What is the stroke risk of drospirenone (DRSP) and ethinyl estradiol (EE)?

From the Guidelines

Drospirenone and ethinylestradiol combination birth control pills carry a small but increased risk of stroke, particularly for women with additional risk factors, with an absolute risk of approximately 3-9 strokes per 10,000 women per year using this combination, compared to 1-5 strokes per 10,000 non-users. This risk is higher in women who smoke, are over 35 years old, have high blood pressure, migraines with aura, diabetes, or a history of heart disease. The stroke risk is related to the estrogen component (ethinylestradiol) which can increase blood clotting factors and potentially lead to thromboembolism, as noted in the 2024 guideline for the primary prevention of stroke 1. The drospirenone component may slightly increase this risk compared to some other progestins due to its potential effects on potassium levels and blood pressure.

Some key points to consider:

• The risk of stroke is greater for ischemic stroke than hemorrhagic stroke, especially in women on higher doses of estrogen, who have hypertension, are smokers, or are aged over 35 1.
• Current users of combined oral contraceptives had a greater risk of developing myocardial infarction and stroke than non-current users of combined oral contraceptives, with the risk increased in women on higher doses of estrogen but not related to the dose, generation, or type of progesterone 1.
• The American Heart Association/American Stroke Association recommends that in individuals considering combined hormonal contraception (CHC), lower doses of ethinyl estradiol are recommended to minimize potential increased stroke risk 1.
• Women should discuss their individual risk factors with their healthcare provider before starting this medication, and should seek immediate medical attention if they experience symptoms such as severe headache, vision changes, weakness, numbness, or difficulty speaking while taking this medication.

It is essential to weigh the benefits and risks of drospirenone and ethinylestradiol combination birth control pills, considering the individual's medical history, lifestyle, and preferences, to make an informed decision about their use. The 2024 guideline for the primary prevention of stroke 1 provides recommendations for hormonal contraception, emphasizing the importance of shared decision-making and considering the best contraceptive choice to balance the risk of stroke from contraception and the risk of stroke with pregnancy.

From the FDA Drug Label

COCs containing DRSP may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing levonorgestrel or some other progestins. Before initiating drospirenone and ethinyl estradiol tablets in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE.

The stroke risk of drospirenone and ethinylestradiol is not directly quantified in the provided drug labels. However, it is mentioned that drospirenone and ethinyl estradiol tablets are contraindicated in females who are known to have or develop cerebrovascular disease.

• The labels also mention that cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.
• Additionally, the labels state that drospirenone and ethinyl estradiol tablets are contraindicated in females who have a high risk of arterial or venous thrombotic diseases.
• The labels recommend considering the risks and benefits of a DRSP-containing COC in light of the woman's risk of a VTE before initiating use. 2 2 2

From the Research

Stroke Risk of Drospirenone and Ethinylestradiol

• The stroke risk of drospirenone and ethinylestradiol is a concern due to the potential for thromboembolism associated with the use of combined oral contraceptives (COCs) containing these hormones 3.
• A study published in 2007 found that the risk of thromboembolism in women taking ethinylestradiol/drospirenone was similar to that of other oral contraceptives, with a rate ratio of 0.9 (95% confidence interval 0.5-1.6) 3.
• Another study published in 2020 found that the use of COCs containing drospirenone and ethinylestradiol was associated with a prothrombotic state, characterized by changes in serum metabolites and oxidative stress markers 4.
• A study published in 2018 found that the use of two COCs containing ethinyl estradiol and drospirenone was associated with a tendency toward a hypercoagulable state, as well as alterations to the biophysical and biochemical characteristics of erythrocytes 5.

Mechanisms of Thromboembolism

• The mechanisms of thromboembolism associated with the use of drospirenone and ethinylestradiol are not fully understood, but may involve the induction of pro-coagulatory factors and the alteration of metabolic and laboratory parameters 6.
• The anti-mineralocorticoid activity of drospirenone may also play a role in the development of thromboembolism, although the clinical relevance of this effect is unclear 6.

Clinical Implications

• The use of drospirenone and ethinylestradiol as a combined oral contraceptive may be associated with an increased risk of thromboembolism, although the absolute risk is still relatively low 3.
• Women using these hormones should be aware of the potential risks and benefits, and should discuss their individual risk factors with their healthcare provider 3, 6, 4, 5.