A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls.

Is there any difference in the clinical performance of the 3-year one-rod etonogestrel (ENG)- and the 5-year two-rod levonorgestrel (LNG)-releasing contraceptive implants during 3 years of insertion, and between implant and intrauterine device (IUD) contraception, in particular complaints possibly related to hormonal contraceptives? The cumulative contraceptive effectiveness after 3 years and method continuation through 2.5 years were not significantly different between ENG and LNG implants, but both outcomes were significantly worse in the non-randomized age-matched group of IUD users than in the combined implant group. ENG- and LNG-releasing implants are safe and highly efficacious contraceptives with pregnancy rates reported to be 0.0-0.5 per 100 women-years (W-Y). No head-to-head comparative study of the two implants has been undertaken, and little information is available on comparisons of complaints of side effects of implant and copper IUD users. This was an open parallel group RCT with 1:1 allocation ratio of the ENG and the LNG implants with non-randomized control group of women choosing TCu380A IUD to address lack of reliable data on common side effects typically attributed to the use of progestogen-only contraceptives. After device(s) placement, follow-ups were at 2 weeks, 3 and 6 months, and semi-annually thereafter for 3 years or until pregnancy, removal or expulsion of the implant/IUD occurred. The study took place in family planning clinics in Brazil, Chile, Dominican Republic, Hungary, Thailand, Turkey and Zimbabwe. Women seeking long-term contraception were enlisted after an eligibility check and informed consent, and 2982 women were enrolled: 1003, 1005 and 974 in the ENG-implant, LNG-implant and IUD groups, respectively; 995, 997 and 971, respectively, were included in the per protocol analysis reported here. ENG and LNG implants each had the same 3-year cumulative pregnancy rate of 0.4 per 100 W-Y [95% confidence interval (CI) 0.1-1.4]. A weight of ≥70 kg at admission was unrelated to pregnancy. Method continuation rates for ENG and LNG implants at 2.5 years were 69.8 (95% CI 66.8-72.6) and 71.8 per 100 W-Y (68.8-74.5), and at 3 years 12.1 (95% CI 5.2-22.0) and 52.0 per 100 W-Y (95% CI 41.8-61.2), respectively. Bleeding disturbances, the most frequent reason for method discontinuation, were significantly more common in the ENG group [16.7 (95% CI 14.4-19.3)] than in the LNG group [12.5 (95% CI 10.5-14.9)] (P 0.019). The 3-year cumulative loss to follow-up was lower in the ENG- than in the LNG-implant group, 8.1 (95% CI 6.4-10.2) and 14.4 per 100 W-Y (95% CI 12.1-17.1), respectively. The median duration of implant removal was 50 s shorter among women with ENG than among women with LNG implant (P < 0.0001). In the observational comparison between IUD and implant users, the 3-year relative risk for pregnancy in IUD group compared with the combined implant group was 5.7 per 100 W-Y (95% CI 4.4-7.3) (P = 0.0003). The 3-year expulsion rate of the IUD was 17.8 per 100 W-Y (95% CI 14.5-21.9), while the discontinuation rate for bleeding disturbances was 8.5 (95% CI 6.7-10.9). Frequency of complaints of headache and dizziness was not significantly different between implant and IUD users (P = 0.16 and 0.77, respectively), acne and bleeding irregularities were more frequent among implant users (P < 0.0001), while heavy bleeding and lower abdominal pain occurred more often among IUD than implant users (P < 0.0001). Few women were ≤19 years old or nulligravida, the proportion of implant users ≥70 kg was <20% and <8% were obese. Findings of the study can inform policy makers and clinicians about choice of implant, but also about TCu380A IUD in relation to implants. UNDP/UNFPA/WHO/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization (WHO). This report contains the views of an international expert group and does not necessarily represent the decisions or the stated policy of the WHO. ISRCTN33378571 registered on 22 March 2004. The first participant was enrolled on 12 May 2003.

Bahamondes L ，Brache V ，Meirik O ，Ali M ，Habib N ，Landoulsi S ，WHO Study Group on Contraceptive Implants for Women ... -  《-》

Extended use up to 5 years of the etonogestrel-releasing subdermal contraceptive implant: comparison to levonorgestrel-releasing subdermal implant.

Is it possible to extend the use of the 3-year one-rod etonogestrel (ENG)-releasing subdermal contraceptive implant to 5 years? The extended use of the one-rod ENG-releasing subdermal contraceptive implant showed 100% efficacy in years 4 and 5. The initial regulated trials on the ENG-releasing subdermal contraceptive implant conducted in the 1990 s were designed to measure cumulative 3-year efficacy. The ENG-implant has both well established safety and efficacy for up to 3 years. Pharmacokinetic data on ENG show high levels at 3 years and some previous clinical research confirms efficacy beyond the current approved duration of 3 years. Today, many women, because the labeled duration has been reached, have the ENG implant removed at 3 years, increasing costs, inconvenience and risks. For the first 3 years, this study was an open-label, multi-centre randomized trial comparing the 3-year ENG implant to the 5-year levonorgestrel (LNG)-releasing implant. After 3 years, a subset of 390 ENG participants, consented to extended use. We compared efficacy, side effects and removal procedures of both implants. We used Kaplan-Meier (K-M) analysis. We included an observational cohort of copper intrauterine device (IUD) users as non-users of hormonal contraceptive method for comparative purposes. The study took place in family planning clinics in seven countries worldwide. Women were enlisted after an eligibility check and informed consent, and 1328 women were enrolled: 390, 522 and 416 in the ENG-implant, LNG-implant and IUD groups, respectively. Over 200 women used the ENG implant for at least 5 years. No pregnancies occurred during the additional 2 years of follow up in the ENG or LNG implant group. The overall 5-year K-M cumulative pregnancy rates for ENG- and LNG- implants were 0.6 per 100 women-years (W-Y) [95% confidence interval (CI): 0.2-1.8] and 0.8 per 100 W-Y [95% CI: 0.2-2.3], respectively. Complaints of bleeding changes were similar; however, ENG-users were more likely than LNG-users to experience heavy bleeding (p < 0.05). The median duration of the implant removal procedure was 64 seconds shorter for the one-rod ENG-implant (inter-quartile range (IQR) = 30.5, 117.5) compared to the two-rod LNG product (IQR = 77.0, 180.0). The 2-year rate for pregnancy in the IUD group compared with the two implant groups combined was 4.1 per 100 W-Y [95% CI: 2.5-6.5]. Few women were ≤19 years old or nulligravida. Although there was no weight limit for enrolment in the study, the number of women ≥70 kg were few. The results from this study corroborate previous evidence showing high contraceptive efficacy through 4 years for the ENG-implant. Data through 5 years are a novel contribution and further proof of the product's capability to provide safe and effective contraception that rivals the current 5-year LNG-subdermal implant. The findings provide valuable information for policy makers, family planning programmers and clinicians that the ENG-releasing subdermal implant is still highly effective up to 5 years after insertion. Compared to previous efforts, our study population was geographically diverse and our study had the highest number of participants completing at least 5 years of use. The trial was registered as ISRCTN33378571. The contraceptive devices and funds for conduct of the study were provided by the United Nations Development Programme/United Nations Population Fund/World Health Organization (WHO)/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), WHO. This report contains the collective views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the WHO. All stated authors have no conflict of interest, except Dr Hubacher who reported grants from United States Agency for International Development, during the conduct of the study; other from Advisory Boards (Teva, Bayer, OCON), outside the submitted work.

Ali M ，Akin A ，Bahamondes L ，Brache V ，Habib N ，Landoulsi S ，Hubacher D ，WHO study group on subdermal contraceptive implants for women ... -  《-》

A multicenter randomized clinical trial of etonogestrel and levonorgestrel contraceptive implants with nonrandomized copper intrauterine device controls: effect on weight variations up to 3 years after placement.

To evaluate weight changes in women randomized to either the etonogestrel (ENG)- or the levonorgestrel (LNG)-releasing contraceptive implants and to compare with users of the TCu380A intrauterine device (IUD). A multicenter randomized trial with 1:1 allocation ratio of the ENG and the LNG implants with nonrandomized, age-matched control group of women choosing TCu380A IUD. The primary objective was to assess contraceptive efficacy and method continuation rates and, secondarily, the incidence of common complaints and side effects (including weight changes) associated with use of the three contraceptives. All women were enrolled in nine centers at seven countries. Weight change was evaluated from time at device(s) placement. Confounders were sociodemographic, baseline weight and body mass index, center and time from insertion. We used a linear mixed-effects regression modeling with random intercept and slope. Weight was compared between the two implants groups and between the implants and the IUD groups through linear mixed multivariable regression model. A total of 995, 997 and 971 users in the ENG implant, LNG implant and IUD groups, respectively, were included. At 36 months of use, ENG and LNG implant users had similar significant mean weight increase of 3.0 kg [95% confidence interval (CI) 2.5-3.5] and 2.9 kg (95% CI 2.4-3.4), respectively (p<.0001), while IUD users had an increase of 1.1 kg (95% CI 0.5-1.7) (p=.0003). On adding the group-time interaction term to the stratified baseline weight models, implant users gained 0.759 kg (standard error [SE] .11) and 0.787 kg (SE .22) more weight than their IUD-user counterparts per year since placement if their baseline weight was in the category 51-69 kg (p<.0001) or ≥70 kg (p=.0005), respectively. ENG and LNG implant as well as IUD users had a small but significant weight increase with little clinical significance during the 3 years of follow-up, and it was slightly higher among implant than IUD users weighing >50 kg. These findings must be useful for clinicians to counsel implant users which could improve method continuation.

Bahamondes L ，Brache V ，Ali M ，Habib N ，WHO study group on contraceptive implants for women ... -  《-》

A randomized clinical trial of the effect of intensive versus non-intensive counselling on discontinuation rates due to bleeding disturbances of three long-acting reversible contraceptives.

Modesto W ，Bahamondes MV ，Bahamondes L 《-》

Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A.

To compare rates of unintended pregnancy, method continuation and reasons for removal among women using the 52-mg levonorgestrel (daily release 20 microg) intrauterine device (LNG-IUD) or the copper T 380 A IUD (TCu380A). This was an open-label 7-year randomized controlled trial in 20 centres, 11 of which in China. Data on 1884 women with interval insertion of the LNG-IUD and 1871 of the TCu380A were analysed using life tables with 30-day intervals and Cox proportional hazards models. The cumulative 7-year pregnancy rate of the LNG-IUD was 0.5 (standard error 0.2) per 100, significantly lower than 2.5 (0.4) per 100 of the TCu380A, cumulative method discontinuation rates at 7 years were 70.6 (1.2) and 40.8 (1.3) per 100, respectively. Dominant reasons for discontinuing the LNG-IUD were amenorrhea (26.1 [1.3] per 100) and reduced bleeding (12.5 [1.1] per 100), particularly in Chinese women and, for the TCu380A, increased bleeding (9.9 [0.9] per 100), especially among non-Chinese women. Removal rates for pain were similar for the two intrauterine devices (IUDs). Cumulative rates of removal for symptoms compatible with hormonal side effects were 5.7 (0.7) and 0.4 (0.2) per 100 for the LNG-IUD and TCu380A, respectively, and cumulative losses to follow-up at 7 years were 26.0 (1.4) and 36.9 (1.3) per 100, respectively. The LNG-IUD and the TCu380A have very high contraceptive efficacy, with the LNG-IUD significantly higher than the TCu380A. Overall rates of IUD removals were higher among LNG-IUD users than TCu380A users. Removals for amenorrhea appeared culturally associated. The 52-mg LNG-IUD and the TCu380A have very high contraceptive efficacy through 7 years. As an IUD, the unique side effects of the LNG-IUD are reduced bleeding, amenorrhea and symptoms compatible with hormonal contraceptives.

Rowe P ，Farley T ，Peregoudov A ，Piaggio G ，Boccard S ，Landoulsi S ，Meirik O ，IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction ... -  《-》