Anticoagulation and Combination Hormone Contraceptives

In this podcast, Jean Connors, MD, answers our questions about her session at the Anticoagulation Forum 2021, during which she presented about combination oral contraceptives, their use among different populations of women, and the research around their efficacy and safety.

Additional Resource:

• Connors J. Anticoagulation and hormones. Talk presented at: Anticoagulation Forum 2021; October 28-30, 2021; Virtual. https://acforum.org/virtual/index.php?page=presentation&session_id=7&presentation_id=16

TRANSCRIPTION:

Amanda Balbi: Hello and welcome to another installment of Podcasts360—your go-to resource for medical news and clinical updates. I’m your moderator, Amanda Balbi with Consultant360.

Today our guest is Dr Jean Connors, who is a hematologist at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

She recently presented about anticoagulation and hormones and the Anticoagulation Forum 2021, and she joins us today to talk about her session.

Thank you for joining us on this podcast, Dr Connors. To start, can you give us a brief overview of your session?

Jean Connors: Sure. At this year's Anticoagulation Forum, I was given the topic of hormones and thrombosis to discuss. I chose the use of combination oral contraceptives, those containing estrogen and progestin agents, because 20% of women in the United States between ages 15 and 30 years are prescribed and take the combination oral contraceptives.

Many different types of prescribers prescribe these. Everyone from primary care physicians to OBGYN, nurse practitioners, hematologists, and so I think it's important for us to understand the risks and benefits associated with this type of contraception, the alternatives that are available, and who should and shouldn't be prescribed these combination oral contraceptives because of risk for thrombosis.

Now, we know that estrogen increases the risk of thrombosis, and this can be seen in women who are pregnant. The risk of thrombosis is highest for women under the age of 50 years during pregnancy. Although the absolute rate for women in childbearing years is low, approximately 5 to 10,000 per patient years, but when we do have thrombosis. 

It can be difficult to manage the risk of thrombosis during pregnancy. It has an odds ratio of about 6 compared with not being in the pregnant state, and in the immediate postpartum period that odds ratio is about 22. So, hormonal contraceptives mimic this pregnancy state to suppress ovulation.

Although the estrogen may not be as high and the VTE risk may not be as high, there are some caveats about the combination oral contraceptives that predispose to similar or even increased risk of thrombosis as compared to pregnancy. Some of these factors include age, obesity, smoking, and others as I described. In addition to those patient-specific risk factors, we also have the type of progestin agent and the amount of estrogen.

When we look at the different generations of progesterone agents, we can see that the first- and second-generation norethindrone and levonorgestrel have the lowest risk associated. With the third-generation progestins, like desogestrel and norgestimate, and the fourth-generations, particularly drospirenone, which is associated with an increased risk of thrombosis. 

The dose of estrogen also is associated with increased risk, with the lowest dose of estrogen usually 20 μg of ethinyl estradiol conferring the lowest risk of thrombosis and the highest dose that's usually in combination oral contraceptives 50 μg is associated with the highest risk. If you look carefully at the data, you can see that the different combinations of high-dose ethinyl estradiol and a third- or fourth-generation progestin will increase the risk of thrombosis.

Now, when we talk about exogenous estrogens, there are differences in risk between the type of estrogen preparation used in oral contraceptives and that used for hormone replacement in women who've undergone menopause, including premature menopause or medically induced menopause. The types, which are similar to the ones used for transitioning women to maintain feminine characteristics, so oral estradiol and transdermal estradiol are lower risk, but the majority of my presentation is focused on the 20% of American women who will be taking oral combination oral contraceptives.

In addition to obesity, smoking, and age as risk factors for thrombosis when oral contraceptives are used are also the inherited thrombophilia. As I point out in my discussion, the prevalence of an inherited thrombophilia in the US population is very low.

Factor 5 Leiden is seen in just 5% of the White population and even lower in Blacks and Hispanic ethnicity. The deficiencies of protein C, protein S, and antithrombin combined are found in just less than 1% to 2% of the population.

While we may be concerned about prescribing oral contraceptives to patients with thrombophilia, we have to recognize that these other risk factors that I've mentioned are higher the odds ratio for having a thrombosis with heterozygous-prothrombin gene mutation is basically the same as it is for someone who's BMI is greater than 30 kg/m2. With an odds ratio of about 2.44 for VTE with an increased BMI and an odds ratio of 24 if someone is obese and takes a combination oral contraceptive.

Before you prescribe these combination oral contraceptives, take a look at your individual patient in front of you ask if they have a personal or family history in a first-degree relative of a venous thromboembolism, assess their typical cardiovascular risk factors, their lipid profile, diabetes, hypertension, obesity, and smoking factors.

Amanda Balbi: Great. That was a great overview. Can you talk a little bit about the research around combination oral contraceptives and what’s still needed to study?

Jean Connors: For women in which combination oral contraceptives are considered high risk, the risk factors that I just mentioned—women who are over the age of 35 years and smoke or have had thrombotic events in the past or have a BMI greater than 31—a viable contraceptive option that also decreases menstrual blood loss is the use of the progestin-coated IUD, which is a progestin-coated IUD that works incredibly well in women who have menorrhagia due to coagulation defects or heavy menstrual periods and want to decrease the burden of menstrual blood loss and for whom combination oral contraceptives are not appropriate, the levonorgestrel-coated IUD is also extremely effective at contraception and preventing pregnancy.

Interestingly, one study demonstrated a lower risk of thrombosis than in women who use the new contraceptives at all. In a study in Denmark—the levonorgestrel-coated IUD is an excellent option for women for whom combination oral contraceptives are not appropriate.

When we look at future research, we will be looking into types of estrogen and progestin agents that decrease the risk of thrombosis, as well as the impact on the cardiovascular risk factors. Already, we see that in trying different progestin types, that we can see that we trade some side effects for others— weight gain, acne. All of these can be fine-tuned by choosing the type of progestin agent, but we, for many of our patients, we need to keep the risk of thrombosis in mind as well.

Amanda Balbi: For this population of women who are taking contraceptives, when they do have a thrombosis, are anticoagulants or thrombolytics still indicated, or is there an alternative?

Jean Connors: So, women who are on combination oral contraceptives and present with thrombosis should be treated as any patient who presents with a thrombosis. So, if they have submassive or life-threatening PE, certainly thrombolysis can be used.

There are no drug-drug interactions with combination oral contraceptives and direct oral anticoagulants such as apixaban or rivaroxaban. What is important is that, when many women take anticoagulation, they find that their menstrual periods become heavier with more blood loss. One strategy that is acceptable in women who have an estrogen or combination oral contraceptive-associated thrombosis is to continue the oral contraceptive while the patient is being anticoagulated.

Many of us would consider a thrombosis that appears to be provoked by combination oral contraceptives as provoked and would give limited-duration anticoagulation of 3 to 6 months. During that time, women can be maintained on the oral contraceptive. Data from the Einstein VTE and PE studies show that there was no difference in the recurrent VTE risk in women who continued the hormonal treatments vs those who stopped.

For women who are on anticoagulation and for whom heavy menstrual bleeding can be an issue, continuing the oral contraceptive is acceptable. Similarly, though, for women who want to avoid the oral contraceptive, even while anticoagulated, the use of the levonorgestrel-coated IUD is one strategy that can be used.

Amanda Balbi: Perfect. Is there anything else that you would like to add, or maybe some final thoughts for our audience?

Jean Connors: As we do for many things in medicine, for the individual woman in front of you for whom you're considering combination oral contraceptives, keep in mind all of the factors that I've discussed in this presentation with regard to risk for thrombosis, as an individual risk assessment profile needs to be considered in all women for whom you are prescribing oral contraceptives.

Amanda Balbi: Thank you so much for joining me today and answering all my questions.

Jean Connors: Well, thank you very much, Amanda. I'm delighted to be able to participate in the AC Forum this year.