The European Journal of Contraception and Reproductive Health Care, December 2010;15:445–446
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LETTER TO THE EDITOR
Consumption of combined oral contraceptives and venous thromboembolism in Zagreb, Croatia .................................................................................................
KEYWORDS
Combined oral contraceptives; Drospirenone; Venous thromboembolism
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SIR: The paper by Maia et al. on the effect of a continuous regimen of drospirenone (DRSP) and ethinylestradiol (EE) on Cox-2 and Ki-67 expression in the endometrium, which appeared in a recent issue of this Journal1, prompts us to share some information about thrombogenic effects the combined oral contraceptive (COC) Yasmin1 (containing 3 mg DRSP and 30 mg EE) may have. This COC was recently introduced in Croatia. We collected data on its prescription rate in the capital city, Zagreb, and assessed whether there might be a link with the incidence of venous thromboembolism (VTE). The total female population, aged 15–49 years, under surveillance in this study was about 210,000. According to the register of drug sales in the city of Zagreb2, the sale of COCs increased from 174,841 strips of tablets (for use during one cycle) in 2005 to 205,056 strips in 2008 (þ17.3%). Assuming that, with negligible exceptions, the women concerned used their contraceptives regularly during the whole year (corresponding to 13 ‘pill-driven’ cycles) their number would have increased from 13,450 in 2005 to 15,770 in 2008. The COC containing DRSP/EE has become ever more popular in Zagreb, yielding a 4.4-fold increase in sales over the study period (2005–2008), from 26,818 strips of tablets (for use during one cycle) in 2005 to 118,334 strips in 2008. If following the same line of thought as for all pills confounded, namely, assuming again that the women concerned used their contraceptives regularly during the whole
ª 2010 The European Society of Contraception and Reproductive Health DOI: 10.3109/13625187.2010.526259
year (corresponding to 13 ‘pill-driven’ cycles) their number would have increased from 2,060 in 2005 to 9,100 in 2008. During that period the Agency for Drugs and Medicinal Products recorded 24 side effects and complications related to the use of the DRSP/EE pill for the whole of Croatia; they steadily increased from one in 2005 to 15 in 2008. Other contraceptives were associated with a small number of reported side effects3. Use of the DRSP/EE preparation was associated with a significantly greater risk of VTE (p 5 0.01; Odds Ratio ¼ 0.18; 95% confidence interval ¼ 0.04–0.68) compared with second generation COCs. There were two lethal outcomes of pulmonary embolism; however, a direct causal relationship was not demonstrated. Among the 24 reports of side effects and complications related to the use of DRSP/EE , there were 13 cases of verified VTE (including deep vein thromboses, pulmonary embolisms, and one case of basilar artery thrombosis), whereas the other reports referred to symptoms such as headache, pain and nausea. However, in over half the cases (n ¼ 7) the outcome of thromboembolic complications remained unknown. Recovery was reported in three cases but, as already mentioned, there were two lethal outcomes where a direct causal relationship with the use of DRSP/EE could not be established; for the last case, ‘failure of recovery’ was reported, but it is not known what this precisely entails as detailed data on the outcome in this case are not on record. According to some authors the risk of VTE associated with the use of DRSP/EE would not be greater than with any other COC4. On the contrary, a meta-analysis supports the view that COCs containing third generation progestins (a class to which, stricto sensu, drospirenone does not belong) are associated with a 1.7-fold increased risk of VTE compared with second generation pills. With regard to all COCs, the risk is highest in first time users. Although confounding factors can never be excluded with certainty in observational studies, it seems that the biases that have been suggested and examined are not sufficient to account for the results5. A survey of medical records of hospitalised women and deaths6
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Letters to the Editor
could determine neither the exact causes, nor the outcomes in most cases of VTE. The discrepancy between the results obtained with these different approaches results from the application of different methods for recording particular events. With regard to hospital mortality, the diagnosis entered in the patient-statistics form filled out at the time the patient is discharged from the hospital is considered to be most relevant, whereas drug-related side effects and complications are reported at different levels (health care, pharmacy, etc.). Discrepancy in the number of deaths recorded may be due to death occurring outside the health care system (hospital, ambulance service, polyclinic, etc). The number of DRSP/EE strips issued during the 2005–2008 period in Zagreb increased 4.4fold whereas, during that same period, the number of packets sold of other hormonal contraceptives declined. Caution must evidently be exerted with regard to attributing a causal role to DRSP-containing COCs in the genesis of thromboembolic events on the basis of the data we gathered. But the latter point in the same direction as recent, authoritative papers7,8. In the light of their ever growing utilisation, physicians should be directly and fully informed of the risks and benefits of COCs. Currently available oral contraceptives still have a major impact on VTE occurrence and many women do not use the safest brands with regard to that risk7. The risk of VTE in current users of COCs decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, COCs containing drospirenone, desogestrel, or gestodene were associated with a significantly higher risk of VTE than those with levonorgestrel8. In addition, promotional material issued by companies distributing these products in Croatia should be surveyed to ascertain that they are consistent with their registration certificates. To ensure the safe use of combined hormonal contraceptives a full clinical, personal and family history must be taken prior to initiation, in order to evaluate risk factors for VTE and cardiovascular disease9. Limitations of the study are the incompleteness of data on drug sales in pharmacies, although most pharmacies in Zagreb were included; the lack of information concerning adherence to pill intake and, finally, the fact that data on side effects and complications pertained to the whole of Croatia.
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Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper. Marcel Leppe´e and Josip Culig Department of Pharmacoepidemiology, Andrija Stampar Institute of Public Health, Zagreb, Croatia E-mail:
[email protected] Mirela Eric Department of Anatomy, School of Medicine, University of Novi Sad, Novi Sad, Serbia
REFERENCES
1. Maia H Jr, Casoy J, Athayde C, et al. The effect of a continuous regimen of drospirenone 3 mg/ethinylestradiol 30 mg on Cox-2 and Ki-67 expression in the endometrium. Eur J Contracept Reprod Health Care 2010;15:35–40. 2. Andrija Stampar Institute of Public Health. Izvanbolnic ka potrosˇnja lijekova u gradu Zagrebu u 2008. godini [Outpatient drug consumption in the city of Zagreb in 2008]. Zagreb 2009. 3. http : //www.almp.hr/?ln ¼ hr & w ¼ publikacije&d ¼ nuspojave_2009 (Accessed 30 August 2010). 4. Shulman LP, Goldzieher JW. The truth about oral contraceptives and venous thromboembolism. J Reprod Med 2003;48(11 Suppl):930–8. 5. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001;323(7305):131, doi: 10.1136/ bmj.323.7305.131 6. http://www.stampar.hr/Default.aspx (Accessed 30 August 2010). 7. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009;339:b2921 doi: 10.1136/bmj.b2921 8. Lidegaard O, Lokkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:b2890 doi: 10.1136/bmj.b2890 9. Martı´nez F, Avecilla A. Combined hormonal contraception and venous thromboembolism. Eur J Contracept Reprod Health Care 2007;12:97–106.
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