It has been assumed since the dawn of angioplasty that coronary artery bypass surgery is superior to coronary angioplasty in patients with multi-vessel disease. It is a belief inculcated in me since my cardiology education started in the nineties. A fact supported by evidence of initial large randomized trials which clearly demonstrated the superiority of coronary artery bypass surgery over angioplasty in particularly three subsets (diabetics, multivessel disease and impaired LV function) in terms of mortality and morbidity benefit.

My upbringing and development as an interventional cardiologist has paralleled the growth of coronary angioplasty over bypass surgery. The turn of the millennium marked the turnaround in numbers of coronary bypass surgery and angioplasty.

The goals of myocardial revascularization include reduction in mortality rate, improvement in symptoms, and prevention of nonfatal cardiac events, such as myocardial infarction (MI), stroke, and repeat coronary revascularization.

Selection of the optimal revascularization strategy depends on several factors like, severity of symptoms of ischaemia and degree of functional capacity, amount of demonstrable ischaemia and jeopardized myocardium, degree, proximity, and anatomical complexity of the CAD, degree of left ventricular dysfunction, presence of comorbid conditions, presence of diabetes, procedural risk, cost considerations and lastly but not the least, patient preference.

The clinical trials have certain limitations which includes1 data are often outdated by completion of the study because of rapid advances in medical, percutaneous, and surgical techniques,2 trial participants are a highly selected population that represents only a small fraction of the real world patients,3 most trials are underpowered to detect differences in mortality rates and4 enrollment excludes patients with significant comorbid conditions (e.g., stroke, renal dysfunction, acute coronary syndromes, significant left ventricular dysfunction, and previous bypass surgery).

Although these large, multicentre, randomized clinical trials have inherent limitations. They address therapeutic issues surrounding proper selection of the optimal revascularization strategy in patients with multivessel CAD. The most recent clinical trials that compare PCI to CABG in multivessel disease are reviewed here.

What did the old trials say?
In general, the initial trials comparing PTCA and CABG performed in the 1990s enrolled patients who had relatively low risk and relatively normal left ventricular function (ejection fraction, > 50%). These randomized trials were performed before the availability of improved anticoagulation during PCI (e.g. GP IIb/IIIa inhibitors, direct thrombin inhibitors) and before the widespread use of coronary stents. Study participants had primarily two-vessel disease that was deemed treatable by either method, had no previous PCI or CABG, and had no serious comorbid conditions. The trials were performed before widespread use of intracoronary stents and glycoprotein IIb/IIIa inhibitors.

In general, the findings of these trials were consistent and revealed no differences in overall survival or rate of Q-wave MI in patients with multivessel CAD who were randomly assigned to PTCA or CABG. There was a lower rate of repeat revascularization in the patients who underwent CABG than in those who had PTCA. The Bypass And Revascularization Investigation (BARI) found that patients with treated diabetes who underwent revascularization had a lower mortality with CABG than with PCI, which was dependent on use of a left internal mammary artery graft to the left anterior descending artery.

What did Bare Metal Stents and newer adjuncts do with the above evidence?
Since publication of results of the initial large, randomized clinical trials that compared PCI using percutaneous transluminal coronary angioplasty (PTCA) to CABG in the 1990s, remarkable advances have been made in percutaneous and surgical methods of revascularization. The increased availability and use of intracoronary stenting have been a major development in PCI.

Currently, more than 80% of PCI procedures are performed using stents, and several clinical trials have demonstrated clear benefits of stents compared with balloon angioplasty in regard to results in acute angiography, need for emergency CABG, and restenosis rates.6 Similarly, there has been concomitant growth in pharmacological adjunctive therapy, including the thienopyridenes (e.g., clopidogrel), and glycoprotein IIb/IIIa inhibitors.

The recent large, randomized trials that compared intracoronary stenting with CABG in treatment of multivessel CAD7-9 are discussed here.

Arterial Revascularization Therapies Study (ARTS) trial : Five-year (long-term) outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease. A total of 1,205 patients with the potential for equivalent revascularization were randomly assigned to CABG (n = 605) or stent implantation (n = 600). The mean age of subjects was 61 years, and patients with diabetes made up 19% of the stent group and 16% of the CABG group (P=ns). Study participants had normal left ventricular function (mean ejection fraction, 61% in the PCI arm and 60% in the CABG arm). About two thirds of the patients had two-vessel CAD and one third had three-vessel CAD; the left anterior descending coronary artery was involved in 90% of both groups.

The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events (MACCE) at one year. MACCE at five-year follow-up constituted the final secondary end point.

Results
At 1 year, no significant differences between the stent and CABG groups were found in death rate (2.5% versus 2.8%) or incidence of stroke (1.7% versus 2.1%), Q-wave MI (5.3% versus 4.3%), or non-Q-wave MI (0.8% versus 0.5%). Among patients who survived without a stroke or MI, a significantly higher percentage of the stent group than the CABG group (16.8% versus 3.5%) needed repeat revascularization. The rate of event-free survival at 1 year was 73.8% in the stent group compared with 87.8% in the CABG group (P< .001 by log-rank test). The better outcome at 1 year in the CABG group was also reflected in the higher rate of freedom from angina (90% versus 79%; P < .001) and the lower use of antianginal medications (42% versus 21%; P < .001).

At five years, there were 48 and 46 deaths in the stent and CABG groups, respectively (8.0% vs. 7.6%; p = 0.83; relative risk [RR], 1.05; 95% confidence interval [CI], 0.71 to 1.55). Among 208 diabetic patients, mortality was 13.4% in the stent group and 8.3% in the CABG group (p = 0.27; RR, 1.61; 95% CI, 0.71 to 3.63). Overall freedom from death, stroke, or myocardial infarction was not significantly different between groups (18.2% in the stent group vs. 14.9% in the surgical group; p = 0.14; RR, 1.22; 95% CI, 0.95 to 1.58). The incidence of repeat revascularization was significantly higher in the stent group (30.3%) than in the CABG group (8.8%; p < 0.001; RR, 3.46; 95% CI, 2.61 to 4.60). The composite event-free survival rate was 58.3% in the stent group and 78.2% in the CABG group (p < 0.0001; RR, 1.91; 95% CI, 1.60 to 2.28).

ARTS also analyzed costs and cost-effectiveness of both stenting and CABG. The investigators found that the cost for the initial procedure was less in patients who underwent PCI than in those who underwent CABG. However, this net difference in favour of stenting was reduced at 1 year because of the need for repeat revascularization and at 3 years stenting was no longer more cost-effective than CABG.

Conclusions
At five years there was no difference in mortality between stenting and surgery for multivessel disease. Furthermore, the incidence of stroke or myocardial infarction was not significantly different between the two groups. However, overall MACCE was higher in the stent group, driven by the increased need for repeat revascularization.

Stent or Surgery (SoS) trial : The Stent or Surgery (SoS) trial,8 performed in 53 centres in Europe and Canada, randomly assigned patients with multivessel CAD to CABG (n=500) or PCI with stent implantation (n=488). The primary end point was repeat revascularization, and secondary end points included death or Q-wave MI and all-cause mortality.

After a median follow-up period of 2 years, additional revascularization procedures were required in 21% (n=101) of the PCI group compared with 6% (n=30) of the CABG group (hazard ratio, 3.85; 95% CI, 2.56-5.79; P<.0001). The incidence of death or Q-wave MI was similar in both groups—9% for PCI and 10% for CABG (hazard ratio, 0.95; 95% CI, 0.63-1.42; P=.80). There were fewer deaths in the CABG group (2%) than in the PCI group (5%) (hazard ratio, 2.91; 95% CI, 1.29-6.53; P=.01). The SoS trial has been criticized for the strikingly low mortality rate after CABG at 1 year (0.8%).

ERACI II trial : Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II).⁹

ERACI II trial Compared PCI-guided stent implantation with conventional CABG in symptomatic patients with multivessel CAD. A total of 2,759 patients with CAD were screened at seven clinical sites, and 450 patients were randomly assigned to undergo either PCI (225 patients) or CABG (225 patients). Only patients with multi-vessel disease were enrolled. Clinical follow-up during five years was obtained in 92% of the total population after hospital discharge. The primary end point of the study was to compare freedom from major adverse cardiovascular events (MACE) at 30 days, 1 year, 3 years, and 5 years of follow-up.

Results
During the first 30 days, rates of major adverse events (i.e., death, MI, repeat revascularization, and stroke) were lower in the PCI group than in the CABG group (3.6% versus 12.3%; P=.002). After a mean follow-up period of 18.5 months (±6.4), the survival rate was higher in the PCI group than in the CABG group (96.9% versus 92.5%; P< .017). More patients in the PCI group were free from MI (97.7% versus 93.4%; P< .017). However, patients in this group were more likely to need repeat revascularization than those in the CABG group (16.8% versus 4.8%; P< .002). ERACI II9 has been criticized for the strikingly high mortality rate at 1 year (5.8%) in the CABG arm.

Immediate and one-year follow-up results of the ERACI II study showed a prognosis advantage of percutaneous coronary intervention (PCI) with stents over coronary artery bypass grafting (CABG).

At five years of follow-up, patients initially treated with PCI had similar survival and freedom from non-fatal acute myocardial infarction than those initially treated with CABG (92.8% vs. 88.4% and 97.3% vs. 94% respectively, p = 0.16). Freedom from repeat revascularization procedures (PCI/CABG) was significantly lower with PCI compared with CABG (71.5% vs. 92.4%, p = 0.0002). Freedom from MACE was also significantly lower with PCI compared with CABG (65.3% vs. 76.4%; p = 0.013). At five years similar numbers of patients randomized to each revascularization procedure were asymptomatic or with class I angina.

Conclusions
At five years of follow-up, in the ERACI II study, there were no survival benefits from any revascularization procedure; however patients initially treated with CABG had better freedom from repeat revascularization procedures and from MACE.

All three of these trials were consistent in the observation that stenting reduced the rate of repeat revascularization by about half that of historical controls treated with PTCA alone. However, this rate was still worse than that of CABG.

What did Drug Eluting Stents do with the accumulated wisdom?
ARTS-2 Trial evaluated patients with multivessel coronary artery disease undergoing coronary angioplasty with stenting drug eluting stents).

607 patients with multivessel coronary lesions (26.2% diabetic 54% 3 vessel disease 13.9% type C lesions) received sirolimus-eluting stents with average of 3.7 stents per patient with an average total length: 73 mm.

Historical Controls from ARTS-1 were used for comparison: 1205 patients with multivessel coronary lesions (18.2% diabetic, 28% 3 vessel disease 7.5% type C lesions).

At one year, there was no difference in event-free survival between the ARTS-2 SES group and the ARTS-1 CABG group. However, the ARTS-2 group showed significantly higher rates of survival free from cardiac death, MI, and reintervention than the ARTS-1 bare metal stent group. The groups were not significantly different in the primary endpoint of survival free from MACE.

Among patients with multivessel coronary lesions, patients treated with sirolimus eluting stents (ARTS-2) had significantly lower rates of MACE compared with a historical registry of similar patients treated with bare metal stents (ARTS-1) and rates of MACE statistically equivalent to patients from the same registry treated with CABG
(ARTS-1).

The majority of the difference in MACEbetween the ARTS-2 and ARTS-1 BMS groups was driven by the increased need for repeat revascularization in the bare metal stent group. The ARTS-2 group (DES) had equal rates of revascularization to the ARTS-1 CABG group, despite having increased length and complexity of lesions.

While this historical registry comparison is promising and statistically significant, a randomized trial is needed to adequately determine the superiority of one therapy over another.

The big bang entry of drug eluting stents has revolutionised the whole thinking behind management of multivessel coronary artery disease.

Impact of Diabetes
What is the impact of diabetes on outcome of these procedures? In ARTS, multivariate analysis revealed that the presence of diabetes was the main predictor of outcome in the stent group. Subgroup analysis evaluating the clinical impact of diabetes revealed that in diabetic patients with multivessel CAD who were treated with stenting, outcome at 1 year was worse than in both patients assigned to CABG with routine use of arterial conduit and nondiabetic patients treated with stenting.¹¹

Also at 1 year, diabetic patients treated with stenting had the lowest event-free survival rate (63.4%) because of a higher incidence of repeat revascularization than both diabetic patients treated with CABG (84.4%, P< .001) and nondiabetic patients treated with stenting (76.2%, P=.04). Conversely, diabetic patients and nondiabetic patients had similar rates of 1-year event-free survival when treated with CABG (84.4% and 88.4%, respectively). The 1-year mortality rate in patients with diabetes who were randomly assigned to the stent arm was twice that of patients in the CABG arm (6.3% versus 3.1%), but this increase was nonsignificant). Among 208 diabetic patients at five years, mortality was 13.4% in the stent group and 8.3% in the CABG group (p = 0.27; RR, 1.61; 95% CI, 0.71 to 3.63).

Risk of plaque rupture is determined not by the patency of the vessel but rather by the stability of the underlying atheromatous plaque. In fact, the majority of episodes of acute coronary occlusion occur in vessels with “mild” lesions that do not limit flow (ie, <70% stenosis).12 The reasons behind the better outcomes demonstrated with CABG than with PCI in treated diabetic patients are multifactorial and relate primarily to issues surrounding the diabetic vascular milieu and more rapidly progressive atherosclerosis.13 PCI improves luminal narrowing at the site of coronary intervention. However, it has no impact on the remainder of the coronary vessel and on the risk of spontaneous plaque rupture and subsequent coronary thrombosis and occlusion.

This risk varies from 1% to 2% per year in nondiabetic patients with single-vessel disease to 10% to 15% per year in diabetic patients with multivessel disease.14 Thus, the increased mortality rate demonstrated in diabetic patients who underwent PCI compared with the rate in those who received CABG is likely due to an increased propensity for progression of atherosclerosis and the inherent inability of PCI to prevent subsequent plaque rupture at a site distant from the stented area. In contrast, coronary occlusion in the left anterior descending artery proximal to the anastomosis of the left internal mammary artery in a patient who had CABG may result in only a mild or subclinical infarction because of the presence of a parallel arterial conduit.

A meta-analysis of 13 randomized trials that compared CABG with PCI in 7,964 patients15 suggested that CABG was associated with less angina and fewer revascularization procedures. Overall, the addition of stents reduced the need for repeat revascularization by about 50%. Thus, the results of these trials are concordant in that the rates of death and MI in the PCI and CABG arms were similar, although the risk of recurrent angina and of repeat revascularization procedures was increased in the PCI group.16 More data are needed to define the optimal revascularization strategy in diabetic patients with multivessel CAD.

Does the future belong to Drug Eluting Stents?
Development of the drug-eluting stent has been one of the most exciting areas of innovation in interventional cardiology. Several studies involving different stent platforms and antiproliferative drug coatings (sirolimus17 and paclitaxel18) have demonstrated reductions of up to 70% in restenosis and repeat revascularization rates compared with the bare-metal stent. However, implantation of a drug-eluting stent does not appear to reduce the frequency of death, MI, or stroke19—a finding consistent with previous data that failed to identify any difference in 6-year mortality rate between patients with and without restenosis.²⁰

In the TAXUS IV trial,21 which enrolled 1,314 patients (315 [24%] with medically treated diabetes), the risk of target vessel revascularization was reduced by 53% (11.3% versus 24%, P<. 004) in patients with diabetes who received a paclitaxel-eluting stent in a single native coronary vessel. These patients and patients without diabetes had similar rates of angiographic recurrence after drug eluting stent implantation. Although the outcomes of drug-eluting stent use in multivessel CAD have not been extensively studied, it seems likely that this stent will result in similar reductions in adverse events after multivessel PCI, considering the favourable results of drug-eluting stent implantation in highly complex lesions.²²

The ARTS-2 trial23 compared the contemporary (sirolimus) a drug-eluting stent outcome against the historical CABG results from the ARTS-1 trial. This registry showed that despite the higher risk profile in ARTS-2, use of a drug-eluting stent resulted in statistically similar freedom from death, cerebrovascular events, MI, or repeat percutaneous or surgical revascularization procedure at 1 year. Thus, use of the drug-eluting stent may eliminate the apparent advantage that patients with CABG currently have over patients with PCI in need for repeat procedures.

Conclusion
Multivessel Coronary artery disease (CAD) remains the major cardiovascular health issue in contemporary clinical practice. Treatment options include percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).

The frequency of death, stroke and MI is nearly equal for PCI and CABG when they are compared as an initial revascularization strategy. Although the frequency of repeat revascularization is lower with stents than was previously reported with balloon angioplasty; it is still higher than with CABG. The cost benefit with coronary angioplasty may be decreased in later years with repeat revascularisation. All surgical results, which show superiority of bypass surgery, have evaluated arterial revascularisation with internal mammary artery. In real world scenario the extent to which patients receive total arterial revascularisation with off pump surgery in bypass surgery is important.

The only apparent advantage (decreased mortality) offered by CABG over PCI may be in patients with diabetes who are treated with CABG that involves grafting of the left internal mammary artery to the left anterior descending artery.

The ARTS II group (Drug Eluting Stent) had equal rates of revascularization to the ARTS I CABG group, despite having increased length and complexity of lesions. While this historical registry comparison is promising and statistically significant, a randomized trial is needed to adequately determine the superiority of one therapy over another.

With the advent of drug-eluting stents and the promise of reduced restenosis rates in multivessel disease, the gap between the rates of repeat procedures after PCI and CABG may eliminate. However the crucial issue of the optimal revascularization strategy in patients with diabetes will need to be determined by large prospective randomized trials.

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