N Engl J Med. 2012 Jun 14;366(24):2257-66. doi: 10.1056/NEJMoa1111840

Thrombotic stroke and myocardial infarction with hormonal contraception

Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N
Gynecologic Clinic 4232, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

BACKGROUND: Although several studies have assessed the risk of venous thromboembolism with newer hormonal contraception, few have examined thrombotic stroke and myocardial infarction, and results have been conflicting.

METHODS: In this 15-year Danish historical cohort study, we followed nonpregnant women, 15 to 49 years old, with no history of cardiovascular disease or cancer. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from four national registries.

RESULTS: A total of 1,626,158 women contributed 14,251,063 person-years of observation, during which 3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred. As compared with nonuse, current use of oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 g was associated with the following relative risks (and 95% confidence intervals) for thrombotic stroke and myocardial infarction, according to progestin type: norethindrone, 2.2 (1.5 to 3.2) and 2.3 (1.3 to 3.9); levonorgestrel, 1.7 (1.4 to 2.0) and 2.0 (1.6 to 2.5); norgestimate, 1.5 (1.2 to 1.9) and 1.3 (0.9 to 1.9); desogestrel, 2.2 (1.8 to 2.7) and 2.1 (1.5 to 2.8); gestodene, 1.8 (1.6 to 2.0) and 1.9 (1.6 to 2.3); and drospirenone, 1.6 (1.2 to 2.2) and 1.7 (1.0 to 2.6), respectively. With ethinyl estradiol at a dose of 20 g, the corresponding relative risks according to progestin type were as follows: desogestrel, 1.5 (1.3 to 1.9) and 1.6 (1.1 to 2.1); gestodene, 1.7 (1.4 to 2.1) and 1.2 (0.8 to 1.9); and drospirenone, 0.9 (0.2 to 3.5) and 0.0. For transdermal patches, the corresponding relative risks were 3.2 (0.8 to 12.6) and 0.0, and for a vaginal ring, 2.5 (1.4 to 4.4) and 2.1 (0.7 to 6.5).

CONCLUSIONS: Although the absolute risks of thrombotic stroke and myocardial infarction associated with the use of hormonal contraception were low, the risk was increased by a factor of 0.9 to 1.7 with oral contraceptives that included ethinyl estradiol at a dose of 20 g and by a factor of 1.3 to 2.3 with those that included ethinyl estradiol at a dose of 30 to 40 g, with relatively small differences in risk according to progestin type. (Funded by the Danish Heart Association.).

Comment: Although the discussion of thrombosis during use of combined hormonal contraceptives is a few years behind us, from time to time we still see unfounded comments that certain progestagens give a higher risk of cardiovascular complications than others. In this very thorough study Lidegaard et al. again showed that there is no difference in thrombosis risk between the different progestagens, but that the amount of estrogen does make a difference. So providers should always advise the lowest dose of hormones which is acceptable. They must also always ask about own history and family history of thrombosis before prescribing a combined hormonal contraceptive. (HMV)