Annotations
The
pill and
circulatory
disease
Two large prospective studies in the United Kingdom recently reported that women who had taken the pill were more likely to die from a wide range of circulatory diseases.‘-” The larger of the studies, the Oral Contraception Study of the Royal College of General Practitioners (RCGP), has been monitoring the health and oral contraceptive use of approximately 46,000 British women since 1968.‘. ’ In this study, the death rate from circulatory disease was five times greater in women who had taken the combined type of pill than in those who had never taken it. The excess mortality rate from circulatory disease among pill users is not an unexpected finding. It was foreshadowed by earlier case-control studies,“-’ by analyses of time trends of cardiovascular mortality in young women,* and by reports of the physiological and metabolic changes associated with pill use.fl-‘l What is important about the two recent studies is that, because they are prospective in design, many of the criticisms that can be directed at retrospective studies do not apply. As well as confirming the findings of other researchers, there are several new observations from these studies. The first is that the pill seems to be associated with an increased risk of a wide range of circulatory conditions. The excess deaths among the pill takers included conditions such as rheumatic and congenital heart diseases, malignant hypertension, cardiomyopathy, subarachnoid hemorrhage, and mesenteric artery thrombosis-as well as the more familiar conditions such as ischemic heart disease and thromboembolic disease. It is interesting that pulmonary embolism made only a minor contribution to the excess deaths. Of the 33 deaths from circulatory disease in women who had taken the pill, only one was from pulmonary embolism, but 12 were from ischemic heart disease and 10 were from subarachnoid hemorrhage. Also in the RCGP study the duration of pill use was found to affect the risk of circulatory disease: women who had taken the pill continuously for more than 5 years had an ageadjusted death rate from circulatory disease double that of women who had taken it for a shorter period. There was also some evidence-although based on small numbers and therefore tentative-that the excess mortality rate associated with pill use may persist even after it has been discontinued. The prospective studies provide the first direct measure of the size of the risk associated with pill use. Clearly this is important for public health considerations. In the RCGP study, women who had used the pill experienced an over-all excess mortality rate from circulatory disease of approximately 1 death per 5,000 pill-users per year. The mortality rate from non-circulatory diseases was similar in both groups. These findings relate predominantly to women taking combined pills which contain 50 pg of estrogen. The excess mortality rate from circulatory diseases was considerably greater than was previously estimated.‘? It was greater than the death rate from accidents in British women of comparable age, and it was greater than the death rate in the study
0002~8703/79/020263
+ 02$00.20/O
6 1979 The
C. V. Mosby
Co.
population from complications of pregnancy in those who had never taken the pill. The excess death rate increased with age and with cigarette consumption. Retrospective studies have indicated that hypertension and hypercholesterolemia may also increase the death rate.’ Unfortunately the role of these factors cannot be assessed from the prospective studies. One major problem in the interpretation of these findings remains. Women who take the pill differ from those who do not. Had they not taken the pill, would they still have developed similar circulatory disease? Available evidence indicates that they probably would not-but we can only speculate about this. We do know that pill users are less likely than non-users to have a past history of myocardial infarction, stroke, hypertension, rheumatic or congenital heart disease, diabetes or other vascular disease’. “; they are less obese”; and they take fewer medications.” Thus there is no evidence to support the claim that the excess mortality rate among pill users may be accounted for by the pill being selectively prescribed for sick women (as a safer alternative to pregnancy). Indeed the reverse seems to be true. We also know that women who take the pill tend to smoke more than women who do not take the pill.‘, ’ The differences in cigarette consumption are not large, however. The comparisons in the RCGP study adjusted for differences between the two groups in past health, smoking habits, age, parity, and social class. The fivefold increase in the mortality rate among pill users was found after these adjustments. Little is known about the personality or behavioral characteristics of pill users. Still less is known about the effect of personality on circulatory disease risk in women. Nevertheless it seems most improbable that differences in personality could account for the large excess of circulatory disease observed in women who had taken the pill, since the relative risk associated with type A behaviour pattern is reported to be only twofold,‘” compared with the fivefold difference noted with pill use. It has also been suggested that pill users may drink more alcohol than non-users.“’ The association between alcohol consumption and heart disease is unclear, but it has been claimed that it may reduce the risk.‘; It therefore seems reasonable to conclude that differences in personality or behavior between pill users and never users would probably have a minor effect on their differential risks of circulatory disease. Moreover, it is not clear whether such differences would increase or decrease the risk of circulatory disease in pill takers. With these recent reports there remains little doubt that the pill has widespread effects on the circulatory system. The consistency of the evidence from a wide variety of sources is most persuasive. In the light of all these findings the Royal College of General Practitioners and the Royal College of Obstetricians and Gynaecologists have suggested to British doctors that renewed caution should prevail when prescribing
American
Heart
Journal
263
Annotcrtions
the pill.” They suggest that women aged 35 years and older should consider the adoption of an alternative method of contraception, and that women aged 30 to 34 should do so if they smoke or have taken the pill for 5 years or longer. Valerie Beral, M.B., M.R.C.P. Department of Medical Statistics and Epidemiology London School of Hygiene and Tropical Medicine Keppel St. (Gower St.) London WClE 7HT Clifford Kay, C.B.E., M.D., Ph.D., F.R.C.G.P. RCGP Oral Contraception Study 8 Barlow Moor Road Manchester M20 OTR England
7.
8.
9.
10.
11.
REFERENCES
1. 2.
3. 4.
5.
6.
Royal College of General Practitioners: Mortality among oral contraceptive users, Lancet 2:727, 1977. Vessey, M. P., McPherson, K., and Johnson, B.: Mortality among women participating in the Oxford/Family planning contraceptive study, Lancet 2:731, 1977. Beral, V., and Kay, C.: Mortality in women on oral contraceptives, Lancet 2:1276, 1977. Royal College of General Practitioners: Oral contraception and health, London, 1974, Sir Isaac Pitman & Sons, Ltd. Inman, W. H. W., and Vessey, M. P.: Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of childbearing age, Br. Med. J. 2:193, 1968. Collaborative group for the study of stroke in young women: An epidemiologic study of oral contraception and cerebrovascular disease, N. Engl. J. Med. 288:871, 1973.
Cardiomyopathy
and
coronary
artery
The word “cardiomyopathy” means a pathological state affecting the myocardium. In the affluent western societies by far the commonest basis to pathological changes in the myocardium is coronary artery disease, but this is not described as cardiomyopathy. Neither is this name usually given to myocardial disease due to rheumatism, thyrotoxicosis, congenital lesions, or syphilis. In general, cardiomyopathy implies myocardial disease without known cause. Goodwin and associates’ (1961) proposed the following definition “A subacute or chronic disorder of heart muscle of unknown or obscure etiology, often with associated endocardial, and sometimes with pericardial, involvement, but not atherosclerotic in origin.” On the other hand, cardiomyopathy is sometimes employed with a qualifying adjective which does indicate an etiology. Examples are alcoholic, diabetic, nutritional, and infective cardiomyopathy, though the last named is more often described as “myocarditis.” Many patients with coronary artery disease give no history of angina pectoris or of cardiac infarction, have no unequivocal ECG evidence of coronary artery disease, and present with congestive cardiac failure. Such patients are therefore often wrongly thought to have idiopathic cardiomyopathy. Raftery,
264
February,
1979,
Vol.
97, No.
2
12. 13. 14.
15.
16. 17.
18.
Mann, J. I., and Inman, W. H. W.: Oral contraceptive and death from myocardial infarction, Br. Med. J. 2:247, 1975. Beral, V.: Cardiovascular disease mortality trends and oral contraceptive use in young women, Lancet 2:1047, 1976. Weir, R. J., Briggs, E., Mack, A., Taylor, L., Browning, J., Naismith, L., and Wilson, E.: Blood pressure in women after one year in oral contraception, Lancet 1:467, 1971. Mason, B., Oakley, N., and Wynn, V.: Studies of carbohydrate and lipid metabolism in women developing hypertension on oral contraceptives, Br. Med. J. 3:317, 1973. Littler, W. A., Bojorges-Buerio, R., and Banks, J.: Cardiovascular dynamics in women during menstrual cycle and on oral contraceptives, Thorax 29:567, 1974. Vessey, M. P., and Doll, R.: Is “the pill” safe enough to continue using? Proc. R. Sot. Lond. B. 195:69, 1976. Fisch, I. R.. and Freedman, S. H.: Smoking, oral contraceptives and obesity, J.A.M.A. 234:500, 1975. Rabin, D. I., and McCarthy, P.: Social and health related characteristics of women using oral contraceptives, Preventive Med. 3:268, 1974. Roseman, R. H., Brand, R. J., Jenkins, C. D., Friedman, M., Strauss, R., and Wurm, M.: Coronary heart disease in the Western Collaborative Group Study. Final followup experience of 8% years, J.A.M.A. 8:872. 1975. Haack, D. G., and McKean, H. E.: Mortality associated with the pill, Lancet 2:1024, 1977. Yano, K., Rhoads, G. G., and Kagan, A.: Coffee, alcohol and risk of coronary heart disease in Japanese-Americans, N. Engl. J. Med. 297:405. 1977. Kuenssberg, E. V., and Dewhurst, J.: Mortality in women on oral contraceptives, Lancet 2:757, 1977.
disease Banks, and Oram’ described four patients in which the diagnosis was changed from idiopathic cardiomyopathy to occlusive coronary artery disease after coronary arteriography (which revealed severe obstructive disease) in three patients and after necropsy (which revealed gross cardiomegaly with severe, diffuse atheromatous coronary artery disease) in the fourth. Because of this diagnostic difficulty a Lancet editorial (1977)’ suggests that “before congestive cardiomyopathy is diagnosed, coronary artery disease should be excluded.” Diagnosis is not an end in itself but a means to helping the patient. Does it matter, therefore, if a patient who in fact has coronary artery disease is wrongly thought to have idiopathic cardiomyopathy? By far the most important reason for making an exact diagnosis is that this influences the treatment. Patients with both conditions are given diuretics (in an amount sufficient to keep them edema-free), digitalis (rightly or wrongly), and the same diet and regimen. Patients with idiopathic cardiomyopathy-in common with the victims of other obscure maladies-have been prescribed steroids, but there is no evidence that this is beneficial. When there is obstruction to left ventricular outflow accompanying idio-
0002-8703/79/020264
+ 02$00.20/O
:I? 1979 The
C. V. Mosby
Co.
The
pill and
circulatory
disease
Two large prospective studies in the United Kingdom recently reported that women who had taken the pill were more likely to die from a wide range of circulatory diseases.‘-” The larger of the studies, the Oral Contraception Study of the Royal College of General Practitioners (RCGP), has been monitoring the health and oral contraceptive use of approximately 46,000 British women since 1968.‘. ’ In this study, the death rate from circulatory disease was five times greater in women who had taken the combined type of pill than in those who had never taken it. The excess mortality rate from circulatory disease among pill users is not an unexpected finding. It was foreshadowed by earlier case-control studies,“-’ by analyses of time trends of cardiovascular mortality in young women,* and by reports of the physiological and metabolic changes associated with pill use.fl-‘l What is important about the two recent studies is that, because they are prospective in design, many of the criticisms that can be directed at retrospective studies do not apply. As well as confirming the findings of other researchers, there are several new observations from these studies. The first is that the pill seems to be associated with an increased risk of a wide range of circulatory conditions. The excess deaths among the pill takers included conditions such as rheumatic and congenital heart diseases, malignant hypertension, cardiomyopathy, subarachnoid hemorrhage, and mesenteric artery thrombosis-as well as the more familiar conditions such as ischemic heart disease and thromboembolic disease. It is interesting that pulmonary embolism made only a minor contribution to the excess deaths. Of the 33 deaths from circulatory disease in women who had taken the pill, only one was from pulmonary embolism, but 12 were from ischemic heart disease and 10 were from subarachnoid hemorrhage. Also in the RCGP study the duration of pill use was found to affect the risk of circulatory disease: women who had taken the pill continuously for more than 5 years had an ageadjusted death rate from circulatory disease double that of women who had taken it for a shorter period. There was also some evidence-although based on small numbers and therefore tentative-that the excess mortality rate associated with pill use may persist even after it has been discontinued. The prospective studies provide the first direct measure of the size of the risk associated with pill use. Clearly this is important for public health considerations. In the RCGP study, women who had used the pill experienced an over-all excess mortality rate from circulatory disease of approximately 1 death per 5,000 pill-users per year. The mortality rate from non-circulatory diseases was similar in both groups. These findings relate predominantly to women taking combined pills which contain 50 pg of estrogen. The excess mortality rate from circulatory diseases was considerably greater than was previously estimated.‘? It was greater than the death rate from accidents in British women of comparable age, and it was greater than the death rate in the study
0002~8703/79/020263
+ 02$00.20/O
6 1979 The
C. V. Mosby
Co.
population from complications of pregnancy in those who had never taken the pill. The excess death rate increased with age and with cigarette consumption. Retrospective studies have indicated that hypertension and hypercholesterolemia may also increase the death rate.’ Unfortunately the role of these factors cannot be assessed from the prospective studies. One major problem in the interpretation of these findings remains. Women who take the pill differ from those who do not. Had they not taken the pill, would they still have developed similar circulatory disease? Available evidence indicates that they probably would not-but we can only speculate about this. We do know that pill users are less likely than non-users to have a past history of myocardial infarction, stroke, hypertension, rheumatic or congenital heart disease, diabetes or other vascular disease’. “; they are less obese”; and they take fewer medications.” Thus there is no evidence to support the claim that the excess mortality rate among pill users may be accounted for by the pill being selectively prescribed for sick women (as a safer alternative to pregnancy). Indeed the reverse seems to be true. We also know that women who take the pill tend to smoke more than women who do not take the pill.‘, ’ The differences in cigarette consumption are not large, however. The comparisons in the RCGP study adjusted for differences between the two groups in past health, smoking habits, age, parity, and social class. The fivefold increase in the mortality rate among pill users was found after these adjustments. Little is known about the personality or behavioral characteristics of pill users. Still less is known about the effect of personality on circulatory disease risk in women. Nevertheless it seems most improbable that differences in personality could account for the large excess of circulatory disease observed in women who had taken the pill, since the relative risk associated with type A behaviour pattern is reported to be only twofold,‘” compared with the fivefold difference noted with pill use. It has also been suggested that pill users may drink more alcohol than non-users.“’ The association between alcohol consumption and heart disease is unclear, but it has been claimed that it may reduce the risk.‘; It therefore seems reasonable to conclude that differences in personality or behavior between pill users and never users would probably have a minor effect on their differential risks of circulatory disease. Moreover, it is not clear whether such differences would increase or decrease the risk of circulatory disease in pill takers. With these recent reports there remains little doubt that the pill has widespread effects on the circulatory system. The consistency of the evidence from a wide variety of sources is most persuasive. In the light of all these findings the Royal College of General Practitioners and the Royal College of Obstetricians and Gynaecologists have suggested to British doctors that renewed caution should prevail when prescribing
American
Heart
Journal
263
Annotcrtions
the pill.” They suggest that women aged 35 years and older should consider the adoption of an alternative method of contraception, and that women aged 30 to 34 should do so if they smoke or have taken the pill for 5 years or longer. Valerie Beral, M.B., M.R.C.P. Department of Medical Statistics and Epidemiology London School of Hygiene and Tropical Medicine Keppel St. (Gower St.) London WClE 7HT Clifford Kay, C.B.E., M.D., Ph.D., F.R.C.G.P. RCGP Oral Contraception Study 8 Barlow Moor Road Manchester M20 OTR England
7.
8.
9.
10.
11.
REFERENCES
1. 2.
3. 4.
5.
6.
Royal College of General Practitioners: Mortality among oral contraceptive users, Lancet 2:727, 1977. Vessey, M. P., McPherson, K., and Johnson, B.: Mortality among women participating in the Oxford/Family planning contraceptive study, Lancet 2:731, 1977. Beral, V., and Kay, C.: Mortality in women on oral contraceptives, Lancet 2:1276, 1977. Royal College of General Practitioners: Oral contraception and health, London, 1974, Sir Isaac Pitman & Sons, Ltd. Inman, W. H. W., and Vessey, M. P.: Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of childbearing age, Br. Med. J. 2:193, 1968. Collaborative group for the study of stroke in young women: An epidemiologic study of oral contraception and cerebrovascular disease, N. Engl. J. Med. 288:871, 1973.
Cardiomyopathy
and
coronary
artery
The word “cardiomyopathy” means a pathological state affecting the myocardium. In the affluent western societies by far the commonest basis to pathological changes in the myocardium is coronary artery disease, but this is not described as cardiomyopathy. Neither is this name usually given to myocardial disease due to rheumatism, thyrotoxicosis, congenital lesions, or syphilis. In general, cardiomyopathy implies myocardial disease without known cause. Goodwin and associates’ (1961) proposed the following definition “A subacute or chronic disorder of heart muscle of unknown or obscure etiology, often with associated endocardial, and sometimes with pericardial, involvement, but not atherosclerotic in origin.” On the other hand, cardiomyopathy is sometimes employed with a qualifying adjective which does indicate an etiology. Examples are alcoholic, diabetic, nutritional, and infective cardiomyopathy, though the last named is more often described as “myocarditis.” Many patients with coronary artery disease give no history of angina pectoris or of cardiac infarction, have no unequivocal ECG evidence of coronary artery disease, and present with congestive cardiac failure. Such patients are therefore often wrongly thought to have idiopathic cardiomyopathy. Raftery,
264
February,
1979,
Vol.
97, No.
2
12. 13. 14.
15.
16. 17.
18.
Mann, J. I., and Inman, W. H. W.: Oral contraceptive and death from myocardial infarction, Br. Med. J. 2:247, 1975. Beral, V.: Cardiovascular disease mortality trends and oral contraceptive use in young women, Lancet 2:1047, 1976. Weir, R. J., Briggs, E., Mack, A., Taylor, L., Browning, J., Naismith, L., and Wilson, E.: Blood pressure in women after one year in oral contraception, Lancet 1:467, 1971. Mason, B., Oakley, N., and Wynn, V.: Studies of carbohydrate and lipid metabolism in women developing hypertension on oral contraceptives, Br. Med. J. 3:317, 1973. Littler, W. A., Bojorges-Buerio, R., and Banks, J.: Cardiovascular dynamics in women during menstrual cycle and on oral contraceptives, Thorax 29:567, 1974. Vessey, M. P., and Doll, R.: Is “the pill” safe enough to continue using? Proc. R. Sot. Lond. B. 195:69, 1976. Fisch, I. R.. and Freedman, S. H.: Smoking, oral contraceptives and obesity, J.A.M.A. 234:500, 1975. Rabin, D. I., and McCarthy, P.: Social and health related characteristics of women using oral contraceptives, Preventive Med. 3:268, 1974. Roseman, R. H., Brand, R. J., Jenkins, C. D., Friedman, M., Strauss, R., and Wurm, M.: Coronary heart disease in the Western Collaborative Group Study. Final followup experience of 8% years, J.A.M.A. 8:872. 1975. Haack, D. G., and McKean, H. E.: Mortality associated with the pill, Lancet 2:1024, 1977. Yano, K., Rhoads, G. G., and Kagan, A.: Coffee, alcohol and risk of coronary heart disease in Japanese-Americans, N. Engl. J. Med. 297:405. 1977. Kuenssberg, E. V., and Dewhurst, J.: Mortality in women on oral contraceptives, Lancet 2:757, 1977.
disease Banks, and Oram’ described four patients in which the diagnosis was changed from idiopathic cardiomyopathy to occlusive coronary artery disease after coronary arteriography (which revealed severe obstructive disease) in three patients and after necropsy (which revealed gross cardiomegaly with severe, diffuse atheromatous coronary artery disease) in the fourth. Because of this diagnostic difficulty a Lancet editorial (1977)’ suggests that “before congestive cardiomyopathy is diagnosed, coronary artery disease should be excluded.” Diagnosis is not an end in itself but a means to helping the patient. Does it matter, therefore, if a patient who in fact has coronary artery disease is wrongly thought to have idiopathic cardiomyopathy? By far the most important reason for making an exact diagnosis is that this influences the treatment. Patients with both conditions are given diuretics (in an amount sufficient to keep them edema-free), digitalis (rightly or wrongly), and the same diet and regimen. Patients with idiopathic cardiomyopathy-in common with the victims of other obscure maladies-have been prescribed steroids, but there is no evidence that this is beneficial. When there is obstruction to left ventricular outflow accompanying idio-
0002-8703/79/020264
+ 02$00.20/O
:I? 1979 The
C. V. Mosby
Co.
