Department of Haematology and Clinical Epidemiology, Leiden University Medical Center, Building 1, C9-P P.O. Box 9600, Leiden 2300, The Netherlands
* Tel.: +31-71-5264037; fax: +31-71-5266994
E-mail address: b.tanis{at}planet.nl
The risk of arterial thrombosis in relation to oral contraceptives (RATIO) study investigated the association between currently used oral contraceptives and myocardial infarction, according to the type of progestagen, oestrogen dose, and the presence of prothrombotic mutations (factor V Leiden and prothrombin G20210A mutation). In this nationwide population-based case-control study 248 women with a first myocardial infarction between 1990 and 1995 were compared with 925 control women without a cardiovascular event. Control women were identified through random digit dialing and they were stratified for age, calendar year of myocardial infarction and the area of residence. Information on oral contraceptive use and cardiovascular risk factors was acquired by standardized questionnaires. Current use was defined as use in the month before the indexdate. Current oral contraceptive use (all types) was associated with a 2-fold increased risk (95% confidence interval (CI) 1.52.8) of myocardial infarction when compared with non-users. The adjusted odds ratio was 2.5 (95% CI 1.54.1) for second generation oral contraceptives and 1.3 (95% CI 0.72.5) for third generation oral contraceptives. The odds ratios did not differ between the 30 and 50µg ethinyl-oestrodiol containing oral contraceptives. Among women who used oral contraceptives and had additional risk factors, the risk of myocardial infarction increased to 6.1-fold (95% CI 3.112.1) for hypertensive oral contraceptive users, 13.6-fold (95% CI 7.923.4) for smoking oral contraceptive users, 17.4-fold (95% CI 3.198.1) for diabetic oral contraceptive users, and 24.7-fold (95% CI 5.6108) for hypercholesterolaemic oral contraceptive users. The odds ratio did not differ for those without or with a prothrombotic mutation (factor V Leiden or prothrombin G20210A).
1. Background
Shortly after the introduction of oral contraceptives in the 1960s, myocardial infarction was found to be associated with oral contraceptive use. Although the association was widely recognized, a clear understanding of its mechanisms and pathophysiology has remained elusive for more than 40 years. Hormonal contents of combined oral contraceptives have changed during the last decades with the aim of reducing the risk of cardiovascular disease. The oestrogen dose has been reduced to 2030µg ethinyl-oestradiol, the so-called low-dose formulations, and new progestagens have been developed to minimize the androgen adverse effects. Among the studies on the association between myocardial infarction and oral contraceptives, a few publications focussed on these currently available low-dose oral contraceptives, and found that the overall estimated risk increased by about 2-fold relative to non-users.14 Among women with major classical risk factors for myocardial infarction who used low-dose oral contraceptives the risk was much higher.5
Many epidemiological studies on myocardial infarction have led to well-established risk factors, such as smoking, hypertension, diabetes mellitus, hypercholesterolaemia, and obesity. These risk factors, however, do not explain all occurrences of cardiovascular events, so it has been suggested that other factors, such as coagulation factors may play a role in the pathogenesis. A large number of coagulation factors are influenced by oral contraceptive use, whose changes are usually within normal ranges.6 Both activation of procoagulant and inhibition of anticoagulant factors have been found, in addition to an increase in fibrinolytic activity.7 Since the identification of the factor V Leiden mutation, which leads to resistance to activated protein C, it became clear that interaction between genetic and environmental factors, such as oral contraceptive use, plays a crucial role in the occurrence of thrombotic disease.8 During oral contraceptive use the risk of venous thrombosis is increased 4-fold in women without factor V Leiden, but the risk rises to 3050-fold in carriers of the factor V Leiden mutation. For myocardial infarction the role of coagulation factors is less clear.9 Although several studies have been published on the association between genetic risk factors and myocardial infarction, studies are limited by their sample size, which was often insufficient to establish the risk of single polymorphisms in a multifactorial disease.10,11
2. Oral contraceptives as a risk factor for myocardial infarction
Studies have indicated that women who take the oral contraceptive pill have an increased risk of myocardial infarction, but there is sparse information available on the association between the newer low-dose oral contraceptives and the risk of myocardial infarction. The overall estimated risk associated with low-dose oral contraceptive use increased by 2-fold. Thus far, five studies have presented a direct comparison of third and second generation oral contraceptives on the risk of myocardial infarction.15 There are only two large studies, the MICA and the risk of arterial thrombosis in relation to oral contraceptives (RATIO) study that compared the risk of myocardial infarction between second and third generation oral contraceptives. The comparison of third generation oral contraceptives versus no use in the MICA study showed an increased odds ratio (OR 1.96, 95% CI 0.874.39). A precision-weighted pooled estimate of these two studies yielded an odds ratio for third generation oral contraceptives versus no use of 1.70 (95% CI 1.052.76), indicative of an increased risk of myocardial infarction for third generation oral contraceptives. A precision-weighted pooled odds ratio for third versus second generation oral contraceptives was 0.81 (95% CI 0.441.51). Taken together, these two studies do not give a definite conclusion whether third generation oral contraceptives increase the risk of myocardial infarction differently than second generation oral contraceptives. An aggregation of the data including the smaller studies showed a slightly lower risk of myocardial infarction for third compared with second generation oral contraceptives,12 but these studies had heterogeneous designs with respect to the selection of the patients and controls.
The absolute risk of myocardial infarction rises steeply at older ages leading to increasing excess deaths, particularly in smokers.13 The part of the world the women live in determines the duration of oral contraceptive use. In the US, women tend to stop using oral contraceptives after bearing children, and thus before they are at risk for myocardial infarction. However, in The Netherlands 25% of women older than 35 years still use an oral contraceptive pill. In recent studies from the US, the current low-dose oral contraceptive use was not associated with myocardial infarction.14,15 It has been suggested that the different prescription habits, with more caution in the US could explain the lower risk of myocardial infarction associated with oral contraceptives. No interaction was found with major cardiovascular risk factors in the study by Sydney et al., but in the study by Rosenberg a synergistic effect was found between heavy smoking of cigarettes and current oral contraceptive use.
In the pathogenesis of myocardial infarction two processes can be identified: the formation of an atherosclerotic plaque and the formation of an occluding arterial thrombus. Past oral contraceptive use does not increase or decrease the risk of myocardial infarction,3,4,15 nor did duration of use.3,5 Given these findings, it can be hypothesized that atherosclerosis does not play an important role in the mechanism by which oral contraceptives increase the risk of myocardial infarction.
3. Clinical implications
What do the findings of the RATIO study mean for the prescription of currently available oral contraceptives? It is important to be aware of the presence of conventional cardiovascular risk factors and women's age when prescribing an oral contraceptive pill. Smoking is by far the most important risk factor for myocardial infarction, therefore women should be encouraged to quit smoking. For women who continue to smoke, oral contraceptive use should not be continued after age 35 and an alternative contraceptive method should be recommended. In addition, combined oral contraceptive users with hypertension appear to be at increased risk of myocardial infarction and stroke relative to users without hypertension.3,16 Blood pressure measurement has to be assessed before prescription of combined oral contraceptive, but it should also be continued during oral contraceptive use to ensure that it stays within the normal range because even after prolonged use blood pressure can increase, probably due to age-related blood pressure increase.17 Although there are numerous studies which reported on glucose and lipid levels during oral contraceptive use in young healthy users, there are no data available on the risk of myocardial infarction in diabetic or hypercholesterolaemic oral contraceptive users.18 A careful prescription is therefore warranted and women with these special conditions should be checked more frequently. Because in recent epidemiologic studies the risk of venous thrombosis was found to be higher for third generation oral contraceptives than for second generation oral contraceptives,19 third generation oral contraceptives should not be the first choice in new users. Finally, a personal history of a thrombotic event is a contra-indication for using oral contraceptives.
Since 1995 the influence of coagulation abnormalities, such as factor V Leiden and prothrombin G20210A mutation, has been investigated with varying outcomes. Most studies did not find an increased risk of myocardial infarction in the presence of prothrombotic mutations.20 Positive associations between prothrombotic mutations and the risk of myocardial infarction were found among patients with normal angiographies,21 and particularly in smokers and patients with other cardiovascular risk factors.2224 In conclusion, routine screening of all new users of combined oral contraceptives for coagulation abnormalities is not justified with respect to arterial disease.
References