Vol. 25, No. 4, April 2013 201

Original ContributionReview

Myocardial Revascularization in Patients With Left Main Coronary Disease

Eirini Apostolidou, MD1, Deepika Kalisetti, MD2, Sachin Logani, MD1, Daniel J. McCormick, DO2, Sheldon Goldberg, MD2

AbstRACt: While coronary artery bypass grafting (CABG) has been the standard of care for patients with unprotected left main coro-nary artery disease, advances in percutaneous coronary intervention (PCI) have made stent placement a reasonable alternative in selected patients. In this review, we address the results of studies comparing PCI with CABG, discuss the invasive evaluation of these patients, and the technical approach to percutaneous revascularization. Further-more, we discuss future pivotal trials, which will help define long-term outcomes comparing PCI with surgery.

J INVASIVE CARDIOL 2013;25(4):201-207

Key words: CABG versus PCI

Significant left main disease (LMD), defined as a stenosis of ≥50%, is found in association with multi-vessel coronary artery disease (CAD) in 75%-90% of patients and occurs in 3%-5% of patients undergoing coronary angiography.1 Left main (LM) lesions are classified as either protected or unprotected. Patients with prior coronary artery bypass graft (CABG) or a patent graft to either the left anterior descending (LAD) artery or left circumflex (LCX) are considered protected. Since the circula-tion from the LM supplies 75% of the left ventricle (LV), oc-clusion of this vessel may lead to extensive myocardial loss and death. While CABG has long been considered the standard for revascularization in patients with LMD,2 recent studies have suggested that percutaneous coronary intervention (PCI) may be a safe and effective alternative in this high-risk group.

In this report, we will review current data regarding surgical versus percutaneous revascularization in patients with unprotected left main disease (ULMD) and discuss the evolving role of PCI.

CAbG Versus Medical treatmentPatients with medically treated LMD have a 3-year mortal-

ity rate of 50%. Trials comparing CABG and medical therapy were initially performed in patients with stable angina and showed that surgical revascularization provided significant

survival benefit. In a Veteran’s Administration study,3 the ben-efit of surgical revascularization was greater in high-risk patients (stenosis >75% and/or abnormal LV function). Similarly, in the CASS registry, patients with LMD were categorized according to the severity of the stenosis and LV function. At 3 years, survival improved with surgery.4 At 15 years, the surgical group had a median survival of 13.3 years compared to 6.6 years in the medi-cally treated group.5 A meta-analysis that included clinical tri-als between 1972-1984 comparing CABG to medical therapy found that CABG was associated with a lower mortality at 10 years, especially in patients with severe CAD and depressed LV function.6 It should be noted there are no randomized controlled trials (RCTs) comparing CABG and medical treatment.

On the basis of these studies, the American College of Car-diology/American Heart Association guidelines give CABG a class I indication for significant LMD.2

CAbG Versus PCIAngioplasty of the LM was first attempted over 30 years ago.

Initial outcomes of PCI for LMD were associated with unac-ceptable rates of restenosis, acute thrombosis, and repeat re-vascularization. With the advent of advanced stent design, im-proved technique, and aggressive adjunctive medical therapy, PCI has evolved over the last 2 decades.

Observational registries. Observational studies (Table 1)7-14 suggest that PCI for LMD may be a reasonable alternative to CABG in terms of myocardial infarction (MI) and mortality. These registries are extremely heterogeneous in terms of clinical characteristics, spectrum of risk of patients, stents used, and PCI technique. CABG has been associated with a higher in-cidence of adverse in-hospital/early outcomes because of sig-nificant peri-procedural MI, stroke, and death. Long term, the endpoints of MI and mortality were similar, but repeat revas-cularization rates were significantly higher for PCI. Clinically asymptomatic occlusions were found in the PCI arms due to routine angiographic follow-up. Graft occlusions probably were under-recognized in the CABG arms as follow-up an-giography was only clinically driven. Most of these registries noted a higher incidence of repeat revascularization in the distal LM/bifurcation location. The CABG arms had longer hospi-tal stays and were accompanied with significant postoperative complications. Although a 25% relative risk reduction in major adverse cardiovascular and cerebrovascular events (MACCE)9 and a lower hazard ratio12 was noted in the drug-eluting stent (DES) group compared to the bare-metal stent (BMS) group, the event-free survival was superior in the CABG-treated arms.

From 1Hahnemann University Hospital, Philadelphia, Pennsylvania and 2the De-partment of Cardiovascular Medicine, Pennsylvania Hospital – University of Pennsyl-vania Health System, Philadelphia, Pennsylvania.

Disclosure: The authors have completed and returned the ICMJE Form for Dis-closure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 3, 2012, provisional acceptance given September 5, 2012, final version accepted December 26, 2012.

Address for correspondence: Sheldon Goldberg, MD, Cardiology Consultants of Philadelphia, Pennsylvania Hospital – University of Pennsylvania Health System, 800 Spruce Street, Second Floor Pine Building, Philadelphia, PA 19107. Email: sheldon-goldberg66@gmail.com

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Meta-analyses. Three meta-analyses comparing CABG and PCI (2905, 3773, and 5479 patients) of ULMD showed that MI, stroke, and death were similar at 1, 3, and 5 years while target vessel revascularization (TVR) was higher for PCI. There was no difference in mortality between the 2 groups.15-17 To address the issue of limited duration of follow-up, Park et al reported long-term results for BMS and DES use.18 At 10 years, the adjusted risks of MI, stroke, and death were similar in the BMS and concurrent CABG groups. At 5 years, there was no difference in the adjusted risk of death in the DES and CABG groups. However, the TVR rates were higher in the PCI group.

Randomized controlled trials. Currently, four RCTs have compared PCI with CABG for the treatment of LMD (Table 2). The main limitation of the LE MANS study19 was the non-specific primary endpoint (change in LV function at 12 months), with both groups demonstrating similar improve-ment in angina and functional capacity at 1 year. The absolute change in LV function was greater after PCI (P=.04) than after CABG (P=.85). There was a significant difference in LV func-tion between the 2 groups after 12 months (P=.01). The MAC-CE-free 1-year survival rate was not significantly lower in the PCI group compared with the CABG group (71.2% vs 75.5%; P=.29), with the difference mainly related to repeat revascular-ization (P=.01). Similarly, MACCE-free survival did not differ significantly between the 2 groups (53.9% vs 56.6%; P=.47). No in-stent thrombosis was noted, which was probably due to selective use of DES/BMS and the technique of LM stenting (provisional stenting of the side branch).

Boudriot et al20 randomized 201 patients with ULMD to CABG and PCI. The primary endpoint of MACCE was 13.9% and 19%, respectively (P=.19 for non-inferiority). Stenting was

inferior to surgery for repeat revascularization (5.9% vs 14%; P=.35). There was a higher incidence of MACCE in distal LM lesions compared to ostial/shaft lesions in both the treatment arms (PCI, 18% vs 1%; CABG, 8.9% vs 5%). The PRECOM-BAT trial21 is the largest RCT comparing CABG and PCI to date. A combined primary endpoint of MACCE at 1 year was 8.7% and 6.7% (P=.01 for non-inferiority) and at 2 years was 12.2% and 8.1% (P=.12) in the PCI and CABG groups, re-spectively. Although PCI was shown to be non-inferior to CABG, the study was underpowered due to low event rates. The apparent safety of PCI compared to CABG at 2 years is consistent with that observed in SYNTAX.

In the SYNTAX trial,22 patients were categorized according to angiographic risk, which took into account lesion character-istics and the amount of myocardium supplied by the affected vessels. Patients were divided into 3 terciles according to their angiographic risk score and clinical outcomes were reported for each tercile. In patients with low and intermediate SYNTAX score (0-32), the combined endpoint of MI, stroke, and death was better in the PCI arm and the rates of repeat revasculariza-tion were similar in the 2 groups. Finally, in the patients with the most complex anatomical disease (≥33), MACE rates were significantly higher in PCI-treated patients (Table 3).

Unfortunately, the issue of restenosis remained the same in the RCTs as in the observational registries. Stent thrombosis was not noted in two RCTs.19,20 A substantial portion of re-stenosis rates occurred in patients with distal LMD. Based on these findings, PCI of LMD now has a class IIB indication.23

DEs versus bMs. Studies comparing DES and BMS for LMD showed lower rates of restenosis and TVR with DES

(Table 4).24-32 One RCT showed a significant reduction in

Table 1. Observational registries of coronary artery bypass graft versus percutaneous coronary intervention.

Registry Year N Mean Follow-Up

MyocardialInfarction

Stroke Repeat Revascularization

Death MACCE

Lee et al7 2006 CABG: 123 6 mo. NA NA NA 10.6% NA

PCI: 50 NA NA 10% 4% NA

Chieffo et al8 2006 CABG: 142 12 mo. 26% 2.1% 5.6% 8.4% NA

PCI: 107 10.3% 0.9% 19.6% 2.8% NA

Palmerini et al9 2006 CABG: 154 13 mo. 4.5% NA 2.6% 12.3% NA

PIC: 157 8.3% NA 25.5% 13.4% NA

Palmerini et al10 2007 CABG: 161 24 mo. 6% NA 3% 17% NA

PCI: 98 4% NA 25% 18% NA

Sanmartin et al11 2007 CABG: 245 12 mo. 1.3% 0.8% 0.8% 8.4% 11.4%

PCI: 96 0% 0% 5.2% 5.2% 10.4%

Seung et al12 2008 CABG: 1138 36 mo. NA NA 2.6% 7.8% 10.2%

PCI: 1102 NA NA 12.6% 7.9% 8.9%

Chieffo et al13 2010 CABG: 142 60 mo. 33.8% 4.2% 8.4% 18.3% 38.3%

PCI: 107 10.3% 0.9% 28% 15.9% 32.4%

Wu et al14 2010 CABG: 245 48 mo. NA NA 9.4% 9.4% 22%

PCI: 131 NA NA 18% 3.6% 27%

PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; MACCE = major adverse cardiovascular and cerebrovascular events.

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restenosis rate with paclitaxel-eluting stents (PES, 6% vs BMS, 22%) and significant improvement in major adverse cardiovas-cular event (MACE)-free survival due to reduction in TVR.27 The DELFT registry showed a high clinical and procedural success rate with DES use at 3 years.33 Recent meta-analyses of >10,000 patients showed that PCI with DES was superior to BMS with respect to MACE and mortality.34,35 Recent stud-ies have shown comparable clinical and angiographic outcomes for SES and PES.36-38 Furthermore, in an observational study, Valenti et al showed PCI with everolimus-eluting stent (EES) to have a reduced incidence of MACE (10.2% vs 21.9%), TVR (7.8% vs 20.5%), and restenosis (5.2% vs 15.6%) at 1 year compared to PES.39

Ostial versus bifurcation lesions. Stenting of ostial and mid-shaft LM lesions appears to be safe and effective with low rates of MACE and restenosis.40 The outcome is significantly worse for patients undergoing PCI of distal LMD with higher rates of MI, death and revascularization.41-43

AngiographyThe angiographic evaluation of LMD should be performed

expeditiously minimizing repeat injections. Multiple dye in-jections in similar views can lead to death in the catheter-ization laboratory. The interventionist should be alert for al-terations in the pressure tracing, including pressure damping

and/or ventricularization. Certain views are useful, including the antero-posterior (AP) caudal view for bifurcation disease and the cranial right anterior oblique (RAO) view for ostial LMD (Figures 1A and 1B).

Evaluation of Ambiguous LM Disease

A precise diagnosis of the severity of LM stenosis is paramount in order to establish appropriate management. Information from IVUS and FFR can help in proper selection of patients for revascularization. By providing a cross-sectional, real-time, direct visualization

of the vessel wall, IVUS can overcome the limitations of an-giography in assessing the severity of LMD.44 Although IVUS provides anatomic depiction and not a physiologic assessment, it clarifies the majority of ambiguous lesions of the LM.45,46 In addition, IVUS aids in assessing adequate stent expansion, apposition and full lesion coverage.47 A combination of mean luminal diameter (MLD) and mean luminal area (MLA) cut-points of 2.8 mm and 5.9 mm2, respectively, are highly predic-tive of physiologically significant LM lesions (Figure 2).48

Another study used a cut-off of 7.5 mm2 lumen area for per-forming revascularization. Deferring revascularization was found to be safe in patients with IVUS lumen area of >7.5 mm2.49 The MAIN-COMPARE registry showed lower 3-year mortality with the use of IVUS compared to angiographic guidance in stenting of ULMD (IVUS, 6.3%; angiography, 13.6%; P=.063).50

FFR, defined as the ratio of maximal blood flow in a stenotic artery to normal maximal flow, is an index of physiological sig-nificance of coronary stenosis. It can be measured by calculat-ing the ratio of distal coronary artery pressure to aortic pres-sure after adenosine infusion. The FFR in a normal coronary artery is 1. An FFR <0.8 identifies ischemia causing stenosis with an accuracy of more than 90%.51 FFR-guided PCI is associated with reduced MACE in patients with multivessel CAD at 1 year.52 Long-term outcomes of patients with LMD in whom surgery was deferred on the basis of FFR values >0.8

Table 2. Randomized controlled trials comparing coronary artery bypass graft with percutaneous coronary intervention.

Registry Year N Mean Follow-Up

MyocardialInfarction

Stroke Repeat Revascularization

Death MACCE

LE MANS19 2007 CABG: 53 12 mo. 5.6% 3.8% 9.4% 7.5% 26.4%

PCI: 52 1.9% 0% 28.8% 1.9% 32.7%

Boudriot et al20 2010 CABG: 101 12 mo. 3% NA 5.9% 5% NA

PCI: 100 3% NA 14% 2% NA

PRECOMBAT21 2011 CABG: 300 12 mo. 1% 0.3% 4.3% 2.7% 6.7%

PCI: 300 1.3% 0% 6.1% 2% 8.7%

24 mo. 1% 0.7% 5.3% 3.4% 8.1%

1.7% 0.4% 9% 2.4% 12.2%

SYNTAX22 2011 CABG: 348 36 mo. 4.1% 4% 11.7% 8.4% 22.3%

PCI: 357 6.9% 1.2% 20% 7.3% 26.8%

PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; MACCE = major adverse cardiovascular and cerebrovascular events.

Table 3. Risk of major adverse cardiovascular and cerebrovascular events at 3 years for patients with low-intermediate and high SYNTAX scores.

Low to Intermediate (0-32) SYNTAX Scores

High(≥33) SYNTAX Score

CABG PCI P-Value CABG PCI P-Value

MI 2.6% 4.6% .33 6.1% 10.9% .18

CVA 3.3% 0.9% .09 4.9% 1.6% .13

Death 9.0% 3.7% .02 7.6% 13.4% .10

MI, CVA, or death 13.2% 8.7% .12 15.7% 20.1% .34

Revascularization 13.7% 15.7% .61 9.2% 27.7% <.001

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are favorable and similar to patients in whom CABG was per-formed for FFR <0.8.53 The correlation between angiographic assessment and FFR is poor because angiography frequently underestimates the severity of LM stenosis.

Since LMD is often found in conjunction with disease in the other coronaries, effective revascularization requires careful assess-ment of these lesions, especially when they are in the intermediate range. FFR and IVUS may be extremely useful in these circum-stances to improve outcomes and decrease complication rates.54

technical Considerationsbifurcation lesions. In bifurcations, PCI might be com-

plicated by plaque shift and occlusion of a major side branch. Techniques have been developed for the treatment of bifurca-tion lesions, including either 1- or 2-stent placement (T-stenting, crush technique, kissing technique, Y-stenting). In general, one stent (simple technique) is preferable since two stents (complex

technique) are associated with higher rates of MACE and resteno-sis.55-57 In addition, simple technique is associated with less contrast use and decreased procedure/fluoroscopy times.57 When deciding upon the approach to bifurcation lesions, several factors need to be taken into account — the size of the LM and ostium of the LCX, and the angulation of the take-off of the LAD and LCX.58 When the LCX is large, free of disease, and comes off at a right angle, the use of one stent that crosses from the LM into the LAD (crossing technique) is preferred. On the other hand, if the LCX has disease and arises at an angle <70°, two stents may be preferable to pre-vent plaque shift (crush and kissing techniques).

Lesion preparation. Calcified lesions of the LM increase the risk of adverse outcomes. Potential complications include inability to deliver stents, incomplete stent expansion, and mal-apposition, which lead to increased restenosis and thrombosis. Lesion preparation with rotational atherectomy increases pro-cedural success and long-term outcomes.59,60

table 4. RCts and observational registries comparing DEs and bMs for PCI of left main disease.

trial Year N Mean Follow-Up

MI Death tVR tLR Restenosis stent thrombosis

MACE

Park et al24

(Obs)2005 SES: 102 12 mo. 6.9% 0% NA 2% 7% 0% NA

BMS: 121 8.3% 0% NA 17.4% 30.3% 0% NA

Valgimigli et al25 (Obs)

2005 SES/PES: 95 16 mo. 4% 14% 6% NA 3.2% NA 24%

BMS: 86 12% 16% 23% NA 15.1% NA 45%

Chieffo et al26 (Obs)

2005 SES/PES: 85 6 mo. NA 3.5% 18.8% 14.1% 19% NA 24.7%

BMS: 64 NA 14.1% 30.6% 24.2% 10.6% NA 42.1%

Erglis et al27

(RCT)2007 PES: 53 6 mo. 9.4% 1.9% 2% NA 6% 0% 13.2%

BMS: 50 14% 2% 16% NA 22% 0% 30%

Kim et al28

(MAIN-COMPARE)(RCT)

2009 SES/PES: 864 36 mo. 6.3% 8% 9.8% 5.4% NA 0.9% NA

BMS: 353 5.4% 9.5% 15.7% 12.1% NA 0% NA

Tamburino et al29 (Obs)

2009 DES: 611 36 mo. 4.6% 13.6% NA 10.8% NA NA NA

BMS: 238 9.2% 27.3% NA 16.8% NA NA NA

Tamburino et al30 (Obs)

2009 DES: 334 NA 16.6% NA 7.9% NA 0.3% 25%

BMS: 145 NA 29.1% NA 10.7% NA 0.6% 37.2%

Buszman et al31 (RCT)

2009 DES: 94 48 mo. 13.8% 9.6% NA 3.2% NA 1% NA

BMS: 158 9.5% 13.3% NA 10.2% NA 0% NA

Pepe et al32

(Obs)2009 DES: 22 12 mo. 0% 19% 0% 0% 0% 0% 19%

BMS: 20 15% 45% 20% 20% 15% 5% 65%

BMS = bare-metal stent; DES = drug-eluting stent; MACE = major adverse cardiovascular events; MI = myocardial infarction; Obs = observational study; RCT = randomized controlled trial; TLR = target lesion revascularization; TVR = target vessel revascularization.

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Hemodynamic support. LV assist devices may be consid-ered in high-risk patients and patients undergoing complex procedures (ULM or LM equivalent, patients with complex multivessel CAD, and reduced LV function).61-63 The vast majority of interventions can be performed without assist devices. Furthermore, there is no evidence that prophylactic insertion of the intra-aortic balloon pump (IABP) is supe-rior to a provisional strategy if hemodynamic compromise occurs. The only randomized trial that compared the IABP to the Impella axial flow pump revealed no difference in MACE.64 It is our practice to perform distal aortography to delineate anatomy at the time of the initial angiography and then make a decision on a prophylactic strategy versus provisional use of LV assist.

Antithrombotic agents. Administration of antithrombotics is critical in preventing stent thrombosis. Premature discontinuation

of thienopyridines is the most important predictor of stent throm-bosis.65,66 Clopidogrel discontinuation within 6 months of DES implantation in an ULM is associated with greater than 4-fold risk of MI and cardiovascular mortality. Antiplatelet therapy after DES implantation is recommended for at least 1 year.2 Two other ad-enosine diphosphate inhibitors, prasugrel and ticagrelor, are more potent, prompt, and predictable compared to clopidogrel. They reduce stent thrombosis, but increase the risk of major bleeding.67,68

Future studies/ConclusionsThe multiple trials comparing CABG with PCI for LMD

have suggested that both strategies have similar rates of MI, stroke, and death and that PCI might be an acceptable or even superior alternative for certain LM subsets. However, SYNTAX was underpowered to specifically address the LM subset. Therefore, the results of trials such as SYNTAX should

Figure 1A. Left coronary angiogram in anteroposterior view; the left main stenosis is not visualized.

Figure 1B. Left coronary angiogram in cranial right anterior oblique view, clearly showing the severe ostial left main disease.

A B

Figure 2. Relationship of mean luminal diameter (MLD) and mean luminal area (MLA) by intravascular ultrasound, using fractional flow reserve as the gold standard. Note that maximum sensitivity and specificity occur at MLD of 2.8 mm and MLA of 5.9 mm2.48 (Figure used with permission).

1101009080706050403020100

1 2 3 4 5 0 2 4 6 8 10 12 14

5.9 mm2

1101009080706050403020100

2.8 mm

Sensitivity 93%Specificity 98%

Sensitivity 93%Specificity 94%

MLD MLA

Per

cent

Per

cent

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be considered as hypothesis-generating. In addition, since SYNTAX, advances have been made in DES technology,39 adjunctive techniques (IVUS/FFR), and pharmacotherapy. The EXCEL trial is expected to address those limitations and determine the optimal revascularization strategy for patients with LMD. EXCEL has been designed to randomize 2634 patients with significant LMD and SYNTAX scores ≤32 to undergo either PCI with EES or CABG. The hard endpoints of MI/stroke/death will be assessed up to 3 years. Awaiting the results of the EXCEL trial, we suggest the following approach for management of LMD:1. There should be a consensus approach to patients with

LMD consisting of an interventional cardiologist and a cardiothoracic surgeon. Risks and benefits should be completely reviewed and ad hoc procedures should be avoided.

2. A SYNTAX score should be calculated for every pa-tient. Patients with a SYNTAX score ≥33 should be referred for CABG.

3. The use of IVUS and FFR is encouraged to assess the need for intervention in ambiguous LM lesions and in-termediate lesions in other vessels.

4. Lesion preparation is critical. Direct stenting, especial-ly of calcified lesions, should not be undertaken. Heav-ily calcified lesions should be treated with rotational atherectomy in preparation for optimal stent delivery and expansion.

5. In bifurcation lesions of the LM, we prefer to use one stent, if possible. Familiarity and experience with bifur-cation techniques and rotational atherectomy are criti-cal when planning to undertake intervention in this challenging group of patients.

6. The majority of PCI cases do not require hemodynam-ic support. Both the IABP and Impella can provide sig-nificant benefit for high-risk patients. In the EXCEL trial, the use of these devices will be at the discretion of the operator.

7. Pharmacology: the use of the following medications is recommended in patients undergoing PCI:• Acetylsalicyclic acid: preloading (325 mg) at

least 2 hours before PCI.• Adenosinediphosphateantagonists:preloading

with either clopidogrel 600 mg (>6 hours before PCI) or 300 mg (>12 hours before PCI) OR prasugrel 60 mg OR ticagrelor 180 mg with re-duced dose aspirin.

• Statins: administer thefirstdose12hoursbe-fore PCI. Atorvastatin 80 mg daily is preferred.

• Anticoagulationduring theprocedure: theuseof bivalirudin is recommended.

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