The Oslo -Heart Study Eleven-Year Report By PAUiL LEREN, M.D. SUMMARY The study deals with 412 men, aged 30 to 64 years, randomized 1 to 2 years after a first myocardial infarction. For the experimental group a diet low in saturated fats and cholesterol, and high in polyunsaturated fats was recommended. After 5 years, as reported previously, the incidence of fatal and nonfatal myocardial reinfarction was found to be significantly reduced. "Sudden death" was uninfluenced. Major coronary heart disease (CHD) relapses, including fatal and nonfatal events (MI), were significantly reduced (P = 0.05). After 11 years, death from all causes had occurred in 101 of the original dieters and 108 controls. A significantly reduced myocardial infarction mortality in the original diet group was found (32 versus 57, P = 0.004). The total number of coronary deaths (fatal myocardial infarction and sudden death) was 79 in the diet group and 94 in the control group (P = 0.097). The CHD mortality was correlated with age, serum cholesterol level, blood pressure, body weight, smoking habits, and a combination of these risk factors. Additional Indexing Secondary prevention Coronary heart disease EXTENSIVE evidence implicates blood cholesterol as an important risk factor for the first event in coronary heart disease. Whether this also is true with regard to recurrent events has not been shown unequivocally. A previous report has been published of a 5-year study in Oslo of the effect of reducing the serum cholesterol level by dietary means in male survivors of myocardial Words: Serum cholesterol controlled dietary trial Mortality rate Myocardial infarction with the infarction.1 The present report deials mortality after 11 years for the patients included in that 5-year study. Methods Experimental Groups The trial includes 412 men, aged 30 to 64 From the Department of Medicine (VIII), Ullevaal Hospital, Oslo University Medical School, Oslo, Norway. Address for reprints: Paul Leren, M.D., Ullevaal Hospital, Oslo, Norway. Received April 15, 1970; revision accepted for publication July 14, 1970. years, discharged from medical departments in Oslo during the 3-year period, 1956-58, with a first diagnosis of myocardial infarction. They were allocated at random to the experimental diet group and to the control group after 1 to 2 years, on the average 20 months after the primary infarction. Factors of age and clinical severity were successfully randomized. Methods The detailed clinical follow-up was undertaken only during the first 5 years of actual trial. This study included clinical examination, diet and weight control, serial serum cholesterol analyses, and electrocardiograms. Subsequent to the 5-year trial all men have been followed through to 11 years after entry to determine those who died. further clinical or laboratory evaluation or dietary advice was given. Tests of significance between the diet and the control groups after 5 years and between various subgroups during the whole study period have been made by means of simple X2 tests. Tests of significance between survival data of those on the diet and the control groups after 11 years have been calculated as described by Cutler and Ederer.2 935 No
936 LEREN Table 1 Daily Food Intake of Experimental Group as Measured During Initial 5-Year Study Grams of calories Carbohydrates (total) 269 45.5 Sugar 51 Protein 92 15.0 Fat (total) 104 39.0 Saturated fat 22 8.3 Monounsaturated fat 27 10.1 Polyunsaturated fat 55 20.7 ary cholesterol 0.264 P/S ratio 2.4 Abbreviation: P/S = ratio of polyunsaturated fat to saturated fat. The Experimental for the 5-Year Trial This cholesterol lowering diet was low in animal fats and dietary cholesterol and rich in vegetable oil. Much emphasis was laid on continuous instruction and supervision of the dieters during the first 5 years of the trial. To obtain more precise information about the diet, 17 dieters were selected, and their diet was weighed or measured under the supervision of the dietitian for a period of 7 to 14 days. The results are presented in table 1. The average reduction in serum cholesterol of these selected dieters was 29% over the period of 5 years. The serum cholesterol values in the two groups are presented in figure 1. Serum Cholesterol (mg/100 ml) 300 r 280 F 2601 240p. 220 Start 3 t --------.x. X- X Five-Year Results There was a statistically significant lower incidence of myocardial reinfarction and of new angina pectoris in the diet group. The incidence of sudden death, however, was the same in the two groups. Table 2 recapitulates the major "harder" events after 5 years (omitting acquired angina). A statistically significant reduced incidence of major CHD relapses was demonstrated. The difference in total cardiovascular deaths and total deaths is large but is not significant on the 5% level of probability. Further details about selection of the patients, randomization, the experimental diet, CHD relapse incidence in various subgroups are presented in the 5-year report.' Eleven-Year Report Clinical and laboratory examinations of the men were discontinued when each man had stayed in the trial for exactly 5 years, as was diet instruction in the diet group. At the end of this 5- year period the surviving dieters were advised to adhere to the cholesterol lowering diet in the future. The surviving controls were informed that a reduced fat intake possibly might be beneficial, but they received no detailed dietary instructions. The death incidence in the diet and the control group, respectively, at the point when the last man to enter the study, had stayed in it for exactly 10 years will be presented. At this point three fourths of the survivors had been in the trial 15 21 27 33 39 45 51 60 Time (months) Figure 1 Mean serum cholesterol levels during the first 5 years of observation time. N Value at entry Mean reduction (at entry) (mg/100 ml) (mg) (%) 206 296 11 3.7 206 296 52 17.6 Republished with permission of Acta Medica Scandinavica.1 I I
OSLO DIET-HEART STUDY Five-Year Results Table 2 No. of men at risk 206 206 Fatal myocardial reinfarction 10 23 Sudden death 27 27 Nonfatal myocardial reinfarction 24 31 Major CHD relapses* 61 81 Total cardiovascular mortalityt 38 52 Total mortalityt 41 55 *P = 0.05 tp = 0.09 tp= 0.13 for 11 years. No person in the original groups has been lost to follow-up. Information on fatal cases in the study groups was obtained through the Life Insurance Companies' Institute for Medical Statistics at Ullevaal Hospital. This institute is following all men in the present trial. Whenever a death took place in hospital, the hospital record including the autopsy report was reviewed. This classification was not carried out blindly with regard to study variables. Information about the mode of death in cases of sudden death outside the hospital was 'obtained by contacting attending physicians, family members, or other witnesses. The conclusion about a fatal CHD relapse was based on the diagnostic criteria defined in the 5- year report. Fatal heart failure was given as a cause of death based on the clinical symptoms and signs of progressive cardiac decompensation in the absence of anginal pains prior to death and absence of other clinical and laboratory evidence of acute myocardial infarction, or autopsy evidence of a fresh myocardial infarction, if autopsy was performed. Results Table 3 presents the overall mortality in the Table 3 Eleven-Year Mortality Cause Fatal myocardial reinfarction 25 34 Heart failure 2 7 Sudden death 52 53 Other cardiovascular deaths 9 8 Cancer 7 5 Pneumonia and sepsis 4 0 Cerebral atrophy 1 0 Unknown cause 1 0 Suicide 0 1 Total mortality 101 108 Sudden Death Table 4 Witnessed deaths Preceded by chest pains 5 16 Instantaneous deaths 33 30 Unwitnessed deaths 14 7 Total sudden deaths 52 53 two groups. In the diet group 101 men died, and in the control group, 108. This difference is not statistically significant (P =0.35). In table 4 the entire sudden death group is displayed according to the mode of death and the overall difference is insignificant. Table 5 presents the incidence for all cardiovascular deaths. Unexplained deaths preceded by chest pains (type II sudden death in the 5-year report) were most probably due to new coronary occlusions, and in the present report they have been regarded as fatal myocardial infarction. Death in heart failure in postinfarct subjects has been called herein "fatal myocardial infarction." By such criteria, myocardial infarction was the cause of death of 32 dieters and 57 controls. This difference is highly significant (P = 0.004). The total CHD deaths (fatal myocardial infarction plus sudden death) were 79 in the diet group and 94 in the control group (P = 0.097). The total number of cardiovascular deaths was 88 in the diet group and 102 in the control group (P = 0.13). These numbers Table 5 Cardiovascular Mortality Fatal myocardial reinfarction 25 34 Fatal heart failure 2 7 Death preceded by chest pains 5 16 Fatal myocardial infarction* 32 57 Instantaneous deaths 33 30 Unwitnessed deaths 14 7 Total CHD mortality t 79 94 Cerebral vascular deaths 7 5 Other vascular deaths 2 3 Total cardiovascular mortalityt 88 102 *P = 0.004 tp = 0.097 tp = 0.13 937
938 LEREN c1. x b, d 9 1-.; 3. z m,. -0 ;. S, 4) 'd a) 'd A4 u 4 OL1-0 1 2 3 4 5 6 7 8 9 10 1 1 Years in Trial Figure 2 Fatal myocardial infarction: Estimated % survival 80.5 66.1 P = 0.004 11 -year survival curves. Standard error 3.2 include 12 cases of fatal stroke, two of ruptured aortic aneurysm, two of atherosclerotic occlusions of aorta, and one of pulmonary emboli. Autopsy was performed in 61 cases of fatal myocardial infarction, in 17 cases of sudden death (instantaneous and unwitnessed death) m 0 t 2 b.-.0 > E.d > 1-1 0 ; 1..i.0 4) 'a u I.D 0 P.. :d C.) 10 ar 80. 60.1, Overall D ie t in four of fatal stroke, and in four of the other types of vascular deaths. The diagnosis of cancer was made at autopsy in all cases. In three of the four cases with fatal pneumonia and sepsis, autopsy was performed. The fourth case has been reported previously and a death of unknown cause has also been reported earlier.' One man committed suicide by hanging. Autopsy was not performed. In figures 2 to 4 data are given relative to the time in the trial at which CHD deaths, as well as deaths from all causes, occurred. The mortality rates have been calculated by the life table method, taking into account the number at risk in the various years of the trial. Figure 2 demonstrates the higher death rate from myocardial infarction in the control group. The difference was small during the 2 first years of the trial. The curves for total CHD deaths (fig. 3), as well as those for total cardiovascular deaths (not given), demonstrate the same trend, although the differences between the two groups are statistically not significant at the 5% level. Figure 4 presents the overall survival rates and demonstrates only a small difference between the groups. 100l.0 0 401 4 ol f0 40; 0 1 2 3 4 5 6 7 8 9 10 11 Years Figure 3 in Trial CHD mortality: 11-year survival curves. Estimated % Standard survival error 59.4 3.6 50.8 P - 0.097 3.8 xs >> ff Controtl- 0 1 2 3 4 5 6 7 8 9 10 1 1 Years in Trial Figure 4 Overall mortality: 11-year survival curves. Estimated % survival 50.3 45.6 P - 0.35 Standard error 3.5 3.6
OSLO DIET-HEART STUDY 939 Table 6 Eleven-Year Incidence of CHD Relation to Age. Mortality in Age < 60 Age > 60 At risk 134 123 72 83 Fatal infarction 23 29 9 28 Sudden deaths 26 21 21 16 Total CHD deaths 49 50 30 44 %, 36.5 40.7 41.7 53.0 CHD Mortality in Relation to Various Factors Age Age refers to age at the start of the trial. The data for the CHD deaths in relation to age are given in table 6. As expected, the mortality in both groups is higher in the older age group (>60) than in the younger ( < 60). The differences between the diet and control age subgroups are small and statistically significant only for fatal myocardial infarction at age > 60. Serum Cholesterol Level The serum cholesterol values refer to the mean values obtained during the first 5 years of the study. It appears from table 7 that at the age < 60, the patients who died of CHD have a higher mean cholesterol value than the survivors (P = 0.01, both groups combined). At the age > 60 there is no such difference. Blood Pressure The data on blood pressure refer to the value at entry. The 5-year report showed that the mean blood pressure, as well as the relative distribution of normotensives and hypertensives in the two groups, remained almost unchanged during the first 5 years of the trial. Table 8 presents the overall CHD mortality rate in relation to normal and elevated diastolic blood pressure. Hypertension seems to be of little importance in this study as an isolated risk factor. Body Weight The mean body weight in the control group remained almost unchanged during the first 5 years of the trial. The dieters, however, had an average weight loss of 2 kg as compared with the controls. For the purpose of evaluating the importance of body weight to CHD mortality, data from both groups have been combined (table 9). In the present study of postmyocardial infarction patients, actual body weight Table 7 Eleven-Year Report: Mean Serum Cholesterol Value in Survivors and Patients Dead of CHD in Relation to Age group at age group at age Both groups at age <60 >60 <60 > 60 <60 > 60 Died of CHD 261* 248 301 276 281 265 Survivors 248 246 285 282 265 265 *Values in mg/100 ml. Table 8 Eleven-Year Incidence of CHD Mortality in Relation to Diastolic Blood Pressure at Entry Diastolic blood pressure (mm Hg) group group 90 or less 95 or more 90 or less 95 or more At risk 84 122 110 96 Age (yr) 56.0 56.3 55.8 56.8 CHD deaths 35 44 46 48 0/0 41.7 36.1 41.8 50.0
940 Table 9 Eleven-Year Incidence of CHD Deaths in Relation to Body Weight: Both Groups Combined Under- Overweight Normal- weight (>10%) weight (>10%) At risk 35 237 140 Age (yr) 56.1 33.9 56.8 Cholesterol 246 268 276 (mg/100 ml) CHD deaths 17 95 61 '70 48.6 40.1 43.6 seems to have had no influence on the CHD mortality rate, but weight change was not analyzed. Smoking Habits Smoking habits were about the same in the two groups at entry and showed practically no change during the first 5 years of the trial. Because of the frequent combination of selfrolled cigaretteis and a pipe, it was impossible to consider cigarette smokers alone. Table 10 presents the overall CHD mortality rate in relation to smoking habits. The death rate in the smokers tends to be higher than in the nonsmokers. However, the difference is small and not statistically significant. The incidence of sudden death was the same (20.3 and 20.5%) in smokers and nonsmokers. Smoking was not related to the serum cholesterol level. Combined Risk Factors Figure 5 evaluates the importance of an elevated serum cholesterol level as a risk factor in the presence of hypertension in smokers. The CHD mortality rate was three Table 10 Eleven-Year Incidence of CHD Deaths in Relation to Smoking Habits: Both Groups Combined Nonsmokers Smokers At risk 146 266 Age (yr) 57.1 55.8 Cholesterol 271 268 (mg/100 ml) CHD deaths 54 119 No, 37.0 44.7 LEREN times higher in the hypertensive smokers with a cholesterol level above 250 compared with normotensive nonsmokers with a cholesterol level below 250. This difference is highly significant (P - 0.007). Discussion In the present study the groups were randomized after accepted statistical principles, and it seems justified to conclude that the two groups were equally at risk at the start of the trial. The size of the test groups, 206 in each, seems to have been too small for the analysis of fatal CHD relapses in the 5-year study. However, this does not seem to he so when the nonfatal CHD events are included. In the present report on the men observed for at least 10 years (three fourths of them for 11 years), the nonfatal events have been CHD Mortality Per cent 50 F 40 30.. 20. 1o4. o. Mean Cholesterol Diast. BP Smoking Habits C HD Deaths At risk Age All Ages Both Groups 15,0-24 9-9 0 Non- Smokers 3 2 0 5 7,4 Figure 5 Co mbined 48,1 250 95- Smokers 3 7 77 55,3 Eleven-year incidence of CHD deaths in relation to combined risk factors. Circalation, Volume XLII, November 1970
OSLO DIET-HEART STUDY disregarded, and the evaluation is limited to death only, Since clinical and laboratory observations were performed only for the first 5-year period, evaluation of risk factors in the present report is based on analysis during that period. Strict diet instructions and supervision of the dieters were also limited to the first 5 years. The success of the present study as a controlled trial depended entirely on the degree of diet adherence of the dieters and was confirmed by serum cholesterol levels that were significantly lower than in the controls during the first 5 years of the trial. We do not know whether this also holds good for the rest of the observation period, as no information is available on the dietary habits and serum lipids of either group after completion of the first 5-year phase of the study. However, even though the dieters who were energetically trained through 5 years, presumably continued more or less to follow their new dietary habits, some relaxation may be assumed. It is likely that the effect on mortality of strictly supervised dietary intervention on the diet group during the latter part of the observation period would be greater than the effect observed in this study; in other words, the results may be considered to underestimate the results of a rigid 11-year dietary trial. In the evaluation of the 11-year results it should be kept in mind that the average age of these postmyocardial patients 11 years after entry was about 67, and that the oldest of the survivors was 78. It should be remembered also that the classification of deaths was not carried out blindly, although it was performed according to precisely defined criteria. The results after 11 years show a reduction in the mortality rate from myocardial infarction in the diet group. However, just as was the case after the 5 years, there was no significant difference in sudden deaths between the groups. It should be remembered that the unexplained deaths preceded by chest pains (type II sudden death of the 5-year report) are regarded in the present report as fatal myocardial infarction, which is indeed the most probable cause of these deaths. It 941 seems as if sudden death in survivors of myocardial infarction is uninfluenced by diet. The reason for this is not clear. A possible explanation might be that fatal arrhythmias in survivors of an infarct may not be directly related to the degree of coronary atherosclerosis and thrombosis, but rather to the localization of atherosclerotic plaques, myocardial fibrosis, and hypoxic areas to vulnerable parts of the heart. Thus, the contention that the recommended diet has an antiatherogenic effect might well be compatible with the absence of effect on the incidence of sudden death in survivors of a myocardial infarction. The relation between the serum cholesterol level in the survivors and those who died of CHD, is of interest. As in the 5-year report, a higher mean cholesterol level was found in the present study in those who died of CHD compared with that of the survivors. Grouping the men by age groups ( <60 and > 60) reveals this difference only in the younger age group. However, unlike the results after 5 years, which also included nonfatal events, the difference in overall CHD mortality between the diet and the control groups is similar in both age groups. The reason for this discrepancy is not understood. However, it should be remembered that we do not know the cholesterol levels for the latter period of the trial. Epidemiologic studies have demonstrated several factors associated with the risk of developing first manifestations of coronary heart disease. Blood lipids, blood pressure, and cigarette smoking are such risk variables. The present study demonstrates that these factors, all amenable to control, are of prognostic significance even after a myocardial infarction. When combining data from both groups, a three-fold greater CHD mottality rate is demonstrable among the hypercholesterolemic, hyperten'sive smokers than among those in whom these factors were low or absent. In spite of the small numbers this observation lends some support to the view that the multifactorial approach is the
942 best way to the solution of the coronary heart disease problem. Acknowledgment Dr. Knut B. Westlund, Life Insurance Companies' Institute for Medical Statistics at the Oslo City Hospitals, provided mortality data and helped with statistical analyses. Mrs. Vera Haakenstad and Mr. K'are Porsbhll gave skillful technical assistance in the LEREN preparation of the manuscript. To all these and many others I express my warm gratitude. References 1. LEREN P: The effect of plasma cholesterol lowering diet in male survivors of myocardial infarction. Acta Med Scand suppl. 466, 1966 2. CUTLER SJ, EDERE:R F: Maximum utilization of the life table method in analyzing survival. j Chron Dis 8: 699, 1958 Early Judean Clinical Trial in Then Daniel said.. "Test your servants for ten days; let us be given seeds to eat and water to drink. Then let our appearance and the appearance of the youths who eat the king's rich food be observed by you, and according to what you see deal with your servants." So he harkened to them in this matter, and tested them for ten days. At the end of ten days it was seen that they were better in appearance and fuller in the flesh than all the youths who ate the king's rich food. So the steward took away their rich food and wine they were to drink, and gave them seeds. (Daniel I: 10-16)-From Israel J Med Sci 1: 399, 1965. Circulation, Volume XLIJ, November 1970