Incidence of venous thromboembolism in users of combined oral contraceptives. Risk is particularly high with first use of oral contraceptives

Leiters

for police surgeons who have been asked to examine people in police custody when consent for such examination is not forthcoming.31 hope that similar guidelines

will be produced for medical practitioners who may be asked to participate in collecting body fluids for drug testing from arrested people without their consent and in analysing, interpreting, and using the results in samples obtained in this way.

A K W Forrest professor offorensic toMcoiogy Department of Forensic Pathology, University of Sheffield, Sheffield S3 7ES

r.forrest@sheffield.ac.uk

1 Another fine mess [editonal] Nm> Lau'Journal 1999,149 1429

2 Tony Blair and hberty [editonal] Econmmst 1999, 353(8139) 19-20

3 Pownall M Doctors should obtain infonned consent for mamate body searches BMJ 1991,318 310

Incidence of venous

thromboembolism in users of

combined oral contraceptives

EDITOR—Lawrenson et al reported a crude incidence of venous thromboembolism of 38 per 100 000 women who used combined oral contraceptives, based on information derived from the General Practice Research Database, without describing how they derived their eslimate.1 This estimate is

closely similar to the incidence reported in a prior publication of theirs, which was based on a different automated medical database.2

In their letter they provide no details on the validity and specificity of the diagnosis of venous thromboembolism or the presence of medical risk factors and no information on the person time at risk for current users of oral contraceptives.

An incidence must be based on person time at risk. Despite apparent deficiencies, the authors provide an incidence that is roughly twice äs high äs the incidence that colleagues and I reported in a paper derived from the General Practice Research Data-base; we included only idiopathic cases of venous thromboembolism (those possibly related directly to use of oral contracep-tives).' Lawrenson et al conclude that our reported estimate was substantially lower than the true incidence.

On die basis of their previous publi-cation,·' Lawrenson et al seem to have included both outpatients and inpatients with any one of five Computer recorded diagnoses äs patients with venous thrombo-embolism, without documentation from clinical records. The five diagnoses include a Computer recorded diagnosis of thrombo-phlebitis. Colleagues and I found that, on the General Practice Research Database, over 90% of subjects with this Computer recorded diagnosis alone were treated äs outpatients, so clinical histories were not available; we did not find any of the

remaining patients with this diagnosis to have idiopathic deep vein thrombosis after review of clinical histories.' Thus we concluded that many young women with a Computer diagnosis of thrombophlebitis do not have documented idiopathic deep vein thrombosis.

The results from the General Practice Research Database provided in Lawrenson et al's letter are uninterpretable because, firstly, it is unclear whether the general prac-titioners reported incidence according to number of users rather than person time at risk, and, secondly, presumably the diagnosis of venous thromboembolism was not vali-dated from clinical records. By contrast, cases of venous thromboembolism that we reported were validated äs idiopathic from clinical records.'

An Interpretation of estimates of the incidence of venous thromboembolism related to current use of oral contraceptives requires that the method for identifying rel-evant cases äs well äs the method for estimating person time at risk be clearly detailed/ äs in our paper.' In die absence of such information, comparison of rates of ill-ness between different reports is unjustified and surely misleading.

Hershel Jick assoaale frrofei mr ofmedtane Boston Collaboraüve Drug Sun eillance Progi am, Boston Umversily School of Mediane, 11 Muzzey Street, Lexington, MA 02421, USA

Compeüng mtei ests Nonc declai ed.

1 Lawrenson RA, V, halle\ A, Simpson E. F,u mei RDT DoH sccms to ha\e underesümatcd mcidencc of \cnous thiom-boembolisrn in usci i, oi combined oral corrcracepü\es Ιίλ!/

1999,319387 (7 August)

2 Faimei RD, Lawrenson RA, Thompson GR, Kenned\ JG, Hambleton IR PopulaUon-based stud\ of nsk of \cnous tliiomboembolism associaUon \vitli \aiious oial conrra-cepmes lAitcel 1997,34983-8

3 Jick H.Jick SS, Gurewich V, Myers MW, Vasilakis G Risk of idiopathic caidiovasculai death and nonfatal \cnous thromboembolism in \\omen usmg oial contracepu\es with diifermg piogestogen components Lanrft 1995.34b 1589-93

4 Jick H, Garcia Rodnguez LA, Pere? Guttliami S Prmuples of epidemiologic icsearch on adveise and beneiicial drug efiects Ijmret 1998,352 1767-70

Risk is particularly high with first use of oral contraceptives

EDITOR—Lawrenson et al sho\\ that the risk of venous thromboembolism during use of oral contraceptives might be higher than estimated by the Medicines Commission of me United Kingdom's Department of Health.1 That is especially likely for first use.

In a paper that was published at about the same time Herings et al found an incidence of 90 per 100 000 woman years in the first episode of use of third generation oral contraceptives; for second generation contraceptives the figure was 24 per 100 000; for the youngest ages and during the first year of use the incidences became higher than 100 per 100 O00.! These data

are in line with those found in earlier case-control studies.

A stratified analysis of the World Health Organisation's study found a 21.6-fold increase in the risk of venous thrombosis among first ever users of third generation oral contraceptives during the first year of use (relative to never use); this relative risk

was 9.1 for second generation oral contra-ceptives.' In the Leiden study we found four-fold to sevenfour-fold risk increases for third versus second generation oral contracep-tives among younger women (most ne\\ users would be young); this was over and above an overall threefold to fourfold risk increase for second generation oral contra-ceptives/

Jick et al found 9.2-fold and 5.6-fold increases in risk between third and second generation oral contraceptives during the first six months of use.' Multiplying these cumulative relative risks with an overall baseline incidence of, say, 5 per 100 000 woman years yields incidences of the Order of magnitude found by Herings et al,· thereby confirming the suspicion that the incidences are higher than generall) believed, especially in young and first time users.

Jan P Vandenbroucke ptof?*\oi, dfpai tment of clinical eptdemwlog)'

vdbi oucke@mail medfac.leidenurm.nl

Kitty W M Bloemenkamp legKlim, depaitmenl n] obstetnc^,g^imecohgy and lepiodiictn'r mcdnmc Frits R RosendaaJ piofessoi, i/nonibou^ and haemoilawi uwmch centie

Frans M Heimerhorst Icchnei, dfpfuhnetif o/ ob^tfti us,gynaecology and tepioducfwe medtctne Leiden Uimei sit\ Medical Centie, PO Bo\ ')600, 2300 RC Leiden, Nethei lands

Compctmg inteiests Piofessois Vandenbroucke and Rosendaal ha\e no competmg interests Di Bloemenkamp has been imohed m, and Di Helmcrhoist has supemsed. studies sponsored 01 assigned b\ \ anous phai maceutical compames that manufactute oial contiaccpti\es. but none of these companies has fiindcd then studies on the compai am e mei its oi second and third generation oral contraceptn es

1 LauiensonRA.Whalta A. Simpson E I j i m e i RD1 DoH seenis to ha\e underestimated incidence oi \enous throni-bocmbohsm m users oi combined oral comiacepmes 11MJ 1999,319387 (7 August)

2 Herings RMG, Lrquhait J, Leufkens HGM Venous Üiioniboembolism among neu useis oi ditfeient oral con-tracepmes Lama 1999.3Ϊ4 127-8

3 Foultet NR Farlcn TMM, Chang GL. Marino! MC,, Meuik O Saieh of combined oial contracepti\e pills laitcil 199b.it7.Vl7

4 Bloemenkamp KW M Rosendaal FR Helmei hörst FM Bullei HR, Yandenb] oucke fP Enhancement b\ factor \ Leiden mutation of nsk of deep-\ein thrombosis associated A\ith oial condaceptues contaimng tlnid-genei auon progcstagen Lancel 1995,Mri Π9>-6 j Jick H Ji( k SS, Gui ew ich \', \h ei s ΜΛ\ \'asilakis G Risk of

idiopathic cai dio\ asculai death and non-fatal \enous thromboembohsm in \\omen using oial contraceptn es uith diöenng progestagen componfnts ΙΑΗΓΡ! 1995 346 1589-93

Authors' reply

EDITOR—Our letter in response to the Department of Health's Statement calcu-lated an incidence of idiopathic venous thromboembolism of 36.5 per 100000 exposed woman years in users of combined oral contraceptives. This was based on a stractured review of published papers and compared well with die Undings from our recent study, for which we used the General Practice Research Database. That study included only cases of diagnosed venous thromboembolism with supporting evi-dence of anticoagulation treatment. Further information from general practitioners showed that in 83% of cases there was supportive evidence (venograms, Doppier ultrasound scans, or lung scans).

Leiters

We have argued that general pracüüon-ers m the United Kingdom do not treat patients with anticoagulants without the support of diagnosis by a hospital consult-ant The general pracüüoners responses mdicated that all our cases had been referred to hospital, although for a fifth this had not been recorded on the General Prac tice Research Database We beheve that the strategy used by Jick et al of requirmg a Computer record of hospital admission led to a 20% underesümate of cases In all our srudies of combmed oral contraceptives we have used person time at risk for calculatmg incidences, based on a 28 day pack Jick et al used 30 days, which would have led to a fur-ther 7% error

Vandenbroucke et al cite a further study by Herings et al that Supports our assertion of a higher inudence of venous throm boembolism than that reported by the Department of Health Their leuer cites examples of higher incidences of venous thromboembohsm among users of third generation compared with second genera-tion combmed oral contraceptives We agree that new users of combmed oral contracep-tives seem to be at an increased risk of idio-pathic venous thromboembohsm this is important when considenng the risk ascnbed to third generation combmed oral contraceptives

In oui studies we have compaied users of levonorgestrel 150 μg plus ethm)loeslra diol 30 μg \\ith users of formulations of combmed oral contraceptives containmg desogestrel and gestodene and found no difference in usk of venous thromboembo-hsm between the formulations Inteiestmgly, a further analysis has shown that, despite a large change m prescnbmg pracüce since November 1995 from third to second generation formulations, the overall risk of venous thromboembohsm m useis of combmed oral contracepüves has not changed

The key pomt of our letter was that the true rate of venous thromboembohsm in users of combmed oral contraceptives is probably nearer 37 per 100 000 exposed woman years and that the figures quoted by the Department of Health are under estimates

R A Lawrenson scmor lecturer m [mbhc Iwalth AWhalley revarch officer

E Simpson lescarch qfficer

R D T Farmer /tro/e^or ofphat macoepidemwloir) and publtc heallh

European Institute of Health and Mcdical Sciences Tjniversity oi Surre \ Guildford GU^ 5RF Competing intetcsts Ihc depaitment in \vhich thc authors \\oik has recu\ed iunding from Oiganon and Schering for in\estigating \enous thrombo-embolism m \\omen using oral contraceptives

1 Fanner RDI lauienson R \ Third gcnci uion onl contraccpmts md \cnous ihiotnbosis. / ancct 1997 M 9 7 i 2 7!

2 JickH JickSS GurcHichV M>eis MW Visilaskis C Riskot idiopathic c~udio\ iscul ir de ith md n o n f i l l l \tnous thrombotmbolism in uomcn usmsjf onl conuactptives \\ith diileiing progestagen componcnts /ancel 1995 ^ Ib l i89 9!

3 iaimti RD1 The impiuof thc 199j pill scare i n t h c L K Pluirmai u/mirmiol I)riur Sn/c/i 1999 S(suppl 2) S187

Some patients are happy for

doctors to make decisions

EDITOR—I agree with Bastian that the relationship between doctors and their patient is fundamentally changing and that many patients should be more closely mvolved m the decision makmg regardmg their health needs ' I do, however, not accept Bastian s Statement that doctors do not have a sophisücated understandmg of the consul-taüon process and wish to raise a pomt that is often overlooked by many people in con sumer orgamsations

An appreciable body of patients in the Community is more than happy to offload the decision makmg about their treatment to the doctor Many of these patients are intelligent, motivated people who approach the medical profession for ad\ice based on knowledge and expeiience As an anaesthet ist I have spent much Urne discussmg \uth patients the pros and cons of one foi m of penoperative analgesta veisus another and almost invaiiably, when I ask the patient about their preference the response is Whatever you thmk best, doctor or 'Which one would )ou have''

Every patient we see is unique and should be treated äs such Some patients clearly gam reassurance ftom the medical profession adopting the pohtically incorrect patcrnalistic approach, and these people must not be forgotten

lan Taylor ^xciah^l reqi\irar in an(i<\lhc>ia

Punccss Mai g iret Hospital Sivindon SM 4JL l R i e h u d s I \ u s t i i l i i s comumu t h u n p i o n UM/ i999

!1')~ϊ<) (ISSeptembei )

Long term vascular

complications of Coxiella

burnetii infection

Cardiovascular risk factors cannot be ignored

FDIIOR—In their paper 011 the potential for infection by Coxiella burnetn to be a nsk factoi for cardiovascular disease Lovey et al suggest that the established mocle of transmission of

C burnetn is unlikely to be associated with risk

factors for cardiovascular disease They also say that the unavaüabüity of basehne data on such nsk is unlikely to influence their Undings ' However, in an outbreak of Q fever pneumoma aifecüng 147 panents m the United Kingdom m 1989 (not referred to by Lovey et al) we found that of 110 patients in whom smoking history was available for ihe time of the infection, 60 were current smokers, 28 were ex-smokers, and only 22 hadne\ersmoked '

A subsequent case-control study m this cohort confirmed smoking to be a nsk factor for Q fever Follow up of 87 (59%) patients m clinic nine years after the ongmal outbreak idenüficd 31 (35%) äs current smokers (mean age 512 (SD 102)), with a mean smoking bürden of 33 0 (l 5 8) pack years In this group one patient had had a cerebrovascular

accident and thiee had ischaemic heart disease Thirty five (40%) patients were ex-smokers (mean age 570 (134)), with a mean smoking bürden of 264 (188) pack years In this group one had had a cerebrovascular accident and six had ischae mic heart disease Only 17 (20%) patients (mean age 53 8 (9 1)) had never smoked, and none of these had vascular disease

Ihese results suggest that smoking is a risk factor for Q fever and show that in our patients it has been the current or ex smokeis who have developed cardiovas culai disease It is theiefore essential that current and past cigarette smoking are addcd to a reanalysis by the Geneva group befoie C bwmtn can be taken äs the cxplanation of the excess cardiovascular moi bidity and mortality observed

Martin Wildman n \κικΙί /ellmi in ti^piraior}

inidititu

usctisMuld t dkl md u>m

Jon G Ayres /;fo/fssf» of ιι\/>/ιαΙυη niidicitu

Hc iitlinds Rcstaich Institute Bnminghim He irtlands Hospital liiinungh im B() "iSS

l I m t v P Moi ibia \ Bind 1) Hettr O Dupuis (, Pctitc ( t ong tu m v tscul u eomplie itions öl (oxielli burncui mteaion in Swit/crland eohoit smdy /i/Vf/ 1999119

'S l h ( i l July )

i Smith DI A\res [G B] m I Buigl PS C irpenter MJ C uil I O et il \ l u gt Q tcver outbrt ik in the West Midlands chnitil asptcti, Ri f i r Vlid 199i 87 >09 I b

! H i » k c r ] I AviesJC, Blair I l v ms MR Smith DI Smith IG cl ü A l nge outbic ik ot Qlever in thc West Midlands vvindboinc spie id into ι metiopohtan aie i ( ommmi Du ΡιώΙιιΙΙ allh 1998 l 180 7

l - \ v i c s j ( I l m t N Smith i G luimicliftc WS I l c t i h u T ) H iinmond K et il Post inftclion latigiie syndrome i o l l o u n ^ Q k v u Q . / \ ) r f l 9 9 8 9 1 l ( ) 5 2 i

Authors' reply

EDITOR—The data leported by Wildman et al cannot be mterpreted äs evidence that smoking is a nsk factoi for Q fever The pre\alence of current smoking in these 110 patients was unusually high (55%), even compared with the general local populaüon of Last Birmingham (35%)' These patients had mostly been admitted to hospital and been idcntifacd on the basis of a recent diag nosis of pneumoma or iever of unknown ongm Smokers may therefore have been overselected simply because they were more se\ erely alfected by respiratory disease This overrepresentation oi smokers among cases may in turn explam the positive association of smoking and Q fever observed in the study by Ayres et al, in which 71 patients with Q fever were compared with patients in general practice who were free of febrile ill-ness By companson, in the Swiss outbreak oi 1983, 191 patients had fever, but 224 otheis were idenufied by serum analysis of the general populaüon (n = -5036)' Q fevei pneumoma affected only 68 patients (36% of the patients with Symptoms and 16% of the whole group) Onl} 8 of the 415 panents (2%) were admitted to hospital

Wildman et al also argue that cardio-vascular disease does not occur in patients mfected with Q fever who never smoked Three cases of ischaemic heart disease in 31 smokers may, however, not be different from no cases in 17 people who have never smoked Their numbers (31+35+17) do