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Risk of venous thromboembolism in users of oralcontraceptives containing drospirenone or levonorgestrel:nested case-control study based on UK General PracticeResearch Database Lianne Parkin, senior lecturer in epidemiology,1 Katrina Sharples, senior lecturer in biostatistics,1 Rohini KHernandez, epidemiologist,2 Susan S Jick, director2 Objective To examine the risk of non-fatal idiopathic In 2002 a series of case reports raised concerns about the venous thromboembolism in current users of a combined risk of venous thromboembolism in users of a recently oral contraceptive containing drospirenone, relative to marketed oral contraceptive containing 30 µg oestrogen current users of preparations containing levonorgestrel.
and a new progestogen, drospirenone.1 These reports emerged in the wake of earlier findings that oral contra- Setting UK General Practice Research Database.
ceptives containing the newer progestogens desogestrel Participants Women aged 15-44 years without major risk and gestodene (“third generation” pills), and cyproter- factors for venous thromboembolism who started a new one acetate, carried higher risks of venous thromboem- episode of use of an oral contraceptive containing 30 µg bolism than did pills containing an older progestogen, oestrogen in combination with either drospirenone or levonorgestrel between May 2002 and September 2009.
Since 2002 several studies have explored the risk of Cases were women with a first diagnosis of venous venous thromboembolism in users of the oral contra- thromboembolism; up to four controls, matched by age, ceptive containing drospirenone.8-11 However, whether duration of recorded information, and general practice, this new oral contraceptive carries a higher risk of were randomly selected for each case.
venous thromboembolism than do preparations con- Main outcome measures Odds ratios and 95% taining levonorgestrel remains uncertain. Two industry confidence intervals estimated with conditional logistic funded cohort studies, which were done to meet post- regression; age adjusted incidence rate ratio estimated marketing surveillance commitments, reported similar risks of venous thromboembolism in users of drospire- Results 61 cases of idiopathic venous thromboembolism none and other oral contraceptives.89 However, in one and 215 matched controls were identified. In the case- study, the reference group was not clearly defined and control analysis, current use of the drospirenone may have included women who took oral contracep- contraceptive was associated with a threefold higher risk tives associated with a higher risk of venous of non-fatal idiopathic venous thromboembolism thromboembolism.8 In the second study, the rates of compared with levonorgestrel use; the odds ratio venous thromboembolism in users of contraceptives adjusted for body mass index was 3.3 (95% confidence containing levonorgestrel were reported to be similar interval 1.4 to 7.6). Subanalyses suggested that referral, not only to those in drospirenone users but also to diagnostic, first time user, duration of use, and switching biases were unlikely explanations for this finding. The contraceptives.9 This last finding is contrary to what crude incidence rate was 23.0 (95% confidence interval would be expected if that group had included users of 13.4 to 36.9) per 100 000 woman years in current users of higher risk contraceptives. Two other studies found a drospirenone and 9.1 (6.6 to 12.2) per 100 000 woman small increase in risk of venous thromboembolism in years in current users of levonorgestrel oral users of the drospirenone oral contraceptive when com- contraceptives. The age adjusted incidence rate ratio was pared with levonorgestrel.1011 In a Danish registry based cohort study, the relative risk was 1.64 (95% con- Conclusions These findings contribute to emerging fidence interval 1.27 to 2.10).10 A population based case- evidence that the combined oral contraceptive containing control study in the Netherlands reported an odds ratio drospirenone carries a higher risk of venous of 1.7 (95% confidence interval 0.7 to 3.9).11 thromboembolism than do formulations containing All four studies included some non-idiopathic cases (women with other known risk factors for venous thromboembolism). The presence of risk factors for restarting after a break). We therefore excluded venous thromboembolism not only affects the prob- women whose only use of a study oral contraceptive ability of the woman developing the condition but during the study period was part of a continuous epi- also influences decisions about prescribing of oral con- sode of oral contraceptive use that had begun before 1 traceptives. Therefore, the inclusion of women with May 2002. We took the date of the first new prescrip- such risk factors in the study populations makes draw- tion for a study oral contraceptive after 1 May 2002 as ing valid causal inferences more difficult.12 Secondary the date of entry into the study cohort.
to this, failure to exclude people with other risk factors To estimate woman years of use of drospirenone and for the disease of interest can also result in a dilution of levonorgestrel oral contraceptives in the study cohort, a real effect.13 For these reasons, the generally pre- we counted the time from the date of the first prescrip- ferred approach in studies of drug safety is to base the tion in each episode of use until the end of the last pre- investigation on a study population without major risk scription plus 45 days. We considered consecutive factors for the disease.12 We therefore did a nested case- prescriptions for a study oral contraceptive to be part control study to estimate the risk of non-fatal idiopathic of the same episode of use if the elapsed time between venous thromboembolism associated with current use the end date of any one prescription and the issue of the of the oral contraceptive containing drospirenone rela- tive to current use of preparations containing levonor-gestrel.
Identification of potential cases and controlsWe carried out all steps in the ascertainment of poten- tial cases and selection of controls without knowledge We did a case-control study nested in a cohort of users of the particular study oral contraceptives women were of oral contraceptives containing 30 µg oestrogen in combination with either drospirenone or levonorges-trel. The study was based on data from the UK General Practice Research Database. This database has been We identified women who had a recorded diagnosis of used previously in several studies of oral contraceptive venous thromboembolism (deep vein thrombosis or use and venous thromboembolism.3 5 7 It contains pulmonary embolism) after their entry into the cohort information derived from the general practice records from the computer records, using the same Read and of more than three million people in the United King- OXMIS codes as previously used in studies based on dom, including demographic data and details of the General Practice Research Database.3 57 We prescribed drugs, medical diagnoses, hospital admis- excluded those who did not have a record of treatment with an anticoagulant, as well as any women who con-tinued to receive prescriptions for oral contraceptives after the index date, because the validity of the diagno- As drospirenone first became available in the UK in sis of venous thromboembolism was less certain in April 2002, we confined the study to the years after such women. We took the date of diagnosis of venous this date. We identified all women who had received thromboembolism as an index date. Women were eli- at least one prescription for an oral contraceptive con- gible for inclusion as potential cases if they were aged taining 30 µg oestrogen in combination with either 15-44 years on the index date and were current users of drospirenone or levonorgestrel between 1 May 2002 a study oral contraceptive. We defined current users as and 30 September 2009 (the study period).
women who received a prescription that would have We excluded women if they had a recorded history extended to the index date or to within 30 days of of risk factors for venous thromboembolism, as well as that date. We took current use as the relevant exposure other conditions that might influence decisions about period, because the risk of venous thromboembolism prescribing of oral contraceptives, such as previous is increased while women are taking oral contracep- venous thromboembolism, cancer (except non- tives and then returns to normal baseline levels once melanoma skin cancer), chronic renal failure, myo- such use is discontinued.14 To be included in the study, cardial infarction, stroke, other cardiovascular disease, current users had to have at least one year of recorded treated hypertension, treated hyperlipidaemia, type 1 medical information before the index date. We defined diabetes, ulcerative and other colitis, systemic lupus the current episode of use as the continuous episode of erythematosus, rheumatoid arthritis, ankylosing spon- oral contraceptive use that led up to the index date.
dylitis and other spondylopathies, psoriatic arthritis, This episode could include the use of only one oral cystic fibrosis, injecting drug use, and coagulation contraceptive or the use of more than one if a woman switched directly from one oral contraceptive to To avoid comparing the risk of venous thromboem- bolism in dissimilar groups of oral contraceptive users, Two researchers, blinded to exposure status, inde- only those women who started a new episode of use of a pendently reviewed the computerised medical records study oral contraceptive after 1 May 2002 were eligible of the potential cases to identify women who had tem- for inclusion in the study cohort (this included women porary risk factors for venous thromboembolism who had never used oral contraceptives previously, as shortly before the index date. We excluded women well as those who had used them in the past and were who had a record of pregnancy, surgery, major injury, or prolonged immobility in the three months before adjustment for body mass index in all models; we the index date. Any disagreement between the included other variables if they were significant predic- reviewers was discussed and a consensus was reached.
tors or if their inclusion altered the odds ratio for the For a subset of the remaining potential cases (the first association with type of oral contraceptive by more 42 identified), we sent for copies of hospital discharge than 10%. For the key analysis, we present both com- letters or outpatient clinic correspondence (as uncom- plete case and imputed data analyses.19 We used Stata plicated deep vein thrombosis is increasingly being version 11.0 for all analyses. We estimated incidence treated in an outpatient setting in the UK15) to deter- rates and age standardised rate ratios by using Stata mine the proportion for whom the diagnosis of venous thromboembolism could be validated and the propor-tion in whom no other major risk factors for venous From the computer records, we identified 65 poten-tially eligible cases of venous thromboembolism. We sent for hospital discharge or outpatient clinic letters For each eligible case, we randomly selected from the for 42 of these women, and we received information study cohort up to four controls matched by year of for 31. We excluded four women on the basis of this birth (within two years), number of years of recorded extra information. One had a basilic vein thrombosis data, and general practice. The index date of each case that was thought to have an anatomical cause; the served as the index date for her matched controls. As remaining three had confirmed venous thrombo- with cases, potential controls had to be current users of a study oral contraceptive and to have had at least one phospholipid syndrome, major trauma, prolonged year of recorded medical information before the index immobility). For a further two women, the information date. Two researchers, blinded to exposure status, we received was minimal and we could not determine independently reviewed the computer records of whether the diagnosis (deep vein thrombosis in one, potential controls. Controls were subject to the same pulmonary embolism in the other) had been made on the basis of objective tests or if any precipitating eventshad occurred. We thus included 61 cases in the study; 27 had a diagnosis of deep vein thrombosis alone, and We used conditional logistic regression to compute odds ratios and 95% confidence intervals in the case- Table 1 summarises the characteristics of the 61 control analyses. The key analysis estimated the risk of cases and 215 controls. The mean age was 32.2 years non-fatal idiopathic venous thromboembolism in cur- for the cases and 31.8 years for the controls. Among rent users of the oral contraceptive containing drospir- those with a recorded body mass index (93% of cases, enone relative to current users of levonorgestrel 86% of controls), 35 (61%) cases and 57 (31%) controls preparations. To do an analysis stratified according to had a body mass index of 25 or above. The median history of oral contraceptive use (first episode of oral body mass index was 26.1 (range 19.1-45.7) in cases contraceptive use or previous episodes of use), we also and 23.3 (17.3-43.2) in controls. Body mass index was did an unmatched analysis but accounted for the unknown for 34 women (four cases); for five of them matched design by adjusting for year of birth and dura- (all controls), smoking status was also unknown. Those tion of recorded medical information and adjusting the with missing body mass index values were more likely standard error for clustering on general practice. We to have had deep vein thrombosis than pulmonary used chained equations to impute missing values of embolism (if cases), be users of levonorgestrel oral con- body mass index and smoking status16-18; we used 100 traceptives, be taking antidepressants, be younger, and imputations to obtain stability to one decimal place.
to be having their first episode of oral contraceptive The variables included in the imputation model were use. A slightly smaller proportion of cases than con- matching variables (year of birth and duration of trols were current smokers. Three cases and nine con- recorded information), outcome (deep vein thrombo- trols had a history of varicose veins; one control had a sis, pulmonary embolism, or control), type of oral con- history of superficial venous thrombosis. Cases were traceptive (drospirenone or levonorgestrel), and more likely to be current users of antidepressants covariates (log(body mass index), age at index date, smoking status, current use of antidepressants, history Table 2 shows the results of the key analysis. Seven- of varicose veins, history of oral contraceptive use teen (28%) cases and 26 (12%) controls were current before the current episode, duration of the current epi- users of the drospirenone oral contraceptive. In the sode of use, and whether the current episode involved matched analysis involving all cases and controls, the the use of more than one oral contraceptive).
unadjusted odd ratio was 3.2 (95% confidence interval Potential confounders explored in the analysis mod- 1.5 to 7.0). The odds ratio adjusted for body mass index els were body mass index (as a continuous variable), was 3.3 (1.4 to 7.6). Further adjustment for a history of history of varicose veins, smoking status (non-smoker, varicose veins, smoking, and the use of antidepressants current smoker, past smoker), and antidepressant use.
(any antidepressant or tricyclic and non-tricyclic anti- We also explored the effect of the duration of the cur- depressants separately) had a negligible effect; the odds rent episode of oral contraceptive use. We retained ratio was 3.1 (1.3 to 7.5). In a model that adjusted for use gave odds ratios of 4.1 (1.4 to 12.2) and 2.4 (0.6 to Table 1 | Characteristics of cases and controls. Values are numbers (percentages) unlessstated otherwise Fourteen (23%) cases and 36 (17%) controls had no record of any previous oral contraceptive use before the current episode. We did an analysis to explore whether the excess risk of venous thromboembolismassociated with the use of the drospirenone oral contra- ceptive differed according to the history of oral contra- ceptive use before the current episode (no previous use, at least one previous episode of use). Among first time users, the unmatched odds ratio from the inter- action model adjusted for the matching factors and body mass index was 8.6 (1.7 to 42.8). For women who had previously used oral contraceptives, the cor- responding adjusted odds ratio was 2.4 (1.1 to 5.2). The P value for the interaction was 0.17.
We also did a matched analysis to examine whether the excess risk of venous thromboembolism in current users of the drospirenone contraceptive differed according to the elapsed time since the product had been introduced on to the market. We chose a cut-off date of 1 January 2007 to allow for sufficient woman years of use of both oral contraceptives to be accumu- lated. We found elevated risks in the periods beforeand after January 2007. The odds ratios from the inter- these factors and the duration of the current episode of action model (adjusted for body mass index) were 2.2 use, the odds ratio was 3.2 (1.3 to 7.6). These odds (0.5 to 9.2) in the first period and 4.1 (1.4 to 11.8) in the ratios from the imputed missing data analysis were second period; the P value for the interaction was 0.5.
slightly higher than those obtained in the complete Six cases and 17 controls had taken more than one case analysis (the analysis that excluded cases and con- oral contraceptive in the course of their current epi- trols with missing body mass index and the controls of sode of continuous oral contraceptive use. When we excluded these women, the adjusted (for body mass We estimated separate associations for validated and index) matched odds ratio was 3.2 (1.1 to 8.7). Adjust- unvalidated cases in a model with an interaction term.
ment for switching (and body mass index), rather than After adjustment for body mass index, the odds ratio excluding these women, produced similar results; the for validated cases was 4.0 (0.9 to 16.5) and that for unvalidated cases was 3.0 (1.0 to 8.5); the P value for We found 318 825 women who met all of the criteria the interaction was 0.8. Further adjustment for anti- for inclusion in the study cohort. This cohort had an depressant use gave odds ratios of 3.4 (0.8 to 14.9) estimated 73 853 woman years of use of the oral contra- ceptive containing 30 µg oestrogen and drospirenoneand 482 229 woman years of use of preparations con- We also examined the risks of pulmonary embolism taining 30 µg oestrogen and levonorgestrel. The crude and deep vein thrombosis separately; the matched incidence rates were 23.0 (95% confidence interval odds ratio for pulmonary embolism (adjusted for 13.4 to 36.9) per 100 000 woman years in current body mass index) was 2.1 (0.8 to 5.6). The unadjusted users of drospirenone oral contraceptives and 9.1 (6.6 matched estimate for deep vein thrombosis (based on to 12.2) per 100 000 woman years in current users of 10 discordant case-control sets) was 8.6 (1.8 to 41.6).
levonorgestrel oral contraceptives. The age adjusted Adjustment for body mass index gave an even higher incidence rate ratio was 2.7 (1.5 to 4.7).
odds ratio with a very wide confidence interval, indi-cating that the estimate was unreliable in this small sub- In this study, women who were current users of the oral We also did matched analyses to examine whether contraceptive containing drospirenone were about the excess risk of venous thromboembolism in current three times as likely to develop non-fatal idiopathic users of the drospirenone oral contraceptive, relative venous thromboembolism as were current users of to users of levonorgestrel, differed according to age (<35 years, ≥35 years); the odds ratios from the inter- matched odds ratio (adjusted for body mass index) in action model (adjusted for body mass index) were 3.7 the case-control analysis was 3.3 (95% confidence (1.3 to 10.7) for the younger women and 2.8 (0.7 to interval 1.4 to 7.6), and the age adjusted incidence 10.7) for the older women; the P value for the inter- rate ratio in the cohort analysis was 2.7 (95% confi- action was 0.7. Further adjustment for antidepressant used multiple imputation methods to impute missing Table 2 | Current use of oral contraceptives and venous thromboembolism data for body mass index and smoking; although this assumes that data are missing at random, non- ignorable mechanisms that would have had more than a minimal effect on the estimated odds ratios are We did not have information about family history of venous thromboembolism, but any difference in the prevalence of this risk factor between users of drospir- enone and levonorgestrel contraceptives would be *Adjusted for body mass index as continuous variable.
unlikely to be of sufficient magnitude to explain a †Missing values for body mass index and smoking are imputed.
‡Effect of multiple imputation is illustrated by presentation of complete case analysis adjusted for body mass threefold elevated risk. Thus, our results seem very index; cases and controls with missing body mass index are excluded from complete case analysis, as are unlikely to be explained by any selective prescribing of the newer product to women at higher risk of venousthromboembolism. Finally, to compare similar groups of users, we confined the study to women who started a The study had several strengths. Firstly, we are likely to new episode of oral contraceptive use after drospire- have identified all potential diagnosed cases of non- none was first available for use. We found no evidence fatal venous thromboembolism in the study cohort, that current users of drospirenone as a group included because information about outpatient and emergency a disproportionate number of short term or first time department visits and hospital admissions in the UK is users (who seem to carry a higher risk of venous sent to general practitioners, and the practices contri- thromboembolism21) than did current users of levo- buting to the General Practice Research Database are norgestrel pills. Moreover, the excess risk associated trained to record the diagnoses associated with such with the drospirenone contraceptive persisted after visits and admissions in the patient’s record. Secondly, adjustment for duration of use; it was also apparent referral and diagnostic biases seem unlikely explana- both in first time users and in women who had taken tions for our results, as an elevated risk in users of the oral contraceptives previously, and it was lower during drospirenone oral contraceptive was also apparent in the period after the introduction of drospirenone the analysis confined to cases of pulmonary embolism (when it might be expected to be higher if drospire- —cases in whom the severity of the condition makes none users were more likely to be first time users than any potential differential referral of users of the newer were women taking levonorgestrel pills) than in later oral contraceptive much less likely. Thirdly, for both years. The point estimate also remained above 3.0 cases and controls, information about the medical his- when we took switching into account.
tory and prescription of oral contraceptives and other The main limitation of this study was the relatively drugs came from medical records and hence was not small number of cases, which inevitably limited the subject to recall bias. Body mass index also came from precision of our estimates of relative risk in the subana- records, rather than self report. Controls came from lyses, as shown by the wide 95% confidence intervals.
the same general practices as cases and were matched Nevertheless, the point estimates obtained in the ana- on the number of years of recorded medical informa- lyses stratified by age, certainty of diagnosis, history of tion, ensuring comparable quality and duration of contraceptive use, and calendar period were all consis- information. Moreover, the duration of recorded infor- tently in the order of at least a twofold to threefold mation was considerable (mean duration 10 years), higher risk of venous thromboembolism in users of permitting the ascertainment of comprehensive medi- the oral contraceptive containing drospirenone rela- cal and contraceptive histories. Fourthly, we restricted tive to users of levonorgestrel. Moreover, the results the study to current users of drospirenone and levonor- of this study are very similar to those of a larger study gestrel contraceptives who received prescriptions from that used data from a US claims database.22 their general practitioners. Although some current We did not obtain copies of hospital discharge or users of oral contraceptives could have been excluded outpatient clinic letters for all potential cases, but in from this study because they obtained their contracep- the subset of women for whom we had such informa- tives from other sources such as family planning tion all had confirmed venous thromboembolism and clinics, the risk of venous thromboembolism in users only four were considered non-idiopathic. This pro- of the drospirenone contraceptive relative to levonor- vides reassurance that virtually all of the women gestrel users would need to be different in the excluded included in this study are likely to be true cases.
group for this to have any relevance to the inter- Although some of the women for whom we did not pretation of our results. Fifthly, confounding of the obtain extra information may have had conditions or key results by age, body mass index, smoking, conco- events that precipitated their venous thromboembo- mitant drug use, or underlying medical conditions is lism, the proportion is likely to be small and, if any- unlikely: we excluded cases and controls with major thing, the inclusion of such women is likely to have risk factors for venous thromboembolism, controls resulted in a slight attenuation of the estimates of rela- were matched to cases for year of birth, and we tive risk. In any event, we found an elevated risk for explored potential confounding in the analysis. We This study adds to emerging evidence that use of the Combined oral contraceptives containing desogestrel, gestodene, and cyproterone acetate oral contraceptive containing drospirenone is asso- are associated with a higher risk of venous thromboembolism than levonorgestrel ciated with a higher risk of venous thromboembolism than are preparations containing levonorgestrel. Per- Limited evidence suggests that an oral contraceptive containing a new progestogen, haps now is the time for a systematic review on this drospirenone, also carries a higher risk of venous thromboembolism topic. In the meantime, as no clear evidence exists toshow that the use of the drospirenone pill confers benefits above those of other oral contraceptives in Current use of the drospirenone oral contraceptive was associated with a threefold increase preventing pregnancy,25 treating acne,26 alleviating in idiopathic non-fatal venous thromboembolism compared with current use of premenstrual syndrome,27 or avoiding weight gain,28 levonorgestrel pills, although the overall risk was still low prescribing lower risk levonorgestrel preparations as Referral, diagnostic, recall, first time user, duration of use, and switching biases, and the first line choice in women wishing to take an oral confounding, are unlikely explanations for these findings The crude incidence rates were 23.0 (95% confidence interval 13.4 to 36.9) and 9.1 (6.6 to We thank David Skegg and Charlotte Paul for their helpful comments on 12.2) per 100 000 woman years in current users of drospirenone and levonorgestrel oral an earlier draft of the paper and Sheila Williams for help with implementing multiple imputation methods in Stata.
Contributors: LP was involved in the conception, design and conduct ofthe study, contributed to the analyses, interpreted the results, and wrotethe manuscript. SSJ was involved in the conception and design of the study, obtained data for and oversaw the conduct of the study, and Our finding of a higher risk of non-fatal venous throm- contributed to the interpretation of the results and the writing of the boembolism in users of oral contraceptives containing manuscript. KS did the imputed data analyses, interpreted the results,and contributed to the manuscript. RKH contributed to the conduct of the drospirenone, relative to levonorgestrel users, is con- analyses, the interpretation of the results, and the manuscript. All authors sistent with the results of two previous epidemiological had full access to all of the data (including statistical reports and tables) in studies.10 11 Our estimate of relative risk was somewhat the study and can take responsibility for the integrity of the data and the higher than those reported in the Danish and Dutch accuracy of the data analysis. SSJ is the guarantor.
Funding: None.
studies,10 11 but some differences in design might Competing interests: All authors have completed the Unified Competing account for this. Unlike the Danish cohort study,10 we Interest form at www.icmje.org/coi_disclosure.pdf (available on request were able to exclude women with temporary risk fac- from the corresponding author) and declare: no support from anyorganisation for the submitted work, no financial relationships with any tors for venous thromboembolism, such as surgery, organisations that might have an interest in the submitted work in the injury, and immobility, and to explore the influence previous three years, and no other relationships or activities that could of body mass index and smoking. In the Dutch appear to have influenced the submitted work.
study,11 the control group may not have provided a Ethical approval: The protocol for this study was approved by theIndependent Scientific Advisory Committee for MHRA (Medicines and good estimate of the prevalence of use of different Healthcare Products Regulatory Agency) database research.
types of oral contraceptives at the time the cases Data sharing: If access to the source data used for this study is required, occurred—about 40% of controls were partners of please contact the data owner at [email protected]
men with venous thromboembolism, and 60% wereselected through random digit dialling; the index Sheldon T. Dutch GPs warned against new contraceptive pill. BMJ2002;324:869.
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