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Avoiding Repeat Cardiac Events

The ABCDESs of Tertiary Prevention

Barry A. Franklin, PhD; Roy J. Shephard, MD, PhD, DPE

THE PHYSICIAN AND SPORTSMEDICINE - VOL 28 - NO. 9 - SEPTEMBER 2000

In Brief: Multifactorial risk-factor modification—especially intensive ways to manage hyperlipidemia—may slow, halt, or even reverse the progression of coronary artery disease. The American Heart Association recently published comprehensive risk-reduction strategies in patients with coronary heart and vascular disease. These recommendations, endorsed by the American College of Cardiology, have been expanded and can be easily remembered as the ABCDESs of tertiary prevention: 'A': aspirin, alpha-tocopherol, and ACE inhibitors; 'B': beta-blockers, B-vitamins, and blood pressure control; 'C': cholesterol management; 'D': diabetes management and diet; 'E': exercise and estrogen therapy; and 'S': social support, smoking cessation, and stress management.

Contemporary studies now suggest that multifactorial risk-factor modification—especially more intensive measures to control hyperlipidemia with diet, drugs, and exercise—may slow, halt, or even reverse the progression of atherosclerotic coronary artery disease (CAD) (1,2). Added benefits include a reduction in anginal symptoms, decreases in exercise-induced ischemic ST-segment depression, fewer recurrent cardiac events, and a diminished need for coronary revascularization procedures.

Several mechanisms may contribute to these improved clinical outcomes, including partial (albeit small) anatomic regression of coronary artery stenoses, a reduced incidence of plaque rupture (figure 1: not shown), and improved coronary artery vasomotor function (3) The promotion of plaque stability appears to be particularly important, because acute myocardial infarction (MI) in medically treated patients with CAD frequently occurs at sites without a significant stenosis on a previous angiogram (4,5). These findings suggest a new paradigm in the treatment of patients with CAD (3).

In 1995, the American Heart Association published a set of comprehensive risk-reduction interventions designed to extend overall survival, improve quality of life, decrease the need for revascularization, and reduce subsequent cardiovascular events in patients with coronary heart and vascular disease (6). These consensus recommendations were endorsed by the American College of Cardiology and, when amplified to include vitamins and psychosocial counseling, can be summarized (and easily remembered) as the ABCDESs of tertiary prevention (table 1): Each letter represents one or more proven or promising interventions.

TABLE 1. The ABCDESs of Tertiary Prevention: Comprehensive Risk-Reduction Strategies For Patients With Coronary and Other Vascular Disease*
Risk Intervention Recommendations
Alpha-tocopherol Supplements of vitamin E (>100 IU/day of alpha-tocopherol) are associated with a reduced risk of heart disease in men and women
Antiplatelet agents/anticoagulants Start aspirin (80 to 325 mg/day) if not contraindicated; consider warfarin to INR equal to 2 to 3.5 for post-MI patients not able to take aspirin
ACE inhibitors Start early post-MI in stable, high-risk patients (eg, anterior MI); continue indefinitely for patients with left ventricular dysfunction (EF<40%)
Beta-blockers Start in high-risk post-MI patients at 5 to 28 days for >6 mo; observe usual contraindications
B vitamins Ensure adequate intake of folate (>0.4 mg/day), vitamin B6 (>2 mg/day for men and 1.6 mg/day for women), and vitamin B12 (>0.002 mg/day for men and women) to reduce elevated homocysteine levels
Blood pressure control Initiate lifestyle modification in all patients if carefully repeated BP measurements are >140 mm Hg systolic or 90 mm Hg diastolic; add BP medications if these goals are not achieved in 3 mo or if initial BP is >160 mm Hg systolic or 100 mm Hg diastolic
Cholesterol management Primary goal, LDL<100 mg/dL; secondary goals, HDL>35 mg/dL; TG<200 mg/dL; initiate lifestyle modifications (eg, low-fat, low-cholesterol diet, exercise, smoking cessation) and, if needed to achieve LDL goals, consider niacin, statin, fibrate
Diabetes mellitus (type 2) Best controlled with exercise, reduction of obesity, and appropriate diet (55% to 70% of energy requirement as complex carbohydrate, <10% glucose-containing disaccharides, <10% fat)
Diet Minimally, start AHA Step II Diet in all patients: <30% fat (ideally <20% food energy from fat), <7% saturated fat, <200 mg/day cholesterol
Exercise Encourage minimum of 30 to 60 min of moderate-intensity activity 3 or 4 times weekly, plus an increase in daily lifestyle activities; maximum benefit requires 5 to 6 hr/wk of physical activity
Estrogen therapy Consider estrogen replacement in all postmenopausal women; individualize recommendations with other health risks
Social support Social support (via spouse, family, friends, and healthcare professionals) may be helpful in reducing the risk of heart disease
Smoking cessation Strongly encourage patient and family to stop smoking; provide counseling, nicotine replacement, and formal smoking cessation programs as appropriate
Stress management series Selected patients should participate in a stress-reduction program involving education, counseling, and psychosocial interventions

*Epidemiologists define tertiary prevention programs as those aimed at preventing a recurrent MI.

MI = myocardial infarction; BP = blood pressure; INR = international normalized ratio; EF = ejection fraction;

LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; TG = triglycerides;

AHA = American Heart Association. Adapted from Smith et al (6).

Epidemiologists distinguish primary, secondary and tertiary prevention programs: Primary refers to the period before the onset of clinical symptoms; secondary refers to the time after symptom onset but before infarction, and tertiary seeks to prevent a recurrence of MI.

'A': Alpha-Tocopherol, Aspirin, and ACE Inhibitors

Alpha-tocopherol. Two important large-scale prospective studies, one in men (7) and one in women (8), showed that taking vitamin E (>100 IU of alpha-tocopherol per day) was associated with a significantly decreased risk of CAD. The main mechanism seems to be a prevention of the oxidation of low-density lipoprotein cholesterol (LDL-C) (9-11), but the vitamin may also act by countering more directly the adverse effects of free radicals on the vascular endothelium (12). After an acute MI, advanced coronary atherosclerotic lesions were stabilized with regular vitamin E dosage (13), yielding a 75% decrease in nonfatal MIs but no change in the mortality rate; most deaths were due to causes other than recurrent MI (14). In a new study (15) in patients with a high risk of cardiovascular events, however, supplemental vitamin E did not show any apparent effect on cardiovascular outcomes.

TAKE-HOME MESSAGE: Vitamin E may be cardioprotective for patients at risk of cardiovascular disease, though recent results have made the degree of benefit less clear.

Antiplatelet agents and anticoagulants. The benefits of aspirin in reducing the risk of a first MI are encouraging (16), but overall clinical gains are not indisputable, due primarily to a slight increase in the chances of a disabling hemorrhagic stroke (17). On the other hand, as long as 2 decades ago, clinically relevant studies had shown that daily aspirin could reduce the risk of reinfarction unequivocally in the months or years after an acute MI (18). Presumably, this stems from the known biologic mechanisms of aspirin (19), including a complete inhibition of platelet aggregation, which has a clinically important antithrombotic effect.

Antiplatelet agents and anticoagulants clearly reduce mortality in patients with established cardiovascular disease. One widely cited meta-analysis (20) of potential treatments of tertiary prevention ranked anticoagulants as the single most effective intervention after an MI, with a cumulative odds ratio of 0.78, signifying a 22% reduction in mortality. Others have reported that warfarin therapy reduces the risk of death and reinfarction after MI, with corresponding reductions in risk of 24% and 35%, respectively (21). Another collective evaluation of 25 randomized trials of patients with a history of transient ischemic attack, occlusive stroke, unstable angina, or MI found that antiplatelet treatment reduced vascular mortality by 15% ± 4% and nonfatal cardiovascular events (stroke or MI) by 30% ± 4%, with no apparent effect on nonvascular mortality (22). The conclusion was that antiplatelet treatment could reduce the incidence of serious cardiovascular events by about 25% among a wide range of patients at increased risk of a recurrence.

Previous aspirin use may also attenuate the manifestations of acute coronary syndromes when they occur. In one series, 539 consecutive patients admitted to a coronary care unit were studied with regard to medical history, aspirin use, and subsequent hospital diagnosis (23). Among the 214 patients who had previously been taking aspirin, the hospital diagnosis was acute MI in 52 (24%), compared with 175 (54%) of the 325 individuals not taking aspirin (P<0.0001), or a 72% reduction in the odds ratio for MI in the former group. Conversely, the qualifying event resulted in unstable angina in 162 of 214 aspirin users (76%) and in 150 of 325 nonusers (46%). Thus, patients who had a cardiac event while taking aspirin were much more likely to experience unstable angina as opposed to an acute MI. Further analyses revealed that aspirin users were also more likely to have a non-Q-wave rather than a Q-wave infarction.

TAKE-HOME MESSAGE: The recommended dosage for most patients with acute MI is 80 to 325 mg of aspirin daily, starting as soon as possible after the clinical impression of the evolving event is confirmed and continuing indefinitely (24). For selected post-MI patients who are unable to take aspirin or other antiplatelet agents (such as ticlopidine and clopidogrel), a warfarin regimen should be considered (25).

ACE inhibitors. Other risk-reduction therapies can improve the prognosis for patients with cardiovascular disease, including those with symptomatic or asymptomatic left ventricular dysfunction. The Survival and Ventricular Enlargement (SAVE) Trial (26) took 2,231 post-MI patients with ejection fractions of 40% or less but without overt heart failure or anginal symptoms and randomly assigned them to either a placebo or treatment with captopril, an angiotensin-converting enzyme (ACE) inhibitor. Patients were then followed for an average of 42 months. Drug therapy reduced total mortality, cardiovascular mortality, recurrent hospitalization, and recurrent MI (table 2), as well as the need for coronary revascularization (27).

TABLE 2. Percent Risk Reduction in the Survival and Ventricular Enlargement (SAVE) Trial*
Variable Risk Reduction (%) P-value
Total mortality 19 0.019
Cardiovascular mortality 21 0.014
Recurrent hospitalization 22 0.019
Recurrent myocardial infarction 25 0.015

*Adapted from Pfeffer et al (26).

The Studies of Left Ventricular Dysfunction (SOLVD) Trials (28,29) assessed the effects of another ACE inhibitor, enalapril, in patients with chronic heart failure and ejection fractions of 35% or less. Follow-up averaged 40 months. Overall, enalapril therapy reduced mortality by 16% (28), with a trend toward fewer cardiovascular deaths (29). ACE inhibitor treatment also reduced the incidence of hospital admissions for heart failure in this population. In both trials, enalapril treatment significantly reduced the incidence of MI, unstable angina, and cardiac mortality, with corresponding risk reductions ranging from 20% to 23% (30).

The results of these well-designed, long-term studies were thus consistent in demonstrating a reduction in overall mortality of about 20% among selected high-risk patients assigned to ACE inhibitor therapy. Nevertheless, until recently it was unclear whether the broader population of patients with CAD and preserved left ventricular function would also benefit from long-term ACE inhibitor therapy. This question was resolved when the Heart Outcomes Prevention Evaluation (HOPE) study was stopped prematurely because of overwhelming evidence that ramipril reduced the total number of cardiovascular events by a remarkable 22% (31). HOPE also found that ramipril-treated patients developed heart failure and diabetes less frequently and had fewer revascularization procedures than controls.

Considerable information thus indicates a potential role for ACE inhibitors in reducing the risk of major ischemic events in coronary patients with left ventricular dysfunction (32). Moreover, new data suggest that these benefits may extend to cardiac patients without heart failure (31). Mechanisms that may contribute to the cardioprotective effects of ACE inhibitor therapy are not entirely clear. One intriguing possibility is that these drugs block some of the direct adverse effects of angiotensin II on the coronary circulation, myocardium, or both. Other possible mechanisms include blood pressure lowering, coronary vasodilatation, an antiproliferative effect on vascular smooth muscle, a prevention of atherosclerosis progression, and favorable effects on endothelial function (30).

TAKE-HOME MESSAGE: ACE inhibitors can reduce the risk of major ischemic events in a broad range of patients, especially those with a history of left ventricular dysfunction and chronic heart failure. The mechanisms, however, are not clear.

'B': Beta-Blockers, B Vitamins, and Blood Pressure Control

Beta-blocker therapy. Long-term administration of beta-adrenergic blockers after MI improves medium-term survival. In the Beta-Blocker in Heart Attack Trial (BHAT), 3,837 post-MI patients were followed for an average of 25 months (33). The mortality rates for patients randomly assigned to receive propranolol or placebo were 3.7% and 6.0%, respectively, corresponding to a 39% risk reduction in the first year post-MI. Over 25 months, beta-blocker therapy reduced the risk of death by 27%. However, among 1-year survivors, continued treatment benefit appeared to be restricted to patients at highest risk (34).

An analysis of 16 randomized trials of long-term prophylactic use of beta-blockers, involving more than 18,000 survivors of acute MI, demonstrated convincingly the therapeutic benefit of initiating treatment soon after an acute cardiac event (35). Beta-blocker therapy reduced the risk of death and reinfarction by 20% to 25%. This figure was based on all randomized patients, irrespective of whether they took their allotted treatment. Accordingly, the benefits may be even greater for compliers and high-risk patients, especially during the first year post-MI.

Others have reported that beta-blocker therapy confers a 23% to 40% reduction in mortality after MI (36,37). Patient subsets who may also benefit from beta-blocker therapy include elderly persons, patients with comorbid conditions that were traditionally considered contraindications to beta-blockade (such as heart failure or pulmonary disease), those with nontransmural infarction, and infarct survivors who have not undergone surgical revascularization (37-39).

Many mechanisms could explain the reduced cardiovascular mortality with long-term beta-blocker therapy after acute MI. Antihypertensive and antiarrhythmic effects may be important: A chief effect of beta-blockers in randomized trials appears to be a reduction in "sudden cardiac death," supporting an antiarrhythmic mechanism (35). Decreased cardiac demands may also be relevant, since silent ischemia has been linked to an increased risk of cardiac arrest during physical exertion (40). However, beta-blocker therapy may also decrease ventricular-wall tension, thus reducing the potential for cardiac rupture. Additional mechanisms may include a reduced infarct size due to the administration of beta-blockade before or in the early minutes or hours following an acute infarction, enhanced vascularity of the myocardium, and a moderate antiplatelet effect of nonselective beta-blockers (35).

Although it has been suggested that beta-blockade may attenuate improvements in aerobic fitness following exercise-based cardiac rehabilitation (41), numerous studies show considerable physiologic benefit from a physical conditioning program in the presence of both cardioselective and nonselective beta-blocking drugs, despite a reduced training heart rate (42). Nevertheless, fewer than half of all eligible post-MI patients receive beta-blocker therapy at hospital discharge (43).

TAKE-HOME MESSAGE: Beta-blocker therapy can be useful for preventing subsequent events in the post-MI patient, including the elderly, patients with comorbid conditions that had contraindicated such therapy previously (heart failure or pulmonary disease), those with nontransmural infarction, and infarct survivors who have not had surgical revascularization.

B vitamins. Vitamins B6, B12, and folate have been suggested as agents that can reduce the risk of MI by modulating plasma total homocysteine levels. Low levels of vitamin B12 have been associated with the incidence of MI, but the relationship to homocysteine remains controversial (44). Nevertheless, a recent meta-analysis of 38 studies led scientists to the startling conclusion that 13,500 to 50,000 heart disease-related deaths in the United States could be prevented annually if people simply consumed more folate (45).

TAKE HOME MESSAGE: Until the role of homocysteine is verified, eating more foods that are rich in B vitamins appears to represent a prudent course for persons with CAD and those trying to prevent it (46).

Blood pressure control. The work rate of the heart is approximately proportional to the product of heart rate and systolic blood pressure. Thus, the work performed (and the risk of myocardial ischemia) is directly proportional to systolic pressure.

In diagnosing hypertension, it is important to ensure that the patient is rested and relaxed; anxieties that develop in a doctor's office are responsible for much misdiagnosis of hypertension (47).

Exercise in itself helps to control blood pressure, reducing the systolic reading by an average of 7 mm Hg in individuals with hypertension (48). If the pressure remains above 140/90 mm Hg after thorough modification of lifestyle (weight reduction, exercise, and reduction of salt intake [to 5 to 6 g per day] and alcohol [to fewer than three drinks per day]) (49), the risk of cardiovascular morbidity and mortality can be reduced by drug treatment (50), beginning with a beta-blocker or a low dose of a thiazide diuretic (51). However, the response should be carefully monitored, as there is some evidence that a reduction of diastolic pressure below 85 mm Hg increases the risk of a recurrent cardiac event (52,53).

TAKE-HOME MESSAGE: If lifestyle modifications do not reduce blood pressure, then drug therapy (eg, beta-blocker, thiazide diuretic) should be implemented with careful monitoring.

'C': Cholesterol Management

High-density lipoprotein cholesterol (HDL-C; especially the HDL2-cholesterol subfraction) is thought to be a scavenger molecule that transports cholesterol away from peripheral tissues (including the coronary vasculature), thus reducing the likelihood of further vascular stenosis. In contrast, LDL delivers cholesterol to the vasculature, enhancing the risk.

Options to enhance the lipid profile include exercise, dieting, administration of drugs, and various combinations of these treatments. Nevertheless, attempts to induce a drastic reduction in patients' total cholesterol by a combination of stringent dieting and pharmacologic treatment (54) remain somewhat controversial. There is undoubtedly a reduction in the recurrence rate for MI, but this may be partially offset by increases in other causes of mortality, including suicide and accidents (55,56), perhaps because of behavioral side effects of the drug treatment (56), family disruptions associated with dieting, or an increase in cancer deaths among smokers (55).

Exercise. Endogenous synthesis of cholesterol is a major determinant of the blood lipid profile, and by burning excess energy, regular, prolonged exercise is an effective method of modifying blood lipids favorably in many patients. Weight loss and any decreases in smoking habits contribute to the improved lipid profile (57). As in ostensibly healthy middle-aged adults, a program of progressive aerobic training can in itself induce beneficial changes in both lipids and lipoproteins following MI (58,59). Plasma triglycerides, total cholesterol, and LDL-C are all reduced; HDL-C is less readily increased (60), although a response is obtained with an adequate energy expenditure.

In men, the response seems greatest in those who enter a program with a high HDL-C and a low plasma triglyceride level. Possibly, such individuals have higher tissue lipoprotein lipase activity, are more tolerant of endurance activity, and thus can exercise enough to improve their lipid profile further. Exercise enhances the lipid profile less readily in women than in men (57). This may reflect higher baseline levels of HDL-C in women and gender differences in fat distribution, associated lipase activity, and the attained volume of exercise. In males, the response is proportional to the weekly energy expenditure (61), and a substantial increase of HDL-C can be induced in those who progress to a sufficient weekly jogging distance (15 to 18 km/wk).

Diet. Total intake of fat should be restricted to 20% of daily energy requirements, with a cholesterol intake of only 100 mg to 150 mg per day (62), particularly for patients with diabetes. It may also be helpful to increase the ingestions of fish oils, or to provide n-3 polyunsaturated fatty acid supplements (5 to 10 g/day) (63,64). This tactic reduces plasma triglycerides and very-low-density lipoprotein cholesterol, while possibly increasing HDL-C. Moreover, the n-3 polyunsaturated fatty acids appear to reduce platelet aggregation and blood coagulability (63).

Lipid-lowering agents. These drugs are particularly important in patients with refractory disease and abnormal lipid metabolism. Potential agents include nicotinic acid (niacin), fibric acid derivatives, (eg, gemfibrozil), bile acid sequestrants (eg, cholestyramine), and HMG-CoA reductase inhibitors (eg, lovastatin). Gemfibrozil (600 mg bid), fenofibrate (200 mg qd), or nicotinic acid (3 to 6 g/day) is the usual initial choice for managing high triglyceride levels; commonly, such treatment also reduces LDL-C by some 10% and increases HDL-C by a similar margin (57). Depending on the statin taken, patients can reduce their total cholesterol and LDL-C significantly and increase their HDL-C levels. Dosages vary from as low as 5 mg per day for atorvastatin to as high as 160 mg per day for simvastatin. Reductions for total cholesterol levels range from 22% to 42%, LDL-C reductions range from 27% to 55%, and HDL-C increases are about 7% (65).

TAKE-HOME MESSAGE: Diet modification, exercise, and drugs can be used to modify cholesterol levels. For patients who do not respond to diet and exercise, drug therapy can be used as an adjunctive intervention.

'D': Diabetes Mellitus and Diet

Type 2 diabetes. Given that type 2 diabetes mellitus is a factor that commonly predisposes patients to coronary atherosclerosis, careful regulation of blood sugar is an important component of tertiary prevention. Exercise and the control of obesity offer the most effective bases of prevention; warning signs of excessive adiposity are a body mass index (BMI) greater than 27 kg/m2 and a waist-to-hip ratio greater than 1.0 in men and greater than 0.8 in women (57).

If evidence of advanced diabetes already exists, exercise must be pursued cautiously because of risks that include hypoglycemia, retinal detachment, neuropathies, and the potential for persistent foot infections that can progress to gangrene. Protein intake should be at least 0.8 g/kg/day and be derived from sources such as lean red meat and skinless chicken that are relatively low in cholesterol, total fat, and saturated fat. Complex carbohydrates should provide the bulk of energy needs (55% to 70%), and substantial fiber intake (20 to 35 g per day) is also recommended. Sucrose and other glucose-containing disaccharides should provide no more than 10% of daily energy needs, and saturated fat should also account for less than 10% of energy needs. Insulin should be administered only if these measures fail to control blood sugar levels.

Diet. An appropriate modification of diet can act with a progressive exercise regimen to control obesity and improve the lipid profile. Obesity continues to impede prognosis for several reasons: (1) It limits the mechanical efficiency of movement and increases the energy cost of any task in which body mass must be displaced (66); (2) it reduces the maximal oxygen intake per kilogram of body mass (mL/[kg*min]), thus increasing the relative strain on the body at any given intensity of exercise; (3) it increases the load to be lifted by the body muscles, thus augmenting the exercise-induced rise in blood pressure; and (4) it is associated with other risk factors for recurrent cardiac events such as hypertension, an adverse lipid profile, and type 2 diabetes mellitus.

Recent reports have demonstrated that phase 2 and phase 3 cardiac rehabilitation programs can reduce body fat content in overweight and obese post-MI patients, either with (67) or without (58) specific dietary restriction. Exercise is an important component of a weight-loss program. It increases resting metabolism (58), countering the suppression of energy expenditure associated with a negative energy balance (68). It also elevates mood and helps to conserve lean tissue as fat is metabolized (69).

TAKE-HOME MESSAGE: Careful regulation of blood sugar, regular exercise to control body mass (BMI<27 kg/m2), and a diet high in carbohydrate (50% to 70% of energy needs) and fiber, sufficient in protein, and low in sucrose and other glucose-containing disaccharides (no more than 10% of daily energy needs) are important modalities for mitigating the risks of a recurrent MI.

'E': Exercise and Estrogen Replacement

Exercise. A progressive exercise program is the cornerstone of any tertiary rehabilitation program designed to prevent recurrent MI.

Cardiac effects. Exercise probably acts in part indirectly by reducing cardiac risk factors such as hypertension, obesity, an adverse lipid profile, and the urge to smoke cigarettes. In addition, enhancement of cardiac function decreases the rate-pressure product (and thus the cardiac demands) at any given intensity of exercise (figure 2: not shown). A relative lengthening of the diastolic phase of the cardiac cycle facilitates myocardial perfusion, and a strengthening of the skeletal muscles decreases the rise of blood pressure induced by performance of any given lifting task. There may also be beneficial actions on coronary vascular dimensions, clotting mechanisms, and the atherogenic activity of blood mononuclear cells (70,71).

Meta-analyses. During and immediately following a bout of exercise, there is a sixfold increase in the likelihood of a recurrent MI, but this is much more than offset by a favorable prognosis during the remainder of the day (72). Several meta-analyses of progressive exercise programs, each based on about 5,000 cases, have shown a 20% to 30% decrease in fatal recurrences in exercisers relative to controls receiving standard treatment (20,73-75). The incidence of nonfatal recurrences was unchanged, but the proportion of recurrences with a fatal outcome was also decreased. One major trial showed no impact on the incidence of fatal recurrences when analysis was based on the assigned treatment (76). However, reanalysis showed that the apparent absence of response was due to departures from the assigned behavior in both exercise and control groups; when the analysis was based on changes in individual fitness level, the data conformed to other meta-analyses (77).

Gender differences and benefits. Some reports suggest a similar training response in female and male patients (78,79), but in our experience the response is smaller in women and in older men, partly because they undertake a lower level of training (80). The underlying reasons remain to be clarified. Female participation may be limited by domestic responsibilities, lack of transportation to the program, and an aversion to male-oriented programs. Older adults may also have poorer overall health, a slower synthesis of cardiac and skeletal muscle protein, less ready reversal of calcified vascular lesions, and a lesser motivation to seek total recovery of function.

Benefit extends to patients with angina (81), those with stable congestive heart failure (82,83), and following cardiac transplantation (82,84). Early fears that a vigorous exercise program might impair global and regional ventricular function in patients with a massive anterior-wall MI and a poor initial ventricular ejection fraction (85) appear to have been groundless.

Optimal dose for effect. The optimal dose of physical activity remains controversial. In Toronto, the normal expectation has been a progression to a walk/jog distance of 4.8 km (3 miles) of endurance exercise per session, completed over 42 minutes in patients younger than age 45, and 45 minutes if the patient is older than age 45 (86). Supervised class sessions are initially held once per week, and patients are encouraged to perform comparable activity at home on at least 4 other days; compliance is monitored by a weekly exercise log (86). Other centers provide as many as three supervised sessions per week. Such a regimen is feasible in a small town, but in a large city repeated travel to and from the rehabilitation center may strongly diminish motivation.

Exercise training as a sole intervention may not necessarily halt the progression of CAD or, for that matter, prevent restenosis or reinfarction. However, intensive multifactorial intervention (including exercise) can result in regression or limitation of progression of angiographically documented coronary atherosclerosis (87). One study (88), which included a low-fat, low-cholesterol diet (fat <20% of energy; cholesterol <200 mg/day) showed that a minimum of 6.5 MJ/wk (1,600 kcal/wk) of physical activity may halt the progression of CAD, whereas regression may be achieved with an energy expenditure of 9 MJ per wk (2,200 kcal/wk) (figure 3: not shown). For many patients, these goals would require walking 24 km (15 miles) and 32 km (20 miles) per week, respectively.

Resistance training. Although most exercise programs maintain a strong aerobic focus, there is growing recognition that recurrence of infarcts is often precipitated by the need to lift heavy objects, and that a complementary muscle-strengthening regimen can reduce this risk. The resistance component should include a single set of 10 to 15 repetitions, involving 8 to 10 different exercises that train the major muscle groups, performed 2 to 3 days per week (89).

TAKE-HOME MESSAGE: An exercise program should progress toward walking 15 to 20 miles per week with resistance training that includes single sets of 10 to 15 repetitions for each of 8 to 10 major muscle groups.

Estrogen replacement. Hormone replacement therapy (HRT) is highly effective in the prevention of heart disease. Meta-analyses, primarily from the United States (90,91), show that postmenopausal estrogen is associated with a 35% to 50% reduced risk of CAD. There are multiple mechanisms whereby estrogen might protect against CAD; for example, raising HDL-C and lowering LDL-C. Additionally, it restores optimal endothelial function, improves hemostatic function, enhances vascular tone, promotes plaque stabilization, and provides antioxidant effects.

The cardiovascular risk reduction associated with estrogen therapy may occur irrespective of effects on blood lipid levels. When progestins were added to the estrogen regimen for women with an intact uterus to reduce the risk of endometrial cancer, decreases in LDL-C and increases in HDL-C were nullified, yet coronary protection remained (92). By contrast, data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial showed that, while combined estrogen and progestin had a less favorable effect on lipoproteins than estrogen alone, combined therapies were better than placebo, and, indeed, estrogen and micronized progestin were almost as effective as estrogen alone (93).

Ettinger et al (94) note that postmenopausal women who took long-term estrogen replacement therapy had a 46% lower mortality from all causes than age-matched nonusers; the reduced mortality was largely due to a lesser incidence of fatal CAD. The Nurses' Health Study (95) showed that women who were taking HRT after menopause had a lower mortality rate (relative risk, 0.63) than women who had never taken hormones; this was particularly true for death due to CAD. A recent Markov analysis (96) postulated that HRT should increase the life expectancy of most postmenopausal women, with gains exceeding 3 years in some individuals. The only women unlikely to realize these gains are those at greatest risk for breast cancer and at least risk for CAD.

The possible benefits of HRT for women with known CAD are somewhat controversial. In cross-sectional studies of postmenopausal women with angiographically documented CAD, HRT reduced the risk of subsequent coronary events whether heart disease was severe or not (97,98). Several observational studies have confirmed the cardioprotective benefits of HRT in women with CAD (90,91). But the Heart and Estrogen/Progestin Replacement Study (HERS) found no reduction of fatal or nonfatal cardiovascular events in postmenopausal women with established CAD who received estrogen plus progestin during an average follow-up of 4.1 years (99). Subsequent observations from this study have demonstrate a slight increase in early mortality and a decrease in later mortality. Moreover, such therapy may be associated with an increased risk of breast and endometrial cancers, gallbladder disease, and venous thromboembolism.

TAKE HOME MESSAGE: HRT may benefit postmenopausal women, but its effects on risk reduction in women with known CAD are somewhat controversial. This intervention may be associated with an increased risk of other disorders.

'S': Social Support, Smoking Cessation, and Stress Management

Social support. Efforts at primary, secondary, and tertiary prevention of CAD have been directed at major risk factors such as cigarette smoking, hypertension, hypercholesterolemia, and, more recently, physical inactivity and obesity. However, fewer than half of all cases of CAD are explained by these variables, either alone or in combination. Although the association between psychological factors and heart disease is still discounted by some primary care physicians and cardiologists, epidemiologic studies have for decades provided circumstantial evidence of higher cardiovascular death rates among people who are socially isolated—particularly those who are living alone or otherwise lack people who make them feel valued and loved.

Social network impact. One of the first studies to identify the importance of social networks and close family ties in buffering the deleterious effects of heart disease involved a small town located in eastern Pennsylvania (100). Epidemiologists were startled to find a strikingly lower death rate from heart disease in Roseto than in neighboring communities. From 1955 to 1961, age-adjusted cardiovascular deaths per 100,000 persons were: Roseto, 157; Nazareth, 603; Bangor, 613; Stroudsburg, 671; and East Stroudsburg, 405. After careful analysis, the researchers concluded that psychosocial factors were largely responsible for the low morbidity and mortality from MI in Roseto. They also predicted that over time, social ties would diminish and death rates from cardiovascular disease would rise—a prediction that proved true over the next 20 years (101).

In Alameda County, California, 4,775 residents underwent a 9-year follow-up (102). The investigators found that (1) married persons, (2) those with several close family members, friends, or both, and (3) those with church membership or other group affiliations had half the mortality from ischemic heart disease as those without such social resources, even after adjustments of the findings were made for conventional coronary risk factors.

Several other studies also reported higher rates of recurrent cardiac events among socially isolated persons with CAD (103). Among 2,320 male survivors of acute MI who were enrolled in the BHAT (33) (beta-blocker trial), patients with elevated scores on indices of life stress and social isolation had a fourfold to fivefold higher 3-year mortality rate (104). Moreover, the severity and mortality experience of CAD are worse in socially isolated coronary patients with type A behavior as compared with their socially integrated counterparts (105,106).

Large studies. New interest was stimulated when several other large studies reported correlations between survival rates of people with coronary disease and their social isolation. For example, the 6-month mortality was 15.8% among patients who lived alone after MI versus 8.8% among those living with others (107). In a follow-up study of patients with angiographically documented CAD, unmarried patients with no confidant had a 5-year survival rate of just 50%, compared with 82% for those who had either a spouse, confidant, or both (108). Another investigation revealed that a lack of emotional support as reported by elderly men and women before MI was directly related to the risk of death in the 6-month period after infarction (109). In all three studies, the impact of social isolation on prognosis was independent of other factors associated with cardiac complications, including the severity of myocardial damage (represented by the ejection fraction), degree of ventricular ectopy, and use of beta-blocker therapy.

It is unclear which factor or factors are responsible for the poorer prognosis among socially isolated people; it may be as simple as a reduced availability of rapid medical assistance or as complex as a proposed neurohumoral response to human contact. Another possibility is that those who lack social ties are less likely to have good health habits. For example, they may not seek medical attention, take prescribed medications, or be encouraged to follow their physician's recommendations.

Lack of social resources offers an important target for cardiovascular education, counseling, and behavioral interventions (87,110). Cardiac patients who live alone can benefit from developing and maintaining a social network. By joining organizations, pursuing continuing education classes, volunteering (eg, in hospitals), or participating in group exercise rehabilitation programs, isolated individuals can begin to establish a network of people to complement and reinforce their ongoing medical management through regular surveillance.

TAKE-HOME MESSAGE: Social networks are important for cardiac patients. Patients can benefit by maintaining ties with friends and relatives. Those who lack these resources can develop networks through diverse activities that include social organizations, volunteer work, and rehabilitation programs.

Smoking cessation. Cigarette smoking is a substantial risk factor both before and after a first MI (111). Potential mechanisms include: (1) a faster heart rate and thus a greater cardiac work rate for any given intensity of exercise (112), (2) an increase in the work of breathing and thus the oxygen cost of effort (113), (3) a decrease in the blood's oxygen-carrying capacity and an altered oxygen dissociation curve from formation of carboxyhemoglobin (114), and (4) a possible but controversial direct action of carbon monoxide on atherosclerosis (115).

Counseling, nicotine replacement, and formal smoking cessation programs should be arranged as seems best suited to the needs of the individual patient. As many as 80% of patients are heavy smokers prior to their MI, but counseling and other forms of treatment received during hospital and phase 2 programs can reduce this figure to about 35% at entry to a phase 3 program (116). In our experience, it is challenging to modify the behavior of this hard-core group, even by a combination of progressive exercise and continued counseling, although an unchanged proportion of smokers 3 years postinfarction may itself be a triumph over the usual tendency to recidivism among heavy smokers (111). Others have reported considerable long-term success from nurse-managed counseling and behavioral interventions (117).

TAKE-HOME MESSAGE: Counseling, nicotine replacement, and formal smoking cessation programs should be arranged to suit the individual patient's needs.

Stress management. The role of emotional stress has long been suspected in the pathogenesis and manifestation of CAD. One hypothesis suggests that stress stimulates the central nervous system in ways that can precipitate malignant ventricular arrhythmias, coronary artery plaque rupture and thrombosis, or both. Mechanisms could include surges in heart rate, blood pressure, catecholamine and cortisol concentrations; platelet aggregability; coronary vascular tone; plasma viscosity; and fibrinolytic activity. Another hypothesis suggests that stress contributes to the development of hypertension, a major risk factor for CAD. Anger and hostility are particularly potent stressors for persons with heart disease, causing a transient decrease in left ventricular ejection fraction (figure 4: not shown) (118).

Although "being stressed" is typically equated to "being anxious," it also is linked with a variety of behaviors that are associated with ischemic heart disease. These include intense anxiety, anger, hostility, depression, feelings of helplessness, and "type A behavior"; the latter is characterized by ambitiousness, competitiveness, impatience, and a sense of time urgency. The Western Collaborative Group Study found that the type A behavior pattern was associated with twice the incidence of heart disease and a fivefold risk of recurrent MI relative to type B (119). More recent investigations have been unable to substantiate the relation between overall type A behavior and cardiovascular morbidity and mortality (120). One study (121) revealed that among cardiac patients with poor ventricular function, patients with a type A personality had a better survival rate than type B. Other investigators have suggested that some components of the type A behavior pattern (eg, hostility) may be more predictive of susceptibility to a cardiac event (120).

One randomized, controlled trial (122) that involved stress management training and an essentially vegan diet produced profound short-term improvements in the cardiovascular status of patients with CAD, including increases in exercise tolerance and left ventricular ejection fraction, a decrease in total serum cholesterol, and a reduced frequency of anginal episodes. Another stress-monitoring and intervention study (123) was shown to lower stress levels and reduce the incidence of cardiac deaths in 453 male post-MI patients by 70% at the fourth month after hospital discharge and by 47% over the study year.

Education, counseling, and psychosocial interventions—either alone or as components of a multifactorial secondary prevention program—enhance psychological well-being and are recommended to complement exercise training (87). Stress management techniques are aimed at attenuating physiologic responses such as heart rate and blood pressure, inducing an improved sense of well-being, modifying behavior patterns (eg, type A), enhancing coping mechanisms, and countering social isolation and depression. Such programs have become an integral component of cardiac rehabilitation initiatives. Effective tactics may include methods to identify and avoid stressful situations, adjustment and/or adaptation techniques to cope more appropriately with stressors, and use of relaxation or biofeedback techniques to moderate physiologic reactions to stress. Among various techniques commonly promulgated for stress management and relaxation training, including yoga, progressive muscular relaxation, and breathing exercises, no single intervention has been universally accepted.

In summary, tertiary preventive programs should assess patients for depression, anxiety, excessive distress/stress, anger, and compulsive work-related behaviors, providing stress management and/or group counseling sessions to modify psychological well-being favorably. Preliminary screening with a variety of psychosocial inventories, including the Jenkins Activity Survey (124), SF-36 (125), Beck Depression Inventory (126), or Spielberger State-Trait Anxiety Inventory (127), can be helpful. Referral liaisons with psychiatrists, psychologists, social workers, or behavioral therapists should be established to assist with continued evaluation and management of patients with evidence of major dysfunction in these areas.

TAKE-HOME MESSAGE: Education, counseling, and psychosocial interventions can improve well-being and are recommended to complement exercise. Patients should be assessed for depression, anxiety, and other nonadaptive behaviors, and encouraged to seek group counseling or, in more serious cases, referred to behavioral therapists or other professionals.

Tertiary Prevention 'A' to 'S'

In the 1960s, the treatment of heart disease involved early ambulation, exercise training, and a prudent diet (3). Since then, therapy has largely evolved to include an array of costly and palliative coronary revascularization procedures (figure 5: not shown) such as bypass surgery, coronary angioplasty, and interventional devices (eg, coronary stents). Unfortunately, physicians too often fail to address the underlying causes of the disease—high-fat and high-cholesterol diets, cigarette smoking, hypertension, obesity, and physical inactivity. However, aggressive risk-factor reduction, including exercise training (128), and complementary pharmacotherapies, can improve coronary artery endothelial function and stabilize and even reverse the atherosclerotic process. Many of these interventions are applicable to primary, secondary, and tertiary prevention and are individually associated with a remarkably consistent reduction (about 20% to 25%) in fatal and nonfatal cardiac events. When selectively combined, even greater reductions in morbidity and mortality are likely to be achieved.

As the late Herman K. Hellerstein, MD, summarized it in 1972 (129), "...a planned program featuring exercise training among other measures (ie, aggressive modification of coronary risk factors) may tangibly reduce the risk of reinfarction and greater myocardial damage." Like all wise statements, this hypothesis is both justifiable and unadorned. It is so clearly evident and acceptable today that we feel we should have known it all along.

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Dr Franklin is the director of the cardiac rehabilitation program and exercise laboratories at the William Beaumont Hospital in Royal Oak, Michigan. Dr Shephard is professor emeritus of applied physiology at the University of Toronto and currently lives in Brackendale, British Columbia. Address correspondence to Barry A. Franklin, PhD, Beaumont Rehabilitation and Health Center, Cardiac Rehabilitation Dept, 746 Purdy St, Birmingham, MI 48009; e-mail to bfranklin@beaumont.edu.

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