NEJM：激素类避孕药增加血栓性卒中和心肌梗死风险

《新英格兰医学杂志》6月14日发表的一项大型丹麦队列研究显示，使用含有少量或极少量雌二醇的口服避孕药的女性，发生血栓性卒中和心肌梗死(MI)的相对风险是不使用者的1~2倍，不过绝对风险仍然非常低(N. Engl. J. Med. 2012;366:2257-66)。
在这项研究中，哥本哈根大学的Øjvind Lidegaard博士及其同事在1,626,158名15~49岁(1995年时)丹麦女性中探讨了新型激素类避孕药与血栓性卒中和MI之间的关系。在截至2009年的15年随访期间，观察到3,311起初次血栓性卒中和1,725起初次MI。卒中和MI的病死率分别为1.0%和10.8%。

使用低剂量口服避孕药(30~40 mcg雌二醇)女性的动脉血栓形成风险是不使用者的1.3~2.3倍，使用极低剂量口服避孕药(20 mcg雌二醇)女性的风险是不使用者的0.9~1.7倍。根据口服避孕药所含的不同类型孕激素进行分析，得出的风险结果无明显改变。

随着年龄的增加，动脉血栓形成风险的增加更加明显。在基线年龄45~49岁的最大年龄组中观察到的血栓性卒中风险和MI风险分别是最年轻组(15~19岁)的20倍和100倍。

该研究还对其他激素类避孕产品进行了评价，结果发现仅含有孕激素的避孕产品(如释放左炔诺孕酮的宫内节育器和皮下埋植剂)并不显著增加血栓性卒中和MI风险。

相比之下，避孕贴剂使用者的相对血栓性卒中风险是未使用者的3.15倍，阴道环使用者的该风险是未使用者的2.49倍。由于避孕贴剂亚组和阴道环亚组的MI数量过少，因此无法可靠估计MI风险。

研究者估计，10,000例女性使用20 mg去氧孕烯炔雌醇1年，将发生2例动脉血栓形成，6.8例静脉血栓形成。尽管在年轻女性中，静脉血栓形成的发生率是动脉血栓形成的3~4倍，但出现动脉血栓形成的患者的死亡率更高，而且即使存活，预后通常也较差。因此，在开具激素类避孕药时，应考虑这些风险。

在随刊述评中，亚利桑那州立大学生物医学信息部的Diana B. Petitti博士指出，尽管该研究显示激素类避孕药可增加卒中风险，但这种风险在可接受范围内，有充分证据表明其足够安全(N. Engl. J. Med. 2012;366:2316-7)。

该研究获丹麦心脏协会支持。研究者与拜耳等多家公司存在联系。Petitti博士声明无经济利益冲突。

爱思唯尔 版权所有


BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Oral contraceptives containing low- or very low-dose estradiol raised the risks of thrombotic stroke and myocardial infarction by a factor of 1 to 2 in a large Danish cohort study. The results were published in the June 14 issue of the New England Journal of Medicine.

Although these risks were high relative to the nonuse of OCs, the absolute risks of thrombotic stroke and MI remained extremely low, said Dr. Øjvind Lidegaard and his associates at the University of Copenhagen.
“We estimate that among 10,000 women who use desogestrel with ethinyl estradiol at a dose of 20 mg for 1 year, 2 will have arterial thrombosis and 6.8 women ... will have venous thrombosis. Although venous thrombosis is three to four times as frequent as arterial thrombosis among young women, the latter is associated with higher mortality and more serious consequences for survivors. Therefore, these figures should be taken into account when prescribing hormonal contraception,” they noted.

Few studies have examined the risks of thrombotic stroke and MI associated with the newer hormonal contraceptives, and those that have examined the issue have produced conflicting results. Dr. Lidegaard and his colleagues assessed this association in a cohort of Danish women aged 15-49 years in 1995 who were followed through 2009.

Among these 1,626,158 study subjects, there were 3,311 first thrombotic strokes and 1,725 first MIs during the 15-year follow-up. The case fatality rates were 1.0% for stroke and 10.8% for MI.

Compared with women who didn’t use hormonal contraceptives, those who used low-dose OCs (30-40 mcg estradiol) had a risk of arterial thrombosis that was 1.3-2.3 times higher, and women who used very-low-dose OCs (20 mcg estradiol) had a risk that was 0.9-1.7 times higher, the investigators said (N. Engl. J. Med. 2012;366:2257-66).

These risks did not vary significantly according to the different types of progestin contained in the OCs.
To put these risk elevations in context, it is useful to note that increasing age raised the risk of arterial thrombosis much more dramatically. The risk of thrombotic stroke was 20 times higher and that of MI was 100 times higher among the oldest study subjects – aged 45-49 years at baseline –compared with the youngest (15-19 years). Several previous studies also have noted the steep rise in thrombotic risk with increasing patient age, the researchers said.

Other hormonal contraceptive products also were assessed in this study. None of the contraceptive products that contained progestin only – such as the levonorgestrel-releasing IUD and subcutaneous implants – raised the risk of thrombotic stroke or MI significantly.

In contrast, contraceptive patches raised the relative risk of thrombotic stroke to 3.15, and vaginal rings raised it to 2.49. “One might expect a higher risk of thrombotic stroke with parenteral administration than with oral administration,” Dr. Lidegaard and his associates said.

The number of MIs in these two subgroups of women was too low to allow for reliable estimates of MI risk.
This study was supported by the Danish Heart Association. Dr. Lidegaard reported ties to Bayer Pharma, MSD Denmark, and Theramex. Coinvestigator Ellen Løkkegaard, Ph.D., reported ties to Pfizer.

Not Risk-Free, But Safe Enough

“Women, their physicians, and the public should be reassured not only by the Danish study but by the vast body of evidence from epidemiologic studies of hormonal contraception that have been done over the past 5 decades,” Dr. Diana B. Petitti noted in an editorial (N. Engl. J. Med. 2012;366:2316-7).

This study showed that the relative risks of thrombotic stroke and myocardial infarction “were increased by a factor of 1.5 to 2 among users of estrogen-progestin oral contraceptives with a low dose of ethinyl estradiol (30 to 40 mcg) for all the progestins studied (norethindrone, levonorgestrel, norgestimate, desogestrel, drospirenone, and cyproterone acetate). In a comparison of such low-dose formulations with different progestins, the relative risks of thrombotic stroke and myocardial infarction were statistically indistinguishable,” wrote Dr. Petitti, of the department of biomedical informatics at Arizona State University, Tucson.

Although the relative risk of thrombotic stroke was higher for users of the vaginal ring and the transdermal patch, the increases still were statistically indistinguishable.

“None of the hormonal contraceptives studied by Lidegaard and colleagues were associated with an excess risk of stroke that was unacceptable, considering their contraceptive and noncontraceptive benefits,” Dr. Petitti said. “For an individual woman, the probability of an event is quite small.”

Hormonal contraception is not risk free, but “the evidence is convincing” that it is “safe enough,” she said.
Dr. Petitti reported no financial conflicts of interest.