###  a. Myocardial infarction

An increased risk of myocardial infarction has been attributed to combined oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current combined oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with combined oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40   
(Figure 3) among women who use combined oral contraceptives.

Figure 3. Circulatory Disease Mortality Rates per 100,000 Woman Years by Age, Smoking Status and Combined Oral Contraceptive Use 

Combined oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Combined oral contraceptives have been shown to increase blood pressure among users (see Section 10 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Combined oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

###  b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of combined oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to combined oral contraceptives is not related to length of use and disappears after combined oral contraceptive pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of combined oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, combined oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, combined oral contraceptives should be started no earlier than 4 to 6 weeks after delivery in women who elect not to breastfeed.

###  c. Cerebrovascular disease

Combined oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used combined oral contraceptives, 2.6 for smokers who did not use combined oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The attributable risk is also greater in older women.

###  d. Dose-related risk of vascular disease from combined oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in combined oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of a combined oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of a combined oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular combined oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of combined oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient.

###  e. Persistence of risk of vascular disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of combined oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing combined oral contraceptives persists for at least 9 years for women 40 to 49 years who had used combined oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of combined oral contraceptives, although excess risk was very small. However, both studies were performed with combined oral contraceptive formulations containing 50 mcg or higher of estrogens.