Annals of Internal Medicine. 1991;114:

Transcription

1 Bypass Surgery for Chronic Stable Angina: Predictors of Survival Benefit and Strategy for Patient Selection Obi N. Nwasokwa, MD, PhD; Jerome H. Koss, MD; Gary H. Friedman, MD; Andrew M. Grunwald, MD; and Monty M. Bodenheimer, MD The variable mortality risk associated with chronic stable angina calls for careful selection of patients for coronary artery bypass grafting (CABG) if the aim of management is to prolong life. The randomized and observational studies done in the last 20 years have identified the variables relevant to patient selection and thus have provided a rational basis for such clinical decisions. These studies showed that the sicker the patient, as gauged by relevant measures of coronary disease and cardiovascular morbidity, the more likely it is that CABG will prolong life. A CABG-related improvement in survival is therefore more likely to occur the worse the left ventricular function; the greater the number of diseased vessels; the more proximal the location of coronary lesions (more muscle is threatened by such lesions); the greater the severity of the lesions as determined by angiography; the more severe the angina; the more easily provocable the ischemia or the more extreme the measures of ischemia; and, within limits, the older the patient. Greater survival gain after CABG also occurs in patients with peripheral vascular disease, in patients with baseline electrocardiographic ST-segment and T-wave changes, and probably in women. Thus, patients are likely to live longer after CABG if they have left main disease; three-vessel disease with left ventricular dysfunction (ejection fraction less than 50%), class III or IV angina, provocable ischemia, or disease in the proximal left anterior descending coronary artery; two-vessel disease with proximal left anterior descending artery involvement; and two-vessel disease with class III or IV angina as well as either severe left ventricular dysfunction alone or moderate left ventricular dysfunction together with at least one proximal lesion. When the decision of whether to do CABG is less clear-cut, the presence of peripheral vascular disease, female sex, baseline electrocardiographic ST-segment and T-wave changes, or older age (over 60 but under 80 years) should weigh in favor of doing CABG. In general, patients with single-vessel disease do not seem to derive survival benefit from CABG. Annals of Internal Medicine. 1991;114: From Long Island Jewish Medical Center, New Hyde Park, New York; and Albert Einstein College of Medicine, Bronx, New York. For current author addresses, see end of text. Not every patient with chronic stable angina benefits from bypass surgery. For some patients, however, bypass surgery may mean the difference between life and death. How then does the clinician decide who is likely to benefit? The key is careful attention to patient characteristics. For instance, when treated medically, patients with single-vessel disease and a left ventricular ejection fraction of at least 50% have a 4-year mortality of 5% (1). In contrast, without coronary artery bypass grafting (CABG), patients with three-vessel disease and an ejection fraction of less than 35% have a 4-year mortality of 50% (1). In the latter case, CABG reduces the mortality considerably but, in patients with singlevessel disease, such surgery may actually result in higher mortality than does medical therapy. Because the operation is expensive and, although continually improving, is associated with some mortality and morbidity (2, 3), patients should undergo CABG only if the desired goal is compelling. Prolongation of life is the most cogent and clear-cut reason to do the operation (4), although improvement in quality of life is also important. Therefore, an effective clinical strategy in managing patients with chronic stable angina should seek to identify patients whose lives would likely be prolonged by CABG. Such patients should undergo cardiac catheterization with a view to possibly undergoing CABG. In this review, we summarize the findings of recent studies and outline principles that should help physicians decide which patients are likely to live longer because of CABG. Information Sources and Their Limitations Our principal sources of information were three randomized trials and two major nonrandomized studies: The former included the Veterans Administration (VA) Cooperative Study (4, 5) of coronary artery surgery, the European Coronary Surgery Study (6, 7), and the Coronary Artery Surgery Study (CASS) (8, 9), and the latter included the CASS registry and the Duke University computerized clinical databank. These studies complement one another because each has different limitations. None of the randomized studies represented a crosssection of the coronary artery disease population. Because of the inclusion and exclusion criteria, the resulting patient samples (4-11; Tables 1 and 2) underrepresented or totally excluded certain important categories of patients with coronary artery disease, including female patients, patients over 65 years of age, patients with moderate and severe angina, patients with new-onset angina or recent myocardial infarction, and patients with severely impaired left ventricular function American College of Physicians 1035

2 Table 1. Baseline Characteristics of Patients in the Randomized Studies of Coronary Artery Bypass Grafting* Characteristic VA Study European Study CASS Trial Recruitment period 1/72 to 12/74 9/73 to 3/76 8/75 to 5/79 Age, y < 67 < 65 ^65 Male, % Angina duration, mo > 6 > 3 ^2 Time since infarction >6mo Not addressed > 3 wk Angina class No angina, 0%; NYHA I, 2.9%; No angina, 0%; CCS I and II, 57%; No angina, 21.8%; CCS I, NYHA II, 39.3%; NYHA III, CCS III, 42%; not classified, 1% 14.5%; CCS II, 59.0%; CCS 54.8%; NYHA IV, 2.8% III and IV, 0%; nonexertional, 4.7% Disease thresholdt ^ 50% > 50% ^ 70%; Left main > 50% but <70% Left ventricular Function impaired in 55% (EF EF > 50%, 100% EF > 50%, 73.7%; EF 35% to function < 50% or contraction grade 49%, 20.5%; EF < 35%, > 2) 0%; not measured, 5.8% Operative mortality, % Crossover rate 5 year, 17.4%; 11.2 year, 38% 5 year, 24%; 12 year, 36% 5 year, 23.5%; 10 year, 40% (medicine to surgery) Graft patency rate 69% at 1 year 75% at 1 to 1.5 years; 69% at 5 years 90% at 2 months; 82% at 1.5 years; 82% at 5 years * VA = Veterans Affairs; CASS = Coronary Artery Surgery Study; NYHA = New York Heart Association; CCS = Canadian Cardiovascular Society; EF = ejection fraction. Data in this table were obtained from references t Percent stenosis. For example (Tables 1 and 2), the VA study (4) and the European study (6) recruited only men; the European study excluded patients with single-vessel disease and patients with a left ventricular ejection fraction of less than 50%; the randomized CASS trial included only patients with angina no worse than class II who also had a left ventricular ejection fraction of at least 35% (8) and excluded patients with left main disease of 70% or greater severity; and the VA study excluded patients who had had myocardial infarction within the previous 6 months and those with angina of less than 6 months duration. It has been estimated that no more than 4% to 13% of patients referred to one university medical center for catheterization would have been eligible for enrollment in the various randomized trials (12). The studies also had other limitations. The relatively modest numbers of patients included in the randomized trials 686 in the VA study, 768 in the European study, and 780 in CASS limited the number of subgroups that could be analyzed with sufficient statistical power. Crossovers also presented a major problem (4-9, 13-17). By 10 to 12 years, 36% to 40% of patients randomly assigned to medical therapy in the trials had had CABG (Table 1). In addition, about 6% of patients randomly assigned to CABG did not have the operation (9). Indeed, in the European study (6), six of the deaths in patients assigned to surgery occurred before CABG could be done. The "intention-to-treat" principle is usually adopted in analyzing data confounded by crossovers. Although ' 'unbiased and... scientifically the most valid method" (9), this principle has limitations (14-16). It not only reduces statistical power (15) but also makes these studies a comparison not of treatment actually received but rather of "treatment policy'' or "assigned treatment" (13, 14-17). To that extent, the randomized studies have been less than conclusive in measuring the differential effects of medical and surgical therapy on the survival of the various patient subgroups. Indeed, some critics (14, 15) have objected strongly to the high crossover rate, hinting that these studies should lose much of their authority and even validity on that account. However, the issue can be overplayed because the treatment policy used in the randomized trials is not much different in principle from the strategy adopted by clinicians in managing their patients (17). That treatment policy may therefore be more relevant to medical practice than one that denied surgery to a group of patients simply to determine absolutely, perhaps unethically, the biologic effect of denial of such therapy (17). A major strength of the observational or nonrandomized studies was their inclusion of large numbers of patients who were more representative of the general coronary artery disease population. The CASS registry in particular included patients (1). Because of this large size, the registry was perhaps the most important source of information because subsets of patients could be studied meaningfully. The nonrandomized studies, however, had one major flaw: Relevant characteristics were not uniformly distributed between medically and surgically treated patients, which raises a question about the extent to which bias contributed to differences in outcome (12). For instance, virtually all observational studies showed that medically treated patients had worse left ventricular dysfunction than surgically treated patients, who, on the other hand, had more severe coronary lesions and more severe angina (18-20). To correct for such differences, investigators use a statistical adjustment technique, the Cox proportional hazards model (20-22). Although it is not altogether certain that such measures eliminate bias (1, 18), the current evidence suggests that the conclusions drawn from the observational studies are similar to those of randomized studies (22). The VA study deserves special mention because it reported an operative mortality that was substantially higher than that observed in the other randomized trials (23, 24). Because the VA study was the first random June 1991 Annals of Internal Medicine Volume 114 Number 12

3 ized trial of CABG (Table 1), this higher mortality may reflect early experience with a new surgical procedure (24). Nonetheless, the relatively high overall operative mortality of 5.8%, as well as the rates of up to 23% in 3 of the 13 hospitals, undercut the authority of this study somewhat, for critics readily cite the higher operative mortality as a possible explanation for any discrepancies among the results of the VA study and those of other studies (24). Despite this drawback, the importance of the VA study is undisputed. It pioneered the systematic investigation of CABG as a therapeutic option for coronary artery disease and was unique not only because it was the first study to show convincingly that CABG prolongs life in patients with left main disease but also because it provided data on a large number of randomized patients with left main coronary disease (25). Moreover, the higher operative mortality notwithstanding, most of its conclusions, such as with respect to patients at "high angiographic risk," were confirmed by later studies (Table 3). In view of their various limitations and flaws, one must exercise caution in extrapolating results of the individual randomized and nonrandomized studies to other populations of apparently similar patients (12). Taken together, however, the various studies provide a useful perspective on the conditions under which physicians may expect CABG to prolong the lives of patients with chronic stable angina. Factors Relevant to Choice of Therapy Left Ventricular Function The status of left ventricular function greatly affects the prognosis of patients with coronary artery disease (1, 19, 26, 27) and is perhaps the most important independent predictor of mortality in medically managed patients with coronary artery disease (1, 26). When left ventricular ejection fraction falls below 40%, the 1-year mortality of coronary artery disease rises sharply, from less than 5% for an ejection fraction of at least 40% to over 45% for an ejection fraction of less than 20% (27). Survival decreases progressively with severity of left ventricular dysfunction, measured by either the ejection fraction or the left ventricular score, and this trend was noted regardless of the number of diseased vessels (1). In patients with at least one diseased vessel who did not have important left main disease, a left ventricular ejection fraction of 50% to 100%, of 35% to 49%, and of less than 35% was associated with a 4-year mortality of 8%, 17%, and 42%, respectively (P < ) (1). The effect of the number of diseased vessels on mortality appeared to interact with that of left ventricular function so that 4-year survival dropped from 95% in patients with single-vessel disease and an ejection fraction of 50% to 100%, to 50% in patients with three-vessel disease and an ejection fraction of 0% to 30% (1). The strong adverse effect of left ventricular dysfunction on survival in medically managed patients with coronary artery disease is matched by the strong favorable influence of CABG on relative survival benefit in patients with impaired left ventricular function (Table 3). In the randomized CASS trial, among the 160 patients with left ventricular dysfunction (left ventricular ejection fraction of less than 50%), the 10-year survival was 79% in patients assigned to CABG and 61% in patients assigned to medical therapy (P < 0.01) (9). In contrast, among the 575 patients with a left ventricular ejection fraction of at least 50%, the corresponding 10- year survival rates were 83% and 84% (P > 0.20) (9). Nonrandomized studies in which left ventricular ejection fraction ranged widely (19, 26) showed that when the ejection fraction ranged below 40%, the survival benefit paralleled the severity of left ventricular dysfunction: the lower the left ventricular ejection fraction, the greater the differential survival benefit with CABG (19, 26). In one CASS registry study (19), for an ejection fraction of 26% to 30%, the 6-year survival was 66% with surgery and 49% with medical treatment (P = ), whereas for an ejection fraction of 3% to 25%, the 6-year survival was 62% with surgery and 38% with medical therapy (P = ) (19). These findings represent a CABG-related improvement in survival of 34% and 63% in patients with an ejection fraction of 26% to 30% and of 3% to 25%, respectively. Indeed, there appears to be no lower limit of left ventricular dysfunction at which the increased operative mortality risk in patients with severe left ventricular dysfunction overrode the long-term survival benefit (19, 28). In general, the coexistence of left ventricular dysfunction with any factor that increased the mortality risk associated with medical therapy escalated the magnitude of this risk so much that when CABG reduced the risk for further deterioration of left ventricular function, the differential survival benefit conferred by surgery also increased commensurately. For example, CABG greatly decreases mortality in patients with both Table 2. Prevalence of Coronary Disease Types among Patients in the Randomized Trials of Coronary Artery Bypass Grafting* Disease Type VA Study European Study CASS Trial >50% Cut-oflft >50% Cut-oflf >75% Cut-oflf 50% Cut-oflf 70% Cut-oflf < % > One vessel Two vessel Three vessel Left main * VA = Veterans Affairs; CASS = Coronary Artery Surgery Study. Data were obtained from references 10 and 11. t Cut-off refers to the threshold or minimum angiographic severity (percent stenosis at which coronary disease was considered important). 15 June 1991 Annals of Internal Medicine Volume 114 Number

4 Table 3. Survival Rates for Different Patient Subsets in the Major Randomized Trials of Stable Ischemic Coronary Disease* Variable VA Study European Study CASS Trial 5 Year 7 Year 11 Year 5 Year 8 Year 12 Year 5 Year 7 Year 10 Year < % > Two-vessel disease Medicine Surgery Difference Three-vessel disease Medicine Surgery Difference LV dysfunction (EF < 50%) Medicine NA NA NA Surgery NA NA NA Difference NA NA NA LV dysfunction (EF < 50%) and three-vessel diseaset Medicine NA NA NA Surgery NA NA NA Difference NA NA NA Normal LV function (EF > 50%)t Medicine Surgery Difference * All analyses, including the Coronary Artery Surgery Study (CASS), are based on a lesion threshold of 50%. (The data may therefore seem to differ from those cited in the text.) Patients with single-vessel disease were included in the CASS trial and in the VA study but were not recruited into the European study. VA = Veterans Affairs; LV = left ventricular; EF = ejection fraction; NA = not applicable. Adapted from Alderman and colleagues (9), with permission from the American Heart Association. t In the VA study, this was the high-risk subset, as determined by angiography. Patients with left main disease were excluded. $ In the European study, patients with left main lesions of 50% or more were not included. three-vessel disease and deficient left ventricular performance (Table 3). Thus, in the CASS trial, in which only patients with no angina or mild angina (Table 1) were randomized, the patients who first showed survival benefit with CABG were those with three-vessel disease and left ventricular dysfunction: The 7-year survival was 88% with CABG and 65% with medical treatment (P = 0.01) (29). At 10 years, this difference in survival was still maintained: 75% and 58% (P = 0.08) of patients in the surgery and medical treatment groups, respectively, were still alive (9). Similarly, the VA study showed a survival advantage for patients with angiographic findings associated with high risk, that is, threevessel disease and left ventricular dysfunction (23); survival at 11 years was 50% with CABG and 38% with medical treatment (P = 0.026). Left ventricular dysfunction also increases relative survival gain after CABG when it is associated with other factors such as left main disease (25), either three-vessel disease alone or two-vessel disease associated with class III or IV angina (30, 31), or provocable ischemia (32). Number of Diseased Vessels The greater the number of diseased vessels, the greater is the amount of myocardium in jeopardy from coronary artery disease and the higher is the mortality independent of left ventricular function. In the CASS registry study done by Mock and colleagues (1), the 4-year mortality was 8%, 16%, and 32% with one-, two-, and three-vessel disease, respectively. Thus, the 4-year mortality doubled with each step increase in the number of diseased vessels. In their observational study, Proudfit and colleagues (33) found 15-year survival rates of 58%, 35%, and 26% for single-vessel disease, two-vessel disease, and three-vessel disease, respectively. These studies also showed that the effects of left ventricular dysfunction and number of diseased vessels interacted so that when both factors coexisted, prognosis was worse than for either factor alone (1, 33). Thus, in patients with one-vessel disease, the 4-year survival was 74% for an ejection fraction of less than 35%, and 95% for an ejection fraction of more than 49% (1); for three-vessel disease, the 4-year survival was 50% for an ejection fraction of less than 35%, and 82% for an ejection fraction of more than 49% (1). In keeping with its effect on mortality risk in patients receiving medical therapy, the number of diseased vessels predicts whether surgical therapy will confer a survival advantage. The European study (6, 10) showed that the patients who had three-vessel disease benefited from CABG; the 8-year survival was 91.8% with CABG and 76.7% with medical treatment (P = ). Patients with two-vessel disease had an 8-year survival of 85% with CABG, which was lower than that seen in the medically treated group (87.4%) (6, 10). Other studies highlighted the importance of the interplay of two or more factors (Table 3). In the VA study, the high-risk angiographic group with three-vessel disease and poor left ventricular function had an 11-year survival of 54% with CABG and of 24% with medical treatment (P = 0.005) if they were also at high clinical risk (23). At the other end of the spectrum were the low-risk angio June 1991 Annals of Internal Medicine Volume 114 Number 12

5 graphic patients who were also at low clinical risk. Medical therapy seemed to be more beneficial in this group (11-year survival, 76% compared with 66% in patients with CABG [P = 0.092]) (23). In the CASS randomized trial, the survival curve at 7 years was better for the patients who had CABG than for patients on medical therapy only in the subset of patients with three-vessel disease and a left ventricular ejection fraction of less than 50% (8). The apparent discrepancy between the results of the European study, which showed a survival benefit in patients with three-vessel disease and an ejection fraction of more than 50% (6, 10), and the other two randomized studies (8, 23), which showed no benefit in such patients, may be explained by certain differences between the patient samples. Patients in the CASS trial, for instance, either did not have angina or had class I or II angina (8), whereas in the European study, 57% of the patients had class I or II angina and 42% had class III angina for at least 3 months (Table 1) (6, 10). The relatively high surgical mortality has been cited as a relevant consideration in the VA study (24). At least two definitive studies have been done on the effect of CABG on patients with two-vessel disease (7, 31). In the European study (7), patients with two-vessel disease did not have improved survival after CABG, despite the fact that 61% of them had disease in the proximal left anterior descending artery. However, all patients in the European study had a left ventricular ejection fraction of at least 50%. A CASS registry study, on the other hand, showed that other variables associated with an increased mortality risk had to be present if CABG was to confer survival benefit in patients with two-vessel disease. Thus, the patients must have class III or IV angina and left ventricular dysfunction to derive the CABG-related survival benefit (31). For patients with severe left ventricular dysfunction (left ventricular score, 16 to 30), survival at 6 years was 49% with medical therapy and 78% with CABG (P = ) (31). For patients with moderate left ventricular dysfunction (left ventricular score, 6 to 15), an additional factor was necessary for survival benefit: At least one of the lesions had to be a proximal lesion (31). The 6-year survival rates with medical and surgical therapy were 76% and 87%, respectively, in patients with no proximal lesions (P = ); 74% and 89% in patients with one proximal lesion (P = ); and 71% and 85% in patients with two proximal lesions (P = ) (31). Thus far, no study has shown that CABG prolongs life in patients with single-vessel disease. Location of Coronary Disease The location of coronary disease is important to outcome because it determines how much myocardium is threatened by a given lesion; the more proximal the lesion, the more extensive is the jeopardized myocardium. Three locations or configurations are therefore particularly important: left main, left main equivalent, and proximal left anterior descending. Left Main Disease A lesion of the left main coronary artery is the single most important lesion because it threatens the blood supply to the entire territory of the left anterior descending and the left circumflex coronary arteries all at once from a single occlusive event (34). Several studies have documented the poor prognosis of patients with left main disease who are treated medically. In the study by Conley and colleagues (35), which was based on the Duke databank, only 41% of patients with left main disease of at least 70% severity were alive after 3 years. In the VA study, the only randomized study involving a large number of patients with clinically important left main stenosis, survival at 42 months was 65% in the medical therapy group and 88% in the CABG group (P = 0.016) (36). Thus, survival was markedly improved by CABG. Similar results were found in the observational studies (18, 34): The CASS registry showed a cumulative 4-year survival of 88% in the CABG group and of 63% in the medical therapy group (18). Left ventricular dysfunction, when found with left main disease, further decreased the survival with medical therapy and, conversely, increased commensurately the relative survival benefit with surgical intervention (25). In patients with left main disease of 75% or greater severity, CABG increased the 4-year survival by 54%: from 59% with medical therapy to 91% with CABG (P = NS [not significant]) for patients with left ventricular score of 5 to 9 (18). In patients with a left ventricular score of more than 9, CABG increased the 4-year survival by 108%: from 37% with medical therapy to 77% with CABG (P = ) (18). Thus, the relative gain in survival at the higher left ventricular score (worse left ventricular dysfunction) was twice that derived at the lower score, which shows that higher-risk or sicker patients derive greater survival benefit from CABG. The coexistence of right coronary artery disease was one other factor that affected prognosis. The 4-year survival rates for medical therapy and CABG, respectively, were 81% and 94% (14% gain) in patients with left main disease who did not have right coronary artery disease of up to 50%. In patients who did have coexisting right coronary artery disease of 50% or greater severity, corresponding 4-year survival rates were 61% and 88% (44% gain) (18). Left Main Equivalent Coronary Artery Disease Disease of both the proximal left anterior descending artery (before the first major septal perforator) and the proximal circumflex artery before any obtuse marginals threatens the same territory as does disease of the left main itself and has therefore been labelled left main equivalent disease (37-39). In a Duke databank study (38), survival rates at 1 and 5 years were, respectively, 69% and 39% in patients with left main coronary artery disease; 76% and 57% in patients with left main equivalent coronary artery disease; 89% and 66% in patients with non-left main equivalent three-vessel disease; and 97% and 86% in patients with non-left main equivalent two-vessel disease involving the left anterior descending and proximal circumflex arteries. Thus, although left main equivalent disease is not really equivalent to left main disease, it carries a high risk with medical therapy (40). This risk is substantially reduced with surgery (37, 40). In two studies, the reported 5-year survival rates 15 June 1991 Annals of Internal Medicine Volume 114 Number

6 with CABG and medical therapy, respectively, were 98.2% and 75.9% (P = ) (37) and 85% and 55% (P = 0.001) (39). Thus, CABG improved 5-year survival by 15% to 50% in patients with left main equivalent disease. Proximal Left Anterior Descending Coronary Artery Disease Disease of the proximal left anterior descending coronary artery is the most important type of single-vessel disease. When treated medically, it carries a mortality greater than that of any other type of single-vessel disease (40-42). In one study, mortality at 5 years was 10% in patients with proximal left anterior descending artery disease compared with 2% in patients with disease of the left anterior descending artery distal to the first septal perforator (41). Samaha and colleagues (42) reported that 5-year mortality rates associated with proximal and distal left anterior descending artery disease depended on whether right coronary artery disease was present; the rates were, respectively, 13.0% and 7.3% (P = NS) if the left anterior descending artery alone was diseased and 34.1% and 16.0% (P = 0.017) if both the right coronary artery and the left anterior descending artery were diseased (42). Consonant with the high risk associated with medically treated proximal left anterior descending coronary artery disease (13, 40), the 10-year survival rates in the European study were 81% and 83% (P > 0.20) for CABG and medical therapy, respectively, in the absence of proximal left anterior descending artery disease (7). If proximal left anterior descending artery disease was present, the survival rates were 76% and 65%, respectively (P = 0.007) (7). Thus, surgery conferred a survival benefit (17% improvement) in the subset of patients with proximal left anterior descending disease in the setting of two- or three-vessel disease, but conferred no benefit in the absence of proximal left anterior descending artery stenosis (7). However, when patients in the randomized CASS trial were categorized by the presence or absence of proximal left anterior descending artery disease, CABG did not confer a survival benefit (9). Again, the discrepancy between the findings of the CASS trial and the European study may be ascribed to differences in patient samples (Table 1). Severity of Coronary Disease That the severity of coronary disease, as determined angiographically, affects prognosis is easiest to demonstrate with left main disease because the lesion threatens a large amount of myocardium by virtue of its location. Left main disease therefore carries a sufficiently high mortality risk to provide adequate statistical power for analysis of differential survival benefit. The study by Conley and colleagues (35), which was based on the Duke database, showed that left main disease of 70% or greater severity was associated with survival rates of 72%, 56%, and 41% at 1, 2, and 3 years, respectively, prognoses worse (P < 0.05) than those for left main disease of 50% to 70% severity (91%, 77%, and 66%, respectively). Moreover, concomitant left main disease increased mortality in patients with three-vessel disease only if the severity of the left main disease was at least 70% (35). A CASS registry study of 1492 patients with left main disease identified a lesion severity of at least 60% as the limit above which mortality with medical therapy parallels the severity of the left main lesion (18). After surgery, no difference was found in the survival curves for patients with left main disease, regardless of lesion severity (18). Without surgery, the mortality in these patients was roughly proportional to lesion severity and because surgery neutralized the effect of lesion severity, one may conclude that the more severe the coronary lesion, the greater is the survival benefit to be derived from CABG. The angiographic assessment of lesion severity calls for a word of caution because angiography is inherently imprecise. Therefore, although both randomized and nonrandomized studies of CABG refer to various disease severity thresholds expressed as percentage stenosis, these should not be viewed as hard and fast cut-off points. For instance, the lesion severity threshold of 60% and 70% used in the studies cited above should not be taken too literally, because angiography lacks the precision to distinguish consistently among lesion severities of 50%, 60%, and 70%. Severity of Angina The presence of angina presumably provides additional information related to functional severity and so should have implications for prognosis. Given similar left ventricular functional status and angiographic severity of coronary artery disease, the presence of angina was associated with an annual mortality of 5.4%, a rate that is twice the 2.7% rate seen in asymptomatic patients treated medically (P < 0.05) (43). The Canadian Cardiovascular Society system (44) grades angina as follows: class 1, angina only with strenuous exercise; class 2, angina with rapid or moderate walking (more than two blocks) or stair climbing (more than one flight); class 3, angina with minimal walking (less than two blocks) or stair climbing (less than one flight); and class 4, angina with any level of physical activity or angina at rest. In a CASS registry study, Kaiser and colleagues (30) investigated the relevance of the severity of angina, as graded by the Canadian Cardiovascular Society classification, to choice of therapy. Patients with class III or IV angina and three-vessel disease had improved survival with surgery, regardless of the functional status of the left ventricle: 5-year survival was 74% with medical therapy and 92% (24% improvement) with CABG (P < ) in patients with normal left ventricular function, and 52% with medical therapy and 82% with CABG (58% improvement) in patients with abnormal left ventricular function (ejection fraction less than 50%) (P < ) (30). On the other hand, among patients with class I or II angina in this study, those with three-vessel disease and left ventricular dysfunction did not derive substantial survival benefit from CABG, let alone those with one- or two-vessel disease and those with normal left ventricular function (30). In patients with class I or II angina, three-vessel disease, and left ventricular dysfunction, 5-year survival was 89% with CABG and 82% June 1991 Annals of Internal Medicine Volume 114 Number 12

7 with medical therapy (9% improvement) (P = 0.17). Thus, the severity of angina is another variable that may interact with other factors to influence the outcome of therapy for coronary artery disease. The importance of the severity of angina in predicting a response to CABG may, however, be overshadowed by an unusually powerful determinant of mortality risk, such as the presence of left main disease. Thus, survival benefits for CABG compared with medical therapy were similar in both the asymptomatic and the symptomatic groups of patients with left main disease (45). Clinical and Demographic Risk Factors Several other clinical factors affect the prognosis of coronary artery disease (18, 23, 35, 46, 47). Clinical and demographic risk factors are important because the clinician can identify them at patient presentation and use them to formulate a judgment regarding the need for catheterization. Age Age affects the prognosis of coronary artery disease (7, 18, 47). In the Seattle Heart Watch study, an observational study, a survival benefit was absent in patients less than 48 years of age and apparently was less in patients 48 to 58 years of age than in patients more than 58 years of age (48). In the CASS registry study of patients with left main disease, older patients had a worse prognosis with medical therapy and accordingly derived a benefit from surgery that was commensurate with the magnitude of their risk without surgery (18). Four-year survival with medical therapy was 68% in patients less than 50 years of age and 51% in patients more than 65 years of age (18); with CABG, survival increased to 95% (P < ) and 82% (P < ) in these age groups, respectively (18), representing survival gains of 40% in the younger patients and 61% in the older patients. The European study, after stratifying patients into three age groups, showed that the older the patient, the greater is the survival benefit with surgery (7). For patients more than 47 years of age, 10- year survival was 79%, regardless of the treatment used (P > 0.20); for patients more than 53 years of age, 10-year survival was 56% with medical therapy and 72% with CABG (P = 0.01) (7). However, when patients in the randomized CASS trial were grouped into these same age categories, no differences in survival were seen (9). This discrepancy may be attributed to differences among patient samples in these studies, especially with respect to severity of angina and presence of left main disease (Tables 1 and 2). No upper limit of age has been defined above which the age-related increase in mortality risk of CABG overrides its potential survival benefit. A CASS registry study of patients more than 65 years of age, with and without left main disease, showed a survival benefit for CABG, even in patients more than 75 years of age (47). Six-year survival rates with medical and surgical therapy were, respectively, 67% and 81% (P < ) in patients 65 to 69 years of age; 51% and 77% (P < 0.001) in patients 70 to 74 years of age; and 56% and 75% (P < 0.14) in 42 patients 75 years of age or more. The CABG-related increase in survival was 22%, 51%, and 34% in the three age groups, respectively. Thus, it appears that the survival gain associated with CABG increases with older age above 50 years, but this trend appears to be blunted somewhat in patients older than 75 years. In patients more than 80 years of age, the mortality risk associated with open heart surgery seems to be as high as 25% (49), making it less likely that on balance there will be a survival benefit with CABG in octogenarians. Nevertheless, each case should be considered on its merits. It is not known whether age is a predictor of survival gain independent of the age-associated increase in the frequency of variables predictive of mortality risk with medical therapy such as diabetes, cerebrovascular disease, more severe angina, congestive heart failure, left main coronary artery disease, and left ventricular dysfunction (50). Female Sex There is little definitive information on the effect of gender on the survival of medically treated patients with coronary artery disease (51, 52). It is likely, however, that relevant data exist, at least in raw form, in some of the larger databases such as the CASS registry. Of the randomized trials, only CASS included women (Table 1) and their number a mere 10% of 780 patients (9) was apparently insufficient to support meaningful gender-based analysis. The only information relating to the effect of gender is on mortality after myocardial infarction, on operative mortality and survival after surgery in observational studies, and on in-hospital and post-discharge mortality after percutaneous transluminal coronary angioplasty. Mortality in women is twice that in men during and after myocardial infarction. In the Gruppo Italiano per 10 Studio della Streptochinasi nelltnfarto miocardico (GISSI) trial (53), a large Italian study comprising patients (19.7% of whom were women), the aggregate mortality rates in women and men 21 days after infarction were 20.5% and 9.7%, respectively (P < 0.001). Overall mortality rates at 1 year were 29.8% for women and 15.2% for men (P < 0.001) (54). Among patients who were discharged after infarction, mortality rates at 1 year were 11.6% for women and 6.3% for men (P < 0.001) (54). The ratio of death rates in women and men was unaffected by therapy with streptokinase, although this drug lowered the death rate in both sexes (53, 54). The Framingham Study data, "collected... when treatment of both angina and myocardial infarction was rather primitive" (55), showed a mortality of 28% in women and 16% in men 30 days after infarction. Another study (56) showed that the disparity in inhospital mortality rates between women and men remained when patients were stratified by type of infarction (anterior or inferior): Rates were 50% and 20.2% (P < 0.001) in anterior infarction and 28.2% and 11.5% (P < 0.01) in inferior infarction. Moreover, the difference in death rates seemed to be age related in that study (56): In patients between 55 and 70 years of age, mortality rates were 38% and 17% in women and men, respectively (P < 0.01), whereas in patients more than 70 years of age, corresponding rates were 56% and 46% 15 June 1991 Annals of Internal Medicine Volume 114 Number

8 (P = NS). In the Multicenter Investigation of the Limitation of Infarct Size (MILIS) (57) the cumulative mortality rate 48 months after infarction was 36% for women and 21% for men (P < 0.001). The in-hospital mortality rates were 13% in women and 7% in men (P < 0.05), whereas for hospital survivors, the corresponding mortality rates were 27% and 15% (P < 0.05) (57). Another study showed a higher 5-year recurrence rate of infarction in women (39%) than in men (13%) (55). The CABG-associated operative mortality in women was about twice that in men, despite the fact that women, although older and with more severe angina, tended to have better left ventricular function and less severe coronary artery disease (58-60). Data from the CASS registry (59) showed that women had an operative mortality of 4.5% compared with 1.9% in men (P = 0.001). Findings from the Cleveland Clinic study (60) were similar: Mortality rates were 2.9% in women and 1.3% in men (P = 0.001). Both these studies and an earlier one by Tyras and colleagues (58) provided persuasive evidence that the greater operative mortality in women was attributable not to gender per se but to the smaller body size and the smaller size of the coronary arteries in women. Despite this higher operative mortality and a lower graft patency rate in women (76.4% compared with 82.1% in men [P = 0.001] in 2 years [60]), there was no difference in long-term survival after surgery. Survival at 5 years was somewhat higher in men (90.6% compared with 93.0% in women [P = 0.035]); 10-year survival was about the same (78.6% in women and 78.2% in men [P = NS]) (60). Thus, the available data suggest that women live as long as men after CABG. A report (61) based on relatively early experience with angioplasty indicated that there were gender-related differences in outcome after angioplasty. Shortterm outcome was worse in women than in men, whereas long-term outcome was either as good or better in women. The following short-term adverse events and outcomes were reported at a higher rate in women than in men: angioplasty-related mortality (1.7% compared with 0.3% [P < 0.001]); need for CABG (30.0% compared with 24.2% [P < 0.05]); mortality related to emergency surgery after angioplasty (17.4% compared with 3.2% [P = 0.001]). Despite these findings, long-term results in women were unmatched in men. These included angiographic re-stenosis (22% in women compared with 36% in men [P = 0.01]); repeat angioplasty (10% compared with 18% [P = 0.01]); additional revascularization (18% compared with 27% [P = 0.01); and cumulative mortality (0.3% compared with 2.2% [P < 0.05]) (61). When all data are considered, angioplasty appears to be at least as effective a therapeutic option for coronary artery disease in women as in men. These studies provide circumstantial evidence that female sex is another factor that decreases survival with medical therapy and that, although short-term outcome with revascularization by angioplasty or CABG is less favorable in women, long-term results are not worse than in men. Therefore, female sex should be considered when deciding whether to do CABG (or possibly angioplasty) to improve survival. Risk Terciles in the Veterans Affairs Study In the VA study, patients were divided into three risk terciles using combinations of the following risk factors: New York Heart Association (NYHA) class III or IV heart failure, a history of hypertension, a history of myocardial infarction, and ST-segment depression of the baseline electrocardiogram (23, 36, 46). The low-risk tercile had one risk factor other than ST depression; the middle-risk tercile had either ST depression alone or NYHA class III or IV heart failure and any other factor; the high-risk tercile had any two or more of the risk factors other than NYHA class III or IV heart failure (23, 36, 46). When patients with left main disease were grouped by these terciles only, the high-risk group alone derived a survival benefit from surgery (36). Survival in the medically treated patients in the low-risk group was better than that of the surgically treated low-risk patients, but the difference did not reach statistical significance (36). Similar results were obtained in the larger number of patients without left main disease (23, 46). In this case, however, when both clinical and angiographic risk factors were used to classify patients, it was found that the only subgroup to benefit from surgery was the patients at both clinical and angiographic high risk (23, 46). Importantly, the patients at low risk, both clinically and angiographically, had better survival with medical therapy (23). These results have been criticized because the numbers of patients in different terciles were small, operative mortality was much higher in the low-risk group, and vein graft patency was lower in the low-risk group (13). However, other studies (18, 35, 47) confirm the importance of considering both clinical and angiographic characteristics. Thus, the patients at higher risk based on clinical and angiographic factors were the ones that derived the greatest relative benefit from surgery (18, 23, 35, 47). Peripheral Vascular Disease In the European study (6), there was a subgroup of patients with peripheral vascular disease whose survival with medical therapy was poor and who therefore benefited from CABG more than did patients without peripheral vascular disease. Eight-year survival rates with medical therapy in patients with and without peripheral vascular disease were 57.1% and 81%, respectively (6). Coronary artery bypass grafting increased these survival rates to 84.8% (P = ) and 90% (P = 0.004) (6). These increases represent survival gains of 48% in patients with peripheral vascular disease and 11% in those without. The greater survival benefit of CABG in patients with peripheral vascular disease was still evident at 10 years (7). This disparity in the improvement in survival afforded by CABG remains unexplained because the extent of coronary artery disease in patients with and without peripheral vascular disease was "remarkably similar" (6, 7). Could it be that peripheral vascular disease is not only associated with coronary artery disease but also is a marker for more aggressive coronary artery disease? Baseline Electrocardiographic Abnormality In the European study, a resting electrocardiographic abnormality (defined as ST depression of at least June 1991 Annals of Internal Medicine Volume 114 Number 12

9 mm, which could be due to silent ischemia, T-wave inversion, or an abnormal Q wave) was associated with improved survival after CABG (6, 7). Patients with an abnormal resting electrocardiogram who were randomly assigned to medical therapy or surgery had survival rates at 5 years of 79% and 90%, respectively (P = 0.005); at 10 years, the corresponding rates were 62% and 71% {P = 0.04). The survival benefit "was smaller in the subgroup with a normal electrocardiogram" (P = at 5 years and P > 0.20 at 10 years) (7). The VA study would appear to support this finding because resting ST depression was one of the clinical characteristics used in defining terciles of clinical risk (23, 36, 46). Hypertension In some studies, hypertension was shown to be an independent predictor of outcome in coronary artery disease (25, 46). In the VA study, hypertension was used to stratify patients into risk terciles and was found to be one of the variables predictive of survival benefit (46). The European study, however, did not show any survival benefit in patients with hypertension (7). In hypertensive patients, 10-year survival was 64% with medical therapy, and 59% with CABG (P > 0.20) (7). In nonhypertensive patients, 10-year survival rates were 71% with medical therapy and 80% with CABG (P = 0.004) (7). In the randomized CASS trial (9), neither the presence nor the absence of hypertension affected survival at 5 or 10 years. Thus, because the data on hypertension are somewhat conflicting, one cannot justifiably select patients for CABG on the basis of whether they have hypertension. Provocable Ischemia The presence of provocable ischemia further refines the selection of patients likely to benefit from bypass surgery because of poor prognosis if treated medically. The European study (7) showed that CABG conferred a greater survival benefit on patients whose exercise test result was abnormal. In that study, the exercise test was graded as normal if the heart rate attained was greater than 120 beats/min or the workload achieved was at least 100 watts, or both, with ST depression of no more than 1 mm; or if the maximal heart rate attained was less than 121 beats/min and the maximal workload achieved was less than 100 watts without either ST depression or angina. The test was graded as positive if the heart rate attained was more than 120 beats/min and the workload achieved was at least 100 watts with ST depression of at least 1.5 mm; or if the maximal heart rate attained was less than 121 beats/min, the maximal workload achieved was less than 100 watts, ST depression was 1 mm, and there was no angina. The test was graded as markedly positive if the heart rate attained was less than 121 beats/min or the maximal workload achieved was less than 100 watts, or both, with ST depression of at least 1.5 mm; or if the maximal heart rate attained was less than 121 beats/min and the maximal workload achieved was less than 100 watts with ST depression of less than 1 mm and no angina. Among patients with a normal or slightly positive test result, 10-year survival was 80% and 77% in the surgery and medical therapy groups, respectively (P > 0.20). Among patients who had a positive exercise test result, the corresponding survival rates were 82% and 72% (P = 0.13). Among patients with a markedly positive test result, survival rates at 10 years with surgery and medical therapy were 75% and 62%, respectively (P = 0.007). These findings represented CABGrelated survival gains at 10 years of 4%, 14%, and 21% in patients with normal, positive, and markedly positive exercise test results, respectively. The CASS randomized trial did not detect a survival benefit with CABG among patients with three-vessel disease and preserved left ventricular function (29). However, in a study of a cohort of patients similar to the one studied in the randomized CASS trial, Bonow and colleagues (62) identified a subset of patients who were at high risk with medical therapy and thus who could potentially benefit from surgery. These investigators showed that ST-segment depression of 1 mm or more, a decrease in ejection fraction, and a low workload (120 watts or less) during exercise testing in patients with class I or II angina, three-vessel disease, and preserved left ventricular function identified those who had an annual mortality of 7% compared with 0% in patients showing no change or an increase in ejection fraction with exercise or no ST-segment response, or both. In another study (63) of medically treated patients from the CASS registry, the duration of exercise and the ST-segment response were found to be the most important exercise test variables. Using these variables, the investigators could stratify patients into a high-risk group with an annual mortality of 5% and a lower-risk group with an annual mortality of no more than 1% (63). Ryan and colleagues (32) studied a subset of patients from the randomized CASS trial who had exercise testing and showed that only those with left ventricular dysfunction who had angina during the test benefited from surgery. Seven-year survival rates with CABG and medical therapy were, respectively, 94% and 87% (P = 0.007) in patients with exercise-induced angina and 86% and 83% (P = NS) in those without exercise-induced angina. In patients with exercise-induced angina and impaired left ventricular function (defined as a left ventricular score of more than 10), 7-year survival rates with CABG and medical therapy were, respectively, 100% and 69% (P = ). If three-vessel disease was also present, 7-year survival rates were 100% and 64% (P = 0.005). Neither the presence nor the degree of ST depression nor the final exercise stage reached identified patients who would have better survival with surgery. This surprising finding may be related to the fact that patients in the randomized CASS trial were either only mildly symptomatic or asymptomatic (8, 32). In contrast, in a CASS registry study, Weiner and colleagues (64) showed that the degree of ST depression was useful in identifying patients most likely to benefit from surgery (64). When exercise-test-related variables were combined with angiographic variables, the selection of patients likely to have improved survival with surgery was narrowed further. An exercise test result indicating high risk (defined as ST-segment depression 15 June 1991 Annals of Internal Medicine Volume 114 Number

10 Table 4. Overall Survival in Randomized Trials of Coronary Artery Bypass Grafting* Variable VA Study European Study CASS Trial 7 Year 11 Year 5 Year 10 Year 12 Year 5 Year 10 Year < % > Medicine t 70$ Surgery t 76$ * Data are from references tp< tp = P = of 1 mm or more with a final exercise stage of 1 or less) combined with three-vessel disease resulted in 7-year survival rates of 81% with CABG and 56% with medical therapy (P < 0.001) (64). When an exercise test result indicating high risk was combined with impaired left ventricular function (left ventricular score of more than 9), 7-year survival was 67% with CABG and 49% with medical therapy (P = 0.005) (64). In high-risk patients with preserved left ventricular function (left ventricular score of less than 10), 7-year survival was 88% with surgery and 83% with medical therapy (P = NS) (64). The European study also showed that a poor exercise test result, as evidenced by the degree of ST depression, identified patients in whom surgery improved survival (6, 7). Thallium-201 scintigraphy and radionuclide angiography have also been found to be useful in selecting patients for CABG. The prognosis of patients with coronary artery disease worsens when scintigraphy shows extensive ischemia (reflected by multiple redistribution thallium-201 defects) (65). Such patients would be the most likely to benefit from CABG. Similarly, radionuclide angiography identifies patients at high risk if it shows a decrease or a lack of increase in exercise left ventricular ejection fraction. One nonrandomized study showed that such patients derived greater differential survival benefit from CABG than did patients with a normal left ventricular ejection fraction on exercise (66). Because the specificity and sensitivity of radionuclide studies is greater than that of the exercise electrocardiographic response (67), these studies may be more useful than the stress electrocardiographic response in identifying patients likely to have prolonged survival with CABG (68). Graft Attrition and Recurrence of Disease in Native Vessels Grafts close over time, and disease tends to recur in both grafted and ungrafted native vessels. Angina recrudesces and the survival benefit of CABG diminishes. In all the randomized studies of CABG, the graft patency rate decreased with time (Table 1) and, when assessed at comparable intervals, tended to be higher after CABG in later than in earlier studies (that is, the graft patency rate in the CASS trial was higher than that in the European study, which in turn was higher than that in the VA study [Table 1]). In the CASS trial, graft patency was 90% at 60 days, 82% at 18 months, and 82% at 5 years (8); in the European study, it was 75% at 12 to 18 months and 69% at 5 years (Table 1); and in the VA study, it was 69% at an average of 1 year after surgery (4). Symptom relief and survival correlate with graft patency. In one study (69), 80% of patients with at least one patent graft were alive after 12 years compared with 42% of patients in whom all grafts were closed (P = 0.001). For all patients in the VA study, including those with left main disease, the 7-year survival rate was 70% in patients who received medical therapy and 77% in patients who had surgery (P = 0.043); the 11- year rates were down to 57% and 58%, respectively (P = NS) (70). In the European study at 5 years (6), survival was 92.4% in surgically treated patients and 83.1% in medically treated patients (P = ); at 12 years (7), the corresponding survival rates had decreased to 70.6% and 66.7% (P < 0.04) (7). In the CASS trial at 5 years (8), the cumulative survival rates for medically and surgically treated patients were, respectively, 90% and 92% (P = NS); at 10-years (9), the rates were 79% and 82% (P = NS) (9). Thus, in the randomized trials, the survival benefit found early in follow-up studies (4, 6, 8) tended to diminish somewhat later (7, 9, 70). When patients with similar descriptors of cardiovascular morbidity were identifiable (Table 3), survival generally tended to mirror the graft patency and surgical mortality experience (Table 3). Survival in CASS was higher than that in the European study, and survival in the European study was higher than that in the VA study (Table 3). However, such comparisons of survival must be made cautiously because patients differed in other pertinent respects (Tables 1 and 2), including angina class and rate of beta-blocker use. Whereas only 12% of patients in the VA study were on beta-blockers, 75% and 43% of patients in the European study and CASS, respectively, were on beta-blockers (9). However, it is not surprising that survival tended to be somewhat better in CASS than in other studies (Table 4) because CASS began at a time when surgeons were undoubtedly more experienced and skilled at doing CABG (Table 1). The benefits of CABG therefore tended to be maintained somewhat better in CASS than in the other randomized studies (Table 3). Although the CABG-related survival benefit diminished over time in the randomized trials (Table 4) in part because more and more of the medically treated patients crossed over to surgery (Table 1), the main reason usually cited for the decrease in survival benefit June 1991 Annals of Internal Medicine Volume 114 Number 12

11 is graft attrition and progression of disease in surgically treated patients (7). Studies have shown that the graft closure rate increases as the low-density lipoprotein and low-density lipoprotein apoprotein B levels increase and the high-density lipoprotein level decreases (71). In addition, graft patency is markedly improved by therapy with dipyridamole and aspirin (72). Thus, reduction of serum lipid levels and antiplatelet therapy may be effective ways to reduce the rate of graft closure and thereby to increase the survival benefit of CABG. Moreover, survival is higher in patients with internal mammary artery grafts than in patients with saphenous vein grafts, regardless of age, sex, left ventricular function status, and presence of left main disease (73, 74). Seven-year survival averaged 90% in patients who received the internal mammary artery graft and 80% in those who did not (74). The internal mammary artery-related survival gain (28%) seemed most pronounced in patients more than 65 years of age; 7-year survival rates in such patients were 88% and 69% (P = 0.01) with and without the internal mammary artery, respectively (74). The internal mammary artery graft reduced the 7-year mortality risk by a factor of 0.64 (74). Thus, the internal mammary artery graft will help maintain the survival benefit of CABG over time better than the saphenous vein graft. Selecting Patients with Chronic Stable Angina for Cardiac Catheterization and Bypass Surgery One important tenet that emerged from the studies of CABG in patients with chronic stable angina is that in a defined population, the survival benefit derived from CABG is proportional to the mortality risk associated with medical therapy. Consequently, the factors associated with a poor prognosis in coronary artery disease that is treated medically are the same ones that make it likely that CABG will confer survival benefit. The greater the number of adverse prognostic factors present in any group of patients and the more severe their expression, the worse is the prognosis with medical therapy and, conversely, the greater is the differential survival benefit to be derived from CABG. In addition, a marginal effect of one adverse factor may be greatly bolstered by the strong effect of another. In plainer language, the sicker the patient, as gauged by relevant measures, descriptors, or correlates of cardiovascular morbidity, the greater is the survival benefit of CABG. Nor surprisingly, most of the adverse prognostic factors that predict a survival gain with CABG are associated with a higher operative mortality (3). This finding has two implications. First, with increasing awareness that sicker and therefore higher-risk patients derive relatively greater survival benefit from CABG, the operative mortality of CABG will likely increase. Second, CABG will confer a net survival benefit only if operative mortality is not so high as to offset the survival gain after surgery (19, 26). The general principles we have discussed may be translated into criteria for selecting patients for cardiac catheterization and CABG with a view to improving their survival. We emphasize that the goal of therapy used as the term of reference in our review is a narrow one: prolongation of life. Although none is as compelling as prolongation of life, other valid goals are recognized (75, 76), notably improvement in quality-of-life factors such as relief of symptoms (75). Moreover, we have discussed only patients with chronic stable angina. Therefore, the indications for catheterization and CABG that we cite are not exhaustive but are simply those likely to result in the identification of patients with chronic stable angina who are likely to have improved survival with CABG. Patients Eligible for Cardiac Catheterization The variables predictive of survival benefit after CABG, as discussed above, may be categorized for practical purposes into those known by the clinician before cardiac catheterization and those known only after cardiac catheterization (Table 5). Only variables known before catheterization can be used to guide selection of patients for cardiac catheterization (Figure 1). Patients with class III or IV angina should have catheterization because they will likely benefit from surgery if they have left main disease (18, 36); three-vessel disease (6, 30); proximal left anterior descending artery disease as part of two-vessel disease (6, 10); two-vessel disease with severe left ventricular dysfunction (31); or two-vessel disease with moderate left ventricular dys- Figure 1. Algorithm for selection of patients for cardiac catheterization. LV = left ventricular; PVD = peripheral vascular disease; ECG = electrocardiogram; ST 1 = ST-segment depression; T i Q's = T-wave inversion and Q waves (in the baseline electrocardiogram). 15 June 1991 Annals of Internal Medicine Volume 114 Number

12 Table 5. Pre- and Postcatheterization Variables Precatheterization variables Demographic variables Age Sex Clinical factors Severity of angina (angina class) History of myocardial infarction Signs and symptoms of left ventricular dysfunction Signs and symptoms of peripheral vascular disease Noninvasively determined factors Electrocardiography Baseline ST-segment and T-wave abnormalities Presence of Q waves Echocardiography Left ventricular dysfunction Exercise test Presence and severity of provocable ischemia as determined by exercise duration, presence of chest pain, degree of ST depression, and workload and heart rate attained Radionuclide studies Left ventricular dysfunction on radionuclide angiography Number of ischemic segments on stress thallium scintigraphy Presence of lung uptake on stress thallium scintigraphy Postcatheterization variables Left ventricular function (ejection fraction or left ventricular score) Number of diseased vessels Location of coronary artery disease Severity of coronary artery disease as determined by angiography function and at least one proximal lesion (31). The presence of class I or II angina by itself is not sufficient to justify cardiac catheterization; the clinician should obtain more data to satisfy the more stringent criteria required for selection for catheterization (Figure 1). The presence of left ventricular dysfunction in association with class I or II angina should make these patients eligible for cardiac catheterization because CABG would prolong survival if they were also found to have left main disease, three-vessel disease (23, 29), or proximal left anterior descending artery disease as part of two-vessel disease (6, 7, 10). Such left ventricular dysfunction is evidenced by one of the following: a history of myocardial infarction or congestive heart failure, symptoms suggesting congestive heart failure, a noninvasively determined ejection fraction of less than 50%, or a left ventricular score of more than 9. If left ventricular dysfunction is absent, then older age (7, 18, 47); female sex; or the presence of peripheral vascular disease (6, 7), or a baseline ECG abnormality (especially ST depression) (6, 7) would make them eligible. If a patient fails to meet these criteria, then a positive exercise test (32, 62-64) or preferably a positive radionuclide study (67) would be required to make them eligible. Patients Eligible for Coronary Artery Bypass Grafting Catheterization provides information on the extent, configuration, and severity of coronary artery disease as well as on the status of left ventricular function (Table 5). Unless otherwise stated, coronary artery disease is considered important if there is a luminal diameter narrowing of at least 50% in the left main artery and of 70% elsewhere (8, 18, 35). The VA study (4) and the European study (6) used a limit of 50% for all vessels (Table 1) without justifying this choice. One must also keep in mind that the degree of stenosis is only an estimate and the clinician must use his or her judgment in cases where lesions seem marginally important. After catheterization, the patients whose survival would be improved by CABG should be selected using a combination of angiographic and nonangiographic factors (Figure 2). Patients with Left Main Lesions In patients with left main lesions, either of the following findings should justify CABG: a left main lesion of at least 60% severity regardless of whether coronary artery disease is present anywhere else (18, 35); and left main disease of 50% to 60% severity in the presence of either right coronary artery disease of at least 50% severity or left ventricular dysfunction (18). Although no study has addressed the issue specifically, it would seem reasonable to recommend CABG for patients with isolated left main lesions of 50% to 60% severity who are 60 to 80 years of age, are female, or have peripheral vascular disease, a positive exercise test, or class III or IV angina. We should also emphasize that because angiography lacks the precision to distinguish between lesions of 50% and 60% severity, these cut-off values should not be applied rigidly. Patients with Three-Vessel Disease To qualify for CABG under the term of reference used here, patients with three-vessel disease should satisfy one of the following conditions (Figure 2): presence of proximal left anterior descending artery disease (6, 7, 10, 40); left ventricular ejection fraction of less than 50% (19, 23, 29); class III or IV angina (30); strongly positive exercise test as defined by combinations of ST depression (1 mm or greater), a short duration of exercise before the test became positive, the presence of chest pain during exercise, and a low workload or heart rate achieved (7, 32, 62-64); presence of multiple ischemic segments on myocardial thallium-201 scintigraphy or a large decrease in left ventricular ejection fraction on exercise radionuclide angiography (67); older age (between 60 and 80 years of age) (7); female sex; presence of a baseline ECG abnormality; or peripheral vascular disease (6, 7, 10, 47). Patients with Two-Vessel Disease Patients with two-vessel disease should be selected for CABG (or possibly angioplasty) if proximal left anterior descending disease is also present (6, 7, 10, 40); there is severe left ventricular dysfunction and the patient has class III or IV angina (31); and left ventricular dysfunction is moderate but there is also at least one vessel with a proximal lesion as well as class III or IV angina (31) (Figure 2). In marginal cases, the presence of peripheral vascular disease (6, 7), older age (between 60 and 80 years of age) (7, 12, 47), female sex, a baseline ECG abnormality (6, 7, 23), or left ventricular dysfunction (19, 23, 29) should argue for CABG June 1991 Annals of Internal Medicine Volume 114 Number 12

13 Areas of Uncertainty The above recommendations reflect the current state of knowledge and will likely change as more information becomes available. Thus, they should not be applied too rigidly for several reasons. First, there are still important unanswered questions. In particular, the subsets of patients studied to date have by no means been exhaustive. As a result of constraints imposed by the limited numbers of patients, important subsets with different possible combinations of characteristics of interest have not been studied and will probably never be studied. For instance, the European study suggested that patients less than 47 years of age did not derive a survival benefit from CABG (7). Would this apply to such patients if they also had left main disease of over 80% severity or if they had threevessel disease with left ventricular dysfunction? Second, the survival benefits reported in the studies that we have reviewed may be conservative by presentday standards. There is evidence that the survival of surgically treated patients has improved steadily over the last 15 years (20). This improvement is most likely a result of better myocardial preservation, more complete revascularization, improved surgical and anesthetic techniques, and increased use of internal mammary artery grafts (20, 73, 74). Although it is likely that the survival of medically treated patients has been influenced by new advances and practices, such as the increased use of beta-blockers, calcium-channel blockers, and antiplatelet agents, there is no evidence that any gains have matched those in surgery-related survival over the same period. Third, uncertainty exists about the cut-off points used for age and left ventricular ejection fraction. Although we suggest limits of 60 to 80 years for age and an upper limit of 50% for ejection fraction, these limits are not intended to be rigid. Moreover, although circumstantial evidence suggests that women may benefit more than men, definitive data are needed on the effect of gender on the CABG-related survival benefit. The CASS registry ought to be useful in this regard. Finally, the role of angioplasty remains undefined. Several randomized trials are currently under way (77) and should help define those patients in whom angioplasty would be more suitable than CABG and vice versa. These trials include the Coronary Artery Bypass Revascularization Investigation (CABRI); the Randomized Intervention Trial of Angina (RITA); the German Angioplasty Bypass Investigation (GABI); the Emory Angioplasty or Surgery Trial (EAST); the Bypass Angioplasty Revascularization Investigation (BARI); and the Angioplasty Compared to Medicine (ACME) trial. Even before the results of these randomized trials are known, data available from other sources suggest that angioplasty is effective therapy for single-vessel disease and probably for multivessel disease (78, 79). In a cohort of 427 patients who underwent angioplasty with surgical backup in 1981, 5-year survival was 96.3% (78). For the 265 patients (62%) in this cohort who had proximal left anterior descending artery disease, 5-year survival was 95.8% and increased to 98.5% when noncardiac deaths were excluded (78). Comparisons with data from other sources on medically treated patients must be made cautiously. However, considering that in various studies (41, 42) the survival of medically treated patients with proximal left anterior descending artery disease ranged from 87% (42) to 90% (41) at 5 years, angioplasty may have prolonged the lives of these relatively high-risk patients with single-vessel disease (40). Although data such as these come from uncontrolled and nonrandomized studies, they provide a basis for the expectation that angioplasty will be an effective surro- Figure 2. Algorithm for selection of patients for coronary artery bypass grafting (CABG). Coronary artery disease (CAD) is considered clinically important if left main disease is at least of 50% severity or disease elsewhere is of at least 70% severity. Cath = cardiac catheterization; LV = left ventricular; LM = left main; LAD = left anterior descending (coronary artery); SVD = single-vessel disease; DVD = double (two)-vessel disease; TVD = triple (three)-vessel disease; RCA = right coronary artery (disease); PTC A = percutaneous transluminal coronary angioplasty; PVD = peripheral vascular disease; med rx = medical therapy; ST 1 = ST-segment depression; T 4 Q's = T-wave inversion and Q waves (in the baseline electrocardiogram). 15 June 1991 Annals of Internal Medicine Volume 114 Number

14 gate for CABG, and will prolong survival, in defined subsets of patients. Even so, it is doubtful that angioplasty will ever be an exact substitute for CABG because some patients considered to be acceptable risks for CABG may be deemed prohibitive risks for angioplasty. Thus, angioplasty is currently contraindicated in patients with left main disease. It is also not recommended in patients who have large areas of myocardium that are dysfunctional because of a previous myocardial infarction as well as severe stenosis in non-infarct-related vessels subtending areas of myocardium, the loss of whose function as a result of acute closure during angioplasty would precipitate cardiogenic shock and probably death (80). The extent to which supportive measures such as cardiopulmonary bypass (81, 82) will expand the indications for angioplasty to such high-risk patients remains to be determined. Besides, angioplasty is generally considered to yield unsatisfactory results in patients with multivessel disease together with chronic total occlusions and also in patients with very long and tortuous lesions (80). Nonetheless, when suitable, angioplasty has clear advantages over CABG; these include the avoidance of sternotomy and its attendant morbidity, a shorter hospital course, and a lower initial cost (80). Consequently, the future role of angioplasty in the treatment of chronic stable angina, although still not fully delineated, is hardly in doubt. Conclusion Medicine is an imprecise science. The clinician often has to make decisions with incomplete information. Accordingly, rather than define a set of rigid criteria, we have attempted to outline principles that may underpin such decisions. We believe that patients are more likely to benefit if the physician's clinical judgment is informed by the principles reviewed in this article about the selection of patients for cardiac catheterization and CABG to prolong life in the setting of chronic stable angina. Acknowledgment: assistance. The authors thank Ms. Beverly Nathan for secretarial Requests for Reprints: Obi N. Nwasokwa, MD, PhD, Division of Cardiology, Harris Chasanoff Heart Institute, Room 2135, Long Island Jewish Medical Center, New Hyde Park, NY Current Author Addresses: Drs. Nwasokwa, Koss, Friedman, Grunwald, and Bodenheimer: Division of Cardiology, Harris Chasanoff Heart Institute, Long Island Jewish Medical Center, New Hyde Park, NY References 1. Mock MB, Ringqvist I, Fisher LD, et al. Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation. 1982;66: Miller DC, Stimson EB, Oyer PE, et al. Discriminant analysis of the changing risks of coronary artery operations: J Thorac Cardiovasc Surg. 1983;85: Kennedy JW, Kaiser GC, Fisher LD, et al. Clinical and angiographic predictors of operative mortality from the collaborative study in coronary artery surgery (CASS). Circulation. 1981;63: Murphy ML, Hultgren HN, Detre K, Thomsen J, Takaro T. Treatment of chronic stable angina. A preliminary report of survival data of the randomized Veterans Administration cooperative study. N Engl J Med. 1977;297: The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina. N Engl J Med. 1984;311: European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina pectoris. Lancet. 1982;2: Varnauskas E. Twelve-year survival in the randomized European Coronary Surgery Study. N Engl J Med. 1988;319: Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation. 1983;68: Alderman EL, Bourassa MG, Cohen LS, et al. Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation. 1990;82: Varnauskas E. Survival, myocardial infarction, and employment status in a prospective randomized study of coronary bypass surgery. Circulation. 1985;72:V Fisher LD, Davis KB. Design and study similarities and contrasts: the Veterans Administration, European, and CASS randomized trials of coronary artery bypass graft surgery. Circulation. 1985;72: VI Califf RM, Pryor DB, Greenfield JC Jr. Beyond randomized clinical trials: applying clinical experience in the treatment of patients with coronary artery disease. Editorial. Circulation. 1986;74: Rahimtoola SH. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation. 1985;72:V Weinstein GS, Levin B. The Coronary Artery Surgery Study (CASS). A critical appraisal. J Thorac Cardiovasc Surg. 1985;90: Weinstein GS, Levin B. Effect of crossover on the statistical power of randomized studies. Ann Thorac Surg. 1989;48: Kannel WB-. Coronary artery surgery study revisited. Limitation of the intent-to-treat principle. Circulation. 1990;82: Fisher LD, Kaiser GC, Davis KB, Mock MB. Crossovers in coronary artery bypass grafting trials: desirable, undesirable, or both? Ann Thorac Surg. 1989;48: Chaitman, BR, Fisher LD, Bourassa MG, et al. Effect of coronary bypass surgery on survival patterns in subsets of patients with left main coronary artery disease. Report of the Collaborative Study in Coronary Artery Surgery (CASS). Am J Cardiol. 1981;48: Alderman EL, Fisher LD, Litwin P, et al. Results of coronary artery surgery in patients with poor left ventricular function (CASS). Circulation. 1983;68: Califf RM, Harrell FE Jr, Lee KL, et al. The evolution of medical and surgical therapy for coronary artery disease. A 15-year perspective. JAMA. 1989;261: Cox DR. Regression models and life-tables. J R Stat Soc. 1972; 34(series B): Hlatky MA, Califf RM, Harrell FE, Lee KL, Mark DB, Pryor DB. Comparison of predictions based on observational data with the results of randomized clinical trials of coronary artery surgery. J Am Coll Cardiol. 1988;11: Detre K, Peduzzi P, Scott SM, Davies B. Veterans Administration Cooperative Study of medical versus surgical treatment for stable angina progress report. Section 4. Long-term survival results in medically and surgically randomized patients. Prog Cardiovasc Dis. 1985;28: Varnauskas E. Lessons learned from the three randomized coronary bypass surgery trials. Cardiology. 1986;73: Takaro T, Hultgren HN, Lipton MJ, Detre KM. The VA cooperative randomized study of surgery for coronary arterial occlusive disease II. Subgroup with significant left main lesions. Circulation. 1976; 54(Suppl 3):III Pigott JD, Kouchoukos NT, Oberman A, Cutter GR. Late results of surgical and medical therapy for patients with coronary artery disease and depressed left ventricular function. J Am Coll Cardiol. 1985;5: Risk stratification and survival after myocardial infraction. N Engl J Med. 1983;309: Zubiate P, Kay JH, Dunne EF. Myocardial revascularization for patients with an ejection fraction of 0.2 or less. 12 years' results. West J Med. 1984;140: Passamani E, Davis KB, Gillespie MJ, Killip T. A randomized trial of coronary artery bypass surgery. Survival of patients with a low ejection fraction. N Eng J Med. 1985;312: Kaiser GC, Davis KB, Fisher LD, et al. Survival following coronary artery bypass grafting in patients with severe angina pectoris (CASS). An observational study. J Thorac Cardiovasc Surg. 1985; 89: Mock MB, Fisher LD, Holmes DR Jr, et al. Comparison of the effects of medical and surgical therapy on survival in severe angina pectoris and two-vessel coronary artery disease with and without left ventricular dysfunction: a Coronary Artery Surgery Study Registry. Am J Cardiol. 1988;61: Ryan TJ, Weiner DA, McCabe CH, et al. Exercise testing in the Coronary Artery Surgery Study randomized population. Circulation. 1985;72:V Proudfit WJ, Bruschke AV, MacMillan JP, Williams GW, Sones FM June 1991 Annals of Internal Medicine Volume 114 Number 12

15 Jr. Fifteen year survival study of patients with obstructive coronary artery disease. Circulation. 1983;68: Hutter AM Jr. Is there a left main equivalent? Circulation. 1980; 62: Conley MJ, Ely RL, Kisslo J, Lee KL, McNeer JF, Rosati RA. The prognostic spectrum of left main stenosis. Circulation. 1978;57: Takaro T, Pifarre R, Fish R. Veterans Administration Cooperative Study of medical versus surgical treatment for stable angina progress report. Section 3. Left main coronary artery disease. Prog Cardiovasc Dis. 1985;28: Tyras DH, Kaiser GC, Earner HB, Pennington DG, Codd JE, Willman VL. Left main equivalent: results of medical and surgical therapy. Circulation. 1981;64: Califf RM, Conley MJ, Behar VS, et al. "Left main equivalent" coronary artery disease: its clinical presentation and prognostic significance with nonsurgical therapy. Am J Cardiol. 1984;53: Chaitman BR, Davis KB, Kaiser GC, et al. The role of coronary bypass surgery for "left main equivalent" coronary disease: The Coronary Artery Surgery Study registry. Circulation. 1986;74:III Rahimtoola SH. Left main equivalence is still an unproved hypothesis but proximal left anterior descending coronary artery disease is a "high-risk" lesion. Am J Cardiol. 1984;53: Califf RM, Yomabechi Y, Lee KL, et al. Outcome in one-vessel coronary artery disease. Circulation. 1983;67: Samaha JK, Connor MJ, Tribble R, et al. Natural history of left anterior descending coronary artery obstruction: significance of location of stenoses in medically treated patients. Clin Cardiol. 1985; 8: Cohn PF, Harris P, Barry WH, Rosati RA, Rosenbaum P, Waternaux C. Prognostic importance of anginal symptoms in angiographically defined coronary artery disease. Am J Cardiol. 1981;47: Campeau L. Grading of angina pectoris [Letter]. Circulation. 1976; 54: Taylor HA, Deumite NJ, Chaitman BR, Davis KB, Killip T, Rogers WJ. Asymptomatic left main coronary artery disease in the Coronary Artery Surgery Study (CASS) registry. Circulation. 1989;79: Detre K, Peduzzi PH, Murphy M, et al. Effect of bypass surgery on survival in patients in low- and high-risk subgroups delineated by the use of simple clinical variables. Circulation. 1981;63: Gersh BJ, Kronmal RA, Schaff HV, et al. Comparison of coronary artery bypass surgery and medical therapy in patients 65 years of age or older. A nonrandomized study from the Coronary Artery Surgery Study (CASS) registry. N Engl J Med. 1985;313: Hammermeister KE, DeRouen TA, Dodge HT. Comparison of survival of medically and surgically treated coronary disease patients in Seattle Heart Watch: a nonrandomized study. Circulation. 1982; 65: Edmunds LH Jr, Stephenson LW, Edie RN, Ratcliffe MB. Openheart surgery in octogenarians. N Engl J Med. 1988;319: Gersh BJ, Kronmal RA, Frye RL, et al. Coronary arteriography and coronary artery bypass surgery: morbidity and mortality in patients ages 65 years or older. A report from the Coronary Artery Surgery Study. Circulation. 1983;67: Kindwall KE. Therapy for coronary heart disease in women. Cardiovasc Clinics. 1989;19: Wenger NK. Coronary heart disease in women: clinical syndromes, prognosis, and diagnostic testing. Cardiovasc Clinics. 1989;19: Gruppo Italiano per lo Studio della Streptochinasi nell'infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1: Gruppo Italiano per lo Studio della Streptochinasi nell'infarto Miocardico (GISSI). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet. 1987;2: Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J Cardiol. 1979;44: Puletti M, Sunseri L, Curione M, Erba SM, Borgia C. Acute myocardial infarction: sex-related differences in prognosis. Am Heart J. 1984;108: Toiler GH, Stone PH, Muller JE, et al. Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women, particularly black women. J Am Coll Cardiol. 1987;9: Tyras DH, Barner HB, Kaiser GC, Codd JE, Laks H, Willman VL. Myocardial revascularization in women. Ann Thorac Surg. 1978;25: Fisher LD, Kennedy JW, Davis KB, et al. Association of sex, physical size, and operative mortality after coronary bypass in the Coronary Artery Surgery Study (CASS). J Thorac Cardiovasc Surg. 1982;84: Loop FD, Golding LR, Macmillan JP, Cosgrove DM, Lyttle BW, Sheldon WC. Coronary artery surgery in women compared with men: analyses of risks and long-term results. J Am Coll Cardiol. 1983;1: Cowley MJ, Mullin SM, Kelsey SF, et al. Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA registry. Circulation. 1985;71: Bonow RO, Kent KM, Rosing DR, et al. Exercise-induced ischemia in mildly symptomatic patients with coronary-artery disease and preserved left ventricular function. Identification of subgroups at risk of death with medical therapy. N Engl J Med. 1984;311: Weiner DA, Ryan TJ, McCabe CH, et al. Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease. J Am Coll Cardiol. 1984;3: Weiner DA, Ryan TJ, McCabe CH, et al. The role of exercise testing in identifying patients with improved survival after coronary artery bypass surgery. J Am Coll Cardiol. 1986;8: Brown KA, Boucher CA, Okada RD, Newell J, Strauss HW, Pohost GM. The prognostic value of serial exercise thallium-201 imaging in patients presenting for evaluation of chest pain: comparison to contrast angiography, exercise electrocardiography and clinical data [Abstract]. Am J Cardiol. 1982;49: Jones RH, Floyd RD, Austin EH, Sabiston DC Jr. The role of radionuclide angiography in the preoperative prediction of pain relief and prolonged survival following coronary artery bypass grafting. Ann Surg. 1983;197: Beller GA, Gibson RS, Watson DD. Radionuclide methods of identifying patients who may require coronary bypass surgery. Circulation. 1985;72(Suppl V):V Gibson RS, Watson DD, Craddock GB, et al. Prediction of cardiac events after uncomplicated myocardial infarction: a prospective study comparing predischarge exercise thallium-201 scintigraphy and coronary angiography. Circulation. 1983;68: Campeau L, Bourassa MG, Enjalbert M, Lesperance J. Improvement of angina and survival 1 to 12 years after aortocoronary bypass surgery: correlations with changes in grafts and in the native coronary circulation. Heart Transplantation. 1984;3: The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina. N Engl J Med. 1984;311: Campeau L, Enjalbert M, Lesperance J, et al. The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation. A study 10 years after aortocoronary bypass surgery. N Engl J Med. 1984;311: Chesebro JH, Clements IP, Fuster V, et al. A platelet-inhibitor-drug trial in coronary-artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency. N Engl J Med. 1982;307: Loop FD, Lytle BW, Cosgrove DM, et al. Influence of the internalmammary-artery graft on 10-year survival and other cardiac events. N Engl J Med. 1986;314: Cameron A, Davis KB, Green GE, Myers WO, Pettinger M. Clinical implications of internal mammary artery bypass grafts: the Coronary Artery Surgery Study experience. Circulation. 1988;77: Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Quality of life in patients randomly assigned to treatment groups. Circulation. 1983;68: Willerson JT. Selection of patients for coronary arteriography. Circulation. 1985;72:V Dimas A, Loop F, Whitlow P, et al. Treatment strategy for coronary artery disease: a balancing act. Clev Clin J Med. 1990;57: Talley JD, Hurst JW, King SB 3d, et al. Clinical outcome 5 years after attempted percutaneous transluminal coronary angioplasty in 427 patients. Circulation. 1988;77: Detre K, Holubkov R, Kelsey S, et al. One-year follow-up results of the National Heart, Lung and Blood Institute's Percutaneous Transluminal Coronary Angioplasty Registry. Circulation. 1989;80: King SB 3d. Percutaneous transluminal coronary angioplasty: the second decade. Am J Cardiol. 1988;62:2K-6K. 81. Vogel RA. The Maryland experience: angioplasty and valvuloplasty using percutaneous cardiopulmonary support. Am J Cardiol. 1988; 62:11K-14K. 82. Shawl FA. Percutaneous cardiopulmonary support in high-risk angioplasty. Cardiol Clin. 1989;7: June 1991 Annals of Internal Medicine Volume 114 Number