Cyproterone Acetate with Ethinylestradiol as a Risk Factor for Venous Thromboembolism: An Epidemiological Evaluation

Abstract Objective: To review the incidence of venous thromboembolism (VTE) in association with combined cyproterone acetate and ethinylestradiol (CPA/EE) use, compared to the incidence of VTE in association with conventional oral contraceptive (OC) use, in women aged 14 to 49 years. Methods: A review consistent with the guidelines of "best evidence synthesis" was conducted on 6 peer-reviewed, controlled epidemiological studies reporting both outcome numerators and exposure denominators. Relative risks as the estimate of the association between CPA/EE and the clinical outcome of VTE were set aside in favour of absolute incidence rates, rate differences, or attributable risks. Results: The range of absolute incidence rates of VTE among CPA/EE users varied from 1.2 to 9.9 per 10 000 women-years (WYs). All other marketed conventional OCs were the reference. In 6 studies conducted in 3 European countries, CPA/EE exhibited an attributable risk in women not higher than 0.04% when compared to approved conventional OCs. Except for I study exhibiting a small statistically significant benefit, there was no difference between the incidence rates of VTE among CPA/EE users and those among conventional OC users. VTE as an adverse event for CPA/EE was either rare or very rare, according to the criteria set by the World Health Organization/Council for International Organizations of Medical Sciences. No deaths were reported in the studies reviewed. Conclusions: The evidence in the worldwide literature does not demonstrate an excess of health-threatening harm for CPA/EE. A best-evidence synthesis, using sound epidemiological methods, showed clearly that the risks of VTE among CPA/EE users do not exceed the risks of VTE among conventional OC users.