Oral Contraceptives and the Progestin Controversy
By Leon Speroff, MD
In october 1995, the united kingdom committee on Safety of Medicines sent a letter to all U.K. physicians and pharmacists stating that women taking oral contraceptives containing desogestrel or gestodene should be urged to complete their current cycle and to continue a formulation with these progestins only if prepared to accept an increased risk of venous thromboembolism. The Committee on Safety of Medicines took this action because of observational studies that indicated a two-fold increase in the risk of venous thromboembolism when desogestrel- and gestodene-containing contraceptives were compared to products with other progestins (mostly levonorgestrel).1-4 This action and the studies upon which it was based immediately became controversial. The controversy went beyond the validity of the epidemiologic data. The publicity surrounding these events reverberated throughout Europe, leading to an immediate overall decrease in oral contraceptive use, an increase in unwanted pregnancies, and an increase in induced abortions.5,6 The controversy involving new progestin oral contraceptives began in late 1995, continued through 1996, and began to reach resolution in 1997. The fundamental question is whether oral contraceptives containing desogestrel and gestodene have a different risk of thrombosis when compared with oral contraceptives containing older progestins.
Is there still a risk of venous thromboembolism with the current low-dose formulations of oral contraceptives? In the first years of oral contraception, the available products, containing 80 mg and 100 mg ethinyl estradiol (a very high dose), were associated with a six-fold increased risk of venous thrombosis. Because of the increased risks for venous thrombosis, myocardial infarction, and stroke, lower dose formulations (< 50 mg estrogen) came to dominate the market, and clinicians became more careful in their screening of patients and prescribing of oral contraception. Therefore, two forces were simultaneously at work to bring greater safety to women using oral contraception: 1) the use of lower dose formulations; and 2) the avoidance of oral contraception by high-risk patients. The new studies also reflect the importance of these two forces, but they still indicate an increased risk.
An immediate problem with the initial studies was how to reconcile the results with the conventional wisdom that thrombosis is an estrogen dose-related complication. Furthermore, progestational agents, and desogestrel and gestodene in particular, have no significant effect on clotting partners.7 Therefore, there was inherent biologic implausibility surrounding the new studies.
Former users discontinue oral contraceptives for a variety of reasons and are often switched to what clinicians perceive to be "safer" products (preferential prescribing). Individuals who do well with a product tend to remain with that product. Thus, at any time, individuals on an older product will be relatively healthy and free of side effects (healthy user effect). This is also called attrition of susceptibles because higher risk individuals with problems are gradually eliminated from the group.8 Comparing users of older and newer products, can, therefore, involve disparate cohorts of individuals.
Because desogestrel- and gestodene-containing products were marketed as less androgenic and, therefore, "better" (a marketing claim not substantiated by epidemiologic studies), clinicians chose to provide these products to higher risk patients and older women.9,10 In addition, clinicians switched patients perceived to be at greater risk for thrombosis from older oral contraceptives to the newer formulations with desogestrel and gestodene. Furthermore, these products were prescribed more often to young women who were starting oral contraception for the first time (these young women will not have experienced the test of pregnancy or previous oral contraceptive use to help identify those who have a congenital predisposition to venous thrombosis). These changing practice patterns exert different effects over the lifetime of a product, and analytical adjustments are extremely difficult. The Transnational Group believes it accomplished an appropriate adjustment by focusing on first-time users and duration of use.11 It is also unlikely that the healthy user effect will be dominant in first-time users. This analysis found no differences between second- and third-generation oral contraceptives.
The challenge for a clinician is to make a decision: Is an observational study with statistically significant results clinically (biologically) real? This controversy illustrates how difficult this can be. When faced with results from observational studies, clinicians want to see uniformity, consistency, and agreementall arguing in favor of a real clinical effect. Examples are the protective effect of oral contraceptives on the risk of ovarian cancer, the benefits of postmenopausal estrogen therapy on the risk of ovarian cancer, and the benefits of postmenopausal estrogen therapy on cardiovascular disease. The initial studies were impressive in their agreement. All of these studies indicated increased relative risks associated with desogestrel and gestodene compared to levonorgestrel. Nevertheless, all of the early studies (somewhat similar in design) were influenced by the same unrecognized biases. Persistent errors will produce consistent conclusions.
It is now clear that the apparent differences associated with the new progestins were due to two major factors: 1) the marketing and prescribing of new products; and 2) the characteristics of the patients for whom the new products were prescribed. Most impressive and important is that there is no evidence of an increase in mortality due to venous thromboembolism since the introduction of new progestin oral contraceptives.12,13
Several European centers have argued that screening for the Factor V Leiden mutation should be routine prior to prescribing contraceptives. The carrier frequencies of the Leiden mutation in the American population (the percentages are similar in men and women) are as follows:14 Caucasian Americans, 5.27%; Hispanic Americans, 2.21%; Native Americans, 1.25%; African Americans, 1.23%; and Asian Americans, 0.45%.
These estimates are consistent with the European assessments, indicating that this is a trait carried in people of European origin. In the United States, of the 10 million women currently using oral contraceptives, about 423,000 women are likely to carry the Factor V mutation. However, because the incidence rate of venous thromboembolism is so low (4-5 per 100,000 young women per year),14,15 the number of women required to be screened to prevent one death is tremendously large. Furthermore, because only a small number of women even with the Leiden mutation have a clinical event, the finding of a positive screening test would be a barrier to the use of oral contraceptives, and a subsequent increase in unwanted pregnancies would likely follow. Most experts believe that screening for the Leiden mutation should only be pursued in women with a previous episode of venous thromboembolism or a positive family history for venous thrombosis.
Does the reduced androgenicity of the new progestins ultimately have a protective effect on arterial thrombosis? Older studies could not detect increased risks of acute myocardial infarction among current users of oral contraceptives, except in women who smoked, and especially in smokers older than age 35. A series of new studies now provides an assessment of acute myocardial infarction and stroke in users of low-dose oral contraceptives.16-21
This outpouring of epidemiologic data in the last few years allows the construction of a clinical formulation that is evidence-based. The following conclusions are consistent with the recent reports:
• Pharmacologic estrogen increases the produc- tion of clotting factors.
• Progestins have no significant effect on clot- ting factors.
• Past users of oral contraceptives do not have an increased incidence of cardiovascular disease.
• All low-dose oral contraceptives, regardless of progestin type, have an increased risk of venous thromboembolism. The actual risk of venous thrombosis with low-dose oral contraceptives is lower in the new studies compared to previous reports. Some have argued that this is due to preferential prescribing and the healthy user effect. However, it is also logical that the lower risk reflects better screening of patients and lower estrogen doses.
• Smoking has no effect on the risk of venous thrombosis. Smoking and estrogen have an additive effect on the risk of arterial thrombosis. Why is there a difference between venous and arterial clotting? The venous system has low flow with a state of high fibrinogen and low platelets, in contrast to the high flow state of the arterial system with low fibrinogen and high platelets. Thus, it is understandable why these two different systems can respond in different ways.
• Hypertension is an important additive risk factor for stroke in oral contraceptive users.
• Low-dose oral contraceptives (< 50 mg ethinyl estradiol) do not increase the risk of myocardial infarction or stroke in healthy, non- smoking women, regardless of age.
• Almost all myocardial infarctions and strokes in oral contraceptive users occur in users of high- dose products, or users with cardiovascular risk factors who are older than age 35.
• Arterial thrombosis (myocardial infarction and stroke) has a dose-response relationship with the dose of estrogen, but there are insufficient data to determine whether there is a difference in risk with products that contain 20 mg, 30 mg, or 35 mg ethinyl estradiol.
The recent studies reinforce the belief that the risks of arterial and venous thrombosis are a consequence of the estrogen component of combination oral contraceptives. Current evidence does not support an advantage or disadvantage for any particular formulation, except for the greater safety associated with any product containing less than 50 mg ethinyl estradiol. Although it is logical to expect the greatest safety with the lowest dose of estrogen, the rare occurrence of arterial and venous thrombosis in healthy women makes it unlikely that there will be any measurable differences in the attributable incidence of clinical events with all low-dose products.
The new studies emphasize the importance of good patient screening. The occurrence of arterial thrombosis is essentially limited to older women who smoke or have cardiovascular risk factorsespecially hypertension. The effect of good screening is evident in the repeated failure to detect an increase in mortality due to myocardial infarction or stroke in several studies.12,22 Although the risk of venous thromboembolism is slightly increased, the actual incidence is still relatively rare, and the mortality rate is about 1% (probably less with oral contraceptives, because most deaths from thromboembolism are associated with trauma, surgery, or a major illness). The minimal risk of venous thrombosis associated with oral contraceptive use does not justify the cost of routine screening for coagulation deficiencies.
If a patient has a family history or a previous episode of idiopathic thromboembolism, an evaluation to search for an underlying abnormality in the coagulation system is warranted.23 The following measurements are recommended, and abnormal results require consultation with a hematologist regarding prognosis and prophylactic treatment: antithrombin III, protein C, protein S, activated protein C resistance ratio, activated partial thromboplastin time, hexagonal activated partial thromboplastin time, anticardiolipin antibodies, fibrinogen, prothrombin G mutation (DNA test), thrombin time, homocysteine level, and complete blood count.
A DNA-based test can be used to verify the presence of the Factor V Leiden mutation. Other risk factors for thromboembolism that should be considered by clinicians include an acquired predisposition such as the presence of lupus anticoagulant or malignancy and immobility or trauma. Varicose veins are not a risk factor unless they are very extensive.24
Combination oral contraception is contraindicated in women who have a history of idiopathic venous thromboembolism and in women who have a family history of idiopathic venous thromboembolism. These women will have a higher incidence of congenital deficiencies in important clotting measurements, especially antithrombin III, protein C, protein S, and resistance to activated protein C.25
The conclusion once again is that low-dose oral contraceptives are very safe for healthy, young women. By effectively screening for the presence of smoking and cardiovascular risk factors (especially hypertension) in older women, we can limit, if not eliminate, any increased risk for arterial disease associated with low-dose oral contraceptives. And, it is very important to emphasize that there is no increased risk of cardiovascular events associated with duration (long-term) use.
References
1. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995; 346:1582-1588.
2. Spitzer WO, et al, on behalf of the Transnational Research Group on Oral Contraceptives and the Health of Young Women. Br Med J 1996;312:83-88.
3. Jick H, et al. Lancet 1996;348:981-983.
4. Bloemenkammp KWM, et al. Lancet 1995;348:1593-1596.
5. Child TJ, et al. Lancet 1996;347:1260-1261.
6. Skjeldestad FE. Contraception 1997;55:11-14.
7. Speroff L, DeCherney A. Obstet Gynecol 1993;81: 1034-1047.
8. Lewis MA, et al. Contraception 1996;54:5-13.
9. Heinemann LAJ, et al. Pharmacoepidemiol Drug Saf 1996;5:285-294.
10. Jamin C, de Mouzon J. Contraception 1996;54:55-56.
11. Suissa S, et al. Contraception 1997;56:141-146.
12. Jick H, et al. Lancet 1995;348:1589-1593.
13. Farmer R, Lewis M. Lancet 1996;348:1095.
14. Ridker PM, et al. JAMA 1997;277:1305-1307.
15. Vandenbroucke JP, et al. Br Med J 1996;313: 1127-1130.
16. Petitti DB, et al. N Engl J Med 1996;335:8-15.
17. Sidney S, et al. Obstet Gynecol 1996;88:939-944.
18. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1996; 348:498-505.
19. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1996;348:505-510.
20. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1997;349:1202-1209.
21. Lewis MA, et al, for the Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception 1997;56:129-140.
22. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995;346:1575-1582.
23. Vandenbroucke JP, et al. Lancet 1994;344: 1453-1457.
24. Royal College of General Practitioners. J Roy Coll Gen Pract 1978;28:393-399.
25. Pabinger I, Schneider B, and the GTH Study Group. Thromb Haemost 1994;5:548-552.
The following statements are all false regarding the association between oral contraceptives and thrombosis (arterial and venous) except:
a. Smoking is a risk factor for myocardial infarctions, stroke, pulmonary embolism, and deep vein thrombosis.
b. Low-dose oral contraceptives containing older second generation progestins do not have an increased risk of venous thromboembolism.
c. Unsuspected hypertension is a major risk factor for myocardial infarction and stroke in patients on low-dose oral contraceptives.
d. Most women with a Leiden factor V mutation will havee a thrombotic event while taking oral contraceptives.
e. Estrogen increases the risk of myocardial infarction with all pharmacologic doses used in oral contraceptives.
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