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- 1. Updates on the Health Benefits & Risks of COCs Dr.Harlina Halizah Siraj MD(UKM) MOG(UKM) Family Planning Unit, Dept O&G, Medical Faculty UKM
- 2. Health Risks of COCs Venous thromboembolism (VTE) Myocardial Infarction (MI) Cerebrovascular accident ( CVA) Hypertension Breast cancer Cervical cancer Liver disease Bowel disease
- 3. Risk of COCs : Venous Thromboembolism (VTE) 1970 - risk of VTE associated with oestrogen dosage. Hence, the rationale for oestrogen reduction is mainly for : reduce frequency of thrombotic events changes in the haemostatic system nausea, breast tenderness , vomiting
- 5. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestogens in low oestrogen OCs on venous thromboembolic disease. Lancet 1995; 346 : 1582-8 Conclusion : COC users had RR of 3.2 - 4.1 of VTE than non-users. (Appeared within 4 months of starting COC and disappeared within 3 months of stopping ) Risk was higher with COCs containing 3rd generation progestogens than the 2nd generation. RR for VTE : LNG ( 2.6), DSG (5.3 ), Gestodene ( 5.7)
- 7. Incidence of VTE new and previously published data incidence per 10,000 woman-years (OCs with 20-35 µg EE) 5 2nd generation 3rd generation 4 3 2 1 0 Previous* BCDSP *: Gerstman (1st and 2nd generation), Vessey (2nd generation) WHO
- 8. Identified biases and confounders Healthy user effect Prescribing bias Correction for exact age or duration of use
- 9. OC/VTE studies (3rd versus 2nd) 1995: limited confounder control 1997-9: better confounder control * 2 * * 1 2nd generation *: statistically significant versus 2nd generation 3rd generation TNS Lewis TNSrepeaters TNSswitchers TNSstarters GPRD Farmer MediPlus G Mediplus UK 1999 Mediplu UK 1997 DCC TNS Spitzer LETS GPRD Jick 0 WHO OR for VTE 3
- 10. Transnational study with adjustment for total duration of OC use OC OR 95% CI Any OC vs no use 2.9 2.1-4.1 1st gen vs no use 8.5 3.0-23.9 2nd gen vs no use 2.9 1.9-4.2 LNG OCs 2.6 1.8-4.0 NGM OCs 3.7 2.2-6.1 3rd vs no use 2.3 1.5-3.5 DSG/30 EE 2.5 1.6-4.1 GSD OCs 2.3 1.4-3.6 DSG/20 EE 1.6 0.9-2.9 3rd gen vs 2nd 0.8 0.5-1.3
- 11. Conclusion VTE Initial studies biased No difference in VTE between 2nd and 3rd generation
- 12. Risk of COCs : Myocardial infarction (MI) Dunn No et al (1999) – MICA case control study association between COCs and MI No difference between 2nd and 3rd generation of progestogens. Related with smoking and age.
- 13. Risk of COCs STROKE High dose COCs doubled risk of stroke Recent studies, RR 1.0-1.73 for haemorrhagic stroke & RR 2.85 for ischaemic stroke.( Jick SS et al,Lewis MA et al 1999) No difference between pills containing different progestogens. HYPERTENSION COC containing 35µg EE – rise of 1.0 mmHg diastolic pressure : statistically significant but clinically unimportant ( Shen Q et al , 1994)
- 14. Risk of COCs : Breast cancer Reanalysis of 54 1996, 347: 1713-27 Small epidemiological studies, Lancet increased risk ( RR 1.24 ) for users & RR 1.07 five to nine years after stopping. No excess risk after 10years of stopping COCs. Breast cancers in users are less advanced than nonusers
- 15. Risk of COCs : Cervical cancer Baird and Glasier et al ( 1993) : ` after differences in sexual activity and the use of barrier methods of contraception (which have a protective effect ) have been accounted for, there appears to be no increase in the risk of cervical cancer among women who take COCs’
- 16. Health Benefits of COCs
- 17. Benefits of Pills: Risk reduction in % Ectopic pregnancy 90 Cancer : Ovary 40 Endometrium 40 Benign 40 breast disease Ovarian cysts : Solid tumours Follicular Luteal cysts cysts 20 49 78 Fibroids ( after 5 years of use ) 15 Pelvic inflammatory disease (PID) 50 Menorrhagia 50 Iron deficiency anaemia 50 Dysmenorrhoea 40
- 18. Mean scores of Q-LES-Q with Mercilon 3 3 .5 4 4 .5 P h y s ic a l h e a lt h M ood W o rk /S c h o o l H o u s e h o ld a c tiv it ie s S o c ia l r e la t io n s h ip s F a m ily r e la t io n s h ip s L e is u r e tim e a c tiv it ie s D a ily life S e x life L iv in g s it u a tio n V is io n G e n e r a l w e ll- b e in g O v e r a ll s a t is f a c t io n Diergarten et al. Gynecol Endocrinol 2000;14 (Suppl 2): 196, P114 A ll s c o r e s a r e s ta tis tic a lly s ig n ific a n t a t p < 0 .0 0 0 1 b e fo r e s ta r t at end
- 19. c u m u la t iv e p e r c e n t a g e Change in total quality of life scores 100 with Mercilon 50 B e fo r e s ta r t At end 0 13 23 32 40 48 t o ta l q u a lit y o f lif e s c o r e Diergarten et al. Gynecol Endocrinol 2000;14 (Suppl 2): 196, P114 56 64
- 20. In summary after taking 3 cycles ® of Mercilon 38% of women reported skin clearance in women reported with skin problems before treatment. No significant change in body weight. Greatest improvement being “sex life” And many other benefits….. K Dietgarten et al. Gynecol Endocrinol 2000; 14 (Suppl 2): 196, P114
- 21. Dysmenorrhea % 100 b a s e lin e C y c le 3 75 50 25 0 D y s m e n o rrh e a 2 d a y s o r m o re D a ily a c tiv itie s N e e d a n a lg e s tic s Mira Scientific Posters: 17th World Congress of Fertility and Sterility, 2001. G e n e r a liz e d s y m p to m s
- 22. Effect of Mercilon on acne and seborrhea 15 (N = 3,242) B a s e lin e C y c le 3 % of w om en C y c le 6 10 5 0 A cne S e b o rrh e a Kahn-Nathan, Lapousterle. Reprod Hum Horm 1991;4, Suppl.1:15-20
- 23. Effect on body weight kg 60 5 9 .1 59 5 7 .7 58 57 56 55 b a s e lin e C y c le 1 3 Lavín P, Bravo C. Scientific Posters: 7 th Congress of the European Society of Contraception, 2002, Genova, Italy. Oss: Organon, 2002.
- 24. Effect on body weight Cycle 6 compared to baseline % of women 25 Mercilon 20 20EE/75SD 15 10 5 0 Decrease 2kg or more Increase 2kg or more Serfaty et al. Eur J Contracept Reprod Health Care 1998;3:1-11
- 25. Compliance User failure rate Irregular bleeding Unwanted pregnancies
- 26. RemindHer card ®
- 27. US research on compliance 1,311 women, avg. age 20, mainly unmarried Results: • 89 % took all the pills in the pack • 38% of the pill users skipped 2 or fewer pills • 11% said they missed 8 - 20 pills !! • Only 20% took the pill at the same time every day • Only 13% took the pill completely and correctly at • all times Rosenberg, J of Reproductive Medicine 1995; 40:355-360
- 28. Mercilon some facts Product of Organon research Prescribed in >50 countries Over 300 million strips used More than 75 studies performed Over 23 million women-years of use Over 3.0 million current users First introduced in 1988; proven experience
- 29. Mercilon State of the art in 21th century Excellent reliability Good cycle control Improvement in dysmenorrhea and PMS Low incidence of side effects Negligible effect on body weight Trusted and most experienced 20 gamma Pill Improves quality of life Improves compliance with RemindHer card
- 30. EE dose and the risk of VTE OR of VTE versus non-use 9 * 8 7 O R ofV TE 6 5 4 * 3 * * * 2 1 0 H ig h d o s e N G M LN G D SG G SD D SG 5 0 + µg E E 3 5 µg E E 3 0 -3 2 µg E E 3 0 µg E E 3 0 µg E E 2 0 µg E E * : s ta t is t ic a lly Lewis. Hum Reprod 1999 s ig n ific a n t
- 31. This decision was derived after consultation with 10 expert witnesses and hearing 42 days’ evidence and submissions.
- 32. Lipid parameters Mercilon vs. no OC 2.6 2.4 ** mmol/l 2.2 No OC Mercilon 2 1.8 * * p<0.05 ** p<0.001 1.6 1.4 1.2 1 HDL-C Godsland et al. Contraception 1993;48:217-27 LDL-C
- 33. Lipid metabolism Mercilon & 20 EE/ 100 LNG - separate studies % change from baseline 40 20 EE / 100 LNG (N=25) Mercilon (N=12) 30 20 10 0 -10 HDL LDL Triglycerides Song et al. Contraception 1992:45;523-32 HDL LDL Triglycerides Young, DelConte. AM J Obstet Gynecol 1999; 181:S59-S62
- 34. Blood pressure Mercilon Mercilon has been shown to have no adverse effect on blood pressure Lammers, Op Ten Berg. Acta Obstet Gynecol Scand 1991;70:497-500
- 35. Carbohydrates Mercilon Mercilon has been shown to have minimal effects on carbohydrate metabolism Fotherby. Contraception 1992;46:477-88
- 36. Risk of acute myocardial infarction Transnational study – case-control analysis 4 * OR of A M I 3 2 ** 1 0 2 n d g e n e r a tio n 3 r d g e n e r a tio n * 2 n d g e n v s . n o n -u s e : 3 .0 (1 .5 -5 .7 ) * * 3 rd g e n v s . n o n -u s e : 0 .8 (0 .3 -2 .3 ) * * * 3 rd g e n v s . 2 n d g e n : 0 .3 (0 .1 -0 .9 ) Lewis et al 1997 n o n -u s e
- 38. Latest Overview Adds More Evidence for Safety of 3rd Generation Oral Contraceptives (Walter O. Spitzer et al. Myocardial infarction and third generation oral contraceptives: aggregation of recent studies. Human Reproduction Journal Vol. 17, No. 9, pg 2307-2314, 2002.) The study has analyzed the risk of heart attack (acute myocardial infarction, AMI) associated with the use of all types of contraceptive pills have no greater risk of AMI than women not taking the pill. In addition the analysis also shows that the risk of AMI incurred by women taking third generation pills is about half that associated with second generation types (a relative risk between 0.44 and 0.62)
- 39. CONCLUSION “ The health benefits of COC use greatly outweigh the risks, provided : contraindications are observed and low dose formulations are used.” Professor John Drife Risks and benefits of high and low-dose oral contraceptive pills, Gynaecology Forum, Vol 5, No. 4, 2000 Pg 16-19
Notas do Editor
- When taken in isolation three of the 1995 studies suggested a higher risk of VTE in users of the newer third generation OCs than in users of the older second generation OCs. When evaluated in the perspective of time, however, it became clear that the absolute risk of VTE was not higher in third generation OC users when compared to 2nd generation OC users 10 years ago. At the time that 2nd generation OC had been available for about 10 years, the epidemiological studies showed that the incidence of VTE in women using these Pills with 30 mcg of EE and levonorgestrel as a progestogen was about 4 cases in 10,000 users per year. At the time that 3rd generation OCs were also for about 10 years available the incidence of VTE with these Pills is between 2 and 3 cases per 10,000 users per year. In fact, the only surprise here is the decrease in the incidence of VTE in users of 2nd generation OCs over time from 4 cases in 10,000 woman-years in the early 1980s to 1.5 in 10,000 woman-years with exactly the same pills ten years later. As the low-dose 2nd generation Pills did not change in composition in those 10 years, there should be other factors that induced this unexpected decrease.
- A first step in interpretation of epidemiological findings is to assess whether the observed associations are the result of chance, bias or biological causality. Unfortunately, such a thorough analysis was prevented by the premature actions by health authorities in the UK and Germany and the subsequent pill scare (created through the media). This, in spite of the fact that soon after the data were made publicly known, a number of inconsistencies became apparent. These suggested involvement of bias and confounding. The two most important forms of bias are the healthy user effect and prescribing bias. Let’s first discuss the healthy user effect.
- This slide gives an overview of all ten epidemiological studies on OCs and VTE. The initial four studies observed differences in risk of VTE between 3rd and 2nd generation OC users that were statistically significant in three of them. Since then, a number of inconsistencies became apparent that suggested the involvement of bias and confounding. Six new analyses were more appropriately adjusted for the two essential biases (prescribing bias, healthy user effect) by adjusting for age and duration of use. The newer analyses consistently observe an absence of a difference in risk of VTE between 2nd and 3rd generation OC users, thus confirming that the initial differences in the 1995 studies were caused by bias and confounding.
- A total of 17,622 separate exposure episodes covering 47,914 woman-years of observation were included in the Cox regression model. The relative risk estimates were adjusted for exposure in each episode by generation, age, BMI, smoking, alcohol use, duration of current use by generation and duration of previous use by generation as linear variables and switching by generation. The comparison of users of 3rd with users of 2nd generation OCs shows that there is no risk difference between the two. The results are consistent with the assumption that this method removes the relevant exposure-dependent cohort effects for the comparison between OC user-groups. This is indicated by the consistency of the results when stratifying by control group and by country, but also by the fact that the dependence of risk estimates on the time of market introduction of the various OCs shown in standard logistic regression is no longer present. The results of this final analysis of the Transnational study suggest that the odds ratios of VTE relates to the dose of estrogen in the OCs as the Pills with 50 mcg of estrogen or more (1st generation OCs in this study) are associated with the highest OR (8.5), followed by the 35 mcg OCs (3.7) and 30 mcg OCs (2.3-2.6). The lowest OR for VTE was found for the OC with the lowest estrogen dose (1.6). When the OCs with 30 mcg of EE are compared, the ORs are practically the same and seem to be independent of the type of progestogen (desogestrel, gestodene or levonorgestrel). These results are in line with the expectations that existed before 1995 based on the previous 35 years of pill research, which suggested that the association of OCs with VTE was likely to be influenced by the amount of estrogen in the Pill and not by the type of progestogen.
- For studies on VTE - the initial studies were biased. In the most recent studies a better adjustment was possible. And these studies show no difference in risk between OC of the 3rd or 2nd generation. For studies on AMI - we see a significant risk for users of the 2nd generation Ocs. This risk is no longer present in users of the modern - 3rd gen - pills. And the difference between 3rd and 2nd generation is a stat sign. In the light of the reasons why we developed OCs containing DSG namely improving safety, we may draw the conclusion that we are on the right track. But - of course - more data is needed to support this further.
- Mercilon use showed a statistically significant improvement in the scores for all 13 quality-of-life items in this study.
- The total quality-of-life scores (Q-LES-Q) also improved significantly in this study.
- In an open, prospective study, 346 women (mean age 22.6) were included in this Mercilon trial on dysmenorrhea. The participants were followed-up for 3 cycles of Mercilon-use. All women included had suffered from dysmenorrhea the last 3 cycles preceding the study. After 3 cycles the dysmenorrhea disappeared in more than 50% of the women, in 86.3% the dysmenorrhea was reduced to a duration of 1 day or less. Also the severity of dysmenorrhea decreased: The need to take analgetics decreased from 99.7 to 40.9%. The precentage of women that experienced interference from dysmenorrhea in their daily lives decreased from 73% to only 9.7%. Generalized dysmenorrhea symptoms such as lumbago and asthenia decrease from 79.2% to 20.8%. In conclusion, Mercilon is highly effective in reducing dysmennorhea, resulting in decreased need for analgestics and interference in daily activities.
- Kahn-Nathan et al found a clear reduction in both acne as seborrhea during 6 cycles of Mercilon use.
- In this non-comparative multi-center study, 542 women participated. Participants were followed-up to 13 cycles. Over 13 cycles, the average body weight decreases from baseline with 1.4 kilograms.
- Compliance to an oral contraceptive regimen is essential to its efficacy. Compliance translates directly into user-failure, a differentiation of the Pearl Index where the incorrect taking of pills is taken into account when calculating the number of pregnancies per 100 women years. The incorrect taking of pills occurs when women do not take one or more pills in the blister strip according to the time schedule, or in case of vomiting, diarrhea and simultaneous use of interacting drugs. A poor compliance can increase the incidence of irregular bleeding, due to a lack of hormonal cycle control.When the time-window for taking the pill has been exceeded, no guarantee can be given for an optimal serum level of the estrogen and progestogen in the pill for inhibiting ovulation and thickening the cervical mucus. The repercussions of poor compliance are clear: a considerable proportion of voluntary abortions carried out each year are linked to one or more missed pills during the reproductive cycle. Compliance with long-term treatment for chronic diseases is usually very poor. Therefore it is hardly surprising that compliance to an oral contraceptive regimen is also poor, especially considering that women who use OCs do not suffer from a disease and have not got any symptoms that need treatment. Physicians play an important role in informing women on the appropriate use of OCs and enhancing their compliance. A useful tool has been developed to aid women in their compliance: it is called the reminder card.
- The RemindHer Card.
- This slide shows the results of a US research on compliance in 1,311 women.
- This is from the most recent study on the issue. The risks of thrombosis associated with different types of OCs are presented in this slide, showing that the highest risk is associated with the higher estrogen dosed OCs, similar risks are associated with OCs with the same estrogen dose but different types of progestogens, and the lowest risk is associated with the group of women using Mercilon and is no longer statistically significant. These data underline prominently that the rationale of estrogen dose reduction in the past 30 years of Pill research has been the right approach in order to limit the occurrence of side effects to the lowest possible incidences.
- In this study from Godsland of the Wynn Institute of Metabolic Research in London, it was confirmed that as a result of the high selectivity of the progestogen in Mercilon it is associated with beneficial changes in the relevant lipid parameters, HDL and LDL. This study was performed in 1993 and could therefore still not be corroborated by epidemiological research. Those studies have only become available since 1995.
- The results of two separate studies (one on Mercilon, one on LNG) are shown in one slide. Song et al.investigated the effects of Mercilon on lipid metabolism and found an increase in HDL and a decrease in LDL, which results in a positive HDL/LDL ratio generally regarded as favorable.
- In the past, long-term use of high-estrogen-dose OCs was reported to cause minimal, reversible increases in bloodpressure. However, Mercilon has been shown to have no adverse effect on blood pressure.
- Insulin resistance and accompanying hyperinsulinemia may induce adverse changes in MI risk via metabolic mechanisms and effects on blood pressure. Insulin can also have deleterious effects on the vascular wall by inducing smooth muscle proliferation and lipid disposition. All oral contraceptives cause some degree of insulin resistance, but the effects of currently used low-estrogen-dose OCs vary considerably. The greatest degree of insulin resistance is seen with Pills containing levonorgestrel and the least with those containing desogestrel. (Godsland and Crook 1996). A study by Godsland et al (1993) investigated the effects of Mercilon on glucose and insulin response to an oral glucose tolerance test (OGTT). Small changes in glucose tolerance and elevated insulin concentrations were seen in Mercilon users compared to nonusers. However, these results were simular to, or lower than those seen with all low-dose, combined oral contraceptives and remain within normal ranges. Of the six studies on carbohydrate metabolism with Mercilon reviewed by Fortherby (1992), none showed any effect on fasting glucose and insulin levels. It is noteworthy that the glycosylated protein and HbAlc levels - sensitive parameters of long-term glucose homeostasis- were also not affected by the use of Mercilon. It may be concluded that Mercilon has minimal and clinically insignificant effects on carbohydrate metabolism.
- Lewis MA. Heinemann LA. Spitzer WO. MacRae KD. Bruppacher R. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Contraception 1997; 56(3):129-40 These are data from the large Transnational study. In this study the risk of AMI appeared to be statistically significantly higher in users of second generation OCs compared to non-users, and no such risk observed in users of 3rd generation OCs. The difference in risk of AMI between the two generations of OCs was also significant and to the benefit of third generation OCs. Based on these and earlier studies, it can be concluded that third generation OCs are the first class of OCs that is not associated with an excess risk of myocardial infarction. It now seems that third generation live up to their promise to have further reduced the incidence of rare but relevant side effects.