Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women
Nelson AL, Kaunitz AM, Kroll R; SECURE Investigators. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: phase 3 clinical trial results. Contraception. 2021;103:137-143.
To assess the contraceptive efficacy, tolerability, and safety of the transdermal patch Twirla (EE/levonorgestrel) over 1 year of treatment (13 cycles), Nelson and colleagues conducted an open-label, multicenter, US-based phase 3 trial of participants aged 18 years and older with regular cycles. There were no restrictions based on BMI. On average, the study population was overweight, with a mean BMI of 28.3 kg/m2 , and 35% of the population was considered obese (BMI ≥30 kg/m2).
Study design
A total of 2,032 participants enrolled in the study, with separate populations defined for specific analysis on safety, contraceptive efficacy, and cycle control. The primary efficacy group included 1,736 participants. Fifty-one percent discontinued the study, most commonly due to “women’s decision” (15%) and lost to follow-up (11%). Users received bleeding diaries and returned periodically throughout the study for evaluation for efficacy, adherence, and adverse events.
Efficacy associated with BMI
The study results demonstrated an overall PI of 5.8 pregnancies per 100 woman-years for users aged younger than 35. TABLE 2 demonstrates the overall trend of efficacy in relation to BMI.10,15-19 Participants with a higher BMI were found to have a higher PI, revealing lower contraceptive efficacy in more overweight and obese patients. The overall cumulative pregnancy rate over 13 cycles was 5.3%
Participants reported decreasing frequency of bleeding/spotting days over the treatment duration of 13 cycles, from a mean (SD) of 6.2 (4.5) days in cycle 1 to 4.9 (3.5) days in cycle 13. Unscheduled bleeding episodes remained high throughout the study period. Initially, 60% of users reported 1 or more days of unscheduled bleeding in cycle 1, and 42% still reported unscheduled bleeding in cycle 13. In light of this, only 45 participants (2.2%) discontinued the study due to bleeding issues, suggesting perhaps that the bleeding was light. Overall, users experienced acceptable wearability of the patch, and the rate of detachment decreased over the study period from 9.9% in cycle 1 to 2.4% in cycle 13. There were also low rates (0.5%) of moderate to severe irritation. Itching at the adhesion site decreased slightly from 13.1% in cycle 2 to 9.6% in cycle 13.
In general, 27.2% of patch users experienced a study-related AE, most reported as mild to moderate. Nausea (4.1%) and headaches (3.6%) were the most common hormone-related AE. Importantly, 4 obese users experienced 5 VTEs (deep vein thrombosis, n = 2; pulmonary embolism, n = 3) between cycle 5 and 13. Three of these users had additional VTE risk factors, such as air travel and a family history of clots. No users who were of normal weight or overweight experienced VTE.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Available data demonstrate that the EE/norelgestromin patch exposes users to higher serum levels compared with the pill or the ring.20 The higher estrogen exposure with the patch may explain higher estrogen-related adverse effects and may result in increased VTE risk. Initial pharmacokinetic data of the EE/levonorgestrel patch showed lower EE concentrations, similar to marketed COCs and lower than EE/norelgestromin.21 Despite this lower estrogen exposure, the phase 3 trial by Nelson and colleagues did not demonstrate a safer profile with respect to thromboembolic events.
Further, the high PI of 5.8 pregnancies per 100 woman-years calls into question the efficacy of this patch compared with already available CHC options. Indeed, the efficacy appears reasonable in normal-weight individuals, with a PI of 3.5 pregnancies per 100 woman-years; however, this is still higher than its contemporary counterpart, Nextstellis, which has a PI of 2.65 pregnancies per 100 woman-years and included users with a BMI of up to 35 kg/m2 (Table 2). Given the evidence of decreased efficacy, clinicians may consider reserving this option for only normal-weight women who cannot use or prefer not to use another CHC method. Obese individuals (BMI ≥30 kg/m2 ) should not use this patch due to decreased efficacy and increased VTE risk. Lastly, although use in overweight individuals (BMI ≥25 kg/m2) is not absolutely contraindicated, clinicians should counsel the overweight patient on the possibility of decreased contraceptive efficacy due to weight, and they may choose to reserve use of this patch in overweight individuals only when no other comparable or more effective method is an option.
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