Thrombotic Risk of Contraceptives and Other Hormonal Therapies

Hormones are administered in various forms for contraception, postmenopausal symptom management, treatment of hormone-responsive cancers, breast cancer risk reduction, and therapy in transgender individuals. This chapter will focus on the association of estrogen and/or progestin therapy with thromboembolic disease. The benefits of these drugs will be discussed in less detail. In deciding whether to prescribe hormone therapy, one must assess the risk-to-benefit ratio for that individual. Although much still needs elucidation, the goal of this chapter is to provide data with which to facilitate these decisions.

Basic Science

The increased risk of thrombosis in association with the use of hormones is well established. In general, the effects of hormonal contraception (HC) and hormone replacement therapy (HRT) on coagulation variables are modest, and reports suggest that the use of oral combined (estrogen plus progestin) HC (CHC) induces changes in the procoagulant and anticoagulant pathways that may counterbalance each other. Baseline epidemiologic studies in healthy women undergoing menopause have demonstrated increased levels of several coagulation factors, including factor VII, factor VIII, and fibrinogen. These changes are due to both estrogen status and aging.

Several studies have shown that estrogens can activate the coagulation system. Caine and coworkers showed that administering 0.625 mg or 1.25 mg of conjugated equine estrogen (CEE) to 29 healthy postmenopausal women (average age, 57 years) for 3 months increased an index of thrombin generation (prothrombin fragments 1 + 2) in a dose-dependent manner. Thrombin activity, as indicated by the generation of fibrinopeptide A, was also increased. Furthermore, levels of inhibitors of thrombin generation (protein S [PS]) and activity (antithrombin [AT]) were decreased relative to placebo. A similar study testing blood samples at baseline and after 3 months of therapy with unopposed estrogen therapy versus placebo in 26 healthy postmenopausal women additionally demonstrated significantly reduced concentrations of tissue factor pathway inhibitor (TFPI), an important inhibitor of the extrinsic pathway of coagulation. These findings are similar in users of oral CHCs with increased levels of factor VII, factor VIII, and factor X and decreased AT and PS levels, contributing to an overall procoagulant state. The effect is greatest during the first month of use.

One of estrogen's procoagulant mechanisms of action may be through first-pass hepatic metabolism. Estrogen has been found to increase hepatic production of several plasma proteins involved in coagulation, including factor VII, factor X, and fibrinogen, and has been implicated in the acquisition of a deficiency in plasma glucosylceramide levels, an activated protein C (APC) anticoagulant cofactor. Sex hormone–binding globulin (SHBG) has been used as a marker of hormone-associated thrombotic risk. It is a carrier protein that is produced in the liver and binds estrogen and testosterone. Estrogens appear to cause a dose-related increase in SHBG levels, whereas progestins produce a decrease, depending on both the dose and type of progestin. Moreover, CHC and oral HRT use have been associated with higher levels of C-reactive protein (CRP) and lower levels of TFPI.

Transdermal therapy should avoid the hepatic first-pass effect, but a decreased risk of thrombosis with the transdermal contraceptive currently available in the United States (norelgestromin/ethinyl estradiol [Xulane]) has not been demonstrated. This may be due to the strong hepatic stimulatory effects of ethinyl-estradiol, the estrogen component in most CHCs. Studies have confirmed less hepatic stimulation with transdermal HRT, which correlates with decreased thrombotic risk compared with oral HRT (see later discussion). Different estrogen components in the preparations also contribute to the risk profile.

Data concerning the effect of estrogen on the fibrinolytic system are conflicting, but on the whole, estrogen seems to induce heightened fibrinolytic activity. This may be due at least in part to a decrease in fibrinogen and plasminogen activator inhibitor (PAI)-1 concentrations and increased plasminogen levels. Levels of PAI-1, a critical inhibitor of fibrinolysis, are generally higher in postmenopausal women. This hyperfibrinolysis may counterbalance the procoagulant effect of estrogen and explain the low absolute risk of thromboembolism in women taking hormonal therapy.

Estrogens have both rapid and longer-term effects on the blood vessel wall. Estrogen influences the bioavailability of endothelial-derived nitric oxide (NO) and causes relaxation of vascular smooth muscle cells. The longer-term effects of estrogen are due at least in part to changes in vascular cell gene and protein expression, which lead to inhibition of the response to vascular injury, reduced oxidation of low-density lipoprotein (LDL), and reduced levels of lipoprotein (a) (LP[a]). However, the decrease in cholesterol levels with HRT has not been shown to correlate with a decreased risk of cardiovascular disease. Once atherosclerotic disease exists, estrogens may exacerbate the proinflammatory state by increasing CRP levels and matrix metalloproteinase activity. Studies have documented a higher incidence of thrombotic risk in women using third-generation CHCs (e.g., containing progestins desogestrel, gestodene, norgestimate, drospirenone) compared with those containing second-generation progestins (e.g., levonorgestrel, norethisterone). It has been postulated that this may be explained by differential effects of progestins on plasma sensitivity to APC. One explanation is a differential increase in factor VIII levels and decrease in PS activity (free PS decreases with desogestrel and increases with levonorgestrel; the increase in free PS with levonorgestrel may be due to a decrease in C4b-binding protein). This suggests the prothrombotic effect of the estrogen may be inadequately counteracted by the lower androgenicity of the progestin component present in third-generation oral CHCs compared with second-generation oral CHCs, thus inducing APC resistance.

Hormonal Contraceptive Use and Thrombosis

Venous Thromboembolism

Since their introduction, use of oral CHCs has been linked to an increased incidence of thromboembolic events. First-generation CHCs included at least 50 µg of ethinyl estradiol or mestranol and a progestin, typically norethindrone. Because estrogen was suspected of increasing the risk for thromboembolism, contraceptives that contained less than 50 µg of estrogen and a new progestin, levonorgestrel, were introduced—second-generation oral CHCs. Initial efforts to reduce the risk of venous thromboembolism (VTE) by reducing the estrogen content proved successful. Bottiger and colleagues noted a marked decline of approximately 80% in reports of nonfatal VTE per 100,000 users when lower-dose estrogen oral CHCs replaced high-dose preparations. In the Oxford Family Planning Study, lower incidence rates were noted among users of lower-dose contraceptives (39 per 100,000 person-years) compared with users of high-dose contraceptives (62 per 100,000 person-years). Compared with non-CHC users, women who take second-generation oral CHCs have a threefold to fourfold increased risk for VTE ( Table 34.1 ).

The progestins desogestrel, gestodene, and norgestimate, in combination with no more than 35 µg of ethinyl estradiol, comprise third-generation oral contraceptives (OCs). Third-generation CHCs increase the risk of VTE approximately twofold over second-generation products. The risk of VTE with oral preparations using fourth-generation progestins (drospirenone or cyproterone acetate) is also increased two to three times over second-generation products, and these produce acquired APC resistance similar to that found in women taking third-generation products. The initial industry-funded postmarketing studies of VTE risk with oral CHCs containing drospirenone were negative, but later population-based studies documented an increased risk. In 2011, using a UK general practice–based database, Parkin et al. compared the risk of VTE in users of drospirenone-containing oral CHCs with users of levonorgestrel and found an increased odds ratio (OR) of 3.3 (95% confidence interval [CI], 1.4 to 7.6) when adjusted for body mass index (BMI). In a similar analysis, Jick et al. found an increased OR of 2.3 (1.6 to 3.3) in a case-control study based on health insurance claims in the United States when adjusted for obesity. Based on these studies, as well as a separate US Food and Drug Administration (FDA)-funded analysis of Kaiser Permanente and Medicaid records, in April 2012 the FDA concluded that drospirenone-containing birth control pills may be associated with a higher risk for blood clots than other progestin-containing pills and advised that “healthcare professionals should consider the risks and benefits of drospirenone-containing birth control pills and a woman's risk for developing a blood clot before prescribing these drugs.” Because of the increased risk of thrombosis with cyproterone acetate–containing preparations (Diane 35, Estelle 35), they are not recommended for routine contraception. In France in late 2012 many women switched from third- and fourth-generation to first- and second-generation products. In 2013 compared with 2012 there was a 10.6% decrease in hospitalizations of females aged 15 to 49 for pulmonary embolism (PE), corresponding to 322 fewer hospitalizations, providing strong support for increased thrombogenicity of third- and fourth-generation CHCs.

Nonoral forms of HC may also increase VTE risk ( Table 31.1 ). Women using transdermal HC (third-generation norelgestromin and ethinyl estradiol as Ortho Evra currently available as generic Xulane; a similar product Evra is available in Canada and Europe) had an increased relative risk (RR) of VTE of 7.9 (95% CI, 3.5 to 17.7) compared to nonusers of CHCs in a national Danish cohort. The VTE risk associated with use of the vaginal ring (ethinyl estradiol and third-generation etonogestrel [Nuva Ring]) is also suspected to be higher; RRs of 6.5 (95% CI, 4.7 to 8.9) compared with nonusers of CHCs and 1.9 (1.3 to 2.7) compared with users of levonorgestrel-containing oral CHCs were found in the Danish cohort. Both the transdermal patch and vaginal ring have been found to increase APC resistance relative to users of oral CHCs. The FDA warned that women who used Ortho Evra (currently available in the United States in generic form as Xulane) are exposed to approximately 60% more total estrogen in their blood than those using an oral CHC containing 35 µg of estrogen. However, a systematic review of studies in transdermal HC users compared with users of second-generation oral CHCs concluded that there was good to fair evidence (level II-2) demonstrating conflicting results as to whether women using the patch or the ring have a higher risk than women using oral CHCs. Of note, no increase in arterial thrombosis was noted. A new patch that releases a lower dose of estrogen and uses levonorgestrel as the progestin is under study and may provide a less thrombogenic alternative.

TABLE 31.1

Risks of Venous and Arterial Events With Oral and Nonoral Hormonal Contraceptive Therapy Compared With Nonusers in the Danish National Cohort and Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis Case-Control Studies

	VTE	MI	CVA
Combined OC With 30 µg Estrogen
2nd-generation: levonorgestrel	2.9 (2.2–3.8) ^a 3.6 (2.9–4.6) ^b	2.02 (1.63–2.50) ^a	1.65 (1.39–1.95) ^a
3rd-generation: desogestrel	6.6 (5.6–7.8) ^a 7.3 (5.3–10.0) ^b	2.09 (1.54–2.84) ^a	2.20 (1.79–2.69) ^a
4th-generation: drospirenone	6.4 (5.4–7.5) ^a 6.3 (2.9–13.7) ^b	1.65 (1.03–2.63) ^a	1.64 (1.24–2.18) ^a
Progesterone Only
Norethindrone	0.68 (0.3–1.51) ^a	0.81 (0.42–1.56) ^a	1.35 (0.93–1.96) ^a
Levonorgestrel IUD	0.6 (0.4–0.8) ^a 0.3 (0.1–1.1) ^b	1.02 (0.71–1.46) ^a	0.73 (0.54–0.98) ^a
Transdermal patch	7.9 (3.5–17.7) ^a	0 (0–63.10) ^a	3.2 (0.8–12.6) ^a
Estrogen vaginal ring	6.5 (4.7–8.9) ^a	2.1 (0.7–6.5) ^a	2.5 (1.4–4.4) ^a

CVA, Cerebrovascular accident; IUD, intrauterine device; MI, myocardial infarction; OC, oral contraceptive; VTE, venous thromboembolism.

a Danish National Cohort.

b MEGA (Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis) case-control study.

In contrast, the levonorgestrel-releasing intrauterine devices (IUDs) (Mirena, Skyla, Kyleena) appear to be very safe contraceptive options in regard to VTE. It was not associated with increased risk of VTE in the large Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) case-control study in the Netherlands (OR, 0.3; 95% CI, 0.1 to 1.1) or in a Danish cohort (RR, 0.6; 95% CI, 0.4 to 0.8). Peak plasma levels of levonorgestrel are markedly decreased compared with a 0.15-mg levonorgestrel-only pill (150 to 200 pg/mL vs. 6400 pg/mL), which may help explain this finding. The levonorgestrel-releasing IUD is safe to use in women with a history of VTE and, because it decreases menstrual flow, counters anticoagulation-related heavy menstrual bleeding.

The VTE-associated risk of HCs that contain progestins only has been evaluated in a recent systematic review. The authors conclude that the majority of evidence does not support an increase in risk for venous or arterial thrombotic events in women using oral progestin-only contraceptives. Limited evidence suggests an increased risk with injectable progestins or progestins used for therapeutic indications. Of note, results of population studies evaluating injectable progestin contraceptives may be influenced, in part, by characteristics and underlying risk factors of the females for whom that approach to contraception is prescribed.

Myocardial Infarction

Current use of CHCs increases the risk for myocardial infarction (MI), but most of the excess risk is attributable to a synergistic interaction with cigarette smoking. Taken together, case-control and cohort studies suggest that current users of CHCs who are younger than 40 years of age and do not smoke have little or no increased risk for MI. Thus most studies have been too small to address whether the risk for MI from CHCs differs according to coronary risk factors other than smoking and perhaps hypertension. Data consistently show that past use of CHCs is not associated with increased risk. In a meta-analysis of 13 studies, Stampfer and coworkers estimated that past users of CHCs had a pooled RR for MI of 1.01 (95% CI, 0.91 to 1.13), confirmed at 0.99 (95% CI, 0.86 to 1.13) in a national Danish cohort. Such findings suggest that any increase in risk for MI due to CHC use occurs only with current use and probably acts through an acute prothrombotic interaction with cigarette smoking. This statement is supported by the finding that angiographic studies of young women with MI tend to show an absence of atherosclerosis in cases associated with current or recent use of OCs. The type of progestin may further impact arterial event risk. The risk was increased in users of CHCs with drospirenone compared with older progestins (OR, 2.01; 95% CI, 1.06, 3.81) but only in women older than 35 years.

Stroke

Prospective studies have not shown an increased risk for stroke among past users of CHCs, and studies of stroke in current users have yielded inconsistent results. The largest study to date, including 1,626,158 Danish women, found that, although the absolute risk of stroke remains low, the RR of thrombotic stroke is increased by 1.5-fold to 2-fold among users of CHCs. Furthermore, the type of contraception impacted stroke risk, with higher risk in users of the transdermal patch (RR, 3.2; 95% CI, 0.8 to 12.6) and vaginal ring (RR, 2.5; 95% CI, 1.4 to 4.4). Progestin-only formulations were not associated with increased risk. In studies that have shown an increased risk, the interaction with smoking does not seem to be as great as that associated with MI, but hypertension has a more important role.

The Nurses' Health Study found no statistically significant increase in risk for stroke among past users (ischemic stroke and subarachnoid hemorrhage were combined in the study). In the Royal College of General Practitioners' Study, past users who were smokers had an increased RR for stroke of 1.8 (95% CI, 1.1 to 2.8). The World Health Organization (WHO) case-control study also suggested that an interaction between smoking and contraceptives was associated with ischemic stroke.

Taken together, studies of low-dose CHCs suggest that these drugs produce little absolute increase in risk for ischemic stroke. Occlusive stroke in young women has an estimated rate of 5.4 per 100,000 person-years, and fatal occlusive stroke is even rarer. Therefore any attributable risk for death from occlusive stroke associated with the use of CHCs is small, and at most 10 to 20 per 100,000 women per year, although smokers and hypertensive women may be more susceptible. Current studies provide no persuasive evidence of any increase in risk for hemorrhagic stroke among young women without risk factors who use current CHCs.

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