Adv. Cardiol., vol. 24, pp.94-104 (Karger, Basel 1978)
General Aspects of Secondary Prevention after Myocardial Infarction DAG ELMFELDT, LARS WILHELMSEN, ANDERS VEDIN, CLAES WILHELMSSON, AKE HJALMARSON and ROBERT BERGSTRAND Department of Medicine I, University of Goteborg, Sahlgren's Hospital, Goteborg
Introduction
Secondary prevention after myocardial infarction (MI) is defined here as reduction of morbidity and nonfatal reinfarctions achieved by special measures. The current great interest in this matter is due to the poor prognosis after an infarct. During 5 years' follow-up of 300 male infarction patients in G6teborg aged 55 years or less, the total mortality (prehospital, hospital and posthospital mortality) was 47 %. Men aged 40-49 years who had sustained a first MI ran a 30 times greater risk of dying or suffering reinfarction during the first year after discharge from hospital than healthy men of the same age. During the second year the risk was 10 times as great as in healthy men of the same age. Cardiovascular diseases were the direct cause of death in 90 % of cases during 2 years' follow-up [32].
Factors related to the mortality and the nonfatal reinfarction rate after a first MI are called secondary risk factors. It is logical to assume that, if it is possible to intervene against such risk factors, a secondary preventive effect will be achieved. Secondary risk factors will also identify those individuals who run an especially high risk of dying or suffering nonfatal reinfarction. This is of great importance since those with high risk obviously need special attention. Furthermore, in connection with follow-up studies and secondary preventive trials, secondary risk factors will make it possible to ensure comparability of groups. The most informative risk factors for death after an in-
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Secondary Risk Factors
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farct all seem to be associated with a complicated clinical course due to extensive myocardial damage, e. g. left ventricular failure, high enzyme maximum and large heart volume. By means of a multiple logistic regression model, developed in Goteborg, the mortality during 2 years' follow-up could be well predicted. In the highest decile of risk of death, according to the function, the mortality was almost 70 % and 80 % of all deaths occurred in the three highest deciles. The risk of nonfatal reinfarction, however, was not related to the factors determining death [34]. Since the most informative secondary risk factors were all associated with the extent of MI, it is not possible to intervene against these factors, hoping for a secondary preventive effect, if the acute stage is already past. However, there is a possibility of intervention during the early, acute stage in order to prevent extension of the infarcted area. This will be discussed later.
Primary Risk Factors
Tobacco Smoking The influence of cessation of smoking on the prognosis after infarction was investigated in Goteborg in a group of 738 male smokers with primary infarcts [39,41]. Of the smokers, 412 (57 %) stopped smoking in connection with their stay in hospital and remained ex-smokers. The patients who had stopped smoking had a higher risk of death according to the secondary risk function than those who continued to smoke. It was therefore very interesting to find that those who stopped smoking had a much more favorable course during follow-up. After up to 7.5 years the total mortality was 10% in the group who stopped smoking compared to 19 % in the group who continued to smoke. The cumulative survival rate was 86 % after 5 years and 84% after 7.5 years in the group who stopped smoking. The corresponding figures for patients who continued to smoke were 71 and 51 %, respectively.
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Since the secondary risk factors seem difficult to attack in order to achieve a secondary preventive effect, much interest has been focused on the primary risk factors. Is it possible to decrease the mortality and the nonfatal reinfarction rate by intervening against primary risk factors? Most interest has been devoted to the three major primary risk factors; tobacco smoking, hypertension and hypercholesterolemia. Physical activity may also be discussed in this connection.
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Other authors have also reported a favorable effect of stopping smoking after infarction [24].
Hypertension
et aZ. [40] studied 504 men with primary infarction, 184 of whom were hypertensive and 320 normotensive. Patients who at any time before their infarction had been informed by a doctor that they had high blood pressure or who had blood pressure values necessitating treatment during the first year of follow-up were considered to have hypertension. Standard criteria for treatment were applied, i. e. systolic blood pressure;;;;. 160 mm Hg and/or diastolic blood pressure ;;;;.105 mm Hg at two consecutive measurements for patients aged below 55 years and diastolic blood pressure ;;;;.105 for patients above this age [8]. During the period of the study, saluretic diuretics were used as basic therapy. The groups were comparable with respect to the most informative variables for prediction. The mortality was the same in both groups (10%), but the group of patients with hypertension had significantly more nonfatal reinfarctions (21 %) than the normotensive patients (10 %) during 2 years' follow-up in spite of the antihypertensive treatment. WILHELMSSON
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Hypercholesterolemia Several studies have dealt with the question whether secondary prevention is possible by lowering serum cholesterol, either by diet or by drugs. The results are conflicting. LEREN [19] allocated at random male patients who had survived a first MI, to 2 groups, with 206 men in each. One group received diet recommendations which reduced serum cholesterol by almost 18 % and the other group continued with their ordinary diet. After 5 years' follow-up the total number of fatal and nonfatal reinfarctions was lower in the diet group compared to the control group. After 11 years' follow-up about 20 % of the men in the diet group had died of MI compared to 35 % in the control group. However, the total mortality did not differ between the two groups, either after 5 or after 11 years. Other workers have failed to show any secondary preventive effect of cholesterol-reducing diets. The Coronary Drug Project group published the final results of their large trial of secondary prevention by cholesterol-lowering drugs in 1975. More than 8,000 patients aged from 30 to 64 years entered the study, most of them more than 2 years after their infarct. The patients were allocated at random to 6 groups, 5 of which were given cholesterol-lowering drugs. The 2 groups who were given estrogen in two different dosages and the group given thyroxine had to stop the drug treatment earlier than planned because of an excess morbidity and mortality
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when compared with the control group. The groups who received clofibrate, niacin and placebo, respectively, were followed as planned. Mter 5 years, as well as after total follow-up, the total mortality and the cause-specific mortality in the clofibrate, niacin and placebo groups were the same. The niacin group had a lower incidence of nonfatal reinfarction than the placebo group, but more general use of the drug could not be recommended because of negative side-effects [5].
Supervised Physical Training The possible secondary preventive effect of supervised physical training after infarction was studied in Goteborg [28,37]. 315 nonselected patients aged 57 years or less were randomly allocated to supervised physical training in a training group (138 men and 20 women) or to a control group (142 men and 15 women). Altogether 27 % of the patients had to be excluded from the training group owing to cardiac contraindications or practical difficulties in carrying out the training program (an equal number for both reasons). The training was started 3 months after the infarction and there were three sessions each week. In spite of several efforts to reduce the dropout, there was a high dropout rate, increasing with the duration of follow-up. After 1 year the maximum work capacity measured on a bicycle ergometer was significantly greater in the patients in the training group than in those in the control group. The best improvement was seen in patients limited by angina pectoris [28]. After training, the same submaximal work could be performed with a lower pulse rate and lower blood pressure, i. e. with considerably reduced cardiac work [37]. During 4lyears' follow-up 28 patients (18 %) in the training group and 35 patients (22 %) in the control group died. The difference is not statistically significant (p = 0.40). The number of nonfatal reinfarctions was 25 (16 %) and 28 (18 %), respectively. Patients from the training group who were really training 1 year after their infarction were compared with patients from the control group, matched with respect to secondary risk. There was a trend towards lower mortality in the patients who were training but the difference was not significant (p = 0.16) [37].
Optimal basic care, including patient education and early detection and treatment of complications and risk factors, may be of secondary preventive value after an MI. The effect of such care in 96 men managed at a special
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Basic Care
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post-MI clinic in Goteborg was compared to traditional outpatient treatment in 85 other male patients [35]. All patients were in the age group 57-67 years. No patient included in this analysis was treated with antiarrhythmic agents, fJ-blockers, lipid-lowering drugs or anticoagulants. The groups were equally burdened by secondary risk factors. After 2 years' follow-up the patients treated at the post-MI clinic had a significantly lower incidence of new coronary artery disease overall (21 %) than the others (41 %). No statistically significant reduction in mortality alone was observed, however.
Intervention against Possible Mechanisms
0/ Rein/arction and Death
Long-Term Anticoagulant Therapy There have been a great number of studies dealing with the possibility of a secondary preventive effect of long-term anticoagulant therapy. A collaborative analysis comprised 2,205 male and 282 female patients included in nine controlled trials [12]. The groups receiving anticoagulant therapy and the control groups were shown to be alike in respect of relevant clinical characteristics. The mortality was less in males given anticoagulants, but the apparent benefit seemed to be restricted to patients reporting either prolonged
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Long-Term fJ-Receptor Blockade The secondary preventive effect of continuous fJ-receptor blockade after infarction was first shown from the post-MI clinic in Goteborg [33, 38]. During the years 1970 and 1971,274 patients, men and women, aged between 57 and 67 years, were treated at the post-MI clinic. Of these, 230 were included in the study, 44 being excluded owing to contraindications to fJ-blockade. The patients were randomly allocated to treatment with alprenolol (n = 114) or placebo (n = 116). No patient was treated with other antiarrhythmic agents or lipid-lowering drugs and no patient took anticoagulants after discharge from hospital. The number of sudden deaths during the 2-year period of follow-up was significantly lower in the group treated with alprenolol (n = 3) than in the placebo group (n = 11). The total mortality in the alprenolol group (n = 7) was half that in the placebo group (n = 14). No significant reduction in the number of nonfatal reinfarctions was found [33, 38]. Since then other workers have also demonstrated a significant reduction in mortality after MI during continuous treatment with fJ-blocking agents [1, 10].
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angina pectoris or a previous infarct at admission. Other studies have shown a positive effect of anticoagulant therapy in other risk groups, e. g. seriously ill patients with left ventricular decompensation, heart enlargement or atrial fibrillation. Other workers have failed to show any secondary preventive effect of long-term anticoagulant therapy. Long-Term Treatment with Other Drugs There is no conclusive evidence of a secondary preventive effect of long-term treatment with antiarrhythmic drugs other than fJ-blockers. For instance, procainamide [18], quinidine and phenytoin [3] have been tried. All these drugs have considerable negative side-effects [6, 18,20, 30]. Conflicting results have been published concerning a possible secondary preventive effect of long-term treatment with estrogens [5, 21] and tolbutamide [26, 31].
Intervention against Atherosclerotic Lesions Coronary Bypass Surgery Most analyses of mortality and reinfarction after coronary bypass surgery deal with patients with angina pectoris and not exclusively with post-MI patients. Improved survival after bypass surgery in selected patients with angina pectoris, e. g. those with a significant stenosis in the main left coronary artery, has been reported in some studies [25], but other workers have not been able to show this. Whether there is a secondary preventive effect of coronary bypass surgery after an MI is still more uncertain.
Since the major secondary risk factors are associated with a large infarction, it is logical to try to limit the myocardial damage, which may be possible during the early acute stage. Such measures may then result not only in a lower acute mortality but also in less invalidity as well as a better long-term prognosis. Myocardial ischemia and infarction are due to an imbalance between the myocardial metabolic demand and the coronary arterial supply of fluid, oxygen and substrate. Adrenergic fJ-blocking durgs will minimize the oxygen demand, partly by decreasing the blood pressure-heart rate product.
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Intervention Aimed at Limiting Myocardial Damage at the Time of the First Infarct
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A double-blind randomized study of metoprolol given intravenously immediately after the patient's arrival at the hospital is now going on in Goteborg with the aim of evaluating the effects of ,8-blockade on infarction size, arrhythmias and the acute and long-term mortality.
It has been claimed that the association between smoking and MI is only apparent and secondary to, e. g., personality or alcohol abuse. Smoking increases the risk of MI irrespective of personality and alcohol consumption, however [13, 36]. There are several theories as to how smoking might have a pathogenetic effect in connection with infarction and it seems reasonable to assume a direct causal relationship. The finding [39] that a secondary preventive effect of stopping smoking after MI was demonstrable within 2 years strongly indicates that smoking is not only associated with MI as such but also has a decisive influence on the etiology and pathogenesis. WILHELMSSON et al. [40] were unable to demonstrate higher mortality in hypertensives during the first 2 years after discharge from hospital following MI, but demonstrated a higher incidence of nonfatal reinfarction, which may be assumed to lead to higher mortality during longer follow-up. Other workers have shown a higher mortality in hypertensives after infarction [4, 11]. The hypertensives thus constitute a risk group that justifies special attention from the secondary prophylactic point of view. High serum cholesterol is a well-documented risk factor for primary MI [17,36]. Certain studies in the USA have shown an association between serum cholesterol and reinfarction [4,14], while other studies have been unable to verify this [15, 23, 29]. These conflicting results can be explained by selection of patients and differences in the duration of follow-up. The fact that the cholesterol level was not related to the prognosis after infarction in some investigations does not exclude the possibility of reduction of serum cholesterol after infarction having a secondary preventive effect. Several studies into this question, with conflicting results, have been published [5, 19]. This controversy can be explained by patient selection, differences in methods of reducing cholesterol, choice of different end points, etc. The lack of a secondary preventive effect in the large Coronary Drug Project [5] would seem to weight heavily in the debate concerning drug treatment. Several previous studies have shown that physical activity improves work capacity in patients who have had MI or who have angina pectoris [2, 28].
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Discussion
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Other authors have claimed that the incidence and severity of reinfarction decrease when patients participate in physical training after infarction [27]. Some workers have also considered that they have been able to demonstrate a reduction in mortality after MI in training studies [16,27]. However, allocation of patients to training or no training has not been done with adequate randomization in the studies showing a positive influence on reinfarction and mortality. It has been claimed that a very high level of physical activity is needed to achieve a primary preventive effect [22] and the same thing might be true for a secondary preventive effect, if it exists. The activity level was kept as high as possible in the Goteborg trial, and the results were also analyzed after exclusion of those not training adequately, but the effect was still nonsignificant. At present it is not possible to identify the factor or factors explaining why treatment at the post-MI clinic in Goteborg was associated with fewer reinfarctions. There are probably several factors contributing to this positive effect. Effective antismoking advice, information to patients about what to do in the event of symptoms occurring and early initiation of treatment when complications arose are possible explanations. Several mechanisms might explain the mortality-lowering effect of continuous f1-blockade after infarction. It might, for example, prevent development of infarction and limit the size of the ischemic area. Another possibility is prevention of malignant arrhythmias during the initial phase of reinfarction. It should be emphasized that the greatest reduction in mortality during f1-blockade related to the incidence of sudden death, which strongly suggests that f1-blockade has a profound effect during the initial phase of development of ischemia. A high proportion of deaths during follow-up after infarction are sudden, obviously due to malignant arrhythmias. Other deaths are due to reinfarction. In some of these cases the infarction is not associated with a coronary thrombosis, either primary or secondary. Any beneficial effect of anticoagulant therapy must be due to prevention of thromboembolic events. Since these do not seem to be responsible for most deaths after infarction, the possible secondary preventive effect of long-term anticoagulant therapy after an MI is limited and any anticoagulants should not be given to nonselected patients series. The conflicting results of secondary preventive trials with antiarrhythmic drugs (apart from f1-blockers), estrogens and tolbutamide, as well as with coronary bypass surgery, seem to rule out these forms of intervention after an MI at present.
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Conclusions On the basis of the findings described and discussed, we draw at present the following conclusions concerning secondary prevention after MI: (1) Optimal basic medical care should be provided, including vigorous treatment of e. g. decompensation, angina pectoris and hypertension, and anticoagulant therapy if indicated bye. g. heart enlargement and atrial fibrillation. (2) Smokers should stop smoking. (3) fJ-Blockers should be given. (4) Physical training should be encouraged in some categories of patients, e. g. those whose level of activity is limited by angina pectoris or nervousness, but it is questionable whether it has any effect on prognosis. (5) Reduction of serum cholesterol may be beneficial in the long run but should not be given high priority since other, more accessible, measures have a dominating influence on the prognosis after infarction.
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AHLMARK, G.; SAETRE, H., and KORSGREN, M.: Reduction of sudden deaths after myocardial infarction. Lancet ii: 1563 (1974). BRUCE, R.A.; GEY, C. 0.; CooPER, M. N.; FISCHER, L. D., and PETERSON, D.: Seattle Heart Watch: initial clinic, circulatory and electrocardiographic response to maximal exercise. Am. J. Cardiol. 33: 459-469 (1974). Collaborative Group: Phenytoin after recovery from myocardial infarction. Lancet ii: 1055-1057 (1971). Coronary Drug Project Research Group: Factors influencing long-term prognosis after recovery from myocardial infarction; three-year finding of the coronary drug project. J. chron. Dis. 27: 267-285 (1974). Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. J. Am. med. Ass. 231: 360-381 (1975). CRAMER, G.: Early and late results of conversion of atrial fibrillation with quinidine. A clinical and hemodynamic study. Acta med. scand., suppl. 490 (1968). ELMFELDT, D.; WILHLEMSEN, L.; TIBBLIN, G.; VEDIN, J. A.; WILHELMSSON, C., and BENGTSSON, C.: Registration of myocardial infarction in the city of Goteborg, Sweden. J. chron. Dis. 28: 173-186 (1975). ELMFELDT, D.; WILHLEMSEN, L.; TIBBLIN, G.; VEDIN, J.A.; WILHELMSSON, C., and BENGTSSON, C.: A postmyocardial infarction clinic in Goteborg, Sweden. Acta med. scand. 197: 497-502 (1975). ELMFELDT, D.; WILHELMSSON, C.; VEDIN, A.; TIBBLIN, G., and WILHELMSEN, L.: Characteristics of representative male survivors of myocardial infarction compared to a representative population sample. Acta med. scand. 199: 387-398 (1976).
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GREENE, K. G.: Improvement in prognosis of myocardial infarction by long term beta-adrenoreceptor blockade using practolol. Br. med. J. iii: 735-740 (1975). HELMERS, C.: Short and long-term prognostic indices in acute myocardial infarction. A study of 606 patients initially treated in a coronary care unit. Acta med. scand., suppl. 555 (1974). International Anticoagulant Review Group: Collaborative analysis of long-term anticoagulant administration after acute myocardial infarction. Lancet i: 203-209 (1970). JENKINS, C. D.; ROSENMAN, R. H., and ZYZANSKI, S. J.: Cigarette smoking. Its relationship to coronary heart disease and related risk factors in the Western Collaborative Group Study. Circulation 38: 1140--1155 (1968). JENKINS, C. D.; ZYZANSKI, S. J., and ROSENMAN, J. M.: Risk of new myocardial infarction in middle-aged men with manifest coronary heart disease. Circulation 53: 342-347 (1976). JOHANSSON, S.; VEDIN, J.A.; WILHELMSSON, C.; ELMFELDT, D., and WILHELMSEN, L.: Hypercholesterolemia after myocardial infarction (in press). KELLERMAN, J. J.: Physical conditioning in patients after myocardial infarction. Schweiz. med. Wschr. 103: 79-85 (1973). KEyS, A.; ARAVANIS, C.; BLACKBURN, H.; BUCHEM, F. S. P. VAN; BUTZINA, R.; DJORDJEVIC, B. C.; FIDANZA, F.; KARVONEN, M. J.; MENOTTI, A.; PuoOU, V., and TAYLOR, H.: Probability of middle-aged men developing coronary heart disease in five years. Circulation 45: 815-828 (1972). KORSOWSKY, B. D.; TAYLOR, J.; LoWN, B., and RITCHIE, R. F.: Long-term use of procaine amide following acute myocardial infarction. Circulation 47: 1204-1210 (1973). LEREN, P.: The Oslo diet-heart study: 11 year-report. Circulation 42: 935-942 (1970). LoWN, B.; TEMTE, J. V., and ARTER, W. J.: Ventricular tachyarrhythmias, clinical aspects. Circulation 47: 1364-1381 (1973). MARMORSTON, J.; MOORE, F. J.; HOPKINS, C. E.; KUZMA, D. T., and WEINER, J.: Clinical studies of long-term estrogen therapy in man with myocardial infarction. Proc. Soc. expo BioI. Med. 110: 400-408 (1962). MORRIS, J. N.; ADAMS, C.; CHAVE, S. P. N.; SIREY, C.; EpSTEIN, L., and SHEEHAN, D. J.: Vigorous exercise in leisure-time and the incidence of coronary heart disease. Lancet i: 333-339 (1973). MULCAHY, R.; HICHEY, N.; GRAHAM, J., and MCKENZIE, G.: Factors influencing long-term prognosis in male patients surviving a first coronary attack. Br. Heart J. 37: 158-165 (1975). MULCAHY, R.; HICHEY, N.; GRAHAM, J. M., and MAcAlRT, J.: Factors affecting the 5 year suvival rate of men following acute coronary heart disease. Am. Heart J. 93: 556-559 (1977). OBERMAN, A.; HARRELL, R. R.; RUSSELL, R. O. jr.; KONCHONKOS, N. T.; HOLT, J. H., and RACKLEY, C. E.: Surgical versus medical treatment in disease of the left main coronary artery. Lancet ii: 591-594 (1976). PAASIKIVI, J.: Long-term tolbutamide treatment after myocardial infarction. Acta med. scand., suppi. 507 (1970). RECHNITZER, P. A.; YUHASZ, M. S.; PAIVIO, A.; PICKARD, H.A., and LEFCOE, N.:
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Effects of a 24-weeks exercise program on normal adults and patients with previous myocardial infarction. Br. med. J. i: 734-735 (1967). SANNE, H.; ELMFELDT, D.; GRIMBY, G.; RYDING, G., and WILHELMSEN, L.: Exercise tolerance and physical training of non-selected patients after myocardial infarction. Acta med. scand., suppl. 551 (1973). SHANOFF, H. M.; LITTLE, J.A., and CslMA, A.: Studies of male survivors of myocardial infarction: relation of serum lipids and lipoproteins to survival over a 100year period. Can. med. Ass. J. 103: 927-931 (1970). STORSTEIN, 0.: Syncope and sudden death as a side-effect of treatment with antiarrhythmic drugs; in SAND/), FLENSTED-JENSEN and OLESEN Symposium on cardiac arrhythmias, pp. 505-514 (AB Astra, SOdertiilje 1970). University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 19: suppl2 (1970). VEDIN, A. : Myocardial infarction in Goteborg 1968-1970. Mortality, recurrencies and prognostic factors during two years' follow-up of patients who survived the hospitalperiod; thesis, pp. 1-128 (Elanders, Kungsbacka 1974). VEDIN, A.; WILHELMSSON, C., and WERK/), L.: Chronic alprenolol treatment of patients with acute myocardial infarction after discharge from hospital. Acta med. scand., suppl. 575 (1975). VEDIN, A.; WILHELMSEN, L.; WEDEL, H.; PETTERSSON, B.; WILHELMSSON, C.; ELMFELDT, D., and fuBLIN, G.: Prediction of cardiovascular deaths and non-fatal reinfarctions after myocardial infarction. Acta med. scand. 201: 309-316 (1977). VEDIN, A.; WILHELMSSON, C.; TmBLIN, G., and WILHELMSEN, L.: The postinfarction clinic in G/)teborg, Sweden. A controlled trial of a therapeutic organization. Acta med. scand. 200: 453-456 (1976). WILHELMSEN, L. ; WEDEL, H., and TmBLIN, G. : Multivariate analysis of risk factors for coronary heart disease. Circulation 48: 950-958 (1973). WILHELMSEN, L.; SANNE, H.; ELMFELDT, D.; GRIMBY, G.; TmBLIN, G., and WEDEL, H.: A controlled trial of physical training after myocardial infarction. Prevo Med. 4: 491-508 (1975). WILHELMSSON, C.; VEDIN, A.; fuBLIN, G.; WILHELMSEN, L., and WERK/), L.: Reduction of sudden deaths after myocardial infarction by treatment with alprenolol. Lancet ii: 1157-1159 (1974). WILHELMSSON, C.; VEDIN, A.; ELMFELDT, D.; fuBLIN, G., and WILHELMSEN, L.: Smoking and myocardial infarction. Lancet i: 415-420 (1975). WILHELMSSON, C.; VEDIN, A.; ELMFELDT, D.; TmBLIN, G., and WILHELMSEN, L.: Hypertension and myocardial infarction. Am. J. Cardiol. (submitted for publication). ABERG, A.; ULVENSTAM, G.; VEDIN, A.; WILHELMSSON, C.; ELMFELDT, D.; WEDEL, H., and WILHELMSEN, L.: Cessation of smoking after myocardial infarction: effects on mortality (in press).
D. ELMFELDT, MD, Department of Medicine I, University of Goteborg, Sahlgren's Hospital, S-413 45 GOteborg (Sweden)
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General Aspects of Secondary Prevention after Myocardial Infarction DAG ELMFELDT, LARS WILHELMSEN, ANDERS VEDIN, CLAES WILHELMSSON, AKE HJALMARSON and ROBERT BERGSTRAND Department of Medicine I, University of Goteborg, Sahlgren's Hospital, Goteborg
Introduction
Secondary prevention after myocardial infarction (MI) is defined here as reduction of morbidity and nonfatal reinfarctions achieved by special measures. The current great interest in this matter is due to the poor prognosis after an infarct. During 5 years' follow-up of 300 male infarction patients in G6teborg aged 55 years or less, the total mortality (prehospital, hospital and posthospital mortality) was 47 %. Men aged 40-49 years who had sustained a first MI ran a 30 times greater risk of dying or suffering reinfarction during the first year after discharge from hospital than healthy men of the same age. During the second year the risk was 10 times as great as in healthy men of the same age. Cardiovascular diseases were the direct cause of death in 90 % of cases during 2 years' follow-up [32].
Factors related to the mortality and the nonfatal reinfarction rate after a first MI are called secondary risk factors. It is logical to assume that, if it is possible to intervene against such risk factors, a secondary preventive effect will be achieved. Secondary risk factors will also identify those individuals who run an especially high risk of dying or suffering nonfatal reinfarction. This is of great importance since those with high risk obviously need special attention. Furthermore, in connection with follow-up studies and secondary preventive trials, secondary risk factors will make it possible to ensure comparability of groups. The most informative risk factors for death after an in-
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Secondary Risk Factors
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farct all seem to be associated with a complicated clinical course due to extensive myocardial damage, e. g. left ventricular failure, high enzyme maximum and large heart volume. By means of a multiple logistic regression model, developed in Goteborg, the mortality during 2 years' follow-up could be well predicted. In the highest decile of risk of death, according to the function, the mortality was almost 70 % and 80 % of all deaths occurred in the three highest deciles. The risk of nonfatal reinfarction, however, was not related to the factors determining death [34]. Since the most informative secondary risk factors were all associated with the extent of MI, it is not possible to intervene against these factors, hoping for a secondary preventive effect, if the acute stage is already past. However, there is a possibility of intervention during the early, acute stage in order to prevent extension of the infarcted area. This will be discussed later.
Primary Risk Factors
Tobacco Smoking The influence of cessation of smoking on the prognosis after infarction was investigated in Goteborg in a group of 738 male smokers with primary infarcts [39,41]. Of the smokers, 412 (57 %) stopped smoking in connection with their stay in hospital and remained ex-smokers. The patients who had stopped smoking had a higher risk of death according to the secondary risk function than those who continued to smoke. It was therefore very interesting to find that those who stopped smoking had a much more favorable course during follow-up. After up to 7.5 years the total mortality was 10% in the group who stopped smoking compared to 19 % in the group who continued to smoke. The cumulative survival rate was 86 % after 5 years and 84% after 7.5 years in the group who stopped smoking. The corresponding figures for patients who continued to smoke were 71 and 51 %, respectively.
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Since the secondary risk factors seem difficult to attack in order to achieve a secondary preventive effect, much interest has been focused on the primary risk factors. Is it possible to decrease the mortality and the nonfatal reinfarction rate by intervening against primary risk factors? Most interest has been devoted to the three major primary risk factors; tobacco smoking, hypertension and hypercholesterolemia. Physical activity may also be discussed in this connection.
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Other authors have also reported a favorable effect of stopping smoking after infarction [24].
Hypertension
et aZ. [40] studied 504 men with primary infarction, 184 of whom were hypertensive and 320 normotensive. Patients who at any time before their infarction had been informed by a doctor that they had high blood pressure or who had blood pressure values necessitating treatment during the first year of follow-up were considered to have hypertension. Standard criteria for treatment were applied, i. e. systolic blood pressure;;;;. 160 mm Hg and/or diastolic blood pressure ;;;;.105 mm Hg at two consecutive measurements for patients aged below 55 years and diastolic blood pressure ;;;;.105 for patients above this age [8]. During the period of the study, saluretic diuretics were used as basic therapy. The groups were comparable with respect to the most informative variables for prediction. The mortality was the same in both groups (10%), but the group of patients with hypertension had significantly more nonfatal reinfarctions (21 %) than the normotensive patients (10 %) during 2 years' follow-up in spite of the antihypertensive treatment. WILHELMSSON
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Hypercholesterolemia Several studies have dealt with the question whether secondary prevention is possible by lowering serum cholesterol, either by diet or by drugs. The results are conflicting. LEREN [19] allocated at random male patients who had survived a first MI, to 2 groups, with 206 men in each. One group received diet recommendations which reduced serum cholesterol by almost 18 % and the other group continued with their ordinary diet. After 5 years' follow-up the total number of fatal and nonfatal reinfarctions was lower in the diet group compared to the control group. After 11 years' follow-up about 20 % of the men in the diet group had died of MI compared to 35 % in the control group. However, the total mortality did not differ between the two groups, either after 5 or after 11 years. Other workers have failed to show any secondary preventive effect of cholesterol-reducing diets. The Coronary Drug Project group published the final results of their large trial of secondary prevention by cholesterol-lowering drugs in 1975. More than 8,000 patients aged from 30 to 64 years entered the study, most of them more than 2 years after their infarct. The patients were allocated at random to 6 groups, 5 of which were given cholesterol-lowering drugs. The 2 groups who were given estrogen in two different dosages and the group given thyroxine had to stop the drug treatment earlier than planned because of an excess morbidity and mortality
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when compared with the control group. The groups who received clofibrate, niacin and placebo, respectively, were followed as planned. Mter 5 years, as well as after total follow-up, the total mortality and the cause-specific mortality in the clofibrate, niacin and placebo groups were the same. The niacin group had a lower incidence of nonfatal reinfarction than the placebo group, but more general use of the drug could not be recommended because of negative side-effects [5].
Supervised Physical Training The possible secondary preventive effect of supervised physical training after infarction was studied in Goteborg [28,37]. 315 nonselected patients aged 57 years or less were randomly allocated to supervised physical training in a training group (138 men and 20 women) or to a control group (142 men and 15 women). Altogether 27 % of the patients had to be excluded from the training group owing to cardiac contraindications or practical difficulties in carrying out the training program (an equal number for both reasons). The training was started 3 months after the infarction and there were three sessions each week. In spite of several efforts to reduce the dropout, there was a high dropout rate, increasing with the duration of follow-up. After 1 year the maximum work capacity measured on a bicycle ergometer was significantly greater in the patients in the training group than in those in the control group. The best improvement was seen in patients limited by angina pectoris [28]. After training, the same submaximal work could be performed with a lower pulse rate and lower blood pressure, i. e. with considerably reduced cardiac work [37]. During 4lyears' follow-up 28 patients (18 %) in the training group and 35 patients (22 %) in the control group died. The difference is not statistically significant (p = 0.40). The number of nonfatal reinfarctions was 25 (16 %) and 28 (18 %), respectively. Patients from the training group who were really training 1 year after their infarction were compared with patients from the control group, matched with respect to secondary risk. There was a trend towards lower mortality in the patients who were training but the difference was not significant (p = 0.16) [37].
Optimal basic care, including patient education and early detection and treatment of complications and risk factors, may be of secondary preventive value after an MI. The effect of such care in 96 men managed at a special
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Basic Care
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post-MI clinic in Goteborg was compared to traditional outpatient treatment in 85 other male patients [35]. All patients were in the age group 57-67 years. No patient included in this analysis was treated with antiarrhythmic agents, fJ-blockers, lipid-lowering drugs or anticoagulants. The groups were equally burdened by secondary risk factors. After 2 years' follow-up the patients treated at the post-MI clinic had a significantly lower incidence of new coronary artery disease overall (21 %) than the others (41 %). No statistically significant reduction in mortality alone was observed, however.
Intervention against Possible Mechanisms
0/ Rein/arction and Death
Long-Term Anticoagulant Therapy There have been a great number of studies dealing with the possibility of a secondary preventive effect of long-term anticoagulant therapy. A collaborative analysis comprised 2,205 male and 282 female patients included in nine controlled trials [12]. The groups receiving anticoagulant therapy and the control groups were shown to be alike in respect of relevant clinical characteristics. The mortality was less in males given anticoagulants, but the apparent benefit seemed to be restricted to patients reporting either prolonged
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Long-Term fJ-Receptor Blockade The secondary preventive effect of continuous fJ-receptor blockade after infarction was first shown from the post-MI clinic in Goteborg [33, 38]. During the years 1970 and 1971,274 patients, men and women, aged between 57 and 67 years, were treated at the post-MI clinic. Of these, 230 were included in the study, 44 being excluded owing to contraindications to fJ-blockade. The patients were randomly allocated to treatment with alprenolol (n = 114) or placebo (n = 116). No patient was treated with other antiarrhythmic agents or lipid-lowering drugs and no patient took anticoagulants after discharge from hospital. The number of sudden deaths during the 2-year period of follow-up was significantly lower in the group treated with alprenolol (n = 3) than in the placebo group (n = 11). The total mortality in the alprenolol group (n = 7) was half that in the placebo group (n = 14). No significant reduction in the number of nonfatal reinfarctions was found [33, 38]. Since then other workers have also demonstrated a significant reduction in mortality after MI during continuous treatment with fJ-blocking agents [1, 10].
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angina pectoris or a previous infarct at admission. Other studies have shown a positive effect of anticoagulant therapy in other risk groups, e. g. seriously ill patients with left ventricular decompensation, heart enlargement or atrial fibrillation. Other workers have failed to show any secondary preventive effect of long-term anticoagulant therapy. Long-Term Treatment with Other Drugs There is no conclusive evidence of a secondary preventive effect of long-term treatment with antiarrhythmic drugs other than fJ-blockers. For instance, procainamide [18], quinidine and phenytoin [3] have been tried. All these drugs have considerable negative side-effects [6, 18,20, 30]. Conflicting results have been published concerning a possible secondary preventive effect of long-term treatment with estrogens [5, 21] and tolbutamide [26, 31].
Intervention against Atherosclerotic Lesions Coronary Bypass Surgery Most analyses of mortality and reinfarction after coronary bypass surgery deal with patients with angina pectoris and not exclusively with post-MI patients. Improved survival after bypass surgery in selected patients with angina pectoris, e. g. those with a significant stenosis in the main left coronary artery, has been reported in some studies [25], but other workers have not been able to show this. Whether there is a secondary preventive effect of coronary bypass surgery after an MI is still more uncertain.
Since the major secondary risk factors are associated with a large infarction, it is logical to try to limit the myocardial damage, which may be possible during the early acute stage. Such measures may then result not only in a lower acute mortality but also in less invalidity as well as a better long-term prognosis. Myocardial ischemia and infarction are due to an imbalance between the myocardial metabolic demand and the coronary arterial supply of fluid, oxygen and substrate. Adrenergic fJ-blocking durgs will minimize the oxygen demand, partly by decreasing the blood pressure-heart rate product.
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Intervention Aimed at Limiting Myocardial Damage at the Time of the First Infarct
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A double-blind randomized study of metoprolol given intravenously immediately after the patient's arrival at the hospital is now going on in Goteborg with the aim of evaluating the effects of ,8-blockade on infarction size, arrhythmias and the acute and long-term mortality.
It has been claimed that the association between smoking and MI is only apparent and secondary to, e. g., personality or alcohol abuse. Smoking increases the risk of MI irrespective of personality and alcohol consumption, however [13, 36]. There are several theories as to how smoking might have a pathogenetic effect in connection with infarction and it seems reasonable to assume a direct causal relationship. The finding [39] that a secondary preventive effect of stopping smoking after MI was demonstrable within 2 years strongly indicates that smoking is not only associated with MI as such but also has a decisive influence on the etiology and pathogenesis. WILHELMSSON et al. [40] were unable to demonstrate higher mortality in hypertensives during the first 2 years after discharge from hospital following MI, but demonstrated a higher incidence of nonfatal reinfarction, which may be assumed to lead to higher mortality during longer follow-up. Other workers have shown a higher mortality in hypertensives after infarction [4, 11]. The hypertensives thus constitute a risk group that justifies special attention from the secondary prophylactic point of view. High serum cholesterol is a well-documented risk factor for primary MI [17,36]. Certain studies in the USA have shown an association between serum cholesterol and reinfarction [4,14], while other studies have been unable to verify this [15, 23, 29]. These conflicting results can be explained by selection of patients and differences in the duration of follow-up. The fact that the cholesterol level was not related to the prognosis after infarction in some investigations does not exclude the possibility of reduction of serum cholesterol after infarction having a secondary preventive effect. Several studies into this question, with conflicting results, have been published [5, 19]. This controversy can be explained by patient selection, differences in methods of reducing cholesterol, choice of different end points, etc. The lack of a secondary preventive effect in the large Coronary Drug Project [5] would seem to weight heavily in the debate concerning drug treatment. Several previous studies have shown that physical activity improves work capacity in patients who have had MI or who have angina pectoris [2, 28].
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Discussion
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Other authors have claimed that the incidence and severity of reinfarction decrease when patients participate in physical training after infarction [27]. Some workers have also considered that they have been able to demonstrate a reduction in mortality after MI in training studies [16,27]. However, allocation of patients to training or no training has not been done with adequate randomization in the studies showing a positive influence on reinfarction and mortality. It has been claimed that a very high level of physical activity is needed to achieve a primary preventive effect [22] and the same thing might be true for a secondary preventive effect, if it exists. The activity level was kept as high as possible in the Goteborg trial, and the results were also analyzed after exclusion of those not training adequately, but the effect was still nonsignificant. At present it is not possible to identify the factor or factors explaining why treatment at the post-MI clinic in Goteborg was associated with fewer reinfarctions. There are probably several factors contributing to this positive effect. Effective antismoking advice, information to patients about what to do in the event of symptoms occurring and early initiation of treatment when complications arose are possible explanations. Several mechanisms might explain the mortality-lowering effect of continuous f1-blockade after infarction. It might, for example, prevent development of infarction and limit the size of the ischemic area. Another possibility is prevention of malignant arrhythmias during the initial phase of reinfarction. It should be emphasized that the greatest reduction in mortality during f1-blockade related to the incidence of sudden death, which strongly suggests that f1-blockade has a profound effect during the initial phase of development of ischemia. A high proportion of deaths during follow-up after infarction are sudden, obviously due to malignant arrhythmias. Other deaths are due to reinfarction. In some of these cases the infarction is not associated with a coronary thrombosis, either primary or secondary. Any beneficial effect of anticoagulant therapy must be due to prevention of thromboembolic events. Since these do not seem to be responsible for most deaths after infarction, the possible secondary preventive effect of long-term anticoagulant therapy after an MI is limited and any anticoagulants should not be given to nonselected patients series. The conflicting results of secondary preventive trials with antiarrhythmic drugs (apart from f1-blockers), estrogens and tolbutamide, as well as with coronary bypass surgery, seem to rule out these forms of intervention after an MI at present.
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Conclusions On the basis of the findings described and discussed, we draw at present the following conclusions concerning secondary prevention after MI: (1) Optimal basic medical care should be provided, including vigorous treatment of e. g. decompensation, angina pectoris and hypertension, and anticoagulant therapy if indicated bye. g. heart enlargement and atrial fibrillation. (2) Smokers should stop smoking. (3) fJ-Blockers should be given. (4) Physical training should be encouraged in some categories of patients, e. g. those whose level of activity is limited by angina pectoris or nervousness, but it is questionable whether it has any effect on prognosis. (5) Reduction of serum cholesterol may be beneficial in the long run but should not be given high priority since other, more accessible, measures have a dominating influence on the prognosis after infarction.
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AHLMARK, G.; SAETRE, H., and KORSGREN, M.: Reduction of sudden deaths after myocardial infarction. Lancet ii: 1563 (1974). BRUCE, R.A.; GEY, C. 0.; CooPER, M. N.; FISCHER, L. D., and PETERSON, D.: Seattle Heart Watch: initial clinic, circulatory and electrocardiographic response to maximal exercise. Am. J. Cardiol. 33: 459-469 (1974). Collaborative Group: Phenytoin after recovery from myocardial infarction. Lancet ii: 1055-1057 (1971). Coronary Drug Project Research Group: Factors influencing long-term prognosis after recovery from myocardial infarction; three-year finding of the coronary drug project. J. chron. Dis. 27: 267-285 (1974). Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. J. Am. med. Ass. 231: 360-381 (1975). CRAMER, G.: Early and late results of conversion of atrial fibrillation with quinidine. A clinical and hemodynamic study. Acta med. scand., suppl. 490 (1968). ELMFELDT, D.; WILHLEMSEN, L.; TIBBLIN, G.; VEDIN, J. A.; WILHELMSSON, C., and BENGTSSON, C.: Registration of myocardial infarction in the city of Goteborg, Sweden. J. chron. Dis. 28: 173-186 (1975). ELMFELDT, D.; WILHLEMSEN, L.; TIBBLIN, G.; VEDIN, J.A.; WILHELMSSON, C., and BENGTSSON, C.: A postmyocardial infarction clinic in Goteborg, Sweden. Acta med. scand. 197: 497-502 (1975). ELMFELDT, D.; WILHELMSSON, C.; VEDIN, A.; TIBBLIN, G., and WILHELMSEN, L.: Characteristics of representative male survivors of myocardial infarction compared to a representative population sample. Acta med. scand. 199: 387-398 (1976).
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D. ELMFELDT, MD, Department of Medicine I, University of Goteborg, Sahlgren's Hospital, S-413 45 GOteborg (Sweden)
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