Applied Radiology

Dr. Best received her medical degree from the Medical College of Pennsylvania and is finishing her cardiovascular and interventional training at the Mayo Clinic.

Dr. Berger is a Professor of Medicine and an Interventionalist at the Mayo Clinic.

Randomized clinical trials per-formed in the 1970s and early 1980s established coronary artery bypass grafting (CABG) as the primary therapy for multivessel coronary artery disease. Although some of the studies revealed disparate results, differences in the baseline patient characteristics contributed to these discrepancies (Table 1 and figure 1).

Of the three major studies, the Coronary Artery Surgery Study (CASS) had the lowest risk population, with more than one-fourth having single-vessel disease. ¹ Since patients with single-vessel disease have a higher mortality with surgery compared with medical therapy, it is not surprising that there was no difference demonstrated in overall survival.

The Veterans Administration Coronary Artery Bypass Surgery Study (VA) had a higher risk population because of the inclusion requirement of an abnormal resting electrocardiogram suggestive of cardiac ischemia. ² In this study, CABG increased survival at 7 years, but this advantage was lost at 11 years. When the highest-risk patients, such as those with left-main disease or three-vessel disease with a reduced left ventricular ejection fraction (EF), were analyzed, a distinct survival advantage with CABG was seen and this was maintained throughout the follow-up period.

The third major trial, the European Coronary Surgery Study (ECSS), required at least two-vessel coronary disease for study entry. ³ This study also demonstrated a significant survival advantage with CABG at 5 years, and although the benefit diminished over the 12-year follow-up, it remained clinically and statistically significant. Patient subgroups that derived the greatest benefit from CABG were older patients with abnormal electrocardiograms and positive treadmill exercise tests, those patients with peripheral arterial disease, and those with a proximal left anterior descending (LAD) coronary artery lesion.

In a meta-analysis of these three studies and four smaller studies comparing CABG to medical therapy by the Coronary Artery Bypass Graft Surgery Trialists Collaboration, CABG reduced symptoms in patients with multivessel disease compared with medical therapy, and increased survival in patients with three-vessel disease, or two-vessel disease involving the proximal LAD (figure 1). ⁴

These studies provided the basis for the belief that single-vessel disease is most appropriately treated medically or with percutaneous coronary intervention (PCI) but generally not with CABG. These studies also supported the concept that the higher a patient's risk for future cardiovascular events, the greater the likelihood of benefit from CABG.

PTCA versus CABG surgery

More than a decade after the trials comparing CABG and medical therapy were performed, randomized clinical trials were performed comparing percutaneous transluminal coronary angioplasty (PTCA) and CABG. The Bypass Angioplasty Revascularization Investigation (BARI) ⁵ is the largest study comparing CABG (n = 914) with PTCA (n = 915) for the treatment of multivessel coronary disease. Three-vessel disease was present in 41% of patients. There were more in-hospital myocardial infarctions (MI) in the CABG group, but the PTCA group had greater need for emergent CABG and repeat PTCA. Survival at 5 years was not different between the revascularization groups (CABG 89.3%, PTCA 86.3%,
P = 0.19). However, there was an increased need for repeat revascularization with PTCA within first 5 years (54% vs. 8%). By 7 years, there was a survival benefit with CABG (84.4% vs. 80.9%, P = 0.043), which could be explained by the treated diabetes group where this difference was marked (CABG 76.4%, PTCA 55.7%, P = 0.0011). There was no difference in survival between the two groups in patients without diabetes (CABG 86.4%, PTCA 86.8%, P = 0.72). ⁶ Furthermore, one of the most important lessons from BARI, which has been borne out in all randomized trials comparing PCI and CABG, is that <50% of patients with multivessel disease are appropriate for PCI, whereas >90% of patients are appropriate for CABG. Therefore, the debate is really about the most appropriate form of revascularization for the minority of patients amenable to both procedures. For most patients with multivessel disease who require revascularization, CABG is the only appropriate therapy.

Eight smaller studies that preceded BARI were analyzed together in a meta-analysis. ⁷ This analysis included 3371 patients with a mean follow-up of 2.7 years (figure 2). No survival difference was found between CABG and PTCA. However, 17.8% of the PTCA group required CABG during the year after enrollment. Thus, data from both the BARI study and a meta-analysis of 8 trials suggest that PTCA does not adversely affect survival, except perhaps in diabetics. Nonetheless, the need for repeat procedures in the PTCA group, including subsequent CABG, is significant.

Coronary stenting compared with PTCA

Within the past decade, stenting has become a routine part of PCI. Stenting increases procedural success rates, decreases major complications, (including the need for emergency CABG), and increases the postprocedural coronary luminal diameter, which is maintained at 6 months. ¹² One of the main setbacks to PTCA is restenosis; stenting decreases the frequency of restenosis by approximately 50%. ¹³ These advantages of stenting over PTCA make it necessary to readdress the role of stenting in the treatment of multivessel coronary artery disease.

Newer developments in CABG surgery

Significant advances have also occurred for surgical revascularization; perhaps the most significant has been the use of the internal mammary artery (IMA) graft. IMA grafts increase 10-year survival in patients after CABG compared with saphenous vein grafts alone (86.6 vs. 75.9%, P <0.0001). ¹⁴ The use of an IMA graft to the LAD reduced the risk of late MI by approximately 40% and the need for repeat cardiac surgery by 50%. Particular benefit from IMA grafts was seen in diabetic patients in the BARI study, where 81% received at least one IMA graft. ^6,15 A survival benefit in diabetics undergoing CABG in BARI was apparent only in patients who received an IMA graft (7-year survival: 83.2%). There was no difference in survival between PCI and CABG among diabetic patients if a saphenous vein graft was placed to the LAD (54.5% vs. 55.5%).

Despite the benefits of surgical treatment for multivessel coronary disease, there are many disadvantages. These include: a prolonged recovery time; cost; the need for repeat procedures, which increases dramatically in the 5 to 10 years after the procedure; the risk of stroke; and even more commonly, a decline in cognitive function. Decline in cognitive function is significant after CABG and is seen in 53% of patients at discharge, 24% at 6 months, and 42% at 5 years. ¹⁶ Of note, however, is that patients at the highest risk for cognitive abnormalities after CABG also tend to be the worst PCI candidates, such as those patients with peripheral and cerebral vascular disease, and the elderly. Newer surgical techniques, such as off-pump bypass grafting and hybrid revascularization with video-thoroscopy­assisted minimally invasive direct coronary artery bypass and PCI, may decrease these complications. ¹⁷ Large prospective studies will be needed to truly define what role, if any, these newer surgical techniques may have.

Randomized trials of stenting versus CABG surgery

As the technology for PCI has advanced and stenting has become used routinely for percutaneous coronary revascularization, the question of the best therapy for multivessel coronary artery disease needs to be revisited. Several randomized studies designed to evaluate modern treatment options for multivessel coronary disease have been performed, and initial results have been reported this past year. These studies contain conflicting findings, and a careful evaluation of the study populations, trial designs, and results is necessary to understand these differences (Table 2).

The Argentine randomized study (ERACI II) compared coronary stenting with CABG in the treatment of 450 patients with symptomatic multiple-vessel disease. ¹⁸ This study included patients with left main coronary artery disease if the left main stenosis was appropriate for stenting (n = 21). Seventeen percent of patients in ERACI II had diabetes. Abciximab was administered to 28% of the PCI group. The Gianturco Roubin II stent (Cook, Bloomington, IN) was the primary stent used. Among the 450 patients in the study, major adverse cardiovascular events (MACE), including death, Q-wave MI, the need for repeat revascularization procedures, or stroke occurred in 3.6% of patients in the PCI group versus 12.3% of patients in the CABG group ( P = 0.002). Thirty-day mortality was also lower with PCI (0.9% vs. 5.7%, P <0.013), although the mortality in the CABG group was higher than might be expected. With a mean follow-up of 18.5 months, the PCI group had greater estimated survival at 900 days compared with CABG (96.9% vs. 92.5%, P <0.017). However, the PCI group had a greater frequency of repeat revascularization (16.8% vs. 4.8%, P <0.001) and were less likely to be free from angina (84% vs. 92.0%, P = 0.01). Thus, in ERACI II, PCI for multivessel or left main coronary artery disease was associated with a lower mortality and lower frequency of other adverse events at the expense of a greater need for repeat revascularization procedures and less complete relief of angina.

The Arterial Revascularization Therapies Study (ARTS) was a multinational study of stenting compared with CABG. ¹⁹ The highest-risk patients were excluded from this study, and approximately two-thirds of the patients had two-vessel disease. At 1 year, there was no difference between the groups in the MACE rate (defined as death, MI, stroke, or reversible ischemic neurologic deficits) or in frequency of mortality alone (CABG 2.8%, PCI 2.5%). The PCI group had an increased repeat revascularization rate (16.8% vs. 3.5%) at 1 year. PCI patients also had an increased requirement for medical therapy and were less likely to be free from angina. Thus, this study suggests that stenting for multivessel disease patients is as efficacious as CABG at 1 year in terms of major adverse events, but with greater incidence of repeat procedures.

Dr. Rodney Stables presented preliminary data from the Stent or Surgery Trial (SOS) ²⁰ at the 2001 American College of Cardiology scientific sessions. Patients with multivessel coronary disease were randomized to either stenting or CABG. This study demonstrated that the primary end point of repeat revascularization was significantly higher for stenting (20.3%) than for CABG (5.8%). Mortality at 1 year was lower in CABG patients (0.5% vs. 2.5%, P = 0.05), and the difference at 2 years was even greater (1.2% vs. 4.1%, P = 0.007). Of note, the chance occurrence of 8 cancer deaths in the PCI group and only 1 in the CABG group largely accounted for the difference in mortality. Furthermore, the CABG group had remarkably low 1-year mortality compared with previous randomized studies and registry reports, further increasing the difference between these groups.

Perhaps the most remarkable finding in the ARTS and ERACI II studies is the reduction in the repeat revascularization rates with stenting compared with prior PTCA studies (Table 3). Despite being able to treat more complex lesions and have more complete revascularization, the frequency of repeat revascularization was less than half of that seen in the earlier trials. This is due primarily to two factors. The first is that stents reduce the frequency of restenosis by approximately one-half. However, the other major reason for the lower frequency of repeat revascularization among PCI patients in the stent versus CABG trials than the PTCA versus CABG trials is that repeat angiography and follow-up functional tests were not performed routinely as part of the study protocol. It is important to recognize that the routine performance of follow-up angiography and functional tests in asymptomatic patients increases the frequency of repeat revascularization procedures, and it does so more among patients initially treated with PCI than among patients initially treated with CABG.

Also at this year's American College of Cardiology meeting, preliminary data from the Medical, Angioplasty, and Surgery Study (MASS II) ²¹ were presented by Dr. Whady Hueb. In this study, 611 patients were randomized to either medical therapy (n = 203), PCI (n = 205), or CABG (n = 203). Preliminary data indicate that the CABG patients had fewer MIs (CABG 1%, medical therapy 2%, PCI 8; P = 0.0015) and greater event-free survival (CABG 98%, medical therapy 94%, PCI 78%). The results of MASS II differ from those of the larger studies described above for reasons that aren't entirely clear. Important data about MASS II have not been reported, including the PCI success rate, number of vessels treated per patient, and the number of vessels treated by each method (PTCA vs. stents, etc.). However, the strength of this study is the inclusion of an arm in which medical therapy was administered. Given the improvements in medical therapy since the early CABG-versus-medical-therapy studies previously described, it remains unclear whether, or to what extent, revascularization provides a survival advantage over current medical therapy.

The most recent study of coronary disease is unique in that it only included groups of patients that have been excluded from all the prior randomized trials comparing PCI and CABG. In the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) study, a multicenter randomized clinical trial performed exclusively at Veteran's Administration hospitals, PCI was compared with CABG in "high-risk" patients known to have an increased risk with CABG. ²² Such patients included those with medically refractory unstable angina and at least one of the following characteristics: age >70 years, prior cardiac surgery, a left ventricular ejection fraction <35%, an MI ¾ 7 days, or the need for an intra-aortic balloon pump. Preliminary data presented at the 2001 Society of Cardiac Angiography and Interventions meeting by Dr. Douglass Morrison demonstrated that there is no difference in 3-year survival between the two groups (CABG ²³ 79%, PCI 80%, P >0.46 ). The AWESOME data indicate that even among these high-risk patients, PCI and CABG appear to be equivalent in terms of survival and survival free of MI, though as in all the studies, repeat procedures were required more frequently among patients initially undergoing PCI.

High-risk populations

Special subgroups are frequently identified within clinical studies that are at high risk of cardiac mortality and at high risk from revascularization. Since sufficiently large studies comparing stenting with CABG for multivessel disease have not been performed in these high-risk groups to be certain about the most appropriate therapy, a discussion of treatment options in these groups is warranted.

Diabetes mellitus

Diabetes is associated with diffuse, severe, and distal coronary disease with more complex coronary lesions and is associated with rapid progression of atherosclerosis. As a result, the mortality rate from coronary disease is four times higher in the diabetic population. ^24-26 Diabetics also have increased morbidity and mortality with coronary revascularization. Despite high initial success rates with PTCA in both diabetics and nondiabetics, the restenosis rate is nearly twice as high in diabetics. ^27-29 Restenosis is lower in diabetics who undergo stenting rather than PTCA, but there is still a 10% greater risk of in-stent restenosis in diabetics than in nondiabetics. ^30-31 CABG is also associated with a higher complication rate in diabetics, including a two-fold higher in-hospital mortality. ^32,33

The results of BARI initiated great concern about PCI in diabetic patients with multivessel coronary disease. ⁶ Among the 353 diabetic patients, 7-year survival was much greater with CABG (76.4% vs. 55.7%, P = 0.0011). Similarly, the Emory Angioplasty versus Surgery trial (EAST) ¹⁰ showed a greater survival in diabetics undergoing CABG versus PCI. Analysis of the New Northern New England registry similarly found a mortality advantage to CABG in diabetic patients who met BARI inclusion criteria, with a hazard ratio (HR) for PTCA of 1.49 (95% confidence interval (CI): 1.02 to 2.17), which increased with three-vessel disease and diabetes (HR 2.02; 95% CI: 1.04 to 3.91). ³⁴ The greater survival after CABG in diabetics may be derived from the high mortality associated with MI in this population. The relative risk of death after an MI in a diabetic with a prior CABG is 0.09 (95% CI: 0.03 to 0.29) compared with a diabetic with no prior CABG. ³⁵

Despite these studies suggesting that CABG is superior to PCI in the treatment of diabetics with multivessel disease, there are still some diabetic patients with multivessel disease in whom PCI may be appropriate. In the BARI registry, which included 2010 patients who fulfilled inclusion criteria but were not randomized (due to physician or patient preference), twice as many patients underwent PCI than underwent CABG. Nevertheless, in the registry, there was no difference in mortality at 7 years between patients who underwent CABG and PCI, even within the diabetic subgroup (CABG 14.2%, PTCA 13.9%, P = 0.66). ^36,37 However, patients in the registry who underwent CABG were more likely to have three-vessel disease and had more complex lesions with more class C lesions, longer lesions, and more proximal LAD lesions. Thus, those diabetics with the greatest number of lesions were preferentially referred for CABG; the remaining two-thirds of the diabetic patients with less severe multivessel disease underwent PCI. Furthermore, stents and glycoprotein (GP) IIb/IIIa inhibitors may be more beneficial in the diabetic population; however, these agents were not utilized in BARI.

Renal failure

Patients with renal failure are at extremely high risk for cardiovascular events. Such patients are also at a greatly increased risk from coronary revascularization. Chronic renal failure (CRF) is one of the most potent risk factors for restenosis after PTCA. ^38,39 Stenting decreases the need for repeat revascularization by more than 50% among CRF patients, but the restenosis rate is still almost twice that of patients without CRF. ⁴⁰ Moreover, procedural success and in-hospital mortality after PCI is decreased. ⁴¹ However, CABG also has a greater morbidity and mortality in the CRF population, with in-hospital mortality reported as high as 20% in such patients. ^42,43 There have been no randomized studies comparing PCI and CABG in CRF patients, and, in fact, such patients have been systematically excluded from all major randomized studies. Only one prospective trial in diabetic patients with coronary disease has been performed, in which an invasive approach (PTCA or CABG) was compared with medical therapy given to patients on dialysis. ⁴⁴ Although the outcome of this trial, performed in 1980s, indicated that an invasive strategy was far superior to that of patients receiving medical management, neither treatment arm is truly reflective of today's practices. Thus, there is no good evidence to guide the clinician in the therapy of multivessel disease in a patient with renal failure . Since CRF patients typically have diffuse, severe coronary disease, one might speculate that CABG might be of greatest benefit in these patients. However, operative mortality is exceptionally high in such patients. The most appropriate therapy for patients with CRF remains unknown.

Beyond the trials

Although randomized controlled trials provide the strongest evidence for a difference in treatment outcomes in patients with multivessel disease, these studies have persistent limitations. Study populations in clinical trials generally represent a select minority of the population of patients being studied because of restrictive inclusion/exclusion criteria, because centers participating in the studies are often different from the majority of hospitals in important ways, and because patients who accept randomization often differ from the population of patients at large. Therefore, further information can be obtained from registry information that may be more reflective of clinical practice.

In the BARI registry, twice as many patients underwent PCI than underwent CABG, indicating patient or physician preference for this less invasive approach. Despite this, there was no difference in mortality between the two treatment arms. Even the mortality difference based on diabetic status was eliminated. ³⁷ Thus, the registry suggests that by encompassing all of the clinical variables present in each individual case, such as extent of coronary disease, feasibility of revascularization with each technique, and overall health of the patient, etc., PCI is an acceptable alternative to CABG. The importance of these more subtle factors that are incorporated into clinical decision-making regarding revascularization techniques is also emphasized by the EAST registry, in which 3-year survival was greater in the registry patients (96.4%) than in randomized patients (93.4%, P = 0.044). ⁴⁵ Thus, PCI or CABG are both acceptable methods of revascularization for patients with multivessel coronary disease. Consideration of individual patient factors may make the choice of revascularization more appropriate for a given patient.

Conclusion

Advances in PCI, cardiac surgery, and medical therapy have improved the prognosis of patients with multivessel coronary artery disease. Large-scale clinical studies are not available to delineate the most appropriate therapy for all clinical decisions. Revascularization of patients with multivessel disease not only reduces symptoms, but also prolongs survival in certain patient subsets. Larger studies with longer follow-up are needed to exclude small differences in outcome between these different revascularization strategies, as well as medical therapy. Currently, the existing data suggest equivalent outcomes in patients with multivessel disease treated with PCI or CABG if they are amenable to both procedures.