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“Prudence” in disease prevention
0895-4356/91 $3.00 + 0.00 Copyright0 1991 PergamonPressplc
J Clin Epidemiol Vol. 44, No. 11, pp. 1127-1130, 1991 Printedin Great Britain.All rightsreserved
Commentary “PRUDENCE”
IN DISEASE and
JACK FROOM’*
PREVENTION
PAUL FRCKIM’
‘State University of New York at Stony Brook, NY 11794, U.S.A. and *Maagan Michael, Israel (Received in revisedform 1 November
Webster’s dictionary defines prudence as “attentiveness to possible hazard or disadvantage” and “providence in the use of resources” [l]. Synonyms for prudence are “wise”, “judicious” and “frugal”. Prudent medical interventions, therefore, should be based on sound scientific evidence of efficacy, safety and benefit balanced by adverse consequences and costs. Frequently, however, disease prevention measures, that have not been subjected to clinical trials are termed prudent. This distorted meaning in intention coupled with questionable application of epidemiological and statistical concepts diminishes the credibility of several currently advocated strategies for the prevention of cardiovascular diseases. The American Heart Association’s (AHA) prudent diet is “based on the concept that modification of risk factors should decrease the danger of CHD” [2]. Initially recommended for obese persons and for men with a personal or family history of cardiovascular disease, elevated blood pressure or cholesterol levels [3] its 1965 iteration [4] was targeted for the entire population. Its goals were achievement of desirable body weight, avoidance of simple sugars, increased consumption of complex carbohydrates and substitution of polyunsaturated fats for saturated fats and cholesterol. When evidence was reported that consumption of
*All correspondence should be addressed to: Jack Froom, M.D., Professor of Family Medicine, Department of Family Medicine, S.U.N.Y. at Stony Brook, Stony Brook, NY 11794, U.S.A. tItalics added by author. CE 44,’ I--A
1990)
polyunsaturates has a co-carcinogenic effect in animals [5,6] and is associated with increased gallstones in humans [7], the AHA modified its position, stating that “While some replacement of saturated fats by polyunsaturates seems safe, it may be prudent? not to exceed 10% of total calories” [2]. The current AHA diet is recommended “for all healthy Americans over the age of two” [8]. The Committee on Nutrition of the American Academy of Pediatrics’ concern over the use of this diet in children is expressed with these statements. “Epidemiological studies are not of themselves sufficient to establish cause-and-effect relationships.” “Clinical trials in the population at risk should be positive before widespread application.” “The safety of diets designed to decrease caloric intake, increase consumption of complex carbohydrates, decrease intake of refined sugars, decrease consumption of fat and cholesterol, and limit sodium intake has not been established in growing children and pregnant women” [9]. In summary, the AHA proposes a dietary intervention to prevent coronary heart disease, without evidence of efficacy from controlled large scale studies and with potential for producing adverse consequences in subsets of the population. The National Cholesterol Education Program (NCEP) for detection and treatment of hyperlipidemia in all adults [lo] also lacks support from adequate clinical trials. The Lipid Research Clinics Coronary Primary Prevention Trial compared the effect of cholestyramine with placebo in 3806 men aged 35-59. After 7 years, mortality from coronary heart disease
1127
1128
Commentary
was 1.6% in the cholestyramine group compared with 2.0% in the group given placebo. Definite non-fatal myocardial infarction was 6.8 and 8.3% in the two groups, respectively. The authors conclude, “These results could be narrowly interpreted to apply only to the use of bile acid sequestrants in middle-aged men with cholesterol levels above 265 mg/dl (perhaps 1 to 2 million Americans). The trial’s implications, however, could and should be extended to other age groups and women and since cholesterol levels and CHD risk are continuous variables, to others with more modest elevations of cholesterol levels” [ 111. Supporting this proposal the (NCEP) recommends serum cholesterol measurements in all adults aged 20 years and older; it also recommends cholesterollowering treatment for persons whose lowdensity lipoprotein (LDL) cholesterol levels are 4.1 mmol/l (160 mg/dl) or greater, and for persons with coronary heart disease or two risk factors for cardiac disease whose LDL cholesterol levels equal or exceed 3.4 mmol/l (130 mg/dl) [I 11. In so doing, however, the NCEP overlooks several compelling arguments against taking such measures. In the elderly, the relationship between total cholesterol levels and coronary heart disease, cardiovascular mortality, or overall mortality is uncertain [ 12, 131; there is no evidence that cholesterol lowering treatment benefits this group. The effects of blood cholesterol reduction in women is also uncertain and their response to therapy may differ from that of men. For example, the effect of diet on HDL-cholesterol levels is greater in men than in women [ 141,and in a treatment trial for mild hypertension “the all cause mortality was reduced in men on active treatment (157 deaths vs 181 in the placebo group; 7.1 and 8.2 per thousand patient years respectively) but increased in women on active treatment (91 deaths vs 72; 4.4 and 3.5 per one thousand patient years respectively). The difference between the sexes in their response to treatment was significant (p = 0.05)” [15]. Estimates of costs indicate that classifying the lipid status of all U.S. adults will exceed $12 billion and that full implementation of NCEP will require more than 15 additional daily physician visits per 1000 adult patients. In addition those physicians not acting in accord with the NCEP guidelines will be at risk for mal*Italics added by author. TBrackets added by author.
practice action from patients who perceive suboptimal outcomes from failure to receive testing for the treatment of hyperlipidemia. Lastly, asymptomatic patients may experience adverse psychological consequences from being labeled as having a disease [16]. Treatment of systolic hypertension in the elderly is yet another example of an attempt to prevent disease without evidence of benefit for the group receiving treatment. A national committee on hypertension in the elderly recommends: “Although convincing evidence that treatment favorably affects the incidence of hypertensive complications in elderly patients with isolated systolic hypertension is not available, it is prudent* to treat these patients non-pharmacologically, and if this fails many physicians advocate pharmacological methods in an attempt to lessen cardiovascular risk” [ 171. It is true that systolic hypertension is more predictive of adverse cardiovascular events than are elevations of diastolic blood pressure [18], but benefit has been demonstrated for treatment only in the latter [19]. Furthermore, antihypertensive therapy has substantial side effects, especially in the elderly. Until recently, similar enthusiasm existed for the treatment of asymptomatic ventricular ectopic beats following myocardial infarction, which are associated with increased risk of sudden death [20,21]. “Although studies using antiarrhythmic agents to suppress ventricular premature beat depolarization [had]t failed to demonstrate improved survival [22], prior to 1985, more than 50% of university cardiologists used these agents to treat asymptomatic postmyocardial ectopic beats [23]. During the period 1970 through 1986 the use of antiarrhythmic drugs by outpatients increased 200%, an increase greater than would be expected either from an increase in total population or from an increase in patients with heart disease and arrhythmia [24]. This practice was recently discredited by the CAST which was a placebo controlled study of the use of encainide and flecainide in asymptomatic patients with 6 or more ectopic beats per hour following myocardial infarction. They demonstrated a cardiac death rate of 16.0% and a total death rate of 19.1% in the drug treated groups compared with 5.0% and 7.3% respectively (p = 0.0003) in those given placebo [25]. Focusing on benefits from therapy reported as relative risk reduction produces misconceptions that can result in aggressive treatments
Commentary
[26,27]. A reduction from 1 disease event in 2 people to 1 in 4 people is a 50% relative risk reduction. Reducing disease incidence from 1 in 2 million to 1 in 4 million gives an identical 50% risk reduction. Reports of relative risk reductions, therefore, should also be scrutinized for absolute risk reductions. Physicians who took aspirin over a 5 year period displayed a 44% reduction in relative risk of myocardial infarction compared with those who took a placebo. Although this risk reduction seems impressive, the absolute risk reduction was 0.0019 per person-year of observation. This benefit was obtained at a cost of consumption of aspirin every other day, increased numbers of bleeding episodes (some of which required blood transfusions), and trends toward increases in hemorrhagic stroke and duodenal ulcer when compared with those taking placebo. There was no significant reduction in mortality from all cardiovascular causes [28]. Based on available information the AHA diet is not prudent for children or pregnant women. Measurement of blood cholesterol levels in all adults is not judicious. The wisdom of treating isolated hypertension in the elderly or administering aspirin to asymptomatic adults for the prevention of coronary heart disease events is questionable. These treatments are neither attentive to possible hazard nor provident in the use of resources. They are, in a word, imprudent. Acknowledgement-The
8.
9. 10.
11.
12.
13. 14.
15.
16. 17.
18.
19.
authors are grateful to Eliza Garth
for editorial assistance.
REFERENCES 1. Webster Third New International Dictionary. Springfield; G and C Merrian; 1967. 2. AHA Nutrition Committee. Retaionale of the dietheart statement of the American Heart Association. Arteriosclerosis 1982; 4: 177-191. 3. Central Committee for Medical and Community Program of the American Heart Association. Dietary fat and its relationship to heart attacks and strokes. Circulation 1961; 23: 133-137. 4. American Heart Association. Diet and Heart Disease. Dallas: American Heart Association; 1965. 5. Gamma1 EB Carroll KK, Plunkett ER. Effects of dietary fat on mammary carcinogenesis by 7, 12-dimethymethy-benz (alpha) anthracene in rats. Cancer Res 1967; 27: 1737-1742. 6. Carroll KK, Gamma1 EB, Plunkett ER. Dietary fat and mammary cancer. Can Med Assoc J 1968; 98: 590-594. I. Sturdevant RAL, Pearce ML, Dayton S. Increased prevalence of cholelithiasis in man ingesting a serumcholesterol-lowering diet. N Engl J Med 1973; 288: 24-27.
21.
22.
23.
24. 25.
1129 American Heart Association. The American Heart Assodation Diet. An Eating PIan for Hen&y Amerlcms. Dallas: American Heart Association; 1985. Committee on Nutrition. Toward a prudent diet for children. PediatrIca 1983; 71: 78-80. Lipid Research Clinics Program. The lipid research clinics coronary primary prevention trial results. 1. Reduction in the incidence of coronary heart disease. JAMA 1984; 251: 351-364. Expert Panel. Report of the National cholesterol education program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 1988; 148: 36-69. Andersen KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years follow-up from the Framingham Study. JAMA 1987; 257: 2176-2180. Benfante R, Reed D. Is elevated serum cholesterol level a risk factor for coronary heart disease in the elderly? JAMA 1990, 263: 393-396. Mensick RP, Katman MB. Effect of diet enriched with monosaturated or polyunsaturated fatty acids on levels of low-density and high-density lipoprotein cholesterol in healthy women and men. N Engl J Med 1989: 321: 436-441. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 94-104. Froom J, Froom P. Consequences of the National Cholesterol Education Program. J Fam Pratt 1990; 30: 1-4. Working Group on Hypertension in the Elderly National High Blood Pressure Education Program. Statement on hypertension in the elderly. JAMA 1986: 256: 70-74. Rutan GH, Kuller LH, Neaton JD, Wentworth DN, McDonald RH, Smith WM. Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial. Circulation 1988; 77: 504-514. Veteran’s Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967; 213: 1143-1152. Bigger TJ Jr, Fleiss JL, Kleiger R, Miller JP, Rolnitzky LM, Multicenter Post-Infarction Research Grouo. The relationships among ventricular arrhythmias, lift ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984; 69: 250-258. Mukharji J, Rude RE, Poole WK, Gustafson N et al. Risk factors for sudden death after acute myocardial infarction; Two-year follow-up. Am J Cardioll984; 54: 31-36. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators: Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction. The CAPS. Am J Cardiol 1988; 61: 501-509. Vlay S. How the university cardiologist treats ventricular premature beats: a nationwide survey of 65 university medical centers. Am Heart J 1985; 110: 904-912. Hine LK, Gross TP, Kennedy DL. Outpatient antiarrhythmic drug use from 1970 through 1986. Arch Intern Med 1989; 149: 1524-1527. The Cardiac Arrhythmia Suppression Trial (CAST). Preliminary report: Effect of encardnide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406-412.
1130 26.
27.
Commentary Male&a D, Baron JA. Cholesterol and coronary heart disease. The importance of patient-specific attributable risk. Arch Intern Med 1988; 148: 2247-2252. Brett AS. Treating hypercholesterolemia: How should practicing physicians interpret the published
28.
data for patients? N Engl J Med 1989; 321: 616-619. Steering Committee of the Physicians’ Health Study Research Croup. Final report on the aspirin component of the ongoing physicians health study. N J&I@ J Med 1989; 321: 129-135.
J Clin Epidemiol Vol. 44, No. 11, pp. 1127-1130, 1991 Printedin Great Britain.All rightsreserved
Commentary “PRUDENCE”
IN DISEASE and
JACK FROOM’*
PREVENTION
PAUL FRCKIM’
‘State University of New York at Stony Brook, NY 11794, U.S.A. and *Maagan Michael, Israel (Received in revisedform 1 November
Webster’s dictionary defines prudence as “attentiveness to possible hazard or disadvantage” and “providence in the use of resources” [l]. Synonyms for prudence are “wise”, “judicious” and “frugal”. Prudent medical interventions, therefore, should be based on sound scientific evidence of efficacy, safety and benefit balanced by adverse consequences and costs. Frequently, however, disease prevention measures, that have not been subjected to clinical trials are termed prudent. This distorted meaning in intention coupled with questionable application of epidemiological and statistical concepts diminishes the credibility of several currently advocated strategies for the prevention of cardiovascular diseases. The American Heart Association’s (AHA) prudent diet is “based on the concept that modification of risk factors should decrease the danger of CHD” [2]. Initially recommended for obese persons and for men with a personal or family history of cardiovascular disease, elevated blood pressure or cholesterol levels [3] its 1965 iteration [4] was targeted for the entire population. Its goals were achievement of desirable body weight, avoidance of simple sugars, increased consumption of complex carbohydrates and substitution of polyunsaturated fats for saturated fats and cholesterol. When evidence was reported that consumption of
*All correspondence should be addressed to: Jack Froom, M.D., Professor of Family Medicine, Department of Family Medicine, S.U.N.Y. at Stony Brook, Stony Brook, NY 11794, U.S.A. tItalics added by author. CE 44,’ I--A
1990)
polyunsaturates has a co-carcinogenic effect in animals [5,6] and is associated with increased gallstones in humans [7], the AHA modified its position, stating that “While some replacement of saturated fats by polyunsaturates seems safe, it may be prudent? not to exceed 10% of total calories” [2]. The current AHA diet is recommended “for all healthy Americans over the age of two” [8]. The Committee on Nutrition of the American Academy of Pediatrics’ concern over the use of this diet in children is expressed with these statements. “Epidemiological studies are not of themselves sufficient to establish cause-and-effect relationships.” “Clinical trials in the population at risk should be positive before widespread application.” “The safety of diets designed to decrease caloric intake, increase consumption of complex carbohydrates, decrease intake of refined sugars, decrease consumption of fat and cholesterol, and limit sodium intake has not been established in growing children and pregnant women” [9]. In summary, the AHA proposes a dietary intervention to prevent coronary heart disease, without evidence of efficacy from controlled large scale studies and with potential for producing adverse consequences in subsets of the population. The National Cholesterol Education Program (NCEP) for detection and treatment of hyperlipidemia in all adults [lo] also lacks support from adequate clinical trials. The Lipid Research Clinics Coronary Primary Prevention Trial compared the effect of cholestyramine with placebo in 3806 men aged 35-59. After 7 years, mortality from coronary heart disease
1127
1128
Commentary
was 1.6% in the cholestyramine group compared with 2.0% in the group given placebo. Definite non-fatal myocardial infarction was 6.8 and 8.3% in the two groups, respectively. The authors conclude, “These results could be narrowly interpreted to apply only to the use of bile acid sequestrants in middle-aged men with cholesterol levels above 265 mg/dl (perhaps 1 to 2 million Americans). The trial’s implications, however, could and should be extended to other age groups and women and since cholesterol levels and CHD risk are continuous variables, to others with more modest elevations of cholesterol levels” [ 111. Supporting this proposal the (NCEP) recommends serum cholesterol measurements in all adults aged 20 years and older; it also recommends cholesterollowering treatment for persons whose lowdensity lipoprotein (LDL) cholesterol levels are 4.1 mmol/l (160 mg/dl) or greater, and for persons with coronary heart disease or two risk factors for cardiac disease whose LDL cholesterol levels equal or exceed 3.4 mmol/l (130 mg/dl) [I 11. In so doing, however, the NCEP overlooks several compelling arguments against taking such measures. In the elderly, the relationship between total cholesterol levels and coronary heart disease, cardiovascular mortality, or overall mortality is uncertain [ 12, 131; there is no evidence that cholesterol lowering treatment benefits this group. The effects of blood cholesterol reduction in women is also uncertain and their response to therapy may differ from that of men. For example, the effect of diet on HDL-cholesterol levels is greater in men than in women [ 141,and in a treatment trial for mild hypertension “the all cause mortality was reduced in men on active treatment (157 deaths vs 181 in the placebo group; 7.1 and 8.2 per thousand patient years respectively) but increased in women on active treatment (91 deaths vs 72; 4.4 and 3.5 per one thousand patient years respectively). The difference between the sexes in their response to treatment was significant (p = 0.05)” [15]. Estimates of costs indicate that classifying the lipid status of all U.S. adults will exceed $12 billion and that full implementation of NCEP will require more than 15 additional daily physician visits per 1000 adult patients. In addition those physicians not acting in accord with the NCEP guidelines will be at risk for mal*Italics added by author. TBrackets added by author.
practice action from patients who perceive suboptimal outcomes from failure to receive testing for the treatment of hyperlipidemia. Lastly, asymptomatic patients may experience adverse psychological consequences from being labeled as having a disease [16]. Treatment of systolic hypertension in the elderly is yet another example of an attempt to prevent disease without evidence of benefit for the group receiving treatment. A national committee on hypertension in the elderly recommends: “Although convincing evidence that treatment favorably affects the incidence of hypertensive complications in elderly patients with isolated systolic hypertension is not available, it is prudent* to treat these patients non-pharmacologically, and if this fails many physicians advocate pharmacological methods in an attempt to lessen cardiovascular risk” [ 171. It is true that systolic hypertension is more predictive of adverse cardiovascular events than are elevations of diastolic blood pressure [18], but benefit has been demonstrated for treatment only in the latter [19]. Furthermore, antihypertensive therapy has substantial side effects, especially in the elderly. Until recently, similar enthusiasm existed for the treatment of asymptomatic ventricular ectopic beats following myocardial infarction, which are associated with increased risk of sudden death [20,21]. “Although studies using antiarrhythmic agents to suppress ventricular premature beat depolarization [had]t failed to demonstrate improved survival [22], prior to 1985, more than 50% of university cardiologists used these agents to treat asymptomatic postmyocardial ectopic beats [23]. During the period 1970 through 1986 the use of antiarrhythmic drugs by outpatients increased 200%, an increase greater than would be expected either from an increase in total population or from an increase in patients with heart disease and arrhythmia [24]. This practice was recently discredited by the CAST which was a placebo controlled study of the use of encainide and flecainide in asymptomatic patients with 6 or more ectopic beats per hour following myocardial infarction. They demonstrated a cardiac death rate of 16.0% and a total death rate of 19.1% in the drug treated groups compared with 5.0% and 7.3% respectively (p = 0.0003) in those given placebo [25]. Focusing on benefits from therapy reported as relative risk reduction produces misconceptions that can result in aggressive treatments
Commentary
[26,27]. A reduction from 1 disease event in 2 people to 1 in 4 people is a 50% relative risk reduction. Reducing disease incidence from 1 in 2 million to 1 in 4 million gives an identical 50% risk reduction. Reports of relative risk reductions, therefore, should also be scrutinized for absolute risk reductions. Physicians who took aspirin over a 5 year period displayed a 44% reduction in relative risk of myocardial infarction compared with those who took a placebo. Although this risk reduction seems impressive, the absolute risk reduction was 0.0019 per person-year of observation. This benefit was obtained at a cost of consumption of aspirin every other day, increased numbers of bleeding episodes (some of which required blood transfusions), and trends toward increases in hemorrhagic stroke and duodenal ulcer when compared with those taking placebo. There was no significant reduction in mortality from all cardiovascular causes [28]. Based on available information the AHA diet is not prudent for children or pregnant women. Measurement of blood cholesterol levels in all adults is not judicious. The wisdom of treating isolated hypertension in the elderly or administering aspirin to asymptomatic adults for the prevention of coronary heart disease events is questionable. These treatments are neither attentive to possible hazard nor provident in the use of resources. They are, in a word, imprudent. Acknowledgement-The
8.
9. 10.
11.
12.
13. 14.
15.
16. 17.
18.
19.
authors are grateful to Eliza Garth
for editorial assistance.
REFERENCES 1. Webster Third New International Dictionary. Springfield; G and C Merrian; 1967. 2. AHA Nutrition Committee. Retaionale of the dietheart statement of the American Heart Association. Arteriosclerosis 1982; 4: 177-191. 3. Central Committee for Medical and Community Program of the American Heart Association. Dietary fat and its relationship to heart attacks and strokes. Circulation 1961; 23: 133-137. 4. American Heart Association. Diet and Heart Disease. Dallas: American Heart Association; 1965. 5. Gamma1 EB Carroll KK, Plunkett ER. Effects of dietary fat on mammary carcinogenesis by 7, 12-dimethymethy-benz (alpha) anthracene in rats. Cancer Res 1967; 27: 1737-1742. 6. Carroll KK, Gamma1 EB, Plunkett ER. Dietary fat and mammary cancer. Can Med Assoc J 1968; 98: 590-594. I. Sturdevant RAL, Pearce ML, Dayton S. Increased prevalence of cholelithiasis in man ingesting a serumcholesterol-lowering diet. N Engl J Med 1973; 288: 24-27.
21.
22.
23.
24. 25.
1129 American Heart Association. The American Heart Assodation Diet. An Eating PIan for Hen&y Amerlcms. Dallas: American Heart Association; 1985. Committee on Nutrition. Toward a prudent diet for children. PediatrIca 1983; 71: 78-80. Lipid Research Clinics Program. The lipid research clinics coronary primary prevention trial results. 1. Reduction in the incidence of coronary heart disease. JAMA 1984; 251: 351-364. Expert Panel. Report of the National cholesterol education program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 1988; 148: 36-69. Andersen KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years follow-up from the Framingham Study. JAMA 1987; 257: 2176-2180. Benfante R, Reed D. Is elevated serum cholesterol level a risk factor for coronary heart disease in the elderly? JAMA 1990, 263: 393-396. Mensick RP, Katman MB. Effect of diet enriched with monosaturated or polyunsaturated fatty acids on levels of low-density and high-density lipoprotein cholesterol in healthy women and men. N Engl J Med 1989: 321: 436-441. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 94-104. Froom J, Froom P. Consequences of the National Cholesterol Education Program. J Fam Pratt 1990; 30: 1-4. Working Group on Hypertension in the Elderly National High Blood Pressure Education Program. Statement on hypertension in the elderly. JAMA 1986: 256: 70-74. Rutan GH, Kuller LH, Neaton JD, Wentworth DN, McDonald RH, Smith WM. Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial. Circulation 1988; 77: 504-514. Veteran’s Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967; 213: 1143-1152. Bigger TJ Jr, Fleiss JL, Kleiger R, Miller JP, Rolnitzky LM, Multicenter Post-Infarction Research Grouo. The relationships among ventricular arrhythmias, lift ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984; 69: 250-258. Mukharji J, Rude RE, Poole WK, Gustafson N et al. Risk factors for sudden death after acute myocardial infarction; Two-year follow-up. Am J Cardioll984; 54: 31-36. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators: Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction. The CAPS. Am J Cardiol 1988; 61: 501-509. Vlay S. How the university cardiologist treats ventricular premature beats: a nationwide survey of 65 university medical centers. Am Heart J 1985; 110: 904-912. Hine LK, Gross TP, Kennedy DL. Outpatient antiarrhythmic drug use from 1970 through 1986. Arch Intern Med 1989; 149: 1524-1527. The Cardiac Arrhythmia Suppression Trial (CAST). Preliminary report: Effect of encardnide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406-412.
1130 26.
27.
Commentary Male&a D, Baron JA. Cholesterol and coronary heart disease. The importance of patient-specific attributable risk. Arch Intern Med 1988; 148: 2247-2252. Brett AS. Treating hypercholesterolemia: How should practicing physicians interpret the published
28.
data for patients? N Engl J Med 1989; 321: 616-619. Steering Committee of the Physicians’ Health Study Research Croup. Final report on the aspirin component of the ongoing physicians health study. N J&I@ J Med 1989; 321: 129-135.