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Aims: In October 1995 in response to the results of three studies, the Committee on the Safety of Medicines advised doctors and pharmacists that oral contraceptives containing desogestrel (DSG) and gestodene (GST) were associated with around a two-fold increase in the risk of thromboembolism compared with those containing other progestogens. The objective of this study was to estimate the risk of idiopathic venous thromboembolic disease (VTE) in users of combined oral contraceptives (COCs), to compare the risk between formulations and to examine the effect of using age banding as opposed to matching by exact year of birth., Methods: A nested case control study was conducted using the General Practice Research Database. Women with a VTE event recorded between 1992 and 1997, who were treated with an anticoagulant, from consideration of their prescription records were likely to have been using a COC prescription on the day of the event and also had no exclusion factors, were deemed cases. For comparison with the previous studies, two nested case control studies were undertaken. Study 1 used controls matched by practice and year of birth. Study 2 used controls matched by practice and within 5 years age bands., Results: We found an incidence of idiopathic VTE amongst users of combined oral contraceptives of 3.8 per 10 000 exposed women years. Incidence rates increased markedly after 35 years of age. The nested case-control study using controls matched by year of birth showed no significant difference in risk between the major COC formulations. With levonorgestrel (LNG) 150 microgram and ethinyloestradiol (EE) 30 microgram as the reference, the adjusted ORs for GST 75 microgram and EE 30 microgram was 1.3 (95% CI 0.8, 2.1), for DSG 150 microgram and EE 30 microgram it was 1.0 (95% CI 0.7, 1.7) and for DSG 150 microgram and EE 20 microgram it was 0.8 (95% CI 0.4, 1.6). Using less rigorous matching criteria, matching controls to cases within 5 years age bands, the ORs increased. When a mixed group of COCs, characterized by having LNG as the progestogen component was used as the reference category, there was an elevation in the ORs for the newer products. We found a significant association between idiopathic VTE and current smoking (OR 2.0 (1.4, 2.7)), BMI over 35 (OR 3.8 (1.8, 8.0)) and asthma (OR 1.9 (1.3, 2.9)). The OR for women who had proxy evidence of general ill health (indicated by the number of prescriptions issued) was 2.2 (1.7, 3.7)., Conclusions: The results of this study indicate that a number of the characteristics of the women taking COCs affect the risk of VTE. There is no evidence to support the hypothesis that there is any difference in risk between COC formulations containing under 50 microg ethinyloestradiol.

The results of three independent studies of venous thromboembolic disease (VTE) and oral contraceptives are reviewed together with two further cohort/case-control studies which we conducted using the MediPlus and General Practice Research Database (GPRD) databases. These latter studies jointly involved 395 cases and uniquely examined the association between VTE and individual combined oral contraceptive (COC) formulations. The two studies yielded very similar results. Crude incidence rates for idiopathic VTE of 4.6 and 3.8 were found per 10,000 exposed woman-years (EWY), in the MediPlus and GPRD studies respectively. Incidence rates increased markedly with age, and in both databases the rates amongst users of levonorgestrel products were lower than those amongst users of desogestrel and gestodene products. A case fatality rate of 3% and a mortality rate of 10 per million EWY were estimated. Odds ratios (OR) were calculated for confounding variables and different COC formulations. Both database studies indicated an excess of current smokers and women with high body mass indices amongst cases. There were significantly more cases with asthma in the GPRD study and cases who had been using their COC for less than a year. No statistically significant differences between COC formulations were found in the analyses where controls were matched to cases by practice and year of birth in both the MediPlus and GPRD studies. In the GPRD study we also ran a study where controls were matched by practice and within 5 year age bands. In this study the OR were consistently higher for the newer or 'third generation' products than when controls were matched by year of birth. However only the acne formulation/OC containing cyproterone acetate and 35 microg ethinyloestradiol yielded a significant OR of 2.3. It may be concluded that improvements in prescribing are paramount as the results strongly indicate that overweight women and those who smoke are at a greater risk of VTE. Further study is required to elucidate the possibility that asthma or its treatment may predispose to VTE, alone or in combination with other risk factors. However, neither the MediPlus nor GPRD studies indicate that any one COC formulation poses a greater risk of VTE than another.

This study investigated the risk of venous thromboembolic disease (VTE) between second and third generation combined oral contraceptives, using the German MediPlus database of patient records. Women studied included 42 patients between the ages of 18 and 49 years, with a diagnosis of VTE treated with an anticoagulant, who were exposed to an oral contraceptive (OC). Four controls per patient (168), matched by year of birth and exposure to an OC on the even day, were identified. More women were users of second generation than third generation OC, and none were using progestogen-only pills. There was no significant difference between patients and control subjects with respect to the type of OC used on the event day (unadjusted odds ratio for third versus second generation users was 0.77; 95% confidence interval [CI] 0.38-1.57). There was no significant age difference between second and third generation users among patients or control subjects. Between January 1 and the event date, there was no significant difference between the patients and control subjects in terms of the number of oral contraceptive prescriptions, number of consultations for psychotherapeutic complaints, or mixed physical and psychotherapeutic consultations; however, patients did demonstrate significantly more consultations for purely physical complaints compared with control subjects (p < 0.0001). There were no significant consultation differences between patients with pulmonary emboli (n = 6) and other VTE patients (n = 36). No significant differences with respect to VTE risk between users of second and third generation oral contraceptives were found in this study. Consultations (physical) for patients were higher than for control subjects before the VTE event. If consultation rate relates to the general health status of a person, this might indicate that VTE risk is higher among women of poorer health, but that this is not related to the type of progestogen in the oral contraceptive that they use.

Study Objective: To investigate whether there has been an increase of venous thromboembolism (VTE) mortality in European countries, concurrent with the replacement of second generation by third generation combined oral contraceptives (COCs). Such an increase has been predicted, and reportedly detected, because published studies have detected an increased incidence of VTE associated with third generation rather than second generation COC use., Design: Data were collected on population and annual VTE mortality in women 15-34 and 35-49 years old, and on second and third generation COC sales, from 1981 to 1994 in 13 European countries. Data from the seven most populous countries were analysed by linear regression of annual VTE mortality, in the 15-34 and 15-49 age groups, with respect to calculated total and third generation COC use rates, and the regression coefficients used to estimate mortality differences between second generation users and non-users and between third and second generation users, respectively., Main Results: The estimated mortality differences in all seven countries had confidence intervals wide enough to contain both zero and the excess mortalities expected from the results of published studies. This was true both for the mortality difference between third and second generation COC users and for that between second generation users and COC non-users., Conclusions: Mortality differences of the size expected from the published studies cannot be measured using annual national VTE mortality and COC sales data alone, because of residual interannual variation in VTE mortality, and possibly confounding between rising third generation market share and total COC use.

A matched case-control study was undertaken in 10 centers in Germany and the United Kingdom to explore the association of current use of major combination oral contraceptives with the occurrence of venous thromboembolism. The cases recruited were 505 women aged 16-44 years with venous thromboembolism, controls were 1877 women (at least 3 controls per case) matched for 5-year age group and region without VTE. The main outcome measures were odds ratios derived by comparing current use of a specific oral contraceptive or group of OC against current use of other groups or against no current use of OC. The odds ratios (95% confidence intervals) for venous thromboembolism were: for third generation products (low dose ethinyloestradiol, gestodene and desogestrel) versus second generation products (low dose ethinyloestradiol, no gestodene and desogestrel, 1.5 (1.1 to 2.0), for third versus second generation products with norgestimate included in third generation, 1.6 (1.2 to 2.2). The odds ratios for current use for women aged 16-44 of specific progestagens versus levonorgestrel-containing compounds were 1.7 (1.1 to 2.6) for gestodene, 1.8 (1.2 to 2.6) for desogestrel, 1.9 (1.0 to 3.6) for norgestimate and 1.3 (0.7 to 2.5) for progestagen-only pills. For women aged 25 to 44 likely to be exposed to any of these progestagens, odds ratios for the comparison of progestagens versus levonorgestrel showed a successive increase by market introduction ranging from 1.5 (0.9 to 2.5) for desogestrel with 30 micrograms oestrogen content (introduced 1981) to 2.8 (1.3 to 6.5) for desogestrel with 20 micrograms oestrogen content (introduced 1992) significant in linear trend analysis (p = 0.00012). The influence of norgestimate classification as third or second generation product does not significantly alter the results regarding the association of third generation products and venous thromboembolism. A direct comparison of current use of norgestimate (which is primarily metabolized to levonorgestrel) versus levonorgestrel shows an increased odds ratio. The trend of increasing risk of progestagens by recency of market introduction when compared with levonorgestrel is strongly indicative of the existence of external bias due to attrition of susceptibles.

Objective: To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of venous thromboembolism., Design: Matched case-control study., Setting: 10 centres in Germany and United Kingdom., Subjects: Cases were 471 women aged 16-44 who had a venous thromboembolism. Controls were 1772 women (at least 3 controls per case) unaffected by venous thromboembolism who were matched with corresponding case for age and for hospital or community setting., Main Outcome Measures: Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables., Results: Odds ratios (95% confidence intervals) for venous thromboembolism were: for any oral contraceptives versus no use, 4.0 (3.1 to 5.3); for second generation products (low dose ethinyl-oestradiol, no gestodene or desogestrel) versus no use, 3.2 (2.3 to 4.3); for third generation products (low dose ethinyloestradiol, gestodene or desogestrel) versus no use, 4.8 (3.4 to 6.7); for third generation products versus second generation products, 1.5 (1.1 to 2.1); for products containing gestodene versus second generation products, 1.5 (1.0 to 2.2); and for products containing desogestrel versus second generation products, 1.5 (1.1 to 2.2). Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year, for women using second generation products it is about 14 per million users per year, and for non-users it is five per million per year., Conclusions: Risk of venous thromboembolism was slightly increased in users of third generation oral contraceptives compared with users of second generation products.