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New oral contraceptive containing estetrol


Summary

Drovelis®, a contraceptive pill containing the new oestrogen estetrol, was recently authorised for the European market by EMA. The reliability of this pill, which combines estetrol with drospirenone has not been assessed in controlled studies. Nor has it been compared with the pill combining 30 µg ethinylestradiol and 150 µg levonorgestrel, which is recommended as the combination oral contraceptive (COC) of first choice in the Netherlands. Research using the biomarkers that predict the risk of thrombosis appears to slightly favour the new combination over the oral contraceptive of first choice. The actual risk of thrombosis has not yet been examined in long-term controlled research. In view of the lack of sufficient information about both reliability and the risk of thrombosis, Drovelis® is not yet a suitable alternative for the standard combination oral contraceptives of first and second choice.


Ge-Bu Indication
What is Ge-Bu’s opinion?
  • No controlled research has been done into the reliability of estetrol/drospirenone compared to that of a combination oral contraceptive containing ethinylestradiol.
  • Studies available so far do not allow definitive conclusions to be drawn about any advantage regarding bleeding patterns or cycle control.
  • The thrombotic risk of estetrol/drospirenone compared to that of existing combination oral contraceptives can not yet be estimated due to a lack of research.
  • There are no arguments to indicate a preference for the new combination oral contraceptive with estetrol over the existing combination pills, with which much more experience has been gained.

In May 2021, two new combination oral contraceptives combining the oestrogen estetrol and the progestin drospirenone were authorised in Europe.1,2 The second of these pills will probably be marketed in the Netherlands under the brand name Drovelis®. Estetrol is an oestrogen that is produced by the human foetus during pregnancy, and occurs in high concentrations in the blood of child and mother.3

According to an ‘advertorial’ by the registration holder Gedeon Richter, ‘Estetrol [is] a natural hormone and is the first oestrogen showing selective activity in tissues, i.e. a so-called NEST (Natural Estrogen, with Selective action in Tissues)’. Unlike other oestrogens, estetrol is said to block the oestrogen receptor on the cell membranes. In theory, this would imply a lower risk of thrombosis as well as a lower risk of, for instance, breast cancer. The term ‘natural’ is often used to suggest that a product is safer. However, the theories concerning a reduced risk of thrombosis have not yet been tested in observational studies of estetrol in combination with drospirenone.

This article discusses the reliability, bleeding patterns and thrombotic risk of the combination of estetrol and drospirenone.

Estetrol

Estetrol is a human oestrogen steroid which is produced by the foetal liver during pregnancy. It reaches the maternal circulation through the placenta. Its physiological function is unknown. Since estetrol has four hydroxyl groups, it is often referred to in the literature as E4.3

Estetrol has antigonadotropic activity and mainly reduces the serum level of follicle stimulating hormone (FSH). After intake, it is quickly absorbed into the blood. It does not bind to ‘sex hormone binding globulin’ (SHBG), which means that the risk of thrombosis should, in theory,  be lower than that for pills containing ethinylestradiol (see the Background Information below). The half-life of estetrol is about 24 hours, and most of it is excreted in the urine (69%).2  

Drovelis®

According to a press release by the developer of estetrol,  the combination pill will be sold in Europe by Gedeon Richter under the brand name Drovelis®.4 At time of publication of the present article, this product is not yet on the market in the Netherlands. Drovelis® contains 15 mg estetrol(monohydrate) (corresponding to 14.2 mg estetrol) and 3 mg drospirenone. The drug is available in strips of 28 tablets (24 pink active tablets and 4 white placebo tablets).2 The drug is sold in the United States under the name Estelle®.

Dutch guideline on contraception

The recent guideline issued by the Dutch College of general Practioners (NHG) proposes the combination oral contraceptive with levonorgestrel 150 µg and ethinylestradiol 30 µg as the preferred option for a combination oral contraceptive. According to the guideline, when choosing a combination pill it is important to take account of its reliability, its ease of use and, related to this, any preferences regarding the blood loss to be expected and the risk of serious adverse effects like venous thromboembolisms.5 The existing combination pill using drospirenone as the progestin is neither first nor second choice. This combination pill belongs to the group of hormonal contraceptives with an elevated risk of thrombosis compared to the risk of the pills of first or second choice. 


Research studies determine the reliability of a contraceptive in a specific study sample. However, the reliability of contraceptives depends on psychological and sociological factors such as education and economic status, making randomised studies expensive and complicated. Hence, the most feasible alternative is controlled observational studies comparing  two combination pills within a specific population.

There are three different outcome measures for the reliability of contraceptives: the Pearl index, the WHO effectiveness rate and the ‘lifetime’ table (see box). The lifetime table takes account of the variable reliability of the contraceptive over time, and is therefore well suited for research.

The reliability of estetrol/drospirenone has only been examined in two open-label, uncontrolled phase 3 studies (efficacy studies) in Europe and North America. No efficacy data are available from controlled observation studies comparing 15 mg estetrol/3 mg drospirenone with the combination of 30 µg ethinylestradiol and 150 µg levonorgestrel which is regarded as the oral contraceptive of first choice in the Netherlands.

Outcome measures for the reliability of contraceptive methods

Pearl index
The Pearl index indicates the number of pregnancies that occur if the method is used for 100 woman-years. A ‘woman-year’ is defined as 12 months, i.e. 13 cycles of an average of 28 days. Hence the Pearl index determines the number of pregnancies in 1300 cycles. In theory, a Pearl index of 2 means that if 100 women use a particular form of contraception for 1 year, two will become pregnant.

WHO effectiveness rate 
The WHO effectiveness rate is based on the number of pregnancies that occur when a particular method is used consistently and correctly by 100 women for 1 year (‘perfect use’). The WHO reports that the effectiveness for combination oral contraceptives, assuming ‘perfect use’, is 0.3.6

‘Lifetime’ table
The disadvantage of both the WHO effectiveness rate and the Pearl index is that they do not take the variability of the reliability of a contraceptive into account. For instance, the Pearl index for the use of the combination  pill tends to decrease over time, because the risk of pregnancy is higher during the first months. This means that comparisons are suboptimal. This problem can be avoided by using the ‘lifetime’ table, which allows the number of pregnancies per month of contraceptive use to be calculated. Thus, the cumulative result over a particular period for one method can be more reliably compared with that of another method. 

European study

The first registration study, carried out in Europe and Russia, aimed to determine the efficacy of estetrol/drospirenone in preventing pregnancies among heterosexually active women aged 18 to 35 years.7 The primary outcome measure was the Pearl index for estetrol/drospirenone. The women in this study used the combination pill for 1 year, corresponding to 13 28-day cycles. 

Of the 1353 women aged between 18 and 35 years who entered the study, 1052 (77.8%) completed the study. Seven women became pregnant; the estimated date of conception of two women was, however, established to lie before the start of the study. The ‘lifetime’ calculation is the generally accepted method to assess the risk of pregnancy during contraception.8 For this study, this was 0.45% (95% confidence interval [CI] 0.19–1.09). The Pearl index  for the five pregnancies in this group was 0.47 (0.15–1.11).7 The NHG contraception guideline uses the WHO effectiveness rate, that is, the number of pregnancies per 100 women per year during consistent and correct use of a combination pill, which is 0.3 for combination oral contraceptives.5,6

The dropout rate in this study was 301 of the 1353 women aged 18 to 35 years, with 97 participants dropping out due to adverse effects not related to bleeding problems and 47 due to bleeding problems. The dropout rates due to withdrawal of consent and loss to follow-up were 72 and 38, respectively.7

US study

The second registration study was carried out in the USA and Canada; its design was largely identical to that of the first registration study.9 One difference was that this study included women aged 16 to 35 years. The primary outcome measure was the Pearl index of estetrol/drospirenone.

Of the 1674 women aged between 16 and 35 years who were enrolled in the study, 899 (53.7%) completed it. Twenty-six pregnancies were reported in this study. The ‘lifetime’ calculation in this study was 2.06% (95% CI 1.40 to 3.04). The Pearl index for the 26 pregnancies in this group was 2.65 (1.73 to 3.88).

The dropout rate in this study was 848 of the 1674 women aged 16 to 35 years, with 118 dropping out due to adverse effects not related to bleeding problems and 46 due to bleeding problems. The dropout rates  due to withdrawal of consent and loss to follow-up were 166 and 268, respectively.9

Discussion

Since neither of the Phase 3 studies used a controlled design, it is impossible to compare the reliability of this new pill with that of other oral contraceptives. The large dropout rates in both studies make the results less robust. Based on the registration studies, there is as yet no place in the guidelines for the estetrol combination pill, nor can it be regarded as an alternative for the combination oral contraceptives with which many years of experience have been gained.

Difference in Pearl index

There is a remarkable difference between the European and American studies in terms of the Pearl index they found. The authors of  the US study state that the Pearl index they found is in line with those of other contraceptives, but they then compare this only indirectly with a very low dose pill (10 µg ethinylestradiol) and a vaginal ring, and not with a second-generation contraceptive pill with a usual dose, for instance one with 30 µg ethinylestradiol and 150 µg levonorgestrel.9 An American cohort study from 2011, using a pill with 20 µg ethinylestradiol and 3 mg drospirenone (24-day regimen) had a ‘lifetime’ calculation of 2.1% (1.7 to 2.4) and a Pearl index of 1.6 (1.4 to 1.9).10

Other studies have indeed reported that the Pearl index in the United States has risen over the years, to a level higher than that preferred by the WHO for a combination oral contraceptive.6 The higher pregnancy rates in the US may be caused by differences in the healthcare system and the associated less ‘perfect’ use of oral contraceptives in that country.11


After reliability, cycle control (breakthrough bleeding, spotting, amenorrhoea) is the most important factor determining the acceptability of an oral contraceptive. Only one study has used cycle control and bleeding pattern as outcome measures.12 This concerned a Phase 2 study examining the optimum dosage of combination oral contraceptives. This study compared estetrol in different dosages (15 or 20 mg) using two different progestins (3 mg drospirenone and 150 µg levonorgestrel), with a multi-phase pill with (1 to 3 mg) estradiol valerate and (2 or 3 mg) dienogest (Qlaira®).12 Estetrol/drospirenone in the eventually authorised dosage (15/3 mg) has not been compared in randomised studies with a pill containing ethinylestradiol and levonorgestrel. Qlaira® is rarely used in the Netherlands (487 users in 2020) and is not an oral contraceptive of first choice.5,13 Comparison with the pill of first choice (30 µg ethinylestradiol and 150 µg levonorgestrel) would be warranted. At this stage, no definitive conclusion can be drawn from the bleeding pattern regarding the ease of use of estetrol/drospirenone.


The use of hormonal contraceptives is associated with an elevated risk of venous thrombosis. In addition to factors like age, smoking and obesity, the dosage of the oestrogen and the type of progestin in a combination oral contraceptive can influence the risk of thrombosis. Data from controlled studies are usually unavailable for newly developed combination pills, as the incidence of venous thrombosis among young women is low (approx. 1/10,000 women a year). Hence, large observational studies with a long follow-up period are required to obtain a precise estimate of the relative risk compared to existing oral contraceptives. This is also true for the combination pill containing 15 mg estetrol and 3 mg drospirenone. 

It is, however, possible to assess the effects of new oral contraceptives on the blood coagulation system at an earlier stage, in the period between the introduction of a new agent and the publication of study findings based on hard outcome measures. Existing combination pills exert a prothrombotic effect by activating various coagulation factors. It is difficult, however, to estimate the net effect on the risk of venous thrombosis. The APC (activated protein C) resistance test has been developed with the aim of offering an overall view of an individual’s coagulation tendency. As has been discussed in Ge-Bu before, ‘thrombin generation-based’ APC resistance tests can be used to estimate the relative risk of thrombosis compared to available preparations, long before the results of large-scale clinical studies using hard endpoints become available.14 This allows the adverse effects of various oral and non-oral hormonal contraceptives to be preliminarily evaluated.

Research into the risk of thrombosis caused by estetrol/drospirenone

Two studies have examined the possible effect of the combination oral contraceptive containing estetrol and drospirenone on the coagulation system. They assessed the effect on individual coagulaion factors, SHBG levels , D-dimer levels  and the APC resistance test  (see background Information below) among young, healthy female volunteers.15,16

Phase 2 study

The oldest of the two studies was a non-randomised open-label ‘dose-finding’ (Phase 2) study.15 The study compared combination oral contraceptives containing low doses (5 or 10 mg) of estetrol and drospirenone with a low-dose combination pill containing 20 µg ethinylestradiol and 3 mg drospirenone, in a total of 48 women. It found that after use of the pills during three cycles, the relative changes from baseline regarding individual coagulation factors, SHBG levels and APC resistance were more pronounced when using ethinylestradiol/drospirenone than when using estetrol/drospirenone. However, the estetrol dosages used in this study were lower than those used in the authorised pill, making it difficult to translate this into the risk of thrombosis with 15 mg estetrol/3 mg drospirenone in clinical practice.15

Randomised blinded study

In a randomised blinded study among 101 women, a pill containing 15 mg estetrol and 3 mg drospirenone was compared with two existing preparations, one containing 30 µg ethinylestradiol and 150 µg levonorgestrel (first choice in the Netherlands) and one containing 20 µg ethinylestradiol and 3 mg drospirenone.16 Comparing estetrol/drospirenone with ethinylestradiol/drospirenone is interesting to assess the effect of the oestrogen independent from that of the progestin. Both combinations affected coagulation. A comparison of the six individual coagulation factors, the SHBG levels and the APC resistance after six cycles with the baseline data showed that both preparations affected coagulation. After six cycles, there appeared to be  no clear differences between the two preparations as regards the individual coagulation factors, but the combination pill with ethinylestradiol appeared to have a greater effect on the laboratory parameters D-dimer and SHBG level, and on APC resistance, than the combination pill with estetrol. 

A comparison between the combination pill containing 30 µg ethinylestradiol and 150 µg levonorgestrel and the pill containing estetrol/drospirenone found minor differences; after six cycles there was only a mild prothrombotic effect of the combination of ethinylestradiol/levonorgestrel in terms of APC resistance. The results of this comparison suggest that estetrol has a smaller prothrombotic effect than ethinylestradiol, while the effect on the coagulation systems appears comparable. Further studies will be needed to establish how this translates into the risk of venous thrombosis.

Discussion

Research into the risk of thrombosis based on hard outcome measures has so far been lacking. Based on surrogate parameters (the laboratory parameters D-dimer and SHBG levels, and APC resistance), the combination of estetrol and drospirenone appears to offer some advantage compared to the combination of ethinylestradiol and levonorgestrel. The extent to which these differences also correspond to actual differences in the risk of thrombosis remains unclear. Hence there is as yet no reason to prefer the combination oral contraceptive with estetrol over those with which more experience has been gained.

Other adverse effects 

According to the registration file, the most common adverse effects are metrorrhagia (4.3%), headache (3.2%), acne (3.2%), vaginal bleeding (2.7%) and menstruation discomforts(2.4%). Other adverse effects, occurring in 1–10%, include mood changes, libido problems, abdominal pains, nausea, painful breasts and weight changes.2

Interactions/contraindications

The registration file shows the same contraindications and interactions as those concerning other combination oral contraceptives containing an oestrogen and a progestin.2 Well-known contraindications are sex-dependent tumours like breast cancer, endometrial hyperplasia, pre-existing risk of thrombosis and liver diseases.17 Well-known clinically relevant interactions include those with the CYP3A4 inductors, HIV medication, bile acid sequestrants and lamotrigine.17


Testing the risk of thrombosis

APC resistance test

The ‘thrombin generation-based APC resistance’ test provides an indication of reduced sensitivity to the anticoagulant effect of activated protein C (APC). The test measures the effect of APC on the total time required for the formation of thrombin in plasma. A reduced sensitivity, in other words a high APC resistance, is associated with an elevated risk of thrombosis.14,18

D-dimer test

The D-dimer test measures the concentration of this compound in the blood. D-dimer is a compound which is released when fibrin is decomposed. The presence of D-dimer in the blood indicates that clots are, or have been, present in the blood. Higher concentrations of D-dimer are associated with a higher risk of venous thrombosis.19

SHBG test

The concentration of ‘sex hormone binding globulin’ (SHBG) is a marker of the risk of thrombosis associated with the use of hormonal contraceptives. SHBG concentrations have been found to be positively associated with APC resistance.20 A higher APC resistance is associated with an elevated risk of thrombosis.14

Study details 

Gemzell-Danielson 20217
Study name: E4 Freedom (Europe/Russia)
Design: multi-centre, non-controlled, open-label Phase 3 registration study
Inclusion criteria: healthy women aged between 18 and 50 years, who were sexually active, had a regular menstrual cycle and a BMI ≤ 35
Major exclusion criteria: categories 3 and 4 of the ‘World Health Organization medical eligibility criteria’ for combination oral contraceptives, such as smoking ≥ 35 years, history of venous thrombosis and/or arterial disease, or hypertension
Intervention: 15 mg estetrol/3 mg drospirenone for 13 cycles
Primary endpoint(s) and duration: efficacy (Pearl index) for women aged between 18 and 35 years. Duration was 13 cycles of 28 days
Intended number of patients and power: 1350 women in the 18-35 year age category were needed to meet the criteria for the reliability of contraceptives, on the assumption that 90% van de cycles would be ‘at risk’ and that 30% of the participants would drop out
Number of patients included and patient characteristics: 1353 women aged 18 to 35 years were included; 1052 of these completed all 13 cycles. Their average BMI was 22.9, average age 25 years
Trial registration: clinicaltrials.gov: NCT02817828
Funding: Estetra SRL (company affiliated with Mithra Pharmaceuticals)
Conflicts of interest: 9 of the 10 authors
Creinin 20219
Study name: E4 Freedom (USA/Canada)
Design: multi-centre, non-controlled open-label Phase 3 registration study
Inclusion criteria: healthy women aged between 16 and 50 years, who were sexually active, had a regular menstrual cycle and a BMI ≤ 35
Major exclusion criteria: categories 3 and 4 of the ‘World Health Organization medical eligibility criteria’ for combination oral contraceptives, such as smoking ≥ 35 years, a history of venous thrombosis and/or arterial disease, or hypertension
Intervention: 15 mg estetrol/3 mg drospirenone for 13 cycles
Primary endpoint(s) and duration: efficacy (Pearl index) for women aged between 16 and 35 years. Duration was 13 cycles of 28 days
Intended number of patients and power: the required number of women aged between 16 and 35 years was estimated at 2000, based on the FDA criteria and the assumption that 80% of the cycles would be ‘at risk’ and assuming a 45% dropout and a Pearl index around 1
Number of patients included and patient characteristics: 1674 women aged 16–35 years, 899 of whom completed all 13 cycles. The average BMI was 25.8; the average age 25.8 years; 1531 of the total number of participants were from the United States 
Trial registration: not reported
Funding: Estetra SRL (company affiliated to Mithra Pharmaceuticals)
Conflicts of interest: 8 of the 9 authors

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Authors

  • Frans M. Helmerhorst, prof. dr
  • Astrid van Hylckama Vlieg, PhD, clinical epdemiologist
  • Marielle A.E. Nieuwhof, pharmacist