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In the decades since coronary artery bypass (CABG) surgery was popularized and coronary angioplasty introduced, an enormous volume of data on the results of invasive revascularization has been collected. Remarkably, almost from the outset many of these studies have been prospectively randomized. Yet in the current era there is a dearth of data concerning pharmacologic therapies for chronic coronary artery disease despite remarkable recent drug development. 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), which demonstrated benefit for patients with mild effort induced angina or silent ischemia.12 A handful of studies of combination therapy with beta blockers and calcium channel blockers have also demonstrated antianginal benefit.13–15
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Surgical versus Medical Therapy
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Three major randomized studies, the Coronary Artery Surgery Study (CASS),16 the Veterans Administration Cooperative Study Group (VA),17,18 and the European Coronary Surgery Study (ECSS),19,20 as well as several other smaller randomized trials,21–23 conducted between 1972 and 1984, provide the foundation for comparing the outcomes of medical and surgical therapy. Despite the limitations noted in the preceding, these studies are remarkably consistent in their major findings, and the qualitative conclusions drawn from them continue to be generalizable to current practice.
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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.24 For example, thus far, no study has shown survival benefit for CABG over medical therapy for patients with single-vessel disease. It should be emphasized, however, that these trials involved primarily patients with moderate chronic stable angina. These conclusions may, therefore, not necessarily apply to patients with unstable angina or to those with more severe degrees of chronic stable angina.
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A meta-analysis of the seven randomized trials cited in the preceding 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.24 The overall survival benefit at 12 years for the three large and four smaller randomized studies is shown in Fig. 19-1. 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.25–28
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There have been three recent randomized controlled trials of invasive revascularization by PCI or CABG versus medical therapy. Their results make an even stronger case for revascularization. In the Asymptomatic Cardiac Ischemia Pilot (ACIP) trial, patients with anatomy amenable to CABG were randomized to angina-directed anti-ischemic therapy, drug therapy guided by noninvasive measures of ischemia, or revascularization by CABG or PCI.29 At 2 years, there was a statistically significant difference in mortality of 6.6% in the angina-guided group, 4.4% in the ischemia-guided group, and 1.1% in the revascularization group. The rates of death or MI were also statistically different at 12.1%, 8.8%, and 4.7%, respectively. The Medicine, Angioplasty, or Surgery Study (MASS-II) trial randomized patients with multivessel disease among medical therapy, PCI, and CABG. Although survival at 1 year was equivalent, freedom from additional intervention was 99.5% for surgical patients and 93.7% for medically treated patients. Reintervention was, incidentally, even higher in the PCI group than the medical group, with 86.7% free of additional intervention. Angina was superior in the CABG group (88%) than in the PCI group (79%) or medical therapy group (46%).30
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In the Trial of Invasive versus Medical Therapy in Elderly Patients with Chronic Symptomatic Coronary-Artery Disease (TIME) study, elderly patients were studied with chronic angina. This failed to demonstrate a difference between optimized medical therapy and an invasive revascularization strategy (PCI or CABG) in terms of symptoms, quality of life, and death or nonfatal myocardial infarction (20% versus 17%, p = .71). However, medically treated patients were at higher risk because of major clinical events (64% versus 26% for invasive, p < .001), which were mainly attributable to rehospitalization and revascularization.31 In this trial of severely symptomatic elderly patients, it was encouraging that the price of an initially conservative strategy, followed by crossover to revascularization in approximately 50% of patients, was not paid for in terms of death or myocardial infarction.31
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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 contraindication—for surgical revascularization.16,24,25,32 Recent evidence that ischemic, viable, hypokinetic myocardium (hibernating or stunned) regains stronger contractile function after 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 in the following.
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In summary, in regard to chronic stable angina, a survival advantage is demonstrable for surgical revascularization over medical therapy in patients with: left main disease;33 triple-vessel disease and left ventricular dysfunction;34,35 two-vessel disease and proximal LAD disease;36 and severe ischemia and multivessel disease (Fig. 19-2).37,38 Those survival advantages have not been demonstrable among patients with single-vessel disease.39–41
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Apart from affording a survival benefit, CABG is indicated for the relief of angina pectoris and improvement in the quality of life. Between 80 and 90% of patients who are symptomatic on medical therapy become symptom-free after CABG. This benefit extends to low-risk patients for whom survival benefit from surgery is not likely.24 Relief of symptoms appears to relate to both the completeness of revascularization and maintenance of graft patency, with the benefit of CABG diminishing with time. Recurrence of angina following CABG surgery occurs at rates of 3 to 20% per year. Although enhanced survival is reported when an ITA graft is used to the LAD, there is no significant difference in postoperative freedom from angina.41 This may be because of vein graft occlusion or progression of native disease in grafted or ungrafted vessels.17
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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 because of perioperative infarctions that offset the lower incidence of infarction in each study follow-up.26,42
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PCI versus Medical Therapy
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Despite the increasing application of catheter-based technology to multivessel disease, the majority of interventions have historically been in single-vessel disease. 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. Many of these trials also antedate the use of IIb/IIIa inhibitors, clopidogrel, 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 PCI over medical therapy in patients with stable angina pectoris. However, the results of several recent studies have demonstrated improvement in symptoms and exercise tolerance.
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In the ACME (A Comparison of angioplasty with MEdical therapy)–I study, 212 patients with documented ischemia and a single coronary artery stenosis greater than 70% were randomly assigned to medical therapy or angioplasty.43 After 6 months, there was no mortality difference in either treatment group; however, PCI 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.43 This benefit came at some cost, however; among the 100 angioplasty patients, 19 underwent repeat PCI and seven underwent CABG during the first 6 months, compared with 11 angioplasty procedures and no CABG surgery in the patients randomized to medical therapy.43 Moreover, nearly half of all patients assigned to initial medical therapy were asymptomatic at 6 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 before PCI.44 In a follow-up study by the same investigators, 101 patients with stable angina and two-vessel disease were randomized to PCI or medical therapy.45 At 6 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.
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Several other studies have included patients with multivessel disease. In the Randomized Intervention Treatment of Angina (RITA)–2, of 1018 patients with stable angina randomized to medicine or PCI, one-third had two-vessel disease and 7% had three-vessel disease.46 Perhaps surprisingly, at a median follow-up of 2.7 years, the primary end points of death or MI had occurred twice as often in the PCI group (6.3 versus 3.3%, p < .02). Surgical revascularization was required during the follow-up interval in 7.9% of the PCI 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 3 years. These results are echoed in the MASS-II trial, in which angina relief was superior with PCI, but rates of intervention/reintervention were actually higher in the PCI group.30 Again, this supports an initial strategy of medical therapy.
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A comparison of PCI versus medicine as initial strategy among patients with hyperlipidemia was examined in the Atorvastatin versus REvascularization Trial (AVERT).47 Among 341 patients with one- or two-vessel disease, ischemic events were actually less common in the medical than PCI groups (13% versus 21%, p < .05). Although criticized for employing outdated angioplasty technology and other issues, the results of this study are consonant with the demonstration that lipid-lowering agents may have a powerful impact on ischemic events.48 In some respects, the lower use of aggressive lipid-lowering agents in the PCI arm biased the results in favor of medical therapy.
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The most recently published trial, COURAGE, randomized 2287 patients with stable angina and objective evidence of ischemia to best medical therapy or PCI and medical management. All patients received long-acting metoprolol, amlodipine, and/or isosorbide mononitrate, as well as lisinopril or losartan. Patients had aggressive antilipid therapy and appropriate antiplatelet therapy. The primary finding of this trial was a lack of benefit of PCI over best medical therapy for death, myocardial infarction, or other major cardiovascular events.49 Although this result has caused much controversy in the cardiology community, it is consistent with older studies.
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A meta-analysis of percutaneous interventions versus medical management was published in 2005.50 In patients with stable coronary artery disease, no benefit was found for invasive therapy in terms of death, MI, or need for subsequent revascularization. These studies provide compelling evidence that, thanks to substantial improvements in medical management, all patients should have a trial of optimized medical therapy before invasive intervention.
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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 on an “intention to treat” basis.
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A single-center Swiss study of 134 patients with isolated LAD disease was reported in 1994.51 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 PCI treatment group, with 25% requiring a second revascularization procedure compared with only 4.4% in the initial CABG group. Although the PCI 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 years52 with no difference between groups with respect to mortality or functional outcome despite repeat procedures in the PCI group.
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The Medicine, Angioplasty or Surgery Study (MASS) from Brazil compared medical therapy, PCI, and CABG using an ITA 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.53 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 PCI. In comparison with medical therapy, however, both PCI 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 with respect to mortality or late MI at 1 year. Similar findings were obtained at 5-year follow-up.54
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The results of the second MASS trial, which enrolled 611 patients with multivessel disease, reported 1-year outcomes as noted in the preceding.39 Although technology is a moving target, this trial has the advantage that approximately 70% of PCI patients had stents placed. Despite this, the results were remarkably similar to MASS, with a lower incidence of adverse events in the medical group than PCI group. Surgical therapy provided the best angina relief and lowest incidence of adverse events. All therapies had similar survival rates.
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A number of larger prospectively randomized studies comparing PCI 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.55,56 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.57 Among clinically eligible patients in the Bypass Angioplasty Reperfusion Investigation (BARI)39 and Emory Angioplasty versus Surgery Trial (EAST)40 trials, approximately two-thirds of patients were excluded on angiographic grounds that included chronic total occlusion, left main coronary artery stenosis, diffuse disease, or other anatomical factors making PCI potentially dangerous. Consequently these randomized trials contain only a portion of the spectrum of patients with coronary artery disease encountered clinically. Entry bias has a significant impact on the likelihood of observing an outcome difference among therapies. Because a high proportion of the randomized patients are in the low-risk group, it is possible that any potential survival benefit of CABG surgery over PCI in high- and moderate-risk groups may be masked.56
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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 to 1986 National Heart, Lung, and Blood Institute PCI Registry, 99% of patients were discharged alive from hospital, and 92% did not sustain a MI or require CABG surgery.58 In the BARI trial, 99% of patients survived hospitalization and 88.6% of PCI-treated patients did not have MI or require repeat revascularization by angioplasty or surgery during the initial hospitalization.39 Employing event-free criteria (death, MI, CABG) for the initial hospitalization, PCI can be judged successful. However, if a repeat revascularization procedure within 5 years is regarded as a negative outcome, then far fewer patients are treated successfully. 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 price with their health.
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In the BARI, EAST, RITA, CABRI, and GABI multivessel PCI versus CABG surgery trials,39,40,57,59,60 mortality was similar between 1 and 5 years of follow-up in both the PCI and CABG treatment groups. Mortality ranged from 3% in the CABRI trial at 1 year follow-up59 and 3.4% in the RITA trial at 2.5 years57 to 13% in the BARI trial at 5 years.61 A slightly higher incidence of MI was noted in some of these trials.
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The incidence of repeat revascularization is higher among patients treated with angioplasty than surgery in all trials carried out to date, ranging from 36.5% in the CABRI trial at 1 year follow-up to 62% in the EAST trial at 3 years. Repeat revascularization in the EAST trial for angioplasty-treated patients was much higher than that in the BARI, CABRI, and RITA trials. In contrast with PCI, 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.40,59 Generally, repeat revascularization procedures were required five to eight 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 PCI-treated patients.
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In the BARI trial at 5 years, 54.5% of patients initially assigned to PCI had undergone a repeat revascularization procedure, including repeat PCI in 23.2%, CABG in 20.5%, and both in 10.8%.61 Among angina-free patients at 5 years, only 48% of the angioplasty-treated patients compared with 94% of the CABG surgery patients had not had an additional revascularization procedure after their initial procedure. An important subgroup analysis of the BARI trial demonstrated a marked survival benefit with surgery for patients with insulin-dependent diabetes receiving an ITA.
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Several more recent studies of PCI versus surgery have confirmed these findings. The Argentine Randomized Trial of Coronary Angioplasty versus Bypass Surgery in Multi-vessel 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.62,63 In the French Monocentric Study, 152 patients with multivessel disease underwent PCI or CABG.64 Again, superior event-free survival was seen in the surgical group, driven predominantly by a lesser need for subsequent revascularization.
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The impact of advanced stent technology on the comparative results of PCI and CABG has been recently investigated as well. In the Arterial Revascularization Therapy Study (ARTS), 1205 patients with multivessel disease underwent CABG or PCI with bare-metal stents.65 No significant differences in the primary end point of freedom from death, stroke, or MI at 1 year were observed, although the need for revascularization remained higher in the angioplasty than surgery groups. Similarly the second Argentine Randomized Trial of Coronary Angioplasty versus Bypass Surgery in multivessel disease (ERACI II) study group66 demonstrated that, even with the use of stents, repeat revascularization was more common in the PCI group, particularly among diabetics in whom repeat revascularization was required in 22.3% versus 3.1% in the CABG group. Of note, in this study, the 30-day mortality was higher in the CABG than PCI group, as was the incidence of Q wave MI. Despite a high operative mortality rate (5.7%) in the surgery group that raised many questions, at 5 years, there was no difference in survival and again, CABG patients had a lower incidence of revascularization. The Surgery Or Stent (SOS study), which compared outcomes in almost 1000 patients with multivessel disease, demonstrated similar all-cause mortality among surgical compared to angioplasty patients and confirmed higher rates of repeat revascularization after angioplasty and lower freedom from angina pectoris in both patients with and without a recent acute coronary syndrome.67 Of interest in this study, the reintervention rate, while still higher than after surgery, was far below that previously reported for angioplasty at only 17%. Mercado et al. performed a meta-analysis of the ARTS, ERATSII, MASSII, and SOS trials that demonstrated similar rates of death, MI, or stroke at 1 year and higher repeat revascularization rates with PCI.68 A meta-analysis of 5-year data was also recently published, confirming the 1-year results with repeat revascularization more frequent after PCI than CABG (29% versus 7.9%, p < .001) (Fig. 19-3).69
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The most recent trial, the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, assessed the optimal revascularization strategy for patients with three-vessel or left main coronary artery disease by randomizing 1800 patients to either CABG or drug-eluting stents.70 At 12 months, the rates of myocardial infarction and death were similar between groups, but stroke was significantly more common in the CABG patients (2.2% versus 0.6% at 1 year). It should be noted that the CABG group had much less aggressive medical management postoperatively, including fewer patients on antiplatelet medications, which may account for some of the increase in stroke risk. Despite the use of DES, the rates of reintervention were still significantly higher (13.5% versus 5.9%) in the PCI group than the CABG group. Because of the lack of difference in early mortality and myocardial infarction, some cardiologists have begun to suggest that left main should no longer be an indication for CABG.71 However, others maintain that the evidence for PCI is still inadequate and that the greater freedom from reintervention with CABG suggests that CABG remains the treatment of choice for patients with left main disease.72
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In conclusion, the randomized trials of PCI versus CABG are useful, but only if results are interpreted in a context of patients entering or eligible to enter these trials.55,56 PCI is a reasonable alternative to CABG surgery, and for many patients it is the preferred initial approach, provided the patient understands that there may be a higher incidence of recurrent angina and need for repeat revascularization procedures, as well as a year-long commitment to use of clopidogrel because of concern regarding catastrophic late stent thrombosis. 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. To extrapolate these results to patients who would not have met entry criteria, however, it is intellectually flawed and potentially misleading.
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Nonrandomized Database Comparisons
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The information provided by randomized studies is complemented by information gleaned from large, prospectively managed, nonrandomized database studies. Such registries provide insight into the management of the sizeable population of patients who would not have been eligible for randomization. The Duke Cardiovascular Disease Databank followed 9263 patients undergoing clinically indicated coronary angiography between 1984 and 1990 for a mean of 5 years after nonrandomized treatment by CABG, PCI, or medical therapy.9 Patients with valvular disease, prior revascularization, significant (>75%) left main disease, and congenital and nonischemic cardiomyopathy were excluded. Overall, 39% of the patients had one-vessel disease, 31% two-vessel disease, and 30% three-vessel disease. Initial therapy was medical in 3053 patients, PCI 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.32 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 Fig. 19-4, PCI versus medicine in Fig. 19-5, and PCI versus CABG in Fig. 19-6.9
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From a practical standpoint, in this database study and in the randomized trials, the effect of revascularization on survival depended largely on the extent of the coronary artery disease and is an example of the concept of benefit in relationship to a “gradient of risk.” For the least severe (one-vessel) disease, there were no survival advantages of revascularization over medical therapy in up to 5 years of follow-up.9 For intermediate levels of coronary artery disease severity (ie, two-vessel disease), there was a higher 5-year survival rate for patients undergoing revascularization than for those treated medically. For patients with the most-severe coronary artery disease (ie, three-vessel disease), CABG surgery provided a significant and consistent survival advantage over medical therapy. PCI appeared prognostically equivalent to medical therapy in these patients, but only a small number of patients in this subgroup underwent angioplasty. In comparing PCI with CABG surgery, PCI demonstrated a small survival advantage over CABG surgery for patients with less-severe two-vessel disease, whereas CABG surgery was superior for more severe two-vessel disease (ie, proximal left anterior descending artery involvement).9
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These important findings have been confirmed in the current era of PCI with stent implantation using the New York State Database published in 1999 using cases from 1993 to 1995.73 In this study, a survival benefit was observed with angioplasty at 3 years for those patients with single-vessel disease not involving the LAD, whereas those with LAD or three-vessel disease had superior outcomes with surgery. In the more recent study of patients with multivessel disease who received PCI, survival was higher among the 37,212 patients who underwent CABG than among the 22,102 patients who underwent stent placement after adjustment for known risk factors. The adjusted hazard ratio for the long-term risk of death after CABG relative to stents was 0.64 (0.56 to 0.74) for three-vessel disease and proximal LAD disease. This hazard ratio increased to 0.76 (0.60 to 0.96) for patients with two-vessel disease and LAD involvement74 (Fig. 19-7). This study has limitations of being a nonrandomized study and subject to bias; however, the surprising finding of a survival advantage apparent as early as 3 years postprocedure suggests that improvements in cardiac surgical anesthetic care, myocardial protection, and intensive care management have at least matched if not surpassed advances in percutaneous technology. It is important to note that PCI targets the culprit lesion. In contrast, CABG surgery targets both the culprit lesion and potential future culprit lesions by bypassing the diseased vessel. This in part may explain the apparent mortality benefit derived with CABG (Fig. 19-8).75
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