Risks and mechanisms of cardiovascular events in users of oral contraceptives

Abstract

Three large British studies on the vascular effects of oral contraceptives have established that the risk of thromboembolic episodes, both venous and arterial, rises with increasing estrogen dose. Two of these studies have also demonstrated a dose-dependent relationship between the progestogenic component of oral contraceptives and the risk of arterial disease, though not of venous events. In men, high levels of factor VII coagulant activity, VIIC, and plasma fibrinogen are associated with an increased risk for ischemic heart disease. In view of the dose-dependent relationship between estrogen and these two clotting factors, especially VIIC, it is likely that the effects of oral contraceptive usage on the risk for thromboembolism are mediated substantially through the level of coagulability. The relationship between the progestogenic component of oral contraceptives and the risk for arterial disease is probably related, at least in part, to the effects of progestogens on blood pressure.

PIP: The results of 3 large British studies on the vascular effects of oral contraceptives are discussed, considering the dose of estrogen and of progestin separately. The studies are of 1305 reports to the Committee on Safety of Drugs between 1965 and 1969; of 2000 reports to the Committee on Safety of Medicines from 1964-1977, and the Royal College of General Practitioners study on 46,000 women beginning in 1968. All 3 studies found that both venous and arterial thromboembolic events increased with dose of mestranol. 2 of the 3 studies showed an increased risk of arterial disease with dose of norethisterone acetate, and 1 found an excess of strokes with higher doses of levonorgestrel. Estrogens are known to raise the level of the clotting factor VIIc in a dose dependent manner in both women taking post-menopausal estrogens and in men being treated for cancer. Analogous reports have appeared for a decrease in antithrombin-III. Progestins seem to increase the incidence of hypertension with increased dose. Thus the effects of progestins on blood pressure may mediate their arterial effects.