Treatment options for multivessel coronary artery disease

Since the first steps of the pioneering work of Andreas Gruentzig, interventional cardiology has evolved and expanded into multiple fields; fields that, in the past, were considered to be mainly surgical territories. Undeniably, the major focus of interventional cardiology is coronary artery disease. Continuous improvement of devices and techniques has progressed from the limited treatment of single, simple lesions to the extensive management of multiple and severely complex stenoses: but are we there yet? Are we where Gruentzig was dreaming to lead us? Is it justified to treat those patients with multivessel coronary artery disease, left main involvement, chronic total occlusions or complex bifurcation lesions? Historical data from early trials comparing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) demonstrated that there were no differences in terms of mortality and myocardial infarction (MI), whereas it showed a more favorable outcome in the CABG arm regarding repeat revascularization and long-term relief from angina. However, these trials were conducted in the bare-metal stent era. The emergence of drug-eluting stents and progress in CABG procedures has rendered mandatory the design and implementation of new studies. The Arterial Revascularization Therapies Study (ARTS) II trial was the first to compare Cypher^TM stent implantation with the bare-metal stent and CABG arms of the ARTS I study. Three major, multicenter trials, SYNergy between PCI with TAXUS^TM and Cardiac Surgery (SYNTAX), Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) and Coronary Artery Risk Development in young adults (CARDia), which compare drug-eluting stent implantation with CABG, are currently ongoing.

Coronary artery bypass grafting versus bare-metal stent trials

In the past, several trials have assessed the long-term effects of PCI and CABG in patients with multiple-vessel coronary artery disease. The largest and most contemporary multicenter, randomized studies were conducted in the mid-to-late 1990s and are presented in table 1. The Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) trial completed enrolment over a period of 5 years [1] and randomly assigned 232 patients to CABG and 222 to PCI. The AWESOME trial was one of the first randomized, multicenter studies to demonstrate that there was not a significant difference in the global survival or the combined end point of survival free of unstable angina among patients with multiple-vessel disease treated with either CABG or PCI with stent implantation. These results were sustained up to 3-year follow-up. However, survival free of unstable angina and repeat revascularizations were observed to be generally greater in the CABG group than the corresponding PCI group [1].

The Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in Multivessel Disease (ERACI) II study included 450 patients; 225 patients were randomized for PCI and 225 for CABG [2]. ERACI II was the first trial to demonstrate a better survival and freedom from MI in the PCI arm compared with the CABG group. This difference in favor of the PCI strategy was mainly observed during the first 30 days, during which more patients died in the surgical group, and was abolished after 1 month. The surgical hospital mortality in the ERACI II study was higher than that demonstrated by other trials [3–5], but was mainly observed in patients with severe unstable angina. On the other hand, freedom from requirement of new revascularization procedures and major adverse cardiovascular events was significantly better with CABG patients [2,6].

The Stent or Surgery (SoS) trial [7], conducted in 53 centers in Europe and Canada, randomized a total of 988 patients. Of the patients initially randomized to PCI, 21% required one or more additional revascularization procedures, whereas in the CABG group, only 6% underwent additional PCI or CABG (p < 0.0001). The incidence of death or nonfatal Q-wave MI was similar in both groups, but survival was significantly lower in the PCI arm. Excess mortality in the PCI group was mainly due to the increased rate of cancer-related deaths in the particular study group [7].

ARTS was one of the largest trials designed to compare CABG and stenting in patients with multivessel disease [8]. In total, between April 1997 and June 1998, 1205 patients from 67 participating centers were randomized to either stent implantation or CABG. Both 1-year [9] and 5-year [10] follow-up results confirmed the findings of previous studies. Indeed, overall freedom from death, stroke or MI was not significantly different between groups, whereas the incidence of repeat revascularization was significantly higher in the PCI group than in the CABG group [9,10].

The same conclusions were drawn from a recent meta-analysis of the aforementioned trials [11]. The meta-analysis demonstrated that patients with multivessel disease undergoing CABG or PCI with stent implantation were protected against death, MI or stroke to a similar degree. By contrast, repeat revascularization procedures were higher after PCI compared with CABG [11]. Therefore, after taking into account these remarkable results, it is only natural to conclude that PCI is a safe option.

The major downside of stenting has been observed to be the increased reccurrence of angina and revascularization. As a consequence, in cost–effectiveness or quality-of-life assessment trials, even if PCI seemed to provide better results compared with CABG during the periprocedural period, these benefits were not sustained [2,9]. Additionally, there has been criticism that the majority of the randomized trials were highly selective and did not include what is commonly referred to as ‘real-world’ patients. Thus, is there a particular subset of patients (e.g., patients with diabetes mellitus, left main disease, chronic total occlusions or bifurcation lesions) that may not benefit in the long term from percutaneous revascularization procedures?

It must be kept in mind that these multicenter, randomized trials were conducted in the bare-metal stent era. Drug-eluting stents, this novel revolutionary breakthrough, appear to address the majority of the drawbacks that restrict the unlimited use of stents. Several studies and registries, such as Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) and TAXUS Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH), have consistently demonstrated promising results regarding high-risk populations with complex lesions [12–16]. Conversely, at a certain point, concerns were raised regarding the long-term safety of drug-eluting stents, as a consequence of the reported late endothelialization and potential induction of thrombosis [17]. Furthermore, drug-eluting stents are more expensive than conventional stents and prolonged, costly, antiplatelet regimens are required. It became apparent that large-scale, randomized trials comparing drug-eluting stents with CABG were mandatory in order to determine the safety, long-term efficacy and cost–effectiveness of drug-eluting stents.

Coronary artery bypass grafting versus drug-eluting stent trials

ARTS II was the first study to compare the effectiveness of sirolimus-eluting stent implantation with the historical two arms of ARTS I (PCI arm with bare-metal stent and CABG arm) [18]. ARTS II enrolled 607 patients (53.5% with three-vessel disease) from 45 centers. The study met its primary end point; the composite major adverse cardiac and cardiovascular events at 1 year were low (10.5%) and within the same range as the historical surgical arm of ARTS I. Even if the reintervention rates in the drug-eluting stent group were still higher than those of the surgical group, this was balanced by a higher incidence of death/stroke and MI in the surgical arm [18]. Additionally, in this particular study, it was striking to note that diabetic patients in the drug-eluting group, despite having markedly reduced event rates compared with those in the bare-metal stent group, still experienced an almost twofold increased need for repeat revascularization in the first year compared with nondiabetic patients.

The SYNTAX trial is a multicenter, randomized study designed to evaluate the optimum revascularization treatment for patients with de novo three-vessel disease and/or left main disease (either isolated or with one-, two- or three-vessel disease) by randomizing patients to either PCI with paclitaxel-eluting stents or CABG [19]. The trial also incorporates two registries that enroll patients, often encountered in real-world practice, who are not eligible for either PCI or CABG. The trial began enrolment in April 2005. A local heart team (consisting of an interventional cardiologist, cardiothoracic surgeon and study coordinator) screens all patients and decides if the individual fulfills the inclusion and exclusion criteria. If both PCI and CABG can achieve comparable revascularization, the patient is assigned to the randomized cohort; otherwise, they are included in one of the nested registries. Randomized patients are stratified at each site, based on the presence or absence of left main disease and medically treated diabetes mellitus (requiring oral medications or insulin). A total of 1500 patients will be randomized from approximately 90 participating centers in Europe and the USA. The primary end point is freedom from major adverse cardiac and cerebral events at 1 year. The CABG registry data may determine the complex, high-risk subsets that are not suitable for PCI with drug-eluting stents. Accordingly, the PCI registry data may define the population that CABG is inappropriate [19]. In the SYNTAX study, a scoring system has been introduced [20]; the SYNTAX score aims to provide a measure of coronary artery disease complexity, taking into account both the number of significant lesions (>50% by visual estimation) and the complexity of each lesion independently [20]. It has been hypothesized that higher scores will correspond to more severe coronary artery disease and will unambiguously identify patients with therapeutic challenge and potentially worse prognosis.

The FREEDOM multicenter trial will randomize 2400 diabetic patients with two- or three-vessel disease to either CABG or PCI with drug-eluting stents. The study will be conducted in the USA and Europe. The primary end point is mortality at 5 years. There will also be nested registries to capture patients treated with either PCI or CABG only.

CARDia is a UK- and Ireland-based trial currently in progress. It will randomize 600 diabetic patients with either complex one-vessel or multivessel disease to CABG or PCI [21]. The primary end point is the composite incidence of death, nonfatal MI or nonfatal stroke at 1 year. What is more, in this trial, a PCI and a CABG registry are incorporated, with the ultimate goal to compare their results with the randomized group.

Conclusion

Multivessel coronary artery disease remains a challenge for the interventional cardiologist. Previous randomized trials comparing PCI with bypass surgery have demonstrated similar medium- and long-term mortality, confirming the safety of stent implantation. However, there was an excess of angina reccurrence and repeat revascularization with bare-metal stents. The promising results demonstrated in small-scale studies and registries suggest that drug-eluting stents may optimally address this limitation. The future results of SYNTAX, FREEDOM and CARDia are anticipated with great interest and will most certainly expand the indications of percutaneous revascularization procedures in more complex and high-risk populations.

Table 1. PCI with bare-metal stents versus CABG trials.

Study	n	Inclusion criteria	End points	Patients with multivessel disease (%)	Follow-up	Outcomes		Ref.
						Survival free of repeat revascularization and angina	Survival
AWESOME	232* 222^†	Medically refractory myocardial ischemia and one or more of the five risk factors associated with increased 30-day operative mortality^§	Primary: survival Secondary: unstable angina, repeat hospitalization, repeat catheterization, repeat revascularization	83* 80†	3 years	55%* 44%^† p = 0.001	73% 78% p = 0.001	[1]
ERACI II	225* 225^†	Stable or unstable angina or mild symptoms, but with a large area of myocardium at risk by thallium scintigraphy	Primary: combined death, Q-wave MI, stroke and repeat revascularization at 30 days, 1, 3 and 5 years Secondary: angina, functional class, completeness of revascularization determined by stress thallium at 1-month follow-up and cost–effectiveness	96* 94.7^†	5 years	92.4%*^a 71.5%^†^a p = 0.019^a 82%*^b 86%^†^b p = 0.916^b	88.4% 92.8% p = 0.095	[2,6]
SoS	500* 488^†	Stable or unstable angina Equivalent revascularization not mandatory	Primary: rate of repeat revascularization Secondary: death or Q-wave MI, all-cause mortality, symptoms of angina, cardiac medication requirements and LVEF	100* 99†	2 years (median)	6%*^a 21%^†a p < 0.0001^a 79%*b 66%^†^b p < 0.0001^b	98% 95% p = 0.01	[7]
ARTS I	605* 600^†	Silent ischemia, stable or unstable angina and at least two de novo lesions located in different major epicardial arteries	Primary: survival free of death, cerebrovascular accident, nonfatal MI or repeat revascularization at 12 months Secondary: comparison of both strategies at 3 and 5 years	100* 98^†	5 years	91.2%*^a 69.7%^†^a p = 0.83^a	92.4% 69.7% p = 0.83	[9,10]

*CABG; ^†Percutaneous coronary intervention; ^§Risk factor: prior open heart surgery, age >70, left ventricular function <35%, MI in the past week or use of balloon pump; ^aSurvival free of repeat revascularization; ^bSurvival free of angina.ARTS: Arterial Revascularization Therapies Study; AWESOME: Angina With Extremely Serious Operative Mortality Evaluation; CABG: Coronary artery bypass grafting; ERACI: Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in Multivessel Disease; LVEF: Left ventricular ejection fraction; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; SoS: Stent or Surgery trial.

Table 2. PCI with drug-eluting stents versus CABG trials.

Study	n	Inclusion criteria	End points	Follow-up	Outcomes		Ref.
					Survival free of repeat revascularization	Survival
ARTS II	ARTS I - CABG: 602 ARTS I - PCI: 600 ARTS II – PCI: 607	Silent ischemia, stable or unstable angina and at least two de novo lesions located in different major epicardial arteries	Primary: all cause death, nonfatal MI, repeat revascularization and cerebrovascular events at 1 year Secondary: MACCE at 30 days, 6 months, 3 and 5 years; combined end-point: death, MI and stroke; and the itemized outcomes death, MI, repeat revascularization, stroke; resource use at 30 days and 1 year; cost–effectiveness at 1 year and quality of life at 6 months, 1, 3 and 5 years	1 year	95.7% 77.6% 91.5%	97.3% 97.3% 99%	[18]
SYNTAX	CABG: 750 PCI: 750	Patients with three-vessel coronary artery disease eligible for both CABG and PCI	Primary: death, MI, repeat revascularization and stroke at 12 months	30 days 6 months 1–5 years		Ongoing trial
FREEDOM	CABG: 1200 PCI: 1200	Patients with diabetes mellitus and multivessel coronary artery disease eligible for both CABG and PCI	Primary: composite of all cause mortality or nonfatal MI or stroke Secondary: death, MI, stroke and repeat revascularization at 1 year, survival at 1, 2, 3 years MACCE components at 30 days and cost–effectiveness	30 days 6 months 1–5 years		Ongoing trial
CARDia	CABG: 300 PCI: 300	Patients with diabetes mellitus and multivessel or complex single-vessel coronary disease eligible for both CABG and PCI	Primary: composite of death, nonfatal MI or nonfatal stroke at 1 year	30 days 6 months 1–5 years		Ongoing trial	[21]

ARTS: Arterial Revascularization Therapies Study; CABG: Coronary artery bypass grafting; FREEDOM: Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivascular disease; MACCE: Major adverse cardiac and cerebrovascular events, composite of death, nonfatal myocardial infarction, nonfatal stroke or any repeat revascularization; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; SYNTAX: SYNergy between PCI with TAXUS^TM and Cardiac Surgery.