Oral Contraceptives and Heart Attack

British Medical_Journal, 1975, 2, 245-248
Oral Contraceptives and Death from Myocardial Infarction
We investigated 219 deaths from myocardial infarction in women under the age of 50. Their histories were compared with those of living age-matched controls selected from the same general practices. The frequency of use of oral contraceptives during the month before death was significantly greater in the group with infarction than during the corresponding month in the control group and the average duration of use was longer. No information on cigarette smoking was available but the proportion of women being treated for hypertension or diabetes was greater among those who died than among the controls. This did not alter the overall conclusion that the risk of fatal myocardial infarction was greater in the women using oral contraceptives, particularly in the older age groups.

Br Med J. 1976 August 21; 2(6033): 445–447.
Oral contraceptive use in older women and fatal myocardial infarction.
J I Mann, W H Inman, and M Thorogood
A previous study of women who had died from myocardial infarction and of a control group of women matched with them for age suggested a fivefold increase in the risk of death from myocardial infarction among users of oral contraceptive aged 40-44 years compared with women not using such preparations. Only a small proportion of women in the infarction and control groups had used oral contraceptives, however, so the margin of error was wide. We therefore investigated a further 54 women in this age group who died from myocardial infarction and compared their oral contraceptive histories with those of age-matched, living controls. Combination of the findings from the present investigation with the previous results have enabled a revised estimate of a threefold increase in risk to be made. Although this risk estimate is similar to that previously shown for a younger age group, the total mortality attributable to complications associated with the use of oral contraceptives remained considerably greater among women over the age of 40.

Br Med J. 1975 May 3;2(5965):241-5.
Myocardial infarction in young women with special reference to oral contraceptive practice.
Mann JI, Vessey MP, Thorogood M, Doll SR.
Sixty-three women discharged from hospital with a diagnosis of myocardial infarction and 189 control patients were studied. All were under 45 years of age at the time of admission. Current oral contraceptive use, heavy cigarette smoking, treated hypertension and diabetes, pre-eclamptic toxaemia, and obesity were all reported by, and type II hyperlipoproteinaemia was found more often in, patients with myocardial infarction than their controls. The relationship between myocardial infarction and oral contraceptives could not be explained in terms of an association between the use of these preparations and the other factors. The combined effect of the risk factors was clearly synergistic.

A retrospective study of 84 women under age 45 years suffering myocardial infarction. These patients were found in the records of 24 hospitals is presented. 16 died in the hospital; 5 died subsequently; of the remaining 50 showed definite evidence and 13 possible evidence of myocardial infarction. Suitable controls were selected from patients with other disorders. Patients were interviewed in their homes, some additional information was supplied by the medical practitioner; and fasting blood samples were obtained from some at more than 6 months after the infarction. The proportion of patients who had used oral contraceptives during the month before admission was significantly higher among infarction patients than among controls (p less than .001). The relative risk was estimated as 4.5 to 1. The proportion of those who had ever used oral contraceptives was higher (p less than .01). Cigarette smoking was reported more often by patients with infarction than by controls. A higher ratio of patients with infarction than controls had been treated for hypertension, diabetes, preeclampsia, and obesity. Blood lipids were examined in 44 patients and 84 controls. Mean levels of serum cholesterol and serum triglycerides were definitely higher in patients who had had infarctions. The estimated yearly hospital admission rate for nonfatal myocardial infraction is 2.1 per 100,000 married women aged 30-39 years who do not use oral contraceptives and 5.6 per 100,000 for married women of this age who do. In the 40-44 year age group the rates are 9.9 and 56.9 per 100,000 respectively. Risk estimates suggest that the combined effects of factors is synergistic. When other risk factors exist, different methods of contraception are advised.

N Engl J Med. 1975 Jul 24;293(4):195-6.
Editorial: Oral contraceptives and myocardial infarction.
Shapiro S.
Studies done in the United Kingdom suggest a correlation between ora l contraceptive (OC) use and increased risk of myocardial infarction (MI ). A study of 153 women under 50 years of age who died of MIs as compar ed with a control group of the same age and marital status showed a significant association between OC use and MI which became stronger with increasing age: e.g., risks for the 30-39 and 40-44 year-old groups were 2.8 and 4.7 respectively. Another study involving 63 MI survivors between 25 and 44 years of age compared with a similar control group showed a strongly positive association: 29% of the patients and 8% of the controls used OCs and risks for the 30-39 and 40-44 year old groups were 2.7 and 5.7 respectively. The risk in OC users was 4.5 times greater than in nonusers. Other risk factors such as diabetes, cigarett e smoking and obesity also have a positive association with MI. Only one of 17 OC users at the time of MI had no other identified risk factor . When ranked according to the number of risk factors present (includin g OCs) risks relative to women in whom none were present were 4.2 for 1 factor, 10.5 for 2 factors and 78.4 for 3 or more factors. These estimates suggest that in women under 45 years of age, OCs act synergist ically with other risk factors rather than additively, to produce MI. Stroke, also identified, did not appear as a result of a synergistic relationship between OC and other risk factors comparable to that found in relation to MI. Further study is needed but estimated incidence rates of fatal and nonfatal MI attributable to OC use are each about 3.5 per 100,000 30-39 year old users per year and each about 45 per 100,000 40-44 year old users per year. Women with more than 1 risk factor for MI should consider alternative methods of contraception. Those women who do use OCs regularly, especially older women, should be followed closely and advised against OC continuation.

Am J Obstet Gynecol. 1990 Jul;163(1 Pt 2):382-7.
Effects of oral contraceptives on carbohydrate and lipid metabolisms in a healthy population: the Telecom study.
Simon D, Senan C, Garnier P, Saint-Paul M, Garat E, Thibult N, Papoz L.
In a cross-sectional study that aimed to identify risk factors for diabetes, 1290 consecutive, healthy, nonpregnant women of child-bearing age were examined in a center for preventive medicine. An in-depth interview about menses, use of oral contraceptives, and menopause was performed. Plasma glucose at fasting and 2 hours after a 75 gm glucose load, glycated hemoglobin A1c, fasting plasma insulin, total plasma cholesterol, and triglycerides were measured. Compared with nonusers taking no progestogens, oral contraceptive users (n = 431; 33.4%) were younger (p less than 0.001) and leaner (p less than 0.001). After adjustment for age and body mass index, oral contraceptive users had higher 2-hour plasma glucose (p less than 0.001), higher fasting plasma insulin (p less than 0.01), and higher triglycerides levels (p less than 0.01). Fasting plasma glucose, glycated hemoglobin A1c, and total cholesterol did not significantly differ between the two groups. In relation to dosage and types of steroid components, few differences have been found between high-dose and low-dose oral contraceptives or according to the estrogen-progestogen balance of the preparations. Use of oral contraceptives appears to induce an increase of insulin-resistance markers, which have recently been cited as risk factors for ischemic vascular diseases. These markers should be carefully monitored in oral contraceptive users.

Free Radic Biol Med. 1991;10(5):325-38.
Oxidative status and oral contraceptive. Its relevance to platelet abnormalities and cardiovascular risk.
Ciavatti M, Renaud S.
Oral contraceptive (OC) use is a risk for thrombogenic events. This paper reviews effects of OC on oxidative status, coagulation, and platelet activity. Complicating effects of cardiovascular risk factors such as smoking, diabetes, hyperpidemia, and hypertension, are discussed. From these data we conclude that: 1. OC use modifies slightly but significantly the oxidative status in women and in animals by decreasing in plasma and blood cells the antioxidant defenses (vitamins and enzymes). 2. The changes in the oxidative status are related to an increase in plasma lipid peroxides apparently responsible for the hyperaggregability and possibly the imbalance in clotting factors associated with the OC-induced prethrombotic state. 3. These effects of OC appear to be increased by a high intake of polyunsaturated fat and counteracted by supplements of vitamin E. 4. The risk factors acting synergistically with OC, have all been shown to increase platelet reactivity. In addition, smoking, diabetes, and, to some extent, dyslipidemia are associated with an increased level of lipid peroxides and concomitant changes in the antioxidant defenses that can be additive to those induced by OC. Thus, free radicals and lipid peroxidation could be the underlying mechanism in the predisposition to thrombosis induced by most risk factors in OC users. 5. Results of epidemiologic and experimental studies in this field will be concordant only when diet and natural antioxidants will be systematically taken into consideration.

Although any cardiovascular complications of combined oral contraceptive (OC) use have dramatically increased in the past decade, both as a result of lower dosages (under 50 mcg) of estrogen in newer OCs and the recommendation that this method be used only by nonsmokers under 35 years of age, there remains a need to deepen understanding of the mechanisms involved. The increased levels of estrogen in OCs, associated with free radical generation, lead to a disruption in oxidative status. Further deterioration occurs when other risk factors (smoking, diabetes, or nutritional insufficiency) that also induce the production of free radicals and promote lipid peroxidation are present. The increase in plasma lipid peroxides appears to be responsible for the hyperaggregability and imbalance in clotting factors associated with the OC-induces thrombotic state. This hyperaggregability is modulated in OC users by the intake of polyunsaturated fat and antioxidants. Key to the avoidance of thrombotic events in OC users is the screening out of potential acceptors with risk factors such as smoking that act synergistically with OCs. Determination of platelet reactivity should be considered in questionable cases. Since vitamin E has been shown to improve platelet reactivity and oxidative status in OC users, its addition directly to the pill should be considered as a preventive measure. Now that the link between thrombogenic mechanisms and lipid peroxidation has been established, research should be undertaken to separate the estrogenic from the free radical-inducing properties of OCs.

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