P~4PEIZS
`
`Prophylactic aspirin and risk of peptic ulcer bleeding
`
`John Weil, Duncan Colin-Jones, Michael Langman, David Iawson, Richard Logan,
`Michael Murphy, Michael Rawlins, Martin Vessey, Paul Wainwright
`
`Abstract
`Objective--To determ9ne the risks of hospitali-
`sarion for bleeding peptic ulcer with the current
`prophylactic aspirin regimens of 300 mg daily or less.
`Design—A case-control study with hospital and
`community controls.
`in Glasgow; Newcastle,
`Setting---Hospitals
`Nottingham, Oxford, and Portsmouth.
`Subjects-1121 patients with gastric or duodenal
`ulcer bleeding matched with hospital and community
`controls.
`Results--144 (12•R%) cases had been regular users
`04' aspi=Kn (taken at least five days a week for at least
`the. previous month) compared w:ih 101 (9.0%)
`hospital and 77 (7.8%) community controls. Adds
`radar were raised for all 3oses of aspirin taken,
`whether compared with hospital or community
`controls (compared with combnned controls: 75 mg,
`2.3 (95%confidence interval 1.2 to 4~4); 150 mg, 3.2
`(1.7 to 6.5); 300 mg, 3~9 (2.5 to 6.3)). Results were not
`explained by confounding influences of age, sex,
`prior ulcer history or dyspepsia, or concurrent non-
`aspirin non-steroidal and-inflammatory drug use.
`Risks seemed particularly high in patients who took
`non-aspirin non-steroidal anti-inflammatory iirugs
`concurrently.
`Conclusion—No convenrionally used prophy-
`lactic aspirin regimen seems free of the risk of pepric
`ulcer complications.
`
`Introduction
`The risks of peptic ulcer con~glications, particularly
`bleeding, are raised in association with aspirin ''' and
`other non-steroidal anti-iuP.ammatory drug ixse.s-fl
`Most information about aspirin use concerns doses of
`more than 300 mg daily and intermittent use's° Less is
`known about risks associated with regular use of doses
`below 300 mg, which are increasingly being used as
`prophylaxis against vascular disease. As standard doses
`seem to be associated with substantial risks, it is
`important to know whether these lower doses are
`significantly safer. We report a case-control study
`conducted to see if important differences in d1e risks of
`hospital admission for talcer bleeding existed between
`dtieient non-steroidal anti-inflammatory drugs.
`
`Patients and methods
`Patients studied and methods used were as detailed
`elsewhere.a Briefly, prior dxu~; intake of all types was
`derermined by ques[ioning patients aged 60 and over
`admitted with haemacemesis and melaena due to
`gastric and duodenal ulceration to hospitals in Glasgow
`(200), Newcastle (124), Nottingham (506), Oxford
`(144), and Portsmouth (170) between April 1987 and
`January 1991. Cases were as far as possible consecutive
`and were diagnosed by conventional clinical criteria.
`Findings were compared with those in age and sex
`
`matched hospital and community cont:•ols. Hospital
`controls were chosen from among all acute medical
`admissions (excluding patients with acute myocardial
`infarction, acute rheumatic diseases, and active non-
`bleeding ulcers); community controls were selected as
`the next person of the same sex and age (within five
`years) on the alphabetically ordered register of the
`same general practitioner as the case.
`Standard questionnaires, in addition to seeking
`information about all prescribed and self administered
`dn~g intake, also asked (among other things) about
`alcohol consumprion, smoking, and any history of
`gastrointestinal disease. Results were analysed by
`calculating odds ratios and 95°io confidence intervals
`by means of unconditional logistic regression. Con-
`ditional methods were rejected because initial analysis
`suggested that similar results but with tighter confi-
`dence intervals were achieved by unconditional
`methods. This mainly arose because the matching code
`for triplets went missing at one of the centres, so
`reducing the number of triplets available. In addition,
`because the referent groups chosen were cases and
`controls not exposed to non-aspirin non-steroidal anti-
`inflammatory drugs or aspirin, a large number of
`triplets became incomplete hecause of the high overall
`rate of non-aspirin non-steroidal anti-inflammatory
`drug or aspirin use.
`Of the 1144 cases intially included, 23 showed no
`evidence of ulcer haemorrhage on review and were
`therefore excluded. Results in tYie remaining 1121 were
`compared with those in the 1126 hospital controls
`selected and the 989 community controls who agreed to
`take part.
`
`Results
`Table I shows chat 144 (13%) cases were daily users
`of aspirin (defined as at least five days a week)
`compared with 101 (9%) of 1126 hospital Controls and
`77 (8%) of 989 community controls. In addition, 42
`cases and 14 hospital and five comm~inicy controls had
`been daily users of aspirin for less than a month. Odds
`ratios calculated by logistic regression to take account
`of confounding factors were consistently slightly
`greater in comparisons with community than with
`hospital controls, but all suggested raised risk (table
`II). Odds ratios increased progressively with aspirin
`dose in people who had been daily users For at least a
`month.
`Daily u,ers appeared :o be at increased risk, by a
`doubling or more, if they had Ueen users t'or less than
`a month compared with users for a monFh or more.
`There were also greater propertions of other regular
`or irregular users of aspirin among cases than among
`controls, defined respectively as used once to four
`times a week for more than a week and less than a
`month, and less than one day a week or only in the
`four days before admission. Table III shows that in
`all takers of aspirin, irrespective o£ dose, odds ratios
`
`West 11Ridlands Regional
`Health Authority,
`Rirn~tttgham
`John Weil, tembr rsgt'strar tii
`pi<blic health medicine
`
`(~uecn Alextandra Hospital,
`Poi~tssnouth P06 SI.Y
`Duncan Colin-Jones,
`consultant physician
`
`Queen Elizabeth 1#ospital,
`Univrrs'rty of Birmingham,
`Birmingham B15 2T'H
`Michael T angman, professor
`of madicine
`
`Royal Infirmary,
`G1asEow G4 OSF
`David Lawson, consultant
`physician
`
`University ofNottingham,
`Plotdngham NG7 2UH
`Richard Logan, reader in
`clinical ep~demioiogy
`
`Unit of Health Care
`Egldemiology,
`University of Oxford,
`Oxford OX2 6AE
`Michael Murphy, consultant
`epidemiologist
`
`University of Newcastle,
`Newcastle upon Ty~~e
`NE24HH
`Michael Rawlins, professor of
`clinical pharmarofogy
`
`Rade;iffe Infitwary,
`University of Oxford,
`Oxfdrd OXZ 6HE
`Martin Vessey, professorof
`yuLlicJ:eakh
`
`Institute ot'Canoer Studies,
`U~iivcrsity of Airminghatn,
`Biroiinghaia S15 217
`Paul WainwNght, research
`associate
`
`Correspondrncc Co:
`Professor Longman.
`
`DMJ ] 995;310:827-30
`
`BMJ VOLUME 31Q
`
`1 n~>ruc. 1995
`
`Page 1 of 4
`
`627
`
`Patent Owner Ex. 2016
`CFAD v. Pozen
`
`

`
`compared with combined controls calculated by doses were similar in cases for enteric coated and
`logistic regression tended to be greatest in those who soluble aspirin, and for aspirin tablets, and slightly
`greater for other commercial varieties.
`had taken aspirin for a week or less and differed little
`Tables VI and VII show the risks associated with
`in those who had taken it longer.
`daily aspirin use In the previous month together with
`Table IV shows the numbers of aspirin takers
`according to formulation in cases and controls, but non-aspirin non-steroidal anti-inflammatory drug
`use. The odds ratios were raised almost eightfold in
`irrespective of the dose taken, with the odds ratios
`calculaTed by logistic regression cornpared with the those who took both drugs, the difference compared
`with users of aspirin alone being significant
`combined controls. Odds ratios were significantly
`raised for all comparisons except for those with (P<0~05).
`enteric coated aspirin and benorylate. Data on
`dosage (table V) showed that average daily aspirin
`
`-rnni.E rAspirin intake i» month before udraission according to dose and duration oj~~se
`
`no~io)ofcontrois
`
`xu c'i) oc
`ca>es
`
`~aa (tz~s)
`27(2.4)
`22 (2~0)
`62(5.5)
`33(29)
`a2 es~~)
`
`55 (4~9)
`
`63 (s~eJ
`-
`soa (a~~t)
`
`Hospital
`
`~~~(9~0>
`30 (2~7)
`21 Q~9)
`35 (i~l)
`15 (1~3)
`iap~2)
`
`~~~~~s>
`
`3i (z~a>
`
`163 (145)
`
`81 i (72 9)
`
`963 (85 5)
`
`Community
`
`77 ~~~R>
`16 (1~6)
`15(LS)
`zh ~2'4~
`22(2.2)
`5,(05)
`
`~o c3~o>
`
`as ~a~e>
`
`157 (t 5~9)
`
`832 (64.1)
`
`D~~~y~se:
`
`..
`For one monde or more
`
`Any dose
`~75 mg
`15o mg
`300 mg
`Others
`For:ess tNanone month (any dose)
`Other mgular use: ~
`Once a week ro four dayx a week for more than
`one month
`trregularuse:
`Less than one day a week or only in the (our
`days before admission
`
`Total users
`
`Nomusers of aspirin
`Non-users of aspirin ornon-s~eroidal
`anci~~inttammacory drugs
`
`Urandtotal
`-
`
`—
`
`Discussion
`We found that no particular dose of aspirin between
`75 mg and 300 mg daily currently used in cardio-
`vascular prophylaxis is free of risk of causing bleeding
`from gastric or duodenal ulcers. Even very low (75 mg)
`,
`doses of aspirin reportedly caused gastric bleeding in
`volun[eers.Z' Nevertheless, evidence that low doses of
`as irin ma or ma not be associated with risks of
`Y
`Y
`P
`peptic ulcer bleeding is limited.
`IR tt1C atrial fibrillation, aspirin, anticoagulation
`(AFASAK) and thrombosis prevention trials there
`W2TC three major episodes of upper gastrointestinal
`bleeding in, respectively, 336 and 907 recipients of
`eSp1T'Iri~ compared with no episodes in 336 and 932
`subjects given placebo."~' In addition, in the Swedish
`aspirin low dose trial (SALT) there were nine episodes
`of severe gastrointestinal bleeding in subjects taking
`aspirin 75 mg daily and four in those taking placebo,"
`whereas In the physicians' health study the relative risk
`-
`of bleeding requiring transfusion (site unspecified) was
`1.71 (95% confidence interval 1.09 to 2 69) in takers
`of aspirin 325 mg every other day compared with
`Placebo.'°
`By contrast, in the research group on instability
`in coronary artery disease (RISC).study thP.re were
`apparently no episodes of gastrointestinal hleeding
`in 399 recipients of 75 mg aspirin daily," and in
`Community conttols ~e Dutch transient ischaemic attack trial there were
`no differences in the rates of gastrointestinal bleeding
`1P, those receiving 30 mg and 283 r,1g aspirin daily.'"
`Case-control studies have been claimed to overestimate
`ale risks of non-steroidal anti-inflammatory drug
`associated upper gastrointestinal bleeding compared
`with randomised trials,' but though we found higher
`CISkS fOC 150 mg and 300 mg than in some vascular
`prevention trials,'"'° they lucre no higher than those
`in the United Kingdom transient ischaemic attack
`SLUC{Y~'"
`Comparisons between the two data sources are,
`however, difficult. Randomised trials can give
`complete sets of unbiased information, but exclusion
`criteria em to ed at trial ent ma limit eneralisation
`Y
`g
`p )'
`ry
`to the population at ~ large. Case-control studies,
`provided that their frame is wide enough, give data
`from a general base, though biases—for insxance,
`jn nUe5T10riltlg a:1C{. iri COritxO~ selection-may skew
`COl]CIUS10riS~
`Our study was conducted in five major urban centres
`and included large numbers of cases and both hospital
`and community controls. Precautions were taken to
`minimise selection and information bias. Thus drug
`histories were checked against hospital and general
`practitioner. records and found to he in substantial
`agreement" We believe that the design was robust,
`though there is evidence of selection bias, in that
`-
`hospital ContPolS were more likely to be 2Xposed
`to aspirin than community controls. Even with this
`28 to 5~8
`COIISCCV2SIV~ X185 L~]2 CeSU~tS showed a significantly
`2~2 to 4.9
`~'4 ~° 3~3 increased risk of hospital admission for ulcer bleeding
`~'xt°32'6
`in association with all aspirin regimens used and
`0~2 to 64
`compared with either set of controls.
`2'4 [u 5'B
`Our main analyses [OO~L aCCOUI7L Of smoking and
`aICOYlOI consumption 8S WC~l 35 of prior histories Of
`
`457 (40~A)
`
`~
`
`1121 (1000)
`
`657 (664)
`A07 (71.7)
`----
`989(~~~~~)
`it2a(too~o)
`
`TAALF. II—OARS ratios avd 95% co>ifidzuce irrzervalr (iu parentheses) esmninirsg relatiory beteucev aspinry
`irnuke ar~d admission with peptic ulcer bieedtng (calrufa~ed bylogis~ic re~ressior, m cake occou»c oJorher rrnn-
`steroila! o~~ri-ir,Jianr»tatory drug use, pre~ioae ulcer or dyspepsia, and smoking and alcohol intake).
`Referents were non-takers of asnirirs or any other sorraspiriu nori-steroidal anti-infim~unatory drx~g
`-
`—
`
`Combined con~rols
`--
`
`Hospital controls
`
`--
`Daily aspirin use (or one month
`oe more:
`Any dose
`~s mR
`lOS mg
`Sou n~
`Daily aspirin ose for less than one
`month:
`Any dose
`
`3~2 (29 to 44)
`z•3 ~i2 co a a>
`32 (I ~7mo•5)
`3.9 (2•S to G3)
`
`2.7 (1~9 to 3•R)
`ra ro a co 3 a>
`2~6 (I.3m5.5)
`3 3 (! 9 m 5 6)
`
`9~2 (2~3 to 160.1) ~
`
`6~5 (32 ro?52)
`
`42 (2~8 to 6.3)
`a•o p~e <<, ~•z>
`4~l (1~7ro9~6)
`s z (2R to e ~)
`
`19 2 (23ro 1601)
`
`rnnc.F m N~nnberc of aspirin takers during previous niarith in cases and controls according to duration of
`use, mgether xuid+ oddr ratios a>id 95 % cartfidence internals ca(tulated b_y untonditinria! logistic regression for
`nccnriaeinn with bleeding peptic tdcers, taking accv~nu oJotl~er factors
`
`'
`
`Time aspirin started
`bcfom admrssiont
`
`One week
`Between one week
`and one month
`Be[weenone and
`three months
`,~no~ecna~ m~ee
`months
`
`N° °r
`hospital
`No of
`<as~~ <o~«ois
`z~~
`
`68
`
`67
`
`45
`
`l24
`
`25
`
`3i
`
`no
`
`to~~~crrv~rw~~~<>mm~~~e~Y~~~v~,i~.
`
`oaa5 r~oo
`
`N° °f
`95 ~
`community Hospital Community Combined Confidence
`~<~~~a>i~ interval
`<o~«o~s
`~~~c~~i4
`<o~«~>is
`
`2i
`
`31
`
`25
`
`so
`
`s~s
`
`3~4
`
`2.3
`
`s~3
`
`s~s
`
`2~5
`
`3.9
`
`3•a
`
`a•s
`
`2~9
`
`2.9
`
`s~z
`
`2.9 to 7~9
`
`1~8 to 4.7
`
`1.7 to 49
`
`2~3to4'S
`
`rnsLe ry—Use of different aspirin preparatior:s at any time in month before admistimi and risks of peptic
`ulcerbleeding. (Odds ratios and 95% m»fidence interua& ca(culo[ed 6y nnconditiona(loQistic regretsiori)
`—
`oaas ravo~ v
`95 i~
`Confidence
`combined
`convols interval
`
`Aspirinformulation
`
`No of
`cases
`
`No or
`hospital'
`comrols
`
`N~ of
`community
`controls
`
`Aspirin tablets
`Soluble aspirin
`Enteric coated
`Alka-Seltzer
`Benorylare
`Other commercial
`•For Alka-Sel[2er, nun-aspirin non-steroidal anti-inflammatory drugs were not included in moAel, as [here were nu
`Cases of community controls also taking non-aspirin non-steroidal anti-inflammatory drugs.
`
`126
`84
`i ~
`io
`6
`77
`
`60
`56
`~2
`z
`4
`30
`
`57
`51
`7
`i
`3
`4l
`
`40
`3'3
`~~~
`~•~
`L I
`3.7
`
`828
`
`Page 2 of 4
`
`$1~1J VOLUME 31 ~
`
`1 nrxi~ 1995
`
`Patent Owner Ex. 2016
`CFAD y. Pozen
`
`

`
`~-ns~ v Average ciorages of different aspirin preparatimu taken daily in month before admission. (Odd. ratios and 95% confidence intervafa
`cakuloted 6y unconditional loguac regression)
`
`Aspirin formulation
`
`Aspirin cables
`Soluble aspirin
`Enteric coated
`Other commercial
`
`No of
`cases
`
`~ A2
`55
`I1
`34
`
`Dose
`(mg)
`
`300
`270
`296
`419
`
`No of
`hospital
`convols
`
`49
`41
`12
`!0
`
`Dose
`(mg)
`
`170
`IAO
`267
`952
`
`No of
`community
`controls
`
`38
`28
`5
`11
`
`Dose
`(mQJ
`
`249
`315
`672
`613
`
`Odds ratio v
`combined
`controls
`
`95
`Confidence
`interval
`
`3.4
`3~7
`1.6
`S•8
`
`2.2 to 5~3
`23ro6.0
`0•S co 4.9
`3~O to 111
`
`*For Alka-Seltzer, non-aspirin non-steroidal anti-inflammatory drugs were not included in model, ass there were no cases of community rontrols also taking
`non-aspirin non-steroidal anti-inflammatory drugs.
`
`Tpxt.a vt—Numbers of daily aspirin tnkers and of takers uJ
`non-aspirin non-steroidal ann-inflamma[ary drugs alone and together
`
`Daily aspirin alone
`Non•aspinn rion-steroidal
`en[i-inflammatory drug
`Daily aspirin+non-aspirin
`non-smroidelanti-inflammatory
`drug
`Neither
`
`No of
`cases
`
`140
`
`340
`
`46
`
`477
`
`No of
`hospital
`cuntiols
`
`No of
`community
`controls
`
`101
`
`137
`
`14
`
`826
`
`7l
`
`142
`
`I1
`
`690
`
`'snore vn—Odds ratios and 95% confid¢nce internals. (in parentheses)
`calculated by uncondinbnal logi.st(c regression for risk in aspirin takers
`anti of takers of non-aspirin non-steroidal ar+ti-inflammatory drugs
`alone axd together
`
`Aspirin alone
`N(m-aspirin non-steroidal
`anti-inflammatory drug
`Aspirin+nr n-aspirin
`non-steroidal
`anti-inflemmarory drug
`
`Hospital Community
`con[rols
`controls
`
`Combined
`convuls
`
`2'8
`
`5~4
`
`4~5
`
`3~3 (2~S to 4~4)
`
`4~7
`
`4~9 (3~9 to 6~1)
`
`7.0.
`
`9~3
`
`P7(3~6 to 16.4)
`
`dyspepsia or peptic ulceration and of non-aspirin non-
`steroidal anti-inflammatory drug use. Further analysis
`of data showed that concurrent non-aspirin non-
`steroidal anti-inflammatory drug use roughly doubled
`risk. Table III indicates that risk tended to be treater
`when aspirin use had been of short duration. This
`increase associated with short term use may be
`explained by the taking of aspirin to alleviate symp-
`toms arising from incipient peptic ulceration, but the
`substantially raised risk associated with daily aspirin
`use fbr less than a month (table Il) suggests that there
`may be particular risks associated with prophylactic
`aspirin use early in treatment. 'These findings are
`consonant with results obtained elsewhere,se:a
`Table IV suggests that enteric coated aspirin and the
`aspirin-paracetamol combination benorylate may be
`free of risk whereas the buffered perparation Alka-
`Seltzer may be associated with high risk. It should be
`noted, however, that confidence intervals were large
`and that because of its high buffering capacity Alka-
`Seltzer may have been used preierentialiy by people
`wide gastric symptoms. "Iliere was no evidence of
`material differences in risk between aspirin tablets,
`soluble aspirin, and other commercial varieties.
`Some 10000 episodes of ulcer bleeding occur in
`
`~
`
`Key messages
`
`~
`
`• Ristcs of peptic ulcer bleeding are signifi-
`candy raised by prophylactic use of aspirin
`n This finding applies to doses in common use
`of 75, 150, and 300 mg daily
`• Despite these results, overall benefits of
`treaunent are likely considerably to outweigh
`possible risks
`
`people aged 60 and over each year in England and
`Wales. Other data of ours suggest that some 3500 of
`these will be takers of non-aspirin non-steroidal anti-
`inflammatory drugs and, if our current figures are
`representative, 1700 or 17% of the total will be taking
`prophylactic aspirin compared with 8% of community
`controls. It may be deduced that 900 of the 1000D
`episodes could be associated with and ascribed to
`prophylactic aspirin use. A general change to low doses
`(75 mg) of aspirin would not eliminate risk but, again if
`our figures are soundly based, would reduce risk by
`about 40°/~ compared with 300 mg doses and b}• 30%
`compared with 150 rig doses. It is unclear if substi-
`[uting enteric coated aspirin would eliminate risk in
`crew of evidence that non-steroidal anti-inflammatory
`drug use can cause haemorrhage, perforation, or
`stricnire in the lower bowel.'°-" Taken overall, benefit
`from prophylactic drug use is likely substantially to
`outweigh risk, but refinements to dosage and delivery
`would clearly be valuable.
`
`We are most grateful for the help given by our clinical
`colleagues and inves[igacors Clare Clift'ord, Gail Faulkner,
`Gillian Paice, Shiiley Powell, Ellen Thompson, and Shirley
`Wood and for the support of the Medical Research Council.
`
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`Lance[ 1958;ii:179.82.
`2 Coggon D, I.angmnn M]S, Spiegelhvlter D. Aspirin, perecetemol end
`heeme¢mcsis end melacna. Gut 1982¢3340-4.
`3 Ixvy M, Miller DR, Knu6nan DW, Siskind V, Sehwingl P, Rosenberg L,
`e~ uL Major upper gasvointesrina~ tract bleeding. Relation ro the use of
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`10 Cenediart Cooperative S:udy Group. A randomised trial of aspirin end
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`]1 Somnsom PS, Pedersen H, Marquardsen I. Pete~eson H, HelFherg A,
`Simonsen N, e~ aL Acerylsaiicylic acid in she prcvennun of stake in parimcs
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`
`Case-control study of migraine and risk of aschaemic stroke in young
`women
`
`Christophe Tzourio, Alain TehindrazanArivelo, Serge Iglesias, Annick Alperovitch,
`Francois Chedru, Jacques d'Anglejan-Chatillon, Marie-Germaine Bousser
`
`Abstract
`Objective—Ta deternvne whether migraine is a
`risk factor for iechaemic stroke in young women.
`Design—Acase-control study.
`Setting—Five hospitals in Parris and suburbs.
`SuLjects-72 women aged under 45 with
`ischaemic stroke and 173 controls randomly. selected
`from women hospitalised in the same centres.
`Main outcome measures--[schaemic stroke
`confirmed by cerebral computerised tomography or
`magnetic resonance imaging; history of headache
`recorded with structured interview, and diagnosis of
`migraine assessed by reproducibility study.
`Result~Ischaemic stroke was strongly associated
`with migraine, both migraine without aura (odds
`ratio 3.0 (95% confidence interval 1•S to S~8)) and
`migraine with aura (odds ratio 6~2 (2.1 to 18.0)).
`The risk of ischaemic stroke was substattrially
`increased for migrainous women who were using
`oral contraceptives (odds rakio 13.9) or who were
`heavy smokers (, 20 cigarettes/day) (odds ratio
`10.2).
`Conclusions—These results indicate an inde-
`pendentassociation between migraine and the risk of
`ischaemic stroke in young women. Although the
`absolute risk of ischaemic stroke in young women
`with migraine is laws the reduction of known risk
`factors for stroke, in particular smoking and use of
`oral contraceptives, should be considered in this
`groap.
`
`Introduction
`Few epidemiological studies have investigated the
`possible association between migraine and stroke. One
`of the main reasons for this was the lack of precise
`criteria for the diagnosis of migraine until 1988,
`when the International Headache Society established
`operational criteria.' Using these criteria, we found
`that migraine was not related to ischaemic stroke
`except in women aged under 45: 65% of young women
`with ischaemic stroke had migraine compared with
`30% of controls (1'-0.03). This result, however, was
`questionable as it' was extracted from a subgroup
`analysis with only 20 pairs of cases and controls.
`The main aim of this study was to im~estigate the
`relation between migraine and ischaemic stroke in
`young women. It was also designed to study the
`relation between migraine, stroke, and two known
`
`vascular risk factors in this group: use of oral contra-
`ceptives and cigarette smoking.
`
`Subjects and methods
`We conducted cease-control study, cases being
`women aged under 45 who were hospitalised for an
`ischaemic stroke, in five neurological deparunents
`from January 1990 to December 1993. Three of the
`departments were in academic centres in Paris that
`were already involved in a study including all young
`patients consecutively admitted for ischaemic stroke.
`The two others were neurological departments of
`general hospitals located in small towns near Paris.
`Patients eligible for inclusion were women aged 16-44
`with a diagc~osis of first ischaemic stroke (codes 433,
`434, and 436 of International Classification of Dt'seases,
`ninth revision). All cases were confirmed by cerebral
`computed tomography or magnetic resonance imaging.
`Of the 85 eligible patients admitted during the study
`period, two died afrer their stroke and one patient with
`dysphasia was excluded. Of the 82 remaining patients,
`10 could not be located despite various efforts. There-
`fore, 72 patients were contacted and agreed to partici-
`pate: 40 were hospitalised in the academic centres, aid
`32 were in xhe general hospitals. The mean elapsed
`time between stroke and interview was 19.5 months
`(SD (2~7).
`Cervical ultrasound examination, electrocardio-
`graphy, and usual laboratory studies were perfor[ned
`on all patients. Most paeients underwent further
`investigations to determine the aetiology of the stroke:
`cerebral angiography (68), echocardiography (63),
`transoesophageal echocardiography (56 (92% of cases
`without arterial dissection)), transthoracic echocardio-
`graphy (7), anticardiolipin antibodies (30), and coagu-
`lation studies (59). These investigations revealed
`various abnormalities associated with a higher risk of
`stroke: arterial dissection (22), carotid occlusion of
`unknown cause (5), carotid atheroma (5), anticardio-
`lipin antibodies (6), essential thrombocytaemia (1),
`paro~cysrnal atrial fibrillation (1), mural valve stenosis
`(2), patent foramen ovate (11), and atrial septa!
`aneurysm (11). This last abnormality was diagnosed
`with transoesophageal echocardiography when the
`atrial septum presented an excursion of more than
`6 mm in the right or lefr atrium. None of the patients
`was pregnant at the time of the stroke.
`Controls were women randomly selected from
`
`BMJ voc.vres 310
`
`1 nrruL 1995
`
`Patent Owner Ex. 2016
`CFAD v. Pozen
`
`INSERIIR U 360,
`Recherches
`Epid~miologiques en
`Neurologie et
`Psychopathologie,
`Cedex 94809 Ville)uif,
`France
`Christophe Tzourio, clinical
`epidemiologist
`Amick Alperovitch, director
`of research
`
`Service de Neurologie,
`Hapital Saint-Mtoine,
`Paris, France
`Alain Tehindrazanarivelo,
`senior registrar
`Serge Iglesias, registrar
`Marie-Germaine Bousser,
`professor of neurology
`
`Service de Neurologie,
`H6p3ta1 de Meaux, France
`Frangois Chedru, head of
`department
`
`Service d~~ Neurologie,
`H&pital de Versanlles,
`France
`Jacques d'Anglejan-
`Chatillon, head of department
`
`Correspondence to:
`Dr'T'zourio.
`
`EM,~ 1995;3L0:830-3
`
`830
`
`Page 4 of 4