Hum. Reprod. Advance Access originally published online on November 10, 2005
Human Reproduction 2006 21(1):295-302; doi:10.1093/humrep/dei273
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A pilot study to assess the effect of three short-term treatments on frequent and/or prolonged bleeding compared to placebo in women using Implanon
1 Sydney Centre for Reproductive Health Research, Research Division of FPA Health, Sydney, 2 Department of Obstetrics and Gynaecology, University of Sydney, 3 School of Women’s and Infants’ Health, University of Western Australia and King Edward Memorial Hospital, Perth, 4 Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women’s Hospital, Melbourne, 5 Department of Obstetrics and Gynaecology, The University of Queensland and 6 Prince Henry’s Institute for Medical Research, Melbourne, Australia
7To whom correspondence should be addressed at: Sydney Centre for Reproductive Health Research, Research Division of FPA Health, 328–336 Liverpool Rd, Ashfield NSW 2131, Australia. E-mail: edithw{at}fpahealth.org.au
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Abstract |
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BACKGROUND: The major side-effect of progestogen-only contraception is disruption of menstrual bleeding patterns, which can lead to a high incidence of early discontinuation. The aim of this study was to compare three treatments with placebo on the duration and recurrence of frequent and/or prolonged bleeding in Implanon users. METHOD: Women between the ages of 18 and 45 years, who had used Implanon for
3 months and were experiencing prolonged or frequent bleeding patterns, were recruited at four Australian sites. Subjects were randomized to treatment using computer-generated random number table if they met the World Health Organization criteria for prolonged and/or frequent bleeding in the previous 90 days [Belsey, E.M., Pinol, A.P.Y. and Taskforce on Long-Acting Systemic Agents for Fertility Regulation, World Health Organization (1997) Contraception 55,57–65]. Treatments were: (1) mifepristone 25 mg given twice on day 1 followed by 4 days of twice daily placebo; (2) mifepristone 25 mg given twice on day 1 followed by 4 days of ethinyl estradiol (EE) 20 µg in the morning and placebo at night; (3) doxycycline 100 mg twice daily for 5 days; and (4) placebo twice daily for 5 days. Analysis was by intention to treat. The primary endpoint was the number of days of bleeding and spotting immediately following initiation of the 5 day course of each active therapy compared with placebo. RESULTS: A total of 179 women was assigned to treatment. Both mifepristone in combination with EE and doxycycline alone were significantly more effective in stopping an episode of bleeding {mean 4. 3 days [confidence interval (CI) 3.5–5.2], and 4.8 days (CI 3.9–5.8) respectively} than mifepristone alone or placebo [5.9 days (CI 4.8–7.2) and 7.5 days (CI 6.1–9.1) respectively]. No effect on subsequent bleeding patterns was observed in any treatment group. CONCLUSION: Both mifepristone plus EE and doxycycline alone were significantly more effective than placebo in terminating an episode of bleeding in women with prolonged and/or frequent bleeding using Implanon. We believe that the observed reduction in the number of bleeding days by almost 50% compared to placebo in both the mifepristone combination group and the doxycycline group demonstrates a clinically significant improvement in bleeding patterns and that further trials are needed to compare different combinations of therapy as well as multiple dosing regimens in order to establish which is the most effective treatment option. The effect of repeat administration or combinations of these preparations on long-term bleeding patterns requires further investigation.
Key words: bleeding/contraception/doxycycline/implants/mifepristone
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Introduction |
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The World Health Organization calculates that, worldwide, >20 x 106 women now use progestogen-only contraceptive methods, mainly in the form of injections, implants or an intrauterine system. Implanon (Organon, Oss, The Netherlands) is a highly effective, simply inserted, single rod system, which releases a relatively constant dose of the progestogen, etonogestrel, over a period of 3 years. Worldwide, 2.54 x 106 Implanon implants have been inserted since its introduction in 1997 (Organon, Oss, The Netherlands). The contraceptive action of Implanon is primarily via suppression of ovulation, but it also has profound effects on cervical mucus and, at least in some women, induces a suppression of endometrial proliferation although data on endometrial effects are limited (Varma and Mascarenhas, 2001
). It is a highly effective contraceptive with method failures estimated to be one per 1000 users (Harrison-Woolrych and Hill, 2005).
Most Implanon users will experience a reduction in the frequency and volume of menstrual bleeding but a substantial minority will experience unpredictable and distressing episodes of prolonged or frequent light bleeding (d’Arcangues et al., 1992). Zheng et al. (1998) reported a reduction in the mean overall incidence of prolonged bleeding in 100 Implanon users from 66% in the first 3 months of use to 27.3% at the end of 4 years. A review of all published Implanon studies by Edwards and Moore (1999) found that the incidence of prolonged bleeding was 10–20%. However, the data in this review included data from the Phase III clinical trials in Indonesia which have since been retracted by Organon (Rekers and Affandi, 2004).
The major side-effect of all progestogen-only contraceptives is disruption of menstrual bleeding patterns (d’Arcangues et al., 1992), which can lead to a high incidence of early discontinuation (Belsey, 1988). Many treatments have been tested in an effort to improve bleeding patterns for women using progestogen-only methods including oral or transdermal estradiol (Alvarez-Sanchez et al., 1996; Boonkasemsanti et al., 1996), oral levonorgestrel (Diaz et al., 1990), a combined oral contraceptive pill containing 50 µg EE (Alvarez-Sanchez et al., 1996), non-steroidal anti-inflammatory drugs (Diaz et al., 1990; Kaewrudee et al., 1999), the anti-progesterone receptor modulator, mifepristone (Cheng et al., 2000), and vitamin E alone or in combination with aspirin (d’Arcangues et al., 2004). Most treatments proved ineffective, and whilst some of these treatments were able to reduce the duration of a bleeding episode, none resulted in long-term improvement in bleeding patterns once treatment was discontinued.
For an individual user, it is not possible to predict how long-acting progestogen-only contraceptives will change bleeding patterns. At present, effective pre-treatment counselling of women about likely changes in bleeding patterns appears to be the major factor in improving continuation rates (Belsey, 1988). The development of an effective short-term treatment regimen which would improve both short and long-term bleeding patterns would be of enormous clinical benefit and may improve both acceptability and continuation rates for these otherwise highly popular contraceptive methods. The ideal therapy would improve long-term bleeding patterns after a single oral treatment, which could be easily repeated if required without compromising contraceptive efficacy or producing side-effects.
The choice of treatments for this study was based on a number of factors. Mifepristone has previously been shown to be effective in reducing the duration of a bleeding episode in Norplant users (Cheng et al., 2000). We combined mifepristone with 4 days of ethinyl estradiol (EE) in order to stimulate endometrial estrogen receptors to a greater extent than would be achieved by mifepristone alone (Glasier et al., 2002). This would provide optimal conditions for the beneficial impact of added estrogen on restoration of stability in both endometrial vasculature and overlying epithelium and thus would produce a more rapid, and hopefully more prolonged, improvement in menstrual bleeding pattern than would mifepristone alone.
Matrix metalloproteinases (MMP) are expressed in the endometrium throughout the menstrual cycle and appear to have a major role in endometrial tissue remodelling (Chegini et al., 2003). Altered MMP activity appears to predispose to endometrial fragility, irregular vessel breakdown and bleeding in progestogen users (Vincent and Salamonsen, 2000). Non-vascular elements of the endometrium regress with continuous progestogen exposure. Hence, continuous low-dose progestogens create an endometrium with increased and disordered micro-vessels, decreased stromal and glandular support and reduced epithelial integrity (Vincent and Salamonsen, 2000). The structural compromise of these micro-vessels and an influx of leukocytes (which contribute MMP and also activators of enzyme action) results in vascular fragility, tissue breakdown and breakthrough bleeding (Fraser et al., 1996). Tetracyclines are widely used antibiotics which also inhibit MMP-mediated matrix degradation in a dose-dependent manner by mechanisms independent of their anti-microbial activity (Smith et al., 1999).
Doxycycline, the most potent MMP inhibitor of the approved tetracyclines, is a widely used drug with minimal side-effects, can be taken orally and is inexpensive (Burns et al., 1989; Vernillo et al., 1994).
Our aim was to conduct a randomized double-blind placebo-controlled trial to examine the effect of three treatments (mifepristone alone, mifepristone plus EE, or doxycycline alone) compared with placebo on the duration and recurrence of frequent and/or prolonged bleeding in Implanon users.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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Women between the ages of 18–45 years, who had used Implanon for contraception for
3 months and were experiencing prolonged or frequent bleeding patterns were recruited at four Australian sites either through clinics or by advertisement.
The women maintained a daily menstrual diary chart for 90 days and were enrolled into the treatment phase provided they had met one of the World Health Organization criteria for prolonged or frequent bleeding (in the 90 day reference period one episode of bleeding and/or spotting lasting >10 days or more than four bleeding/spotting episodes) (Belsey et al., 1997). An independent statistician provided the randomization scheme through computer generation of a random number table for each centre in blocks of 20 with equal numbers in each of the four groups. The design of this double-blind, randomized, placebo-controlled trial met the criteria proposed by the CONSORT statement (www.consortstatement.org).
Subjects were randomized to one of the following treatments: mifepristone 25 mg (Hualin Company, Shanghai, China), doxycycline 100 mg (Douglas Pharmaceuticals, Sydney, Australia), mifepristone 25 mg plus EE 20 µg (10 µg twice daily) (Progynon C; Schering AG, Berlin, Germany), or placebo, according to the regimens shown in Table I, with treatment to be started on the second day of the next bleed.
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The three active treatment regimens in tablet form were incorporated into identical opaque gelatine capsules with starch filling. The placebo capsules containing only starch were identically packed. The blister pack manufacturer assigned the treatments and placebo as 1, 2, 3 or 4 without reference to the investigators and presented the treatments and placebo in identical foil blister packs containing 10 capsules. The day and time of administration were marked on the back of the pack. Both subject and prescriber were blinded to the treatment allocation. The treatment packs were placed in sequentially numbered and sealed opaque envelopes which also contained detailed instructions for taking the drugs. In the event of the randomization code needing to be broken, two sealed ‘master’ envelopes were lodged with the chair of the Data and Safety Monitoring Board and the Chief Executive Officer of FPA Health. Women were advised to take the medication with a glass of water following food and not to lie down for 30 min after ingestion of the capsules as recommended for doxycycline.
Exclusions from the study included all contraindications to the active treatments used. These included a history of heart attack or stroke, thromboembolism, severe liver or kidney disease, blood pressure >160 mm systolic or >95 mm diastolic, focal migraine, breast cancer or any genital cancer, or any possible sensitivity to EE, tetracyclines or lactose. Women taking phenytoin, carbamazepine, phenobarbital, retinoids or vitamin A or unwilling to keep a daily menstrual diary or otherwise unwilling to follow the study criteria were also excluded.
The primary endpoint was the number of days of bleeding and spotting immediately following initiation of the 5 day course of each active therapy, compared with placebo to demonstrate the speed at which an episode of bleeding could be stopped by the study medication.
Secondary endpoints were: the number of days of bleeding and spotting immediately following initiation of the 5 day course of therapy compared with the other two therapies; the duration of the first bleeding and spotting-free interval after the initiation of treatment (compared with placebo, and with the other two treatments); the mean number of episodes of bleeding and spotting during the 90 day ‘treatment’ reference period compared with the pre-treatment reference period (calculated as percentage reduction) and with placebo and the other two treatments; the mean duration of individual bleeding and spotting episodes in the 90 day ‘treatment’ reference period, compared with pre-treatment reference period (calculated as percentage reduction), and with placebo and the other two treatments; the total number of days of bleeding and spotting during the pre- and post-treatment reference periods, and compared with placebo and with the other two treatments; any adverse events.
Statistics
This was a pilot study to determine whether any of the treatments were better than placebo. A sample size of 44 subjects in each group gave a power of 96% to detect an effect size of 0.33 and a type 1 error of 0.05.
The primary endpoint, the number of days to stop bleeding, included the first day of treatment. Analysis of the pre-treatment bleeding pattern included the 90 days immediately preceding the bleeding episode in which treatment started. The 90 days post-treatment phase was calculated from the first day of treatment. Statistical analysis of this parallel group randomized trial was carried out with SPSS base 13.0. Because the data had significant positive skew, geometric means obtained by logarithmic transformation were used for analysis. The univariate general linear model was used to compare geometric means with planned contrasts with the primary outcome measure. Analysis of the primary endpoint was carried out on an intention-to-treat basis for all enrolled subjects prior to breaking the randomization code.
The trial was approved by the Ethics Committees of each clinical site and by the Therapeutic Goods Administration (TGA) of Australia. Permission to import mifepristone into Australia for the purposes of this study was obtained from the Therapeutic Goods Administration, Canberra. All women gave informed consent.
Subjects
A total of 244 women who had been using Implanon for 3 months were enrolled in the study. Of these, 65 were withdrawn prior to randomization: 24 were ineligible, 26 had the Implanon removed early, four for protocol violations, four no longer wished to participate, four were lost to follow-up and three for a variety of other reasons (Table I). In all, 179 women were randomized, 45 women allocated to placebo, 45 to mifepristone plus EE, 45 to doxycycline and 44 to mifepristone alone (Table II). There was no statistically significant difference in demographic factors between the women who withdrew and those who were randomized or between the women allocated to different treatment groups (Table III).
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Results |
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There was no statistical difference between the four treatment groups in the mean number of bleeding/spotting days or in the mean number of bleeding/spotting episodes in the 90 day pre-treatment phase (Tables IV and V). Six women who were randomized did not take the medication: three who wished to have the Implanon removed, one who was lost to follow-up, one who was ineligible and one for other reasons. Compliance with the treatment regimen was good. Only 25 women (10%) missed any tablets and, of these, only three missed more than one. There were no pregnancies.
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Two active treatment regimens were significantly more effective than placebo in terminating a bleeding episode. Both mifepristone in combination with EE and doxycycline alone were significantly more effective than mifepristone alone or placebo in stopping an episode of bleeding. Mifepristone with EE and doxycycline were equally effective in stopping bleeding (Figure 1). Mifepristone with EE terminated a bleeding episode after a mean duration of 4.2 days (CI 3.5–5.2), compared to 4.8 days (CI 3.9–5.8) for doxycycline, 5.9 days (CI 4.8–7.2) for mifepristone alone and 7.5 days (CI 6.1–9.1) for placebo (Tables VI and VII). Six women withdrew following the treatment bleed, so data on the duration of the bleed-free interval after treatment were available for 168 (96.5%) treated women. A total of 162 (93%) of the treated women completed the full 90 day post-treatment diary.
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There were no significant differences between treatment groups and placebo nor between different treatment groups in the number of bleed-free days after the treatment bleed, in the duration of the first post-treatment bleed or in the number of bleeding/spotting days or episodes in the 90 day post-treatment phase (Tables IV, V, VII, VIII and IX). The percentage reductions in the mean number of bleeding and spotting days in the 90 days following treatment were 1.5% for placebo, 14.5% for mifepristone plus EE, 8% for doxycycline and 6.1% for mifepristone. None was statistically significant.
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Women in the mifepristone plus EE, doxycycline and placebo groups experienced a non-significant reduction in the number of bleeding/spotting episodes post-treatment compared to pre-treatment, but the only significant difference (P = 0.04) was between mifepristone plus EE and mifepristone alone in the post-treatment phase (4.0 and 4.7 episodes respectively, Table V).
More than half the women changed their perception of their bleeding patterns following treatment and this did not differ between the groups (51% for placebo, 57% for mifepristone plus EE, 57% for doxycycline and 63% for mifepristone). Before treatment, 88% of Implanon users studied felt that the duration of their bleeding was ‘too long’. Following treatment 69% still felt that the duration of their bleeding was ‘too long’. Before treatment, 76% of Implanon users felt that the duration of the interval between bleeding episodes was ‘too short’. Following treatment, 58% still felt that the interval between bleeding episodes was ‘too short’.
Women in each treatment group reported a wide range of side-effects and this did not differ according to the treatment used or between those taking active treatment and those taking placebo. Side-effects occurred in 23 women on placebo, 28 women using mifepristone plus EE, 19 women using doxycycline and 21 women using mifepristone alone. These side-effects were usually minor and did not result in women stopping treatment (Table IX; and data not shown). The most common side-effect was nausea, occasionally accompanied by vomiting which occurred in eight women on placebo, four using mifepristone plus EE, two using doxycycline and five using mifepristone. There were no serious adverse events during the study.
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Discussion |
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This is the first report of effective treatments (mifepristone plus EE and doxycycline) to reduce the duration of prolonged bleeding and/or the frequency of bleeding in Implanon users.
The primary aim of the study was to determine the most effective agent to stop an episode of bleeding within a clinically significant time. Many other studies have addressed the problem of troublesome bleeding with other long-acting progestogen-only contraceptives. Although studies differ in the contraceptive studied, inclusion criteria, drug dosages, timing for initiation of treatment, numbers of treatments and measurement of endpoints, certain conclusions can be drawn from the literature. Mifepristone has previously demonstrated efficacy in stopping a bleeding episode. Massai et al. (2004) reported that Norplant users treated with 100 mg mifepristone or placebo for 2 consecutive days at 30, 60 and 90 days (unrelated to bleeding episodes) significantly shortened the total duration of bleeding compared to placebo. They did not find any continued improvement in bleeding after treatment was stopped. Mifepristone 50 mg reduced the duration of bleeding episodes in Norplant users given on a 4 weekly basis with no impairment of contraceptive efficacy (Cheng et al., 2000). In contrast there is some evidence from Massie et al. (2004) and Glasier et al. (2002) using 2 successive days of 100 mg and 200 mg dose respectively that higher doses of mifepristone in Norplant users might impair efficacy of the contraceptive, which influenced our choice of dose.
We considered including an EE-only arm in the study but an extra arm would have increased the number of volunteers required to give sufficient power to the study. We preferred to study novel short treatments which might prove effective and could be given repeatedly if necessary. Several studies using EE have already been published (Diaz et al., 1990; Alvarez-Sanchez et al., 1996).
Alvarez-Sanchez et al. (1996) found that giving 20 days of either a 50 µg EE–250 µg LNG combined pill (COC) or 50 µg EE alone resulted in a shortening of the bleeding episode to 2.6 days and 5.4 days respectively and prevented further bleeding during the duration of the treatment. However, estrogen at this dose resulted in a clinically significant incidence of nausea and gastrointestinal disturbance. This was not observed with the lower dose of EE used in our study. These results suggest that although the COC pill may terminate a current bleeding episode and control subsequent bleeding during the pill cycle, it is unlikely to improve subsequent bleeding episodes. No studies to date have demonstrated a subsequent improvement in bleeding patterns following cessation of therapy.
In our study both mifepristone plus EE and doxycycline alone effectively reduced the duration of a bleeding episode when compared with placebo. However, unlike other studies, mifepristone alone was not significantly better than placebo in stopping an episode. Our small study may have been skewed by the inclusion of one subject in the mifepristone-alone group, who bled for the 86 days immediately pre-treatment and then for a further 62 days after taking mifepristone. In each of the other treatment groups there was one woman who bled almost for the whole 90 days pre-treatment but in these two cases both the mifepristone combination and doxycycline were successful in stopping the bleeding episode. We believe that the observed reduction in the number of bleeding days by almost 50% compared to placebo in both the mifepristone combination group and the doxycycline group demonstrates a clinically significant improvement in bleeding patterns and that further trials are needed to compare different combinations of therapy as well as multiple dosing regimens in order to establish which is the most effective treatment option.
In our study as in previous studies, a single treatment did not seem to have a significant effect in delaying the onset or reducing the duration of the next bleed or reducing the number of bleeding/spotting days in the whole post-treatment phase. Although there was a small percentage reduction between the pre- and post-treatment phases in all groups including placebo, this did not translate into any significant clinical benefit.
The improvement in perception of bleeding by subjects was noted in all treatment groups, including placebo—a finding previously noted by d’Arcangues et al. (2004). This suggests that perception does not relate closely to the actual number of days of bleeding or spotting in Implanon users.
One concern about using multiple doses of mifepristone and EE is the possibility of loss of contraceptive efficacy by the combined action of a progesterone receptor modulator increasing the possibility of ovulation and the estrogen counteracting the cervical mucus protection in women using a progestogen for contraception. We are encouraged that no pregnancies have been reported in small studies using repeated higher doses of mifepristone (50 mg) and only one pregnancy in a woman using Norplant in a study using mifepristone 100 mg for 2 days at monthly intervals over a period of 6 months (Cheng et al., 2000; Massie et al., 2004). Adequately powered studies are needed to confirm that mifepristone 50 µg alone and in combination with EE 20 µg does not interfere with contraceptive function.
In conclusion, both mifepristone plus EE and doxycycline alone were significantly more effective than placebo in terminating an episode of bleeding in women with prolonged and/or frequent bleeding using Implanon. Mifepristone alone appears to be less effective. The availability of a simple, safe and effective treatment for problematic bleeding with long-acting progestogen-only methods would be a major clinical breakthrough and is likely to improve both the acceptability and continuation rates of these methods. The effect of repeat administration or combinations of these preparations on long-term bleeding patterns requires further investigation.
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Acknowledgements |
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We acknowledge with gratitude the donation of mifepristone 25 mg tablets from the Hualin Company, Shanghai, China. We are indebted to Georgina Luscombe for statistical advice and research assistants Erica Ferguson, Lee Anne Mahoney, Corrine Garamszegi, Miranda Wheeler, Lorraine Edney and research coordinator Sue Stuart for their participation in the study. Without their efforts the study would not have been possible. This study was funded by grant number 5R01 HD 43192-03 from the National Institutes of Child Health and Human Development, National Institutes of Health, Washington DC USA. Lois A.Salmonsen and John K.Findlay are supported by the NHMRC of Australia (Fellowships #143798, #198705).
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Submitted on June 22, 2005; resubmitted on July 25, 2005; accepted on July 27, 2005.
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