The utilization of coronary artery bypass surgery

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1 EDITORIAL REVIEW Coronary Artery Bypass is Superior to Drug-Eluting Stents in Multivessel Coronary Artery Disease* Robert A. Guyton, MD Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia Percutaneous intervention for the treatment of multivessel coronary artery disease continues to displace coronary artery bypass graft surgery. But controlled trials of percutaneous intervention versus coronary bypass, in meta-analysis, have shown a significant survival advantage for coronary bypass. Studies of bare metal stents have not presented any data to prompt reversal of this conclusion for all but the small portion of patients most suited for stenting. Drug-eluting stents have no survival advantage compared with bare metal stents. Data from real-world registries have shown that the current therapy of multivessel disease patients has resulted in a relative excess mortality of as much as 46% in patients with initial stenting compared with patients with initial coronary bypass. Ethical considerations demand that patients with multivessel disease be informed of the documented mortality benefit of coronary bypass graft surgery. (Ann Thorac Surg 2006;81: ) 2006 by The Society of Thoracic Surgeons The utilization of coronary artery bypass surgery (CABG) for revascularization of patients with coronary artery disease has been the subject of extensive scrutiny for more than a quarter century, beginning with randomized trials of CABG versus medical therapy conducted in the late 1970s [1]. Percutaneous intervention (PCI) for coronary revascularization has improved and has been used progressively more frequently compared with CABG, proponents of PCI claiming equivalent survival with a strategy of initial PCI compared with a strategy of initial CABG. Improvement in restenosis with drug-eluting stents has accelerated the utilization of PCI in patients with multivessel disease (MVD) [2]. This analysis of recent publications will examine the studies comparing CABG with PCI and combine this evidence with studies comparing bare metal stents and drug-eluting stents. This combination presents compelling evidence that CABG as initial therapy is superior to initial PCI with drug-eluting stents in the treatment of patients with MVD. The accelerated application of PCI to patients with MVD is not warranted. More importantly, patients are not being given adequate information about relative survival outcomes. Survival Advantage of CABG Compared With Medical Therapy for Patients With MVD Numerous trials of CABG versus medical therapy were conducted in the late 1970s and early 1980s. These trials, taken separately, demonstrated that CABG was significantly better than medical therapy for left main disease *Much of this review was presented as the Blalock Lecture at Johns Hopkins School of Medicine, November 3, 2005, Baltimore, MD. Address correspondence to Dr Guyton, Section of Cardiothoracic Surgery, The Emory Clinic, 1365 Clifton Rd, Atlanta, GA 30322; robert_guyton@emoryhealthcare.org. and triple-vessel disease with some left ventricular dysfunction. An important reanalysis of data from these trials was published by Yusef and coworkers [1] in In the Yusef data reanalysis, the CABG versus medical therapy survival curves converge at 12 years, related to graft closure (almost all veins grafts were used in these patients), cross-over from medical therapy to CABG in 41% of patients by 10 years, and simple aging of the patients (all survival curves eventually converge). This convergence of survival curves does not imply equivalent survival benefit after 12 years. Yusef appropriately compared extension of life (the integration of the area under the survival curves) by initial CABG compared with initial medical therapy. A significant survival benefit was seen for CABG in patients with angina (class I to II, 3.3 months; class III to IV, 7.3 months), or with abnormal exercise tests (5.1 months), or with left ventricular dysfunction (10.6 months), or with triple-vessel disease (5.7 months). Subgroup analysis even revealed a significant 5-year survival benefit for patients with one- or twovessel disease if there was disease of the proximal left anterior descending artery [1]. These trials of CABG versus medical therapy are the basis for current recommendations for the use of CABG for extension of survival in patients with MVD. Major improvements in medical therapy have occurred in the last 25 years, but these improvements apply to surgical patients as well as to medically treated patients. These trials are also the underpinning of inferences that PCI During the past 36 months, the author has received research grants, consultation fees/honoraria, and travel expenses from US Surgical Corporation, Guidant, Quest Medical, Medtronic, and Chase Medical. He has no investment interest in any of these corporations by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 1950 EDITORIAL REVIEW GUYTON Ann Thorac Surg CABG VERSUS STENTS IN MULTIVESSEL DISEASE 2006;81: extends survival, based upon comparative studies of PCI versus CABG. Comparative Studies of PCI Versus CABG Beginning in 1980, multiple randomized controlled trials (RCTs) of PCI versus CABG were conducted. The Emory Angioplasty Surgery Trial (EAST) screened 5118 patients and found 842 patients (16.5%) sufficiently suitable for either PCI or CABG who were eligible for enrollment. Three hundred ninety-two patients with MVD were randomly assigned (7.7% of 5,118 screened patients, mean age 62 years, 60% double-vessel disease, 40% triple-vessel disease) to PCI or CABG [3]. This author participated in EAST. Enrollment became difficult at the end of the trial as referring cardiologists frequently sent patients to Emory with expressed preferences for PCI or CABG. Patients tended to be enrolled when the referring cardiologist thought that there would be no difference in outcomes. Eight-year mortality in the CABG group was 17.3% compared with a mortality of 21.7% in the PCI group. The relative mortality difference of 20% in the 7.7% of MVD patients most suitable for either PCI or CABG was not statistically significant because of the small size of the groups [4]. Notably, the wisdom of steerage by referring cardiologists toward PCI or CABG (even within the small portion of MVD patients most suitable for either procedure) was validated by results from the EAST registry. Registry patients (eligible, but not randomized) had a significantly better 5-year survival compared with randomized patients [5]. This registry versus randomized results makes it difficult to find fault with the behavior of clinicians in other PCI versus CABG studies in which selective enrollment of patients is commonplace. Unfortunately, such selective enrollment makes it very difficult to extend the results of randomized trials to the general population of patients with MVD. The largest randomized controlled trial of CABG versus PCI in MVD was the Bypass Angioplasty Revascularization Investigation (BARI) trial, conducted in 18 centers from 1988 to An analysis of enrollment was published by Bourassa and colleagues [6]. A total of 25,200 patients with MVD was screened. Approximately half were excluded for clinical, administrative, or major angiographic reasons (eg, left main stenosis). The analysis states: Of 12,530 patients who met clinical eligibility for BARI, 67% were unsuitable for one or both procedures. In 95% of the time this was due to technical unsuitability for PTCA. Although complete revascularization was not a requirement, the protocol called for anticipation of successful relief of the major areas of ischemia. To leave patients with large areas of unrevascularized myocardium was clearly not in the patient s best interest [6]. In all, 1,829 patients entered the trial. Mean age was 61 years; 59% had two-vessel disease and 41% had threevessel disease [7]. Only 7.3% of screened MVD patients were randomized [6]. At 7 years, there was a significant survival advantage for CABG versus PCI (absolute survival difference 2.5%, relative survival difference 15%; p 0.043, Fig 1) [8]. This significant 15% relative survival Fig 1. In the Bypass Angioplasty Revascularization Investigation, the 7-year mortality rate was 16.6% for coronary artery bypass graft surgery (CABG) and 19.1% for percutaneous transluminal coronary angioplasty (PTCA [p 0.043]). Relative to CABG, PTCA mortality was 15% higher [8]. advantage for CABG occurred in the 7.3% of MVD patients screened in BARI who were most suitable for either procedure. A subgroup of 934 BARI patients were followed for 10 to 12 years in a study of outcome and cost. Costs for CABG were 53% higher initially, but the cost difference narrowed to 2% after 12 years, primarily because of repeat coronary intervention in the PCI group. The projected extension of life in the CABG group was 0.24 years, leading to a cost-effectiveness estimate of $11,300/ quality adjusted life year (QALY) compared with PCI. (A cost effectiveness of less than $20,000/QALY is considered to be a highly effective treatment [9]). Results from other trials of CABG versus PCI in MVD, in aggregate, are consistent with the result from the BARI trial. A meta-analysis of nine randomized controlled trials of CABG versus PCI in MVD revealed that survival was equivalent in these selected randomized patients at 1 year and 3 years, but initial CABG compared with initial PCI had a significant survival advantage at 5 years and 8 years (Figs 2 and 3) [10]. Rapid Evolution of Revascularization Technology The response of the interventional cardiology community to the survival advantage demonstrated in the RCTs of CABG versus PCI was rapid and, from a marketing perspective, effective. The RCTs were dissected in a post hoc manner, claiming that if high-risk subgroups were removed (specifically diabetic patients), then the residual patients exhibited no survival benefit from CABG [7]. The RCTs were already compromised by low enrollment and by a selection of patients thought not to be clinically disadvantaged by use of either technique. One may be somewhat incredulous that any reasonable reviewer might find it appropriate to peel off another layer of

3 Ann Thorac Surg EDITORIAL REVIEW GUYTON 2006;81: CABG VERSUS STENTS IN MULTIVESSEL DISEASE 1951 Fig 2. Meta-analysis of nine randomized controlled trials: percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG) in multivessel disease. (pts patients.) (Reprinted from J Am Coll Cardiol, 41, Hoffman SN et al, A meta-analysis of randomized controlled trials comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty: one- to eight-year outcomes, , copyright 2003, with permission from American College of Cardiology Foundation [10].) higher risk patients from this highly selected subgroup of MVD patients. The second, and equally effective, response of the interventional cardiology community was that PCI in the mid 1990s had evolved rapidly with the introduction of stenting and antithrombosis drugs, which almost eliminated acute occlusion, dramatically reduced the need for emergency CABG, and decreased the rate of restenosis of treated lesions. An equally strong argument can be made that the quality and efficacy of CABG improved in the early 1990s. Weintraub and associates [11] at Emory examined outcomes and costs from 12,200 CABG patients from 1988 to1996. Multiple risk factors were significantly increased: age, prior coronary artery bypass, diabetes mellitus, prior myocardial infarction, class III or IV angina, congestive heart failure, hypertension, multivessel coronary disease, and low ejection fraction. Despite increased severity of disease, multiple outcome variables improved. Notably, operative mortality decreased from 4.7% to 2.7%. Accounting for the increased severity of patients, this was a 10% decrease in mortality per year (p ). Postoperative length of stay decreased from 9.2 to 5.9 days. Fig 3. Data from meta-analysis of nine randomized controlled trials of coronary artery bypass graft surgery (CABG) versus percutaneous transluminal coronary angioplasty (PTCA) in multivessel disease. The 8-year mortality rate was 13.7% with CABG versus 17.1% with PTCA (p 0.03). Relative mortality with PTCA was 25% higher than with CABG [10]. Related to this decrease in length of stay, hospital costs importantly decreased from $22,700 to $16,000 per case. Adjusting for increased patient severity, hospital costs decreased by $1,118 per year during this 9-year period [11]. PCI Versus CABG Data From Registries of Entire Populations In addition to randomized controlled trials, a very important comparison of the relative utility of PCI and CABG comes from analysis of outcomes of the application of these interventions in the treatment of coronary artery disease in entire captive populations. As described above, the RCTs of PCI versus CABG are limited by highly selected enrollment and extrapolation of RCT results to entire MVD populations is simply inappropriate. Prospectively gathered data on the outcome of PCI and CABG as applied to an entire captive population provides our best evaluation of how successfully practioners have applied the evidence from RCTs, metaanalyses, and uncontrolled trials to the treatment of patients in the real world. A very important comparison of PCI versus CABG in the treatment of coronary disease comes from the New York State Cardiac Procedure Registries. Hannan and associates [12] compared results of PCI versus CABG in New York State residents from 1993 to Three-year mortality rates were adjusted using proportional hazards methods to account for baseline differences in patients severity of illness. Practioners were skilled, with excellent results in both PCI and CABG (hospital mortality 0.4% for PCI and 1.9% for CABG). With 3-year follow-up, repeat revascularization rate was 11 times higher in the PCI group (37% PCI, 3.3% CABG). Most importantly, however, in MVD, mortality was significantly elevated in the PCI patients compared with CABG. In the case of triple-vessel disease, 3-year adjusted mortality was 43% higher with primary PCI relative to primary CABG (absolute 3-year mortality 13.9% with PCI, 9.7% with CABG). It certainly appears that, at least in 1993 to 1995, the enthusiasm of cardiologists for PCI led to utilization of PCI relative to CABG in a manner that may not have been in the best interests of New York State patients with MVD.

4 1952 EDITORIAL REVIEW GUYTON Ann Thorac Surg CABG VERSUS STENTS IN MULTIVESSEL DISEASE 2006;81: Randomized Controlled Trials of PCI With Stents Versus CABG in Multivessel Disease Three major RCTs of PCI with stents versus CABG have been reported: the Arterial Revascularization Therapies Study (ARTS) with 5-year follow-up [13], the Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in Multivessel Disease (ERACI II) with 5-year follow-up [14], and the Stent or Surgery Trial (SoS) with 2-year follow-up [15]. The ARTS trial randomly assigned 1,205 patients with MVD in 67 centers [13]. The ARTS was a very PCIfriendly trial with enrollment only when the cardiologist and surgeon agreed that equivalent revascularization of two or more lesions could be achieved with either method. Only 5% of screened patients were enrolled. Patients enrolled were very low risk patients: no previous intervention, no congestive heart failure, no recent myocardial infarction, no cerebrovascular accident, mean age 61 years, and mean ejection fraction A major concern in the ARTS trial is a problematic difference between the PCI group and the CABG group in timely therapy after randomization. Treatment with with stents occurred an average of 11 days after randomization with no deaths, 1 myocardial infarction, and no strokes in this interval. Treatment with CABG averaged 27 days after randomization with 3 deaths, 4 myocardial infarctions, and 1 stroke in this interval. Delay in initiation of therapy in the surgical group led to a 0.5% mortality and more than 1% major adverse cardiac and cerebral event rate before therapy was initiated [16]. The authors analysis of results included these pretreatment events despite this problematic difference between the groups. The following paragraphs present a postprocedure outcomes analysis, which accommodates the difference in timeliness of therapy in the two groups. One-year results in ARTS were not surprising, with equivalent mortality and major adverse cardiac and cerebral event rate in each group. But despite PCI-friendly enrollment, deaths after the procedure were the same (15 in stent group, 14 in CABG group) at 1 year. As in EAST and BARI, percutaneous intervention for MVD does not have a lower early (1-year) mortality rate compared with CABG. This equal 1-year mortality is not the general perception of the public or of cardiologists. Additionally, 16.8% of the stent group versus only 3.5% of the CABG group required repeat revascularization by 1 year. Even with repeat revascularization, significantly more of the stent group had angina (21%) compared with the CABG group (10%) [16]. Five-year follow-up of the ARTS trial revealed postprocedure mortality of 7.1% at 5 years in the CABG group and 8% in the stent group (yielding a rough relative risk of 1.13). Five-year postprocedure death, myocardial infarction, or stroke rate was 13.5 % for CABG and 18% for PCI/stents (relative risk approximately 1.33). Repeat revascularization was 8.8% for CABG and 30% for PCI/ stents (relative risk approximately 3.46). Despite the fact that the study was not powered to detect a mortality, myocardial infarction, or stroke difference between groups and the postprocedure data favored CABG, the authors of the 5-year follow-up concluded: At five years there was no difference in mortality between stenting and surgery for MVD. Furthermore, the incidence of stroke or myocardial infarction was not significantly different between the two groups. They further endorse stenting by stating that the difference in outcomes seen between bare metal stents (BMS) versus CABG is likely to narrow substantially with the advent of drug-eluting stents (DES) [13]. The not-so-subtle bias of the ARTS authors favoring stenting is a particular concern because of at least one major conflict of interest that was not disclosed in the 1-year and 3-year reports. Doctor Brian Firth was on the board of governors of the study group and was acknowledged for... careful review of the manuscript and for... constructive suggestions [16]. Undisclosed was the fact that Dr Firth was Vice President of Cordis, a division of Johnson and Johnson, the stent manufacturer that supported the study [17]. In the report of 5-year results, Dr Firth was a coauthor of the report, and it was disclosed that he was an employee of Cordis [13]. The extent of this conflict is beyond the usual standards for properly run RCTs. The ERACI II trial randomly assigned 450 MVD patients over 2 years in seven Argentine centers. The mean age of patients was 61 to 62 years; 40% of the patients had two-vessel disease. The 30-day mortality was 5.6% in the CABG group and 0.9% in the stent group. The remarkably high CABG mortality was attributed to unstable angina in 91% of the CABG patients. As in the ARTS trial, there was a relative delay in therapy for CABG patients after randomization (13.2 days for CABG and 4.2 days for stent). One death occurred in the CABG group before the procedure and no deaths in the stent group. The high 30-day mortality for CABG led to a significantly better 5-year mortality with stenting: 7.2% versus 11.6%. Fiveyear major adverse cardiac and cerebral event rate was better with CABG: 23.6% versus 34.7% (related to more revascularization in the stent group) [14, 18]. The major issue related to the outcomes in ERACI II is concern about the high 30-day CABG mortality. The yearly average CABG volume in the seven participating centers was 57 patients! Internal mammary artery use was 89% in these approximately 62-year-old patients. With an institutional CABG volume of 1 patient per week, a delay of 13 days for CABG (these would have to be called elective patients, despite the fact that they may have been unstable at the time of enrollment), internal mammary artery use in less than 90%, and a CABG operative mortality of 5.6%, a very serious question must be raised about the quality of surgical therapy in this study. The authors expressed concern about the unusually large percent of patients with unstable angina, stating that results could change if the patient population treated had different baseline clinical characteristics or if technical proficiency for either treatment was altered [14, 18]. The SoS trial from 53 centers in Europe and Canada randomly assigned 988 patients for whom revasculariza-

5 Ann Thorac Surg EDITORIAL REVIEW GUYTON 2006;81: CABG VERSUS STENTS IN MULTIVESSEL DISEASE 1953 tion was indicated and appropriate by either strategy. The study sample size was calculated to detect a difference in revascularization in the two treatment strategies, assuming a repeat revascularization rate of 5% in the CABG group and 10% in the PCI group. At 2 years median follow-up, revascularization was dramatically higher than assumed in the PCI group at 21%, compared with 6% in the CABG group (a 15% absolute difference rather than the 5% difference assumed when the study was designed, hazard ratio 3.85, p ). Again there was a delay between randomization and therapy (mean 14 days for PCI and 23 days for CABG), but the CABG group was not disadvantaged by this delay (1 pretreatment death occurred, in the PCI group). The authors struggled with the fact that the CABG group had a significantly lower cumulative risk of death than the PCI group. At 2 years median follow-up, mortality was 2% CABG versus 5% PCI (8 deaths versus 22 deaths, hazard ratio 2.91, p 0.01). There was a higher rate of noncardiovascular death in the PCI group (9 versus 3, ratio 3:1), but even with the noncardiovascular deaths excluded, there were 13 deaths in the PCI group compared with 5 deaths in the CABG group (ratio 2.6:1). The authors acknowledged that surgical mortality in SoS was low. To some extent this result is an indication of the nature of the trial population, who had a favorable coronary anatomy and surgical risk profile. They further state: Our findings are most applicable to patients matching our trial population, many of whom would currently be offered a PCI procedure [15]. The outcome of SoS clearly favored CABG as a superior treatment for MVD. But despite a difference in repeat revascularization rate for stenting that was three times the assumed difference (p ) and a mortality in the PCI group that was 2.9 times the mortality in the CABG group (p 0.01), the authors made the following interpretation as the entire conclusion of the Summary: The use of coronary stents has reduced the need for repeat revascularization compared with previous studies that used balloon angioplasty, though the rate remains significantly higher than in patients managed with CABG. The apparent reduction in mortality with CABG requires further investigation [15]. It is certainly notable that the conclusion of the summary failed to state the superior results observed with CABG versus PCI, and, instead, the conclusion provides yet another endorsement of PCI. In the SoS authors discussion of the low surgical mortality in SoS, they state: Further information is required before any definitive conclusion can be drawn. Such information might become available with extended follow-up and a meta-analysis of the current stent versus surgery trials is planned. The SoS trial was supported by funding from a consortium of stent manufacturers: Bard (now Medtronic), Guidant, and Schneider (now Boston Scientific). There is no robust follow-up in progress for SoS; funding from these sources stopped after the 2-year report. There will be a mortality follow-up funded by a grant from the British Heart Foundation (personal communication from Dr R. H. Stables, Cardiothoracic Center, Liverpool, England). There will be no 5-year comprehensive report as there was for ARTS and ERACI II. Any meta-analysis will not include robust follow-up of SoS patients. In a way, a change in funding sources has led to a relative censoring of data that appeared to be not favorable to PCI. Drug-Eluting Stents The response of the interventional cardiology community to the data from SoS or the meta-analysis showing that CABG is superior to PCI for MVD is simple and predictable. Again, there is a claim of evolving and improving technology supposedly outpacing progression of improvement in CABG. The drug-eluting stent (DES), they say, has dramatically reduced restenosis and this change, by itself, is sufficient to move most of MVD into the realm of PCI. But equivalent survival compared with CABG in MVD can be accomplished by PCI with DES only if the reduction in restenosis rate translates into reduced mortality. This translation does not occur. No mortality benefit of DES compared with bare metal stents has been demonstrated. A meta-analysis examined 11 trials of DES versus bare metal stents. Not a single trial demonstrated a mortality benefit for DES and, in aggregate, the mortality outcomes appeared to be identical (Fig 4) [19]. Not only was there no benefit of DES with regard to mortality, there was also no benefit with regard to myocardial infarction (Fig 5) [19]. A second very important consideration is related to the fact that after PCI a decrease in in-stent or in-lesion restenosis is not equivalent to a decrease in subsequent revascularization. Although this is considered to be a new observation by some [2], data relative to restenosis versus total need for revascularization have been available for more than a decade [20]. Two hundred patients were followed for 5 to 10 years after successful PCI, with repeat revascularization performed only in symptomatic patients. Restenosis was the isolated cause of repeat revascularization only 43% of the time. Progression of disease elsewhere in the coronary system was operative in repeat revascularization in 57% of patients. Percutaneous coronary intervention generally treats proximal lesions and is more susceptible to progression of disease (and sudden vascular occlusion, which causes myocardial infarction) than CABG, in which the anastomosis is in the distal portion of the vessel. Even if in-lesion restenosis is zero, about half of the subsequent revascularization associated with PCI will still occur. British Assessment of Drug-Eluting Stents In Great Britain, the National Health Service Health Technology Assessment Programme conducted a recent assessment: Coronary Artery Stents: A Rapid Systematic Review and Economic Evaluation, published in 2004 [21]. Economic modeling was done with projections of benefits extending beyond the short follow-up of published studies. Their evaluation of mortality for CABG and stenting in MVD found that stenting was minimally superior until 18 months (accumulated extension of life 3

6 1954 EDITORIAL REVIEW GUYTON Ann Thorac Surg CABG VERSUS STENTS IN MULTIVESSEL DISEASE 2006;81: Fig 4. Forest plot of mortality from trials comparing drug-eluting stents (DES) with bare metal stents (BMS). (Reprinted from The Lancet, 364, Babapulle MN, A hierarchical Bayesian metaanalysis of randomized clinical trials of drug-eluting stents, , copyright 2004, with permission from Elsevier [19].) days), but after 18 months, CABG was progressively more beneficial. By 10 years, accumulated extension of life by CABG was 6 months compared with stents. A detailed model was constructed for a low-risk patient with double-vessel disease, since approximately 90% of single-vessel disease was treated by PCI and approximately 90% of triple-vessel disease was treated by CABG in Great Britain. The model corrected for bias created by delay in treatment. Because of progressive benefits of CABG, by 5 years, CABG had cost effectiveness in simple two-vessel disease of 69,619 pounds/ly compared with bare metal stents and 52,411pounds/LY compared with DES. Cost effectiveness for CABG was projected to continue to improve for subsequent years [21]. Modeling was then done for MVD with higher risk patients (eg, poor left ventricular function, more than two vessels diseased, diabetic, and so forth). In patients with moderately increased risk compared with the low risk double-vessel disease patient, CABG became very cost effective compared with PCI with either bare metal stents or drug-eluting stents. The study concluded that In the case of multiple-vessel disease the accumulated trial evidence comparing CABG with PTCA with bare metal stents is sufficient to project over 5 years an important and substantial survival advantage for CABG over PTCA with bare metal stents. Given that CABG is the standard therapy for most patients with multiple-vessel disease, it is difficult to justify substitution by a less effective treat- Fig 5. Forest plot of myocardial infarction from trials comparing drug-eluting stents (DES) with bare metal stents (BMS). (Reprinted from The Lancet, 364, Babapulle MN, A hierarchical Bayesian meta-analysis of randomized clinical trials of drugeluting stents, , copyright 2004, with permission from Elsevier [19].)

7 Ann Thorac Surg EDITORIAL REVIEW GUYTON 2006;81: CABG VERSUS STENTS IN MULTIVESSEL DISEASE 1955 Fig 6. Adjusted 3-year mortality for initial coronary artery bypass graft surgery (CABG [gray bars]) versus initial stenting (black bars). Data for patients with nonproximal left anterior descending artery (LAD) disease obtained from Dr Michael J. Racz [23], University at Albany, State University of New York. (2VD two-vessel disease; 3VD three-vessel disease; prox proximal.) ment simply on the grounds that it is cheaper.... This argument remains valid also in the case of DES, since the the apparent additional benefits from fewer interventions and consequent QoL (Quality of Life) gains are balanced by the extra costs of the new stents. Hence we find no grounds for the substitution of CABG by DES in multiple vessel disease. Indeed we find that higher risk individuals gain greater relative benefit from CABG, not less [21]. The British conclusion was supported by a study from Stanford by Yock and colleagues [22], which used modeling to compare life-time cost effectiveness of PCI and CABG by updating and extending the results of BARI, updating the results for the effect of stents on PCI results. The model predicted a life-time survival benefit of CABG over PCI with stenting of 0.83 years. Initial CABG was a dominant therapy compared with initial stenting, with a lower life-time cost ( $8,400) and a higher effectiveness ( 0.31 QALY) compared with initial stenting. To accommodate the possibility that progressive improvements in drug-eluting stents may minimize restenosis, a sensitivity analysis was done to examine the effect of complete elimination of restenosis after stenting in the model. Even with complete elimination of restenosis, CABG remained a dominant therapy compared with PCI with stenting. The lifetime cost benefit was still less ( $150), and a clinical benefit remained: 0.27 QALY. The authors concluded:... although elimination of target lesion restenosis does improve the short-term outcomes of catheter-based interventions.... these improvements are not enough to make primary stenting less costly and more effective than CABG for relieving angina in patients with multivessel disease [22]. Stents Versus CABG in Clinical Practice Review of the outcomes of PCI and CABG in entire captive populations, as discussed previously, provides powerful insight into the real-world clinical application of revascularization strate gies. The New York State Registry data, reported by Hannan and associates [23] in 2005 gives us a real world comparison of the clinical use of PCI with stents and CABG for MVD. Approximately 60,000 MVD patients in 1997 through 2000 underwent CABG (n 37,212) or PCI with stents (n 22,102). Again, 3-year mortality rates were adjusted using proportional hazards methods to account for differences in patients severity of illness. Again, the overall quality of PCI and CABG was excellent (hospital mortality: CABG 1.75%, PTCA 0.68%). Results of 3-year follow-up revealed that repeat revascularization rate was reduced compared with the PCI without stent data presented in 2000, but not nearly so much as one would expect. Repeat revascularization rate was reduced from 37% to 35.1% after PCI between the two studies. Repeat revascularization rate after CABG increased from 3.3% to 4.9%. The relative risk of repeat revascularization after PCI compared with CABG was reduced from 11 times to 7 times higher [12, 23]. This result is consistent with and supports the concept presented earlier that a decrease in restenosis rate does not translate into an equivalent decrease in repeat revascularization rate. As in the SoS trial, the repeat revascularization rate after PCI with stenting was reduced, but not nearly so much as interventionalists would predict. Mortality outcomes in the New York Registry report were most enlightening. For patients with two-vessel disease including the proximal left anterior descending artery (LAD), 3-year adjusted mortality was 7.9% with CABG versus 10.2% with stents; relative 3-year mortality with stents was 29% higher than with CABG. For patients with triple-vessel disease including the proximal LAD, the 3-year adjusted mortality was 10.7% with CABG versus 15.6% with stents. Relative mortality with initial stent therapy was 46% higher than with initial CABG. Mortality data for all categories of patients with MVD are presented in Figures 6 and 7 [23]. (Data for patients with Fig 7. Relative excess mortality at 3 years with initial stenting versus initial coronary artery bypass graft surgery (CABG). Data for patients with nonproximal left anterior descending artery (LAD) disease obtained from Dr Michael J. Racz [23], University at Albany, State University of New York. (2VD two-vessel disease; 3VD three-vessel disease; prox proximal.)

8 1956 EDITORIAL REVIEW GUYTON Ann Thorac Surg CABG VERSUS STENTS IN MULTIVESSEL DISEASE 2006;81: MVD and nonproximal LAD disease obtained from Dr Michael J. Racz, University at Albany, State University of New York.) Most remarkable from the New York Registry is a comparison with the 2000 report of CABG versus PCI with minimal stent use. The widespread use of stents, as applied clinically in the State of New York, led to no reduction in 3-year mortality relative to CABG for patients with three-vessel disease including the LAD (43% increased relative mortality with PCI in the 2000 report, 46% increased relative mortality with PCI in the 2005 report) [12, 23]. These outcomes are as predicted by the British Health Service analysis: In the case of MVD the evidence is sufficient to project an important and substantial survival advantage for CABG over PTCA with BMS [21]. As restenosis is minimally related to mortality and since multiple trials have shown no survival benefit of DES compared with bare metal stents, there is every reason to believe the remainder of the British Health Service conclusion, that this substantial survival advantage for CABG is valid also in the case of DES [21]. Observations on Appropriate Patient Education Are patients facing the need for revascularization for MVD aware of the survival advantage of initial CABG compared with initial PCI? In 1981, I stood outside the door of a patient s room, awaiting my turn to speak to a patient about the relative advantages of CABG versus angioplasty for revascularization. I overheard Dr Andreas Gruntzig tell the patient: I can fix your blockage with this little catheter or I can have Dr. Guyton crack your chest. The intuitive, emotional appeal of Dr Gruntzig s statement was overpowering. There were no data to support the use of PCI in 1981, but I had no response that had any chance of persuading the patient that CABG was a more proven option. I capitulated. In 2006, the statement of interventional cardiologists is: The drug eluting stents have solved the problem that we used to have with restenosis. You read about it in the newspaper and you saw it on TV. Let us fix your blockages with the stents. There is no difference in mortality and we can always go back and do a coronary bypass procedure if we have to. I just don t want you to have your chest cracked. Note that Dr Guyton is no longer the perpetrator of the chest cracking. That is because Dr Guyton no longer has an opportunity to speak to the patient. But there is another big difference in 2006: we do have data on CABG versus PCI. If the mortality of initial stenting were the same as the mortality of initial CABG, we would all choose stenting (including this author). But the mortality of initial CABG versus initial stenting for MVD is emphatically not the same! Surgeons cannot continue to capitulate to the intuitive and emotional arguments of interventional cardiologists. We surgeons must present our argument with the same conviction that cardiologists present their argument. For the patient with triple-vessel disease including the proximal LAD, the patient should hear our message: Coronary bypass is the procedure that gives you the best chance of being free from angina, and, if you have stenting as your first procedure instead of CABG, you have, on average, a 46% higher chance of dying in 3 years compared with CABG as your first procedure (or a 24%, 28%, or 29% higher chance of dying for lesser MVD [Fig 7]). In discussing coronary revascularization with a MVD patient, it is neither appropriate patient education nor good medical practice for the interventionalist to present only one argument. But do the interventionalists present both arguments? Can the interventionalist present both arguments? Is the interventionalist really going to say to the patient, If you choose PCI for initial therapy compared with initial CABG, you will have a significantly higher 3-year risk of death? For years, surgeons have been reluctant to dispute the arguments of local interventional cardiologists. This reluctance is understandable, as these cardiologists are the source of many CABG referrals, referrals that can be sent elsewhere if the surgeon is confrontational. But the application of PCI and CABG to MVD in the real world in a setting of good PCI and good surgeons in New York State, has resulted in a significantly higher 3-year mortality for initial PCI compared with initial CABG for all categories of MVD. There has been no improvement in this excess relative mortality in the stent era compared with the prestent era. Data presented above make a strong argument that drugeluting stents will have little impact on mortality. It is the responsibility of surgeons to participate aggressively in the decision of revascularization modality for patients with MVD. We must educate primary care physicians, physician extenders, noninvasive cardiologists, invasive cardiologists, and patients. For surgeons to continue to accept passively whichever patients arrive at the operating room door in the hope of preserving personal referrals is a serious disservice to the patients whom we seek to serve. The author wishes to acknowledge the advice and insight of Manuel J. Irarrazaval, MD, Catholic University Hospital, Santiago, Chile, in the analysis of randomized controlled trials of CABG versus stents. References 1. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994;344: Klein LW. 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