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Association between extended oral contraceptive use, increased VTE risk may not be clinically significant
Extended and continuous combined oral contraceptive use was associated with a slightly elevated, but potentially clinically insignificant risk for venous thromboembolism compared with traditional cyclic use, according to research published in JAMA Internal Medicine.
“Continuous/extended cyclic estrogen use (84/7 or 365/0 days cycles) in combined oral contraceptives could potentially expose women to an increased cumulative dose of estrogen, compared with traditional cyclic regimens (21/7 days cycle), and may increase the risk for venous thromboembolism (VTE),” Jie Li, PhD, from the Center for Drug Evaluation and Research at the FDA, and colleagues wrote.
To determine whether the use of extended cyclic and continuous combined oral contraceptives is associated with a higher risk for VTE when holding the progestogen type (levonorgestrel) constant compared with cyclic combined oral contraceptives, Li and colleagues performed a retrospective cohort study of women aged between 18 and 50 years who initiated a combined oral contraceptive containing ethinyl estradiol or levonorgestrel of any dose between May 2007 and September 2015.
The researchers identified 210,691 women taking continuous/extended combined oral contraceptives (mean age, 30.4 years) and 522,316 women taking cyclic combined oral contraceptives (mean age, 28.8 years).
At baseline, continuous/extended cyclic combined oral contraceptives users were slightly more likely to have cardiovascular and metabolic conditions (7.2% vs. 4.7%), gynecological conditions (39.7% vs. 32.3%) and health services utilization than cyclic combined oral contraceptive users.
When the researchers analyzed the data using a propensity score matching approach, HR estimates declined from 1.84 (95% CI, 1.53-2.21) to 1.32 (95% CI, 1.07-1.64) for continuous/extended use compared with cyclic use. The two propensity score–matched cohorts had low absolute risk differences (0.27 per 1,000 persons) and incidence rate differences (0.35 cases per 1,000 person-years).
“Because of the small absolute risk difference and potential residual confounding, these findings did not show strong evidence supporting a VTE risk difference between noncyclic and cyclic estrogen use,” Li and colleagues concluded. “Accordingly, we do not recommend selective prescribing of combined oral contraceptives based on the cyclic and continuous/extended type. Clinicians should prescribe combined oral contraceptives based on patients’ individual risk factors and preferences.” – by Alaina Tedesco
Disclosure: The authors report no relevant financial disclosures.
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This study does not try to refute past findings, but attempts to ask a question that has not really been asked. Some women use birth control pills in a pattern of 21 days of active pills and 7 days of placebo or hormone free days pattern, others take their pills “continuously” or “extended” cycle which means they have more active days in a row without a break from estrogen and progestin. The researchers looked to determine if skipping the placebo, or not taking a break, leads to more risk of risk of venous thromboembolism, or blood clots.
This appears to be a well-done study, so the findings are likely valid, but significance is the real question. This is a retrospective cohort study based on insurance claims and hospital data, and there are always limitations to these types of studies. Further they only have data for 6 months before initiating the birth control method in question and are assuming the women were hormone naive. Most importantly, the increase in risk they demonstrate is minimal (less than 1 in 1,000 women increase) and much less than you would see with pregnancy or in the postpartum period.
Women often elect continuous use because they are using these hormones not only for birth control, but also to manage issues related to menses — painful periods, long periods, heavy periods, acne, headaches or mood changes — so it is important to weigh the potential quality of life improvement with this option versus this very small possible increase in risk of VTE.
I do not anticipate that these findings will change practice. A randomized control trial is the only way to see if the potential increase risk demonstrated in this epidemiological study actually exists, but completing such a study would be extremely difficult — especially since women feel strongly about how they take their hormones and may not want to be randomized. Many women would say, “I will take an increased risk of less than 1 in 1,000 women of a blood clot in order to have lighter, less painful, shorter periods.” Providers should be reassured that there is not strong evidence that that there is a VTE risk difference between 21/7 regimens and variations.
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The Li et al study is the first to specifically evaluate the difference between continuous use and cyclic use oral contraceptives. They sought to determine if patients taking continuous oral contraceptives experienced higher rates of VTE using a database of medical and prescription drug claims. They find a slight increase risk of VTE in the patients taking extended use oral contraceptives, however this difference is very small and likely does not have clinical significance.
There are several limitations to the study:
- The patients in the two cohorts may have differences that are unmeasured. Even though the patients are matched – there may be important differences that lend to an increased risk of VTE in the extended use group (or decreased risk in the cyclic group) that are unmeasured.
- Women who are prescribed extended use oral contraceptives may be inherently different than women who take them cyclically. Continuous use oral contraceptives can be used to treat many gynecologic conditions – PMS, heavy periods resulting in anemia due to a variety of etiologies, menstrual migraines, abnormal uterine bleeding from anovulation.
- There is no way to guarantee that patients prescribed cyclic use OCPs did not take them in a continuous manner. Many prescribers prescribe generic brands and instruct patients to take them continuously.
Overall this study should not impact prescribing patterns as the incidence rate difference between the groups is very small. There are numerous advantages of extended use oral contraceptives and is a useful treatment for many gynecologic conditions. Providers should still consider risk factors for VTE (age, hypertension, smoking status) and counsel patients appropriately.