'Safe Enough': Arterial-Thrombosis Risk of Hormonal Contraceptives Acceptable

June 14, 2012

June 13, 2012 (Copenhagen, Denmark) — The largest-study ever to examine the influence of hormonal contraception on arterial thrombosis--MI and stroke--has found that most modern products have an acceptable increased risk of such events, given their contraceptive and other benefits [1].

Lead author Dr Øjvind Lidegaard (University of Copenhagen, Denmark) told heartwire he is "happy with a headline of 'safe enough' " when it comes to hormonal contraceptives, but it is absolutely vital that the age of a woman and also other risks--importantly that of venous thrombotic events associated with each product--are taken into account when choosing a contraceptive method.

"I think there are one neutral message, two good pieces of news, and one bad," says Lidegaard, a gynecologist, who reports the new findings with his colleagues in the June14, 2012 issue of the New England Journal of Medicine. "All in all, we have information that improves our ability to counsel women at different ages for the most appropriate type of hormone contraceptive method."

We have information that improves our ability to counsel women at different ages for the most appropriate type of hormone contraceptive.

The first encouraging finding is that the newer, lower-dose, combined oral contraceptive pills increase the risk of arterial thrombotic events by 50% to 80%, which is less than the doubling or 2.5 fold increased risk seen with older-generation pills, says Lidegaard. "So it's a good message that the low-dose pills are better [in terms of arterial-thrombosis risk] than the high-dose pills."

Second, "we now have evidence that some products don't confer any increase in risk of thrombosis at all--the progestogen-only products, which includes progestin-only pills, hormone intrauterine devices (IUDs), and soft cutaneous implants. These three product types you can take safely even if you are predisposed to thrombotic events, and therefore it's a good message for all those women who are not able to take combined pills that they now have an option that they can continue to use until menopause."

The bad news is that two newer products--transdermal contraceptive patches and the vaginal ring--both confer a risk of arterial thrombosis that is comparable with the risk for the high-dose pills, "so therefore these two products are not very suitable for women over 35," Lidegaard says. However, he stresses, "I do not think any of these products should be withdrawn from the market, but women need to be aware of the risks, so they can make an informed choice."

In an editorial accompanying the paper [2], Dr Diana B Petitti (Arizona State University, Tucson) says Lidegaard et al's work shows that, when it comes to arterial thrombosis, hormonal contraceptives are "not risk-free, [but] the evidence is convincing that the low and very low doses of ethinyl estradiol (<50 µg)--whatever the progestin and whether delivered orally or by means of the patch or ring--are 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 . . . done over the past five decades."

Cardiologist Dr C Noel Bairey Merz (Cedars-Sinai Medical Center, Los Angeles, CA) commented to heartwire that she "agrees" with the authors and editorialist in general. "These results are helpful with regard to the concern about fourth-generation progestins and reassuring that they may be safe enough for very young women to use for acne and other quality-of-life/noncontraceptive purposes." She also points out that "all these event rates are still lower than the risks of pregnancy, so hormonal contraception remains a good choice when used for that purpose."

Nevertheless, she says, "This and other studies are looking at relatively short-term risks--we and others have demonstrated that hormonal contraception is associated with long-term downstream protection from CVD. We need further work to carefully look at short-term risk vs longer-term benefit."

Almost 15,000,000 Person-Years of Observation in Largest-Ever Study

Lidegaard and colleagues say only a few studies have assessed the risk of arterial thrombotic events with newer hormonal contraceptive products, and the results of these have been conflicting. To assess these risks, they examined data from the entire population of Danish women of childbearing age--just over 1.6 million, aged 15 to 49--all of whom were free of thrombotic disease at baseline, from 1995 through to 2009, merging results from five national registries.

They calculated risks of arterial thrombotic events, with stratification according to estrogen dose (50 µg, 30 to 40 µg, or 20 µg of ethinyl estradiol or progestin-only contraceptive), progestin type, route of administration, and duration of use. The reference group comprised nonusers (women who had never used hormonal contraception as well as former users), and the estimates of relative risk were adjusted for age, calendar year, education, smoking, and status with respect to hypertension, heart disease, diabetes, and hyperlipidemia (defined by the use or nonuse of medications for these conditions).

There were 3311 strokes (21.4 per 100 000 person years) and 1725 MIs (10.1 per 100 000 person-years) over the course of the study.

The relative risks of stroke and MI were increased by a factor of 1.3 to 2.3 among users of estrogen-progestin oral contraceptives with a low dose of ethinyl estradiol (30 to 40 µg), with only small differences according to the progestin in the products (norethindrone, levonorgestrel, norgestimate, desogestrel, drospirenone, and cyproterone acetate), as compared with nonuse.

For those combined oral contraceptives containing a very low dose of ethinyl estradiol (20 µg), the relative risks of stroke and acute MI were increased by a factor of 0.9 to about 1.7, again with only small differences according to progestin, compared with nonuse.

The relative risk of thrombotic stroke and MI were not significantly increased for any of the progestin-only formulations studied (levonorgestrel-releasing IUD and subcutaneous implants).

But for users of the vaginal ring and the contraceptive transdermal patch, which are combined estrogen-progestin formulations, the relative risks of stroke were 2.5 and 3.2 respectively. (The number of MIs was too low among users of these products to provide reliable estimates.) Taken together with the fact that the vaginal ring and transdermal patch also appear to increase the risk of venous thrombosis six to eight times, Lidegaard reiterates that women over 35 should probably avoid these products.

"We estimate that among 10 000 women who use desogestrel with ethinyl estradiol at a dose of 20 µg for one year, two will have arterial thrombosis and 6.8 women taking the same product will have a venous thrombosis," say he and his colleagues, trying to put their findings into perspective.

Age Key for Thrombotic Risk; Major Factor When Choosing a Product

Lidegaard stressed to heartwire that arterial thrombotic complications "increase very rapidly with age, so a woman at 20 years of age and a woman at 40 are in very different situations. Both of these two groups will double their risk with use of some kind of combined hormonal contraception, but the 20-year-old will have a very low baseline risk, and therefore it is not that serious if she doubles her risk. On the other hand, when you have passed 35 you should consider more seriously choosing a contraceptive product that is not increasing your thrombotic risk any further."

We shouldn't take the pill off the market for those above 35, but we should tell them that there are good alternatives.

And "while we shouldn't take the pill off the market for women above 35, we should tell them that there are good alternatives," he notes. However, he adds that as long as they are armed with the facts and understand them, he is happy to support individual choice. "A woman might say this product is safer, but for other reasons I want to continue with my less safe product. That's okay with me as long as they are informed."

For younger women, they "can take whichever product they want," he says. However, he notes that the risk of venous thrombosis is three to four times as frequent as arterial thrombosis among young women, and he and his team have previously shown that the newer (third- and fourth- generation) combined oral contraceptives have a doubling of venous-thrombosis risk compared with the older (second-generation) ones, with differences in venous-thromboembolism risk according to progestin type, something that was not seen when looking at arterial thrombosis.

Nevertheless, arterial thrombotic events are associated with higher mortality and more serious consequences for survivors, they conclude.

Petitti says in her editorial that the "small magnitude" of the problem of arterial thrombotic events in women using combined estrogen-progestin hormonal contraceptives "could be minimized and perhaps eliminated by abstinence from smoking and by checking blood pressure, with the avoidance of use if BP is high."

Lidegaard reports receiving grant support from Bayer Pharma and lecture fees and travel reimbursements from Bayer Denmark, MSD Denmark, and Theramex and providing testimony in a US legal case on oral contraception and venous thromboembolism. Disclosures for the coauthors are listed in the paper. Petitti reports no conflicts of interest.


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