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Progestins and Risk of Venous Thromboembolism: What's the Deal with Drospirenone?
Abstract & Commentary
By Elizabeth Micks, MD, Fellow in Family Planning, Department of Obstetrics and Gynecology, Oregon Health & Science University
Alison Edelman, MD, MPH, Associate Professor, Assistant Director of the Family Planning Fellowship, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, is Associate Editor for OB/GYN Clinical Alert.
Dr. Micks reports no financial relationship to this field of study. Dr. Edelman is an Implanon trainer for Merck.
Synopsis:The risk of venous thromboembolism was significantly higher for users of combined oral contraceptives containing drospirenone compared to users of pills containing levonorgestrel.
Sources: Parkin L, et al. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: Nested case-control study based on UK General Practice Research Database. BMJ 2011;342:d2139. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: Case-control study using United States claims data. BMJ 2011;342:d2151.
Two independent case-control studies investigating the risk of venous thromboembolism (VTE) in users of oral contraceptives (OC) containing 30 mcg of ethinyl estradiol and a progestin component of either drospirenone or levonorgestrel found that VTE risk was two to three times higher in those using a drospirenone pill.1,2 Data were extracted from the UK General Practice Research Database (2002-2009)1 and from the PharMetrics database of U.S. insurance claims (2002-2008).2 A VTE case was included only if it was not associated with other risk factors like pregnancy, surgery, trauma, or immobilization. In the UK General Practice Research Database, 61 VTE cases and 215 matched controls were identified out of 318,825 women using an OC with a drospirenone or levonorgestrel progestin component. Unadjusted odds ratio (OR) for VTE among drospirenone users was 3.2 (95% confidence interval [CI] 1.5-7.0). Adjusting for risk factors such as body mass index, smoking, history of varicose veins, and antidepressant use did not significantly change the odds ratio (OR 3.1, 95% CI 1.3-7.5). As for the findings based on the insurance claims data, 186 VTE cases and 681 matched controls were identified out of 937,408 users of OCs containing drospirenone or levonorgestrel. Unadjusted OR for VTE in drospirenone users was 2.3 (95% CI 1.6-3.2). This association did not change significantly when adjusted for duration of exposure. The effect was larger for women younger than 30 years old, with an OR of 3.7 (95% CI 2.0-6.9).
The alarm has sounded once again that an increased risk of VTE may exist with the use of a certain newer progestin. Two independent case-control studies investigating the risk of VTE in users of OCs containing 30 mcg of ethinyl estradiol and a progestin component of either drospirenone or levonorgestrel found that the VTE risk was two to three times higher in those using a drospirenone-based pill.1,2 The authors conclude that drospirenone-containing pills should not be first line for oral contraception.
Should we stop prescribing drospirenone based on these findings? What other literature exists to help direct clinical practice? Four previous studies have examined the association between drospirenone and VTE risk;3-6 two demonstrate an increased risk and two do not. All of the studies have significant methodological flaws, as do the two articles highlighted in this editorial. The two supporting an increased risk were retrospective, which means they have many potential sources of bias, such as in the diagnosis or reporting of VTE. One found a small but significant increase in the risk of VTE with drospirenone use (rate ratio 1.64, 95% CI 1.27-2.10),3 while the other found a non-statistically significant increase in risk (OR 1.7, 95% CI 0.7-3.9).4
Two large prospective studies performed for post-marketing surveillance purposes (phase IV studies) found no increased risk associated with drospirenone. The first study, performed in the United States, did not find a difference in VTE risk in users of a drospirenone-based OC vs other OCs (RR 0.9, 95% CI 0.5-1.6).5 This study did not separate out levonorgestrel users specifically like Parkin et al1 and Jick et al.2 The second study followed 58,674 OC new starts at several centers in Europe.6 VTE incidences were similar among users of all types of pills. The hazard ratio for VTE comparing users of pills containing drospirenone vs levonorgestrel was 1.0 (95% CI 0.6-1.8), in other words, no difference.
Although these two new studies addressed certain methodological concerns from the previous retrospective studies, they have their own problems. For instance, Jick et al2 and Parkin et al1 only included "idiopathic" cases of VTE by excluding pregnancy, cancer, recent trauma, or surgery. However, chart reviews were unable to be performed for each case, and the authors did not have access to information regarding other important risk factors such as family history of VTE or prothrombotic mutations such as Factor V Leiden. While Parkin et al1 ended up excluding four of 31 VTE cases based on additional chart review, they included all of the remaining 34 cases for which they had no information beyond what was in the database.
Furthermore, since initial studies showing increased risk of VTE in drospirenone users led to considerable publicity, the current studies are subject to diagnostic bias. The study period for the UK study extended to September 2009, and for the PharMetrics study until December 2008. Given the television ads from drug companies and from attorneys seeking women who took drospirenone contraceptive pills and developed blood clots, undoubtedly patients were more likely to seek care for unusual symptoms and physicians were more suspicious of VTE when evaluating users of these pills. Due to the small numbers of cases in these studies, this could have significantly increased the observed effect size.
It also is plausible that in these retrospective studies, the cases and controls differed in ways besides the progestin component of their birth control pill. Confounding by indication may have occurred if clinicians were more likely to prescribe drospirenone pills to women thought to have polycystic ovarian syndrome or other medical conditions that would cause them to have a significantly higher baseline risk of VTE. The PharMetrics study showed that drospirenone users were in fact more likely to have menstrual disorders, though controlling for this factor did not change the odds ratio for VTE. And what about obesity? In the UK study, controlling for BMI did not decrease the observed association. In the PharMetrics study, BMI data were not available so the authors relied on ICD codes for obesity. Only 13% of cases and 6% of controls were found to have this code, which indicates that data on obesity were likely missing for a significant number of patients.
VTE "scares" appear to occur with every new pill formulation or contraceptive system. Remember the pill scare of the mid-1990s or the more recent patch scare?7 It is known that the highest risk of VTE occurs in the first few cycles of any hormonal contraceptive and decreases over time.8,9 Stopping and restarting the pill or switching to a different pill increases VTE risk. Efforts were made to control for the early use effect in both studies; however it is not clear that this was accounted for fully.10
As for biologic plausibility, two small observational studies found increased prothrombotic changes associated with contraceptive pills containing drospirenone vs those with levonorgestrel.11,12 Women taking drospirenone pills had significantly lower free protein S levels, but levels of total protein S and tissue factor pathway inhibitor were not statistically significantly different.12 Thrombotic biomarkers for 14 individual women who switched from levonorgestrel to drospirenone pills became less favorable.11 However, thrombotic biomarkers have not been associated with actual risk of VTE. Also, it is not clear why drospirenone would have a different effect on thrombotic biomarkers than other progestins.
Most importantly, this new information must be kept in perspective, as prior pill scares have been associated with women acutely stopping their birth control, placing them at even higher risk for VTE due to pregnancy. VTE risk in modern-day OC users (12-20 cases/100,000 women per year) is significantly lower than compared to pregnancy (48-60 cases per 100,000 women per year).8 Even if drospirenone is confirmed to have a two-fold or three-fold higher risk of VTE over other progestins, the absolute risk of VTE is still rare. The safest contraceptive is the one that a woman takes consistently.
For our patients who are happy with drospirenone-containing pills, we would not recommend that they switch to a different pill, particularly since VTE risk is highest when first starting or switching to a new pill. For women choosing to initiate oral contraception, we must consider the individual patient and possible non-contraceptive benefits that will promote long-term and consistent use of the method. For many patients, drospirenone-containing contraceptive pills will continue to be a safe and effective option.