By Jeffrey T. Jensen, MD, MPH
A large case-control study done in Sweden that evaluated thromboembolic complications in users of hormonal contraception found an increased risk in users of depomedroxyprogesterone acetate and the combined pill. Desogestrel-containing oral contraceptives showed an increase in risk relative to levonorgestrel pills.
Bergendal A, et al. Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes. Obstet Gynecol 2014;124:600-609.
The Thrombo Embolism Hormone Study was a nationwide case-control study conducted in Sweden between January 1, 2003, and March 31, 2009. Cases (n = 948) were all women with a first episode of deep venous thrombosis (VTE) or pulmonary embolism diagnosed at 43 hospitals geographically spread throughout Sweden. The diagnosis was confirmed by imaging, and only those patients who received anticoagulation therapy were considered to be a valid case. Control subjects (n = 902) were randomly selected from the general Swedish Population Register and frequency-matched by age only. Exclusions for either group included a previous thrombosis, recent pregnancy, or current malignancy. Consenting subjects in both groups underwent a phone interview to evaluate risk factors for thrombosis including use of hormonal contraception, and were also asked to submit a blood sample to evaluate for common thrombophilias. Odds ratios (OR) were adjusted for smoking, body mass index (BMI), and immobilization.
Overall, the adjusted odds ratio (aOR) for current use of combined hormonal contraception (CHC) compared to nonusers was 5.3 (95% confidence interval [CI], 4.0-7.0). Relative to levonorgestrel (LNG) combined pills, the odds of VTE were increased for users of desogestrel (aOR, 2.6; 95% CI, 1.3-5.4) and decreased for women taking norethindrone (aOR 0.4; 95% CI, 0.2-0.9) combined pills. There was no significant difference seen with respect to LNG with drospirenone-containing pills (aOR, 2.0; 95% CI, 0.9-4.3) or the etonogestrel ring (aOR, 1.6; 95% CI, 0.4-6.1). Although there was no overall increase in VTE risk seen in users of progestin-only products (aOR, 0.9; 95% CI, 0.7-1.2), users of DMPA had a 2-fold increase (aOR, 2.2; 95% CI, 1.3-4.0). For those women who carried the factor V Leiden mutation and used a CHC, the aOR was 20.6 (95% CI, 8.9-58). The authors concluded that the increased risk of VTE associated with CHC varies by the type of progestogen and that this is independent of BMI and smoking, but further increased by thrombophilic genotypes such as factor V Leiden.
COMMENTARY
Long-time readers of OB/GYN Clinical Alert might conclude that I am obsessed with writing about VTE risk and hormonal therapy. Given that thrombosis represents the most significant risk associated with hormonal therapy, this obsession is not without merit. Also, there seems to be no end to new publications that attempt to parse out the relationship between type of progestogen and thrombosis risk. Unfortunately, in my opinion, most of what is published in this area fails to bring clarity to clinicians and frightens women away from hormonal therapy.
This most recent publication from Sweden published in the prestigious Green Journal is a big step backward. To date, the controversy has revolved primarily around the increased risk for desogestrel and drospirenone products relative to LNG observed in the quasi-prospective Danish database studies performed by Lidegaard, and the absence of association in the true prospective post-marketing studies conducted by Dinger and the ZEG institute. The passion of the debate has rocked Europe. The European Medicines Agency (EMA, a central regulatory agency similar to our FDA) issued a statement on November 21, 2013, concluding that the benefits of combined hormonal contraceptives (preventing unwanted pregnancies) outweigh their risks, and that the well-known risk of VTE with all CHCs is small and similar. In contrast, France has issued recommendations to restrict the prescription of desogestrel and drospirenone products as first-line formulations.
Since I last wrote on this topic, the long-awaited results of the International Active Surveillance Study were published in Contraception.1 This paper by Dinger et al described the FDA-mandated post-marketing study of the safety of the 24 day 20 mcg EE/3 mg drospirenone pill. The results (no increased risk relative to LNG) were consistent with the other studies by Dinger that showed no increase in risk with 30 mcg EE drospirenone (EURAS) or the etonogestrel ring (TASC).2,3 Strengths of these studies include the true prospective design that provides an ability to collect information on important baseline confounders such as age, family history, and BMI. Even more importantly, since these studies only enroll new starts and pill switchers, duration of use is also controlled. For readers interested in a more detailed discussion of the strengths and weaknesses of this design, a letter to the editor from Dr. Lidegaard with a critique of the INAS study4 and a response from Dr. Dinger5 are available on the journal’s website.
Rather than adding clarity, the Swedish study is a big step backward. As we evaluate epidemiologic studies, the lowest level of evidence is a descriptive series. A case-control study is an improvement over a simple case series, but the inherent biases associated with selection of controls and assessment of baseline characteristics of cases and controls greatly limits the validity of conclusions. One of the primary problems with the Swedish study was the inability to control for duration of use or for other aspects of preferential prescribing. Inconsistencies are seen with respect to both the Dinger (no increase in risk with desogestrel) and Lidegaard (significant reduction in the odds ratio for VTE seen with norethindrone pills relative to LNG but no significant elevation with either etonogestrel or drospirenone) studies. The strong increase in VTE risk seen in users of DMPA is also not supported by other studies.
To summarize, the paper by Bergendal provides no new useful information on this topic. My recommendations are to approach the subject of pill prescription in terms of efficacy and safety. For many women, a long-acting reversible contraception method may be better. For women who prefer to use an oral contraceptive, most will do very well on low-cost generic pills, and these should generally be recommended first. Some women may have baseline concerns about androgen-related side effects such as acne, and this should be taken into account during counseling. While there are insufficient data to compare various preparations head-to-head, low androgen pills may be preferable under these circumstances. Other medical problems (cyclic mood disorders, heavy bleeding) should also be considered. All combined products carry an increase in risk of VTE that is 2-3 times higher than baseline, but about half as high as the risk seen in pregnancy. Although I personally disagree with the conclusion that drospirenone and desogestrel (including the etonogestrel ring) products are associated with an increase in risk, the FDA-mandated package inserts of drospirenone pills discuss this, so it needs to be mentioned. You and your patient need to decide on her priorities and goals for prescription of a combined hormonal method. You should carefully document both the pertinent positive and negative findings on your history and exam and the clinical decision making used to choose a product. As I have mentioned previously, I think that this practice provides protection to you, and choice to your patient.
References
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Dinger J, et al. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: Final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception 2014;89:253-263.
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Dinger JC, et al. The safety of a drospirenone-containing oral contraceptive: Final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344-354.
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Dinger J, et al. Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring. Obstet Gynecol 2013;122:800-808.
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Lidegaard Ø. The INAS-OC study. Contraception 2014; Sept 6. doi:http://dx.doi.org/10.1016/j.contraception.2014.08.012. [Epub ahead of print].
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Dinger J. Reply to letter to the editor: "The INAS-OC study". Contraception 2014; Sept. 6. doi:http://dx.doi.org/10.1016/j.contraception.2014.08.015. [Epub ahead of print].
