ORAL CONTRACEPTIVES

Risks
The risk of cardiovascular disease among women attributed to the use of oral contraceptives became immediately apparent following the use of these agents more than 40 years ago. The risk was alarming in women older than age 30 who smoked cigarettes. The use of third generation oral contraceptives is purported to have a lower risk of myocardial infarction compared with second generation oral contraceptives. Recent studies do not indicate that third generation contraceptives possess a lower risk for infarction and most important, the studies indicate a significantly increased risk for deep vein thrombosis (DVT) and pulmonary embolism compared with users of second generation contraceptives. Because the risk for myocardial infarction in women before age 35 is extremely low, studies are confounded.

The risk of heart attack has not been minimized by the use of third generation oral contraceptives. Cigarette smoking continues to be the major factor for increased risk of heart attacks in older, childbearing women aged 33–45 and second or third generation contraceptives increase that risk. Most important, the increased risk for DVT and thromboembolism has not been removed.

1. Increased Coagulation Factors
The identification of a poor anticoagulant response to activate protein C (aPC) has far reaching consequences and has provoked new directions in the field of prothrombotic markers. Individuals with aPC resistance have inadequate partial thromboplastin time (PTT) prolongation which increases hypercoagulability. The PTT gives a measure of clotting factors except the factor caused by prothrombin. Normal levels of PTT range from 30 to 40
seconds. When heparin, the well-known intravenous anticoagulant, is administered to thin the blood the PTT goal is set at 1.5–2.3 times the mean control range, which corresponds to a PTT of 50–80 seconds. At these levels some clots are partly dissolved and further clotting is prevented.

Most important, aPC resistance occurs more frequently with DVT as seen from two studies. This incidence is considerably higher than that observed with well-known coagulation protein deficiencies which include protein C at 3%, protein S at 4%, antithrombin at 2%, and plasminogen at 1%. Normally, a specific amount of aPC added to plasma causes a calculated prolongation of the PTT, but in patients with aPC resistance inadequate PTT prolongation is observed.

The factor V Leiden mutation is an important risk for DVT. In a case control study of premenopausal women who developed DVT, the risk of thrombosis among users of oral contraceptives was increased fourfold. The risk for DVT was eightfold among carriers of the factor V Leiden versus noncarriers. Women with the factor V Leiden mutation who used oral contraceptives had a 30-fold increase in risk.

2. Deep Vein Thrombosis
The phenotype of aPC resistance is associated with a single point mutation, designated factor V Leiden in the factor V gene. Factor V Leiden mutation results from a single nucleotide substitution of adenine for guanine 1691. Thus, the amino acid arginine is replaced with glutamine at position 506. This unfortunate change eliminates the protein C cleavage site in factor V. The frequency of this mutation was found to be about 3% in healthy male
physicians in the United States and did not appear to increase the risk of stroke or heart attack in the Physicians Health Study. But the incidence of the factor V mutation was observed to be three times higher among men who developed DVT. Thus coagulation and clotting in veins of the lower limbs and pelvis and veins that drain into the right atrium is a different phenomenon from that observed in the coronary arteries supplying the heart with blood
and the branches of the aorta that circulate blood to the head and lower limbs. A good example is set forth by the proved fact that aspirin and other antiplatelet agents are useful in preventing clots in the coronary arteries and in the prevention of strokes, but they are of little or no value in the prevention of clot formation in the veins of the lower limbs.

Thus it is advisable to screen for factor V Leiden in women older than age 35 who take oral contraceptives. This advice is particularly important if there is concomitant hypertension, hyperlipidemia, cigarette smoking, or a family history of DVT.

3. Myocardial Infarction
Second and third generation oral contraceptives generally contain a small dose of synthetic estrogen and a synthetic progestin. The risk of myocardial infarction is currently believed to be low, but the risk is increased in women older than age 35 and in those with hypertension, hyperlipidemia, and in those who are cigarette smokers.

The estrogenic contents of the pill modestly increases good cholesterol HDL levels, lowers LDL cholesterol (bad) levels, and mildly increases serum triglycerides. The progestin component increases LDL levels, causes a decrease in HDL levels, and may increase coagulopathy. Agents such as desogestrel, gestodene, norgestimate, and norethindrone may have modest beneficial effects on lipoprotein levels, but they are associated with an increase in DVTand thromboembolism which includes pulmonary embolism.

4. Hypertension
Although second and third generation oral contraceptives rarely cause an increase in blood pressure in younger women, in those over 35 a mild increase in blood pressure that returns to normal has been observed. The incidence of increased blood pressure is low, but it is increased in individuals who are overweight or who have had hypertension in previous pregnancies, and perhaps in those who abuse alcohol. In rare instances blood pressure may accelerate rapidly and cause renal damage. Thus, caution is necessary and adequate follow up is essential. In addition, plasma insulin levels are increased reflecting peripheral insulin resistance, a harbinger for subtle cardiovascular damage.

Clinical Study: Tanis et al.
Methods: This study consisted of 248 women who had a first myocardial infarction and were identified and enrolled in a nationwide population-based case control study and 925 control women who had not had a heart attack and  who were matched for age and calendar year of the index event. Subjects supplied information on all contraceptive use and cardiovascular risk factors.
Results: The alteration for heart attack among women who used any type of combined oral contraceptive as compared with nonusers was 2.0. The adjusted alteration was 2.5 among women who used second generation and 1.3 among those who used third generation oral contraceptives.
Conclusions: The authors of the study concluded: ‘‘the risk of myocardial infarction was increased among women who used second generation oral contraceptives. Results with respect to use of third generation oral contraceptives were inconclusive but suggested that the risk was lower than the risk associated with second generation oral contraceptives.’’

Perspective

Although the majority of patients with a heart attack in the study quoted above were between the age of 35 and 49 (72%), only 74 patients with acute myocardial infarction were using oral contraceptives and 134 were not. The wide confidence interval observed in the study highlights the low statistical power of the study and indicates that random variation is an alternative explanation for the results.