Thrombosis and the New Progestins Several studies found increased risk of venous thrombosis when users of OCs containing the newer progestins desogestrel or gestodene combined with 20 to 30 μgof EE were compared with users of levonorgestrel combined with the same doses of estrogen (115). A controversy resulted. It is likely that the biases “attrition of susceptibles,” “adverse selection,” and “healthy user bias” explain the apparent increase in thrombosis. Most cases of venous thrombosis attributable to OCs occur during the initial months of use (116). Comparing new users to women already taking OCs for some time without incident will demonstrate an apparent increase with the new product that is artificial. Physicians may presume that newer drugs are safer and prescribe them selectively for women with risk factors. Additional studies have not resolved this controversy. Heinemann and colleagues found no difference in thrombosis risk in users of OCs containing desogestrel or gestodene compared to users of OCs with other progestins in a large study of cases occurring between 2002 and 2006 in Austria (139). In contrast, both Lidegaard’s group in Sweden and van Hylckama Vlieg’s group in the Netherlands reported increased risk with the newer progestins (130,140).
Ischemic Heart Disease Ischemic heart disease and stroke were the major causes of death attributed to OC use in the past. It is known that the principal determinants of risk are advancing age and cigarette smoking (141). With the higher-dose OCs used in the 1980s, smoking had a profound effect on risk. Women smoking 25 or more cigarettes per day had a 30-fold increased risk for myocardial infarction if they used OCs, compared with nonsmokers not using OCs (142). Use of OCs is became safer because most women are taking low-dose pills and because physicians prescribe selectively, excluding women with major cardiovascular risk factors. A very large study in the United States confirmed the safety of OCs as currently prescribed. A total of 187 women aged 15 to 44 years with confirmed myocardial infarction were identified during 3.6 million woman-years of observation in the Kaiser Permanente Medical Care Program in California from 1991 to 1994. This is a rate of 3.2 per 100,000 woman-years (143). Nearly all of the users took OCs with less than 50 μgof EE. After adjusting for age, illness, smoking, ethnicity, and body mass index, risk for myocardial infarction was not increased by OC use (odds ratio [OR], 1.14; 95% CI, 0.27–4.72). Of heart attack victims, 61% smoked; only 7.7% were current users of OCs. In a later study, the same investigators pooled results from the California study with a similar study from Washington State. The results were the same. Current users of low-dose OCs had no increased risk for myocardial infarction after adjustment for major risk factors and sociodemographic factors (144). Past use of OCs does not increase risk for subsequent myocardial infarction (145). These observations are supported by another population-based prospective study. OC use and myocardial infarction were studied prospectively among 48,321 randomly selected women aged 30 to 49 in the Uppsala Health Care Region of Sweden (146). There was no association between current or past OC use and myocardial infarction. Most current users were taking low-dose estrogen pills (defined as less than 50 μg of ethinyl estradiol or less than 75 μgof mestranol) with second or third generation progestins, more than half were aged 35 or older, and 26% were current cigarette smokers.