Satisfaction and compliance in hormonal contraception: the result of a multicentre clinical study on women's experience with the ethinylestradiol/norelgestromin contraceptive patch in Italy

Combined oral contraceptives are one of the most effective and commonly used forms of reversible contraception, used by more than 100 million women worldwide for family planning [1, 2]. If taken exactly according to the provided instructions (perfect use), oral contraceptives are almost 100% reliable, with a failure rate of 0.1 per 100 women in the first year of use [2]; in clinical practice (typical use), the failure rate can be up to 5 per 100 women years [2], mainly due to non-compliance or imperfect compliance with the once daily regimen [3‐5]. For this reason, a new technology with comparable contraceptive efficacy and safety, but not requiring daily compliance, was developed [6].

The application of transdermal technology to a birth control product was considered a milestone in transdermal drug delivery development and the ethinylestradiol/norelgestromin patch (EE/NGMN patch) was the first and unique contraceptive patch to receive worldwide regulatory approval [7]. The EE/NGMN patch marketed in Europe is a three layer 20 cm² patch containing ethinylestradiol 0.6 mg and norelgestromin 6.0 mg, applied once weekly for 3 consecutive weeks followed by a patch-free week [8]. During the 7-day wear period, the patch continuously delivers ethinylestradiol and norelgestromin, thereby avoiding peaks and troughs seen with oral contraceptives [9]. The steady-state concentrations are reached after about 48 hours. There are fewer consequences of dosing errors with the patch than with oral contraceptives: even if a scheduled patch change is delayed for 2 days during weeks 2 and 3, clinical efficacy is maintained, and backup contraception is not needed [10].

The synthetic progestin norelgestromin (17-deacetyl norgestimate, active metabolite of norgestimate) was chosen for the patch [8]. Both norgestimate and norelgestromin, virtually equivalent from metabolic and endocrine perspectives, have a low androgenicity due to their negligible binding affinities for the androgen receptor and for the sex hormone-binding globulin (SHBG) [11, 12]. A clinical study showed that the patch had an effect comparable to the norgestimate-containing oral contraceptives on several key androgenic markers, suggesting this patch containing norelgestromin may improve disorders resulting from androgen excess [13]. In vitro studies demonstrated that norgestimate is a strong inhibitor of 5α-reductase (responsible for transforming testosterone to more potent dihydrotestosterone) in the skin [8, 14]; in addition, the antiandrogenic activity of these progestins has been recently confirmed in an in vitro study where norgestimate and norelgestromin activity was 50% that of cyproterone acetate [15].

Several clinical studies showed that the clinical efficacy of the contraceptive patch in preventing unintended pregnancy is similar to that of oral contraceptives, with the benefit of once-weekly administration [16, 17]; in a pooled analysis of three Phase III studies (3.319 women, 22.160 treatment cycles), the overall annual probability of pregnancy was 0.8% and the method failure probability was 0.6%, without differences across age [18]. The follicular size and the incidence of ovulation were significantly reduced in contraceptive patch users compared with oral contraceptive users, both in normal cycles and after planned dosing errors [19].

A pooled analysis of the same three Phase III studies previously mentioned, but limited to the subset of North America centers (1.785 women, 11.772 treatment cycles), showed that compliance (adherence to the regimen or perfect use) with the contraceptive patch was remarkably good: the rate of cycles with perfect use of the patch ranged within age groups from 88.1% to 91.0%, and adherence to the weekly schedule was significantly better than with daily oral contraceptives (p < 0.001), especially in younger women (< 20 years: 67.7% vs 87.8%) [20‐22]. Another pooled analysis of the same three Phase III studies, integrated by 30 women from a three-period crossover exercise study (3.349 women, 70.639 patches worn), showed that the reliability of adhesion of the contraceptive patch was excellent and consistent across all studies [23]. Heat, humidity and exercise did not affect adhesion [23].

Finally, the adverse effect profile of the contraceptive patch is similar to that of oral contraceptives (most frequent adverse events: headache and nausea), with the exception of a higher incidence of application site reactions, breast discomfort and dysmenorrhoea in the patch group, most of them mild or moderate in severity [24]. Recent epidemiologic case-control studies conducted in the United States reported that the risk (i.e., odds ratio OR) of venous thromboembolism with the contraceptive patch compared to that of oral contraceptives containing ethinylestradiol 35 μg and norgestimate or ethinylestradiol 30 μg and levonorgestrel ranged from 0.9 (indicating no increase in risk, 95% CI 0.5–1.6) to 2.4 (indicating an approximate doubling of risk, 95% CI 1.1–5.5) [25‐29].

However, in the contraceptive setting, other factors beyond efficacy and safety of the method (i.e. simplicity and ease of use, women's acceptability, satisfaction, additional benefits) can influence women's choice, adherence and persistence of use. In general, nearly half of contraception users are not completely satisfied with their current method: actual or expected side effects, difficulty of use, worry about effectiveness and reduced sexual pleasure are just some of the many reasons women give for being dissatisfied. Obviously, women who are not completely satisfied are more likely than satisfied users to make mistakes (e.g. gap in use, incorrect or inconsistent use) and to discontinue the method, putting themselves at high risk of unintended pregnancy [3]. So, contraceptive success and long-term adherence is strongly related to the subject's satisfaction [3].

In order to investigate women's experience with the EE/NGMN patch, a pan-European study, named "EVRA Contrast" (NRGEEP-CON-402), was carried out [30, 31]. The primary objective of the study was to evaluate, specifically, user satisfaction and, if applicable, user preference in comparison with the previous contraceptive method. The secondary objectives were to monitor contraceptive efficacy, safety, and user compliance with the transdermal patch. Italy took part in this study, but with different timelines compared to other countries, because Italian Investigators added an additional sub-study to assess body composition with bioelectrical impedance analysis (BIA). Italian data regarding women's experience with the patch are now presented in this paper.

The primary objective of this multicentre study was to evaluate satisfaction, preference, compliance and well-being following use of the contraceptive patch, in a naturalistic setting as close to the real-life situation as possible ("real world" use), in order to have data reflecting how the patch is normally used by European/Italian women.

In Italy, after 6 cycles of patch treatment, the satisfaction rate in all women was 88%; considering only the women using a contraceptive method at baseline, their satisfaction increased from 45% with the previous method to 86,3% with the patch while the dissatisfaction decreased, respectively, from 27% to 4%. This is in agreement with other studies with the contraceptive patch: Wan reported significantly higher levels of satisfaction in the women who used the contraceptive patch compared to the oral contraceptive users (OR = 2.05; p = 0.001) [35], while Weisberg showed that out of 279 participants who completed 9 cycles, 91% were satisfied with the patch [36]. In an international randomized trial conducted on 1489 women, significantly more users were very satisfied with the contraceptive patch compared to oral contraceptives (p > 0.05) and, in contrast to oral contraceptives, the percentage of women being very satisfied with the patch, gradually increased with age, resulting in a more pronounced difference in women aged > 34 [37]. Finally, 97% of adolescents evaluated in a recent study were very satisfied/somewhat satisfied with the contraceptive patch and 93% of them stated that they would recommend it to a friend/relative [22].

Concerning the comparison with the method used in the 3 months before study enrolment, 78.1% of subjects had a preference/strong preference for the patch due to convenience, ease of use/simplicity and fewer side effects of the patch over the other methods; similarly, Weisberg reported that almost 3 out of 4 participants preferred the patch to their previous method [36]. In this regard, 93% of adolescents reported that they remembered to apply the patches on time, and 40% of them stated that its use was easier than that of previous contraceptive methods [22].

The high level of satisfaction and preference with transdermal contraception may be considered important when trying to maximize long-term compliance. In this study, compliance was very high (93,2% perfectly dosing cycles), in accordance with the pooled analysis of randomized controlled trials (88.7% vs 79.2% of oral contraceptives, p < 0.001). In the observational study conducted in Canada, patch perfect compliance was high across all cycles (88%) and did not differ significantly across age [36]. Similarly, Urdl demonstrated that compliance was consistently better in the patch group (range 90 to 97%) compared to the oral contraceptive group (85 to 92%) [37]. The once-weekly application schedule for the patch is desirable because it is well suited to the lifestyle of European women, including younger women for whom compliance with oral contraceptives is a particular issue [20, 37].

The improved compliance observed with the patch may lead to fewer unintended pregnancies [8, 16, 21], although confirmation of this would require additional clinical studies. Only 1 pregnancy was reported and occurred during the study (confirmed by urine and blood positive pregnancy tests, gynaecological examination and ultrasound). These data are consistent either with those of the pooled analysis [18] or with the more recent multicentre studies, evaluating a high number of women in conditions very close to real use in daily life [36, 37].

In this study, the reporting frequency for each adverse event was lower than rates for the same adverse events reported in other clinical trials. Headache was the most frequently reported event, followed by spotting between menses, itching, breast pain, localized skin reaction, nausea, and breast tension. In our study, application-site reactions (2.9%) were significantly lower than the 17.4% in the phase III studies pooled analysis [24] and the 13.8% reported by Urdl [37]. According to Weisberg, application site reaction was the most common patch-related adverse event in cycle 1, but diminished greatly in the successive cycles [36]. In general, < 2% of participants discontinued patch treatment for this reason [24, 37].

Severity of the events, withdrawal due to safety and improvement of tolerability with progressive cycles were consistent with, or better than, those seen in previous studies [24, 36, 37]. In aggregate, these safety data indicate that the patch is well tolerated, with an adverse event profile similar to oral contraceptives [24, 37].

The main strength of our findings is the fact that this is the first multicentre Italian study specifically designed to evaluate women's satisfaction and preference with the contraceptive patch in comparison to the previous methods. Even if several trials evaluated these items in Europe (but not in Italy) and in South Africa [37], in the United States [35] and in Canada [36], our data are the first published regarding Italian women. The open study design with broad selection criteria enabled data to be gathered on the patch in everyday woman use, with the minimum of interventions, and the results reflected how the contraceptive patch is normally used in Italy. These results can be considered innovative if we take into account that the choice and the preference for a contraceptive method could be different from country to country and influenced by different factors such as cultural and religious ones.

However, our study has also several limitations. Firstly, this is a non-randomized observational trial. This kind of approach can introduce bias, because a subject could be unconsciously predisposed to favour the new therapeutic option. But, in this study, only 50% of participants adopted a contraceptive method in the 3 months before enrolment, and the degree of satisfaction at study end was very high in all the subjects. In addition, an open-label, single arm design was chosen to reflect how women under "real world" circumstances normally use the contraceptive patch. Secondly, the characteristics of women who perfectly adhere to the regimen, as well the possible factors associated with the women who were very satisfied/satisfied with the patch, were not investigated in details; however, considering the relatively small number of our population (207 women, 175 of them are completers), we think that this type of analysis (e.g. analysis per age classes, per number of previous pregnancies/deliveries) could not be feasible and/or significant from a statistical point of view. Thirdly, women could use condoms during the study and a monogamous relationship without the need for STI protection was not an eligibility requirement. This strict lifestyle criterion was not adopted because the objective of this study was to evaluate the real-life use of the patch and not to collect information on a restricted population of women (observational study, without any registration purpose). For this reason, information about condom use, as well as the number of intercourses by cycle, were not collected. Finally, because all of the women agreed to use the patch, the adherence and acceptability results might not be representative of the general population, with a possible over-estimation of the satisfaction and adherence. By contrast, also in this case, the study reflects real-life situation: in clinical practice, woman are usually used to discussing the choice of a contraceptive method with their own Gynaecologist/GP, and this mutual decision making with her doctor is very important to reach a "therapeutic alliance", valuable predictor of patient's adherence and persistence.

In addition to clinical efficacy in preventing unintended pregnancies, the choice of a contraceptive method should take into account other important attributes of the treatment that impact on compliance, such as women's preference, satisfaction, well-being and ease of use. Specifically, satisfaction with the contraceptive method is essential for long-term adherence because human behaviour tends to be repeated when it is rewarding (e.g. when the method satisfies the personal needs of the woman and her partner). In this sense, transdermal contraception has provided an important new option for many women. The EE/NGMN contraceptive patch is as effective and well tolerated as oral contraceptives; the convenience and simplicity of a weekly change schedule for the patch may contribute to its high degree of satisfaction. In conclusion, high satisfaction levels, coupled with excellent compliance, make the contraceptive patch a reasonable option for women desiring hormonal contraception.