Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile
Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7:e1054-e1064.
Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99:323-328.
Archer and colleagues reported the results of 2 pivotal multicenter, open-label, phase 3 trials, which included 2,265 users, conducted to evaluate efficacy and return to menses or pregnancy after use of the 1-year (13 cycles) SA/EE contraceptive vaginal system (CVS).
Details of the efficacy study
The study included 1,130 women in a US-only study and 1,135 women in an international study with sites in the United States, Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, and Sweden. Participants used the CVS for 21 days followed by a 7-day use-free interval for up to 13 consecutive cycles; they were instructed not to remove the CVS for more than 2 hours during the 21 days of use.
Primary and secondary efficacy outcomes were calculated using the Pearl Index and an intention-to-treat Kaplan-Meier life table, respectively. At the end of the study, users who desired not to continue hormonal contraception or to become pregnant were followed up for 6 months to evaluate return to menses or pregnancy.
The investigators reported an overall Pearl index of 2.98 (95% confidence interval [CI], 2.13-4.06) and a Kaplan-Meier life table cumulative efficacy rate of 97.5% (FIGURE 1), consistent with other recently approved CHC methods. Women from non-European sites, who primarily were US participants, had a Pearl Index of 3.25 (95% CI, 2.35-4.37), and participants from the European sites had a Pearl Index of 0.47 (95% CI, 0.03-2.07). Importantly, CVS removal had a significant impact on efficacy, with a Pearl Index of 5.98 (95% CI, 2.46-9.27) in users reporting CVS removals for longer than 2 hours, suggesting escape ovulation with improper use. The Pearl Index was highest in users aged 18 to 19 years and was not affected by body mass index (BMI), although 91% of users had a BMI of 29.0 kg/m2 or lower.
There was no trend for a change in pregnancy risk across 13 cycles, providing evidence of CVS efficacy throughout a full year's use. The follow-up portion of the study included 290 users who were not continuing hormonal contraception at study end; all follow-up participants reported return to menses after method discontinuation.
Clinical safety data
To evaluate safety outcomes from clinical studies on the CVS containing SA/EE, Gemzell-Danielsson and colleagues analyzed 9 studies. Most of the data were derived from 2 phase 3, multicenter trials (as discussed above), with supporting evidence from 7 other studies.
Adverse events reported
Among 2,308 CVS users in the phase 3 trials, 87% reported at least 1 adverse effect, with most of mild or moderate severity. These included headache, 26%; nausea, 18%; vaginal discharge, 10%; and metrorrhagia, 7%. Overall, 12% of CVS users discontinued use due to an adverse effect. Two percent of users experienced severe adverse effects, including venous thromboembolism (VTE), allergic reaction, gallbladder disease, and spontaneous abortion.
In the US-only phase 3 trial, 2 VTE events occurred in the first 6 months in women with baseline BMI greater than 29.0 kg/m2; therefore, enrollment of patients with a BMI greater than 29.0 kg/m2 was halted and current users meeting that criteria were discontinued. Notably, no cases of VTE occurred in studies with a segesterone acetate-only CVS; this suggests that risk can be attributed to the estrogen component. Overall, 4 nonfatal VTEs occurred, all among the 1,536 women enrolled in the phase 3 trials (4 of 1,536 [0.3%]); at least 3 of these cases occurred in users with VTE risk factors (TABLE 1). The estimated VTE rate in CVS users with a BMI greater than 29.0 kg/m2 is 10.8/10,000 women-years (95% CI, 8.9-13.1).
Complete expulsion of the CVS occurred in 7% of cycles and partial expulsion in 19.5% of cycles; users reported expulsion more frequently in the first cycle, most (about 70%) of which were partial expulsions. Of the laboratory values and vital signs studied, including weight, users had no clinically relevant changes from baseline.
The 13-cycle efficacy and general adverse events rates of the new SA/EE CVS are consistent with those of other CHCs. However, the efficacy and safety findings are not necessarily generalizable to all patients. Because users with a BMI greater than 29.0 kg/m2 were excluded following 2 early VTE events in women with a BMI of 29.1 and 30.8 kg/m2 , only 9% of the phase 3 study population had a BMI greater than 29.0 kg/m2 . Clinicians may question whether the 1-year SA/EE CVS is an acceptable method for obese users. We know that EE causes similar changes in hemostatic factors regardless of oral or vaginal route,9 but these studies as well as pharmacokinetic studies typically include relatively few participants. While studies demonstrate that the SA/EE CVS delivers EE 13 µg daily,1 individual hormone absorption can vary. It is possible that the amount of EE in the CVS (17.4 mg) could, in a person predisposed to higher absorption, increase VTE risk. We do not know if this potential or actual risk is different for nonobese and obese users. To be fair, most of the EE-containing combined hormonal contraceptives were approved with study data that did not include obese women; the FDA first discussed the importance of including obese women in contraceptive approval studies in 2007.10 Thus, we do not know if this CVS has a significantly higher VTE risk in obese users than other methods.
All available information is based on cyclic CVS use (28-day cycles with a 7-day use-free interval). No data are available on drug levels, safety, or efficacy over extended periods of continuous use with the same CVS. During counseling, special emphasis should be placed on the increased pregnancy risk for patients who remove the ring for more than 2 hours.
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