Serum cholesterol and long-term prognosis in middle-aged men with myocardial infarction and angina pectoris

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1 European Heart Journal (1997) 18, Serum cholesterol and long-term prognosis in middle-aged men with myocardial and angina pectoris A 16-year follow-up of the Primary Prevention Study in Goteborg, Sweden A. Rosengren, M. Hagman, H. Wedel and L. Wilhelmsen Section of Preventive Cardiology, Ostra University Hospital, Goteborg, Sweden Objective To compare the role of serum cholesterol in the long-term prognosis of men with a history of myocardial, in men with clinical angina without myocardial, and men without clinical coronary disease. Methods In the second screening of the Primary Prevention Study in Goteborg which comprised 7100 men aged 51 to 59 years at baseline in , 314 men with clinical angina but no myocardial at baseline were identified and 195 men who had survived a myocardial for 0 to 19 years (median 3 years). Results Of the men without clinical coronary disease at baseline and cholesterol at or below 5-2 mmol. 1~ ', 2-7 per 1000 observation years died from coronary disease compared to 8-5 per 1000 of the men with serum cholesterol of 7-2 mmol. 1 ~ ' or more. Corresponding figures for men with angina was 5-5 and 310 per 1000 observation years, and for men with prior myocardial 19-8 and 58-3, respectively, per After adjustment for age, smoking, systolic blood pressure, body mass index and diabetes the risk of coronary death in men with serum cholesterol above 7-2 mmol. 1 ~ ' compared to below 5-2 mmol. 1 ~ ' was 2-42 ( ) in healthy men, 4-82 ( ) in men with Introduction The role of serum cholesterol in predicting first coronary events is well established' 1 ' 21 and reduction of serum cholesterol decreases the risk of coronary heart disease' 3 '. Elevated serum cholesterol levels have also been convincingly shown to be associated with an adverse Revision submitted 15 November and accepted 20 November Correspondence: Annika Rosengren, Department of Medicine, Ostra University Hospital, S Goteborg, Sweden. angina, 2-70 ( ) in survivors of myocardial, and 407 ( ) in the combined group of men with either angina or prior. The strongest effect was seen during the first half of the follow-up, with an adjusted relative risk for high in relation to low serum cholesterol of 808 ( ) in men with preexisting coronary disease. Non-coronary deaths varied little by serum cholesterol or coronary disease status at baseline. After 16 years, 76% of the healthy men with low cholesterol and 65% of healthy men with cholesterol above 7-2 mmol. 1 ~ ' were still alive. Of the men with prior myocardial, 50% in the group with low cholesterol were alive after 16 years, as compared to 21% of those with high cholesterol. Conclusion The long-term absolute risk of death in men with coronary disease and elevated serum cholesterol is very high. Implementation of lipid-lowering strategies shown to be efficacious is important in this high-risk group. (Eur Heart J 1997; 18: ) Key Words: Angina pectoris, myocardial, coronary disease, serum cholesterol, risk factor, population studies. prognosis in persons with established cardiovascular' 41 and coronary heart disease' 3^131. A recent intervention study demonstrated that lowering serum cholesterol by pharmacological means reduced mortality in selected populations of patients with coronary disease' 141. In another pharmacological trial, the incidence of myocardial and cardiovascular death in men with moderate hypercholesterolaemia and no history of myocardial was reduced by treatment' 151. In the Scandinavian Simvastatin Survival Study' 141 treatment with simvastatin reduced mortality by 30% as compared to placebo, yet 92% of men below X/97/ SI8.00/0 V, 1997 The European Society of Cardiology

2 Prognosis in middle-aged men with MI and A P years of age in the placebo group were still alive after a median follow-up period of 5-4 years and in the West of Scotland study [15] 96% of the men treated with placebo were alive after 5 years. The cost-benefit ratio of pharmacological treatment of hyperlipidaemia is currently under debate' 161. For obvious reasons intervention studies deal with selected populations and outcome in the placebo groups of such studies may not adequately describe the true prognosis in an untreated population. Previous observational studies on serum cholesterol and prognosis in persons with coronary disease have either not been population-based' 4 ' 61, have not included persons without coronary disease for comparison[7,n,i2] Qr ^ not p resent c j ata on survival' 5 ' 8 " 101. In a 7-year follow-up of the present study population serum cholesterol predicted coronary events in men with uncomplicated angina' 101. The aim of the present study was to determine the long-term prognostic value of serum cholesterol concentrations in relation to death from coronary disease and from all causes in a large random population sample of men, with separate analyses in 314 men with angina pectoris and 195 survivors of myocardial. All men were below 60 years of age at baseline and the mean follow-up was 16 years. Subjects and methods The multifactor primary prevention trial started in Goteborg in 1970 and was originally an intervention trial, with intervention against smoking, hypercholesterolaemia and hypertension at predefined levels in an intervention group comprising men, a random third of all the men in the city who had been born between 1915 and 1925, except those born in There were two control groups of men each. After 11-8 years follow-up serum cholesterol, smoking and blood pressure had decreased in all three groups but no significant differences in the pattern of risk factors or in outcome were detected between the intervention and the control groups' 171. Any changes brought about by the intervention took place among the general population as well, and the present study group is considered to be representative of the background population in the city. The present study deals only with the men in the intervention group (n=10 000). A first screening examination took place between January 1970 and March In the present study, data were used from the second screening, which started in 1974 and was completed in 1977' 181. All surviving men from the intervention group who still lived in Goteborg (9411) were invited for screening; the response rate was 76%. Altogether 7122 men took part in the examination; 7100 men with complete data form the basis for the present investigation. Data on smoking habits, treatment for hypertension and diabetes were collected by postal questionnaire. This postal questionnaire also contained a shortened version of the Rose questionnaire for the diagnosis of ischaemic heart pain in field surveys' 19 ' 201. Smoking was coded as 1= never smoked, 2 = former smoker of more than one month's duration, 3 = smoking 1-14 g of tobacco per day, 4 = smoking 15 g or more per day. One cigarette was considered to contain 1 g of tobacco, a cigarillo 2 g, and a cigar 5 g of tobacco. Screening examinations were performed in the afternoon. Blood pressure was measured after 5 min rest with the subject seated. Body mass index was calculated as weight/(height) 2. Serum cholesterol concentration (from a sample taken after fasting for at least 2 h) was determined according to standard laboratory procedures' 211. All cases of non-fatal myocardial in Goteborg are recorded according to specific predefined criteria since 1970' 221. These criteria include admission to hospital with a clinical diagnosis of myocardial and fulfilment of at least two of the following: (1) central chest pain, shock, syncope or pulmonary oedema suggesting a myocardial, (2) typical enzyme changes, (3) development of electrocardiographic changes with either development of Q waves or serial ST-T changes. The group of men with prior myocardial comprised men identified by this register before the examination. For men with a history of myocardial either before 1970 or who had been treated elsewhere than in Goteborg hospital records were scrutinized after the examination and myocardial was verified in cases meeting the same criteria as in the register. The median period between the and the baseline investigation was 3 years (range 0-19 years). Angina pectoris was diagnosed solely on clinical grounds. All men who, according to the postal questionnaire, had chest pain brought on by exercise, and relieved by resting, were interviewed by a physician at the screening examination according to a more detailed questionnaire' 231. Men who were judged to have definite or suspected angina pectoris were invited to another examination by a single physician (M.H.). This examination was a final evaluation comprising another interview and a clinical examination. Men born in 1915 and 1916 did not take part in this examination. In these men, chest pain brought on by exercise, and relieved within 10 min by resting, according to the questionnaire was accepted as angina. Altogether, 314 men with angina pectoris but no myocardial prior to the examination (=uncomplicated angina) were identified. Follow-up procedures All subjects in the study were followed until 31 December 1993 (mean 16 years). The Swedish national register on deaths due to specific causes from the years 1970 to 1993 was matched against a computer file of the men in the study. In 1987, there was a change from the 8th to the 9th revision of the International Classification of Diseases, but for the broad groupings used in the present study this will have made no difference.

3 756 A. Rosengren et al. Table 1 Coronary risk factors by coronary disease status at baseline Risk factor No clinical coronary heart disease (6591) Uncomplicated angina (314) P value* Myocardial (195) Angina and/or P myocardial P value* value* (509) Mean age (SD) age at baseline (years) Mean (SD) serum cholesterol (mmol.r') Mean (SD) systolic blood pressure (mmhg) Mean (SD) diastolic blood pressure (mmhg) Mean (SD) body mass index (kg x m ~ 2 ) Never smokers (%, n) Former smokers (%, n) Current smokers (%, n) 1-14 g. day" 1 >14g.day"' Treatment for hypertension (%, n) Diabetes (%, n) 55-8 (20) 6-40 (106) 146 (20) 93 (12) (1584) 17 (1096) 15 3 (3-2) (1951) (1960) (957) (203) *Comparison with men without coronary disease. Statistical methods 55-9 (1-9) 6-58 (118) 149 (22) (95) 19 (61) 27 9 (13) (3-5) (75) (83) (84) (28) We used the SAS statistical package (version 6.10). T-tests were used for the comparison of means between groups. Mantel-HaenszePs tests or Fisher's exact test were used for graded variables. A proportional hazards analysis was used to adjust for covariates in the prospective part of the study, and the regression coefficients were used to calculate the unadjusted and adjusted relative risks' 24 '. Serum cholesterol concentrations were coded into three dummy variables, with predetermined cut-off points of 5-2, 6-5 and 7-2 mmol. 1~ '. Age, current smoking, systolic blood pressure, body mass index, and diabetes were used as covariates. As former smokers had the same risk as never smokers and as there was no dose-response relationship between coronary death and amount of tobacco consumed among those who were smokers at the time of the screening, never smokers and former smokers were considered together and coded as zero, whereas all smokers were coded as 1. Systolic blood pressure and body mass index were entered as continuous variables. Results Men with angina at baseline had a significantly higher mean serum cholesterol, higher blood pressure, and higher body mass index (Table 1). More men with angina were smokers, they were more often treated for hypertension, and had diabetes to a higher extent than men with no history of coronary disease. Men with myocardial prior to screening had a higher serum cholesterol and body mass index, compared to the healthy men. There were more former smokers and (1-14) 144 (18) 93 (12) 26-5 (30) 11 (22) 45 (87) 34 (66) 10 (20) 29 9 (1-9) (56) (18) (1-9) 6-67 (117) 147 (20) 94 (12) 26-4 (3-3) 19 (97) 33 (170) 32 (161) 16 (81) 28 (140) 9 (46) more men treated for hypertension but no significant differences with respect to blood pressure, compared to healthy men. Of the non-lipid coronary risk factors smoking high systolic blood pressure, treatment for hypertension, high body mass index, and diabetes all predicted coronary death after 16 years in the group of men with no clinical coronary heart disease at baseline (Table 2). In men with angina, only systolic blood pressure and diabetes predicted coronary death, whereas among men with prior myocardial only diabetes predicted coronary death. Of the men with no clinical coronary disease at baseline 8% died from coronary disease during followup, as did 25% of the men with angina and 45% of the men with myocardial, corresponding to 5-3, 17-6 and 379 deaths per 1000 observation years, respectively (Table 3). Altogether, almost 30% of the men in the study died from any cause during follow-up, as did 28% with no coronary disease at baseline, 47% with angina and 66% with prior myocardial, corresponding to 177, 330 and 55-2 deaths per 1000 observation years, respectively. The risk of coronary death increased with increasing serum cholesterol in all groups, although not significantly so among the men with prior myocardial. Compared to men with serum cholesterol of 5-2 mmol. 1 ~' or less, healthy men with serum cholesterol of above 7-2 mmol. 1 ~ ' had an adjusted relative risk of dying from coronary disease of 2-42 ( ). Corresponding figures for men with angina, for men with prior and in the combined group of men with angina or was 4-82 ( ), 2-70 ( ) and 407 ( ). The increase in risk in men with myocardial was not significant, but

4 Prognosis in middle-aged men with MI and AP 757 Table 2 Death from coronary heart disease by non-lipid risk factors among men with and without clinical manifestations of coronary heart disease at baseline. Rates are per 1000 person-years of follow-up (number of deaths) Baseline coronary disease status Risk factor No clinical CHD (6591) Uncomplicated angina (314) Myocardial (195) Angina and/or myocardial (509) Smoking habits Never smoker Ex-smoker 1-14 (g. day" 1 ) >14(g.day-') P for trend Systolic blood pressure (mmhg) < = > P for trend* Treatment for hypertension No 5634 Yes 957 P Body mass index (kg < >26-8 P for trend* Diabetes No Yes P xm" 2 ) (111) 4-4 (140) 7-6 (183) 7-4 (123) 2-9 (97) 4-9 (184) 8-1 (276) 4-8 (434) 8-4 (123) 4-6 (164) 4-7 (167) 6-7 (225) (509) 17-6 (48) (16) 12-4 (15) 24-1 (32) 19 3 (16) (11) 19-4 (30) 21-9 (38) (54) 21-0 (25) (23) 13-2 (15) 211 (41) (63) 48-4 (16) Two subjects had missing values for systolic blood pressure and 13 for body mass index. *Tested as a continuous variable. on the other hand very few men with prior had serum cholesterol of 5-2 or lower. The effect of serum cholesterol did not differ significantly by baseline disease status and tests for an interaction between serum cholesterol and disease status at baseline were non-significant. With respect to mortality from all causes, the increase in risk with increasing serum cholesterol level was less steep. Healthy men with serum cholesterol above 7-2 mmol. 1 ~' had a significantly higher risk than men with low cholesterol (adjusted relative risk 1-21 ( )). The increase in the combined group of men with angina and prior was also significant (relative risk 1-73 ( )) although not in either group separately. Among the men with high cholesterol and prior myocardial the absolute risk of dying was considerable, at 75-3 deaths per 1000 years. In the present analyses only one single cholesterol measurement was done at baseline. To investigate whether the increase in risk with increasing serum cholesterol remained constant throughout the follow-up period, the follow-up of 16 years was divided into two of 8 years each (Table 4). In this analysis men with angina and men with prior were analysed together. The relative risks of coronary death associated with high (9) 34-9 (38) 48-7 (35) 23-6 (6) (34) 34-7 (27) 36-6 (27) (66) 31-4 (22) (19) 461 (34) 31 6 (34) (75) 88-1 (13) (25) 231 (53) 32-8 (67) 20-3 (22) (45) 24-6 (57) 26-2 (65) (120) 24-9 (47) (42) 26-3 (49) 24-9 (75) (138) 61-2 (29) serum cholesterol both among healthy men and men with coronary disease were much higher during the first part of the follow-up, compared to the second. The adjusted relative risk of dying from coronary causes during the first 8 years of the study in men with coronary disease at baseline and serum cholesterol above 7-2 mmol. I" 1 was 8-08 ( ) and from any cause 2-28 ( ), compared to men with coronary disease and serum cholesterol of 5-2 mmol. 1 ~' or below. During the last 8 years of the follow-up the relative risks both for death from coronary disease, as well as from any cause in the men with prior coronary disease was not significantly elevated. However, due to the high early mortality in the group with coronary disease and serum cholesterol of above 7-2 mmol. 1~', this group was reduced by one third during the late follow-up period. Finally, survival over the entire 16 year follow-up period was analysed (Table 5). In the group of men who were free from clinical coronary disease at baseline 75-8% survived if they had low serum cholesterol and 64-6% if they had serum cholesterol above 7-2 mmol. 1~'. Among the men with prior myocardial, corresponding figures were 500 and 20-9% survivors, respectively. Non-coronary deaths did not

5 758 A. Rosengren et al. Table 3 Death from coronary heart disease among men with and without clinical manifestations of coronary heart disease at baseline. Rates are per 1000 person-years of follow-up (number of deaths) Baseline coronary disease status Cholesterol level No clinical coronary heart disease (6591) Uncomplicated angina (314) Myocardial (195) Angina and/or myocardial (509) Mortality from coronary < = 5-2 (mmol.r') (mmol. 1 ~ ') (mmol.i" 1 ) >7-2 (mmol.r 1 ) All Crude relative risk (95% CI)* Adjusted relative risk (95% CI)f Mortality from all causes < = 5-2 (mmol. I" 1 ) (mmol. I" 1 ) (mmol. 1~ ') >7-2 (mmol.r 1 ) All Crude relative risk (95% CI)* Adjusted relative risk (95% CI)t disease ( ) 2-42 ( ) (34) (203) (140) (180) (557) (197) (715) (456) (482) (1850) 1-24 ( ) 1-21 ( ) (3) 140 (25) 150 (15) 31-0 (36) 17-6 (79) 4-62 ( ) 4-82 ( ) (16) (51) (25) (56) (148) 1-40 ( ) 1-36 ( ) ( ) ( (1-99 (0- (4) (25) (18) (41) (88) ) (7) (41) (27) (53) (128) 01^-94) ) (7) 19-4 (50) 200 (33) 41 2 (77) 24-5 (167) 4-06 ( ) 407 ( ) 30-7 (23) 35-7 (92) 31-6 (52) 58-3 (109) 40-5 (276) 1-79 ( ) 1-73 ( ) *>7-2 mmol. 1 ' compared to < = 5-2 mmol. 1 '. f Adjusted for age, systolic blood pressure, smoking, body mass index and diabetes. vary according to serum cholesterol or to disease status at baseline and all excess mortality, accordingly, was due to deaths from coronary disease. Of all deaths in healthy men with low serum cholesterol only 17% was due to coronary disease, compared to 77% in the men with high cholesterol and prior myocardial. Discussion The present study confirms findings from other studies which have demonstrated that elevated serum cholesterol continues to be important in men who show clinical evidence of coronary heart disease' 4 " 131. In the subset of the population with both prior myocardial and serum cholesterol above 7-2 mmol. 1 ~' only one in five survived the entire follow-up period of 16 years. The excess mortality was entirely due to deaths from coronary diseases. Mortality from coronary disease among men with prior myocardial in the present study was higher than that of the British regional heart study 181. In that study coronary or total mortality was not specified but the total non-fatal and fatal coronary event rate was 28 per 1000 observation years among men with a doctor's diagnosis of a heart attack or electrocardiographic evidence of a heart attack, as compared to 38 coronary deaths per 1000 years in the present study. The strict criteria for defining myocardial in the present study may explain some of the difference in mortality. Conversely, the Framingham study 1 "' 251 had higher mortality but they included subjects who were older, on average, when they had their and also, the average time from to examination was only approximately one year. Definitions of prevalent coronary disease For the definition of myocardial we used strict, objective criteria. Silent s, as defined by electrocardiographic criteria only, were not included but have been shown to have as poor prognosis as clinically evident s' 26 ' 27 '. Angina pectoris is considerably more difficult to define. In the present study all men born in 1917 and after who had chest pain were interviewed in a structured manner using an extended Rose questionnaire by the same physician throughout the study' 231 and angina was defined according to the clinical judgement of this physician. Exercise tests were not done routinely. Men born in 1915 and 1916 were not interviewed, only defined according to the Rose questionnaire. However, in a separate analysis, coronary mortality in the men defined as having angina in this manner was as high as for the men in the same age group who had had prior myocardial. In the Reykjavik study' 281, angina with objective signs of ischaemia, by clinical judgement by a physician, or by

6 Prognosis in middle-aged men with MI and AP 759 Table 4 Death from coronary heart disease among men with and without clinical manifestations of coronary heart disease at baseline by a period of follow-up. Rates are per 1000 person-years (number of deaths) Baseline coronary disease status Cholesterol level No clinical coronary disease Coronary deaths Deaths from all causes Angina and/or myocardial Coronary deaths 1Deaths from all causes First 8 years of follow-up < = 5-2 (mmol. I" 1 ) (mmol. I" 1 ) (mmol. 1" ') >7-2 (mmol. I" 1 ) All Crude relative risk (95% CI)* Adjusted relative risk (95% CI)t Second 8 years of follow-up < = 5-2 (mmol. I" 1 ) (mmol.r') (mmol. I" 1 ) 1427 >7-2 (mmol.r 1 ) 1179 All 5952 Crude relative risk (95% CI)* Adjusted relative risk (95% CI)t 1-4 (9) 2-6 (64) 40 (54) 6-9 (82) 3-7 (209) 4-22 ( ) 3-90 ( ) 4-0 (25) 6-5 (139) 7-3 (86) 10-5 (98) 7-1 (348) 1-99 ( ) 1-86 ( ) 9-6 (63) 9-9 (242) 111 (151) 15-4 (183) 113 (639) 1 39 ( ) 1-41 ( ) 21-5 (134) 22-2 (473) 26-1 (305) 32-1 (299) 24-8 (1211) 1-17 ( ) 1-12 ( ) (2) 189 (28) 120 (11) 41-9 (50) 22-6 (91) 7-54 ( ) 8-08 ( ) 14-8 (5) 19-9 (22) 31-5 (22) 40-7 (27) 27-0 (76) 2-57 ( ) 2-46 ( ) 19-7 (8) 310 (46) 16-3 (15) 46-1 (55) 30-8 (124) 216 (1-02^-69) 2-28 (1-07^1-84) 44-3 (15) 41-5 (46) 53-0 (37) 81-4 (54) 54-1 (152) 1-61 ( ) 1-44 ( ) *>7-2 mmol. 1 ' compared to < = 5-2 mmol.1 '. f Adjusted for age, systolic blood pressure, smoking, body mass index and diabetes. Rose questionnaire only had much the same ten-year coronary mortality, ranging between 11 and 13 deaths per 1000 observation years, which is fairly close to our estimation for coronary death in men with angina during the first half of the follow-up, which was 15 coronary deaths per 1000 (not shown). Accordingly, we believe our definition of angina pectoris to have been valid but it is not possible to exclude the possibility that some of the men who were defined as having angina did not have coronary disease. In the present study, as in the Reykjavik study and in the British Regional Heart study' 8 ', angina had better prognosis than prior myocardial. Non-lipid risk factors Only diabetes was a significant predictor of coronary death among the men with prior. In men with angina, high systolic blood pressure and diabetes predicted coronary death. Smoking was not a significant risk factor among men with coronary disease, but smoking habits may have been particularly prone to change during the long follow-up. Quitting smoking has been shown to be beneficial in patients with prior myocardial ' 29 ' 301. The British regional heart study had essentially the same findings as in the present study, with no effect on coronary end-points of either smoking or blood pressure among men with prior myocardial. However, it is known that systolic as well as diastolic blood pressure decreases after a myocardial and remain on average 10 mm lower for at least 2 years after a myocardial ' 311. Serum cholesterol and coronary mortality The results of the present study, with respect to increased risk of men with preexisting coronary disease and hypercholesterolaemia, are in agreement with several previous studies' 4 " 13 ' 281. Generally, as in the present study, relative risks of elevated serum cholesterol have been found to be approximately the same as for men without pre-existing disease but the absolute risks are high. Pekkanen et a/.' 41 found that men with pre-existing cardiovascular disease and high serum cholesterol defined as more than 6-2 mmol. 1 ~' had a risk of coronary death of 17 per 1000 observation years. However, less than 20% of these men had a prior myocardial. Approximately half of the men in the study had an abnormal exercise test and the rest had miscellaneous other conditions such as arrhythmias, stroke and congestive heart failure. Possibly, the probability of having true coronary disease in this mixed group increased with increasing serum cholesterol. This line of reasoning, however, would apply also to the results of the present study for the men with angina. Conversely, low serum cholesterol in a man with

7 760 A. Rosengren et al. Table 5 Outcome after 16 years follow-up by serum cholesterol concentration and coronary disease status at baseline. Figures are percentages (number of men). Per cent deaths from coronary disease are shown in parentheses Baseline coronary disease status No clinical coronary heart disease Uncomplicated angina Myocardial <5-2mmol. I" 1 (, n) Coronary deaths Non-coronary deaths Survived (Per cent deaths from coronary disease) mmol. I" 1 (, n) Coronary deaths Non-coronary deaths Survived (Per cent deaths from coronary disease) mmol. I" 1 (, n) Coronary deaths Non-coronary deaths Survived (Per cent deaths from coronary disease) >7-2mmol.l"' (, n) Coronary deaths Non-coronary deaths Survived (Per cent deaths from coronary disease) (814) 4-2 (34) 200 (163) 75-8 (617) (17) (2837) 7-2 (203) 18-0 (512) 74-8 (2122) (28) (1578) 8-9 (140) 20-0 (316) 71-1 (1122) (31) (1362) 13-2 (180) 22-2 (302) 64-6 (880) (37) suspected angina pectoris might be seen as reassuring, with either a low probability of having coronary disease or low risk of death from coronary disease. Cholesterol levels were generally high in the present study. In Sweden, a nihilistic attitude with respect to lipid-lowering drugs has been preponderant until recently. The study protocol for the Primary Prevention study specified serum cholesterol at or above 7-8 for pharmacological intervention. Men with serum cholesterol of 6-8 to 7-7 mmol. 1" ' received diet information in group sessions. In 1974 to % of the men with uncomplicated angina and 22% of the men with prior myocardial were on lipid-lowering agents. In 1981 to 1982, a subsample of the study population was again examined. By then, only five out of 1358 men in the subsample were on lipid lowering agents. This reduction was mostly due to the publication of the WHO clofibrate study' 32 ' 33 '. Data from a mixed population of Swedish patients with angina and past myocardial referred for coronary angiography and revascularization and who were examined in 1990 indicate that only 10% were treated with lipid lowering agents' 341. Notwithstanding, in the intervention group serum cholesterol decreased from a mean of 6-46 mmol. 1 ~ ' initially to 604 mmol. 1" ' at follow-up in 1981 to However, an almost identical decrease was found in the control group. At baseline, few men with prior myocardial had desirable cholesterol levels of (38) 7-9 (3) 34-2 (13) 57-9 (22) (19) (123) 20-3 (25) 211 (26) 58-5 (72) (49) (63) 23-8 (15) 15 9 (10) 60-3 (38) (60) (90) 40-0 (36) 22-2 (20) 37-8 (34) (64) (14) 28-6 (4) 21-4 (3) 500 (7) (57) (65) 38-5 (25) 24-6 (16) 36-9 (24) (61) (49) 36-7 (18) 18-4 (9) 44-9 (22) (67) (67) 61-2 (41) 17-9 (12) 20-9 (14) (77) 5-2 mmol.1 'or lower and consequently, the estimate of risk in men with low cholesterol is somewhat uncertain. Even so, a considerable proportion of men with pre-existing disease had severe hypercholesterolaemia and estimates of risk in this range of serum cholesterol should be more accurate. If anything, the true risk might be underestimated as only one single cholesterol reading was used in the present analysis' 21. Implications In this population-based study of men with coronary disease with a follow-up extending through many years we found very high absolute risks associated with hypercholesterolaemia, particularly in those with very high serum cholesterol concentrations. Results in selected populations may lead to an underestimation of the true risk associated with elevated serum cholesterol in men with coronary disease. A recent meta-analysis indicated that lowering cholesterol is of greater benefit with higher absolute risk' 341. In the present study, one in three of the men with coronary disease had serum cholesterol of 7-2 mmol. 1 ~ ' or above. The implementation of lipidlowering strategies in this extreme high-risk group is of great importance. This study was supported by the Swedish Medical Research Council, the Swedish Labour Market Insurance Company, the Goteborg Medical Society and the Knut and Alice Wallenberg Foundation.

8 Prognosis in middle-aged men with MI and AP 761 References [1] Martin MJ, Browner WS, Hulley SB, Kuller LH, Wentworth D. Serum cholesterol, blood pressure, and mortality: implications from a cohort of men. Lancet 1986; ii: [2] Law MR, Wald NJ, Wu T, Hackshaw A, Bailey A. Systematic underestimation of association between serum cholesterol concentration and ischemic heart disease in observational studies: data from the BUPA study. BMJ 1994; 308: [3] Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischemic heart disease. BMJ 1994; 308: [4] Pekkanen J, Linn S, Heiss G et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990; 322: [5] Heliovaara M, Karvonen MJ, Punsar S, Haapakoski J. Importance of coronary risk factors in the presence or absence of myocardial ischemia. Am J Cardiol 1982; 50: [6] Schlant RC, Forman S, Stamler J, Canner PL. The natural history of coronary heart disease. Prognostic factors after recovery from myocardial in 2789 men. The 5-year findings of the Coronary Drug Project. Circulation 1982; 66: [7] Ulvenstam G, Bergstrand R, Johansson S et al. Prognostic importance of cholesterol levels after myocardial. PrevMed 1984; 13: [8] Phillips AN, Shaper AG, Pocock SJ, Walker M, Macfarlane PW. The role of risk factors in heart attacks occurring in men with pre-existing ischemic heart disease. Br Heart J 1988; 60: [9] Suhonen O, Reunanen A, Knekt P, Aromaa A. Risk factors for sudden and non-sudden coronary death. Acta Med Scand 1988; 223: [10] Hagman M, Wilhelmsen L, Pennert K, Wedel H. Factors of importance for prognosis in men with angina pectoris derived from a random population sample. The Multifactor Primary Prevention Trial, Gothenburg, Sweden. Am J Cardiol 1988; 61: [11] Wong ND, Wilson PWF, Kannel WB. Serum cholesterol as a prognostic factor after myocardial : the Framingham study. Ann Intern Med 1991; 115: [12] Yano K, Grove JS, Reed DM, Chun HM. Determinants of the prognosis after a first myocardial in a migrant Japanese population. The Honolulu Heart Program. Circulation 1993; 88: [13] Tervahauta M, Pekkanen J, Nissinen A. Risk factors of coronary heart disease and total mortality among elderly men with and without preexisting coronary heart disease. Finnish Cohorts of the Seven Countries Study. J Am Coll Cardiol 1995; 26: [14] Scandinavian Simvastatin Survival Study. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: [15] Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: [16] Pharoah PD, Hollingworth W. Cost effectiveness of lowering cholesterol concentration with statins on patients with and without pre-existing coronary heart disease: life table method applied to health authority population. BMJ 1996; 312: [17] Wilhelmsen L, Berglund G, Elmfeldt D et al. The multifactor primary preventive trial in Goteborg, Sweden. Eur Heart J 1986; 7: [18] Rosengren A, Welin L, Tsipogianni A, Wilhelmsen L. Impact of cardiovascular risk factors on coronary heart disease and mortality among middle aged diabetic men: a general population study. Br Med J 1989; 299: [19] Rose GA, Blackburn H. Cardiovascular survey methods. Geneva: WHO, 1968: 64. [20] Cook DG, Shaper AG, Macfarlane PW. Using the WHO (Rose) angina questionnaire in cardiovascular epidemiological studies. Int J Epidemiol 1989; 18: [21] Leffler HH. Estimation of cholesterol in serum. Am J Clin Pathol 1959; 31: [22] Elmfeldt D, Wilhelmsen L, Tibblin G, Vedin JA, Wilhelmsson C, Bengtsson C. Registration of myocardial in the city of Goteborg, Sweden. J Chronic Dis 1975; 28: [23] Hagman M, Wilhelmsen L, Wedel H, Pennert K. Risk factors for angina pectoris in a population study of Swedish men. J Chronic Dis 1987; 40: [24] Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research: principles and quantitative methods. Belmont, California: Lifetime Learning Publications, 1982: [25] Cupples LA, Gagnon DR, Wong ND, Ostfeld AM, Kannel WB. Preexisting cardiovascular conditions and long-term prognosis after initial myocardial : the Framingham Study. Am Heart J 1993; 125: [26] Sigurdson E, Thorgeirsson G, Sigvaldason H, Sigfusson N. Unrecognized myocardial, epidemiology, clinical characteristics and the prognostic role of angina pectoris. Ann Intern Med 1995; 122: [27] Kannel WB, Abbott RD. Incidence and prognosis of unrecognized myocardial. An update on the Framingham study. N Engl J Med 1984; 311: [28] Sigurdsson E, Sigfusson N, Agnarsson U, Sigvaldason H, Thorgeirsson G. Long-term prognosis of different forms of coronary heart disease. The Reykjavik Study. Int J Epidemiol 1995; 25: [29] Aberg A, Bergstrand R, Johansson S et al. Cessation of smoking after myocardial effects on mortality after 10 years. Br Heart J 1983; 49: [30] Wilhelmsen L. Benefits of quitting smoking for cardiac disease. Cardiovascular Risk Factors. 1996; 6: [31] McCall M, Elmfeldt D, Vedin A, Wilhelmsson C, Wedel H, Wilhelmsen L. Influence of a myocardial on blood pressure and serum cholesterol. Acta Med Scand 1979; 206: [32] Committee of principal investigators (prepared by Oliver MF, Heady JA, Morris JN, Cooper J). A co-operative trial in the primary prevention of ischemic heart disease using clofibrate. Report from the committee of principal investigators. Br Heart J 1978; 40: [33] Committee of principal investigators. WHO co-operative trial in the primary prevention of ischemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Lancet 1980; ii: [34] Bengtson A, Herlitz J, Karlsson T, Hjalmarsson A. The epidemiology of a coronary waiting list. A description of all of the patients. J Intern Med 1994; 235: [35] Davey Smith G, Song F, Sheldon TA. Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ 1993; 306: