Complex and Multivessel Percutaneous Coronary Intervention

Key Points

Myocardial revascularization, which aims to relieve the negative prognostic impact of coronary artery disease left untreated, has emerged as a strategy to improve prognosis and quality of life in patients with multivessel disease (MVD).
Over the past four decades, percutaneous coronary intervention (PCI) has evolved into a safe and reproducible procedure that, using an armamentarium of cutting-edge devices, has extended the possibility of noninvasive revascularization in complex anatomical settings.
Results of the recent landmark clinical trials in patients with MVD have consistently shown a substantial equipoise between PCI and coronary artery bypass grafting (CABG) in terms of hard clinical outcomes (i.e., mortality, myocardial infarction), with the exception of MVD in the context of diabetes mellitus.
Consistently across trials, differences favoring CABG over PCI were mainly driven by higher rates of repeat revascularization.
The adoption of clinical and interventional strategies (i.e., risk stratification, use of ischemia- or imaging-guided percutaneous revascularization) to properly guide the selection of PCI candidates, as well as to improve PCI procedural results, will hopefully contribute to filling the observed gap between CABG and PCI outcomes.
Translating rigorous scientific evidence into clinical practice will further contribute to refining our understanding of proper anatomical and clinical thresholds for the appropriateness of percutaneous revascularization in patients presenting with MVD.

Introduction

A complex interplay of clinical and anatomical factors lies behind the naive angiographic definition of multivessel coronary artery disease (CAD). Indeed, while multivessel disease (MVD) is scholastically defined as the presence of significant atheromatous disease involving two or three coronary arteries as detected by coronary angiography, a wide spectrum of clinical and anatomical circumstances enters the clinical definition of MVD in the real world. Thoroughly weighting all these factors challenges decision making in daily clinical practice, so that pinpointing the optimal balance between safety and efficacy issues in the selection of a proper revascularization strategy becomes a clinical hurdle. Comprehensively looking at these clinical and angiographic factors in the context of multidisciplinary heart team discussion, as advocated by current guidelines, has emerged as a key factor for improving outcomes after revascularization. Also, risk stratification tools have been developed to accurately support decision making between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI).

PCI has evolved from a hazardous technique allowing simple balloon angioplasty of isolated proximal coronary lesions to a safe and reproducible procedure that, using an armamentarium of cutting-edge devices, has extended the possibility of noninvasive revascularization in complex anatomical settings. The advent and iteration of stent device technology has been crucial in this process. Newer generation drug-eluting stents (DES) have consistently demonstrated to sizably improve the safety and efficacy outcomes of coronary stenting. As such, nowadays studies looking at plain old balloon angioplasty (POBA) or the use of bare-metal stents (BMS) for PCI in patients with MVD can be considered mainly of historical interest since these procedural strategies are not used any longer as a default approach in modern interventional cardiology practice. This chapter will provide a comprehensive overview of the modern strategies to properly select patients, as well as perform and optimize PCI results in patients with MVD based on available evidence from landmark studies in the field.

Multivessel Disease: Prevalence and Prognostic Implications

Estimating the true unbiased prevalence of MVD is challenging since patients undergoing coronary angiography generally have a clinical indication prompting for invasive cardiac catheterization. Patients with cardiac valve diseases undergoing preoperative coronary angiography represent a cohort where the risk of referral bias for angiography is lowered. In these patients, a small study found that the prevalence of MVD, defined as two or more vessels with clinically significant stenosis or stenosis of the left main (LM) coronary artery, was 21.2%. As expected, the prevalence of MVD is higher, reaching 32.3% for three-vessel disease, in patients undergoing clinically driven angiography as reported in the Swedish Coronary Angiography and Angioplasty Registry. Similarly, data from the CathPCI registry in the United States showed a prevalence of two- and three-vessel disease in patients undergoing coronary angiography for different clinical indications of 29.3% and 16.0%, respectively.

It is intuitive that the higher the burden and extent of CAD the poorer the prognosis and the expected survival. Indeed, a simultaneous presence of CAD in multiple coronary arteries increases the total amount of myocardium at jeopardy and increases the risk of myocardial ischemia. The negative clinical consequences of ischemia, including myocardial infarction (MI), arrhythmias and heart failure, clinically translate into poorer outcomes and survival in the long term. Data on the prognostic impact of MVD left untreated mainly derive from the first randomized clinical trials comparing CABG with optimal medical therapy and no revascularization. A patient-level meta-analysis of these trials showed that patients undergoing revascularization with CABG had significantly lower mortality compared to patients who were managed conservatively both at 5 years (10.2% vs. 15.8%; odds ratio [OR] 0.61; 95% confidence interval [CI] 0.48 to 0.77; P = .0001) and at 10 years (26.4% vs. 30.5%; OR 0.83; 95% CI 0.70 to 0.98; P = .03). The risk of mortality at 5 years was reduced by 68% and 42% in patients with LM and three-vessel disease, respectively. Also, the prognostic benefits of revascularization are demonstrated when looking at the outcomes of patients who are denied surgery due to the presence of distal CAD. Indeed, among these patients, cardiac mortality and MI at 1 year were excessively high, reaching 39.2% and 37.2%, respectively. Patients with three-vessel CAD left untreated had a significant (fourfold) increase in the risk of death (51.6% vs. 20%, P = .039; OR 4.26; 95% CI 1.16 to 15.69). As such, revascularization, which aims to relieve the negative prognostic impact of CAD left untreated, has emerged as a strategy to improve prognosis and quality of life in this scenario and, nowadays, is the cornerstone of treatment in patients with MVD.

Revascularization in Patients with Multivessel Disease: Strategies, Landmark Studies, and Outcomes

While surgical revascularization initially represented the only option for myocardial revascularization, the advent of PCI opened a clinical path to a less-invasive revascularization strategy. A plethora of randomized clinical trials have compared the clinical outcomes following revascularization with CABG or PCI. The initial studies were conducted comparing CABG with POBA or PCI with BMS implantation. However, drawbacks of POBA and BMS use (e.g., procedural complications, restenosis, need for repeat revascularization) are well known, especially in patients with MVD. Therefore, studies comparing the outcomes of CABG versus POBA or BMS implantation can nowadays be considered of historical interest since, as reported above, these procedures do not represent a default approach in modern interventional cardiology practice. Results of studies comparing CABG with POBA, or PCI with BMS implantation are summarized in Table 25.1 .

TABLE 25.1

Randomized Controlled Trials Comparing Noncontemporary Percutaneous Coronary Intervention Strategies with Coronary Artery Bypass Grafting

Trial	Population	Treatment	Follow-Up	Principal Findings
BARI	Symptomatic patients with MVD ( n = 1,829)	POBA vs. CABG	10 years	Survival was 71% for PTCA and 73.5% for CABG ( P = .18). The PTCA group had substantially higher subsequent revascularization rates compared with the CABG group (76.8% vs. 20.3%, P < .001)
RITA	1,011 patients (45% single-vessel and 55% multivessel disease)	POBA vs. CABG	6.5 years (median)	Death or nonfatal MI occurred in 17% of the PTCA group and in 16% of the CABG group ( P = .64). The prevalence of angina and repeat CABG were consistently higher in the PTCA group
GABI	Symptomatic patients with MVD ( n = 8,981)	POBA vs. CABG	1 year	One year after treatment, 74% of the patients in the CABG group and 71% of those in the PTCA group were free of angina
EAST = Emory Angioplasty versus Surgery	Patients with MVD ( n = 392)	POBA vs. CABG	3 years	The primary end point of death, MI, or a large ischemic defect was not different, and repeat revascularization was significantly greater in the angioplasty group. Survival was comparable at 8 years
CABRI	Patients with MVD ( n = 1,054)	POBA vs. CABG	1 year	Patients randomized to PTCA required significantly more reinterventions, took more medications and more frequently had clinically significant angina
ERACI = Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease	Patients with MVD ( n = 127)	POBA vs. CABG	3 years	Freedom from death, Q-wave MI, angina, and repeat revascularization procedures was significantly greater for the CABG group
ARTS	Patients with MVD ( n = 1,205)	BMS vs. CABG	5 years	The overall freedom from death, stroke, or MI was not significantly different between the groups. The incidence of repeat revascularization was significantly higher in the stent group
AWESOME = Angina With Extremely Serious Operative Mortality Evaluation	Patients with refractory angina and one risk factor for adverse outcome with CABG ( n = 454)	BMS vs. CABG	3 years	No significant difference in survival was reported, which was 79% and 80% for CABG and PCI, respectively. However, there was a difference in survival free of revascularization: 66% and 44% for CABG and PCI, respectively ( P = .001)
MASS II = Medicine, Angioplasty, or Surgery Study II	611 patients randomly assigned to undergo CABG ( n = 203), PCI ( n = 205), or medical therapy ( n = 203)	MT vs. BMS vs. CABG	10 years	After multivariate Cox analysis at 10-year follow-up, a protective effect of CABG compared with MT = medical therapy (HR 0.43; 95% CI 0.32 to 0.58; P < .001) and PCI (HR 0.53; 95% CI 0.39 to 0.72; P < .001) was observed for the combined incidence of overall mortality, MI, or refractory angina
SoS = Stent or Surgery	Symptomatic patients with multivessel CAD ( n = 988)	Stent-assisted PCI vs. CABG	6 years (median)	Higher risk of death with PCI (HR 1.66; 95% CI, 1.08 to 2.55; P = .022). The combined incidence of death or Q-wave MI was similar in both groups
ERACI II	450 patients with MVD	BMS vs. CABG	5 years	Similar survival and freedom from nonfatal acute MI was observed between PCI and CABG (92.8% vs. 88.4% and 97.3% vs. 94%, respectively, P = .16).

ARTS, Arterial Revascularization Therapies Studies; AWESOME, Angina With Extremely Serious Operative Mortality Evaluation; BARI, Bypass Angioplasty Revascularization Investigation; BMS , bare-metal stents; CABG , coronary artery bypass grafting; CABRI , Coronary Angioplasty versus Bypass Revascularisation Investigation; CAD, coronary artery disease; CI , confidence interval; EAST, Emory Angioplasty versus Surgery; ERACHI, Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease; GABI , German Angioplasty Bypass Surgery Investigation; HR , hazard ratio; MASS II, Medicine, Angioplasty, or Surgery Study II; MI , myocardial infarction; MT, medical therapy; MVD , multivessel disease; PCI , percutaneous coronary intervention; POBA , plain old balloon angioplasty; PTCA, percutaneous transluminal coronary angioplasty; RITA , randomized intervention treatment of angina; SoS, Stent or Surgery.

The iteration of stent device technology has been crucial to fill the consistent gap in terms of clinical outcomes seen between CABG and PCI using BMS/POBA. Indeed, DES have been consistently demonstrated to sizably improve the safety and efficacy of coronary stenting. DES iteration has proceeded along two main directions: a progressive reduction of stent strut thickness, and the use of antiproliferative drugs eluted from permanent or bioresorbable polymers, to counteract neointimal hyperplasia.

Almost 10 years ago, the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) trial was the first of a series of landmark studies assessing the comparative performance of PCI using DES and CABG in patients with MVD.

The SYNTAX Trial

The SYNTAX trial was an all-comer, multicenter, noninferiority randomized clinical trial that enrolled and randomized 1800 patients with three-vessel/LM CAD to undergo CABG or PCI with paclitaxel-eluting stents in a 1:1 ratio. A total of 705 patients had CAD with isolated LM involvement, while three-vessel disease (not including LM) was encountered in 1095 patients. Patients were enrolled only if the local cardiac surgeon and the interventional cardiologist deemed the patient equally eligible to undergo revascularization by CABG or PCI. The primary clinical end point of the study was a composite of major adverse cardiac and cerebrovascular events (MACCE) including death from any cause, stroke, MI, or repeat revascularization at 1 year after randomization. For the first time in a revascularization trial, the evaluation of the anatomical burden and complexity of underlying CAD for each patient was evaluated using the SYNTAX score (SS). The SS is a multiparametric angiographic quantification tool (i.e., 12 questions ranging from anatomy to characteristics of lesions subsets such as bifurcations or chronic total occlusions), which numerically expresses the complexity of CAD in patients undergoing revascularization. A user-friendly online calculator of the score is available at http://www.syntaxscore.com/calculator/start.htm . Patients in the SYNTAX trial were stratified according to the SYNTAX into: low SS group defined as SS ≤22, intermediate SS ranging from 23 to 32, and a high SS when the SS was ≥33. The study was powered to demonstrate noninferiority of PCI as compared to CABG at 1 year using a noninferiority margin of 6.6%.

In the overall study cohort, the 1-year rates of MACCE were significantly higher in the PCI group (17.8% vs. 12.4% for CABG, P = .002) and noninferiority was not met. The difference in the primary end point was largely driven by the higher rates of repeat revascularization in patients treated with PCI (13.5% vs. 5.9%, P < .001). The number needed to treat; that is, the number of CABG procedures needed to prevent one repeat revascularization, was 13.2. There was a significant interaction between the SS and the treatment groups concerning the primary end point ( P = .01). Indeed, PCI was comparable to CABG in the lower SS group but had significantly higher rates of MACCE in the intermediate and high SS groups.

In the subgroup of patients with LM disease (36.6% of these patients had three-vessel disease), the rate of MACCE was similar between CABG and PCI groups (13.7% and 15.8%, respectively; P = .44), while in patients having three-vessel disease without LM involvement, MACCE rates were significantly increased in the PCI group compared to the CABG group (19.2% vs. 11.5%, P < .001).

The results of the SYNTAX trial, stratified by the anatomical burden of CAD (LM involvement or MVD without LM disease), were consistent at the intermediate and longest available follow-up (3 and 5 years, respectively). In analyses based on SS terciles, PCI had comparable clinical outcomes for patients with LM disease in the low and intermediate SS groups, while in patients with three-vessel disease, PCI and CABG had similar rates of MACCE only in the lowest SS tercile.

The BEST Trial

The Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease (BEST) trial compared the outcomes of CABG and PCI with second-generation everolimus-eluting stents in patients with MVD. The study was conducted at 27 centers in East Asia, and a total of 880 patients were randomized to CABG or PCI in a 1:1 ratio. The primary end point of the study was a composite of death, MI, or target-vessel revascularization. Due to slow enrollment, the initial sample size of 1776 patients—required to demonstrate the noninferiority of PCI with respect to CABG at 2 years using a noninferiority margin of 4%—was not achieved. MVD was defined in the study as the presence of two- or three-vessel disease without LM involvement. At 2 years, the primary end point occurred in 11.0% of patients assigned to PCI and in 7.9% of patients randomly assigned to CABG (absolute risk difference, 3.1 percentage points; 95% CI −0.8 to 6.9; P = .32 for noninferiority). During long-term follow-up, the primary end point was more frequently encountered in the PCI group than in the CABG group (15.3% vs. 10.6%; hazard ratio [HR] 1.47; 95% CI, 1.01 to 2.13; P = .04). Consistent with the results of the SYNTAX trial, the difference was mainly driven by significantly higher rates of repeat revascularization in the PCI group. The composite of death, MI, or stroke did not differ between PCI and CABG (11.9% and 9.5%, respectively; P = .26).

The FREEDOM Trial

The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial explored the comparative performance of CABG and PCI in diabetic patients with MVD. MVD was defined as the presence of a stenosis of more than 70% by angiography in two or more major epicardial vessels involving at least two separate coronary-artery territories and without LM involvement. Sirolimus- or paclitaxel-eluting stents were the types most frequently used in the study. The primary outcome of the trial was a composite of all-cause death, nonfatal MI, and nonfatal stroke. A total of 1900 patients with a mean SS of 26.2 ± 8.6 were randomized in the study. The median follow-up time was 3.8 years (interquartile range, 2.5 to 4.9). The rate of the primary end point was significantly lower in the CABG group as compared to the PCI group ( P = .005 by the log-rank test). The divergence of the curves started to become more evident at 2 years. At 5 years, the event rates were 26.6% and 18.7% in the PCI and CABG groups, respectively (absolute difference of 7.9 percentage points, 95% CI, 3.3 to 12.5; number of CABG procedures needed to prevent one event = 12.7). Importantly, all-cause death was significantly increased in patients who underwent PCI ( P = .049). The results were consistent in the subgroup of patients with two-or three-vessel disease ( P for interaction = .75).

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