Hannaford, Philip C

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P. C. Hannaford

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The progestogen content of combined oral contraceptives and venous thromboembolic risk

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The progestogen content of combined oralcontraceptives and venous thromboembolic riskNew evidence confirms that differences exist between preparations with different progestogensPhilip C Hannaford Grampian Health Board chair of primary careAcademic Primary Care, University of Aberdeen, Aberdeen AB25 2ZD, UKIn the linked study (doi:10.1136/bmj.d6423), Lidegaard andcolleagues assess the effect of different types of combined oralcontraceptive, according to progestogen type and oestrogendose, on the risk of venous thromboembolism.1Over the past four decades, more than 25 epidemiological studieshave examined the risk of venous thromboembolism in currentusers of combined oral contraceptives.2All but two studies founda significantly higher risk among current users compared withnon-users. The risk is probably greater during the first fewmonths of use, before falling to a level that remains above thatof non-users until the use of these contraceptives is stopped,when the excess risk rapidly disappears. Early studies examiningthe effects of the hormonal constituents tended to focus on theoestrogen content of particular products, although one reportsuggested that the progestogen content may also be important.3Focus on the progestogen content sharpened in the mid-1990s,when several publications reported a higher risk of venousthromboembolism in users of combined oral contraceptivescontaining the more recently introduced progestogens,desogestrel or gestodene, compared with those using productswith the older progestogen levonorgestrel. These results,replicated in subsequent studies, have been subjected to intensescientific and legal scrutiny.Recent studies reporting a higher risk—again relative to usersof levonorgestrel containing preparations—of venousthromboembolism in users of combined oral contraceptives thatcontain the latest progestogen, drospirenone, have also comeunder close scrutiny. In the largest study,4 the usual trend ofdeclining risk after the first few months of use was absent inwomen using levonorgestrel containing pills. Commentatorssuggested that this might have been because of “left censoringbias” as a result of periods of higher risk during early use beingincompletely recorded for older levonorgestrel containing pills,unlike the newly introduced drospirenone containing products.5Thus, the observed incidence of thrombosis in the levonorgestrelusing comparator group may have been artificially low, whichwould have exaggerated the risk in drospirenone users.Lidegaard and colleagues report findings from a four yearextension of their previous study.4 The study used four nationalregistries to linked data about citizenship, hospital dischargediagnoses, deaths, and medicinal products. All Danish womenaged 15-49 years between 1995 and 2009 were identified andthose with recorded previous thrombosis, cancer, andcoagulation disturbances were excluded or censored, as werethose who were pregnant or who underwent hysterectomy,bilateral oophorectomy, or sterilisation. First episodes of venousthromboembolism were identified from hospital records, andevents that were treated with anticoagulants for at least fourweeks were considered confirmed (67% of all identified cases).An independent assessment of 200 cases indicated that venousthromboembolism was confirmed in most women givenanticoagulation. The authors calculated person time exposureto hormonal contraception using information from the nationalregistry of medicinal products about hormonal contraceptiveprescriptions redeemed between 1995 and 2009. Although thestudy focused on the period after the launch of drospirenonecontaining combined oral contraceptives in Denmark (2001-9),prescription data from 1995 were used for the calculation ofduration of hormonal contraceptive use. This greatly reducedthe potential for left censoring bias. Sensitivity analyses testedassumptions made in the construction of periods of exposure,with generally few differences between results.During the eight million women years of observation, 4246 firstepisodes of venous thromboembolism occurred. Among theconfirmed cases, and after adjustment for age, calendar year,education, and length of use, the relative risk of venousthromboembolic risk in women who used pills with desogestrel,gestodene, or drospirenone was twice that of those who usedpills with levonorgestrel. The estimated average absolute riskin current users of newer pills was about 10 per 10 000 womenyears. Although the corresponding relative risks innon-confirmed cases tended to be smaller, those for combinedoral contraceptives containing gestodene or drospirenone werestill significantly greater than for those containinglevonorgestrel. Preparations with a newer progestogen and 20µg of oestrogen did not have a significantly lower risk of venousthrombosis than those with the same progestogen and 30 µg ofoestrogen. Progestogen only oral contraceptives and thep.hannaford@abdn.ac.ukFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2011;343:d6592 doi: 10.1136/bmj.d6592 Page 1 of 2EditorialsEDITORIALSbrought to you by COREView metadata, citation and similar papers at core.ac.ukprovided by Aberdeen University Research Archivelevonorgestrel releasing intrauterine device were not associatedwith an increased risk of venous thromboembolism.A key concern with any data linkage study is the quality ofinformation collected, often recorded during everyday practicein an unstructured way. A crucial consideration is whether thereis likely to be differential recording of information among thevarious exposure groups, and if so, whether this is related tooutcome. There is little reason to suspect that this occurred inthis study. Furthermore, the similar proportion of confirmedcases in the different groups argues against differential referralor diagnostic bias as an explanation for the study’s results.Information about important potential confounders—such asbody mass index and family history of venousthromboembolism—is often absent, incomplete, or out of datein routine datasets. Residual confounding should thereforealways be considered in the assessment of results from datalinkage studies. Such effects, however, would have to be largeto account for a doubling of risk.This new study has tackled many of the concerns expressedabout the earlier investigation. Although unpalatable to some,it is difficult not to conclude that combined oral contraceptiveswith desogestrel, gestodene, or drospirenone confer a higherrisk of venous thromboembolism than those with levonorgestrel.Many clinicians will choose to minimise the risk by prescribinga combined oral contraceptive with levonorgestrel wheneverpossible. It is crucial, however, not to exaggerate the risk—oralcontraceptives are remarkably safe and may confer importantlong term benefits in relation to cancer and mortality.6 7Competing interests: The author has completed the ICMJE uniformdisclosure form at www.icmje.org/coi_disclosure.pdf (available onrequest from the corresponding author) and declares: no support fromany organisation for the submitted work; his academic department hasreceived payments from Schering Plough and Wyeth Pharmaceuticalfor lectures and advisory board work provided by PCH; no otherrelationships or activities that could appear to have influenced thesubmitted work.Provenance and peer review: Commissioned; not externally peerreviewed.1 Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venousthromboembolism from use of oral contraceptives containing different progestogens andoestrogen doses: Danish cohort study, 2001-9. BMJ 2011;343:d6423.2 Hannaford PC. Epidemiology of the contraceptive pill and venous thromboembolism.Thromb Res 2011;127(suppl 3):S30-4.3 Inman WHW, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and thesteroidal content of oral contraceptives. A report to the Committee on Safety of Drugs.BMJ 1970;2:203-9.4 Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk ofvenous thromboembolism: national follow-up study. BMJ 2009;339:b2890.5 Shapiro S, Dinger J. Risk of venous thromboembolism among users of oral contraceptives:a review of two recently published studies. J FamPlann Reprod Health Care 2010;36:33-8.6 Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk amongoral contraceptive users: cohort data from the Royal College of General Practitioner’soral contraception study. BMJ 2007;335:651-4.7 Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V, Lee AJ. Mortality amongcontraceptive pill users: cohort evidence from Royal College of General Practitioners’ oralcontraception study. BMJ 2010;340:c927.Cite this as: BMJ 2011;343:d6592© BMJ Publishing Group Ltd 2011For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2011;343:d6592 doi: 10.1136/bmj.d6592 Page 2 of 2EDITORIALS

The progestogen content of combined oral contraceptives and venous thromboembolic risk

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