manuscript. Both authors will act as guarantors for
`the paper.
`Funding: SD was supported by a grant from the Sir Jules
`Thorne Trust.
`Competing interests: None declared.
`
`1 Bayer Pharmaceuticals. Facts about aspirin. www.wonderdrug.com/press/
`factsheets/aspirin_fact_sheet.pdf (accessed 28 July 2000).
`2 Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal toxicity of aspi›
`rin: an overview of randomised controlled trials. Br J Clin Pharmacol
`1993;35:219›26.
`3 Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse
`events that have not yet occurred: a statistical reminder. BMJ 1995;311:
`619›20.
`4 Zanchetti A, Hansson L. Risk of major gastrointestinal bleeding with
`aspirin. Lancet 1999;353:148›50.
`5 Collaborative overview of randomised trials of antiplatelet therapy—I:
`Prevention of death, myocardial infarction, and stroke by prolonged
`antiplatelet therapy in various categories of patients. Antiplatelet Trialists’
`Collaboration. BMJ 1994;308:81›106.
`6 Clarke M, Oxman AD, eds. Optimal search strategies for RCTs. Cochrane
`reviewers’ handbook 4.0 (appendix 5c). In: Review Manager (RevMan)
`[computer program]. Version 4.0. Oxford: Cochrane Collaboration,
`1999.
`7 Loke YK, Edwards J, Derry S. Conventional search strategies cannot eas›
`ily identify those trials of drug therapy which provide quantitative adverse
`effects data [abstract]. Proceedings of the VII Cochrane Colloquium, Rome
`1999. www.clinpharm.ox.ac.uk/SearchStrategy.htm (accessed 28 July
`2000).
`8 Deeks JJ, Bradburn MJ, Localio R, Berlin J. Much ado about nothing:
`meta›analysis for rare events [abstract]. Proceedings of 2nd symposium on
`systematic reviews: beyond the basics, Oxford 1999. www.ihs.ox.ac.uk/csm/
`talks.html#p23 (accessed 28 July 2000).
`9 Sharp S. she 23: meta›analysis regression. Stata Technical Bulletin
`1998;42:16›22.
`10 Tramer MR, Moore RA, Reynolds DJM, McQuay HJ. Quantitative estima›
`tion of rare adverse events which follow a biological progression: a new
`model applied to chronic NSAID use. Pain 2000;85:169›82.
`11 Weil J, Colin›Jones D, Langman M, Lawson D, Logan R, Murphy M, et al.
`Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995;310:827›
`30.
`12 Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk
`of aspirin›associated major upper›gastrointestinal bleeding with enteric›
`coated or buffered product. Lancet 1996;348:1413›6.
`13 Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30
`mg vs 283 mg a day) in patients after a transient ischemic attack or minor
`ischemic stroke. N Engl J Med 1991;325:1261›6.
`14 Duval S, Tweedie R. Nonparametric “trim and fill” method for accounting
`for publication bias in meta›analysis. J Am Stat Assoc 2000;95:89›98.
`
`(Accepted 15 August 2000)
`
`Wet combing versus traditional scalp inspection to detect
`head lice in schoolchildren: observational study
`Jan De Maeseneer, Ineke Blokland, Sara Willems, Robert Vander Stichele, Filip Meersschaut
`
`Lice infestation is a problem in local communities,
`probably because reservoirs remain undetected. Wet
`combing (combing systematically through wet, well
`conditioned hair with a fine toothed comb) has been
`presented as a cheap, ecological, self sufficient, and
`feasible technique for diagnosis and treatment of head
`lice.1–3 Compared with traditional scalp inspection it
`uses five elements to make living lice more visible, to
`better distinguish them from dandruff, and to assess
`the maturity of the infestation: water, conditioner, a
`fine toothed comb, a systematic sweep of the scalp, and
`a magnifying glass (10(cid:215)). However, its efficacy as a
`
`BMJ VOLUME 321 11 NOVEMBER 2000 bmj.com
`
`diagnostic tool and as a therapeutic intervention has
`not been proved; hence it is not evidence based.
`
`Subjects, methods, and results
`We did an observational study comparing detection of
`head lice using traditional scalp inspection and wet
`combing. After ethical approval had been obtained, all
`260 pupils, aged 2›12 years, of a primary school in a
`socially deprived urban area in Ghent, Belgium, were
`invited for a screening test during a three day
`campaign to detect head lice in November and
`
`Department of
`General Practice
`and Primary Health
`Care, Ghent
`University, 1K3 UZ,
`B›9000 Ghent,
`Belgium
`Jan De Maeseneer
`professor
`Sara Willems
`researcher
`
`continued over
`
`BMJ 2000;321:1187–8
`
`1187
`
`Page 5 of 5
`
`Patent Owner Ex. 2013
`CFAD v. Pozen
`IPR2015-01718