Original research articleRisk of venous thromboembolism from oral contraceptives containing gestodene and desogestrel versus levonorgestrel: a meta-analysis and formal sensitivity analysis☆
Introduction
Oral contraceptives (OCs) have been used since the 1960s and are currently taken by approximately 100 million women worldwide [1]. Desogestrel- and gestodene-containing OCs (sometimes called third generation OCs) were introduced in Europe in 1981 and 1987, respectively [2], [3]. In 1995, data began to emerge from observational studies suggesting that desogestrel and gestodene may be associated with a higher risk of pulmonary embolism and deep vein thrombosis (collectively referred to as venous thromboembolism or VTE) than were OCs containing levonorgestrel with comparable amounts of ethinyl estradiol (EE). However, as additional data and re-analyses emerged, these results were not always replicated.
The likelihood of a cause-effect relationship has been the subject of protracted debate. As summarized elsewhere [4], [5], [6], the most plausible arguments that the observed associations are spurious take two related forms. The first is that the association is due to unmeasured confounding. Confounding is the presence of a factor that is associated both with the exposure of interest (in this case, the selection of an OC containing desogestrel or gestodene rather than levonorgestrel) and with the outcome of interest (in this case, VTE). To have affected the study results, a confounder would need to have been inadequately adjusted for in the studies showing an association. For example, if third generation OCs were preferentially prescribed to women who, because of factors not adequately adjusted for, were at an increased risk of VTE, then these agents would be associated with VTE even if there were no cause-effect relationship. This concern is often referred to as “selection bias,” “prescription bias,” “confounding by indication,” or “channeling.” [4], [5], [6], [7], [8]. The degree of unmeasured confounding that could have produced the observed associations has not been formally characterized.
A second argument that the observed association is spurious involves a phenomenon known as “depletion of susceptibles.” Depletion of susceptibles occurs when the risk of an outcome appears to decline over time because those at highest risk for the event experience it early, leaving fewer high-risk individuals remaining in the population at later time periods. According to this argument, because desogestrel and gestodene were introduced into the market more recently than levonorgestrel, any given group of desogestrel and gestodene users is likely to contain a higher proportion of new starters of OCs than any given group of levonorgestrel users, and thus to contain a higher proportion of individuals with an elevated risk for VTE, because the “susceptibles” have not yet been depleted. Therefore, according to this argument, the observed associations may have resulted from the comparison of new users of desogestrel and gestodene with longer-term users of levonorgestrel. Thus, the “depletion of susceptibles” concern can be re-stated as failure to adequately account for duration of oral contraception use.
We set out to assemble all of the available data that assess the relative risk of VTE from desogestrel and gestodene versus levonorgestrel, to perform a quantitative synthesis, and to explore explanations for any variability in study results. In addition, we wished to characterize the degree of confounding that could have produced the observed association if, in truth, there were no cause-effect relationship. This would permit future discussion to focus on the plausibility of a given degree of confounding. We therefore performed a meta-analysis and formal sensitivity analysis of studies that examined the relative risk of VTE for OCs containing desogestrel and gestodene versus levonorgestrel.
Section snippets
Identification and abstraction of data
In accordance with a written protocol, we performed a computer literature search in March 2000 using the search strategy listed in the Appendix. All citations identified by this search (including the abstract, where available electronically) were reviewed by two reviewers, and the article was obtained if either reviewer thought that the article might meet the inclusion criterion or might contain references to papers meeting the inclusion criterion. We also examined the reference lists of
Meta-analysis
The computer literature search produced a total of 2609 references, and the manual methods produced an additional 36 references, for a total of 2645 citations screened. From these, we identified a total of 11 studies of different populations that met the inclusion criterion. Two additional studies meeting the inclusion criterion and published after our initial literature review [14], [15] were also included (Table 1). One of these studies [14] supplanted the originally selected study [45] of
Discussion
The summary relative risk of VTE associated with use of desogestrel and gestodene versus levonorgestrel was 1.7 (1.3–2.1) from the available studies, all of which are observational. The direction of the association was reasonably consistent across studies and across study designs. Although consistency enhances the plausibility of an association, it also remains possible that the same sources of bias, or even different sources of bias acting in the same direction, could have produced such
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Supported by a research contract from Wyeth-Ayerst Research. The sponsor was given the opportunity to provide nonbinding comments on the manuscript. The authors retained publication rights, including freedom to determine the final wording.