**2. Left main coronary artery disease**

#### **2.1 Introduction**

LMCA is a disease with significant morbidity and mortality, since it threatens a large myocardial territory. LMCA stenosis occurs in approximately 15% of patients with symptomatic ischemic heart disease [24]. The most common cause of LMCA disease is atherosclerosis, which is rarely focal and involves bifurcation in 80% of cases, which usually extends from the LMCA to the LAD [25]. In the beginning, the treatment of choice for this disease was the CABG [26]. However, after the introduction of PCI, there was a growing interest in the treatment of the LMCA. Both European [20] and American [21] guidelines recommend CABG (class I) as the treatment of choice for LMCA in patients with low risk score. These recommendations were based mainly on the results of the LMCA subgroup analysis of the SYNTAX trial (705 patients) that showed no differences in the MACCE between CABG and PCI in patients with LM disease [27]. Patients treated with PCI had a lower stroke but a higher revascularization rate than CABG. The results of the PRECOMBAT trial [28] compare PCI to CABG in the treatment of LMCA. The two groups did not differ significantly in MACCE. Ischemia-driven revascularization occurred more frequently in the PCI group than in the CABG group. In addition, the LE MANS trial [29] with a 10-year follow-up compared PCI and CABG in patients with LMCA with low or medium SYNTAX score. The primary end point was the left ventricular ejection fraction (LVEF) that was slightly higher in the PCI group than the CABG group. The introduction of new-generation DES with proven efficacy and safety prompted the design of two large randomized trials: the Nordic-Baltic-British Left Main Revascularization Study (NOBEL) [30] and the Evaluation of Xience versus Coronary artery bypass surgery for Effectiveness of Left main revascularization (EXCEL) trial [31]. It is important to note that, when an LMCA PCI is performed, there is a greater awareness of the need to achieve optimal procedural results by using the available technologies, including the most effective stents, intravascular evaluation of image, and physiology. And when one faces a real bifurcation with a Medina classification [32], it is necessary to use two stents. It would seem that the best technique is double kissing balloon with crush (DKC) [33].

**11**

*Current Status, Perspectives, and Future Directions of Multivessel Disease and Left Main…*

LE MAS trial, [29] in this prospective, multicenter trial, randomly assigned 105 patients with LMCA with low and medium complexity of coexisting coronary artery disease according to SYNTAX score to PCI with stenting (n = 52) or CABG (n = 53). DES were implanted in 35%, whereas arterial grafts to the left anterior descending artery were utilized in 81%. This study is very interesting because it offers a 10-year follow-up, which as a primary end point was the evaluation of the ejection fraction between PCI and CABG in the treatment of LMCA. Although there were no significant differences, there was a tendency in favor of PCI

(54.9 ± 8.3% vs. 49.8 ± 10.3%, p = 0.07). Regarding mortality, MI, and TVR, there were no statistical differences between the two groups, although there was also a trend of greater MACCE-free survival in the PCI group (34.7% vs. 22.1%, p = 0.06; reason risk, 1.71; 95% confidence interval (CI), 0.97–2.99). The Nordic-Baltic-British Left Main Revascularization Study [30] is a prospective, randomized, open-label, non-inferiority trial done at 36 centers in Europe. Patients were randomized to CABG or PCI. LMCA were visually assessed with diameter ≥ 50% or fractional flow reserve ≤0.80 in different segments of the left main coronary artery. SYNTAX score was calculated and all patients with low, medium, and high score were included. Patients were treated with the intention of achieving CR. Biolimuseluting stent was the recommended stent in this trial. Distal bifurcation lesions could be treated with various techniques preferably by the "culotte" technique. IVUS was strongly recommended pre- and post-stent deployment. In the CABG group, the left internal mammary artery was recommended for revascularization of the left anterior descending coronary artery, and for the other lesions, saphenous venous grafts, free arterial grafts, or the right internal mammary artery could be used. The primary end point was a MACCE. About 1184 patients were included in the analysis (592 patients in each group). The SYNTAX scores were similar between the two groups (22.4 in the PCI group and 22.3 in the CABG group). CABG was performed with the on-pump technique in 84% of patients, and 96% of patients underwent arterial grafting of the left anterior descending artery. Kaplan-Meier estimates of MACCE were significantly higher in PCI (28%) than in CABG (18%). The rate of MI and revascularization was significantly higher in PCI group than in CABG, but the overall mortality and stroke were not statistically significant. At 30 days, the stroke rate in PCI group was significantly less than in the CABG group, but this difference was not seen at 1- and 5-year follow-up. The EXCEL trial [31] was a prospective randomized open-label, non-inferiority trial undertaken at 126 centers in 17 countries around the world. Patients were randomized to receive either CABG or PCI. Patients who had stable and unstable angina were included in the study; however patient who were having MI were excluded. Patients were included if they had LMCA of 70% assessed visually or 50–70% determined by means of invasive or noninvasive methods. SYNTAX score was determined and patients who had score of higher than 33 were excluded. CR was the intention of treatment in both groups. A second-generation DES EES was used in this study. Distal bifurcating lesions were treated with a two-stent strategy using various techniques. CABG was performed both on- and off-pump, with the aim of CR for vessels with 50% stenosis. Arterial grafts were strongly recommended. The primary end point was MACCE at 3 years. The intention-to-treat (ITT) analysis was used in this trial. A total of 1905 patients underwent randomization, 948 were assigned to the PCI group and 957 to the CABG group. The SYNTAX score according to assessment at local sites was low (≤22) in 60.5% of the patients and intermediate (23–32) in 39.5% of the patients. Distal LMCA was present in 80.5% of the patients. IVUS imaging guidance was used in nearly 80% of the patients in the PCI group. There was no

*DOI: http://dx.doi.org/10.5772/intechopen.89419*

**2.2 Main trials of the LMCA**

*Current Status, Perspectives, and Future Directions of Multivessel Disease and Left Main… DOI: http://dx.doi.org/10.5772/intechopen.89419*

#### **2.2 Main trials of the LMCA**

*The Current Perspectives on Coronary Artery Bypass Grafting*

with radiographic capability [23].

**2. Left main coronary artery disease**

**1.7 Conclusions**

**2.1 Introduction**

Everolimus-Eluting Metallic Stents evaluates the efficacy of hybrid coronary revascularization (HCR) combining CABG and PCI in the treatment of MVD. CABG is to be performed in the left anterior descending artery and the left circumflex artery using only arterial grafts, whereas PCI is to be conducted for the treatment of the right coronary artery with everolimus-eluting stents (EESs) [22]. The Comparison of One-stop Hybrid Revascularization vs. Off-pump Coronary Artery Bypass for the Treatment of Multi-vessel Disease combines minimally invasive direct CABG and PCI to be performed in the hybrid operating suite, an enhanced operating room equipped

In our long experience in the treatment of MVD for more than two decades and according to our score, we believe that the stratified treatment can be divided into two groups, patients with low and intermediate scores in whom the results of PCI are comparable with surgery. The other group of patients are those with high scores, we think that the current state-of-the-art CABG is the treatment of choice. However, with the increase in stent technology this difference can be reduced.

LMCA is a disease with significant morbidity and mortality, since it threatens a large myocardial territory. LMCA stenosis occurs in approximately 15% of patients with symptomatic ischemic heart disease [24]. The most common cause of LMCA disease is atherosclerosis, which is rarely focal and involves bifurcation in 80% of cases, which usually extends from the LMCA to the LAD [25]. In the beginning, the treatment of choice for this disease was the CABG [26]. However, after the introduction of PCI, there was a growing interest in the treatment of the LMCA. Both European [20] and American [21] guidelines recommend CABG (class I) as the treatment of choice for LMCA in patients with low risk score. These recommendations were based mainly on the results of the LMCA subgroup analysis of the SYNTAX trial (705 patients) that showed no differences in the MACCE between CABG and PCI in patients with LM disease [27]. Patients treated with PCI had a lower stroke but a higher revascularization rate than CABG. The results of the PRECOMBAT trial [28] compare PCI to CABG in the treatment of LMCA. The two groups did not differ significantly in MACCE. Ischemia-driven revascularization occurred more frequently in the PCI group than in the CABG group. In addition, the LE MANS trial [29] with a 10-year follow-up compared PCI and CABG in patients with LMCA with low or medium SYNTAX score. The primary end point was the left ventricular ejection fraction (LVEF) that was slightly higher in the PCI group than the CABG group. The introduction of new-generation DES with proven efficacy and safety prompted the design of two large randomized trials: the Nordic-Baltic-British Left Main Revascularization Study (NOBEL) [30] and the Evaluation of Xience versus Coronary artery bypass surgery for Effectiveness of Left main revascularization (EXCEL) trial [31]. It is important to note that, when an LMCA PCI is performed, there is a greater awareness of the need to achieve optimal procedural results by using the available technologies, including the most effective stents, intravascular evaluation of image, and physiology. And when one faces a real bifurcation with a Medina classification [32], it is necessary to use two stents. It would seem that the

best technique is double kissing balloon with crush (DKC) [33].

**10**

LE MAS trial, [29] in this prospective, multicenter trial, randomly assigned 105 patients with LMCA with low and medium complexity of coexisting coronary artery disease according to SYNTAX score to PCI with stenting (n = 52) or CABG (n = 53). DES were implanted in 35%, whereas arterial grafts to the left anterior descending artery were utilized in 81%. This study is very interesting because it offers a 10-year follow-up, which as a primary end point was the evaluation of the ejection fraction between PCI and CABG in the treatment of LMCA. Although there were no significant differences, there was a tendency in favor of PCI (54.9 ± 8.3% vs. 49.8 ± 10.3%, p = 0.07). Regarding mortality, MI, and TVR, there were no statistical differences between the two groups, although there was also a trend of greater MACCE-free survival in the PCI group (34.7% vs. 22.1%, p = 0.06; reason risk, 1.71; 95% confidence interval (CI), 0.97–2.99). The Nordic-Baltic-British Left Main Revascularization Study [30] is a prospective, randomized, open-label, non-inferiority trial done at 36 centers in Europe. Patients were randomized to CABG or PCI. LMCA were visually assessed with diameter ≥ 50% or fractional flow reserve ≤0.80 in different segments of the left main coronary artery. SYNTAX score was calculated and all patients with low, medium, and high score were included. Patients were treated with the intention of achieving CR. Biolimuseluting stent was the recommended stent in this trial. Distal bifurcation lesions could be treated with various techniques preferably by the "culotte" technique. IVUS was strongly recommended pre- and post-stent deployment. In the CABG group, the left internal mammary artery was recommended for revascularization of the left anterior descending coronary artery, and for the other lesions, saphenous venous grafts, free arterial grafts, or the right internal mammary artery could be used. The primary end point was a MACCE. About 1184 patients were included in the analysis (592 patients in each group). The SYNTAX scores were similar between the two groups (22.4 in the PCI group and 22.3 in the CABG group). CABG was performed with the on-pump technique in 84% of patients, and 96% of patients underwent arterial grafting of the left anterior descending artery. Kaplan-Meier estimates of MACCE were significantly higher in PCI (28%) than in CABG (18%). The rate of MI and revascularization was significantly higher in PCI group than in CABG, but the overall mortality and stroke were not statistically significant. At 30 days, the stroke rate in PCI group was significantly less than in the CABG group, but this difference was not seen at 1- and 5-year follow-up. The EXCEL trial [31] was a prospective randomized open-label, non-inferiority trial undertaken at 126 centers in 17 countries around the world. Patients were randomized to receive either CABG or PCI. Patients who had stable and unstable angina were included in the study; however patient who were having MI were excluded. Patients were included if they had LMCA of 70% assessed visually or 50–70% determined by means of invasive or noninvasive methods. SYNTAX score was determined and patients who had score of higher than 33 were excluded. CR was the intention of treatment in both groups. A second-generation DES EES was used in this study. Distal bifurcating lesions were treated with a two-stent strategy using various techniques. CABG was performed both on- and off-pump, with the aim of CR for vessels with 50% stenosis. Arterial grafts were strongly recommended. The primary end point was MACCE at 3 years. The intention-to-treat (ITT) analysis was used in this trial. A total of 1905 patients underwent randomization, 948 were assigned to the PCI group and 957 to the CABG group. The SYNTAX score according to assessment at local sites was low (≤22) in 60.5% of the patients and intermediate (23–32) in 39.5% of the patients. Distal LMCA was present in 80.5% of the patients. IVUS imaging guidance was used in nearly 80% of the patients in the PCI group. There was no

difference between the two groups in respect to the primary composite end-point event of death, stroke, or myocardial infarction at 3 years (15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group). At 3 years, the composite end-point event of death, stroke, myocardial infarction, or ischemiadriven revascularization had occurred in 23.1% of the patients in the PCI group and in 19.1% of the patients in the CABG group. Ischemia-driven revascularization during follow-up was more frequent after PCI than after CABG (in 12.6% vs. 7.5% of the patients, p < 0.001). Stent thrombosis occurred in only 0.7% of patients within 3 years after the procedure and was less common than symptomatic graft occlusion. In the Premier of Randomized comparison of Bypass surgery versus Angioplasty using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) [28] trial was a randomized study where 600 patients with LMCA went to PCI with a first-generation of DES or CABG. The primary end point was the combined events, MACCE, at 5 years of follow-up 17.5% were observed in the PCI and 14.3 % in the CABG group, p = 0.26. Regarding the mortality of all causes, MI or stroke, there were no significant differences. The TVR was more frequent with PCI than with CABG (11.4% vs. 5.5%, p = 0.012).

### **2.3 Analysis of the two principal trials**

As we could see in these last two studies on PCI and CABG in the LMCA, we can see that the NOBLE [30] study included higher-risk patients and used a pharmacological stent with biodegradable polymer. In addition to the fact that the most frequently used technique was "culotte" by recommendation, the use of IVUS was only 75% in post PCI patients, and only 55% of the kissing balloon was performed. In addition the use of the proximal optimization (POT) was not specified, and firstgeneration stent was also used in 8% of patients. In the EXCEL study [31], a secondgeneration stent was used in patients with low and intermediate SYNTAX scores, and the amount of IVUS used reached 77%. The use of POT was also not specified, no special bifurcation technique was recommended, and the use of kissing balloon was also not specified (**Table 3**).

#### **2.4 Meta-analysis**

The objective was to compare clinical results and safety during short- and long-term follow-up by conducting a meta-analysis of large pooled data from randomized controlled trials and updated observation. The primary outcome was MACCE, MI, stroke, all-cause mortality, and revascularization after at least 1 year of follow-up. A subgroup analysis was also performed with a follow-up of over 5 years. A total of 29 studies with 21,832 patients (10,424 with PCI and 11,408 with CABG) were analyzed. At 1-year follow-up there was a significant difference in favor of the CABG in MACCE, TVR, and MI, but the stroke was significantly lower in the PCI group. In the 5-year group analysis, it showed similar results except that the MACCE showed no inferiority in the PCI group. This meta-analysis concludes that the PCI for the LMCA can be applied in carefully selected patients. The MI and the TVR remain worrying, although we must consider that most of these studies have used first-generation DES [34].

### **2.5 PCI strategy and technique**

Angioplasty is a specialty where the practice generates a greater capacity to solve problems during the procedure. It has been seen that those operators who perform at least 15 PCI of LMCA per year in 3 consecutive years obtain better results [35].

**13**

*Current Status, Perspectives, and Future Directions of Multivessel Disease and Left Main…*

(ULMCA) disease or left main equivalent








131 36

occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the

disease and low or intermediate SYNTAX scores, PCI was non-inferior to CABG


Sample size 1.905 1200

CK-MB prior randomization

includes universal registry


for at least 1 year

SYNTAX score ≥ 33

Main results At 3 years, a primary end-point event had

Conclusion In patients with left main coronary artery

CABG group

**EXCEL NOBLE**






MI, and new revascularization

At 5 years, primary end points occurred in 28% of the patients in PCI group and in 18% of the patients in the CABG group

CABG might be better than PCI for treatment of left main stem coronary artery disease

(LMCA stenosis and > 3 or complex additional coronary lesions)

PCI lesions

CABG and by PCI

24 h

ticlopidine

option

(PCI or CABG)


The PCI of the ostium and the middle third of the LMCA is technically easier if we analyze it by the ERACI score this doesn't give more than 5 points, unlike the distal third that compromises ostium of the two coronaries and presents higher ERACI scores [36]. When one faces the distal third of the LMCA, there is a totally different approach. Anyway there are different types of bifurcations, where we prefer to use the Medina classification [32]. To assess them, the provisional stent technique has become a technique with a lot of boom and has had good results compared to techniques with two stents [37]. The technique of the provisional stent has been used in up to two thirds of the branches of the LMCA. However, after two RCTs where the DKC was used as a technique, these tests presented better results than the culotte technique or the provisional stent for the treatment of bifurcations

*Modified from "NOBLE and EXCEL: The debate for excellence in dealing with left main stenosis" (Hamood Al Kindi,* 

*DOI: http://dx.doi.org/10.5772/intechopen.89419*

Inclusion criteria - Unprotected left main coronary artery

disease

team

Main exclusion criteria

Angiographic exclusion criteria

Primary end point

Participating centers

*Amir Samaan, Hatem Hosny)*

*Comparison of EXCEL and NOBLE trials.*

**Table 3.**

*Current Status, Perspectives, and Future Directions of Multivessel Disease and Left Main… DOI: http://dx.doi.org/10.5772/intechopen.89419*


#### **Table 3.**

*The Current Perspectives on Coronary Artery Bypass Grafting*

PCI than with CABG (11.4% vs. 5.5%, p = 0.012).

**2.3 Analysis of the two principal trials**

was also not specified (**Table 3**).

have used first-generation DES [34].

**2.5 PCI strategy and technique**

**2.4 Meta-analysis**

difference between the two groups in respect to the primary composite end-point event of death, stroke, or myocardial infarction at 3 years (15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group). At 3 years, the composite end-point event of death, stroke, myocardial infarction, or ischemiadriven revascularization had occurred in 23.1% of the patients in the PCI group and in 19.1% of the patients in the CABG group. Ischemia-driven revascularization during follow-up was more frequent after PCI than after CABG (in 12.6% vs. 7.5% of the patients, p < 0.001). Stent thrombosis occurred in only 0.7% of patients within 3 years after the procedure and was less common than symptomatic graft occlusion. In the Premier of Randomized comparison of Bypass surgery versus Angioplasty using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) [28] trial was a randomized study where 600 patients with LMCA went to PCI with a first-generation of DES or CABG. The primary end point was the combined events, MACCE, at 5 years of follow-up 17.5% were observed in the PCI and 14.3 % in the CABG group, p = 0.26. Regarding the mortality of all causes, MI or stroke, there were no significant differences. The TVR was more frequent with

As we could see in these last two studies on PCI and CABG in the LMCA, we can see that the NOBLE [30] study included higher-risk patients and used a pharmacological stent with biodegradable polymer. In addition to the fact that the most frequently used technique was "culotte" by recommendation, the use of IVUS was only 75% in post PCI patients, and only 55% of the kissing balloon was performed. In addition the use of the proximal optimization (POT) was not specified, and firstgeneration stent was also used in 8% of patients. In the EXCEL study [31], a secondgeneration stent was used in patients with low and intermediate SYNTAX scores, and the amount of IVUS used reached 77%. The use of POT was also not specified, no special bifurcation technique was recommended, and the use of kissing balloon

The objective was to compare clinical results and safety during short- and long-term follow-up by conducting a meta-analysis of large pooled data from randomized controlled trials and updated observation. The primary outcome was MACCE, MI, stroke, all-cause mortality, and revascularization after at least 1 year of follow-up. A subgroup analysis was also performed with a follow-up of over 5 years. A total of 29 studies with 21,832 patients (10,424 with PCI and 11,408 with CABG) were analyzed. At 1-year follow-up there was a significant difference in favor of the CABG in MACCE, TVR, and MI, but the stroke was significantly lower in the PCI group. In the 5-year group analysis, it showed similar results except that the MACCE showed no inferiority in the PCI group. This meta-analysis concludes that the PCI for the LMCA can be applied in carefully selected patients. The MI and the TVR remain worrying, although we must consider that most of these studies

Angioplasty is a specialty where the practice generates a greater capacity to solve problems during the procedure. It has been seen that those operators who perform at least 15 PCI of LMCA per year in 3 consecutive years obtain better results [35].

**12**

*Comparison of EXCEL and NOBLE trials.*

*Amir Samaan, Hatem Hosny)*

The PCI of the ostium and the middle third of the LMCA is technically easier if we analyze it by the ERACI score this doesn't give more than 5 points, unlike the distal third that compromises ostium of the two coronaries and presents higher ERACI scores [36]. When one faces the distal third of the LMCA, there is a totally different approach. Anyway there are different types of bifurcations, where we prefer to use the Medina classification [32]. To assess them, the provisional stent technique has become a technique with a lot of boom and has had good results compared to techniques with two stents [37]. The technique of the provisional stent has been used in up to two thirds of the branches of the LMCA. However, after two RCTs where the DKC was used as a technique, these tests presented better results than the culotte technique or the provisional stent for the treatment of bifurcations

with Medina 1,1,1 or 0,1,1 [33, 38]. In both studies, a reduction in ischemic events was observed. The decision to use a bifurcation technique with one or two stents is basically in the exact evaluation of the compromise of the origin of the left coronary circumflex or the left coronary ramus in a trifurcation. The best way to assess these vessels is with the images of the IVUS or the optimal coherence tomography (OCT) [39]. When the provisional stent technique is used and a residual obstruction of around 50% is observed, the measurement with functional study with iwFR or FFR could be considered as a complement in the decision-making of its definitive treatment. The use of kissing balloon and POT has been invoked as optimizers for this complex carrefour. Also, the post-stent images or stents of both the IVUS and the OCT are important when making decisions, since these elements clearly inform two elements that are key such as uncovered dissections or stent not well positioned [40]. The technique used in the treatment of LMCA is extremely important, just as training in true bifurcation is also difficult. Patients with true bifurcation are those who have Medina 1,1,1 or 0,1,1 and should be treated with two stents and we believe that the technique of choice is DKC. Another important element is to only include patients with low and intermediate ERACI score [17] and leave patients with high scores for very selected centers and true contraindication or patients who really refuses surgery. The use of images in diagnosis, implantation, and postimplantation has become a mandatory strategy, including the use of IVUS and optimal coherence tomography [41]. An element that has been incorporated into the technical arsenal is the technique of proximal optimization. The proximal optimization technique is a key part of treating large bifurcation lesions and will optimize results of both single- and two-stent strategies. An appropriately sized balloon should be positioned and inflated just up to the carina. When performed well, the enhanced lesion scaffolding, reduced strut mal-apposition, and improved flow dynamics are likely to translate into improved clinical results [42].
