ArticlesPopulation-based study of risk of venous thromboembolism associated with various oral contraceptives
Introduction
Four papers, published since December, 1995, reported a slightly increased risk of venous thromboembolism (VTE) in women who used combined oral contraceptives (OCs) containing third-generation progestagens (desogestrel and gestodene) compared with women who used OCs containing second-generation progestagens (mainly levonorgestrel).1, 2, 3, 4 These findings were unexpected because previous studies had suggested that the risk of VTE was associated only with the dose of oestrogens in combined OCs.5, 6, 7 Most of the investigators interpreted their findings cautiously and did not claim to have shown a causal relation between the type of progestagen and risk of VTE. Nevertheless, action was taken by some licensing authorities before the publication of the reports.
The UK Committee on Safety of Medicines recommended that the use of OCs containing third-generation progestagens be restricted.8 Since then, the findings of these four studies have been scrutinised, and other investigators have suggested that confounding, bias, or both, may account for some of the apparent differences in incidence of VTE.9, 10, 11, 12, 13 Our population-based study used a UK general-practitioner database to re-examine the association between different types of combined OCs and risk of VTE.
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Methods
There were two parts to this study: a cohort analysis, in which we estimated and compared the incidence rates of VTE among users of the most commonly prescribed OC preparations; and a case-control study, in which we calculated the odds ratio of VTE associated with use of different types of OCs, after adjustment for potential confounding variables.
For both parts of the study we used computer records of patients from 143 general practices in the UK that used the Meditel system for patients'
Results
491 908 women were included in the study, and there were a total of 234 899 woman-years of exposure to steroid contraceptives. The numbers of woman-years of exposure to each of the major types of steroid contraceptives are given in table 1. Of the 234 899 woman-years of exposure to OCs, 108 842 (46·3%) were exposure to third-generation progestagens. The mean ages of users of each type of steroid contraceptive are also shown in table 1. Women prescribed OCs containing third-generation
Cohort investigation
We estimated that the absolute risk of VTE (pulmonary embolism and deep-venous thrombosis) among women exposed to any combined OC was 4·1 per 10 000 woman-years. This finding accords with those of most previous studies: Gerstman et al17 reported an incidence rate of 4·2 per 10 000 woman-years among users of OCs containing less than 50 μg oestrogen; Vessey and colleagues6 found an incidence rate of 4·3; and Farmer and Preston's study18 reported an incidence rate of 3·0. By contrast, Jick and
Conclusions
The WHO1 and Transnational studies3 cautioned that their findings could have been affected by bias and confounding. Indeed, Lewis and colleagues' study9 confirmed that the so-called healthy-user effect19 could result in an increased incidence of VTE among users of third-generation OCs. Our study accords with the view that bias and confounding have substantial effects on the results of investigations of the risk of VTE associated with different types of OCs. The findings from our cohort study
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