1 Chilean Institute of Reproductive Medicine, Santiago, Chile and the 2 Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary and 3 Scientific Development Group, NV Organon, Oss, The Netherlands
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Abstract |
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Key words: contraceptive implant/efficacy/Implanon®?/safety/vaginal bleeding
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Introduction |
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The study was designed to determine contraceptive reliability by means of a pregnancy rate, safety by means of regular medical examinations and assessment of adverse experiences, and acceptability by means of vaginal bleeding patterns. Data were collected in 21 centres situated in nine different countries. The number of women required to provide at least 10 000 cycles of 28 days was calculated to be ~600.
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Materials and methods |
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The implant was inserted in the inner aspect of the non-dominant upper arm. The woman had to be on or between days 15 of a spontaneous menses. The protocol for the study was submitted to National Health Authorities and to Ethics Committees of the respective sites. The study started in November 1991 and was completed in December 1996. Originally the study was designed to last for 2 years, which was later extended to 3 years in two centres. The decision was based upon data obtained in-vitro, ex-vivo and non-human data. Human data, obtained in sterilized women exposed to an extracted implant, revealed that ovulation inhibition was sustained for longer than 2 years (Davies et al., 1993).
The assessment schedule was as follows: at baseline medical history and gynaecological history were taken and a physical and pelvic examination including a cervical smear according to Papanicolaou (Pap) were done. The Pap smear at baseline was omitted if results Pap I or II were obtained <1 year previously. The medical examinations were repeated once every year or at the time of implant removal. Body height was recorded at baseline and so were weight and blood pressure (BP). The latter two variables were also recorded at months 3, 6, 12, 18, 24, 27, 30, 33 and 36. Status at implant site was checked once every 3 months and so was the bleeding card to see whether a pregnancy test was indicated in case of amenorrhoea. Women were asked to communicate unwanted effects at each visit and were instructed in further proceedings of the study.
Statistical methods
In the calculation of the percentages of discontinuation, the denominator excluded women who were lost to follow-up. The analysis of the bleeding pattern was done using 90-day reference periods (Rodriguez et al., 1976; Belsey et al., 1986; Belsey and Farley, 1988
). The first reference period of 90 days started on the day of implant placement. For the analysis of the bleeding pattern, the following definitions were used: amenorrhoea was defined as no bleeding or spotting throughout the reference period. Infrequent bleeding was defined as fewer than three bleeding-spotting episodes (B-S) starting within a reference period, excluding amenorrhoea. Frequent bleeding was defined as more than five B-S episodes starting within a reference period and prolonged bleeding was defined by at least one B-S episode starting within a reference period and lasting >14 days. A B-S episode was defined as any set of
1 consecutive bleeding or spotting days bounded at each end by at least 1 bleeding-free day. Coding of adverse experiences was done using the WHO adverse reactions terminology (WHO Adverse Reaction Dictionary, 1994).
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Results |
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Centres varied in size between six and 114 volunteers. The centres in Budapest (n = 114) and Santiago (n = 107) contributed substantially more volunteers than the other centres. A total of 147 volunteers from these two centres entered the third year of study. Safety and bleeding data from Chile (n = 107), Hungary with three centres (n = 195) and the remaining centres (n = 333) were compared to detect possible centre effects. Regarding bleeding data, no major differences were observed. Safety reporting, however, showed a difference which is the reason for presenting the adverse experiences by centre (region).
Relevant characteristics of the study population are presented in Table I. The average age at baseline of the total study population was 29 years and 41% of the women were smokers. Baseline characteristics of those who continued for a third year are also presented. Although those who continued were slightly younger at baseline, they were also of slightly higher parity. Of the total study population, 9% were >75 kg in weight at the start of the study, with one woman weighing as much as 110 kg. Those who continued with the implant for a third year were, in 3.4% of cases, >75 kg in weight at the start of the study.
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Discontinuation was as follows: 10% (n = 64) after 6 months. At 12 months, another 62 women had discontinued treatment, resulting in a total of 126 (20%). After 24 months the total number of women who discontinued was 196 (31%). In the third year, 6% (n = 9) discontinued. For calculation of the percentage of discontinuation at 36 months, a different denominator (n = 147) is required due to extension of the study in a sub-group of women only. The reasons for discontinuation are presented in Table II, together with numbers and percentages.
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Of the total study population, 603 women contributed at least one reference period for analysis. If a woman had taken sex steroids or liver enzyme inducing drugs during the study, which was not allowed according to protocol, her data were (partly) excluded from the bleeding analysis. The reasons for discontinuation due to an unacceptable bleeding pattern are categorized and presented in Table III. The clinically most important bleeding indices, together with the numbers of women contributing, are presented in Table IV
. It must be borne in mind that the high percentages reported for `infrequent bleeding' do not include those women having amenorrhoea. The bleeding categories mentioned in Table IV
are distinctly different from each other, except for `prolonged bleeding' which may occur together with `infrequent bleeding' as well as with `frequent bleeding'. From reference period 9 onwards the study population is different. Only Budapest and Santiago contributed to reference periods 912. The declining incidences of amenorrhoea over the first eight reference periods subsequently show an increase at reference period 9 due to the different population involved.
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The severity of serious adverse experiences as well as of adverse experiences was classified by the investigator as mild, moderate or severe. In Table V, an overall assessment is presented of adverse experiences during 3 years of treatment. Those adverse experiences that were in the investigator's opinion possibly, probably or definitely drug-related are presented as drug-related.
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Adverse experiences that were reported by >5% of the volunteers are presented in Table VI. Reporting in Santiago (Chile) is substantially higher than in the other centres, due to a different method of recording. Hungary consisted of three centres, one of which was Budapest in which the study extension took place. Adverse experiences reported in the third year are shown separately. These are newly reported, i.e. first occurrences in the third year. There were no remarkable changes in physical and pelvic examination findings.
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At the start of the study, 36% of the women had a history of dysmenorrhoea. At the end of the study dysmenorrhoea had improved in 87% of the women who had dysmenorrhoea before they received the implant. In 4% this symptom was reported as a new occurrence or as worsening of existing dysmenorrhoea.
Acne, which is one of the most frequently reported adverse experiences, was also recorded at baseline (history). At the end of the study, women were asked about this adverse experience. In 12.8% of the women, acne had improved during treatment with Implanon®, whilst in 12.6% this symptom was new or had worsened.
The BP was measured frequently during the period of study. A systolic BP recording that was >140 mmHg and had increased >20 mmHg from baseline during at least two assessments or at the last assessment (single recording) was considered clinically significant. A clinically significant diastolic BP had to read >90 mmHg and increase >10 mmHg from baseline during at least two assessments or at last assessment. In 10 women clinically significant BP readings occurred; five (0.8%) had a clinically significant systolic reading and seven (1.1%) had a clinically significant diastolic reading during or at the end of the study. The mean systolic as well as diastolic BP showed a small decrease over time.
The body mass index (BMI) showed an increase from baseline >10% once or over several measurements in 20.2% of the women. There was a gradual mean increase in BMI over the full study period. The mean change was 0.80 kg/m2 (SD 1.59) which also included women who discontinued due to weight gain. The mean percent increase in BMI was 3.5%. In 15 (2.4%) women the weight gain was the reason given for discontinuing treatment.
Swelling, redness, pain and/or haematoma at implant site were rarely reported. A combination of symptoms may have occurred in an individual. In that case each symptom was counted separately and percentages shown indicate not only each woman but also each symptom reported. Incidences are shown in Table VII. Insertion of the implant took on average 2.2 min (SD 2.1) with a minimum of 0.03 and a maximum of 10 min. In eight cases (1.3%), some complication related to the insertion occurred (e.g. tip of implant visible, some blood loss from injection site etc.). Average time needed for removal was 5.4 min (SD 5.4). The minimum time required was 0.33 and the maximum 45 min. Removal was complicated in 19 cases (3.0%), usually caused by too deep insertion.
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Discussion |
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In the absence of a control group, comparisons between methods have intrinsic limitations due to the multiplicity of factors that affect their performance. In the case of contraceptive implants, the only objective measure of clinical performance is the pregnancy rate, which has been shown to be affected by factors such as age and body weight (Sivin, 1988, 1994
). With due consideration to these caveats, at the present time, the performance of Implanon® can only be compared with the performance of other contraceptive implants, using literature reports. This exercise should include Norplant® (six capsule levonorgestrel system), Norplant®-II (two rod levonorgestrel system), Uniplant (nomegestrol acetate) and Nestorone® implants. Literature reports of the latter two implant systems remains very limited, whereas there is a vast literature on Norplant®. Notwithstanding, only recent large studies deal with the present soft tubing formulation. Annual pregnancy rates during 3 years of use ranged from 0.0 to 0.4 per 100 women in a trial that encompassed 1530 users of Norplant® (Sivin, 1994
). No pregnancies were reported in another trial encompassing 598 users of the six-capsule system (Norplant®) and 600 users of the two-rod system (Norplant®-II) over 3 years (Sivin et al., 1997
). Most recently, results were reported of the six-capsule system in 511 women, in the United States. The annual pregnancy rate ranged from 0.0 to 0.3 per 100 women over 3 years which rose to 1.0 per 100 women over 5 years (Sivin et al., 1998
). Therefore, as far as contraceptive efficacy is concerned, Implanon® is as good or better than the only marketed implant.
As for the bleeding pattern, this study confirms the well established concept that the use of continuous progestagen-only methods is associated with a disturbed pattern in a high proportion of users and that this is the main reason for discontinuation of the method, as is the case with Norplant® (Sivin et al., 1997).
The bleeding pattern reported here, shows a shift towards amenorrhoea and infrequent bleeding. Although the incidence of amenorrhoea was just below 20% during most of the time, it was the reason for discontinuation in only 1.7% of the women. An objective study of the bleeding cards indicated that the acceptance of an irregular bleeding pattern was greatly at variance. Some women accepted very little in the way of an irregular bleeding pattern, while others accepted `frequent irregular patterns' for long periods of time. Discontinuation rates, therefore, are in the first place a reflection of tolerance, rather than safety.
The percentages of discontinuation due to adverse experiences other than bleeding were 8.5 and 3.4 respectively in the first 2 years and in year 3, whereby weight increase was the most frequently reported reason for discontinuation (2.4%).
Although reporting of adverse experiences was substantially more frequent in Chile, the discontinuation rate was generally lower than in other centres. This most probably was the result of good counselling. The reporting of adverse experiences may be subject to methodological differences, which was also the case in the study reported here. In Chile, women were given ample opportunity to express their complaints freely, which were recorded each time they were expressed. In a study with Norplant® in the same clinic, a symptom was only recorded when it was reported in at least three follow-up visits. Moreover, there had to be an increase from the baseline situation. Using this method of assessment, headache occurred with an incidence of 32.6% (Diaz et al., 1979). In the present study the incidence of headache was 69.2% in Chile, which was in contrast to the average incidence of 6.5% in the other centres.
The low incidence of adverse experiences at the site of implant placement, together with the fast insertion and removal, stand out as practical advantages over multiple unit implants.
Results from this study show that Implanon® has excellent contraceptive action. The bleeding pattern generally was irregular whereby the main tendency was towards amenorrhoea and infrequent bleeding. Weight increase was a side effect that was less well tolerated. There was no untoward effect on BP as reflected in a small mean decrease in systolic as well as in diastolic BP. Implant insertion and removal were fast and uncomplicated in the vast majority (97%) of cases.
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Acknowledgments |
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Notes |
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4 To whom correspondence should be addressed at: Clinical Development Department, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands
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References |
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Submitted on May 7, 1998; accepted on November 30, 1998.