Secondary Prevention of Coronary Heart Disease
The risks of myocardial infarction (MI) and cardiac death can be as high as 5%/year to 10%/year in persons with preexisting coronary heart disease (CHD) or CHD equivalents (peripheral arterial disease and diabetes). When these risks are added to the disease’s physical and psychological tolls, the importance of a comprehensive program of secondary prevention becomes readily evident. The goals of such a program include (a) improvement of functional capacity and quality of life, (b) reduction in the risks of future cardiac events (e.g., MI, cardiac arrest, need for revascularization), and (c) prolongation of survival. The results of major long-term, randomized, controlled trials indicate that these goals can be achieved cost-effectively through the concerted application of preventive measures. Some components of the program focus on lifestyle changes, and others include medical therapies and revascularization procedures; the control of atherosclerotic risk factors is paramount. Together, they make for an effective program that can save lives and improve quality of life. Despite substantial evidence for efficacy, there is a high prevalence of failure to implement these measures, particularly for patients at highest risk.
Although some elements of the secondary prevention program can be carried out by others, the primary physician has a major responsibility for program design, coordination, and compliance. One needs to know what interventions are effective and how to tailor a secondary prevention program to the needs and capabilities of the individual patient. On receiving a diagnosis of coronary artery disease or experiencing a MI, most
patients become highly motivated to live a healthier lifestyle, which provides an excellent opportunity to effect important changes in diet and exercise as part of a comprehensive program of risk reduction through secondary prevention.
patients become highly motivated to live a healthier lifestyle, which provides an excellent opportunity to effect important changes in diet and exercise as part of a comprehensive program of risk reduction through secondary prevention.
ESTIMATING RISK
As noted, the risks of a CHD event (i.e., MI, cardiac death) can be as high as 5%/year to 10%/year in persons with preexisting coronary artery disease. In population studies, CHD event risk is highest in persons with a prior history of an ischemic event; followed by those with stable coronary, cerebrovascular, or peripheral artery disease; and followed by those with CHD risk factors. In one multivariate analysis, polyarterial vascular disease confers the highest risk, followed by an ischemic event in the previous year, and followed by diabetes. Attention to these readily elicited clinical risk factors can facilitate risk assessment, risk stratification, and design of an effective, personalized secondary prevention program.
Lifestyle modification is a key component of the comprehensive rehabilitation and secondary prevention program. Along with dietary modification (see later discussion), exercise is an essential element of the lifestyle-modification agenda and the centerpiece of rehabilitation programs.
Outcomes
Effects on Morbidity, Mortality, and Quality of Life
Cardiac rehabilitation programs for secondary prevention reduce all-cause mortality, cardiovascular mortality, and fatal reinfarction by 20% to 25%. The best effect is on sudden death, which declines by greater than 35%. Quality of life also increases as patients regain confidence and develop a better sense of physical well-being. Benefits accrue to the elderly as well as to younger patients. Because most data derive from comprehensive exercise rehabilitation programs that also incorporate such efforts as smoking cessation, dietary modification, and stress reduction, it is difficult to know the precise proportion of benefit due to exercise alone, but the training effect achieved contributes markedly to quality of life, and there are improvements in many important physiologic and biochemical parameters (see later discussion). Such programs are cost-effective, often achieving considerable savings through reductions in rates of rehospitalization, revascularization, length of stay, charges per hospitalization, and lost productivity.
Mechanisms of Benefit from Exercise
Increases in cardiac stroke volume and skeletal muscle oxygen extraction constitute a training effect. The trained subject is able to deliver a given quantity of oxygenated blood to the peripheral tissues at a lower heart rate and at lower systolic pressure. The decline in rate-pressure product (heart rate × systolic arterial pressure) corresponds to a reduction in myocardial oxygen demand for a particular level of exercise, allowing the trained patient to achieve a higher level of activity before demand outpaces blood supply.
Myocardial perfusion has been observed to increase by 25% to 50%, presumably through the vasodilation of coronary arteries and improvement of collateral blood flow to ischemic zones.
There is an 8% to 25% rise in the concentration of high-density lipoprotein cholesterol, a 22% reduction in triglycerides, improved glycemic control in diabetes, increase in fibrinolytic response to occlusive stimuli, and an increase in the myocardial ventricular fibrillatory threshold, rendering it less vulnerable.
Candidates, Goals, and Program Phases
Candidates
All persons with established coronary disease are candidates for a program of exercise and lifestyle modification. Those recovering from MI often get the most attention and referrals to formal programs, but significant functional and survival benefits accrue to other persons with CHD, including those with chronic stable angina (see Chapter 30) and persons who have recently undergone revascularization. Benefits are not restricted to younger patients; the elderly also achieve reductions in cardiac morbidity and mortality.
Goals: Rehabilitation and Lifestyle Modification
Goals differ according to the clinical circumstances. For the post-MI patient, rehabilitation to counter physical deconditioning and psychological disability is the immediate priority, supplemented by teaching the importance of vigorously controlling CHD risk factors. Shortly after discharge, the goal turns toward restoring former physical capacity, followed later by achieving an enhanced level of performance and lifelong adherence to good health habits. The ultimate goals for all CHD patients are improved functional capacity and quality of life, reduced risks of future cardiac events (e.g., infarction, cardiac arrest, need for revascularization), and prolonged survival.
Phase I: Early Rehabilitation
This phase begins during hospitalization for an acute coronary event. Physical deconditioning is avoided by initiating a program of low-level activity as soon as possible after clinical stability has been achieved (usually by day 3 post-MI or as soon as the patient who has undergone revascularization can walk). Before hospital discharge, most patients should be observed by their physician while climbing a flight of stairs. This will provide confidence that such tasks can be performed safely and will often uncover specific questions about what should and should not be done during the first weeks at home. Educational efforts emphasize risk-factor control (see later discussion).
Submaximal exercise testing (to a level of 5 metabolic equivalents [METs]) before hospital discharge can provide important prognostic information and help to restore patient confidence. A negative test predicts an excellent prognosis during the subsequent year, whereas a positive one with or without anginal symptoms indicates a poorer outcome and the need for consideration of revascularization. Serious ventricular dysrhythmias requiring attention may also be uncovered. Radionuclide scintigraphy or echocardiography is required for the stress test if the resting electrocardiogram is abnormal (see Chapter 36).
Phase II: Early Convalescence
This phase encompasses the time from hospital discharge to 3 to 6 weeks later. The prescribed activity level remains relatively low because high-level physical activity risks infarct expansion or possible ventricular aneurysm formation. Exercise intensity is regulated by monitoring the peak heart rate, which should not exceed the level achieved during the predischarge submaximal exercise test. If the predischarge exercise test discloses ischemic electrocardiographic (ECG) changes, anginal
symptoms, or ventricular dysrhythmias, then the heart rate during exercise training sessions should be maintained below the heart rate at which any of these pathologic events was observed. The exercise training modalities used during phase II, as in phase I, usually consist of walking and stationary bicycling. The process of educating the patient and the family about coronary risk factors continues and is reinforced (see later discussion).
symptoms, or ventricular dysrhythmias, then the heart rate during exercise training sessions should be maintained below the heart rate at which any of these pathologic events was observed. The exercise training modalities used during phase II, as in phase I, usually consist of walking and stationary bicycling. The process of educating the patient and the family about coronary risk factors continues and is reinforced (see later discussion).
Phase III: Late Convalescence/Physical Training
The program intensifies to increase the patient’s level of physical conditioning. A maximal exercise stress test is performed at 3 to 6 weeks, quantifying the patient’s heart rate and blood pressure responses to exercise and screening tests for latent myocardial ischemia and ventricular dysrhythmias. The exercise training modalities are broadened to establish a balanced exercise program of long-term patient appeal. Upper extremity conditioning may be added, especially in patients for whom upper extremity work is important to daily activity.
During phase III, efforts to modify risk factors continue and intensify. These include dietary interventions to correct lipid abnormalities and achieve ideal body weight (see later discussion and Chapters 27 and 233). Hypertension control (see Chapter 26) and smoking cessation (see Chapter 54) are critically important. Management of psychological stress and depression should also be addressed (see Chapters 226 and 227), particularly as the patient returns to work. A well-balanced cardiac rehabilitation program attends to all of these factors and should involve the patient’s family as well.
Phase IV: Maintenance/Follow-Up
The goal is to encourage lifelong adherence to the healthy habits established during phase III. Follow-up visits at 6- to 12-month intervals are important. Blood pressure and pulse measurement, serum lipid levels, and even repeat maximal exercise tolerance tests can provide useful feedback to the patient and indicate areas that may require lifestyle changes to minimize coronary risk.
Program Design, Safety, and Compliance
Program Design: How Much and What Type of Exercise?
The classic assumption is that one must achieve a physiologic training effect to obtain health benefits; such a training effect requires aerobic (endurance) exercise (running, jogging, fast walking, cycling, rowing, cross-country skiing, swimming) performed at least four times a week for at least 30 minutes a session, resulting in a heart rate of 70% to 85% of a predicted maximum. However, significant reductions in coronary risk do not require the attainment of maximum cardiopulmonary fitness. Moderate degrees of exercise may provide nearly equivalent results. Persons with low baseline levels of activity demonstrate the greatest improvement in outcomes with exercise training, even if they exercise with only moderate intensity (e.g., walking 3 to 4 miles/h). Epidemiologic data suggest that simple informal exercise carried out as part of everyday life (e.g., walking, stair climbing, working in the yard) confers survival benefit. The current consensus recommendation for the inactive person is to accumulate a total of 30 minutes of moderate exertion over the course of the day rather than to put in 30 minutes of exercise at a single session.
The traditional approach to determining the proper intensity of exercise for a cardiac rehabilitation program is to calculate 70% to 85% of a measured maximal heart rate (usually as determined by exercise stress test using the form of exercise anticipated, e.g., treadmill testing for a walking/jogging program, bicycle ergometer testing for a cycling program). This exercise intensity translates to 60% to 80% of maximal oxygen consumption. Patients taking beta-blocker therapy require a formal graded exercise test under the influence of a beta-blocker to establish their proper intensity of exercise.
The current consensus regarding the approach to exercise is shifting from an emphasis on maximizing intensity to maximizing compliance. For previously inactive patients, this translates into a program of a moderate degree of exercise, usually prescribed as starting with walking at a rate of 3 to 4 miles/h for 30 minutes each day. This more practical and sustainable approach to exercise training is designed to increase long-term compliance and extend participation in exercise programs beyond the meager 25% who currently engage in them for cardiac rehabilitation.
Program Safety
Rates of adverse coronary events are very low in supervised programs in post-MI patients. The reported rates for cardiac arrest and fatal MI are 1 per 112,000 and 1 per 294,000 patient-hours, respectively. Home programs supplemented by occasional institutional visits and regular nurse follow-up can also be carried out safely, provided there is careful patient selection (e.g., no ischemia or dysrhythmias on stress testing, good functional capacity, frequent exercising, good reliability). Those at greatest risk, requiring close supervision, are persons who exercise infrequently and manifest poor functional capacity at baseline.
Exercise in unsupervised settings is associated with a small transient increase in the risk of sudden death during moderate to vigorous exercise, which is ameliorated by habitual exercise. In the Nurses’ Health Study (which included women with prior MI), the rate of exercise-related sudden death was extremely low (1 per 36.5 million hours of exertion); the rate among men in the Physicians’ Health Study was 19 times higher but still low (1 per 1.5 million episodes of exercise). In a meta-analysis of MI and sudden cardiac death risk with sudden exertion, risk was increased threefold by episodic physical or sexual activity but significantly mitigated by high levels of habitual exercise.
Improving Compliance
It is estimated that only one fourth of CHD patients who would benefit from a well-designed exercise/rehabilitation program actually take part in one. Part of the reason is that many programs are institutionally based out of concern for safety. The increasing appreciation for the importance of maximizing patient compliance and the established safety of home programs for properly selected and supervised candidates have encouraged the use of home-based programs, which should facilitate participation. Physician counseling, encouragement, close supervision, and the adoption of a moderate exercise program rather than one that stresses more-intensive exertion all help the patient to get started and continue. Most important to compliance is the design of a program that the patient likes to do and finds doable (see Chapter 18, Appendix 18-1-31-31).
TARGETED RISK-FACTOR REDUCTION (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 and 68)
Aggressive risk-factor reduction is essential to a comprehensive program of secondary prevention. Significant reductions in cardiovascular morbidity and mortality are achievable. The magnitude of improvement in outcomes can be as large as or larger than interventions for the primary prevention of coronary disease.
Intensive Treatment of Established Major CHD Risk Factors
The effective treatment of hypertension (systolic pressure <140 mm Hg; see Chapter 26), hypercholesterolemia (low-density lipoprotein [LDL] cholesterol <70 mg/dL; see Chapter 27), and smoking (see Chapter 54) can each reduce cardiovascular morbidity and mortality significantly (by as much as 50%) in patients who have suffered MI. With full cessation of smoking among post-MI patients, the risk of a recurrent coronary event falls to that of nonsmokers after 3 years. The treatment of obesity (see Chapter 233) and glycemic control in diabetes (see Chapter 102) are critical to the effective control of key CHD risk factors (e.g., lipids, blood pressure, hyperinsulinism) and may also have a direct effect on outcomes. The identification and treatment of underlying chronic renal dysfunction and depression are often overlooked and require attention.
Addressing Intensity of LDL Cholesterol Reduction
Statin therapy in persons with CHD significantly reduces CHD event risk and mortality, even among those with normal LDL cholesterol. Intensive statin therapy (e.g., atorvastatin 80 mg/d, rosuvastatin 40 mg/d) that targets an LDL cholesterol of less than 70 mg/dL causes regression of coronary atherosclerotic plaque and significantly, though not uniformly, improves many CHD outcomes when applied across a broad spectrum of CHD patients; best results have been found in persons with stable coronary disease and after acute coronary syndrome; however, mortality is not consistently improved. Such therapy also reduces stroke risk by 20% in persons with carotid disease (see Chapter 171). The National Cholesterol Education program recommends an LDL cholesterol of less than 70 mg/dL as an optional goal in persons at very high CHD risk (see Chapter 27).
Addressing Intensity of Glycemic Control
Standard glycemic control in diabetic with heart disease (target hemoglobin A1c 7.0% to 7.9%) reduces microvascular risk and, in some instances, has been shown to reduce rates of macrovascular complications (see Chapter 102). More-intensive therapy to achieve tighter glycemic control (target hemoglobin A1c <6.0%) in high-risk patients fails to significantly improve most cardiovascular outcomes and increases cardiovascular mortality (ACCORD study). Reasons for the increased mortality remain to be defined, but in the ACCORD study, rates of hypoglycemia were similar in both groups, raising suspicion that the cause of the increased risk may be more related to treatment modalities than to hypoglycemia per se. Nonetheless, severe hypoglycemia correlates with CHD event risk (see Chapter 102).
Addressing Renal Failure and Associated Vitamin D Deficiency
Chronic renal dysfunction is a powerful determinant of cardiovascular complications and death, especially in CHD patients. The risk correlates strongly with glomerular filtration rate (GFR); once it falls to less than 60 mL/min, the risk rises significantly. Even mild to moderate renal insufficiency confers significant risk. The risk is independent of other CHD risk factors. The early detection and treatment of renal dysfunction (see Chapter 142) hold considerable promise for improving CHD outcomes, yet such measures are often overlooked.
Concerted efforts to improve early detection of renal dysfunction are being implemented nationally. Many laboratories now routinely calculate and report GFR along with every serum creatinine determination. Urine microalbumin determinations are readily available and provide another means of early detection. Renal assessment in the elderly is especially important because of heightened CHD risk; however, advancing age and loss of muscle mass may reduce the sensitivity of creatinine-based GFR determinations. Serum measurement of cystatin C concentration (a circulating cysteine protease inhibitor freely filtered by the glomerulus) provides a promising alternative means of determining renal function and cardiovascular risk in the elderly; it is not affected by age, gender, or muscle mass, which reduces the sensitivity of serum creatinine-based GFR determinations in older patients.
Improved detection should facilitate more timely treatment. Observational studies of post-MI patients with renal dysfunction find inappropriately low prescribing rates for therapies of proven efficacy (e.g., angiotensin-converting enzyme [ACE] inhibitors, beta-blockers, antiplatelet agents; see later discussion), suggesting ignorance of renal dysfunction’s significance or an unnecessarily nihilistic approach to management. Even in post-MI patients with chronic kidney disease (in which there may be little that is renally reversible), attention to the preservation of existing kidney function and aggressive treatment of other major CHD risk factors holds considerable promise for improving cardiovascular outcomes.
Chronic kidney disease patients with CHD, especially those requiring hemodialysis, are often very deficient in 1,25-dihydroxyvitamin D due to inability to hydroxylate the 25-OH form of the vitamin. These very low levels of vitamin D in hemodialysis patients correlate with markedly increased rates of CHD mortality. Meta-analysis of prospective observational studies of vitamin D supplementation in dialysis patients suggests a significant CHD survival benefit.
Attending to Anxiety and Depression
Anxiety and situational stress play important roles in secondary prevention; stress management programs can help to reduce the number of cardiac events (see Appendix 226.1-31-31). Depression increases the risk of adverse CHD events in persons with coronary disease, and CHD events can precipitate or worsen depression, yet the majority of post-MI patients with depression go undetected and untreated. The use of semiselective serotonin reuptake inhibitor (SSRI) antidepressants is safe and effective for the treatment of major depression in persons with CHD; moreover, their use in the acute hospital setting has been found to reduce rates of ischemia and heart failure (at the cost of a small increase in risk of bleeding when taken in the setting of heparin/antiplatelet therapy). SSRIs are preferred in CHD over tricyclic antidepressants because of the arrhythmic potential of the latter (see Chapter 227). SSRI therapy can also be useful for its anxiolytic effects (see Chapter 226). Referral for interpersonal psychotherapy appears to be no better than standard comprehensive care by one’s personal physician.
Consideration of Other Risk Factors
Homocysteine
Excess levels of homocysteine may be injurious to vascular endothelium. Epidemiologic data indicate a dose-dependent association between plasma homocysteine and the risk of cardiovascular disease. The association appears to be independent of other cardiovascular risk factors and was initially believed to account for a substantial percentage of “idiopathic” cases, triggering enthusiastic efforts to lower homocysteine through use of folate and B vitamin supplements. Subsequent studies suggest a more modest contribution to risk and fail to demonstrate a significant cardiovascular benefit from reducing elevations of the purported risk factor; in some instances,
vitamin supplementation was paradoxically associated with an increased risk.
vitamin supplementation was paradoxically associated with an increased risk.
Measurement of Plasma Homocysteine.
Homocysteine determinations are now widely available, though often expensive. Accuracy is facilitated by fasting, and sensitivity is enhanced by methionine loading, which stresses the involved metabolic pathways. Despite the test’s ready availability, the decision to order it must take into account the expected contributions to risk assessment and treatment decisions.
Lowering Homocysteine Levels.
Vitamin supplementation effectively lowers elevated levels of plasma homocysteine. Folic acid supplementation (0.4 to 0.8 mg/d) with or without vitamins B6 (25 to 50 mg/d) and B12 (0.5 mg/d) lowers homocysteine levels by nearly 25% in 2 to 6 weeks, even in persons who are not deficient in these vitamins. The higher the pretreatment homocysteine level and the lower the folate stores, the greater is the reduction in homocysteine.
Impact on Cardiovascular Outcomes.
Despite the enthusiasm that accompanied the discovery of an association between homocysteine levels and cardiovascular risk and the availability of practical, effective means of measuring and lowering homocysteine, proof of benefit remains elusive, and some concern has emerged about possible harm from the use of folate and B vitamin supplements. In some small-scale, randomized, placebo-controlled trials of homocysteine-lowering therapy in high-risk patients, such as those requiring angioplasty, rates of restenosis actually increased. Large-scale prospective studies involving persons with diabetes, known vascular disease, or previous MI revealed no significant reduction in CHD event risk with homocysteine-lowering therapy. The reasons for the unexpected failure of folate/B vitamin therapy remain the subject of ongoing debate and study. Pending evidence of safety and efficacy, it is best to advise CHD patients to refrain from taking high-dose folate/B vitamin (“healthy heart”) supplements.
C-Reactive Protein
C-Reactive protein (CRP) is an acute-phase reactant that increases in the setting of inflammation. It activates both complement and endothelial cells. Recent interest in atherosclerosis as an inflammatory process has drawn attention to CRP as a possible marker/risk factor for CHD events. Initial observations suggested that CRP was a powerful independent predictor of CHD events, with an association similar to that for LDL cholesterol; subsequent studies found the association to be more moderate. Nonetheless, the relationship between CRP elevations and cardiovascular events in persons with CHD has led some to speculate that lowering CRP might improve outcomes. There are no randomized, prospective studies examining the effect of lowering CRP on CHD risk. In fact, the best means of lowering CRP levels is unclear. Of interest are the findings from retrospective analyses that statin drugs appear to lower CHD risk in persons with elevations in CRP and that the effect can be independent of the effect on lipids. Similar findings have been found with aspirin and beta-blockers. The literature should be watched closely for developments in this potentially promising area.
Environmental Factors and Polypharmacy
Air Pollution.
Evidence linking air pollution with CHD risk continues to accumulate. Both short-term exposure to diesel exhaust and long-term exposure to air pollution have demonstrated independent associations with CHD morbidity and mortality. In men with coronary disease, brief exposure to diesel exhaust promoted myocardial ischemia and inhibited fibrinolytic activity. In postmenopausal women, chronic air pollution was associated with increased rates of cardiovascular disease and death.
NSAID Use.
The nonsteroidal antiinflammatory drugs (NSAIDs) may have short-term antithrombotic actions related to their cyclooxygenase-1 (COX-1) inhibition in platelets, but this action may interfere with the more durable protective effect of lowdose aspirin by blocking aspirin’s access to the acetylation site on platelet COX-1. Moreover, these drugs also have potential prothrombotic actions, related to the degree to which they inhibit cyclooxygenase-2 (COX-2), which is necessary for the synthesis of vasodilatory prostaglandins. Evidence of increased cardiovascular morbidity and mortality has emerged with NSAID intake, particularly with extended use of the most potent of the selective COX-2 NSAIDs, leading to removal of some from the market and making others poor choices for use in persons with CHD (see Chapter 157). Systematic review confirms the finding of a markedly increased cardiovascular risk with rofecoxib (now removed from the market) and less with celecoxib and refutes the purported protective effects of naproxen and diclofenac.
Avoidance of Unnecessary Treatment for Secondary Prevention: Disproven or Unproven Risk Factors
Hormone Deficiency
Because menopause is a risk factor for CHD, hormone replacement therapy (HRT) has been examined as a possible means of achieving primary and secondary prevention of CHD events in menopausal women. Although observational epidemiologic data suggested a strong association between HRT use in postmenopausal women having CHD and reduced cardiovascular risk, a prospective, randomized study of the question (the Heart and Estrogen/Progestin Replacement Study [HERS]) found worse rather than improved cardiovascular outcomes (see Chapter 118). Secondary analysis of the data found that HRTassociated CHD risk was greatest among women more distant from menopause and was minimal when used for short-term periods closer to menopause.
Bacterial Infection/Periodontal Disease
Bacterial antigens have been proposed as potential stimulants of the inflammatory process associated with atherosclerosis. Chlamydia pneumoniae is a leading candidate, being an intracellular pathogen found with increased frequency in persons with MI. Cytokines from infection have also been proposed as triggers of plaque rupture. In the largest randomized study of the question (the Weekly Intervention with Zithromax for Atherosclerosis and Its Related Disorders trial), a 3-month course of azithromycin (Zithromax) in patients with prior MI did not reduce the rate of adverse cardiac events after 14 months. A weekly azithromycin dose for 1 year produced no improvement in CHD outcomes compared to placebo after nearly 4 years of follow-up.
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