The prevention of cardiovascular disease: Emphasis on Secondary Prevention

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THE PREVENTION OF CARDIOVASCULAR DISEASE Emphasis on Secondary Prevention Jennifer C. Robinson, MD, and Arthur S. Leon, MD, MS

EXTENT OF THE PROBLEM

Despite declining incidence rates over the last two decades, cardiovascular diseases (CVD), including coronary heart disease (CHD), stroke, and occlusive peripheral arterial disease (PAD), continue to be the major cause of morbidity and mortality in the United States and other industrialized countries. One million deaths a year are due to CHD and stroke, with about half the victims of CVD under 65 years of age. The morbidity associated with CVD is even greater, with more than 6 million Americans having a history of myocardial infarction or angina and almost 3 million having had a stroke.5 PAD is estimated to affect 10% to 15% of individuals over age 60, with 2% to 3% of the population having intermittent claudication.44,73 Individuals with a history of CVD are at the greatest risk for future premature cardiovascular mortality and morbidity, with their relative risk five to seven times higher than individuals the same age without a history of CVDYo, 125 Further, a history of previous CVD doubles one's chance of dying from an acute cardiovascular event. Clearly a history of CVD is the strongest predictor of future CVD events, and that person deserves aggressive intervention to improve surviva1.62, 111 Although advances have been made in the medical and surgical management of clinical CVD, long-term survival appears to depend on modification of the underlying disease process. Considerable evidence From the Department of Medicine (JGR) and the Division of Kinesiology (ASL), Heart Disease Prevention Clinic, University of Minnesota, Minneapolis, Minnesota MEDICAL CLINICS OF NORTH AMERICA VOLUME 78 • NUMBER 1 • JANUARY 1994

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exists that secondary prevention programs to reduce CVD risk factors can significantly reduce CVD morbidity and mortality. In contrast to primary prevention, there is large potential benefit from even modest treatment effects, given the large number of patients at increased risk. Finally, risk factor modification has been shown to be a cost-effective secondary prevention measure. CORONARY HEART DISEASE Incidence

More than 1 million cases of myocardial infarction occur each year, and approximately 7 out of 10 survive the acute event. Mortality rates following first myocardial infarction are greatest in the first year. Thereafter the risk of dying is about 5% per year for men and 7% per year for women. 125, 177, 219, 261 After first infarction, the rate of subsequent infarction is increased three to six times. The risk of any CVD event within 5 years of a first myocardial infarction is as high as 80%.219 Conditions other than myocardial infarction similarly increase the risk of subsequent CHD events and mortality (Fig. 1). The presence of angina pectoris doubles the relative risk of subsequent CHD mortality. Mortality is approximately 3% per year in patients with angina pectoris. Unstable angina has an 8% mortality rate per year, and the rate of

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Figure 1. Risk of CHD death after 5 and 10 years for men and women who have experienced the following cardiovascular events: P = peripheral arterial disease; S = stroke or TIA; A = angina; M = myocardial infarction. (Data from Kannel WB, Wolf PA, Carrison RJ: The Framingham Study, Section 35: Survival following initial cardiovascular events. National Heart, Lung,and Blood Institute. NIH Publication No. 88-2969, 1988.)

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nonfatal myocardial infarction within 2 weeks is 8% to 10%.102 Multivessel disease on coronary angiography in persons with angina increases the 3-year mortality rate sixfold. 185 Angina more frequently predates myocardial infarction in women than in men.125 Sudden death also occurs more frequently in persons with overt CHD.119 Congestive heart failure is almost as common as reinfarction in patients following a myocardial infarction with an incidence of 14% in 5 years. 125 Once heart failure develops, the mortality rate is 50% at 5 years without vasodilator therapy, such as angiotensin converting enzyme (ACE) inhibiting agents. 43,89, 166 The risk of noncoronary events is also increased in patients with overt CHO, Patients with symptomatic CHD have an ischemic stroke risk of 1% to 2% a year, which is intermediate to that seen in the agematched general population and those with previous transient ischemic attack or stroke213 (Fig, 2), In addition, intermittent claudication is 4 to 10 times more frequent in persons with CHD, and approximately 10% to 20% of CHD patients have evidence of PAO,123,214 Interventions

Short-term prognosis, in the 2 to 3 years post-myocardial infarction, is mainly influenced by myocardial factors, such as infarct size and 40~---------------------------------------------------------.

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Figure 2. Risk of stroke or transient ischemic attack (TIA) after 5 and 10 yea~s for men and women who have experienced the following cardiovascular events: P = peripheral arterial disease; S = stroke or TIA; A = angina; M = myocardial infarction. (Data from Kannel WB, Wolf PA, Carrison RJ: The Framingham Study, Section 35: Survival following initial cardiovascular events. National Heart, Lung, and Blood Institute. Bethesda, MD, NIH Publication No. 88-2969, 1988.)

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location, number of previous infarctions, left ventricular function, arrhythmias or conduction disturbances, and continued ischemiaYs, 169, 219 Advanced age also appears to be an important prognostic factor, both acutely and long term.24, 267 Women have also been reported to have higher early mortality than men, even after adjustment for age. 24, 125 Remarkable improvements have been made reducing acute and 1year mortality following myocardial infarction. Meta-analysis of randomized, controlled trials of thrombolytic agents, beta blockers, intravenous magnesium, vasodilators, anticoagulants, aspirin, and early ambulation in acute myocardial infarction has shown a significant reduction in in-hospital mortality of 12% to 25%. In addition, a 10% to 25% reduction in 3- to 5-year CVD mortality rates has been observed in controlled trials in patients following a myocardial infarction with anticoagulant, beta-blocker, cholesterol-lowering, ACE inhibitor, and antiplatelet agents as well as cardiac rehabilitation programs including an exercise componene 43, 193, 256 (Table 1). Low-dose aspirin (75 mg/ day) has also been shown to reduce second CHD events in women and men with stable angina by approximately 35%,113 similar to the reduction in first nonfatal myocardial infarction in men seen in primary prevention trials. 161 No primary prevention trials of aspirin have yet been done in women. AnTable 1. TREATMENTS OF ACUTE MYOCARDIAL INFARCTION AND SECONDARY PREVENTION: RESULTS OF CUMULATIVE META-ANAL YSIS Treatment Acute myocardial infarction IV magnesium IV vasodilators IV thrombolytic agents Aspirin Anticoagulants Oral and IV beta-blocking agents Calcium channel-blocking agents Prophylactic lidocaine Secondary prevention Anticoagulants Rehabilitation Beta-blocking agents Cholesterol-lowering agents Antiplatelet agents Calcium channel-blocking agents Class I anti arrhythmic agents

No. of Trials

No. of Patients

7 11 60 5 7 51

1304 2170 46,916 19,077 4075 31,669

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Cumulative Odds Ratio (95% Cl)

0.44 0.57 0.75 0.77 0.78 0.88

Cumulative PValue

(0.27-0.71) (0.41-0.79) (0.71-0.79) (0.70-0.84) (0.65-0.92) (0.80-0.98)

<0.001 <0.001 <0.001 <0.001 0.004 0.024

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1.12 (0.92-1.37)

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1,28 (1.02-1.61)t

<0.001 0.012 <0.001 <0.001 0.002 0.91* 0.03

*Not significant. tExcess mortality in treatment group. Adapted from Lau J, Antman EM, Jimenez-Silva J, et al: Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 327:248-254, 1992; with permission.

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tioxidant therapy with beta-carotene following myocardial infarction also has shown some promise. 238 In addition, although coronary artery bypass grafting (CABG) after myocardial infarction has not been specifically studied, subgroup analysis of trials in angina patients who have later suffered myocardial infarctions has suggested benefit. 29 Certain other groups of patients with angina also have derived long-term benefit from CABG. 184 Coronary angioplasty following acute myocardial infarction may also be beneficial in certain patients, but the long-term effect on mortality remains to be proved. 8s, !40, 270 These medical and surgical interventions appear to benefit primarily those at highest risk for subsequent CHD events. Longer term prognosis, beyond 3 to 5 years, depends on progression of the underlying atherosclerotic process and left ventricular function. 169 The major risk factors for recurrent CHD are the same as those implicated in its initial development: hypercholesterolemia, smoking, hypertension, sedentary lifestyle, and diabetes mellitus. 267 Benefits of risk factor modification are usually evident within 2 to 3 years of intervention.!6,42,116 Cholesterol Reduction

Cholesterol lowering for secondary prevention of CHD is discussed in detail elsewhere in this issue. In the Coronary Drug Project, niacin therapy resulted in an 11% lower mortality rate in the treatment group versus placebo after 15 years. No difference was seen at 5 years. Niacin was given only for the first 6 years. Maximum benefit from cholesterol lowering was seen after 12 years of follow-up. An estimated 1.6 years of additional life followed 6 years of niacin therapy and mean total cholesterollowering of 10% at 1 year?! The trials of lipid lowering and angiographic regression have consistently shown not only angiographic stabilization or regression of atherosclerotic lesions, but also significant reductions in CHD events and mortality. In contrast to primary prevention trials, they have also shown reductions in total mortality. The effects of therapy were seen within 2 years.!6,2],22,35, 116,260 Lipid-lowering therapy for secondary prevention and for primary prevention in high-risk individuals also appears to be cost-effective.84 Hypertension Primary Prevention

Hypertension has consistently been shown to be a major risk factor in the development of CHD, stroke, and PAD.235 Hypertension alone does not appear to induce atherogenesis, but in the presence of a critical level of total and low-density lipoprotein (LDL) cholesterol, it markedly accelerates atherosclerosis. 9 , 117 Meta-analysis of randomized antihypertensive trials has not shown the reduction in primary CHD events pre-

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dicted by epidemiologic observational studies. A 5 to 6 mm Hg reduction in diastolic blood pressure would be expected to yield a 20% to 25% reduction in CHD mortality based on prospective epidemiologic studies, but only a 14% reduction in CHD mortality over 4 to 6 years has been noted in clinical trials. 42 Recently, however, three trials in older persons have demonstrated more significant 13% to 27% reductions in CHD events.48, 98,175,224 There is some evidence that simultaneous reduction in cholesterol levels and blood pressure more effectively reduces the risk of CHD mortality.2l8 Part of the explanation for the less than expected impact of antihypertensive therapy alone on CHD mortality may be that several commonly used antihypertensives have adverse lipid effects. Low diastolic blood pressure has been associated with excess mortality in some studies, particularly in those patients with CHD, although this effect appears to be independent of left ventricular function and antihypertensive therapy.47 Thiazide diuretics have also been associated with excess mortality in persons with evidence of CHD.178 Secondary Prevention

Hypertension is twice as common in men under 60 years old with angiographic evidence of CHD when compared with controls.81 Following myocardial infarction, persistent hypertension predicts a worse prognosis in almost all studies. Reinfarction rates are 40% higher and CHD mortality is 20% higher in those with persistent hypertension. 124, 177 Although no clinical trials of antihypertensive therapy have specifically been done in survivors of myocardial infarction, there is some suggestive evidence of the benefit of hypertension treatment in survivors of myocardial infarction. For example, those participants with a history of myocardial infarction in the Hypertension Detection and Follow-up Program (HDFP) had a highly significant 20% reduction in total mortality rate. 141 Those men in Multiple Risk Factor Intervention Trial (MRFIT) who had abnormal stress tests benefited substantially from risk factor reductions, including management of hypertension, as compared with those with negative stress tests. 208 The greater benefit seen in the trials of antihypertensive therapy in elderly as compared with middle-aged individuals may actually reflect the benefit of secondary prevention given the high prevalence of severe atherosclerotic disease in the elderly.48, 175, 224 The recent report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure has emphasized the special importance of treating hypertension in those with evidence of target organ disease. 1l1 Therapy should be initiated with lifestyle modification, including weight loss, reduction of sodium and alcohol intake, and increased physical activity.s,z4o Hygienic intervention also appears to be effective in the elderly? Because no trials have been performed comparing relative benefits of various antihypertensive therapies in those with preexisting coronary disease, the initial choice of drug should be based on other factors. For example, a beta blocker may be the drug of choice in post-myocardial infarction patients because this may reduce

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subsequent ischemic events and sudden death. 143 Patients with angina pectoris may benefit from either a beta blocker or a calcium channel blocker for symptom control. For patients with left ventricular dysfunction,89 diabetes,39, 209 or coexisting renal disease,172 an ACE inhibitor may be the drug of choice. It should also be kept in mind that dyslipidemia can be exacerbated by thiazides and loop diuretics, at least short term. Although nonintrinsic sympathomimetic activity beta blockers are the only agents that have been shown to protect against recurrent CHD events, they can increase triglycerides and reduce HDL cholesterol levels. Beta blockers with intrinsic sympathomimetic activity or labetalol have minimal effects on lipids, but a cardioprotective effect has not been demonstrated for these agents. ACE inhibitors, calcium channel blockers, alpha 1-receptor blockers, and central adrenergic agents have no detrimental effect on lipids.142, 268 All classes of antihypertensive agents appear to be similarly tolerated/50 and the elderly tolerate low-dose diuretics and beta-blocking agents well. 48, 175, 224 Smoking

Primary Prevention

Cigarette smoking increases the risk of first myocardial infarction up to 2.5 times that of a nonsmoker and increases CHD mortality by 70%.= It is estimated that 30% to 40% of CHD deaths each year can be attributed to smoking. 53 Smoking acts synergistically with other risk factors for CHD. Relative risk of myocardial infarction declines rapidly after smoking cessation, with the risk of an ex-smoker returning to baseline levels within 2 to 5 years. 161 This reduction likely represents changes in coagulability, coronary vasospasm, and oxygen-carrying capacity of the blood rather than changes in the severity of underlying atherosclerosis. Passive smoking has also been associated with a 20% greater risk of CHD.237 Fortunately cigarette smoking appears to be declining in the United States, although rates seem to be declining more slowly in women and certain subgroups of the population with lower educational levels?O, 194 Meta-analysis of primary intervention trials has shown that successful long-term smoking cessation depends on multiple intervention modalities and on the number of reinforcing sessions attendedY6 Nicotine patches appear to be more effective than nicotine gum but are usually successful only in the setting of a behavioral modification program, with a reported 35% I-year cessation rate. 52 Secondary Prevention

Smoking rates among persons with an initial myocardial infarction range from 46% to 88%.81,177,244 There have been no randomized, controlled intervention trials to determine the effect of smoking cessation on CHD morbidity and mortality in postinfarction patients, nor are there likely to be for ethical reasons. Observational studies, however, indicate

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that smokers who quit smoking after a myocardial infarction have a 40% to 90% reduction in subsequent CHD events when compared with those who continue to smoke, after statistical adjustment for other risk factors? 176 Smokers who continue to smoke after infarction appear to be primarily at increased risk of sudden death.92,231 This is similar to the 50% higher risk of sudden death in patients with angiographic evidence of CHD who continue to smoke,257 A 70% reduction in myocardial infarction and death also was seen in men and women over age 65 with angiographically documented CHD who quit smoking. 100 Smoking has also been associated with increased silent myocardial ischemia during exercise in those with CHD.S1 Despite the increased risk of continued smoking after myocardial infarction, only about one third to one half of smokers quit or even cut back on their smoking. 25 Most patients quit on their own, but smoking cessation rates may be proportional to the intensity of the antismoking effort and the severity of disease. A physician's repeated, emphatic advice to stop is important, particularly in the peri-infarction period when patients are highly motivated. 1s6 Behavioral therapy in conjunction with transdermal nicotine patches or gum has been shown to be effective and safe in the postinfarction period. 66 , 69

Diabetes Mellitus

CHD mortality is two to four times higher in diabetic as compared with age-matched nondiabetic individuals. The frequency of nonfatal CHD events is also markedly increased in diabetic compared with nondiabetic individuals. The excess risk attributable to diabetes persists after statistical adjustment for other risk factors, which are more prevalent in diabetics. 202 Diabetes has a greater impact in women than in men, cancelling the lower CHD risk in premenopausal women compared with agematched men.l22 The poorer prognosis of diabetic women is primarily due to in-hospital mortality rates nearly twice that of diabetic men. Complications are more common among diabetic men and women after myocardial infarction, including a higher incidence of recurrent myocardial infarction, cardiogenic shock, conduction disturbances, congestive heart failure, and myocardial rupture. 1,232 Improved glucose control has to date not been proved experimentally to improve risk of CHD or outcomes, for either primary or secondary prevention. Reduction of CHD risk in diabetic individuals depends more on control of other coexisting risk factors, such as obesity, hypertension, smoking, physical inactivity, and blood lipid abnormalitiesYs Obesity and poor glycemic control can exacerbate or cause dyslipidemia, particularly hypertriglyceridemia and low HDL cholesterol levels. Dyslipidemia promotes the atherosclerotic process, particularly in the presence of hypertension and smoking. Beta-blocker drugs and aspirin have both proved to be of benefit in diabetic patients after a myocardial

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infarction. 60, 133 Following CABG, after adjustment for other risk factors, diabetic individuals have long-term survival rates similar to nondiabetic individuals.14, 41, 67 Obesity

Obesity has been found to be an independent risk factor for CHD in some,101, 159, 204 but not all, studies. m Even in those studies showing an association, obesity appears to be weaker than the major CHD risk factors. Methodologic problems may account for the contradictory findings. These include using relative weight as a method for judging fatness and not taking fat distribution into consideration. 160 Observational studies, however, have consistently shown that obesity is related to hypertension and hypercholesterolemia13, 246,259 and type II diabetes mellitus85 and that weight loss is effective in reducing blood pressure and blood cholesterol and triglyceride levels and in raising HDL cholesterollevels. 111 , 230, 263 The pattern of fat distribution seems to be more important than excessive weight. Abdominal or centrally obese men and women appear to be at higher risk for hypertension, hyperinsulinemia, type II diabetes mellitus, and blood lipid disorders than obese individuals with peripheral or uniform fat distributions. 54, 71 It has been hypothesized that the insulin resistance associated with visceral fat accumulation is the mediator for the excess risk associated with obesity. Further, large fluctuations in weight, either up or down, may also increase the risk for CHD. 93,144 There have been no randomized trials of weight reduction for primary or secondary prevention of CHD. Those patients who are more than 20% above the midrange of desirable weight may benefit from weight reduction, particularly if associated with other risk factors.227 All patients following myocardial infarction should be at least be on a StepOne American Heart Association diet with caloric restriction to avoid weight gain. Weight loss can be better maintained with a regular modera te exercise program. 149. 154, 239 Psychosocial Factors

Social factors, such as social isolation, low education level, and work-related stress (high demand and low decision latitude), have been associated with an up to two to four times increased risk of myocardial infarction.228, 247 It is unclear if type A behavior, manifested by competitiveness, excessive drive, and time urgency, is a risk factor for CHD. Type A behavior has not been shown to affect long-term prognosis after myocardial infarction in most studies.34, 163, 206 The hostility component has been more closely related to CHD than type A behavior in some, but not all, studies. Physiologic changes associated with stress may provide possible explanations for increased cardiac risk, such as sustained increased catecholamine excretion and their effect on heart rate, blood pressure, and coagulation. 247

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Some intervention trials have shown a reduction in recurrent cardiac events in survivors of myocardial infarction with type A behavioral patterns following behavioral modification or instruction in relaxation techniques. An approximate 40% reduction in CHD morbidity and mortality has been seen,77, 254 but these studies have been criticized because of methodologic problemsY' 198 Ornish et aP89 have demonstrated significant but minimal regression of stenoses but with no morbidity or mortality outcomes in a small randomized trial of patients with severe CHD following a multifactorial 1-year lifestyle intervention that included relaxation techniques along with exercise and a vegetarian diet. Other studies have shown that persons with lower levels of education are less likely to modify risk factors after myocardial infarction. 247 The potential contribution of behavioral interventions on CHD morbidity and mortality remains unclear. Hormone Replacement Therapy

Primary Prevention

At least 32 published epidemiologic studies have evaluated the effect of noncontraceptive hormone replacement therapy on CHD mortality. Women who used estrogen had an estimated 35% to 45% reduction in CHD mortality as compared with those who had never used estrogen.86, 236 Possible protective mechanisms of estrogen include an improved lipid profile/6,90 alterations in vascular tone,264 and reduced risk of thrombosis?9 Progestin is usually added to estrogen therapy to reduce the risk of endometrial carcinoma in women with an intact uterus.157 Although certain progestins, especially at higher doses, attenuate the beneficial effect of estrogen on lipids, 171,225,248 animal studies have shown protection against atherosclerosis with combined estrogen and progestin therapy similar to that provided by estrogen alone,Ho Indeed in humans, replacement doses of estrogen and progesterone appear to be at least as effective as estrogen alone for preventing CHD morbidity and mortality.63, 181, 182 Selection biases, however, have occurred in previous trials, and the results of large, randomized trials are needed. Hormone replacement therapy may be a cost-effective primary and secondary prevention measure but requires further study of risks and benefits. 38 Continuous, rather than cyclical, combined estrogen and progesterone therapy may be a more desirable regimen because it prevents endometrial hyperplasia with smaller doses of progestin and eliminates cyclic menstrual flow.158, 201, 262 Secondary Prevention

One study in women with angiographic evidence of CHD showed an 84% reduction in recurrent CHD events when treated with estrogen alone. 242 The benefit of estrogen combined with estrogen replacement therapy in women with an intact uterus remains to be determined. A

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major intervention trial, the Heart and Estrogen-Progestin Replacement Study sponsored by Wyeth-Ayerst, is ongoing. It is reasonable to consider hormone replacement therapy for all postmenopausal women with CHD after weighing potential risks and benefits.4 Additional health benefits include protection against osteoporosis and endometrial carcinoma when using combined estrogen and progestin replacement. A modest increase in breast cancer does not appear until after 8 to 12 years of hormonal therapy.86, 157 Physical Activity

A marked reduction in physical activity, associated with the modern mode of living, appears to be an important contributor to the emergence of CHD as a public health problem. A sedentary lifestyle also contributes to other prevalent medical conditions, including obesity, hypertension, hyperlipidemia, type 11 diabetes, stroke, osteoporosis, some forms of cancer (breast and colon), and perhaps mental health problems. National surveys in North America during the past 20 years estimate that at least 40% of the adult population is completely sedentary, whereas another 40% is insufficiently active to improve physical fitness significantly.95 In addition, there appears to be a recent downward trend in the number of adults performing vigorous exercise, Because rigorous experimental proof does not exist on the association between physical activity and CHD, careful analysis of observational study data is crucial before this relationship can be examined, Extensive reviews and critiques of more than 100 such studies currently in the medical literature have been published?8, 146, 150, 151, 174, 190, 197 A variety of different epidemiologic approaches were employed in these studies. They include cross-sectional comparisons, case-control studies, and longitudinal or prospective cohort studies. Since 1970, most studies have emphasized recent leisure-time physical activity (LTP A) or assessed a combination of LTP A and job activity. About two thirds of the observational studies reported in the literature support an inverse relationship between physical activity and the risk of CHD and all-cause mortality, Of particular interest are the following large-scale prospective studies, which include an assessment of LTPA: almost 10-year follow-up of Morris et aP73 of from 9000 to 18,000 British executive male clerks and civil service; a follow-up of more than 20 years of almost 17,000 college alumni by Paffenbarger et al/ 91 7 and 10.5-year follow-up of more than 12,000 men at high risk for CHD because of high blood cholesterol and blood pressure and cigarette smoking habits (MRFIT);152, 153 a 14-year follow-up of more than 4000 men and women participating in the Framingham Study.126 Meta-analysis of the "better" quality studies by Powell et aP97 and Berlin and Colditz 12 indicates that the risk of death was doubled in those who were physically inactive when compared with more active individuals. Further, statistical adjustment for confounding risk factors only slightly weakened the association between physical

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inactivity and excess CHD risk. This finding suggests that sedentary lifestyle is an independent risk factor for CHD. Because of the high prevalence of sedentary lifestyle in the United States and the relatively high risk of CHD associated with it, the authors have postulated that successful population-wide strategies to increase physical activity would have a substantial impact on the population burden of CHD. Definitive experimental proof of the exercise-CHD hypothesis by a large, randomized, controlled clinical trial is not feasible owing to the large sample size required, major potential adherence problems, and huge costs. ISO An alternative approach to study the physical activityCHD relationship experimentally is a controlled secondary prevention trial of exercise training after a myocardial infarction. More than 20 randomized secondary prevention trials, which included an exercise training component or simply exercise advice, have been conducted. None had sufficient power to determine an independent effect of exercise on recurrent myocardial infarction, but meta-analysis of pooled data from 22 trials, using an intention-to-treat analysis, reveals a statistically significant reduction of 25% in 1- to 3-year rates of CVD and total mortality in the patients receiving cardiac rehabilitation when compared with control patients. 187 It was impossible to determine, however, the independent role of exercise, if any, owing to study design. Further, no significant difference was found in the rate of recurrent nonfatal myocardial infarction between pooled intervention and control patients. There are many plausible mechanisms to help explain how hard physical lab or, regular physical activity as part of one's daily routine or for recreation during leisure time, or exercise conditioning programs can reduce the risk of initial and recurrent CHD events and improve survival after myocardial infarction. Anatomic, physiologic, and metabolic adaptations resulting from physical conditioning have been demonstrated by cross-sectional comparisons of athletes and matched sedentary subjects and by controlled small-scale experimental studies in animals and humans. The following postulated mechanisms may contribute to the apparent protective effects of physical activity against CHD morbidity and mortality: (1) reduced severity or progression of coronary atherosclerosis, (2) reduced risk of coronary thrombosis, (3) increased myocardial vascularity and coronary blood flow, (4) improved myocardial metabolic capacity and mechanical performance, (5) improved cardiovascular efficiency, and (6) reduced myocardial vulnerability to ventricular fibrillation.14s, 147, 148 The extent of adaptations attained from physical exertion depend on the type, frequency, intensity, and duration of the physical activity performed and the length of the participation. Although much remains to be learned about the dose-response relationship to specific adaptations, it appears that to attain the full gamut of the beneficial physiologic and metabolic adaptations, physical activity should be performed to generate significant improvement in the level of \702 max (i.e" an intensity of 50% to 80% of \702 max for at least 20 to 60 minutes, three or more times per week). It should be recognized, however, that the mass of observational data suggests that physical exertion of any intensity, if performed for

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more than half an hour a day, is associated with a reduced risk of death from CHD. STROKE

Although the incidence of stroke has dramatically declined over the past few decades, approximately 500,000 new and recurrent strokes occur each year in the United States, and almost one third are fatal within the first year. Almost 3 million Americans have suffered a stroke with various degrees of disability.s Seventy percent of strokes are attributable to hypertension. s8 Most commonly, stroke occurs in the setting of endorgan damage from hypertension, as defined by left ventricular hypertrophy by X-ray or electrocardiogram, history of stroke or transient ischemic attack, myocardial infarction or intermittent claudication, or serum creatinine level greater than 1.7 mg/ dL. 106, 129 Other established risk factors for ischemic stroke include age, male gender, smoking, diabetes, elevated hematocrit and fibrinogen levels, high-dose oral contraceptives, atrial fibrillation, and structural heart disease. 58, 162, 269 In an asymptomatic patient, a carotid bruit with evidence of atherosclerotic narrowing on carotid ultrasound increases stroke risk to 2% to 4% a year. If an individual has symptoms of a transient ischemic attack, he or she has a 30% probability of a subsequent stroke in the next 3 to 5 years. S8, 131, 258 In addition, if a greater than 70% carotid stenosis is identified in a patient with a transient ischemic attack, the risk of a major ischemic stroke increases to 25% in the next 2 years. 183 Only 10% to 20% of strokes, however, are preceded by a transient ischemic attack. S8 The presence of a previous stroke, CHD, or PAD also greatly increases the risk of subsequent stroke (see Fig. 2). Following stroke, short-term survival depends on retention of consciousness, younger age, and degree of functionality before stroke. 18 Short-term and long-term prognosis also depend on the severity of underlying atherosclerotic disease. 215 More than 50% of individuals with carotid artery disease also have clinical evidence of CHD, which more than doubles subsequent CVD mortality when compared with those without clinical CHD.30, 105, 216 Hypertension

Risk reduction has been clearly demonstrated for antihypertensive treatment. Clinical trials of the treatment of mild, moderate, or severe hypertension have demonstrated a consistent 40% reduction in stroke incidence. 42, 167 Most of the benefit of diastolic blood pressure reduction was seen within 3 years of beginning treatment. Treatment of diastolic or isolated systolic hypertension reduces the risk of stroke in the elderly as well. 48, 175, 224 Following stroke, uncontrolled hypertension has been associated

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with a poor prognosis. 37, 1RR, 2ll3, 216 A reduction in the rate of stroke recurrence, however, has not been demonstrated in all hypertension treatment trials/ 2, 107, 168 although a study comparing aggressive antihypertensive treatment with usual care did show a 10% lower incidence of strokes in patients with evidence of end-organ damage, including prior stroke. 106 Further, the wealth of data from primary prevention trials, especially those in the elderly/s, 175, 224 suggests that benefit should be obtained through prudent blood pressure control. Care should be taken, however, to avoid excessive blood pressure reduction, particularly in persons with coexisting CHD. Thus the bulk of the available evidence supports the need for reduction of diastolic and systolic blood pressure at all ages for both primary and secondary prevention of stroke. Goals of therapy should be 85 to 90 mm Hg for diastolic blood pressure and 140 to 160 mm Hg for systolic blood pressure. m Low doses of thiazides and betablocking agents have both been shown to be well-tolerated antihypertensive therapy in the older age group. Smoking

Smoking cessation is an effective primary prevention measure for stroke as well as for CHD. 19, 226, 266 Smoking cessation also reduces the risk of stroke in the elderly.266 No secondary prevention trials of the value of smoking cessation have been done, but it is reasonable to assume that risk reduction for recurrent stroke would be similarly reduced, as discussed earlier. Cholesterol Reduction

Although lipid abnormalities have been associated with cerebral atherosclerosis,21O, 217 the relationship to cerebrovascular events is not as well established as for coronary artery disease. 245 Most studies have shown a relationship between low plasma HDL cholesterol level and stroke in men.12l, 180,249 Lipoprotein(a) has also been found to be an independent risk factor.1l2, 252 Paradoxically, a relationship between very low cholesterol and hemorrhagic stroke has been noted in hypertensive men. 108, 114 The role of lipid-lowering therapy for primary prevention is unclear. There is some evidence that carotid artery lesions can regress with LDL cholesterol reduction. 99 Clinical trials to date have been small in number and of insufficient power to determine effect of lipid lowering on reducing stroke incidence and mortality.139 Nonrheumatic Atrial Fibrillation

Although not necessarily atherosclerotic in origin, cardiogenic embolism is a common cause of ischemic stroke, particularly in the el-

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derly.265 One in six strokes is due to embolism from the heart. Nonrheumatic atrial fibrillation increases the risk of stroke 2-fold to 18-fold. Stroke incidence in persons with atrial fibrillation is 5% per year. Predictors of stroke in the presence of atrial fibrillation are previous history of a stroke or transient ischemic attack, hypertension, diabetes, or age over 65. 28,241 Ischemic heart disease (25%), rheumatic mitral stenosis (10%), and prosthetic cardiac valves (10%) as well as patent foramen ovale55 are also major sources of cardiogenic embolism. Warfarin therapy reduces risk of stroke associated with nonrheumatic atrial fibrillation by 60% and aspirin therapy by 40%.27 Further, warfarin therapy in patients with atrial fibrillation appears to be a cost-effective primary prevention measure, provided that the risk of hemorrhagic complications is low. 91 Anticoagulant therapy for stroke prophylaxis has also been recommended for rheumatic valvular disease or congestive cardiomyopathy.36, 96 The routine use of anticoagulant drugs for long-term primary stroke prophylaxis following myocardial infarction is controversial. The long-term value of warfarin prophylaxis for the reduction of recurrent myocardial infarction, however, is well established.143, 253 The risk of recurrent stroke in nonrheumatic atrial fibrillation is substantial. Two trials specifically addressing long-term anticoagulation for nonvalvular atrial fibrillation are ongoing (V A Stroke Prevention in Nonvalvular Atrial Fibrillation and the European Atrial Fibrillation Trial). Hormone Replacement Therapy

Postmenopausal estrogen replacement has not consistently been shown to reduce stroke significantly,86 although combined estrogen and progesterone replacement recently has been shown to reduce the mortality rate from initial stroke by 60% in observational studies. 64, 68 Diabetes Mellitus

Diabetics have twice the risk of subsequent stroke and myocardial infarction compared with nondiabetics. 188 As with CHD, however, there have been no primary or secondary intervention trials to determine the effect of improved glucose control on CVD events. Antiplatelet and Anticoagulation Agents

Although primary prophylaxis with aspirin in healthy men has been demonstrated to decrease initial nonfatal myocardial infarction by 30%,161 a reduction in initial stroke has not been seen. In fact, an excess of hemorrhagic strokes has been noted.192, 238 Secondary prophylaxis with aspirin, however, clearly reduces the risk of subsequent stroke by 20% to 40%.6,243 Ticlopidine, a new antiplatelet drug, has been shown to be as

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effective as aspirin for preventing strokes.82 , 97 In addition, ticlopidine appears to be superior to aspirin in reducing the risk of subsequent stroke after an initial stroke;91 however, it should be reserved for those who are intolerant of aspirin, however, owing to serious potential side effects, primarily severe neutropenia. The value of long-term anticoagulant therapy for secondary prevention of stroke, other than in the setting of nonrheumatic atrial fibrillation, remains unproven. 213 Surgical Intervention

A stroke reduction benefit has yet to be demonstrated for asymptomatic patients undergoing carotid endarterectomy, 103, 165 although the largest trial is ongoing (Asymptomatic Carotid Atherosclerosis Study).lO The role of carotid endarterectomy is well established for symptomatic carotid artery stenosis exceeding 70% if performed by an experienced surgeon. 61 , 164, 183 The role of surgery, however, in preventing future events in patients with lesser degrees of stenosis has yet to be established. In addition, approximately 20% of patients subsequently develop 50% or greater stenosis within 2 years following carotid endarterectomy. A trial of aggressive cholesterol reduction to prevent restenosis has been proposed. 207 PERIPHERAL ARTERIAL DISEASE

Occlusive atherosclerotic PAD is usually seen in patients older than age 40. Asymptomatic disease can be detected through careful examination of the pulses or through noninvasive methods, such as the ratio of the Doppler measurements of the ankle and brachial systolic blood pressures. Major asymptomatic PAD affects approximately 10% to 15% of the population. The prevalence of intermittent claudication in the general population ranges from 2% to 4% of both men and women. 44, 73, 214 Risk factors for the development of PAD include smoking, diabetes mellitus, hypertension, blood lipid abnormalities,74, 123 and high fibrinogen72, 120 and blood leukocyte levels. 155 The presence of CHD increases the probability of developing PAD l.l-fold to l.6-fold. 44,74 Conversely, approximately 40% of those with PAD have clinical evidence of CHD. Among those with intermittent claudication, 70% have clinical evidence of CHD. 44,49 Evidence of largevessel PAD increases subsequent overall mortality twofold to threefold and the risk of CVD death sixfold over the next 10 years, after adjustment for other cardiovascular risk factors. In those with intermittent claudication, CHD and CVD mortality is twice as great than it is if the PAD is asymptomatic. 45,49 The presence of severe PAD is a marker for poor longterm prognosis, with only one in four patients with severe disease surviving 10 years. Intermittent claudication in the setting of diabetes is a predictor of an even poorer prognosis, with CVD risk triple that of

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intermittent claudication without diabetes. 2o In turn, the absence of clinical CHD is the best predictor of long-term survival in patients with PAD.212 If CHD is detected on noninvasive testing of an individual with PAD, his or her risk for CVD events is fivefold greater than if no CHD had been detected. 87, 205 The risk of other CVD events is also increased in those with PAD. Stroke rates are three to five times higher in those with intermittent claudication.49, 223 Although asymptomatic carotid artery stenosis is more common among patients with peripheral vascular disease, it does not appear to be a marker for excess CHD mortality compared with those who do not have it?5 No primary intervention trials have been aimed specifically at preventing PAD, and there are minimal data regarding PAD from primary CVD intervention trials. Aspirin does not appear to prevent the development of intermittent claudication but may reduce the need for amputation. s3 Intervention efforts in persons with PAD have been aimed primarily at amelioration of existing disease. Smoking

Cigarette smoking appears to be the most important risk factor predisposing to PAD, with more than 90% of persons with aortoiliac and femoropopliteal disease identified as current or past smokers.65 A doseresponse relationship exists between smoking and subsequent development of PAD, with risk increased two to six times risk in current and exsmokers of less than 5 years. Smoking has also been associated with more rapid progression of PAD. Following peripheral arterial reconstruction, smokers had 25% less graft patency after 1 year. Smoking cessation is the single most important intervention in patients with PAD.l96 Diabetes Mellitus

Diabetes has consistently been associated with the development of PAD, with more than 45% of diabetics having this condition. 56 Middleaged and elderly diabetic individuals have 3 to 6 times higher rates of intermittent claudication than nondiabetics20 and 15 times higher rates of nontraumatic amputation than nondiabetics,zo2 Amputation rates in diabetics have been correlated with duration and severity of disease and low plasma HDL cholesterol levels but surprisingly do not appear to be related to hypertension or smoking. 211 Women with diabetes tend to have an even higher incidence of PAD than diabetic men. 202 There have been no intervention trials of glucose control on the progression of PAD. Hypertension

Systolic hypertension has been associated with the development of intermittent claudication, with risk increased twofold for men and five-

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fold for women.123 There is a weaker relationship with diastolic hypertension. The relationship between hypertension and PAD may be confounded by the decrease in vascular compliance that occurs with age. 23 There have been no intervention trials of antihypertensive therapy targeted at persons with PAD. One trial of ketanserin, an antihypertensive agent that also inhibits serotonin-induced platelet aggregation and improves blood rheologic properties, showed a 47% reduction in the amputation rate. 199 Cholesterol Lowering

Serum cholesterol and triglyceride levels have shown an association with the development of PAD, but this relationship has not always persisted after multivariate analysis. Plasma HDL cholesterol has consistently shown an inverse relationship with the presence of PAD,15, 195, 221, 222,255 even in the elderly.22o Elevated lipoprotein(a) level has also shown an association with the risk of PAD.251 Cholesterol lowering appears to result in angiographic stabilization or regression of peripheral arterial lesionsY' 57, 59 The only study with clinical end points found no change in symptoms or ankle-brachial index.135 To date, end points have not included cardiovascular morbidity and mortality, although a pilot study has been initiated (Arterial Diseases Multiple Intervention Trial). Exercise

Little data exist on the relationship between exercise and the risk of developing PAD. An association has been noted in observational studies.104, 126, 130 Physical inactivity is a relatively weak but independent risk factor for ischemic heart disease. A similar relationship likely holds true for PAD. Given the high prevalence of inactivity in the population,95 the impact of increased population-wide exercise is potentially great. The effect of exercise training on CVD morbidity and mortality in PAD patients is unknown. zoo Psychosocial Factors

Although a modest association between some aspects of personality, particularly hostility, and PAD have been found, there have been no intervention trials. 5o, 156 Antioxidants

Treatment of claudication with vitamin E has shown mild symptom improvement in three small trials. so, 134

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SUMMARY

Atherosclerosis is a progressive disease affecting all major arteries. Clinical evidence of atherosclerosis increases the risk of subsequent morbid and mortal events fivefold to sevenfold over the next 5 to 10 years. The same risk factors contribute to the initial development of CVD events as to their recurrence. Both coronary and noncoronary events, such as stroke or PAD, reflect the severity of the underlying atherosclerotic process and strongly predict future excess CVD morbidity and mortality. Short-term and long-term survival depends on modifying the risk factors that contribute to CVD events. Although absolute proof of benefit for secondary prevention does not exist for all risk factors, the data from primary prevention trials and the secondary prevention trials that have been done argue strongly for aggressive intervention. Benefit has been demonstrated for smoking cessation, cholesterol reduction, and blood pressure control. Selected patients may benefit from additional medical, procedural, or surgical interventions to prolong life, such as beta-blocking agents, aspirin, or carotid endarterectomy. Many secondary prevention measures are a cost-effective way to reduce the substantial morbidity and mortality due to CVD. Contrary to primary prevention, even modest treatment effects from secondary prevention efforts can benefit large numbers of patients. Finally, secondary prevention may be more successful because patients with clinical evidence of CVD may be more highly motivated than their healthy counterparts to make and maintain lifestyle changes. References 1. Abbott RD, Donohue RP, Kannel WB, Wilson PW: The impact of diabetes on survival following myocardial infarction in men vs women. JAMA 260:3456, 1988 2. Aberg A, Bergstrand R, Johansson S, et al: Cessation of smoking after myocardial infarction. Effects on mortality after 10 years. Br Heart J 49:416, 1983 3. Adams MR, Kaplan JR, Manuck SB, et al: Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis 10:151, 1990 4. American College of Physicians: Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med 117:1038-1041,1992 5. American Heart Association: 1993 heart and Stroke Facts. Dallas, TX, American Heart Association; 1992 6. Antiplatelet Trialists Collaboration: Secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ 296:320, 1988 7. Applegate WB, Miller ST, Elam JT, et al: Nonpharmacologic intervention to reduce blood pressure in older patients with mild hypertension. Arch Intern Med 152:1162, 1992 8. Arroll B, Beaglehole R: Does physical activity lower blood pressure? A critical review of the clinical trials. J Clin Epidemiol 45:439, 1992 9. Assman G, Schulte H: The Prospective Cardiovascular Munster Study: Prevalence and prognostic significance of hyperlipidemia in men with systemic hypertension. Am J CardioI59:9G, 1987 10. Asymptomatic Carotid Atherosclerotic Study Group: Study design for randomized prospective trial of carotid endarterectomy for asymptomatic atherosclerosis. Stroke 20:844,1989

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11. Barndt R, Blankenhorn DH, Crawford DW, Brooks SH: Regression and progression of early femoral atherosclerosis in treated hyperlipoproteinemic patients. Ann Intern Med 86:139, 1977 12. Berlin JA, Colditz GA: A meta-analysis of physical activity in the prevention of coronary heart disease. Am J Epidemiol132:612, 1990 13. Berns MAM, deVries JH, Katan MB: Increase in body fatness as a major determinant of changes in serum total cholesterol and high density lipoprotein cholesterol in young men over a lO-year period. Am J EpidemioI130:1109, 1989 14. Bhan A, Das B, Wasir HS, et al: Profile of coronary arterial disease in diabetic patients undergoing coronary arterial bypass grafting. Int J CardioI31:155, 1991 15. Bihari-Varga M, Szekely J, Gruber E: Plasma high density lipoproteins in coronary, cerebral and peripheral vascular disease. Atherosclerosis 40:337, 1981 16. Blankenhorn DH, Nessim SA, Johnson RL, et al: Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis on coronary venous bypass grafts. JAMA 257:3233, 1987 17. Blumenthal JA, Levenson RM: Behavioral approaches to secondary prevention of coronary heart disease. Circulation 76(suppl 1):1-130, 1987 18. Bonita R: Epidemiology of stroke. Lancet 339:342,1992 19. Bonita R, Scragg R, Stewart A, et al: Cigarette smoking and risk of premature stroke in men and women. BMJ 293:6,1986 20. Brand FN, Abbott RD, Kannel WB: Diabetes, intermittent claudication, and risk of cardiovascular events: The Framingham Study. Diabetes 38:504,1989 21. Brown G, Albers JJ, Fisher LD, et al: Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 323:1289,1990 22. Buchwald H, Varco RL, Matts JP, et al: Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 323:946,1990 23. Bulpitt CJ: Blood pressure. In Fowkes FGR (ed): Epidemiology of Peripheral Vascular Disease. London, Springer-Verlag, 1991, pp 181-186 24. Burke GL, Sprafka JM, Folsom AR, et al: Trends in CHD mortality, morbidity and risk factor levels from 1960 to 1986: The Minnesota Heart Survey. Int J Epidemiol 18:S73, 1989 25. Burling TA, Singleton GE, Bigelow GE, et al: Smoking following myocardial infarction: A critical review of the literature. Health PsychoI3:83, 1984 26. Bush TL, Barrett-Connor E, Cowan LD, et al: Cardiovascular mortality and noncontraceptive use of estrogen in women: Results from the Lipid Research Clinics Program Follow-up Study. Circulation 75:1102, 1987 27. Cairns JA, Connelly SJ, et al: Meta-analysis of anticoagulation in atrial fibrillation. Submitted for publication 28. Cairns JA, Connelly SJ: Nonrheumatic atrial fibrillation: Risk of stroke and role of antithrombotic therapy. Circulation 84:469, 1991 29. Califf RA, Harrell FE, Lee KL, et al: The evolution of medical and surgical therapy for coronary artery disease: A IS-year perspective. JAMA 261:2077,1989 30. Canadian Cooperative Study Group: A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 299:53, 1978 31. Canner PL, Berge KG, Wenger NK, et al: Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J Am Coll Cardiol 8:1245, 1986 32. Carter B: Hypotensive therapy in stroke survivors. Lancet 1:485, 1970 33. CASANOVA Study Group: Carotid surgery versus medical therapy in asymptomatic carotid stenosis. Stroke 22:1229, 1991 34. Case RB, Helier SS, Case NB, et al: Type A behavior and survival after acute myocardial infarction. N Engl J Med 312:737, 1985 35. Cashin-Hemphill L, Mack WJ, Pogoda JM, et al: Beneficial effects of colestipol and niacin on coronary atherosclerosis: A 4-year follow-up. JAMA 264:3013,1990 36. Cerebral Embolism Task Force: Cardiogenic brain embolism. Arch Neuro143:71, 1986 37. Chambers BR, Norris JW, Shruvell BL, Hachinski VC: Prognosis of acute stroke. Neurology 37:221, 1987

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38. Cheung AP, Wren BG: A cost-effectiveness analysis of hormone replacement therapy in the menopause. Med J Aust 156:312, 1992 39. Christleib AR: Treatment selection considerations for the hypertensive diabetic patient. Arch Intern Med 150:1167, 1990 40. Clarkson TB, Shively CA, Morgan TM, et al: Oral contraceptives and coronary artery atherosclerosis in cynomolgus monkeys. Obstet Gynecol 75:217, 1990 41. Clement R, Rousou JA, Engelman RM, Breyer RH: Perioperative morbidity in diabetics requiring coronary artery bypass surgery. Ann Thorac Surg 46:321, 1988 42. Collins R, Peto R, Macmahon S, et al: Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context. Lancet 335:827, 1990 43. CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429, 1987 44. Criqui MH, Fronek A, Barrett-Connor E, et al: The prevalence of peripheral arterial disease in a defined population. Circulation 71:510, 1985 45. Criqui MH, Langer RD, Fronek A, et al: Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 326:381, 1992 46. Cupples LA, Gagnon DR, Wong ND, et al: Preexisting cardiovascular conditions and long-term prognosis after initial myocardial infarction: The Framingham Study. Am Heart J 125:863, 1993 47. D' Agostino RB, Belanger AI, Kannel WB, Cruickshank JM: Relation of low diastolic blood pressure to coronary heart disease death in the presence of myocardial infarction: The Framingham Study. BMJ 303:385, 1991 48. Dahliif B, Lindholm LH, Hansson L, et al: Morbidity and mortality in the Swedish Trial in Old Patients with hypertension (STOP-Hypertension). Lancet 338:1281,1991 49. Davey-Smith G, Shipley MI, Marmot MG: Prognosis of intermittent claudication. In Fowkes FGR (ed): Epidemiology of Peripheral Vascular Disease. London, SpringerVerlag, 1991, pp 315-324 50. Deary lJ: Personality. In Fowkes FGR (ed): Epidemiology of Peripheral Vascular Disease. London, Springer-Verlag, 1991, pp 217-226 51. Deedwania Pc, Jamner L, Carbajal E: Cigarette smoking increases risk of silent ischemia and alters cardiovascular reactivity during exercise. Circulation 84(suppl II):II538, 1991 52. DeNelsky GY: Transdermal nicotine patches: How effective are they? Cleve Clin J Med 60:252, 1993 53. Department of Health and Human Services: Reducing the health consequences of smoking: 25 years of progress: A report of the surgeon general. DHHS publ. no. (CDC) 89-84111.) Washington, DC, Government Printing Office, 1989 54. Despn2s J-p, Moorjani S, Lupien PI, et al: Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 10:497,1990 55. Di Tullio M, Sacco RL, Gopal A, et al: Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 117:461, 1992 56. Diabetes. In Office of Disease Prevention. Disease Prevention/Health Promotion. US Public Health Service and US Department of Health and Human Services. Palo Alto, CA, Bulletin Pub I Co, 1988 57. Duffield RGM, Miller NE, Brunt JNH, et al: Treatment of hyperlipidemia retards progression of symptomatic femoral atherosclerosis: A randomized controlled trial. Lancet 1:639, 1983 58. Dunbabin DW, Sandercock PAG: Preventing stroke by modification of risk factors. Stroke 21(suppl IV):IV-36, 1990 59. Erikson U, Helmius G, Hemmingsson A, et al: Repeat femoral arteriography in hyperlipidemic patients: A study of progression and regression of atherosclerosis. Acta Radiol 29:303, 1988 60. ETDRS Investigators: Aspirin effects on mortality and morbidity in patients with diabetes mellitus: Early Treatment Diabetic Retinopathy Study report 14. JAMA 268:1292, 1992 61. European Carotid Surgery Trialists' Collaborative Group: MRC European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70-90%) or with mild (0-29%) carotid stenosis. Lancet 337:1235, 1991

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62. Expert Panel: National Cholesterol Education Program: Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. (Adult Treatment Panel Il). JAMA 269:3015, 1993 63. Falkeborn M, Persson I, Adami H-O, et al: The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol 99:821, 1992 64. Falkeborn M, Persson i, Terent A, et al: Hormone replacement therapy and the risk of stroke. Follow-up of a population-based cohort in Sweden. Arch Intern Med 153:1201, 1993 65. Fielding JE: Smoking: Health effects and control (first of 2 parts). N Engl J Med 3l3:491, 1985 66. Fielding JE: Smoking: Health effects and control (second of 2 parts). N Engl J Med 3l3:555,1985 67. Fietsam R, Bassett J, Glover JL: Complications of coronary artery surgery in diabetic patients. Am Surg 57:551, 1991 68. Finucane FF, Madans JH, Bush TL, et al: Decreased risk of stroke among postmenopausal hormone users: Results from a national cohort. Arch Intern Med 153:73, 1993 69. Fiore MC, Novotny TE, Pierce JP, et al: Methods used to quit smoking cessation in the United States: Do cessation programs work? JAMA 263:2760, 1990 70. Fiore MC, Novotny TE, Pierce JP, et al: Trends in cigarette smoking in the United States: The changing influence of gender and race. JAMA 261:49, 1989 71. Folsom AR, Kaye SA, Sellers TA, et al: Body fat distribution and 5-year risk of death in older women. JAMA 269:483,1993 72. Fowkes FGR, Connor JM, Smith FB, et al: Fibrinogen genotype and risk of peripheral atherosclerosis. Lancet 339:693, 1992 73. Fowkes FGR, Housley E, Cawood EHH, et al: Edinburgh Artery Study: Prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J EpidemioI20:384, 1991 74. Fowkes FGR, Housley E, Riemersma RA, et al: Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am J Epidemioll35:331, 1992 75. Franks PJ, Ellis MR, Cuming R, et al: AsymptomatiC carotid stenosis in peripheral vascular disease: Prevalence, incidence, and natural history. In Fowkes FGR (ed): Epidemiology of Peripheral Vascular Disease. London, Springer-Verlag, 1991, pp 333342 76. Friedman M, Thoreson CE, Gill JJ, et al: Alteration of the type A behavior and reduction in cardiac recurrences in postmyocardial infarction patients. Am Heart J 108:237,1984 77. Friedman M, Thoreson CE, Gill JJ, et al: Alteration of type A behavior and its effect on cardiac recurrences in post myocardial infarction patients: Summary results of the recurrent coronary prevention project. Am Heart J 112:653, 1986 78. Froelicher VF: Exercise, fitness and coronary heart disease. In Bouchard C, Shepard RJ, Stephens T, et al (eds): Exercise, Fitness, and Health: A Consensus of Current Knowledge. Champaign, IL, Human Kinetics, 1990, p 429 79. Gangar KF, Reid BA, Crook D, et al: Oestrogens and atherosclerotic vascular diseaselocal factors. Bailliere's Clin Endocrinol Metab 7:47, 1993 80. Gaziano JM, Manson JE, Buring JE, Hennekens CH: Dietary antioxidants and cardiovascular disease. Ann NY Acad Sci 669:249, 1992 81. Genest JJ, McNamara JR, Salem DN, Schaefer EJ: Prevalence of risk factors in men with premature coronary artery disease. Am J CardioI67:1185, 1991 82. Gent M, Blakely JA, Easton JD, et al: The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1:1215,1989 83. Goldhaber SZ, Manson JE, Stampfer MJ, et al: Low-dose aspirin and subsequent peripheral arterial surgery in the PhYSicians' Health Study. Lancet 340:143, 1992 84. Goldman L, Gordon DJ, Rifkind BM, et al: Cost and health implications of cholesterol lowering. Circulation 85:1960,1992 85. Gordon T, Castelli WP, Hjortland MC, et al: Diabetes, blood lipids, and the role of obesity in coronary heart disease risk for women: The Framingham Study. Ann Intern Med 87:393, 1977

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86. Grady D, Rubin SM, Pettiti DB, et al: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 117:1016, 1992 87. Graor RA, Whitlow P: Coronary artery diseases associated with peripheral vascular disease. In Young JR, Graor RA, Olin JW, Bartholomew JR (eds): Peripheral Vascular Diseases. St. Louis, CV Mosby, 1991; P 201 88. Grines CL, Browne KF, Marco I, et al: A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 328:673, 1993 89. Groden DL: Vasodilator therapy for congestive heart failure: Lessons from mortality trials. Arch Intern Med 153:445, 1993 90. Gruchow HW, Anderson AI, Barboriak JJ, Sobocinski KA: Postmenopausal use of estrogen and occlusion of coronary arteries. Am Heart J 115:954, 1988 91. Gustafsson C, Asplund K, Britton M, et al: Cost effectiveness of primary stroke prevention in atrial fibrillation: Swedish national perspective. BMJ 305:1457,1992 92. Hallstrom AP, Cobb LA, Ray R: Smoking as a risk factor for recurrence of sudden cardiac arrest. N Engl J Med 314:271, 1986 93. Hamm P, Shekelle RB, Stamler J: Large fluctuations in body weight during young adulthood and 25-year risk of coronary death in men. Am J EpidemioI129:312, 1989 94. Harbison JW for the Ticlopidine Aspirin Stroke Study Group: Ticlopidine versus aspirin for the prevention of recurrent stroke: Analysis of patients with minor stroke from the Ticlopidine Aspirin Stroke Study. Stroke 23:1723, 1992 95. Harris SS, Casperson CJ, Defriese GH, Estes H Jr: Physical activity counseling for healthy adults as a primary preventive intervention in the clinical setting: Report of the US. Preventive Task Force. JAMA 261:3590,1989 96. Hart RG: Cardiogenic embolism to the brain. Lancet 339:589, 1992 97. Hass WK, Easton JD, Adams HP, et al: A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 321:501, 1989 98. Hebert PR, Moser M, Mayer J, Hennekens CH: Recent evidence on drug therapy of mild hypertension and decreased risk of coronary heart disease. Arch Intern Med 153:578,1993 99. Hennerici M, Kleophas W, Gries FA: Regression of carotid plaques during low density lipoprotein elimination. Stroke 22:989, 1991 100. Hermanson B, Omenn GS, Kronmal RA, et al: Beneficial six-year outcome of smoking cessation in older men and women with coronary artery disease: results from the CASS registry. N Engl J Med 319:1365, 1988 101. Higgins M, Kannel WB, Garrison R, et al: Hazards of obesity-the Framingham experience. Acta Med Scand (suppl 723):23, 1988 102. Hilton TC, Chaitman BR: The prognosis in stable and unstable angina. Cardio Clin 9:27, 1991 103. Hobson RW Il, Weiss DG, Fields WS, et al: Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med 328:221, 1993 104. Housley E: Exercise. In Fowkes FGR (ed): Epidemiology of Peripheral Vascular Disease. London, Springer-Verlag, 1991, pp 227-234 105. Howard G, Evans GW, Murros KE, et al: Cause specific mortality following cerebral infarction. J Clin EpidemioI42:45, 1989 106. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the Hypertension Detection and Follow-up Program: Ill. Reduction in stroke incidence among persons with high blood pressure. JAMA 247:633,1982 107. Hypertension Stroke Cooperative Study Group: Effect of antihypertensive treatment on stroke recurrence. JAMA 229:409,1974 108. Iso H, Jacobs DR, Wentworth D, et al: Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med 320:904, 1989 109. Jarrett RJ: Diabetes mellitus. In Fowkes FGR (ed): Epidemiology of Peripheral Vascular Disease. London, Springer-Verlag, 1991, pp 187-196 110. Johanssen S, Bergstrand R, Ulvenstam G, et al: Sex differences in preinfarction characteristics and long-term survival among patients with myocardial infarction. Am J EpidemioI119:61O, 1984 111. Joint National Committee on Detection, Evaluation, and Treatment of High Blood

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