VTE is the third most common cardiovascular complication and occurs when you have either deep vein thrombosis (DVT) or a pulmonary embolism (PE). Deep vein thrombosis is a condition when a blood clot forms in a deep vein in the body. DVT could block blood flow through the veins. A pulmonary embolism can then occur if a blood clot breaks loose from the vein and travels through the body into the lung. This can lead to death.
Past research has documented that the use of combination hormonal birth control may increase your chances of experiencing venous thromboembolism - VTE (also known as blood clots) or other types of cardiovascular complications. Rates of VTE in women who use the pill are in the range of 3-9 per 10,000 women per year whereas VTE rates for non-pill users of reproductive age approximate 1–5 per 10,000 women per year. The good news: This means a relatively low risk for either group. But should you still be concerned?
Studies have shown that all combination hormonal contraception may pose some sort of risk for developing VTE. It is thought that the estrogen found in hormonal birth control may be the major contributing factor. Due to new European research published in mid-2011 that showed a higher risk of developing VTE in women using newer combination birth control pills that contain the progestin drospirenone, the FDA in the United States decided to conduct an in-depth investigation to evaluate the relationship between VTE risk and combination hormonal contraception. Again: It is important to note, however, that even though VTE risk may be higher in women who use this type of contraception, the overall risk is still relatively low.
The bottom line: Newer hormonal birth control methods that contain the progestin drospirenone may indeed increase your risk of VTE, more so than if you took an older hormonal birth control method.
The FDA analysis, which contains the most comprehensive data available, consisted of a study that examined seven year’s worth of data from four geographically diverse locations. At least 835,826 women, ages 10-55 years, who had at least one prescription for a combination hormonal contraceptive were evaluated. The goal of this research was to assess three newer hormonal contraceptive formulations to determine if the risk of VTE, DVT, PE and/or cardiovascular death is higher than it would be for four older oral contraceptive formulations with similar low levels of estrogen. The following combination birth control methods were examined (the first 3 are the newer methods):
- 3.0 mg Drospirenone/30 mcg ethinyl estradiol oral contraceptive (Yasmin)
- 6 mg Norelgestromin/750 mcg ethinyl estradiol transdermal patch (Ortho Evra Patch)
- 11.7 mg Etonogestrel/2700 mcg estradiol vaginal ring (NuvaRing)
- .10 mg Levonorgestrel /20 mcg ethinyl estradiol (like Alesse, Aviane-28)
- .15 mg Levonorgestrel /30 mcg ethinyl estradiol (like Seasonique, Nordette)
- 1 mg Norethindrone/20 mcg ethinyl estradiol (Loestrin 1/20)
- .18-.25 mgs Norgestimate /35 mcg ethinyl estradiol (Ortho Tri-Cyclen)
Understanding the Results:
When interpreting the results from this FDA study, it is important to understand that in research, a result is considered statistically significant (or significant) when it has been determined that the result is very likely to have been caused by something (in the case of this FDA study, the newer formulations). In other words, the result is considered significant if it extremely probable that it did not occur by chance.
Some Key Results From This FDA Study:
- For all users, the drospirenone/ethinyl estradiol pills, the patch and NuvaRing were linked with a significantly higher risk of VTE (as compared to the 4 older formulations). This is especially the case for women ages 10-34.
- New users (women who used a combination hormonal contraceptive for the first time during this study) taking drospirenone/ethinyl estradiol pills showed a significantly higher risk of both ATE (arterial thrombosis – a blood clot in an artery that often leads to heart attack or stroke) and VTE.
- Drospirenone/ethinyl estradiol pills were associated with significantly higher risk of VTE when used for 0-3 months as well as for 7-12 months of use.
- For new users, the contraceptive patch was linked to a 3-fold increase in risk of VTE when used for more than 12 months as compared to the same duration of use of the older formulas.
- Drospirenone/ethinyl estradiol pills showed a statistically significant risk for VTE in women 10-34 years old and an increased risk for ATE in women 35 years and older.
- Even though the .15 mg levonorgestrel/30 mcg ethinyl estradiol pills contained the same amount of estrogen as the drospirenone/ethinyl estradiol pills, the drospirenone pills posed more VTE risk to all users.
- When the patch was only compared to the older formulation .15 mg levonorgestrel/30 mcg ethinyl estradiol pills, there was an increased risk for VTE for women who used the patch for 0-3 months and 12 or more months (this risk was not seen in the comparison formulation).
- There may be an increase risk for ATE in women who use NuvaRing for more than 12 months, but this data is based on 1 case, so this potential risk needs to be examined further.
Additional Research Considered:
Part of this investigation also consisted of reviewing six published studies that had analyzed the risk of VTE with birth control pills containing drospirenone. The results from these studies have been mixed; yet four of them concluded that there is definitely an increased VTE risk for women who use these pills. In fact, the two most recent studies (from April 2011) suggest that the risk of developing blood clots for women using drospirenone-containing is 1.5- to 2 times higher than for women who use birth control pills containing a different progestin.
The FDA also reviewed seven research studies on VTE risk and the Ortho Evra Patch. In general, these reports indicate that, as compared to other combination birth control pill formulations, the contraceptive patch likely increases the risk of VTE. Because women are exposed to much higher levels of estrogen with the patch, it is estimated that they are 2-3 times more likely to experience some type of VTE symptom.
What Does All This Mean?
Based on the results of its own investigation, in combination with existing literature, the FDA has concluded that use of continuous exposure combination hormonal contraceptives, such as the Ortho Evra Patch (which is left on the body for one week at a time) and the NuvaRing (that remains inserted in the body for three weeks at a time), could potentially result in higher sustained exposure to estrogen -- leading to an increased blood clot or VTE risk. Thus, the FDA stands behind its original conclusion (prompting an updated black box warning on the patch in January 2008) – that the use of the Ortho Evra patch is associated with a higher risk of VTEs as compared to standard combination pills.
The results indicating an increased risk of VTE with NuvaRing use (as compared to combination pills) raised some concern. But, the FDA believes this finding needs to be replicated in additional research before the agency will take a definitive stance on it or announces any official warning on NuvaRing use.
The FDA suggests that the use of pills containing drospirenone are also connected to an approximate 1.5-fold increase an increased risk of VTE/blood clots when compared to standard low-dose oral contraceptives. This means that if the risk of developing a blood clot for a woman using other hormonal birth control is about 6 in 10 thousand, then the risk of developing a blood clot among women using pills with drospirenone would be about 10 in 10 thousand. Additionally, the VTE risk with these pills appears to be significantly increased during the first three months of use as well as during 7-12 months of use.
There also appears to be a significant link between age, drospirenone-containing pill use and VTE/ATE occurance. Women under the age of 35 are at a higher risk of VTE but have a lower risk of ATE. The FDA hypothesizes that the progestin drospirenone may be more likely to increase heart rhythm problems and sudden deaths among users because it has certain properties that affect salt and water balances and can increase potassium levels.
At this time, the FDA has not issued an official warning on the use of birth control pills that contain drospirenone. The agency has only indicated in its most recent safety announcement on April 10, 2012,
"The U.S. Food and Drug Administration (FDA) has completed its review of recent observational studies regarding the risk of blood clots in women taking drospirenone-containing birth control pills. Based on this review, the FDA has concluded that drospirenone-containing birth control pills may be associated with a higher risk for blood clots than other progestin-containing pills."The FDA's review of the results of this study (especially the data resulting from the evaluation of drospirenone-containing birth control pills) was submitted and discussed at the joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on December 8, 2011. The advisory panel voted 21-5 that the FDA should require new labeling for drospirenone-containing pills such as Yaz, Yasmin, Beyaz, Safyral (and their generic versions); they felt the current labels are insufficient since they only include information about the conflicting research on VTE risks. The labeling should be advised to more clearly articulate the potential VTE risk as well as making it clear that VTE (blood clots) could be fatal. In April 2012, the FDA issued a requirement for updated labeling. However, the new labels requirements did not follow the advisory panel's recommendations. The FDA is mandating that labels of drospirenone-containing birth control pills now contain information about the recent observational studies that the FDA has just reviewed. Additionally, the revised drug labels will now have to state that some studies revealed up to a three-fold increase in the risk of blood clots for drospirenone-containing products when compared to products containing levonorgestrel or some other progestins, yet other studies found no additional blood clot risk for drospirenone-containing products. The new labels will also reference the results of the FDA's own investigation of VTE risk.
FDA Office of Surveillance and Epidemiology. [10-27-2011] Combined Hormonal Contraceptives (CHCs) and the Risk of Cardiovascular Disease Endpoints. Accessed 11/15/11.
Reid, R. "Oral Contraceptives and the Risk of Venous Thromboembolism: An Update." JOGC 2010; No. 252: 1192-1197. Accessed 11/15/11.