Indications for Coronary Revascularization

	INTRODUCTION

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In the three and a half decades since coronary artery bypass (CABG) surgery was popularized¹ and the 25 years since the introduction of coronary angioplasty,² an enormous volume of data has been collected concerning the results of invasive revascularization. Remarkably, from the outset, many of these studies have been prospectively randomized. Equally remarkable is the dearth of data concerning pharmacologic therapies for chronic coronary artery disease despite remarkable progress in the area. For example, although nitrates are unquestionably effective in relieving symptoms, the impact of long-acting nitrates on clinical outcomes has never been rigorously tested. Furthermore, there has been only one trial of beta-blocker therapy in the treatment of angina, the Atenolol Silent Ischemia Study (ASIST) study, which demonstrated benefit for patients with mild effort-induced angina or silent ischemia.³ A handful of studies of combination therapy with beta blockers and calcium channel blockers have also demonstrated antianginal benefit.^4–6 Most recently randomized trials of two new drugs, Nicorandil and Ranolazine, have been reported.^7,8 Beyond these, however, few studies of medical therapy alone have been performed.

	CLINICAL AND LABORATORY ASSESSMENT OF CORONARY ARTERY DISEASE

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A surgeon's first introduction to a patient with coronary artery disease is frequently an angiogram. In addition to the coronary anatomy, however, the clinical presentation as well as the results of noninvasive studies of myocardial perfusion and function are necessary to characterize the pathophysiologic implications of the angiographic disease and its impact on prognosis.

The system proposed by the Canadian Cardiovascular Society for grading the clinical severity of angina pectoris is widely accepted (Table 19-1).⁹ Unfortunately, angina is a highly subjective phenomenon for both patient and physician, and prospective evaluation of the assessment of functional classification by the CCS criteria has demonstrated a reproducibility of only 73%.¹⁰ Furthermore, there may be strikingly poor correlation between symptoms and ischemia, as is notoriously the case among diabetic patients with asymptomatic "silent ischemia."

Perfusion imaging with thallium-201 or a technetium-99m tracer may be particularly useful in patients with abnormalities on their baseline ECG. A demonstration of reversible defects by comparison of images obtained after injection of the tracer at peak stress with rest images is indicative of ischemia, and hence viability. An irreversible defect indicates nonviable scar.^17,18 The results obtained with both tracers are similar, with the average sensitivity around 90% and specificity of approximately 75%.¹³ For patients unable to exercise, pharmacologic vasodilators such as adenosine or dipyridamole may be used with similar sensitivity.^19–23

Echocardiographic imaging during exercise or during pharmacologic stress has gained increasing popularity among cardiologists. Comparative studies have demonstrated accuracy similar to nuclear studies^12,24,25 with sensitivity and specificity both around 85%.¹³ Patients unable to exercise may be stressed with high-dose dipyridamole^26,27 or more commonly dobutamine at doses from 5 to 40 µg/kg/min.^13,26,27 An initial augmentation of contractility followed by loss or "drop out" is diagnostic of ischemia (and accordingly viability), while failure to augment contractility at low dose suggests scar.^18,28,29

	GUIDELINES FOR REVASCULARIZATION

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The guidelines for surgical revascularization have been established by the American College of Cardiology and American Heart Association as shown in Table 19-2.³⁰ The basis for these guidelines resides in the large body of literature comparing medical therapy with surgical revascularization and, more recently, percutaneous transluminal coronary angioplasty (PTCA).

Secondly, as a consequence of the overrepresentation of patients at lowest risk of death in randomized trials, most are statistically underpowered with respect to survival analysis. They therefore frequently employ softer end points such as angina or quality of life, or composite end points of death and myocardial infarction (MI). This is further complicated by relatively short-term follow-up in most studies. Since events such as the need for subsequent revascularization characteristically occur at different time intervals after these therapies (restenosis after PTCA vs. graft occlusion after CABG), an 8- to 10-year follow-up period is needed to adequately compare long-term results.

Finally, significant improvements in each of these treatment strategies are occurring constantly. Examples include the use of antiplatelet agents,³³ angiotensin-converting enzyme inhibitors, intravascular stents,³⁴ internal thoracic aortic grafts, and most recently the impressive beneficial effect of lipid-lowering therapy on the subsequent incidence of coronary events.^35,36 These advances along with aggressive risk factor modifications have steadily reduced the morbidity and mortality of coronary artery disease, making differences in the hard end points of survival difficult to demonstrate for any therapy.³⁷

	COMPARATIVE TRIALS OF REVASCULARIZATION VS. MEDICAL THERAPY IN STABLE ANGINA

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Surgical vs. Medical Therapy

Three major randomized studies, Coronary Artery Surgery Study (CASS),³⁸ the Veterans Administration Cooperative Study Group (VA),^39,40 and the European Coronary Surgery Study (ECSS),^41,42 as well as several other smaller randomized trials conducted between 1972 and 1984^43–45 provide the most reliable outcome data comparing medical and surgical therapy. Despite the limitations noted above, these studies are remarkably consistent in their major findings and the qualitative conclusions drawn from them can continue to be generalized to our current practice.

The central message from all of these studies is that the relative benefits of bypass surgery over medical therapy on survival are greatest in those patients at highest risk as defined by the severity of angina and/or ischemia, the number of diseased vessels, and the presence of left ventricular dysfunction (Figure 19-1). ^39,46,47

View larger version (25K): [in this window] [in a new window]   FIGURE 19-1 The decision regarding mode of therapy for coronary artery disease depends upon the individual patient's prognosis as determined by both cardiac and noncardiac conditions.

A meta-analysis of the seven randomized trials cited above demonstrated a statistically enhanced survival at 5, 7, and 10 years, for surgically treated patients at highest risk (4.8% annual mortality) and moderate risk (2.5% annual mortality), but no evidence of a survival benefit for those patients at lowest risk.⁴⁶ The overall survival benefit at 12 years for the three large and four smaller randomized studies is shown in Figure 19-2. Nonrandomized studies have also demonstrated a beneficial effect of surgery on survival of patients with multivessel disease and severe ischemia regardless of left ventricular function.^50–53

View larger version (17K): [in this window] [in a new window]   FIGURE 19-2 Survival (mortality) curves for all medically and surgically treated patients with chronic stable angina enrolled in seven prospective, randomized, controlled trials. (Reproduced with permission from Yusuf S, Zucker D, Peduzzi P, et al: Effect of coronary artery bypass graft surgery on survival: overview of ten-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialist Collaboration. Lancet 344:563, 1994.)

Early concern over a prohibitive operative mortality among patients with impaired ventricular function has been superseded by the recognition that the survival of these patients on medical therapy was much worse than their survival with revascularization. This, coupled with ever improving surgical techniques, such as advances in myocardial preservation and perioperative support, has made this specific subgroup the one in which the relative survival benefit of surgical therapy is the greatest. Accordingly, left ventricular dysfunction in patients with documented ischemia is now considered an important indication—rather than a contraindication—for surgical revascularization.^{38,46,50,56,57} Recent evidence that ischemic, viable, hypokinetic myocardium (hibernating or stunned) regains stronger contractile function following effective revascularization has prompted expansion of the indications for surgical revascularization among patients with severe left ventricular dysfunction to include patients who would otherwise be considered candidates for cardiac transplantation. This subject is discussed in more detail below.

In summary, a survival advantage is demonstrable for surgical revascularization over medical therapy in patients with left main disease,⁵⁸ those with triple-vessel disease and left ventricular dysfunction,^59,60 those with two-vessel disease and proximal LAD disease,⁶¹ and in patients with severe ischemia and multivessel disease (Figure 19-3).^62,63 Those survival advantages have not been demonstrable among patients with single-vessel disease.^64–66

View larger version (20K): [in this window] [in a new window]   FIGURE 19-3 Extension of survival in months for various subgroups of patients with chronic stable angina treated by surgery as compared with those treated by medicine in seven prospective, randomized, controlled trials. (Reproduced with permission from Yusuf S, Zucker D, Peduzzi P, et al: Effect of coronary artery bypass graft surgery on survival: overview of ten-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialist Collaboration. Lancet 344:563, 1994.)

Unfortunately, few patients experience an advantage in work rehabilitation with surgery as compared with medical management. Generally, employment declines in both groups and is determined nearly as much by socioeconomic factors as age, preoperative unemployment, and type of job as by type of therapy or clinical factors such as postoperative angina. Notably, surgical revascularization has not been shown to reduce the incidence of nonfatal events such as myocardial infarction (MI) although this may be due to perioperative infarctions that offset the lower incidence of infarction in each study follow-up.^51,67

PTCA vs. Medical Therapy

Despite the increasing application of catheter-based technology to multivessel disease, the majority of interventions have been historically in single-vessel disease.³² Accordingly, most of the data comparing angioplasty with medical therapy are derived from studies comprised principally or exclusively of patients with a limited extent of obstructive disease, although most people with angiographically detectable stenosis in one vessel have more extensive atherosclerotic changes throughout most of their coronary vessels. Also, many of these trials antedate the use of IIb/IIIa inhibitors, clopidegrel, and stents. Although angiographic success rates of 85% to 90% are commonplace, no study to date has ever shown a benefit in survival or subsequent MI for PTCA over medical therapy in patients with stable angina pectoris. The results of several recent studies have, however, demonstrated improvement in symptoms and exercise tolerance.

In the Angioplasty Compared with Medical Therapy-I (ACME-I) study, 212 patients with documented ischemia and a single coronary artery stenosis greater than 70% were randomly assigned to medical therapy or angioplasty.⁶⁸ After six months, there was no mortality difference in either treatment group; however, PTCA provided more complete angina relief with fewer medications and better quality of life scores as well as longer exercise duration on stress testing than medical therapy.⁶⁸ This benefit came at some cost, however; among the 100 angioplasty patients, 19 underwent repeat PTCA and 7 needed CABG surgery during the first six months, compared with 11 angioplasty procedures and no CABG surgery in the patients randomized to medical therapy.⁶⁸ Moreover, nearly half of all patients assigned to initial medical therapy were asymptomatic at six months. Because this modest symptomatic benefit was achieved at such a large procedural and financial cost, patients who are either asymptomatic or have mild symptoms should have objective evidence of ischemia prior to PTCA.⁶⁹ In a follow-up study by the same investigators, 101 patients with stable angina and two-vessel disease were randomized to PTCA or medical therapy.⁷⁰ At six months, both groups had similar improvement in exercise duration, freedom from angina, and overall quality of life. These studies together suggest that, in many patients, an initial trial of medical therapy is appropriate.

Several more recent studies have included patients with multivessel disease. In the Randomized Intervention Treatment of Angina-2 (RITA-2) trial, of 1018 patients with stable angina randomized to medicine or PTCA one third had two-vessel disease and 7% had three-vessel disease. At a median follow-up of 2.7 years, the primary end points of death or MI had occurred twice as often in the PTCA group (6.3 vs. 3.3%, p < .02). Surgical revascularization was required during the follow-up interval in 7.9% of the PTCA group, and repeat angioplasty was required in 11%. In the medical group, 23% of patients required revascularization. Angina relief and exercise tolerance were improved to a greater degree in the angioplasty group early, but this difference disappeared by three years.⁷¹ Again, this supports an initial strategy of medical therapy.

Finally, PTCA and medicine as initial strategy were compared among patients with hyperlipidemia in the Atorvastatin vs. Revascularization Trial (AVERT).⁷² Among 341 patients with single- or double-vessel disease, ischemic events were actually less common in the medical than in the PTCA groups (13% vs. 21%, p < .05). Although criticized for employing outdated angioplasty technology and other issues, the results of this study are consonant with the recent demonstration that lipid-lowering agents may have a powerful impact on ischemic events.^73–75

PTCA vs. CABG

RANDOMIZED STUDIES

A number of studies comparing an initial strategy of angioplasty versus early surgery have been carried out, all with similar results. It is important to recognize that these studies are comparisons of treatment strategies and not head-to-head comparisons of revascularization techniques. Accordingly, crossover is permitted and end points are selected to determine adverse consequences of the algorithm.

A single-center Swiss study of 134 patients with isolated LAD disease was reported in 1994.⁴⁹ At 2.5 years of follow-up there was no significant difference in combined outcomes of MI and cardiac death between treatment groups. There was, however, a greater need for surgical revascularization in the initial PTCA treatment group with 25% requiring a second revascularization procedure compared with only 4.4% in the initial CABG group. Although the PTCA patients were taking significantly more antianginal medication, clinical impairment level, stress test performance, and quality of life indices did not differ at 2 years. These findings held up at 5 years⁷⁶ with no difference between groups with respect to mortality or functional outcome but more repeat procedures in the PTCA group.

The Medicine, Angioplasty or Surgery Study (MASS) from Brazil compared medical therapy, PTCA, and CABG using an internal thoracic artery bypass at a single center in 214 patients with stable angina, normal left ventricular function, and proximal stenosis of the left anterior descending coronary artery.⁴⁸ In this relatively small but nonetheless important randomized trial, the combined end point of cardiac death, MI, or refractory angina requiring revascularization was statistically significantly less in surgically treated patients. Moreover, there was no significant difference between patients treated medically or with PTCA. In comparison with medical therapy, however, both PTCA and CABG surgery were shown to provide improved relief of severe symptoms of angina pectoris and a lower frequency of inducible ischemia on treadmill exercise testing. There was no difference among the three strategies at the end with respect to mortality or late MI. Similar findings were obtained at 5-year follow-up.⁷⁷

The results of the second MASS trial, which enrolled 611 patients with multivessel disease, have been reported in abstract form.⁷⁸ Although technology is a moving target, this trial has the advantage that approximately 70% of PTCA patients had stents placed. Despite this, at one year the medical treatment group had a lower incidence of adverse events and actually had superior angina relief to the PTCA group. Surgical therapy provided the best angina relief and lowest incidence of adverse events.

A number of larger prospectively randomized studies comparing PTCA with CABG have been reported in recent years. All share the limitation that, in general, only a very small minority of patients undergoing revascularization at any center were entered into these trials.^79,80 Accordingly the populations included in the trials may not be generally reflective of clinical practice. For instance, few patients in these studies had significant LV dysfunction, and most randomized patients had only one- or two-vessel disease. In the RITA trial, approximately one third of patients had single-vessel disease.⁸¹ Among clinically eligible patients in the Bypass Angioplasty Revascularization Investigation (BARI)⁶⁴ trial and Emory Angioplasty versus Surgery Trial (EAST),⁶⁵ approximately two thirds of patients were excluded on angiographic grounds that included chronic total occlusion, left main coronary artery stenosis, diffuse disease, or other anatomic factors making PTCA potentially dangerous.^64,65 Consequently these randomized trials contain only a portion of the spectrum of patients with coronary artery disease encountered clinically.

This has an obvious impact on the likelihood of observing an outcome difference between therapies. As a high proportion of the randomized patients are in the low-risk group, in whom no survival advantage could be demonstrated when CABG surgery was compared with medical therapy in the earlier CAST, ECSS, and VA surgery randomized trials,^38–41 it is possible that any potential survival benefit of CABG surgery over PTCA in high- and moderate-risk groups may be masked.⁸⁰

A second consideration in evaluating these studies is that the success of revascularization procedures depends not only on the criteria employed to define success, but also on the interpretation of those criteria by both patient and physician. In the 1985–1986 National Heart, Lung and Blood Institute PTCA Registry, 99% of patients were discharged alive from hospital and 92% did not sustain a MI or require CABG surgery.³¹ In the most recent BARI trial, 99% of patients survived hospitalization and 88.6% of PTCA-treated patients did not have MI or require repeat revascularization by angioplasty or surgery during the initial hospitalization.⁶⁴ Employing event-free criteria (death, MI, CABG) for the initial hospitalization, PTCA can be judged successful. However, if a repeat revascularization procedure within five years is regarded as a negative outcome, then only 45.5% of PTCA treated patients are treated successfully.⁶⁴ Regardless, the lack of differences in mortality or MI rates permits individuals to select one or the other procedure as initial therapy without the likelihood that they will pay a serious price.

In the BARI, EAST, Coronary Artery Bypass Revascularization Investigation (CABRI), German Angioplasty Bypass Surgery Investigation (GABI), and RITA multivessel PTCA versus CABG surgery trials,^64,65,81,82 mortality and recurrent MI were generally low and similar between 1 and 5 years of follow-up in both the PTCA and CABG treatment groups. Mortality ranged from 3% in the CABRI trial at 1-year follow-up⁶⁵ and 3.4% in the RITA trial at 2.5 years⁸¹ to 13% in the BARI trial at 5 years.⁶⁴ A similar but slightly higher incidence for MI was noted in some of these trials.

The incidence of repeat revascularization is higher among patients treated with angioplasty than with surgery in all trials carried out to date (Fig. 19-4). The incidence of repeat revascularization in the PTCA-treated patients ranged from 36.5% in the CABRI trial at 1-year follow-up to 62% in the EAST trial at 3 years. The repeat revascularization rate in the EAST trial for angioplasty-treated patients was much higher than that noted in the BARI, CABRI, and RITA trials. There was a concentration of repeat revascularization procedures in trials that required a stress thallium and angiography studies at 1 year; thus some of these procedures may have occurred in the EAST trial as a consequence of protocol-mandated tests rather than clinical indications.²⁰ In contrast to PTCA, repeat revascularization is less common after CABG in these same studies. The incidence of repeat revascularization procedures in multivessel patients randomized to CABG surgery ranged from 3.5% in the CABRI trial to 13.5% in the EAST trial. Generally, repeat revascularization procedures were required 5 to 8 times more often in patients with multivessel disease initially treated with angioplasty as compared with those randomized to initial CABG surgery. The incidence of angina at follow-up also was generally greater in the PTCA-treated patients than in those randomized to CABG surgery.

View larger version (23K): [in this window] [in a new window]   FIGURE 19-4 Risk of repeat revascularization in six randomized trials of PTCA versus CABG surgery. (See refs. 64, 81, 65, 82, and 83 for explanation of acronyms.)

Several more recent studies of PTCA versus surgery have confirmed these findings. The Argentine Randomized Trial of Coronary Angioplasty vs. Bypass Surgery in Multivessel Disease (ERACI) trial conducted between 1998 and 1990 demonstrated no difference in death or MI, but superior event-free survival in the CABG group at 1 and 3 years.^83,84 In the French Monocentric Study, 152 patients with multivessel disease underwent PTCA or CABG.⁸⁵ Again superior event-free survival was seen in the surgical group, driven predominantly by a lesser need for subsequent revascularization.

The impact of stent technology on the comparative results of PTCA and CABG has been recently investigated. In the Arterial Revascularization Therapy Study (ARTS), 1205 patients with multivessel disease underwent CABG or PTCA with stents.⁸⁶ No significant differences in the primary end point of freedom from death, stroke, or MI at one year were observed, although the need for revascularization remained higher in the angioplasty than surgery groups. A similar study was performed by the ERACI-2 study group⁸⁷; however, in this study, 30-day mortality was higher in the CABG than in the PTCA group, as was the incidence of Q-wave MI. Repeat revascularization rates were not compared. A concern about the study was the relatively high operative mortality rate (5.7%) in the surgery group as compared with the angioplasty group. The findings of the Surgery or Stent (SOS) study, which compared outcomes in 900 patients with multivessel disease, demonstrated lower all-cause mortality among surgical than angioplasty patients and confirmed higher rates of repeat revascularization after angioplasty.⁸⁸ Of particular interest in this study was the reintervention rate, which while still higher than after surgery, was far below that previously reported for angioplasty at only 17%.

It is important to recognize that recent progress in stent technology promises to further reduce the incidence of restenosis, narrowing the gap in late outcome between PTCA and CABG. It is possible that we are on the cusp of a revolution in catheter-based technologies. The use of stents has certainly reduced adverse remodeling,⁸⁹ and recent antimitotic drug-eluting stents appear to reduce the restenosis rates even further. The early results with rapamycin suggest that restenosis can be virtually eradicated.⁹⁰ Other antimitotic drugs are being tested as well, but results are only preliminary.

In conclusion, the randomized trials of PTCA versus CABG are useful, but only if results are interpreted in the context of the types of patients entering or eligible to enter these trials.^79,80 PTCA is a reasonable alternative to CABG surgery, and for many patients is the preferred initial approach, provided the patient understands that there is a higher incidence of recurrent angina and need for repeat revascularization procedures. This applies to patients with multivessel disease and preserved left ventricular function in the main. For most patients similar to those included in these published trials, it is reassuring that a nonsurgical revascularization procedure does not place them at increased risk of MI or death in comparison with the outcomes of surgical therapy. Extrapolating these results to patients who are not eligible for entry is intellectually flawed and potentially misleading, however.

NONRANDOMIZED DATABASE COMPARISONS

Additional information on the long-term outcome of coronary angioplasty and CABG surgery in patients may be obtained from large, prospectively managed, unrandomized database studies. In the Duke Cardiovascular Disease Databank, 9263 patients undergoing clinically indicated coronary angiography between 1984 and 1990 were followed a mean of 5 years after nonrandomized treatment by CABG, PTCA, or medical therapy.³² Patients with valvular disease, prior revascularization, significant (more than 75%) left main disease, and congenital and nonischemic cardiomyopathy were excluded. Overall, 39% of the patients had single-vessel disease, 31% two-vessel disease, and 30% three-vessel disease. Initial therapy was medical in 3053 patients, PTCA in 2788 patients, and CABG in 3422 patients. To correct for baseline differences among treatment groups, a standard covariate adjustment was performed that included all identified prognostic factors in a multivariate survival model. Complete follow-up was obtained in 97% of patients. The 5-year survival was 91%, remarkably similar to that reported from Emory, which showed an overall adjusted 5-year survival rate of 93% in both groups.⁵⁷ The mortality hazard ratios derived from the Cox regression model to evaluate relative survival differences in this database study are shown for medicine versus CABG surgery in Figure 19-5, PTCA versus medicine in Figure 19-6, and PTCA versus CABG in Figure 19-7.³²

View larger version (19K): [in this window] [in a new window]   FIGURE 19-5 Hazard (mortality) ratios for CABG surgery versus medicine calculated from the Cox regression model to evaluate relative survival differences. Points indicate hazard ratios for each level of a weighted (0 to 100), hierarchical, prognostic coronary artery disease index. Bars indicate 99% confidence intervals. Horizontal line at 1.0 indicates point of prognostic equivalence between treatments. Hazard ratios below this line favor CABG; those above the line favor medicine. VD, vessel disease; Prox LAD, proximal left anterior descending coronary artery. (Reproduced with permission from Mark DB, Nelson CL, Califf RM, et al: Continuing evolution of therapy for coronary artery disease; initial results from the era of coronary angioplasty. Circulation 89:2015, 1994.)

View larger version (19K): [in this window] [in a new window]   FIGURE 19-6 Hazard ratios for PTCA versus medicine. See Fig. 19-5 for explanation. Points below the horizontal line favor PTCA. (Reproduced with permission from Mark DB, Nelson CL, Califf RM, et al: Continuing evolution of therapy for coronary artery disease; initial results from the era of coronary angioplasty. Circulation 89:2015, 1994.)

View larger version (19K): [in this window] [in a new window]   FIGURE 19-7 Hazard ratios for CABG surgery versus PTCA. See Fig. 19-5 for explanation. Points below the horizontal line favor CABG (not PTCA as mislabeled). (Reproduced with permission from Mark DB, Nelson CL, Califf RM, et al: Continuing evolution of therapy for coronary artery disease; initial results from the era of coronary angioplasty. Circulation 89:2015, 1994.)

	SPECIAL CIRCUMSTANCES

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Acute Coronary Syndromes

The acute coronary syndromes (ACS) cover a wide spectrum from ST-segment elevation MI with underlying coronary obstruction or Prinzmetal's to variant angina in patients with coronary vasospasm in the absence of significant underlying obstruction. The rubric of the non–ST-segment elevation ACS encompasses the entities of unstable angina, non–Q-wave MI, and postinfarction angina. They denote acute, symptomatic changes in the myocardial oxygen supply demand ratio over a short time span. Prinzmetal's angina, or coronary vasospasm, is diagnosed definitively by electrocardiograms obtained during the episode of pain and is treated medically. Unstable angina is not a uniform clinical entity but describes the spectrum of myocardial ischemia between chronic stable angina and MI. Unstable angina implies a recent change in the severity, character, or trigger threshold of chronic stable angina or new onset angina. Approximately 5.6 million Americans have chronic angina, and about 350,000 develop new angina each year.⁹¹ Unstable angina develops in approximately 750,000 Americans each year and is associated with subsequent MI in approximately 10%. Postinfarction angina is defined as the presence of angina or other evidence of myocardial ischemia in a patient with a recent (one to two weeks) Q-wave or non–Q-wave MI.

Unstable and postinfarction angina are classified into subsets according to the triggering stimulus (A-C) and frequency of pain (I-III).⁹² Class A indicates angina precipitated by an extracardiac or indirect stimulus such as an arrhythmia or hypotension that can be reversed by medical management. Class B indicates angina without an extracardiac or indirect stimulus, and class C indicates angina in the presence of acute MI. Class I is new or accelerated angina without pain at rest. Class II is angina at rest within one month but not within 48 hours. Class III is angina at rest within 48 hours.

The initial approach to the patient with non–ST-segment elevation ACS is pharmacologic stabilization followed by risk stratification. The latter is based upon multiple clinical, demographic, and ECG variables in addition to the use of serum biomarkers. In institutions with facilities for early angiography, patients at intermediate or high risk (the majority) undergo early angiography with a view to revascularization. In many parts of the world, however, angiographic facilities are limited and an alternative approach based upon pharmacologic stabilization followed by mobilization and risk stratification utilizing stress testing is employed.

The most recent randomized controlled trials of aggressive versus conservative approaches to non–ST-segment elevation ACS are the second Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II), Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS), and Value of First Day Angiography/Angioplasty in Evolving Non-ST Segment Elevation Myocardial Infarction: Open Multicenter Randomized Trial (VINO) trials.^93–95 Despite differences between these trials, the results favor an aggressive strategy with a view towards revascularization in the majority of the patients shown to be at high risk (e.g., older patients, diabetics, those with ST-segment depression on ECG, and those with elevated CPK-MB or serum troponins).

CABG VS. MEDICAL THERAPY

The technical advances in PTCA in the setting of ACS have relegated CABG largely to a secondary position in most acute cases. The special circumstances of postinfarction mechanical complications of papillary muscle rupture, ventricular septal defect, and shock are specifically treated in other chapters of this text. It should be noted, however, that two multicenter trials and one single-center randomized trial involving a total of 823 patients have evaluated the relative merits of CABG surgery and medical therapy in unstable angina between 1972 and 1982.^96–98 Patients with left main disease, poor left ventricular function (ejection fraction less than 30%), and those over age 70 were not included. In the VA cooperative study, improved survival and a lower rate of recurrent angina were shown with surgery, and at both 5 and 8 years there were fewer subsequent hospitalizations in the surgical group for cardiac reasons.⁹⁶ Interestingly, there was no difference in progression to Q-wave MI between medical and surgical groups.⁹⁶ Like the VA study, the National Cooperative Study Group Trial⁹⁷ showed no difference in progression to Q-wave MI and less severe subsequent angina with operation. Unlike the VA trial, however, there was no survival difference at two years (90% in both groups). Of note, 32% of the medical group crossed over to surgery by 24 months. As current medical therapy was not available to these patients, there is significant difficulty in extrapolating the results of these trials to current clinical practice. Finally, Bertolasi et al reported a single-center study of 113 patients, which demonstrated less subsequent angina, fewer infarctions, and a survival benefit for surgery in short-term follow-up.⁹⁸

Among patients with unstable angina or non–Q-wave MI, medical management followed by earlier delayed PTCA or CABG resulted in 6-week mortality and nonfatal MI rates of 2.1% and 6.1% in the Thrombolysis in Myocardial Ischemia (TIMI)-IIIB trial involving 1473 patients.⁹⁹ This study compared the results of a strategy of initial stabilization and an aggressive arm involving routine angiography followed by revascularization in the presence of suitable anatomy with a conservative arm reserving angiography for those with recurrent angina or a positive stress test. At 42-day and 1-year follow-up there was no difference in death or MI between the two groups. Subsequent subset analyses have demonstrated a trend in favor of an aggressive approach to revascularization over medical therapy in patients at higher risk as characterized by an elevated CPK-MB fraction (non–Q-wave MI).⁹⁹ Somewhat surprisingly, revascularization rates were similar, with only the timing of that revascularization event being different. The addition of thrombolytic therapy in these patients is not beneficial and may be harmful.

The Veterans Affairs Non-Q-Wave Infarcts and Strategies in Hospitals (VANQWISH) trial¹⁰⁰ had a similar design to TIMI-IIIB. In this study, however, a higher early mortality rate was observed in the invasive group than in the medical group, possibly due to the extraordinarily high perioperative mortality rate of 7.7% in the CABG group. The opposite result was found in the FRISC II.⁹³ These investigators found a benefit with early revascularization, particularly among patients with elevated troponin. The reasons for such different results among these studies is likely due to differences in patient populations studied. It is likely that the higher-risk patients benefit from an aggressive approach, while lower-risk patients have less to gain and so are more likely to suffer adverse consequences.

PTCA FOR ACUTE MYOCARDIAL INFARCTION

Because of the rapidity with which vessel patency can be restored using percutaneous techniques, PTCA has all but replaced CABG in the setting of acute MI. Both thrombolytic therapy and direct or primary angioplasty can restore coronary artery patency and flow during acute MI, but multiple randomized controlled trials have demonstrated the superiority of PTCA when performed promptly. In the absence of hemorrhagic concerns, however, thrombolytic therapy is more widely available and is standard early therapy for acute transmural MI when immediate angioplasty is unavailable.

Several early myocardial reperfusion trials have assessed the role of routine adjunctive angioplasty, given that not all arteries can be reopened by thrombolysis, that reocclusion occurs in some arteries initially opened, and that reocclusion is associated with increased morbidity and mortality.^101,102 In these studies the addition of routine angioplasty to thrombolytic therapy did not enhance patency, improve left ventricular function, or reduce early mortality in comparison with a more conservative approach of ischemia-driven angiography, but did increase expense and vascular bleeding problems.^103–105 A meta-analysis of adjunctive PTCA and thrombolysis versus thrombolysis showed no early benefit of PTCA except in patients who have clinical indications for early revascularization (e.g., postinfarction angina).¹⁰⁶ These studies were performed in an early phase of PTCA, however, and the addition of stents as well as IIb/IIIa inhibitors and new lytics have more recently renewed interest in a combined strategy.

Asymptomatic Coronary Artery Disease

The role of revascularization, either by PTCA or CABG, versus medical therapy in the setting of asymptomatic coronary artery disease has been studied in the ACIP trial.¹⁰⁷ Of 558 patients with coronary artery disease and medically controlled angina, treatment was randomized to revascularization or medical therapy directed toward eliminating angina or eliminating ischemia during ambulatory ECG. Revascularization was more effective than medical therapy in relieving ischemia, and CABG was superior to PTCA (70% freedom from ischemia vs. 46%, p < .002). Mortality at one and two years was superior for revascularization as compared with angina-directed medical therapy, but not superior to ischemia-directed medical therapy.^55,108 The greatest benefit was among those patients with the most severe disease.

The documentation of ischemia, however, is critical. Several studies emphasize the flaws in the assumption that one can identify future culprit lesions in the absence of symptoms or documentation of ischemia.¹⁰⁹ Among patients undergoing serial coronary arteriography who subsequently developed acute MI or unstable angina, the severity of stenosis at the time of initial angiogram is poorly predictive of the culprit lesion causing the acute ischemic syndrome.^109–112 In most cases the severity of the lesion responsible for subsequent ischemia was less than 50%, and in many patients it was not present at all on the initial angiogram. The lack of benefit of prophylactic revascularization incidentally raises concern regarding the number of patients undergoing angioplasty who have not undergone stress testing to document objective evidence of ischemia when severe symptoms at the time of presentation were absent.¹¹³ Bech et al have demonstrated that fractional flow reserve exceeded 0.75 in 91 of 325 patients planned for PTCA without noninvasive evaluation of ischemia, and that among those patients angioplasty had no impact on event-free survival or angina.¹¹⁴

The Elderly

Age is a predictor of operative risk in most models, but is also a predictor of poor outcome with medical therapy in the presence of coronary artery disease. The Swiss TIME trial was recently reported.⁵⁴ In this study, 301 patients over the age of 75 were randomized to medical therapy with or without invasive evaluation. Of those undergoing angiography, two thirds had revascularization. Among those not initially assigned to invasive evaluation, one third had revascularization at some time during the study interval. Approximately two thirds of revascularizations were PTCA. During the 6-month follow-up interval, adverse events (death, MI, rehospitalization) occurred in one half of those assigned to initial therapy without invasive evaluation and in one fifth of the other group. These data suggest that invasive evaluation should be offered to the elderly who are symptomatic on adequate medical therapy.

The choice of mode of revascularization will be particularly impacted in this group of patients by the presence of comorbidities that may increase the risk of surgical intervention, such as cerebrovascular disease, renal dysfunction, and pulmonary disease. The impact of a reduction in operative morbidity through "off-pump" coronary bypass on this choice is as yet unclear. There are an increasing number of studies to suggest that "off-pump" surgery offers its greatest advantage over conventional surgery in just this group of patients with comorbid conditions (see Ch. 22). The majority of these studies are not randomized, however, making their results less conclusive than one would hope. A recently published randomized trial from the Netherlands demonstrated slightly improved neurocognitive outcomes among off-pump patients at 3 months, but this difference became negligible at one year.¹¹⁵ The Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2) demonstrated a reduction in morbidity as assessed by atrial fibrillation, sternal wound infection, inotropic requirement, transfusion, and hospital stay, but did not assess neurocognitive outcomes.¹¹⁶ The impact, therefore, of newer technologies on broadening the indications for CABG in the elderly is as yet unclear.

Severe Left Ventricular Dysfunction

Left ventricular dysfunction is a predictor of increased operative risk for most cardiac surgical procedures, and in the early days of coronary revascularization these patients were not offered CABG. Like age, however, it is also a strong predictor of poor outcome with medical therapy. Accordingly, more recently significant LV dysfunction has been considered an indication rather than contraindication to surgical revascularization. In some patients, LV function has been shown to improve—sometimes dramatically so—after revascularization, leading to the concept of "hibernating" or "stunned" myocardium.^117–120 The diagnosis of viable myocardium that is potentially recoverable depends upon the identification of preserved metabolic activity by positron emission tomography (PET), cell membrane integrity by thallium-201 or technetium-99m SPECT, or dobutamine stress echocardiography.^18,120,121

Thus far, no prospective randomized trials of medical versus surgical therapy in patients with severe LV dysfunction have been reported, although the NIH-sponsored Surgical Treatment for Ischemic Heart Failure (STICH) trial has just begun. A number of retrospective analyses of the impact of revascularization on outcome in patients with LV dysfunction with or without demonstrable viability have been reported. Recently Allman et al reported the results of a meta-analysis of these studies.¹²² Their analysis demonstrated a 79.6% reduction in annual mortality (16% vs. 3.2%, p < .0001) when patients with severe three-vessel disease and severely depressed LV function with evidence of viability underwent surgery versus medical therapy. Among those patients without demonstrable viability, the mortality rates were similar (7.7% vs. 6.2%, p = NS). This study is subject to all of the limitations of a retrospective surgical series, including perhaps most importantly the unaccountable effect of the clinical judgment employed in selecting patients for one therapy versus another. The results have been remarkably consistent over the years among virtually all studies, with the greatest benefit of surgical revascularization being sustained by the patients with the worst ventricular function.

The relative roles of CABG and PTCA in this population are not clearly defined despite the number of trials of angioplasty versus surgery. Patients with left ventricular dysfunction may be at higher mortality risk following revascularization by PTCA than by CABG surgery, but the potential survival benefits of CABG surgery have not been demonstrated, perhaps because these patients are underrepresented in these prospective, randomized studies. In a multicenter study of patients with left ventricular dysfunction (ejection fraction less than 40%), slightly more than one quarter of the patients were dead in the 2 years following multivessel angioplasty.¹²³ Similar results have been reported from other studies of PTCA in patients with multivessel disease and left ventricular dysfunction. Overall, the outcome with PTCA appears less favorable than that obtained after CABG surgery,⁵⁷ possibly as a function of more complete revascularization in surgical patients.¹²⁴

Completeness of revascularization may be particularly important in patients with left ventricular dysfunction. An analysis of data from the CASS registry demonstrated that, among patients with triple-vessel disease, 4-year survival was dependent upon the number of vessels bypassed, particularly among those with more severe angina and those with worse ventricular function.¹²⁴ For PTCA, complete revascularization of target arteries ranged from 57% to 61% in the prospective, randomized trials in which complete revascularization was not a protocol requirement (BARI, EAST, CABRI). In the GABI and RITA trials, complete revascularization by PTCA was targeted and was achieved in 86% in GABI and in 81% and 63% of patients with two- or three-vessel disease in RITA.^81,82

Total Occlusion

Revascularization is not possible in most patients with chronic, totally occluded coronary arteries, although the advent of stent technology has offered some improvement in this area. In the randomized trials of multivessel PTCA versus CABG, 35% to 37% of the patients excluded were excluded because of the presence of a chronic total occlusion of a coronary artery serving viable myocardium. Thus the high proportion of trial patients with less than three-vessel disease, well-preserved ventricular function, and absence of chronically occluded arteries produces a study population that favors a higher incidence of complete revascularization by PTCA and attenuated consequences of incomplete revascularization than would be expected in community practices. Among patients with severe angina, triple-vessel disease, and ventricular dysfunction, survival is greater in those with three or more coronary arteries bypassed than in those with only two vessels bypassed.^46,124 CABG surgery improves survival in patients with three- and two-vessel disease with left ventricular dysfunction compared with medical therapy. Although angioplasty may have a similar survival benefit, its influence on this high-risk subgroup has not been fully tested or reported.

Diabetes Mellitus

It has been recognized for many years that patients with diabetes mellitus are at higher risk following percutaneous¹²⁵ or surgical^125–128 revascularization. The BARI trial was the first trial large enough to identify significant differences in outcome between diabetic and nondiabetic patients. In this study, which included 353 diabetic patients, a survival benefit was observed among patients undergoing CABG as compared with those undergoing PTCA. The explanation for this is not entirely clear, although an intriguing observation is that while the incidence of subsequent MI is similar between groups, survival following MI is superior among those who have undergone surgical revascularization.¹²⁹ In fact, diabetics suffering spontaneous Q-wave MI were more than 10 times as likely to die with their infarction if they had been treated with PTCA as compared with CABG. No such protective effect was seen among nondiabetic patients either with or without Q-wave MI. This survival difference was even more pronounced at 7 years, with 76.4% of diabetics in the surgical arm alive as compared with 55.7% in the angioplasty arm.¹³⁰

The physiologic basis for this difference remains a matter of speculation, although the completeness of revascularization may be a factor. Because of the significant incidence of restenosis after PTCA in diabetics, Van Belle et al analyzed ejection fraction at 6 months and long-term cardiac mortality and morbidity among 513 diabetic patients stratified according to the presence of occlusive restenosis (n = 94), nonocclusive restenosis (n = 257), and no restenosis (n = 162).¹³¹ The mortality rose with restenosis (24% without restenosis, 35% with nonocclusive restenosis, and 59% with occlusion), and ejection fraction fell with occlusion (decrease of 4.8% ± 12.6%). Coronary occlusion was strongly predicted by coronary occlusion by multivariate analysis.

The results of the BARI trial prompted retrospective post hoc analyses of several earlier trials. The results have been variable. An analysis of diabetic patients from the CABRI trial at 8 years demonstrated a mortality rate of 3.5% for CABG patients versus 15.6% for PTCA.¹³² There was also a nonsignificant trend for better survival among diabetic patients in the EAST trial.¹³³ A meta-analysis of pooled data pertaining to diabetic patients from CABRI, EAST, and RITA, however, found similar 5-year mortality rates following CABG or PTCA.¹³⁴ Several other data bank studies have also been conducted. The Northern New England Cardiovascular Disease Study Group evaluated survival 5 years after treatment among 7159 diabetic patients with multivessel disease who were treated with CABG or PTCA between 1992 and 1996.¹³⁵ Of this group, 38.6% of patients were clinically and angiographically similar to those randomized in BARI. Patients were treated according to physician preference. Those undergoing CABG were more likely to have three-vessel disease and tended to be older with greater degrees of ventricular impairment and obstructive lung disease. There were more women and more urgent interventions in the PTCA group. After adjusting for these variables, PTCA was associated with a significantly greater mortality rate at 5 years (risk ratio = 1.49; 95% CI, 1.02 to 2.17; p = .037) and particularly among diabetics with three-vessel disease (hazard ratio 2.01; CI, 1.04 to 3.91; p = .038).

Diabetes is a condition characterized biologically by an inflammatory, proliferative, and prothrombotic state. This may account in part for the increased risk of restenosis and occlusion. Since diabetics tend to have more diffuse disease, the importance of complete revascularization—which is more often achieved surgically than percutaneously—may be enhanced. Another explanation may have more to do with patient selection than vascular biology. It has long been recognized from the previously cited studies that the survival advantage of CABG over medical therapy is greater the more extensive the coronary disease, and more recent studies of PTCA versus CABG have demonstrated similar trends. Diabetic patients tend to have more extensive disease, and in the BARI trial diabetics had a higher frequency of three-vessel disease, diffuse disease, proximal LAD disease, and left ventricular dysfunction.

In this respect it is interesting to note that in community studies¹³⁶ and the BARI registry,¹³⁷ there were no significant differences in outcomes between these therapies in the diabetic subgroup, although diabetics have a poorer outcome with both PTCA and CABG in comparison with nondiabetics. It must be emphasized that in these nonrandomized trials in which the selection of therapy was at the discretion of the physician and the patient, a very clear trend was noted. The "sicker" patients with left ventricular dysfunction and triple-vessel disease were far more likely to undergo CABG in contrast to patients with double-vessel disease and preserved left ventricular function. Therefore, these registry studies suggest that although the differences between bypass surgery and PTCA in diabetics may be due to altered vascular biology, these differences are magnified by the process of randomization in which patients who probably would have been treated with CABG in clinical practice were randomized to PTCA.

From a clinical standpoint in regard to patient selection for coronary revascularization and the method of revascularization, the assessment of diabetics should be based upon standard principles: the severity and extent of coronary disease, the potential for complete revascularization, the presence or absence of left ventricular dysfunction, and the technical suitability of the lesions for PTCA. The results of the aforementioned studies suggest that a preference for surgical over percutaneous revascularization is, at this time, appropriate among diabetics—at least those with extensive disease and/or ventricular dysfunction, although this recommendation may change if new technologies such as coated stents and antiplatelet agents are successful in reducing the risk of restenosis and occlusion. Furthermore, the potential impact of risk factor reduction and the use of insulin providers rather than insulin sensitizers on long-term survival may alter the risk/benefit balance in the future in this important and increasing subset of patients presenting with coronary artery disease. Irrespective of the mode of therapy, an aggressive approach to risk factor modification is required.