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Cardiovascular safety of oral contraceptives
ORIGINAL RESEARCH ARTICLES
Cardiovascular Safety of Oral Contraceptives What Has Changed in the Last Decade? Howard W. Ory Within the last 10 years, the cardiovascular safety record of oral contraceptives (OC) has improved dramatically. The excess risk of venous thromboembolism (VTE) has been reduced and OC use no longer has any meaningful impact on risk of myocardial infarction (MI) or stroke among healthy, nonsmoking women.1 What has changed in the last decade to produce these important developments? Current prescribing practices and careful patient selection are critical factors, and the information derived from epidemiologic studies has also contributed to the excellent safety record. Physicians deserve a major share of the credit for responding to the research findings and prescribing improved formulations as they became available. Formulations containing ,50 mg ethinyl estradiol (EE) today account for nearly all OC use in this country. Epidemiologic findings are consistent with these indicators: investigators have reported that among women enrolled in a large managed care organization, stroke and myocardial infarction (MI) is now exceedingly rare among users of OCs containing #35 mg EE.2,3 More precise and detailed epidemiologic risk estimates have clarified the importance of hypertension, smoking, and other factors in the etiology of cardiovascular disease (CVD), enabling providers to select appropriate candidates for OC use. Consequently, in the developed world, current users are women who are at low risk for CVD.2– 4
Myocardial Infarction As early as 1980, Meade and colleagues5 reported that use of formulations containing ,50 mg EE did not increase the risk of MI in nonsmoking women. Several studies have now confirmed this observation. Data from the Royal College of General Practitioners’ oral contraceptive study6 collected between 1968 and 1987 show that current use of OCs increased risk of Epidemiologic Consultant, Atlanta, Georgia Name and address for correspondance: Howard Ory, MD, Epidemiologic Consultant, 882 Barton Woods Rd., Atlanta, GA 30307
© 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
MI only among women who also smoked cigarettes. Thorogood and colleagues7 reported that relative risk of fatal MI among nonsmokers was not significantly increased by current OC use; compared with neverusers, the adjusted relative risk among current and past users considered together was 1.1 (95% confidence interval, 0.3 to 3.8). Past use of OCs also does not increase risk for MI after discontinuation among nonsmoking women without major risk factors for CVD.8 In a study examining the risk of MI associated with remote or recent past use (at least 5 years of use) of OC among such past users aged 25 to 64 years, the age-adjusted relative risk estimate compared with never-users was 1.2 (95% confidence interval, 0.7 to 2.2).8 Two large-scale studies have recently confirmed that combined formulations containing ,50 mg EE have a negligible impact on the risk of MI in women who do not have major risk factors for CVD.3,9 Sidney and colleagues3 conducted a population-based, casecontrol study to investigate the risk of MI in women aged 15 to 44 years. Odds ratios were calculated relative to noncurrent users, after adjusting for smoking, hypertension, body mass index, and other factors. As shown in Table 1, current use of low-estrogen-dose OCs does not significantly increase the risk of MI. On the basis of these data, these investigators stated that, at most, only 5% of MI in women of reproductive age—that is, less than 3 cases per 1 million womanyears— could be attributable to OC use. This study provided further evidence that women who use OCs tend to be selected for low levels of CVD risk factors: among the subjects in this population without MI, the prevalence of several risk factors for MI was lower in OC users than in nonusers. Jick and colleagues9 investigated acute MI risk in 303,470 women under age 45 with no known MI risk factors who had used or were using low-dose OCs containing levonorgestrel, desogestrel, or gestodene. They reported that there were no differences in acute MI risk among the formulations, nor between the groups of women who were current and past users. They concluded that the risk of acute MI in users of ISSN 0010-7824/98/$19.00 PII S0010-7824(98)00077-8
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Table 1. Adjusted odds ratios of myocardial infarction according to oral contraceptive use Variables Current or noncurrent use Current use† Noncurrent use Current or past use and no use Current use† Past use No use Any or no use Any use No use
Myocardial infarction odds ratio (95% Cl)* 1.67 (0.48, 5.85) 1.00 (referent) 1.14 (0.28, 4.72) 0.60 (0.25, 1.44) 1.00 (referent) 0.64 (0.27, 1.53) 1.00 (referent)
Cl 5 confidence interval. *Adjusted for treated hypertension (yes/no), treated diabetes (yes/no), treated/diagnosed high cholesterol (yes/no), smoking (current/occasional/ past), race or ethnicity (Hispanic/black/Asian/other/white), and body mass index (continuous). †Use in the month before the index date. Reproduced with permission of the American College of Obstetricians and Gynecologists from Sidney et al. Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol 1996;88:939 – 44.
low-dose OCs is low and mainly restricted to OC users who smoke cigarettes. World Health Organization (WHO) investigators also studied the relation between OC use and MI in an international, hospital-based, case-control study (368 cases and 941 controls).10 The WHO group found that the overall odds ratio for acute MI with OC use was 5.01 (95% confidence interval, 2.54 to 9.90) among European women and 4.78 (95% confidence interval, 2.52 to 9.07) among women in developing countries compared to age-matched non-OC users. In nonsmoking OC users, the relative risk among those who had their blood pressure measured was 1.10 (95% confidence interval, 0.12 to 9.69) in Europe and 1.10 (95% confidence interval, 0.09 to 12.9) in developing countries. For the European women under age 35 who were nonsmokers, the maximum estimated excess risk with OC use was about 3 per 100,000 womanyears, and the investigators stated that this risk would probably have been even lower if the women in this group had been screened for blood pressure abnormalities before and during OC use. In conclusion, excess risk of MI has been virtually eliminated by use of all OC formulations containing ,50 mg EE in nonsmoking, healthy, normotensive women.
Hemorrhagic and Ischemic Stroke Findings with respect to OC use and stroke risk parallel those on MI. There is no evidence that formulations containing ,50 mg EE significantly increase the risk of hemorrhagic stroke in nonsmok-
ers.2,11–13 Thorogood and colleagues13 reported that the adjusted relative risk of fatal subarachnoid hemorrhage associated with formulations containing ,50 mg EE was 1.1 (95% confidence interval, 0.6 to 1.9). Investigators with the WHO Collaborative Study14 also reported that overall risk of hemorrhagic stroke was only slightly increased with OC use; among European women risk was not significantly increased by OC use (odds ratio 1.38 [95% confidence interval, 0.84 to 2.25]), but the relative risk was significantly increased in developing countries (relative risk 1.76 [95% confidence interval, 1.34 to 2.30]). The risk was significantly increased, however, only among OC users who smoked or who had a history of hypertension compared to women with these risk factors who were not OC users. Data from WHO15 show that the overall risk of ischemic stroke was 2.99 (95% confidence interval, 1.65 to 5.40) in Europe and 2.93 (95% confidence interval, 2.15 to 4.00) in developing countries, with the risk being lower in all countries among OC users who did not smoke, and among those who did not have hypertension prior to their OC use. However, a history of hypertension among current OC users was associated with an odds ratio of 10.7 (95% confidence interval, 2.04 to 56.6) in European women and 14.5 (95% confidence interval, 5.36 to 39.0) in women in developing countries. Data from both the Royal College of General Practitioners’ study11 and the Oxford Family Planning Association contraception study16 also provide evidence that the risk of ischemic stroke is not significantly elevated among nonsmokers who used OC formulations containing ,50 mg EE. Two recent studies have confirmed the safety of formulations containing ,50 mg EE with respect to overall stroke risk in women with no major risk factors for CVD. Petitti and colleagues2 calculated the incidence of ischemic and hemorrhagic stroke in women aged 15 through 44 years who were enrolled in a large health maintenance organization. The data, which were adjusted for several risk factors (including treated hypertension, diabetes, and smoking status), indicate an incidence of ischemic stroke among current users of low-dose OCs of 5.4 per 100,000 womanyears; the incidence of hemorrhagic stroke was 5.6 per 100,000 woman-years. The adjusted odds ratio for ischemic stroke was 1.18 for current use of OCs versus 1.0 for noncurrent use; the odds ratio for hemorrhagic stroke was 1.14 for current use versus 1.0 for noncurrent use.2 Both risks were not statistically significant. These data are summarized in Table 2. Finally, WHO data14 also confirm that overall stroke risk is not significantly increased in healthy
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Table 2. Adjusted odds ratios for ischemic infarction and hemorrhagic stroke, according to oral contraceptive use Hemorrhagic stroke†
Ischemic infarction*
Variable Current use vs. noncurrent use Current use Noncurrent use‡ Current use vs. past use and no use§ Current use Past use No use‡ Any use vs. no use§ Any use No use‡
No. of women with stroke
No. of matched controls
OR (95% Cl)
No. of No. of women matched with stroke controls
17 125
43 335
1.18 (0.54–2.59) 1.00
21 127
50 346
1.14 (0.60–2.16) 1.00
14 82 28
43 271 64
0.65 (0.25–1.70) 0.49 (0.25–0.98) 1.00
14 81 14
50 272 74
1.02 (0.37–2.82) 0.89 (0.41–1.91) 1.00
96 28
314 64
0.52 (0.27–1.00) 1.00
95 14
322 74
0.91 (0.43–1.93) 1.00
OR (95% Cl)
The numbers of subjects in the adjusted analyses do not total the numbers shown in Table 2 because women with missing values were not included. OR denotes odds ratio, and Cl confidence interval. Current use denotes use in the month before the index date. Noncurrent use includes past use and no use. *Odds ratios have been adjusted for the presence or absence of treated hypertension, the presence or absence of treated diabetes, smoking status, race or ethnic group, and body-mass index. †Odds ratios have been adjusted for the presence or absence of treated hypertension, the presence or absence of treated diabetes, smoking status, and race or ethnic group. ‡Reference category. §Women for whom proxy respondents were interviewed have been excluded. Reproduced with permission from Petitti et al. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996;335:8 –15.
nonsmoking women using formulations containing ,50 mg EE. The odds ratio associated with current use of low-dose OCs was 1.41 (95% confidence interval, 0.90 to 2.20) in Europe, leading the authors to estimate that excess risk for all women using lowestrogen-dose formulations was, at most, 2 per 100,000 woman-years in this population. For women with no risk factors, the estimated attributable risk of stroke with OC use is, at most, about 0.5 per 100,000 woman-years. In summary, the excess risk of stroke among healthy, nonsmoking, normotensive women has been virtually eliminated since the EE dose was reduced below 50 mg.
of developing VTE three- to four-fold.19,20,22–25 This means that the annual risk of VTE in OC users is approximately 10 – 40 per 100,000. Although risk of VTE has declined as the estrogen dose has been reduced from 150 to 30 to 35 mg, the epidemiologic evidence to date provides no indication that the use of 20-mg EE formulations further reduces the risk of VTE. The authors of four recent studies who analyzed VTE risk associated with the progestin components of different formulations also reported values for VTE risk as a function of estrogen dose.19,20,26,27 As shown in Table 3, the risk associated with 30-mg formulations was consistently lower
Risk of Venous Thromboembolism
Table 3. VTE risk with 20 mg or 30 mg EE/DSG OCs
Venous thromboembolism (VTE) occurs more commonly than other cardiovascular disease in women during the childbearing years. Unlike stroke and MI, however, VTE is typically nonfatal and it rarely has lasting consequences unless it causes a pulmonary embolism.17,18 The baseline rate of VTE among healthy women of reproductive age who do not use OCs is approximately 4 –10 per 100,000 women per year.19 –22 Pregnancy increases the risk about 6 –15-fold: of every 100,000 pregnant women, approximately 60 will experience deep vein thrombosis or pulmonary embolism.21 High-estrogen-dose OC formulations increased VTE risk about ten-fold, and use of formulations containing ,50 mg EE increases the risk
Estrogen dose Study WHO Collaborative Study (WHO, 1995)* UK General Practice Research Database (Jick et al., 1995)† Transnational Study (Lewis et al., 1996)† UK MediPlus Database (Farmer et al., 1997)†
20 mg
30 mg
38.2
7.6
2.7
1.9
2.8
1.5‡
2.5
1.2‡
*Risk estimates relative to nonusers. †Risk relative to levonorgestrel (30 mg EE). ‡Not statistically significant. Data from World Health Organization (WHO)20; Jick et al.19; Lewis et al.26; and Farmer et al.27
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than that associated with OCs containing 20 mg EE. Because the number of cases was small and the between-group differences were not significant, it should not be inferred that 20-mg EE formulations are less safe than 30- to 35-mg pills with respect to VTE. As of now, however, there is no evidence which indicates that there is a lower risk of VTE with 20-mg compared with 30- to 35-mg formulations.
Progestins and VTE: The Evidence Does Not Support a Change in Prescribing Behavior The authors of four studies published since 1995 have suggested that use of formulations containing desogestrel or gestodene may increase the risk of VTE compared with levonorgestrel-containing agents,19,20,24,28 whereas a fifth study27 failed to show a statistically significant difference in VTE risk among users of these various formulations. Because there is good evidence that VTE risk is related to the estrogen component of OCs and that the progestin components have minor effects on clotting parameters, a biologically plausible explanation for these findings is lacking.5,20,26,27,29 It is probable that these results are due to prescribing bias and differences in duration of use—the so-called healthy long-term user bias.1,29,30,31 According to the US Food and Drug Administration, no change in prescribing practice with desogestrel-containing compounds is warranted at this time.32
Conclusions Now that virtually all women in the US use formulations containing ,50 mg EE, the threat of cardiovascular disease no longer overshadows the benefits of OCs. The excess risk of MI and stroke has been virtually eliminated among healthy, normotensive, nonsmoking OC users with no major risk factors. Moreover, the risk of VTE has been markedly reduced. Additional cardiovascular benefits from 20-mg EE formulations are theoretically possible, but no epidemiologic evidence for this finding has yet been published. It is important to note that the greatest risk of an arterial cardiovascular event comes from smoking while taking OCs.
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4. 5.
6.
7.
8. 9. 10.
11.
12.
13. 14.
15.
16. 17.
References 1. Carr BR, Ory H. Estrogen and progestin components of oral contraceptives: relationship to vascular disease. Contraception 1997;55:267–72. 2. Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel HK. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996;335:8 –15. 3. Sidney S, Petitti DB, Quesenberry CP Jr, Klatsky AL,
18.
19.
Ziel HK, Wolf S. Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol 1996;88: 939 – 44. Stergachis A. Epidemiology of the noncontraceptive effects of oral contraceptives. Am J Obstet Gynecol 1992;167:1165–70. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-mg oestrogen preparations. Br Med J 1980;280:1157– 61. Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraception study. Br Med J 1989;298:165– 8. Thorogood M, Mann J, Murphy M, Vessey M. Is oral contraceptive use still associated with an increased risk of fatal myocardial infarction? Report of a case-control study. Br J Obstet Gynaecol 1991;98:1245–53. Rosenberg L, Palmer JR, Lesko SM, Shapiro S. Oral contraceptive use and the risk of myocardial infarction. Am J Epidemiol 1990;131:1009 –16. Jick H, Jick SS, Myers MW, Vasilakis C. Risk of acute myocardial infarction and low-dose combined oral contraceptives (letter). Lancet 1996;347:627– 8. World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet 1997;349:1202–9. Hannaford PC, Croft PR, Kay CR. Oral contraception and stroke: evidence from the Royal College of General Practitioners’ oral contraception study. Stroke 1994;25: 935– 42. Longstreth WT, Nelson LM, Koepsell TD, Jan Belle G. Subarachnoid hemorrhage and hormonal factors in women: a population-based case-control study. Ann Intern Med 1994;121:168 –73. Thorogood M, Mann J, Murphy M, Vessey M. Fatal stroke and use of oral contraceptives: findings from a case-control study. Am J Epidemiol 1992;136:35– 45. World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996; 348:505–10. World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, casecontrol study. Lancet 1996;348:498 –505. Vessey MP, Lawless M, Yeates D. Oral contraceptives and stroke: findings in a large prospective study. Br Med J 1984;289:530 –1. Spitzer WO. Rebuilding confidence in oral contraceptives: a new imperative in family planning. Br J Clin Pharmacol 1996;41:359 – 63. Harlap S, Kost K, Forrest JD. Preventing Pregnancy, Protecting Health: A New Look at Birth Control Choices in the United States. New York: The Alan Guttmacher Institute, 1991. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contra-
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20.
21. 22.
23. 24.
25.
ceptives with differing progestagen components. Lancet 1995;346:1589 –93. World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582– 8. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynaecol 1995;15:195–200. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994;344:1453–7. Porter JB, Hunter JR, Jick H, Stergachis A. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1– 4. Spitzer WO, Lewis MA, Heinemann LAJ, et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Br Med J 1996;312:83– 8. Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 1991;133:32–7.
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26. Lewis MA, Heinemann LAJ, MacRae K, et al. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. Contraception 1996;54:5–13. 27. Farmer RDT, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997;349:83– 8. 28. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a thirdgeneration progestagen. Lancet 1995;346:1593– 6. 29. Lidegaard O, Milsom I. Oral contraceptives and thrombotic diseases: impact of new epidemiological studies (editorial). Contraception 1996;53:135–9. 30. Farmer RDT, Lawrenson R. Utilization patterns of oral contraceptives in UK general practice. Contraception 1996;53:211–5. 31. Jamin C, de Mouzon J. Selective prescribing of third generation oral contraceptives (OC). Contraception 1996;54:55– 6. 32. US Food and Drug Administration. Oral contraceptives and risk of blood clots. FDA Talk Paper T95-61. Rockville, MD; November 14, 1995.
Cardiovascular Safety of Oral Contraceptives What Has Changed in the Last Decade? Howard W. Ory Within the last 10 years, the cardiovascular safety record of oral contraceptives (OC) has improved dramatically. The excess risk of venous thromboembolism (VTE) has been reduced and OC use no longer has any meaningful impact on risk of myocardial infarction (MI) or stroke among healthy, nonsmoking women.1 What has changed in the last decade to produce these important developments? Current prescribing practices and careful patient selection are critical factors, and the information derived from epidemiologic studies has also contributed to the excellent safety record. Physicians deserve a major share of the credit for responding to the research findings and prescribing improved formulations as they became available. Formulations containing ,50 mg ethinyl estradiol (EE) today account for nearly all OC use in this country. Epidemiologic findings are consistent with these indicators: investigators have reported that among women enrolled in a large managed care organization, stroke and myocardial infarction (MI) is now exceedingly rare among users of OCs containing #35 mg EE.2,3 More precise and detailed epidemiologic risk estimates have clarified the importance of hypertension, smoking, and other factors in the etiology of cardiovascular disease (CVD), enabling providers to select appropriate candidates for OC use. Consequently, in the developed world, current users are women who are at low risk for CVD.2– 4
Myocardial Infarction As early as 1980, Meade and colleagues5 reported that use of formulations containing ,50 mg EE did not increase the risk of MI in nonsmoking women. Several studies have now confirmed this observation. Data from the Royal College of General Practitioners’ oral contraceptive study6 collected between 1968 and 1987 show that current use of OCs increased risk of Epidemiologic Consultant, Atlanta, Georgia Name and address for correspondance: Howard Ory, MD, Epidemiologic Consultant, 882 Barton Woods Rd., Atlanta, GA 30307
© 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
MI only among women who also smoked cigarettes. Thorogood and colleagues7 reported that relative risk of fatal MI among nonsmokers was not significantly increased by current OC use; compared with neverusers, the adjusted relative risk among current and past users considered together was 1.1 (95% confidence interval, 0.3 to 3.8). Past use of OCs also does not increase risk for MI after discontinuation among nonsmoking women without major risk factors for CVD.8 In a study examining the risk of MI associated with remote or recent past use (at least 5 years of use) of OC among such past users aged 25 to 64 years, the age-adjusted relative risk estimate compared with never-users was 1.2 (95% confidence interval, 0.7 to 2.2).8 Two large-scale studies have recently confirmed that combined formulations containing ,50 mg EE have a negligible impact on the risk of MI in women who do not have major risk factors for CVD.3,9 Sidney and colleagues3 conducted a population-based, casecontrol study to investigate the risk of MI in women aged 15 to 44 years. Odds ratios were calculated relative to noncurrent users, after adjusting for smoking, hypertension, body mass index, and other factors. As shown in Table 1, current use of low-estrogen-dose OCs does not significantly increase the risk of MI. On the basis of these data, these investigators stated that, at most, only 5% of MI in women of reproductive age—that is, less than 3 cases per 1 million womanyears— could be attributable to OC use. This study provided further evidence that women who use OCs tend to be selected for low levels of CVD risk factors: among the subjects in this population without MI, the prevalence of several risk factors for MI was lower in OC users than in nonusers. Jick and colleagues9 investigated acute MI risk in 303,470 women under age 45 with no known MI risk factors who had used or were using low-dose OCs containing levonorgestrel, desogestrel, or gestodene. They reported that there were no differences in acute MI risk among the formulations, nor between the groups of women who were current and past users. They concluded that the risk of acute MI in users of ISSN 0010-7824/98/$19.00 PII S0010-7824(98)00077-8
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Table 1. Adjusted odds ratios of myocardial infarction according to oral contraceptive use Variables Current or noncurrent use Current use† Noncurrent use Current or past use and no use Current use† Past use No use Any or no use Any use No use
Myocardial infarction odds ratio (95% Cl)* 1.67 (0.48, 5.85) 1.00 (referent) 1.14 (0.28, 4.72) 0.60 (0.25, 1.44) 1.00 (referent) 0.64 (0.27, 1.53) 1.00 (referent)
Cl 5 confidence interval. *Adjusted for treated hypertension (yes/no), treated diabetes (yes/no), treated/diagnosed high cholesterol (yes/no), smoking (current/occasional/ past), race or ethnicity (Hispanic/black/Asian/other/white), and body mass index (continuous). †Use in the month before the index date. Reproduced with permission of the American College of Obstetricians and Gynecologists from Sidney et al. Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol 1996;88:939 – 44.
low-dose OCs is low and mainly restricted to OC users who smoke cigarettes. World Health Organization (WHO) investigators also studied the relation between OC use and MI in an international, hospital-based, case-control study (368 cases and 941 controls).10 The WHO group found that the overall odds ratio for acute MI with OC use was 5.01 (95% confidence interval, 2.54 to 9.90) among European women and 4.78 (95% confidence interval, 2.52 to 9.07) among women in developing countries compared to age-matched non-OC users. In nonsmoking OC users, the relative risk among those who had their blood pressure measured was 1.10 (95% confidence interval, 0.12 to 9.69) in Europe and 1.10 (95% confidence interval, 0.09 to 12.9) in developing countries. For the European women under age 35 who were nonsmokers, the maximum estimated excess risk with OC use was about 3 per 100,000 womanyears, and the investigators stated that this risk would probably have been even lower if the women in this group had been screened for blood pressure abnormalities before and during OC use. In conclusion, excess risk of MI has been virtually eliminated by use of all OC formulations containing ,50 mg EE in nonsmoking, healthy, normotensive women.
Hemorrhagic and Ischemic Stroke Findings with respect to OC use and stroke risk parallel those on MI. There is no evidence that formulations containing ,50 mg EE significantly increase the risk of hemorrhagic stroke in nonsmok-
ers.2,11–13 Thorogood and colleagues13 reported that the adjusted relative risk of fatal subarachnoid hemorrhage associated with formulations containing ,50 mg EE was 1.1 (95% confidence interval, 0.6 to 1.9). Investigators with the WHO Collaborative Study14 also reported that overall risk of hemorrhagic stroke was only slightly increased with OC use; among European women risk was not significantly increased by OC use (odds ratio 1.38 [95% confidence interval, 0.84 to 2.25]), but the relative risk was significantly increased in developing countries (relative risk 1.76 [95% confidence interval, 1.34 to 2.30]). The risk was significantly increased, however, only among OC users who smoked or who had a history of hypertension compared to women with these risk factors who were not OC users. Data from WHO15 show that the overall risk of ischemic stroke was 2.99 (95% confidence interval, 1.65 to 5.40) in Europe and 2.93 (95% confidence interval, 2.15 to 4.00) in developing countries, with the risk being lower in all countries among OC users who did not smoke, and among those who did not have hypertension prior to their OC use. However, a history of hypertension among current OC users was associated with an odds ratio of 10.7 (95% confidence interval, 2.04 to 56.6) in European women and 14.5 (95% confidence interval, 5.36 to 39.0) in women in developing countries. Data from both the Royal College of General Practitioners’ study11 and the Oxford Family Planning Association contraception study16 also provide evidence that the risk of ischemic stroke is not significantly elevated among nonsmokers who used OC formulations containing ,50 mg EE. Two recent studies have confirmed the safety of formulations containing ,50 mg EE with respect to overall stroke risk in women with no major risk factors for CVD. Petitti and colleagues2 calculated the incidence of ischemic and hemorrhagic stroke in women aged 15 through 44 years who were enrolled in a large health maintenance organization. The data, which were adjusted for several risk factors (including treated hypertension, diabetes, and smoking status), indicate an incidence of ischemic stroke among current users of low-dose OCs of 5.4 per 100,000 womanyears; the incidence of hemorrhagic stroke was 5.6 per 100,000 woman-years. The adjusted odds ratio for ischemic stroke was 1.18 for current use of OCs versus 1.0 for noncurrent use; the odds ratio for hemorrhagic stroke was 1.14 for current use versus 1.0 for noncurrent use.2 Both risks were not statistically significant. These data are summarized in Table 2. Finally, WHO data14 also confirm that overall stroke risk is not significantly increased in healthy
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Table 2. Adjusted odds ratios for ischemic infarction and hemorrhagic stroke, according to oral contraceptive use Hemorrhagic stroke†
Ischemic infarction*
Variable Current use vs. noncurrent use Current use Noncurrent use‡ Current use vs. past use and no use§ Current use Past use No use‡ Any use vs. no use§ Any use No use‡
No. of women with stroke
No. of matched controls
OR (95% Cl)
No. of No. of women matched with stroke controls
17 125
43 335
1.18 (0.54–2.59) 1.00
21 127
50 346
1.14 (0.60–2.16) 1.00
14 82 28
43 271 64
0.65 (0.25–1.70) 0.49 (0.25–0.98) 1.00
14 81 14
50 272 74
1.02 (0.37–2.82) 0.89 (0.41–1.91) 1.00
96 28
314 64
0.52 (0.27–1.00) 1.00
95 14
322 74
0.91 (0.43–1.93) 1.00
OR (95% Cl)
The numbers of subjects in the adjusted analyses do not total the numbers shown in Table 2 because women with missing values were not included. OR denotes odds ratio, and Cl confidence interval. Current use denotes use in the month before the index date. Noncurrent use includes past use and no use. *Odds ratios have been adjusted for the presence or absence of treated hypertension, the presence or absence of treated diabetes, smoking status, race or ethnic group, and body-mass index. †Odds ratios have been adjusted for the presence or absence of treated hypertension, the presence or absence of treated diabetes, smoking status, and race or ethnic group. ‡Reference category. §Women for whom proxy respondents were interviewed have been excluded. Reproduced with permission from Petitti et al. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996;335:8 –15.
nonsmoking women using formulations containing ,50 mg EE. The odds ratio associated with current use of low-dose OCs was 1.41 (95% confidence interval, 0.90 to 2.20) in Europe, leading the authors to estimate that excess risk for all women using lowestrogen-dose formulations was, at most, 2 per 100,000 woman-years in this population. For women with no risk factors, the estimated attributable risk of stroke with OC use is, at most, about 0.5 per 100,000 woman-years. In summary, the excess risk of stroke among healthy, nonsmoking, normotensive women has been virtually eliminated since the EE dose was reduced below 50 mg.
of developing VTE three- to four-fold.19,20,22–25 This means that the annual risk of VTE in OC users is approximately 10 – 40 per 100,000. Although risk of VTE has declined as the estrogen dose has been reduced from 150 to 30 to 35 mg, the epidemiologic evidence to date provides no indication that the use of 20-mg EE formulations further reduces the risk of VTE. The authors of four recent studies who analyzed VTE risk associated with the progestin components of different formulations also reported values for VTE risk as a function of estrogen dose.19,20,26,27 As shown in Table 3, the risk associated with 30-mg formulations was consistently lower
Risk of Venous Thromboembolism
Table 3. VTE risk with 20 mg or 30 mg EE/DSG OCs
Venous thromboembolism (VTE) occurs more commonly than other cardiovascular disease in women during the childbearing years. Unlike stroke and MI, however, VTE is typically nonfatal and it rarely has lasting consequences unless it causes a pulmonary embolism.17,18 The baseline rate of VTE among healthy women of reproductive age who do not use OCs is approximately 4 –10 per 100,000 women per year.19 –22 Pregnancy increases the risk about 6 –15-fold: of every 100,000 pregnant women, approximately 60 will experience deep vein thrombosis or pulmonary embolism.21 High-estrogen-dose OC formulations increased VTE risk about ten-fold, and use of formulations containing ,50 mg EE increases the risk
Estrogen dose Study WHO Collaborative Study (WHO, 1995)* UK General Practice Research Database (Jick et al., 1995)† Transnational Study (Lewis et al., 1996)† UK MediPlus Database (Farmer et al., 1997)†
20 mg
30 mg
38.2
7.6
2.7
1.9
2.8
1.5‡
2.5
1.2‡
*Risk estimates relative to nonusers. †Risk relative to levonorgestrel (30 mg EE). ‡Not statistically significant. Data from World Health Organization (WHO)20; Jick et al.19; Lewis et al.26; and Farmer et al.27
12S
Ory
than that associated with OCs containing 20 mg EE. Because the number of cases was small and the between-group differences were not significant, it should not be inferred that 20-mg EE formulations are less safe than 30- to 35-mg pills with respect to VTE. As of now, however, there is no evidence which indicates that there is a lower risk of VTE with 20-mg compared with 30- to 35-mg formulations.
Progestins and VTE: The Evidence Does Not Support a Change in Prescribing Behavior The authors of four studies published since 1995 have suggested that use of formulations containing desogestrel or gestodene may increase the risk of VTE compared with levonorgestrel-containing agents,19,20,24,28 whereas a fifth study27 failed to show a statistically significant difference in VTE risk among users of these various formulations. Because there is good evidence that VTE risk is related to the estrogen component of OCs and that the progestin components have minor effects on clotting parameters, a biologically plausible explanation for these findings is lacking.5,20,26,27,29 It is probable that these results are due to prescribing bias and differences in duration of use—the so-called healthy long-term user bias.1,29,30,31 According to the US Food and Drug Administration, no change in prescribing practice with desogestrel-containing compounds is warranted at this time.32
Conclusions Now that virtually all women in the US use formulations containing ,50 mg EE, the threat of cardiovascular disease no longer overshadows the benefits of OCs. The excess risk of MI and stroke has been virtually eliminated among healthy, normotensive, nonsmoking OC users with no major risk factors. Moreover, the risk of VTE has been markedly reduced. Additional cardiovascular benefits from 20-mg EE formulations are theoretically possible, but no epidemiologic evidence for this finding has yet been published. It is important to note that the greatest risk of an arterial cardiovascular event comes from smoking while taking OCs.
Contraception 1998;58:9S–13S
4. 5.
6.
7.
8. 9. 10.
11.
12.
13. 14.
15.
16. 17.
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Ziel HK, Wolf S. Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol 1996;88: 939 – 44. Stergachis A. Epidemiology of the noncontraceptive effects of oral contraceptives. Am J Obstet Gynecol 1992;167:1165–70. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-mg oestrogen preparations. Br Med J 1980;280:1157– 61. Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraception study. Br Med J 1989;298:165– 8. Thorogood M, Mann J, Murphy M, Vessey M. Is oral contraceptive use still associated with an increased risk of fatal myocardial infarction? Report of a case-control study. Br J Obstet Gynaecol 1991;98:1245–53. Rosenberg L, Palmer JR, Lesko SM, Shapiro S. Oral contraceptive use and the risk of myocardial infarction. Am J Epidemiol 1990;131:1009 –16. Jick H, Jick SS, Myers MW, Vasilakis C. Risk of acute myocardial infarction and low-dose combined oral contraceptives (letter). Lancet 1996;347:627– 8. World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. Lancet 1997;349:1202–9. Hannaford PC, Croft PR, Kay CR. Oral contraception and stroke: evidence from the Royal College of General Practitioners’ oral contraception study. Stroke 1994;25: 935– 42. Longstreth WT, Nelson LM, Koepsell TD, Jan Belle G. Subarachnoid hemorrhage and hormonal factors in women: a population-based case-control study. Ann Intern Med 1994;121:168 –73. Thorogood M, Mann J, Murphy M, Vessey M. Fatal stroke and use of oral contraceptives: findings from a case-control study. Am J Epidemiol 1992;136:35– 45. World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996; 348:505–10. World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, casecontrol study. Lancet 1996;348:498 –505. Vessey MP, Lawless M, Yeates D. Oral contraceptives and stroke: findings in a large prospective study. Br Med J 1984;289:530 –1. Spitzer WO. Rebuilding confidence in oral contraceptives: a new imperative in family planning. Br J Clin Pharmacol 1996;41:359 – 63. Harlap S, Kost K, Forrest JD. Preventing Pregnancy, Protecting Health: A New Look at Birth Control Choices in the United States. New York: The Alan Guttmacher Institute, 1991. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contra-
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26. Lewis MA, Heinemann LAJ, MacRae K, et al. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. Contraception 1996;54:5–13. 27. Farmer RDT, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997;349:83– 8. 28. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a thirdgeneration progestagen. Lancet 1995;346:1593– 6. 29. Lidegaard O, Milsom I. Oral contraceptives and thrombotic diseases: impact of new epidemiological studies (editorial). Contraception 1996;53:135–9. 30. Farmer RDT, Lawrenson R. Utilization patterns of oral contraceptives in UK general practice. Contraception 1996;53:211–5. 31. Jamin C, de Mouzon J. Selective prescribing of third generation oral contraceptives (OC). Contraception 1996;54:55– 6. 32. US Food and Drug Administration. Oral contraceptives and risk of blood clots. FDA Talk Paper T95-61. Rockville, MD; November 14, 1995.