A Cochrane review[Abstract] 5 included 24 case control studies estimating the risk of myocardial infarction or ischemic stroke in users compared with non-users of different types, doses and generations of combined oral contraception (COC) by a network meta-analysis. COC users were not at increased risk of myocardial infarction or ischemic stroke compared with non-users (OR 1.0, 95% CI 0.9 to 1.0). These ORs were similar for myocardial infarction alone (odds ratio, OR, 0.9, 95% CI 0.8 to 1.0) and ischemic stroke alone (OR 1.0, 95% CI 0.9 to 1.1). The risks did not vary according to the generation of progestagen or according to progestagen type. However, the risk of myocardial infarction or ischemic stroke was only increased in women using COCs containing ≥ 50 µg of estrogen.
A database cohort study 6 included 4 945 088 women aged 15-49 years using combined oral contraception. 1800 pulmonary embolisms (33 per 100 000 women years), 1046 ischaemic strokes (19 per 100 000 women years), and 407 myocardial infarctions (7 per 100 000 women years) were observed. After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg v 30-40 µg) were 0.75 (95% CI 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel.
According to the EMA's Pharmacovigilance Risk Assessment 2 the risk of arterial thromboembolism (ATE, blood clots in arteries, which can potentially cause a stroke or heart attack) is very low. There is no evidence for a difference in the level of risk between products depending on the type of progestogen.
In a 15-year Danish historical cohort study 3, nonpregnant women (15-49 years), with no history of cardiovascular disease or cancer were followed. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from Danish national registries.A total of 1 626 158 women contributed, 3 311 thrombotic strokes (21.4 per 100 000 person-years) and 1725 myocardial infarctions (AMI) (10.1 per 100 000 person-years) occurred. Relative risks were calculated for contraceptives with ethinyl estradiol (EE) at a dose of 30 to 40 μg and different progestin types as well as for EE at a dose of 20 μg and different progestins. Although the absolute risks of thrombotic stroke and AMI associated with the use COC were low, the risk was increased by a factor of 0.9 to 1.7 with COC that included EE at a dose of 20 μg and by a factor of 1.3 to 2.3 with those that included EE at a dose of 30 to 40 μg, with relatively small differences in risk according to progestin type.
In a hospital-based case-control study 4 in UK, among women who did not use COC, smoke nor had any other cardiovascular risk factors total incidence of stroke and AMI were less than 2 events per 100 000 woman years in those aged 20-24 years and rose exponentially with age to 8 events per 100 000 among women aged 40-44 years. Cardiovascular mortality associated with smoking was greater than that associated with COC use at all ages. Attributable risk associated with COC use was 1 death per 370 000 users annually among women aged 20-24 years, 1 per 170 000 at ages 30-34 years, and 1 per 37 000 at ages 40-44 years. Among smokers, the cardiovascular mortality attributable to COC use was estimated to be about 1 per 100 000 users annually among women aged less than 35 years, and about 1 per 10 000 users annually among those above the age of 35 years.
A cohort study 7 (UK Biobank) included 161 017 women who had no CVD at baseline and reported their OC use. Overall, 131 131 (81.4%) of 161 017 participants reported OC use at baseline. The multivariable-adjusted hazard ratios for OC ever users versus never users were 0.92 (95% CI 0.86 to 0.99) for all-cause death, 0.91 (95% CI 0.87 to 0.96) for incident CVD events, 0.88 (95% CI 0.81 to 0.95) for coronary heart disease, 0.87 (95% CI 0.76 to 0.99) for heart failure, and 0.92 (95% CI 0.84 to 0.99) for atrial fibrillation. However, no significant associations of OC use with CVD death, myocardial infarction, or stroke were observed. Furthermore, the associations of OC use with CVD events were stronger among participants with longer durations of use (P for trend <0.001).
Comment: The quality of evidence is upgraded by large magnitude of effect.
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