Oral contraceptives and myocardial infarction

Volume [63 I\:umber 4, Part 2

and may thereby directly retard atherogenesis, I I Although we have not yet studied effects of ethinyl estradiol on this process, it seems reasonable to speculate that it will be even more potent as an inhibitor of lowdensity lipoprotein uptake. Regardless of the mechanism, we conclude from our findings that contraceptive progestin-induced lowering of HDL is not atherogenic if a sufficiently potent estrogen is coadministered. The striking difference between the expected and observed outcome suggests a beneficial effect of ethinyl estradiol on the coronary wall. REFERENCES I. Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham Study. Ann Intern Med 1979;90:85-91. 2. Tikkanen MJ. Nikkila EA. Oral contraceptives and lipoprotein metabolism. J Reprod Med 1986;31:898-905. 3. Koritnik DR, Clarkson TB, Adams MR. Cynomolgus macaques as models for evaluating effects of contraceptive steroids on plasma lipoprotein and coronary artery atherosclerosis. In: Blye R, Gregoire A, eds. Contraceptive steroids: pharmacology and safety. New York: Plenum Press, 1986 :303-19.

Oral contraceptives, lipoproteins, and atherosclerosis

4. Hamm TE Jr, Kaplan JR, Clarkson TB, Bullock BC. Effects of gender and social behavior on the development of coronary artery atherosclerosis in cynomolgus macaques. Atherosclerosis 1983;48:221-33. 5. Adams MR, Kaplan JR, Clarkson TB, et a!. Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis 1985;5: 192-200. 6. Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks JS, Wolfe MS, Clarkson TB. Inhibition of coronary artery atherosclerosis by 17 -beta estradiol in ovarectomized monkeys: lack of an effect of adding progesterone. Arteriosclerosis (in press). 7. Adams MR, Clarkson TB, Koritnik DR, Nash HA. Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques. Ferti! Steril 1987;47: 1010-8. 8. Clarkson TB, Shively CA, Morgan TM, Korill1ik DR, Adams MR, Kaplan JR. Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys. Obstet Gynecol 1990;75:217-22. 9. Mishell DR Jr. Use of oral contraceptives in women of older reproductive age. AM .I OBSTET GY:-JECOL 1988; 158:1652-7. 10. Stampfer MJ, Willett WC, Colditz GA, Speizer FE, Hennekens CH. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N EnglJ Med 1988;319:1313-7. II. Wagner JD, Clarkson TB, St. Clair RW, Schwenke DC, Adams MR. Estrogen replacement therapy and coronary artery atherogenesis in surgically postmenopausal monkeys [Abstract]. Circulation 1989;80:II-331.

Oral contraceptives and myocardial infarction Ian H. Thorneycroft, PhD, MD New Orleans, Louisiana The risk of myocardial infarction in contraceptive users is limited to women over 35 years of age who smoke. The cause of myocardial infarction in oral contraceptive users is thrombotic and not atherosclerotic. Minor lipid changes have no clinical relevance to myocardial infarction in contraceptive pill users and do not appear to increase coronary plaques. (AM J OSSTET GVNECOL 1990;163:1393-7.)

Key words: Myocardial infarction, oral contraceptives A number of both case-control and prospective studies have examined the relationship between oral contraceptives and myocardial infarction. A thorough review of this epidemiologic evidence is not the purpose of this article. I The most recent analyses of the Royal College of General Practitioners' Study are reviewed in detail, as are potential mechanisms by which oral contraceptives could cause myocardial infarction. Particular attention is paid to the relevance of lipid studies.

From the Department of Obstetrics and Gynecology, Tulane University. Reprint requests: Ian H. Thorne.veroft, PhD, MD, Department of Obstetrics and G,vneeology, Universit), of South Alabama, 2451 Fillingim St., Mobile, AL 36617.

610122640

Epidemiology

Early retrospective studies demonstrated approximately a fourfold increase in myocardial infarction in women ingesting oral contraceptives. More recent studies and several prospective studies have not come to the same conclusion. I The 1981 analysis of the prospective Royal College of General Practitioners' Study" found an increased risk for myocardial infarction in women ingesting oral contraceptives only if they were over the age of 35 years and smoked. The Oxford Family Planning Study' found no association with current or past use of oral contraceptives in the analysis of their data published in 1987. They also noted that smokers were at increased risk. The Puget Sound and the Kaiser Walnut Creek studies in the United States failed to confirm an associated risk. I.' 1393

1394 Thorneycroft

October 1990 Am J Obslet Gynecol

Table III. Relative risk of major coronary disease among past users of oral contraceptives based on time since last use

Table I. Royal College of General Practitioners' data: Factors increasing relative risk of myocardial infarction 95% confidence internal

Relative risk

Oral contraceptive use Never Previous Current Smoking Nonsmoker <15 cigarettes/day >15 cigarettes/day Toxemia Hypertension Diabetes

1.0 1.0 1.8

0.7-1.6 0.9-3.6

1.0 1.7 4.3 2.8 2.4 6.9

1.1-2.7 2.6-6.9 1.7-4.8 1.4-4.1 1.1-43.8

Data from Croft P, Hannaford PC. Br Med j 1989;298: 165-8.

Table II. Risk factors for myocardial infarction and use of oral contraceptives Oral contraceptive use Risk factor

Hypertension No Yes Toxemia No Yes Cigarettes Never <151day >15/day

Never

Current

1.0 5.4*

1.5 2.6*

2.0* 7.7*

1.0 2.6*

1.3 4.0*

2.0 3.2*

1.0 2.0 3.3*

1.1 1.3 4.3*

0.9 3.5* 20.8*

Data from Croft P, Hannaford Pc. Br Med j 1989;298: 165-8. *Significant rise.

The most recent analysis of the data of the Royal College of General Practitioners' Study by Croft and Hannaford6 identified several factors that increase the relative risk of myocardial infarction in young women (Table I). Neither current nor past oral contraceptive users had an increased risk of myocardial infarction. Although current users had a 1.8 times relative risk, the 95% confidence interval includes 1.0. Smoking was a significant risk factor for myocardial infarction. Smoking < 15 cigarettes a day led to a 1.7-fold increased risk and> 15 cigarettes a day led to a 4.3-fold increased risk. A history of toxemia, hypertension, or diabetes was also a significant risk factor for myocardial infarction. The data were also analyzed to determine if oral contraceptive use further increased the other known risks of myocardial infarction (Table II). Hypertension and toxemia were again associated with myocardial in-

Time since last use (yr)

Never used <1 1-3 3-5 5-10 10-15 >15

95% confidence internal

339 I

8 8 33 54 18

1.0 0.3 0.7 0.6 0.7 1.2 1.0

0.1-2.2 0.3-1.5 0.3-1.2 0.5-1.0 0.9-1.6 0.7-1.4

Data from Stampfer Mj, Willett WC, Colditz GA, Speizer FE, Hennekens CH. N Engl j Med 1988:319:1313-7. Reprinted by permission of the New England Journal of Medicine.

farction, but there were no differences among never, former, and current oral contraceptive users. The confidence intervals were wide. More data are needed on any potential interaction between oral contraceptives and hypertension, toxemia, diabetes, and abnormal baseline lipid studies. Current use of oral contraceptives, in combination with smoking> 15 cigarettes a day, had the highest high relative risk for myocardial infarction. Oral contraceptive use amplified the risk associated with smoking. These data expand those previously published by the Royal College of General Practitioners, which demonstrated that the real risk factor for myocardial infarction in women using oral contraceptives is smoking. Pills of <50 Ilg have not been associated with any myocardial infarctions. 3 The differences between early studies and recent analyses are that the early studies did not control for smoking and patients smoking < 15 cigarettes a day were classified as nonsmokers. If the rate of myocardial infarction was as great as originally estimated (fourfold increase), then mortality studies would clearly show an increased rate of death from ischemic heart disease or myocardial infarction after the introduction of oral contraceptives. Fig. 1 illustrates such data from the United Kingdom. 7 After the introduction of oral contraceptives, cardiovascular disease declined slightly and ischemic heart disease was stable. Therefore no relationship could be found between the introduction of oral contraceptives and heart disease.

Causes of myocardial infarction Possible causes of myocardial infarction in women ingesting oral contraceptives include increased atherogenesis, increased coronary thrombosis, and coronary artery spasm. The belief that increased atherosclerosis may cause myocardial infarction is derived from the cholesterol hypothesis. Elevated total and low-density lipoprotein

Oral contraceptives and myocardial infarction

Volume 163 Number 4, Part 2

OC sales, millions 50 40

1395

Rate per 100000

Prepill era

30

10

20

8

6 4

10

2

o~~~--~~~--~~--~--~~--~--~~

195658

60

62

64

66

68

70

72

74

76

78

Fig. 1. Mortality rates in women, ages 15 to 44 years inclusive, per 100,000 population in England and Wales for cerebrovascular disease (CVD) and ischemic heart disease (IHD). ac, Oral contraceptive. (From Wiseman RA, MacRae KD. Fertil Steril 1981;35:277-83. Reproduced with permission of the publisher, The American Fertility Society.)

Table IV. Relative risk of mcUor coronary disease among past users of oral contraceptives based on duration of use Duration of use (yr)

None <1 1-3 3-5 5-10 <10

No. of cases

Relative risk

95% confidence interval

339 45 32 20 25 10

1.0 1.0 1.0 1.0 0.8 0.7

0.7-1.4 0.7-1.4 0.6-1.7 0.5-1.2 0.4-1.2

Data from Stampfer Mj, Willett WC, Colditz GA, Speizer FE, Hennekens CH. N Englj Med 1988;319:1313-7. Reprinted by permission of the New England Journal of Medicine.

(LDL) cholesterol or decreased high-density lipoprotein (HDL) cholesterol are atherogenic and associated with an increased rate of myocardial infarction. Progestins present in oral contraceptives lower HDL and raise LDL cholesterol; all estrogens have the opposite effect. Older, high-dose progestin oral contraceptive preparations were associated with what could be interpreted as adverse changes in lipid profiles. B The lipid profile depends on the balance between the estrogen and progestin components. Modern low-dose oral contraceptives are not associated with clinically significant lipid changes." If the mechanism of action of oral contraceptives in increasing myocardial infarction is related to lipid changes, then the following findings should be evident: (1) Past use of oral contraceptives should increase myocardial infarction. (2) The rate of myocardial infarction should increase with increased duration of use. (3) Oral contraceptives should be associated with adverse lipid profiles. (4) These adverse lipid changes should translate into increased coronary artery atherosclerosis. (5) Patients ingesting preparations with adverse lipid changes or a high progestin content should have a higher myocardial infarction

rate. (6) Autopsy and angiographic studies should show premature and extensive coronary atherosclerosis. Table III, which is adapted from the Nurses Health Study, 10 clearly demonstrates that women who used oral contraceptives in the past have no increased risks of myocardial infarction. Nine other studies have demonstrated that past use of oral contraceptives is not associated with an increased rate of myocardial infarction.!O One study showed a small subset at increased risk ll ; however, Stampfer et al.!O were not able to confirm that this subset was at greater risk. Table IV illustrates that duration of use also was not related to the incidence of myocardial infarction. Lipid changes in women ingesting oral contraceptives have been the subject of many publications. Fig. 2 illustrates LDL and HDL levels from selected oral contraceptives from the study of Wahl et al. B The vast majority of values from women ingesting oral contraceptives are well within the normal range and unlikely to be atherogenic, even though their mean values may be changed. Whether adverse lipid changes noted with oral contraceptive use translate into coronary atherosclerosis is

1396 Thorneycroft

October 1990 Am J Obstet Gynecol

:J ~

0'1

g

.!!l CD

~

...J

C

...J

220 200 180 160 140 120 100

80 60 40 20 O+-~--~~--~-r-

ON NOR OV OEM OVU

ON NOR OV OEM OVU

Contraceptive Fig. 2. LDL and HDL levels of selected oral contraceptives (mean ± 2 SOl. ON, Ortho-Novum, norethindrone + mestranol; NOR, Norlestrin, norethindrone acetate + ethinyl estradiol; OV, Ovral, norgestrel + ethinyl estradiol; DEM, Demulen, ethynodiol diacetate + ethinyl estradiol; OVU, OVlllen, ethynodiol diacetate + mestranol. (Data from Wahl P, Walden C, Knopp R, et al. N Engl] Med 1983;30:862-7.)

a difficult question to answer. The elegant cynomolgus macaque studies are reviewed in Adams' presentation in this symposium.' 2 . 13 Briefly, significant lipid changes were induced in macaque monkeys given oral contraceptive preparations that lowered HDL and raised LDL cholesterol. These lipid changes induced by oral contraceptives did not translate into increased atherogenesis. In fact, the macaque monkeys ingesting oral contraceptives had fewer coronary plaques than did control animals. Such an experiment is not possible in women. However, Engel et al. 14 analyzed coronary angiograms in 76 young women who had suffered a myocardial infarction. Forty-two women used oral contraceptives and 34 did not. Thirty-six percent of women using oral contraceptives had diffuse atherosclerosis, whereas the 79% not using oral contraceptives had diffuse atherosclerosis. Clearly, women undergoing myocardial infarction while taking oral contraceptives did not have atherosclerotic myocardial infarction. Numerous autopsy studies have shown that myocardial infarction in women ingesting oral contraceptives was thrombotic and not atherosclerotic. 14 Some lipid studies have demonstrated that high-dose levonorgestrel-containing oral contraceptives have the more unfavorable lipid profile. This is not true for all studies. Comparisons between progestins are difficult, because unequivalent doses of progestin and estrogen are usually compared. It is the dose of the progestin and not the specific progestin that affects lipid levels. Croft and Hannaford 's were unable to find any evidence or examination of their data base to support the hypothesis that levonorgestrel increases the risk of

myocardial infarction over other progestins. The relative risk was 0.55 for levonorgestrel and 1.24 for other progestins. The confidence intervals both included 1.0. These differences were not significant. One study showed a dose-response curve between myocardial infarction and [he dose of progestin. '6 However, patients did not take the various progestin doses in the same time span. Those patients who ingested the higher doses were probably older, since these were the older preparations. The increased rate of myocardial infarction may simply be the result of the patient's age. Comment

Myocardial infarctions are extremely rare events in women ingesting oral contraceptives and are usually limited to women over the age of 35 years who smoke. Women who are hypertensive, diabetic, or have a history of toxemia have a higher rate of myocardial infarction. Women with hypertension and toxemia are no more likely to have myocardial infarction if they are ingesting oral contraceptives; however, the confidence limits are large. The risk for persons with diabetes ingesting oral contraceptives is unknown. The mechanism of action for myocardial infarction in women ingesting oral contraceptives is not atherosclerotic but thrombotic or possibly spasm. Accelerated atherosclerosis is not a characteristic feature in patients with myocardial infarction who use oral contraceptives. Minor lipid changes, noted mainly with oral contraceptives with a high progestin content, may be statistically significant but without clinical significance. It is too simplistic and invalid to extrapolate to oral contra-

Volume 163 !\umber 4, Part 2

ceptive data from epidemiologic studies examining the role of cholesterol in myocardial infarction in men. As Adams et al. demonstrated in their contribution to this symposium, the estrogen component in birth control pills may directly protect the coronary arteries from such atherosclerosis by inhibiting the entry of LDL cholesterol into blood vessel walls. REFERENCES I. Realini ]P, Goldzieher ]W. Oral contraceptives and cardiovascular disease: a critique of the epidemiologic studies. AM] OBS1'ET GY~ECOL 1985;152:729-98. 2. Royal College of General Practitioners' oral contraceptive study. Further analysis of mortality in oral contraceptive users. Lancet 1981; I :541. 3. Mant D, Villard-Mackintosh L, Vessey MP, Yeates D. Myocardial infarction and angina pectoris in young women. ] Epidemiol Commun Health 1987;41:215-9. 4. Petitti DB, Wingerd], Pellegrin F, Ramcharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens and other factors. J AMA 1979;242: I J 50-4. 5. Porter ]B, lick H, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32. 6. Croft P, Hannaford Pc. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' oral contraception study. Br Med ] 1989;298:165-8. 7. Wiseman RA, MacRae KD. Oral contraceptives and the decline in mortality from circulatory disease. Ferti! Steri! 1981 ;35:277-83.

Oral contraceptives and myocardial infarction

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8. Wahl P, Walden e, Knopp R, et al. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl] Med 1983;308:862-7. 9. Notelovitz M, Feldman EB, Gillespy M, Gudat]. Lipid and lipoprotein changes in women taking low-dose, triphasic oral contraceptives: a controlled, comparative, 12month clinical trial. AM ] OIlS1'ET GYNECOL 1989; 160: 1269-80. 10. Stampfer M], Willett we, Colditz GA, Speizer FE, Hennekens CH. A prospective study of past use of oral contraceptive agents and risk of cardiovascular disease. N EnglJ Med 1988;319:1313-7. II. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl] Med 1981 ;305:420-4. 12. Adams MR, Clarkson TB, Koritnik DR, Nash HA. Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques. Ferti! Steril 1987;47:1010-8. 13. Clarkson TB, Adams MR, Kaplan JR, Shively CA, Koritnik DR. From menarche to menopause: coronary artery atherosclerosis and protection in cynomolgus monkeys. AM] OBSTET GYNECOL 1989; 160: 1280-5. 14. Engel H-], Engel E, Lichtlen PRo Coronary atherosclerosis and myocardial infarction in young women-role of oral contraceptives. Eur Heart] 1983;4: 1-8. IS. Croft P, Hannaford P. Risk factors for acute myocardial infarction in women [Letter]. Br Med] 1989;298:674. 16. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30 fJ-g oestrogen preparations. Br IVIed] 1980;280: 1157-61.