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Effectiveness and Failure Rates of Oral Contraceptives
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Extended (24-day) oral contraceptive regimens are more effective than standard (21-day) cycles during typical use, and drospirenone pills had lower failure rate than other preparations..
Source: Dinger J, et al. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol 2011;117:33-40.
Outcome data from 52,218 u.s. participants in the international Active Surveillance of Women Taking Oral Contraceptives (INAS) study were used to analyze contraceptive failure in association with typical use of oral contraceptive (OC) pills. The INAS study is a large, prospective, controlled, noninterventional, long-term cohort study with active surveillance of study participants designed to reduce loss to follow-up. Contraceptive failure rates were statistically analyzed (Pearl Index, life-table analysis, inferential statistics with Cox regression model) for failure rate, quality-of-life indices, and confounders. The primary analysis was based on 1,634 unintended pregnancies during 73,269 woman-years of oral contraceptive pills exposure. Life-table estimates of contraceptive failure for a 24-day regimen of drospirenone (DRSP) and ethinyl estradiol and 21-day regimens of other progestogens were 2.1% and 3.5% after the first study year, and 4.7% and 6.7% after the third year. The adjusted hazard ratio (HR) was 0.7 (95% confidence interval [CI] 0.6–0.8). Direct comparisons of the 24-day and 21-day regimens of drospirenone and norethisterone (norethindrone) showed lower contraceptive failure rates for 24-day regimens. Contraceptive failure rates adjusted for age, parity, and educational level showed a slight increase with higher body mass index.
About half of all pregnancies in the United States are unintended at conception, and about half of these occur among users of a contraceptive method.1 OCs currently are used by about 11 million American women.2 All of the approved products have perfect-use failure rates of less than 1%. In Phase 3 clinical trials in the United States, the typical use failure for most recently approved products has been around 2%. Estimates of typical use failure for OC use in the general population are closer to 8%.3
There are several explanations for typical use failure, but non-compliance with the regimen likely represents the biggest factor. Most women taking the pill will occasionally miss a dose. The fact that oral contraceptive pills work as well as they do is a credit to the multiple mechanisms of action of combined pills (e.g., inhibition of ovulation and cervical mucus effects). The many improvements in oral contraceptives over the last 50 years also have influenced compliance. Women who associate pill intake with a non-contraceptive benefit may be better pill takers. Therefore, linking pill use with improvement in acne, menstrual cycle-related symptoms, and heavy bleeding all have an important impact on contraceptive effectiveness.
The 7-day hormone free interval (HFI) presents an opportunity for failure. Women show reactivation of the hypothalamic-pituatry-ovarian axis during the HFI, and delaying the initiation of a new cycle pack may result in an increased rate of ovulation.4 Is there any benefit to a 7-day HFI? Apparently not, as studies have demonstrated that women using OCs experience more symptoms during the HFI than at other times in the cycle, and that continuous use reduces or eliminates these symptoms.5
Careful investigations of meaningful surrogates (gonadotropins, follicle growth and rupture, steroid hormone production) in women using standard (21-day active pills and extended (≥ 24 days of active pills) show that the longer regimens reduce the likelihood of ovulation.4
Surrogates are one thing, but the critical issue for clinicians is real-world effectiveness. The current study provides meaningful information with an important impact on patient care. I have written several times about results from the INAS (USA population) and EURAS (European) studies. These large prospective population-based Phase 4 postmarketing studies were mandated by the FDA and European regulatory authority to monitor the health effects of dropirenone oral contraceptives. Although the studies were commissioned by Bayer Healthcare, they were conducted by an independent research organization with a data safety monitoring board and independent data analysis team. The studies already have contributed useful information about thrombisis risk.6,7
The strengths of the INAS study are its large size and real-world prospective enrollment. More than 5,000 gynecologists in private practice and clinics in all U.S. states, representing metropolitan as well as rural areas, enrolled women receiving a new prescription for an oral contraceptive pill. Prescribing habits were not influenced by participation in the study, and there was no incentive to prescribe or receive any particular pill. Participating subjects needed to be new users of the pill prescribed; either first-time users, recurrent users after a break in oral contraception, or users who switched to a different type of pill. This design prevented the "healthy user" effect seen in database studies evaluating thrombosis risk.
The main result of this paper, that extended regimen (24-day) preparations were more effective than 21-day products, is not surprising given what we know about the HFI, but nonetheless extremely meaningful to our contraceptive counseling. The fact that DRSP pills were more effective than other OCs is harder to explain, but given the magnitude and statistical significance of the findings (first-year contraceptive failure [95% CI] for DRSP/EE 24-day 2.1% [1.7–2.4], DRSP/EE 21-day 2.8% [2.2–3.3], and other OCs 3.5% [3.3–3.7]), there is level 2 evidence to support superiority of these products. This could be related to better tolerability (and therefore compliance) with these pills, although we have no data to support this conclusion. Given that both the 21-day and 24-day DRSP products now have generic equivalents, there is no reason to look at this as a "brand" issue.
The other important finding of the study was that failure was higher in obese women. The adjusted HR for contraceptive failure in women with a BMI ≥ 35 compared with < 35 was 1.5 (95% CI, 1.3–1.8). Interestingly, the 2%-3.5% first year failure with combined pill use in this large prospective trial is still lower than that estimated by Trussell3 (e.g., 8%), suggesting that the INAS study represents a more compliant patient group overall.
We can expect even more interesting and clinically useful information from these important Phase 4 studies of oral contraceptives. Stay tuned.