https://orcid.org/0000-0002-9551-2847
Abstract
Objective
Progestin-only pills are associated with irregular bleeding patterns, including amenorrhea. Desogestrel (DSG) 75 mcg, a pill that inhibits ovulation, shows poor cycle control that may harm acceptability and compliance. A Drospirenone (DRSP)-only pill was developed with 24 & 4 days of active & placebo days every 28-day cycle to improve cycle control.
Study Design
A phase III study in healthy women aged 18 to 45 years was performed to compare the bleeding profile of women taking a DRSP versus DSG over nine cycles. 249 women were older > 35 years: 173 using DRSP and 73 DSG. 259 women had a BMI > 25 kg/m2: 189 using DRSP and 70 DSG and 340 women were smokers: 237 using DRSP and 103 DSG. The amount of unscheduled bleeding/spotting days was analyzed in each of these sub-groups and compared statistically.
Results
Age: During cycles 2-4, the mean number of unscheduled bleeding days and spotting was 8.1 (SD10.53) for DRSP and 20.1 (19.41) for DSG; p = .0089. BMI > 25 kg/m2: During cycles 2-4 the mean number of unscheduled bleeding days and spotting was 7.8 (SD 12.18) for DRSP and 17.7 for DSG (SD 19.39); p = .0001. Smokers: During cycles 2-4, the mean number of unscheduled bleeding days and spotting was 9.6 (SD 11.69) for DRSP and 17.4 for DSG (SD 17.47); p = .0016.
Conclusions
These analyses show the improvement in the bleeding profile of women with specific cardiovascular risk factors using the DRSP only oral contraceptive product compared to DSG.
An improvement in the bleeding profile of women with specific cardiovascular risk factors like age > 35 years, BMI > 25kg/m2, and smokers using the DRSP only oral contraceptive product is described.
Herby a higher contraceptive efficacy in these patients that additionally benefit from estrogen-free contraceptive methods is expected.
Implications
比较具有心血管危险因素的女性单用4毫克屈螺酮片剂与0.075毫克去氧孕烯至少9周期的出血情况 摘要
目的：单孕激素片剂与包括闭经在内的月经模式紊乱有关。去氧孕烯（DSG）75mcg是一种抑制排卵的药物, 但由于周期控制不佳, 可能会降低患者接受度和依从性。单屈螺酮（DRSP）片剂的28天周期含24天有效成分和4天安慰剂, 可改善周期控制。 研究设计：一项在18至45岁健康女性中进行的III期研究比较了服用DRSP与DSG至少九个周期的出血情况。年龄>35岁的女性249人：其中176人服用DRSP, 73人服用DSG。体重指数>25kg/m2的女性259人：其中189人服用DRSP, 70人服用DSG。吸烟的女性340人：其中237人服用DRSP, 103人服用DSG。分析每个亚组的计划外出血/点滴出血天数, 并进行统计学比较。 结果：年龄>35岁：在第2至4周期, DRSP计划外出血与点滴出血天数平均为8.1（SD 10.53）天, DSG平均为20.1（19.41）天, p=0.0089。BMI>25kg/m2：在第2至4周期, DRSP计划外出血与点滴出血天数平均为7.8（SD 12.18）天, DSG为17.7（SD 19.39）天, p=0.0001。吸烟者：在第2至4周期, DRSP计划外出血与点滴出血天数平均为9.6（SD 11.69）天, DSG为17.4（SD 17.47）天, p=0.0016。 结论：这些分析显示, 与DSG相比, 单DRSP口服避孕药可改善具有特定心血管危险因素女性的出血状况。
意义
具有年龄>35岁、BMI>25kg/m2或吸烟等特定心血管危险因素的女性服用单DRSP口服避孕药后, 出血状况得到了改善。同时她们还可以预期, 从无雌激素避孕药中获得更可靠的避孕效果。
Introduction
Starting with the first combined oral contraceptive (COC) in 1957, a continuous development regarding the type and dosage of estrogens and the type of progestogens has been implemented. These changes, especially the kind of progestogens, have produced different non-contraceptive features to the COC due to the different pharmacological l activities of the molecules [Citation1]. The management of medical conditions like endometriosis, dysmenorrhea, hypermenorrhea, ovarian and endometrial cancer can be improved by the mode of action of the different progestogens, either in combination or as monotherapy [Citation2]. Except for medroxyprogesterone acetate, progestogens do not influence the coagulation balance, and they do significantly impact the blood flow and contractility of venous or arterial vessel walls [Citation3]. Epidemiological studies have not shown any significantly increased risk of thromboembolic venous or arterial disease versus non-users when progestogens are used in contraception as estrogen-free drugs [Citation4]. This is the reason why progestogen-only contraceptives are even indicated in women with a World Health Organization medical eligibility criterion (WHO MEC) of the category four or where the use of COC is not recommended (Category 3) [Citation5].
The lactation period is also a situation where progestogen-only contraception confers a significant additional benefit as no reduction in milk production and no adverse effects on the newborn are anticipated with their use. Due to their decidualization transformation on endometrial cells and their antimitotic mode of action, progestogens can reduce the frequency and intensity of uterine bleeding. It has also been described that those progestogens that exhibit a central ovulation inhibition ability reduce painful menstrual bleedings by blocking the synthesis of prostaglandins in the endometrium [Citation6,Citation7].
One widely used product is the 75 μg desogestrel (=DSG) progestin-only pill. This pill inhibits ovulation and is as effective as combined hormonal contraceptives, and it’s taken continuously without a hormone-free interval. No significant health risks are known, and the pearl index is like COCs. In addition to the above-mentioned clinical benefits, alleviation of menstrual migraine has been described [Citation8].
Nevertheless, the most frequent side effect of the continuous use of progestogens is irregular bleeding [Citation9]. And in general progestin-only pills are still not widely used. New estrogen-free products are needed as these unpredictable bleeding patterns might affect contraceptive reliability [Citation10].
A new estrogen-free contraceptive containing 4 mg drospirenone (DRSP) has been developed to address this need.
In previous studies [Citation11,Citation12], the efficacy of DRSP alone has been proven, and the first clinical data regarding the bleeding profile have been presented.
The present investigation aims to describe the bleeding profile of women with risk factors for the development of venous thromboembolism. And to compare the bleeding profile between two different progestogens.
Material and methods
This phase III study was a double-blinded, double-dummy randomized controlled trial including 73 primary and secondary gynaecological health care centers including university hospitals in Austria, Czech Republic, Germany, Hungary, Poland, Romania, Slovakia, and Spain. The studies were performed between August 1, 2012, and January 27, 2014. The protocol was designed and conducted according to existing legal regulations and following good clinical practice in conducting clinical trials and the declaration of Helsinki, including recommendations made in the European Medicines Agency (EMA) CHMP Guideline on Clinical Investigation of Steroid Contraceptives in Women. Institutional review board approval was obtained for all study sites.
Ethical approval
After obtaining the correspondent ethical committee's approval, all participants gave their written informed consent to participate in the clinical trial.
The overall approval for the trial with the leading ethical committee was given the 13.07.2012 by the Landesamt für Gesundheit und Soziales Berlin, Geschäftstelle der Ethik Kommission des Landes Berlin, number 11/0606 EK.
EudraCT registration number: 2011-002396-42.
Study medication
Study medication was DRSP, one tablet of 4 mg non-micronized DRSP per day, via the oral route, with consecutive administration of 24 active pills and four placebo tablets, and no tablet-free interval between 2 successive cycles.
DSG 0.075 mg (in a regimen of 28 active pills, marketed under trade names such as Cerazette® and Cerazet®) was chosen as the comparator for safety, as it also inhibits ovulation as a POP. It is also the first POP with a missed pill window of 12 h, instead of the 3 h allowed by conventional POPs, and is one of the leading POPs on the European market.
Study populations
A total of 858 women with 6691 DRSP and 332 women with 2487 DSG treatment cycles were the hole collective from which the subgroups were analyzed (see and ).
Figure 1. Consort diagram.
Table 1. Demographical data of the global study population.
The subgroups were women with an age > 35 years (group a), BMI > 25 kg/m2 (group b) and smokers (group c).
Women included in this study were all the child-bearing potentials, at risk of pregnancy, agreeing to use only the study medication for contraception for the duration of the study medication treatment, aged 18 to 45, with systolic blood pressure (SBP) < 140 mmHg, diastolic blood pressure (DBP) < 90 mmHg. They could either start the study medication with a break of at least one day after the administration of another hormonal contraceptive (‘starters’) or switch directly from another hormonal contraceptive to the study medication with no break in administration (‘switchers’).
After obtaining the correspondent ethical committee's approval, all participants gave their written informed consent to participate in the clinical trial.
Bleeding
Unscheduled bleeding or spotting days were defined as any day with bleeding/spotting that occurred while taking active hormones (days 2 − 23).
Scheduled bleeding or spotting was defined as any bleeding or spotting that occurred during hormone-free intervals (defined as days 25-28 ± 1). Up to 8 consecutive bleeding/spotting days were considered as scheduled bleeding days.
No scheduled bleeding is expected as DSG is administered without any free period. The women recorded any vaginal bleeding or spotting by intensity (slight, moderate, heavy) per each medication cycle in an electronic diary.
Study endpoint
The study endpoint was the number of days with unscheduled bleeding/spotting in each cycle, from cycles 2 to 9, cumulative in cycles 2 to 4, 5 to 7, and 7 to 9.
Safety
Adverse events (AEs), any untoward medical occurrence in a woman, reported by the women or observed by the clinical investigator during the study was registered using the case report form (CRF), including duration, causality assessed by investigator, seriousness, severity, frequency, treatment, action is taken and outcome. Deviations from the reference ranges of laboratory parameters (thyroid function, hematology, urinalysis, biochemistry, pregnancy test) were evaluated regarding clinical significance by the investigator. Serious adverse events (SAEs) were AEs with any of the following criteria: resulted in death, were life-threatening, required hospitalization resulted in significant disability or incapacity, congenital abnormalities. Deep vein thrombosis or pulmonary embolism and hyperkalaemia were considered AEs of particular interest and would lead to discontinuation in the clinical trial.
Sample size
The subgroups were evaluated from the overall collective of 858 women with 6691 DRSP and 332 women with 2487 DSG treatment cycles.
Randomization was performed using a validated system that automates the random assignment of treatment groups to randomization numbers. The randomization scheme was completed in a 5:2 ratio using blocking methodology via a center-based randomization method. The randomization data were kept strictly confidential, accessible only until the time of unblinding. The DRSP only group received the test product (DRSP 4.0 mg) in blister a + reference placebo in blister b. The DSG group received the test placebo in blister a + reference product (DSG0.075 mg) in blister b.
Bleeding records
The tolerability assessments were based on the vaginal bleeding pattern. From Day 1 of Medication cycle 1 (i.e. the start of use of the intake of the drugs) to the end of the clinical trial at day 29 of the last cycle, the women had to record daily any vaginal bleeding or spotting in their electronic diary, which comprised the following details:
Presence of any vaginal bleeding or spotting (Yes, No)
Bleeding intensity (light, moderate, heavy)
Statistics
The vaginal bleeding pattern statistic was performed on the FAS. Bleeding data were summarized by treatment groups using the default summary statistics. The hypothesis that DRSP is non-inferior to DSG regarding the proportion of subjects with unscheduled bleeding/spotting during cycles 2 to 9 was tested confirmatory using the chi-square test. The number and rate of women with different bleeding patterns were presented for each cycle and cumulative in cycles 2 to 4, 5 to 7, and 7 to 9. The Chi-square test was applied to compare rates in both treatment groups. Numbers of bleeding/spotting days and bleeding/spotting episodes were presented by each cycle and by cycles 2 to 4, 5 to 7, 7 to 9, and 2 to 9. The treatment groups were compared using a Wilcoxon rank-sum test. Data were also tested for normality. The treatment cycle presented the number of missed tablets or entries in the e-diaries for subjects with unscheduled bleeding/spotting.
Results
Group a) age > 35 years
In total, 83 women in the DRSP group and 28 women in the DSG had evaluable data for cycles 2-9.
For the cycles 2-9 the mean number of unscheduled bleeding days and spotting was 20.9 (SD 29.45) for DRSP and 40.8 (SD 38.36); p = .0089. When performing the analyses for cycles, 2-4 following results were obtained: 8.1 (SD 10.53) days of unscheduled bleeding/spotting were observed in the group of women using DRSP. In comparison, in the DSG group, the number of bleeding days and spotting was 20.1 (SD 19.41). The difference was significant. p < .001 (see ).
Table 2. Number of unscheduled days with spotting and/or bleeding of women with age >35 years by cycle.
Group b) BMI > 25 kg/m2
Eighty-one women in the DRSP group and 28 women in the DSG had evaluable data for cycles 2-9.
For cycles 2-4, the mean number of unscheduled bleeding days and spotting was 7.8 (SD 12.18) for DRSP and 17.7 for DSG (SD 19.39); p = .0001.
For cycles 2-9, the mean number of unscheduled bleeding days and spotting was 15.0 (SD 21.23) for DRSP and 25.1 for DSG (SD 29.80); p = .0694 (see ).
Table 3. Number of unscheduled days with spotting and/or bleeding of women with BMI >25 kg/m2 by cycle.
c) smokers
Seventy-one women in the DRSP group and 29 women in the DSG had evaluable data for cycles 2-9.
For cycles 2-4, the mean number of unscheduled bleeding days and spotting was 9.6 (SD 11.69) for DRSP and 17.4 for DSG (SD 17.47); p = .0016.
For the cycles 2-9 the mean number of unscheduled bleeding days and spotting was 17.9 (SD 20.25) for DRSP and 31.6 for DSG (SD 30.85); p = .0730.
There was also a trend toward a lower number of bleeding and spotting days in the group of former smokers.
For cycles 2-4, the mean number of unscheduled bleeding days and spotting was 9.8 (SD 10.79) for DRSP and 13.9 for DSG (SD 15.27); p = .3478 (see ).
Table 4. Number of unscheduled days with spotting and/or bleeding of smokers by cycle.
Discussion
The Lancet women and cardiovascular disease Commission stated in 2021 that cardiovascular diseases are the leading cause of mortality for women and were responsible for 35% of total deaths in women in 2019. In 2019, there were an estimated 275.2 million (95% uncertainty interval [UI] 261.4 million to 289.8 million) cases of cardiovascular disease in women worldwide [Citation13]. There were an estimated 6.10 million (95% UI 5.62 million to 6.41 million) deaths from cardiovascular disease in women in 1990, rising to 8.94 million (95% UI 7.92 to 9.71 million) in 2019. The global age-standardized cardiovascular disease mortality in women in 2019 was estimated at 204 deaths per 100 000, representing 35·1% (95% UI 30·1% to 40·3%).
Obesity is highly prevalent and increasing globally. Obesity and insufficient physical activity are closely associated with hypertension and are more prevalent in women than men. Analyses of US National Health and Nutrition Examination Survey data [Citation14] have identified obesity (body-mass index ≥30 kg/m2) as the most important modifiable risk factor for hypertension and pre-hypertension in women of reproductive age. Data suggest that a similar increase in the male or female body mass index is associated with a more significant increase in systolic blood pressure in women than in men [Citation15]. In addition, data from the Framingham Heart Study showed that the excess risk of cardiovascular disease attributed to obesity was 64% in women versus 46% in men [Citation16].
It is estimated that, together with diabetes, obesity contributes substantially to cardiovascular disease prevalence and mortality in women and should be a significant target for health interventions [Citation17].
Globally, tobacco smoking and the use of electronic cigarettes (also known as e-cigarettes, vape pens, and vaping devices) are increasing in younger women (≤25 years). This epidemic could represent significant harm to women. A large meta-analysis found that the increased risk of cardiovascular disease associated with smoking was 25% higher in women than in men [Citation18].
Data from the GBD 2015 study show that the worldwide age-standardized smoking prevalence in 2015 was 5.4% (95% UI 5·1–5·7), although in 34 (17%) of 195 countries analyzed, the smoking prevalence in women exceeded 15.0%. Mostly, countries in western and central Europe greatly exceeded the global average in women's smoking prevalence, with an exceptionally high prevalence among women aged 15–19 years [Citation19].
Combined estrogen-progestin hormonal contraceptives include the pill, vaginal ring, and patch formulations. Available progestin-only methods include medroxyprogesterone injections, etonogestrel implants, progesterone-only pills, and levonorgestrel-releasing intrauterine devices [Citation20]. Hormonal contraceptives are generally considered safe and effective for preventing pregnancy, with y few contraindications. However, women with specific risk factors for venous thromboembolism, acute myocardial infarction, or both (e.g. smokers aged 35 years or older, history of venous thromboembolism or pulmonary embolism, or hereditary thrombophilia) should be strongly advised to consider non-hormonal or progestin-only contraceptives. The risks of using hormonal contraceptives should be constantly balanced against the potential risks of unintended pregnancy [Citation20,Citation21].
Although the overall risk is low, evidence suggests that combined hormonal contraceptives are associated with a 12 times increase in the risk of myocardial infarction in women with hypertension [Citation22]. If multiple risk factors exist, combined hormonal contraception could increase a woman’s cardiovascular disease risk to an unacceptable extent [Citation20]. There is no robust evidence that past use of hormonal contraceptives significantly affects the risk of subsequent cardiovascular disease, regardless of the duration of use or time since last use [Citation23].
Women older than 40 should be screened for additional cardiovascular disease risk factors, such as smoking, obesity, diabetes, hypertension, or migraine with aura. Progesterone-only oral contraceptives, subdermal implants, and levonorgestrel-releasing intrauterine devices are options to use in women with a history or at risk of myocardial infarction or stroke [Citation20].
Previous authors have described that the use of combined contraceptives accelerates the cascaded of coagulation and fibrinolysis (Kuhl [Citation24], Winkler [Citation25], and Schindler [Citation26]). They could describe an increase of haemostasis and fibrin turnover markers because of the pro coagulator effects of estrogens, especially ethinyloestradiol. The action of ethinylestradiol on hepatic and vascular function is well documented by the rise of sex hormone-binding globule (SHBG) [Citation26]. In the combined drugs (COC), progestogens with pronounced androgenic properties, e.g. levonorgestrel, may partially counteract the estrogen-induced changes in the hepatic synthesis of coagulation factors. Other progestogens with antiandrogenic or neutral androgenetic properties may not have this effect [Citation26]. Nevertheless, the VTE risk of COCs containing levonorgestrel is three times higher than the risk of non-users.
In this context, the use of estrogen-free formulations is gaining more relevance.
In parallel to the reduced VTE risk under the use of POP to increase satisfaction with contraception is essential to continue a contraceptive method. The bleeding profile is one of the most common reasons for stopping a contraceptive method due to possible dissatisfaction.
A previous study could be described that the overall and bleeding-related discontinuation rates between DRSP and DSG were significantly different.
Regarding the bleeding after nine months of use, women receiving DRSP had a 55.7% lower discontinuation rate than women using the POP DSG [Citation27].
This study also proofed in the special group of women the superiority of DRSP versus DSG even though the regimen of both contraceptives used in this trial were different: DRSP was administered for 24 days followed by a 4-day hormone-free interval, whereas DSG was administered for 28 days without any interval. Therefore, subjects who received DRSP experienced both scheduled and unscheduled bleeding, whereas the users of DSG experienced unscheduled bleeding only.
One weakness of the study is that it is an analysis of a subgroup of patients of a greater collective. On the other side, the high number of analyzed patients enrolled in this trial gives the results a high statistical power that enables extrapolating the data to the general population.
Improving women's health and reducing the side effects of a contraceptive method will enhance the acceptability of POP and improve efficacy. The DRSP-only pill is, in this context, a significant step forward as DRSP will enhance compliance as the bleeding profile is improved, widening the group of women able to use this contraceptive method.
Disclosure statement
Pedro-Antonio Regidor and Enrico Colli are employees of Exeltis. Santiago Palacios declares no conflict of interest.
Funding
The study was funded by Insud Pharma.
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