Contraception 89 (2014) 235 – 236
Editorial
Oral hormonal contraception and venous thromboembolism (VTE) We have yet to develop the perfect contraceptive. This would require a drug or device that was readily accessible (available and affordable), easy to use, highly efficacious and completely without risk. It is clear that no available contraceptive method meets these criteria. Since no single method appeals to, or is the perfect fit for, all women, we are left with a range of options with varying degrees of efficacy and safety. In the United States, survey data indicate that about 30% of women between the ages of 15 and 24 yrs use coitus interruptus for contraception at least some of the time [1]. Unintended pregnancies result in more than 20% of these women, almost double the rate seen in contraceptive users. Pregnancy increases the risk of venous thromboembolism (VTE) 5–10-fold above the risk in the nonpregnant state, with absolute rates of VTE of 10-20/10,000 women and a 1% fatality rate among these cases (mortality of 1–2/ 100,000) [2,3]. Reliable contraceptive methods, when employed effectively, reduce the risk of pregnancy and thereby the absolute risk of VTE. Many hormonal contraceptives, however, increase the risk of VTE above baseline. The extent to which various hormonal contraceptives and the differing routes of hormone delivery influence VTE risk remains the focus of controversy and confusion. At a societal level, most understand and are willing to accept some level of risk with contraception in return for the benefit of avoiding unplanned pregnancy. The expectation of most individuals is that serious adverse events related to contraception (such as VTE) will happen to someone else. However, when a contraceptive method results in a side effect or complication at a personal level, tolerance for risk generally evaporates. Human nature leads to a search for the reason. Would the same contraceptive method have been chosen if counseling had been different? Was counseling about potential risks complete and accurate? Who is to blame? What factors influence our beliefs about risks in our dayto-day lives? Personal or first-hand reports of tragic events often have a defining influence on our perception of risk. The tragic death of a young woman on hormonal contraception creates a heart-wrenching news story that, in most cases, ends with finger pointing about who should be held 0010-7824/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2014.02.002
accountable. “Stimulated reporting” of other adverse events among women using the same product or method through social media or through reports to government regulatory agencies soon draws in the legal profession, and their recruiting of other “victims” on TV and in the print media soon generates widespread concern about the safety of the product/method. While important as potential markers for risk, such isolated postmarketing case reports should carry no more weight in clinical decision making or health policy than would individual testimonials about how great a product might be. Medical care and public policy should be based on solid science. Safety of new hormonal contraceptives is assessed in a number of stages. Initial studies prior to market approval examine immediate side effects and changes on a variety of biochemical and clinical parameters that could indicate the potential for future health problems. Rare but serious events attributable to new hormonal contraceptives can only realistically be assessed in postmarketing surveillance with populations large enough to assess the frequency of events that occur infrequently or after years of exposure. Venous thromboembolism is one such adverse event. Recently, regulatory authorities in the United States (the Food and Drug Administration) and Europe (the European Medicines Agency) have mandated that companies introducing new hormonal contraceptives onto the market must simultaneously initiate surveillance studies to address such rare risks as VTE and stroke. The study design must be preapproved by the regulatory authorities, and the sponsoring company must shoulder the entire cost. To mitigate criticisms of pharmaceutical company influence on the study and its results, the study should be conducted by an independent organization with all aspects of design, conduct and outcomes reviewed by an independent Data and Safety Monitoring Board (who is blind to the treatment assignment at the time of review of adverse events). In this issue of Contraception, Dinger et al. [4] have reported the results of one such study — a large international prospective controlled active surveillance study of oral contraceptive users in which cardiovascular outcomes were compared among women using a new Bayer product
236
Editorial / Contraception 89 (2014) 235–236
containing the progestin drospirenone in two different regimens to other marketed products. The methodology is similar to the European Active Surveillance Study published by Dinger’s group in 2007 [5]. This paper is important for several reasons. First, the study sample comprises a large population of 85,109 “realworld users” from multiple sites across the United States as well as six European countries. Secondly, the study establishes a “gold standard” for postmarketing research into rare cardiovascular events. Critical to the design was careful documentation of possible confounding variables (such as duration of use, age, body mass index, family history of VTE). Regular contact with participants and a well-defined protocol for aggressive follow-up enabled evaluation of all suspected adverse events and an extremely low lost-to-follow-up rate (3.3%), which is remarkable for a study of this magnitude and duration (up to 6 years). All reported serious adverse events were validated by review of medical records, and the possibility of causation by hormonal contraception was adjudicated by the independent Data and Safety Monitoring Board who was blind to the treatment involved. Thirdly, it provides the strongest evidence that available oral contraceptives have similar risks for serious adverse cardiovascular events — in particular VTE. The current study was powered to exclude a twofold increase in risk associated with drospirenone-containing oral contraceptives, which it did [4]. The existing controversy about the safety of drospirenone-containing oral contraceptives arises from a number of database studies which purport to establish an increased VTE risk with hazard ratios around 1.6–1.7 [6,7]. Database studies have been criticized for a number of reasons [8,9]. Administrative databases frequently lack critical information on confounding variables, and the diagnostic codes are often inaccurate [10–12]. They rely on pharmacy records rather than patient interview to determine drug usage, and they do not allow validation of events from medical records. Given the limitations of observational research and the fact that hazard ratios less than 2 may well be the result of residual bias and confounding [13,14], it seems clear that the current study affords the best evidence on the VTE risk associated with different oral hormonal contraceptives.
Robert L. Reid Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Queen’s University, Kingston, Ontario, Canada, K7L 2V7 E-mail address: [email protected] References [1] Dude A, Neustadt A, Martins A, Gilliam M. Use of withdrawal and unintended pregnancy among females 15–24 years of age. Obstet Gynecol 2013;122(3):595-600. [2] James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. AJOG 2006;194(5):1311-5. [3] Wu P, Poole TC, Pickett JA, Bhat A, Lees CC. Current obstetric guidelines on thromboprophyaxis in the United Kingdom: evidence based medicine? Eur J Obstet Gynecol Reprod Biol 2013;168:7-11. [4] Dinger J, Bardenheuer K, Hienemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the international active surveillance study of women taking oral contraceptives. Contraception 2014. [5] Dinger JC, Heinemann LAJ, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344-54. [6] Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ 2011;343:d6423. [7] Sidney S, Cheetham TC, Connell FA, Oullet-Hellstrom R, Graham DJ, Davis D, et al. Recent combined hormonal contraceptives and the risk of thromboembolism and other cardiovascular events in new users. Contraception 2013;87:93-100. [8] Grimes DA. Epidemiologic research using administrative databases: garbage in, garbage out. Obstet Gynecol 2010;116(5):1018-9. [9] Dinger J, Shapiro S. Combined oral contraceptives, venous thromboembolism, and the problem of interpreting large but incomplete datasets. J Fam Plann Reprod Health Care 2012;38:2-6. [10] White RH, Brickner LA, Scannell KA. ICD-9-CM codes poorly indentified venous thromboembolism during pregnancy. J Clin Epidemiol 2004;57:985-8. [11] Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium — a registerbased case–control study. Am J Obstet Gynecol 2008;198:233 e7. [12] Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A, Johnsen SP. Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution. J Clin Epidemiol 2010;63:223-8. [13] Spitzer WO. Oral contraceptives and cardiovascular outcomes: cause or bias? Contraception 2000;62(2 Suppl):3S-9S. [14] Grimes DA, Schulz KF. False alarms and peudo-epidemics: the limits of observational research. Obstet Gynecol 2012;120:920-7.
Editorial
Oral hormonal contraception and venous thromboembolism (VTE) We have yet to develop the perfect contraceptive. This would require a drug or device that was readily accessible (available and affordable), easy to use, highly efficacious and completely without risk. It is clear that no available contraceptive method meets these criteria. Since no single method appeals to, or is the perfect fit for, all women, we are left with a range of options with varying degrees of efficacy and safety. In the United States, survey data indicate that about 30% of women between the ages of 15 and 24 yrs use coitus interruptus for contraception at least some of the time [1]. Unintended pregnancies result in more than 20% of these women, almost double the rate seen in contraceptive users. Pregnancy increases the risk of venous thromboembolism (VTE) 5–10-fold above the risk in the nonpregnant state, with absolute rates of VTE of 10-20/10,000 women and a 1% fatality rate among these cases (mortality of 1–2/ 100,000) [2,3]. Reliable contraceptive methods, when employed effectively, reduce the risk of pregnancy and thereby the absolute risk of VTE. Many hormonal contraceptives, however, increase the risk of VTE above baseline. The extent to which various hormonal contraceptives and the differing routes of hormone delivery influence VTE risk remains the focus of controversy and confusion. At a societal level, most understand and are willing to accept some level of risk with contraception in return for the benefit of avoiding unplanned pregnancy. The expectation of most individuals is that serious adverse events related to contraception (such as VTE) will happen to someone else. However, when a contraceptive method results in a side effect or complication at a personal level, tolerance for risk generally evaporates. Human nature leads to a search for the reason. Would the same contraceptive method have been chosen if counseling had been different? Was counseling about potential risks complete and accurate? Who is to blame? What factors influence our beliefs about risks in our dayto-day lives? Personal or first-hand reports of tragic events often have a defining influence on our perception of risk. The tragic death of a young woman on hormonal contraception creates a heart-wrenching news story that, in most cases, ends with finger pointing about who should be held 0010-7824/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2014.02.002
accountable. “Stimulated reporting” of other adverse events among women using the same product or method through social media or through reports to government regulatory agencies soon draws in the legal profession, and their recruiting of other “victims” on TV and in the print media soon generates widespread concern about the safety of the product/method. While important as potential markers for risk, such isolated postmarketing case reports should carry no more weight in clinical decision making or health policy than would individual testimonials about how great a product might be. Medical care and public policy should be based on solid science. Safety of new hormonal contraceptives is assessed in a number of stages. Initial studies prior to market approval examine immediate side effects and changes on a variety of biochemical and clinical parameters that could indicate the potential for future health problems. Rare but serious events attributable to new hormonal contraceptives can only realistically be assessed in postmarketing surveillance with populations large enough to assess the frequency of events that occur infrequently or after years of exposure. Venous thromboembolism is one such adverse event. Recently, regulatory authorities in the United States (the Food and Drug Administration) and Europe (the European Medicines Agency) have mandated that companies introducing new hormonal contraceptives onto the market must simultaneously initiate surveillance studies to address such rare risks as VTE and stroke. The study design must be preapproved by the regulatory authorities, and the sponsoring company must shoulder the entire cost. To mitigate criticisms of pharmaceutical company influence on the study and its results, the study should be conducted by an independent organization with all aspects of design, conduct and outcomes reviewed by an independent Data and Safety Monitoring Board (who is blind to the treatment assignment at the time of review of adverse events). In this issue of Contraception, Dinger et al. [4] have reported the results of one such study — a large international prospective controlled active surveillance study of oral contraceptive users in which cardiovascular outcomes were compared among women using a new Bayer product
236
Editorial / Contraception 89 (2014) 235–236
containing the progestin drospirenone in two different regimens to other marketed products. The methodology is similar to the European Active Surveillance Study published by Dinger’s group in 2007 [5]. This paper is important for several reasons. First, the study sample comprises a large population of 85,109 “realworld users” from multiple sites across the United States as well as six European countries. Secondly, the study establishes a “gold standard” for postmarketing research into rare cardiovascular events. Critical to the design was careful documentation of possible confounding variables (such as duration of use, age, body mass index, family history of VTE). Regular contact with participants and a well-defined protocol for aggressive follow-up enabled evaluation of all suspected adverse events and an extremely low lost-to-follow-up rate (3.3%), which is remarkable for a study of this magnitude and duration (up to 6 years). All reported serious adverse events were validated by review of medical records, and the possibility of causation by hormonal contraception was adjudicated by the independent Data and Safety Monitoring Board who was blind to the treatment involved. Thirdly, it provides the strongest evidence that available oral contraceptives have similar risks for serious adverse cardiovascular events — in particular VTE. The current study was powered to exclude a twofold increase in risk associated with drospirenone-containing oral contraceptives, which it did [4]. The existing controversy about the safety of drospirenone-containing oral contraceptives arises from a number of database studies which purport to establish an increased VTE risk with hazard ratios around 1.6–1.7 [6,7]. Database studies have been criticized for a number of reasons [8,9]. Administrative databases frequently lack critical information on confounding variables, and the diagnostic codes are often inaccurate [10–12]. They rely on pharmacy records rather than patient interview to determine drug usage, and they do not allow validation of events from medical records. Given the limitations of observational research and the fact that hazard ratios less than 2 may well be the result of residual bias and confounding [13,14], it seems clear that the current study affords the best evidence on the VTE risk associated with different oral hormonal contraceptives.
Robert L. Reid Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Queen’s University, Kingston, Ontario, Canada, K7L 2V7 E-mail address: [email protected] References [1] Dude A, Neustadt A, Martins A, Gilliam M. Use of withdrawal and unintended pregnancy among females 15–24 years of age. Obstet Gynecol 2013;122(3):595-600. [2] James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. AJOG 2006;194(5):1311-5. [3] Wu P, Poole TC, Pickett JA, Bhat A, Lees CC. Current obstetric guidelines on thromboprophyaxis in the United Kingdom: evidence based medicine? Eur J Obstet Gynecol Reprod Biol 2013;168:7-11. [4] Dinger J, Bardenheuer K, Hienemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the international active surveillance study of women taking oral contraceptives. Contraception 2014. [5] Dinger JC, Heinemann LAJ, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344-54. [6] Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ 2011;343:d6423. [7] Sidney S, Cheetham TC, Connell FA, Oullet-Hellstrom R, Graham DJ, Davis D, et al. Recent combined hormonal contraceptives and the risk of thromboembolism and other cardiovascular events in new users. Contraception 2013;87:93-100. [8] Grimes DA. Epidemiologic research using administrative databases: garbage in, garbage out. Obstet Gynecol 2010;116(5):1018-9. [9] Dinger J, Shapiro S. Combined oral contraceptives, venous thromboembolism, and the problem of interpreting large but incomplete datasets. J Fam Plann Reprod Health Care 2012;38:2-6. [10] White RH, Brickner LA, Scannell KA. ICD-9-CM codes poorly indentified venous thromboembolism during pregnancy. J Clin Epidemiol 2004;57:985-8. [11] Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium — a registerbased case–control study. Am J Obstet Gynecol 2008;198:233 e7. [12] Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A, Johnsen SP. Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution. J Clin Epidemiol 2010;63:223-8. [13] Spitzer WO. Oral contraceptives and cardiovascular outcomes: cause or bias? Contraception 2000;62(2 Suppl):3S-9S. [14] Grimes DA, Schulz KF. False alarms and peudo-epidemics: the limits of observational research. Obstet Gynecol 2012;120:920-7.
