This chapter will deal with the detection and treatment of stable coronary disease. It does not address in-hospital coronary syndromes such as unstable angina or acute myocardial infarction.

Knowing that coronary artery disease is the leading cause of death in the United States, that about one and one-half million people will have myocardial infarctions this year, and that about one third of those people will not survive, shouldn’t we be screening our patients for coronary disease? Indeed, it would seem so given (a) the substantial morbidity from coronary disease, (b) the presence of a "latent" or asymptomatic period and (c) effective treatment - all attributes of so-called "screenable diseases." However, an additional attribute - that early treatment is better than later treatment - is absent. At the present time, convincing evidence that treatment of asymptomatic persons offers better outcomes than later treatment (e.g. when people become symptomatic), is lacking.

As noted in Chapter 1, the characteristics of a good screening test are accuracy (sensitivity and specificity), acceptability and low cost. The resting EKG is relatively cheap and easy, but has unacceptably low sensitivity and specificity. The exercise EKG is considerably more accurate, though considerably more expensive (particularly with the addition of thallium). Despite the relatively high sensitivity and specificity of radioisotope imaging, the low prevalence of disease in an asymptomatic population will nevertheless result in a high number of false positive results.

While it is certainly true that many people have asymptomatic coronary disease, and that the presentation for many - approximately one quarter - is sudden death, there is currently no evidence that screening for coronary disease results in better outcomes. It is worth noting that the majority of people with silent ischemia have one or two vessel disease, rather than three vessel or left main disease,^, and that intervention even if coronary artery disease were detected in these patients would be controversial.

Therefore, at the present time, screening for coronary disease in asymptomatic patients with either resting or exercise EKG is not recommended. Exceptions are often made for people who, because of their occupations, might pose a substantial risk to others - airline pilots, for example. It is often recommended that older individuals with cardiac risk factors undergo stress testing prior to starting an exercise program, although there is no evidence that this is an effective intervention.

We might, however, distinguish the screening EKG from the "baseline" EKG. The purpose of screening is to detect asymptomatic disease. This is not the objective of the "baseline" EKG. The rationale for the "baseline" EKG is that this EKG might help us to interpret a patient’s EKG at a later date - when they come to the emergency department complaining of chest pain, for example. Knowing that the patient’s flipped T-waves, bundle branch block and perhaps even Q-waves on the electrocardiogram are "old" might prevent an unnecessary admission to the hospital for a "ROMI." While this is a tempting hypothesis, there have been no randomized trials assessing it, and our experience might suggest that patients get admitted for "ROMI" with or without baseline EKGs. Lee et al. studied 5,673 patients presenting to the ER complaining of chest pain, 14 percent of whom ruled in for acute MI - 55 percent had a prior EKG available in the ER. After adjusting for potential confounders, patients with a prior EKG and no MI were twice as likely to be discharged home from the ER as patients without prior EKGs. Nonetheless, the USPS Task Force, in its 1996 Guide, concluded "there is insufficient evidence to recommend for or against screening middle aged and older men and women for asymptomatic coronary artery disease."

The initial approach to the evaluation and treatment of the patient complaining of chest pain is a topic of considerable debate. This debate usually centers on the question of initial non-invasive evaluation vs. initial invasive evaluation (i.e. cardiac catheterization) vs. empiric anti-anginal therapy.

It is important, first of all, to be clear exactly what question is being asked. In a 60 year old man complaining of substernal chest pain brought on by exertion and relieved by rest, the question is not whether the patient has coronary disease (he almost certainly does), but what is his prognosis? In therapeutic terms, this can be rephrased as "Will he benefit from surgical treatment, i.e. revascularization?" It is primarily this question we want answered when we order a stress test in a patient whose pre-test probability is very high. The answer to this question depends on coronary anatomy, left ventricular function, and exercise tolerance. Therefore, in this instance, the stress test is used primarily to make a prognosis rather than a diagnosis.

An abundant literature exists on the estimation of the pre-test likelihood of coronary disease based on clinical variables. This estimate is of obvious importance, as it not only helps us decide whether to pursue further testing, but also which test to perform, as well as how to interpret the results of the chosen test. The history (e.g. typical vs. atypical chest pain) is by far the most useful piece of information, with additional clinical variables such as age, gender and cardiac risk factors providing additional information. Diamond’s table (Table 1) enables us to estimate the likelihood of disease based on history, age and gender. Additionally, Prior et al., have developed a nomogram taking additional risk factors such as smoking and diabetes into account. Though these estimates are derived from large databases, it should nevertheless be kept in mind that these were patients who underwent angiography, and therefore that there is likely to be some "work up bias." At least one study found historical variables to be less predictive in an unselected population with chest pain.

TABLE 1: Pretest likelihood of coronary disease according to age, gender and symptoms

The initial strategy depends on the likelihood of coronary disease, i.e. whether high, intermediate or low. For our purposes, we will designate high as greater than 85 percent, low as less than 15 percent and intermediate as everything in between. These designations are, of course, arbitrary.

High probability:

As mentioned above, in patients with a high clinical suspicion of coronary disease, the question is one of prognosis rather than diagnosis. Possible options include empiric medical therapy, non-invasive testing (i.e. exercise stress testing with or without radionuclide scanning), or invasive evaluation (i.e. cardiac catheterization). Advocates of empiric therapy point out that if patients have good exercise tolerance, no evidence of heart failure and symptoms easily controlled by medical therapy, it is very unlikely that revascularization would be of any benefit to them. Proponents of further testing maintain that it is nevertheless important to document the extent of disease, and that there will be some in this group who would benefit from revascularization. They argue that a stress test would identify this "high risk group" - those unable to achieve 85 percent predicted maximum heart rate, those with abnormal blood pressure response or those with markedly positive electrocardiographic or scan response. This group would then proceed to cardiac catheterization. Those who advocate initial invasive testing maintain that some patients with "low risk" scans will have "surgical" disease and, therefore, that angiography should be the initial test. Furthermore, it is only for angiographically defined coronary disease that we have evidence from randomized trials of surgical treatment.

What then should the initial strategy be in this group of patients? While there is no definitive answer to this question, we believe that it is reasonable to empirically treat patients who have mild symptoms and good exercise tolerance. If response to medical therapy is suboptimal, one would then proceed with further testing. This should certainly be the strategy in patients who would not be willing to have surgery or are otherwise not surgical candidates. An alternative strategy would be to evaluate ejection fraction (EF) by echocardiography or MUGA, and to proceed with further testing only if the EF is below normal. It is not unreasonable, however, to proceed initially with non-invasive testing, particularly in patients with poor exercise tolerance and/or depressed EF. For most patients, initial invasive testing is not recommended.

Intermediate probability:

For patients with an "intermediate" probability, initial non-invasive testing is recommended, with the goal of establishing a diagnosis.

Low probability:

For patients whose likelihood of coronary disease is very low based on clinical evaluation (for example, a 35 year-old woman with episodes of pinching left-sided chest pain lasting for a few seconds), no further evaluation is indicated.

The clearest indication for radionuclide scanning is in patients with baseline EKG abnormalities (such as bundle branch block, LVH or baseline ST segment abnormalities that confound interpretation of ST segment changes) and patients who are unable to exercise. It is unresolved which other patients should have radioisotope scanning.

The sensitivity and specificity of EKG stress testing are approximately 70 percent and 80 percent respectively, with sensitivity improving with increasing numbers of vessels involved. The sensitivity and specificity of planar thallium are about 85 percent (ranging from 68 to 96 percent), with quantitative analysis improving both specificity and sensitivity. SPECT scanning is even more sensitive than planar scanning but may be considerably less specific. Thallium scanning is much more expensive than electrocardiographic stress testing, requires technical expertise, and offers about 40 chest x-rays worth of radiation. Proponents of radioisotope scanning point to its improved sensitivity, as well as its ability (particularly SPECT scanning) to identify specific coronary territories. However, at least one careful study suggests that radioisotope scanning adds little incremental information to that obtained by electrocardiographic testing and clinical variables. Therefore, for patients without baseline EKG abnormalities, electro- cardiographic stress testing is the recommended initial test. This is certainly the case in patients with low pretest probabilities. As the pretest probability increases, the argument for thallium becomes stronger, as the likelihood of a false negative test increases with increasing pretest probability, and a test with greater sensitivity would be theoretically preferable in these patients.

Stress echocardiography is becoming increasingly popular, and offers the advantage of being "radiation-free." In a recent meta-analysis of 44 studies evaluating exercise echocardiography and SPECT imaging, echocardiography was found to be as sensitive as SPECT (sensitivity of echo 85%, 95%CI, 83-87%; SPECT 87%, 95%CI, 86-88%) and was more specific (specificity of echo 77%, 95%CI, 74-80%; SPECT 64%, (95%CI, 60-68%). In only six of these studies, however, were echo and SPECT evaluated head to head, though results were similar in these studies. Also "verification bias" (resulting from the fact that patients with more severe disease are referred for the gold standard test) likely operated in many of these studies.

A possible explanation for the improved specificity of echocardiography is its shorter time in use compared to thallium imaging, as studies have shown that diagnostic tests lose specificity with time, as they are applied to more diverse patient populations. In fact, publication date was a predictor of test performance in the above mentioned meta-analysis.¹²

While both radionuclide and echocardiography appear to be more accurate than electrocardiography, and are the preferred tests for patients with resting EKG abnormalities, for the majority of patients--in particular patients with low pre-test probability of coronary disease based on clinical variables--an EKG stress test will suffice to rule out significant coronary disease. Additional modalities, such as MRI and electron beam CT ("fast CT") are promising noninvasive means of detecting the presence or severity of coronary disease. Their clinical role, however, is undefined at present.

It seems to be common knowledge that stress testing is less accurate in women. However, it is far from clear that this is the case. Though specificity is often impugned, the lower predictive value of stress testing in women may be a reflection not of the decreased specificity but of the lower pre-test probability, i.e., prevalence, in this population.

Some studies have suggested, however, that the specificity of EKG stress testing is lower in women, while others have found the sensitivity to be lower.⁷ Similarly, studies have suggested that the sensitivity of exercise thallium may be lower in women.⁸ When selection bias is taken into account, however, accuracy of SPECT may not vary between sexes. In a study using the Duke database, the Duke Treadmill Score stratified women equally well as men into diagnostic and prognostic categories. It is difficult to recommend "gender-based" testing strategies. Decisions should be based on pre-test probability, as above.

Assuming we have decided upon medical therapy, what should our initial therapy be? Perhaps surprisingly, it doesn’t much matter: all anti-anginals are equivalent in regard to anti-anginal efficacy, and none has been shown to provide any benefit in terms of preventing MI or death in patients with angina. Choice of initial therapy, therefore, is guided by individual patient response, preference and comorbid illness. For example, while there is to date no evidence that beta blockers improve survival "pre-MI" (despite proven benefit post-MI), they have clearly been shown to prolong life in patients with hypertension, and we would recommend using a beta blocker as initial therapy in patients with coronary disease and hypertension. In non-hypertensive patients, sublingual nitroglycerin may be sufficient for those with mild and infrequent symptoms. If long-acting nitrates are used they should be dosed so as to provide a "nitrate free" period to avoid the development of tolerance. For this reason, long-acting nitrates are not appropriate as anti-hypertensive agents as 24-hour blood pressure control will not be achieved. Because of concern regarding increased mortality in patients taking short-acting calcium channel blockers^, (discussed at greater length in Chapter 7), these agents should probably be drugs of last choice for patients with angina, to be used if there is an inadequate response, contraindication or intolerance to beta blockers or nitrates.

While PTCA may be more effective than medical therapy in regard to symptom relief and exercise tolerance, there is no evidence that it provides a survival advantage or reduces the incidence of myocardial infarction. Therefore, PTCA is not indicated in patients responsive to medical therapy and, given the cost and potential complications, we believe that it should not be the initial management strategy in patients with stable angina. It may be an appropriate alternative to CABG in selected patients with multivessel disease and persistent symptoms despite maximal medical therapy. Current clinical investigation focusing on the addition of stents and new drugs to inhibit restenosis may provide evidence of benefits of an invasive strategy in selected patients with stable angina.

There is good evidence that aspirin is effective in preventing MI in patients with chronic stable angina. For instance, subgroup analysis of the Physicians’ Health Study of 333 men with chronic stable angina demonstrated an adjusted 87 percent relative risk reduction and 13 percent absolute risk reduction (from 20 to 7 percent) in the men assigned to alternate day 325 mg ASA. There was, however, a statistically significant increased risk of stroke in the ASA group (11 strokes vs. 2 in the placebo group, P = 0.02, CI 1.3 to 22.1). There were 11 deaths in the placebo group vs. 7 deaths in the treatment group, a difference that was not statistically significant (p = 0.51). In the Swedish Angina Pectoris Aspirin Trial, 2,035 patients with stable angina were treated with 75 mg of aspirin daily or placebo. The incidence of MI or sudden death was reduced by 34 percent (95% CI 24 to 49 percent). Patients at "high risk for vascular events" (chronic stable angina, peripheral vascular disease, atrial fibrillation) were examined as part of the Antiplatelet Trialists’ Collaboration, an overview of 133 trials of antiplatelet therapy in patients with cardiovascular disease. When these groups were combined, aspirin therapy was associated with a 32 percent decrease in vascular events. These results were similar in men and women and there was no evidence that higher doses of aspirin were superior to lower doses. It is recommended that all patients with stable angina receive aspirin. ASA taken for two years by 1,000 subjects would prevent 10 deaths and 20 non-fatal events. This is a benefit substantially greater than that achieved in the treatment of mild hypertension.

Silent ischemia is common in subjects with coronary disease, and its presence is a predictor of morbidity and mortality. Whether or not morbidity and mortality are reduced by its treatment, however, is presently uncertain--and there is at least some theoretical concern that such treatment might be harmful. Studies of the treatment of silent ischemia to date have included patients with symptomatic CAD (stable angina, previous MI, CABG), who demonstrate evidence of asymptomatic ischemia. No study has examined the "entirely asymptomatic" population (i.e., the population that might be "screened" for silent ischemia), and results of these studies should not be generalized to these populations.

The Atenolol Silent Ischemia Study, involving 306 subjects previously presenting with coronary disease, showed a statistically significant reduction in anginal symptoms in those treated with atenolol; however the reduction in the combined endpoints of death, VT/VF, MI, or hospitalization (13 in the atenolol group and 7 in the placebo group) was not statistically significant (RR = 0.55, p = 0.175, 95% CI 0.22- 1.33).

In the Asymptomatic Cardiac Ischemia Pilot Study, 614 subjects with angiographically demonstrated coronary disease amenable to revascularization were randomized to angina-guided therapy, ischemia-guided therapy, or revascularization. At two years, the rate of death or MI was 12.1 percent in the angina-guided group, 8.8% in the ischemia guided group, and 4.7 percent in the revascularization group. The difference between the angina-guided and revascularization groups was statistically significant. The full study, now called the Study of Coronary Revascularization and Therapeutic Evaluation (SOCRATES), began in 1999.