Article

Percutaneous Coronary Intervention for Left Main and Multivessel Coronary Artery Disease - A Review of Strategies

Abstract

Patients with complex and multivessel disease present challenging clinical problems in defining treatment strategies. The Synergy between PCI with taxus and cardiac surgery (SYNTAX) trial, which included both a randomised as well as a registry experience has clarified many issues. These include the extent and severity of the disease, the clinical presentation, and the metrics used for comparison. The development, validation and application of the SYNTAX score has been of fundamental importance. In those patients with the least complex coronary anatomy, using hard endpoints such as death and myocardial infarction, the outcomes of treatment with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) are similar although repeat revascularisation rates remain higher with PCI. In those patients with more extensive and complex disease, coronary artery bypass remains the standard of care. It must be remembered that the drug-eluting stent tested in SYNTAX was a first generation device and that newer generations are safer and more effective. Perhaps the most important guidance in the field of treatment of complex multivessel coronary disease is the attention paid to the Heart Team concept wherein both interventional cardiologists and cardiovascular surgeons are strongly encouraged to work together in these patients to identify the optimal approach consistent with the patients needs and objectives.

Disclosure: The authors have no conflicts of interest to declare.

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Accepted:

Citation:Interventional Cardiology 2012;7(2):86–90

Correspondence: David Holmes Jr, Professor of Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, US. E: Holmes.david@mayo.edu

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Coronary artery bypass graft (CABG) has been the traditional method of revascularisation for left main (LM) coronary artery disease and current practice guidelines recommend CABG as the standard procedure for unprotected LM disease in patients who are good surgical candidates.1 Improvements in interventional techniques, adjunctive pharmacology and stent technology have led to increasing recognition of percutaneous coronary intervention (PCI) as a viable treatment option for revascularisation in selected patients with significant LM coronary artery disease.

The aforementioned improvements in interventional techniques have been translated into improved clinical outcomes in non-randomised, registry as well as randomised studies. These studies in carefully selected patients have shown no difference in clinical outcomes when PCI for LM has been compared to CABG in terms of combined safety outcomes of death, myocardial infarction and stroke.2 Based on increasing data supporting the efficacy and safety of LM PCI the recent American College of Cardiology (ACC), American Heart Association (AHA) and the Society for Cardiovascular Angiography and Interventions (SCAI) support the use of PCI for LM stenosis in patients with low risk of procedural complications and clinical conditions that predict increased risk of adverse surgical outcomes.1

This article will focus on the issues to be considered by interventional cardiologists who wish to undertake stenting of unprotected LM coronary artery (LMCA) with the aim of achieving excellent short- and long-term outcomes.

Anatomy

The LMCA arises from the superior margin of the left aortic sinus just below the sinotubular junction and consists of an ostium, mid portion and distal segment. It usually runs leftward, superiorly and anteriorly. In 70 % of people, the LM bifurcates into the left anterior descending (LAD) and the left circumflex (LCX) coronary arteries and in 30 % it trifurcates into the LAD, LCX and ramus intermedius arteries. It has an average length of 10.8 ± 5.2 mm and an average diameter of 4.9 ± 0.8 mm.3

The LM ostium is rich in smooth muscle cells and elastic fibres and resembles the aorta histologically; the distal bifurcation is the most likely area to develop atherosclerosis because of low-shear flow disturbance.4 Based on the histology of the LM ostium, it is subjected to more recoil and restenosis after PCI compared to the other coronary circulation. In addition, the majority of patients with significant LM stenosis usually have co-existing significant stenosis of one or more additional major epicardial coronary artery. Isolated LM stenosis is seen predominantly at the ostium and has been noted to be more frequent in women.5 In the Synergy between PCI with taxus and cardiac surgery (SYNTAX) trial, only 7 % of the patients with LM disease enrolled in the study had isolated ostial or mid-shaft disease.6

Location and distribution of stenosis along the LMCA has implications for procedural planning and execution, short- and long-term outcomes after PCI. Treatment of ostial or mid-shaft lesions has been shown to have excellent outcomes in terms of cardiac death and repeat revascularisation,7 while treatment of distal LM bifurcation or trifurcation is more challenging and has been linked to increased major adverse cardiac events (MACE) and repeat target lesion revascularisation (TLR).8

Other anatomical considerations include the discrepancy in size and angulation between the LM and its daughter vessels – the LM typically has a diameter ranging between 4.5– 6.0 mm in a majority of cases while the LAD and LCX have diameters ranging from 3.5–4.5 mm and 3.0–4.5 mm respectively. Similarly, the take-off angle of the LCX is greater than 90° in about 70 % of patients. The size discrepancy and take-off angle of the LCX have great implications for distal LM bifurcation stenting. The ostium of the LCX has the highest restenosis risk in the drug-eluting stent era and loss of the LCX or LAD acutely during PCI may have severe haemodynamic consequences.

Patient Selection

Patient selection for LM PCI is critical to short- and long-term outcomes. Traditionally patients referred for LM PCI are those who have been turned down for conventional surgery because of excessive surgical risk. Reasons include poor left ventricular function, porcelain aorta, advanced age, poor distal targets and the presence of severe co-morbidities.

Using anatomical criteria as mentioned earlier, patients with ostial or mid-shaft disease have improved short- and long-term outcomes compared with patients with distal bifurcation or trifurcation disease after PCI. Similarly, the extent and complexity of disease in other coronary arteries also portends increased risk. For example, a patient with concomitant chronic total occlusion involving the right coronary artery has higher risk of adverse outcomes compared to one without. Risk prediction models and algorithms have been developed to determine the clinical outcomes after PCI and CABG. The SYNTAX score is a risk score that is based on angiographic assessment of disease burden and complexity. In the SYNTAX trial the outcomes of the LM subset varied based on baseline SYNTAX score. In patients with low (0–22) or intermediate (23–32) SYNTAX score, MACE outcomes at one year were comparable between PCI and CABG.6 In the high SYNTAX score tertile, MACE outcomes were higher in patients treated with PCI compared to CABG which was driven by increased repeat revascularisation.6 However at one year, the rate of cerebrovascular accident (CVA) was significantly greater in patients with CABG compared to those with PCI, 2.7 % CABG versus 0.3 % PCI.6 The four-year follow-up data revealed no differences in the rates of overall major adverse cardiac and cerebrovascular events 27.8 % CABG versus 33.2 % PCI, also there was similar overall safety outcomes between the two groups PCI and CABG, 17.1 versus 17.7 % respectively. There was a higher rate of repeat revascularisation with PCI and a higher rate of CVA in the CABG group.9

Assessment of patient’s clinical risk is also important prior to performing LM PCI. Several clinical risk assessment tools are readily available to accomplish this. The EuroScore has been tested in this regard. Min et al.10 in an analysis of the MAIN-COMPARE registry found that a EuroScore ≥6 was an independent predictor of death in patients undergoing PCI or CABG for LM disease. The artificial separation of anatomical or clinical components in risk scores is somewhat inadequate so in response to this, a new scoring system which combines both the SYNTAX score and the EuroScore has been developed. Capodanno et al. examined this risk assessment tool in patients undergoing LM PCI and found an increase in the predictive value of the GRS compared to the SYNTAX score for predicting cardiac mortality.11 In their study, adding the Euroscore to the SYNTAX score led to reclassification of approximately 25 % of patients undergoing LM PCI into different risk categories translating into improved predictive ability to determine long-term outcomes. Similarly, fractional flow reserve (FFR) has been integrated in addition to the traditional SYNTAX score. Nam et al.12 evaluated the discriminative ability of this ‘Functional SYNTAX Score’ (FSS) in a recently published study. In their analysis of 497 patients enrolled in the Fractional flow reserve versus angiography for multivessel evaluation (FAME) study, the use of FFR moved 32 % of patients to a lower-risk group and the FSS demonstrated a better predictive accuracy for MACE compared with the traditional SYNTAX score.

Technical Issues

Assessment of Left Main Stenosis

Coronary angiography remains the gold standard for assessment of coronary stenosis. However, the LM segment of the coronary vasculature remains the most difficult to assess by angiography, with great interobserver variability in lesions of the LMCA especially in cases of angiographically indeterminate lesions.13 Obtaining adequate views is essential, the LM is frequently foreshortened in the standard 30° right anterior oblique and 60° views and may also have varying take-off and angulation. The anteroposterior view has been shown to be particularly useful in evaluation of LM lesions. In cases of stenosis of indeterminate severity, the use of intravascular ultrasound (IVUS) and FFR has shown to be useful in discriminating between significant and non-significant LM lesions.

Intravascular Ultrasound

There is poor correlation between angiography and IVUS14 – it allows an assessment of reference vessel size, burden of atheroma, lesion composition especially the extent of calcification and lesion length, parameters that are usually underestimated by angiography. An IVUS-derived minimal lumen area of <6 mm2 has been associated with significant LM disease and has been correlated with a haemodynamically significant FFR value of <0.75.15,16 A recent study by Oviedo et al. describes the plaque distribution in the distal LM using IVUS.17 They concluded that in distal LM disease, the carina is usually spared and the lesion is usually diffuse rather than focal, which has implications for planning stent strategies as PCI is considered for distal LM lesions. IVUS is also important for optimal stent deployment as it provides useful information regarding stent expansion and apposition and guides post-stent dilation. Park et al. examined the outcomes of 145 propensity matched pairs of patients undergoing LM PCI with or without IVUS guidance. They concluded that elective stenting with drug-eluting stent (DES) using IVUS guidance reduced mortality outcomes at three years (4.7 versus 16 %) compared to angiographically guided LM PCI.18

Fractional Flow Reserve

The use of FFR for assessment of indeterminate lesions and FFR-guided revascularisation strategies has been associated with favourable outcomes in patients with single or multivessel disease.19,20 In a study involving 213 patients with angiographically equivocal LM stenosis, a cut-off FFR value of 0.80 was used to discriminate between patients randomised to medical or surgical therapy.21 Five-year survival estimates were 89.8 % in the medical therapy group (FFR >0.80) and 85.4 % in the surgical group (FFR <0.80). In the same study it was noted that 23 % of patients with LM diameter stenosis <50 % had haemodynamically significant FFR. In post-stent deployment for treatment of the distal LM stenosis, FFR may be used to assess severity of the side branch post-stent deployment in the main branch using the provisional approach. For LM assessment, intravenous adenosine is preferred to intracoronary administration, especially in cases of ostial LM stenosis.

Haemodynamic Support

PCI guidelines conclude that haemodynamic support should be reserved for patients at the extreme end of haemodynamic compromise, such as those with severely depressed left ventricular function and patients in cardiogenic shock.22 In most situations haemodynamic support is not required in LM PCI but because haemodynamic compromise can occur rapidly during LM occlusion, elective haemodynamic support may be indicated with the use of the intra-aortic balloon pump (IABP), Impella device or the TandemHeart device. Benefits of the use of support devices includes maintenance of pressure and flow across the system if LM occlusion or compromise occurs, maintenance of perfusion during LM manipulation limiting ischaemic cycles and haemodynamic stabilisation allowing operator tranquility and concentration. The use of the IABP in patients undergoing LM PCI was studied by Brigouri et al.23 They concluded that IABP may be beneficial in patients with a Euroscore >6 plus bifurcation lesion.

Lesion Preparation

Lesion preparation is essential in LM PCI. The LM coronary artery is often large, calcified with a large volume of plaque most frequently at the site of the stenosis. Debulking of the LM prior to stent placement allows for adequate stent expansion leading to optimal results post-PCI. This can be achieved by the use of compliant and non-compliant balloons, cutting balloons and rotational atherectomy. In a study by Park et al.24 the benefit of debulking and use of IVUS was evaluated in a series of 127 patients undergoing unprotected LM stenting. There was a benefit with debulking on univariate analysis with a reduction in angiographic restenosis (8.3 versus 25 %, p=0.034) but this was not significant on multivariate analysis.

Antiplatelet Therapy

Stent thrombosis involving the LM is uncommon but if it occurs it would be expected to result in either mortality or significant morbidity. The ISAR-LEFT MAIN trial reported the rates of stent thrombosis of 0.5 % with no incidence of late or very late stent thrombosis.25 The use of DES mandates the use of dual antiplatelet therapy for six months to one year. Although it is established that early/premature discontinuation of dual antiplatelet therapy is a risk factor for stent thrombosis, the optimal duration of dual antiplatelet therapy in patients undergoing LM PCI is yet to be determined.26 In their study involving 894 patients undergoing LM PCI, Palmerini et al. examined the pattern of ischaemic events in relation to dual antiplatelet therapy.27 They found an increased risk of cardiovascular mortality and morbidity when dual antiplatelet therapy was stopped, between 31–180 days as compared to 18–360 days. It is important to ensure that the patient would be able to take dual antiplatelet therapy for one year or longer. Circumstances that may necessitate premature discontinuation of DAPT including lack of insurance coverage, bleeding diathesis or likelihood of noncardiac surgery in the next 1–2 years after the procedure, should be evaluated before performing the procedure.

Stent Selection

There is increased evidence of improved outcomes with the use of DES compared to bare metal stents (BMS) in the treatment of LM coronary artery.28–31 Several studies have compared DES and BMS for LM PCI,29,31–40 the majority of which have been observational, but they have all been concordant, reporting a significant reduction in repeat revascularisation with DES compared to BMS. A recently published meta-analysis comparing DES to BMS for LM PCI, (n=5,081) revealed continued benefit and superiority of DES compared to BMS at three years in terms of mortality 0.70 (95 % CI: 0.53–0.92; p=0.01), MI 0.49 (95 % CI: 0.26–0.92; p=0.03), TVR/TLR 0.46 (95 % CI: 0.30–0.69; p<0.01), and MACE 0.78 (95 % CI: 0.57–1.07; p=0.12).41

The specific DES to be used has also been studied. Several studies have compared sirolimus-eluting stents (SES) to paclitaxel-eluting stents (PES), which include four observational studies and one randomised trial.25,42–45 The observational studies concluded that there was no difference between the two stent platforms in terms of mortality, repeat revascularisation and myocardial infarction. Their findings were confirmed in the only randomised trial (ISAR-LEFT MAIN trial) focused on this issue. In this trial, 607 patients undergoing unprotected LM PCI were randomised to receive either SES or PES. This study documented that there were no differences in mortality – 10.7 % in the PES and 8.7 % in the SES group (RR: 1.14, 95 % CI: 0.66–1.95, p=0.64) and angiographic restenosis 16.0 % with PES and 19.4 % with SES (RR: 0.82, 95 % CI: 0.57–1.19, p=0.30).25

Stent Technique

Ostial and Mid-shaft Left Main Lesions

Aorto-ostial and mid-shaft LM lesions comprise 30 % of LM lesions25 and appear relatively straightforward although they require precise stent placement with adequate coverage and stent expansion. Optimal projections using left anterior oblique (LAO) caudal or cranial, straight antero-posterior (AP) or right anterior oblique (RAO) projections that allow for full visualisation of the ostium should be selected. Before stent deployment adequate visualisation of the stent in two orthogonal views should be obtained to ensure the stent protrudes 1–2 mm into the aorta and that there is distal coverage of the lesion. A less supportive guide e.g. the Judkins left 4 guide is usually sufficient for treatment of LM ostial and mid-shaft lesions as support is not usually required for the treatment of this lesion subset.

Bifurcation Lesion

Bifurcation disease comprises the majority of the LM lesion subset. It has been shown that treatment of unprotected LM bifurcation lesions is associated with an increased risk of repeat revascularisation and adverse cardiac outcomes.45 In terms of complexity, bifurcation lesions range from those that require a one-stent strategy to those that require a two-stent strategy.

Current data favours the use of a single-stent strategy whenever possible. This was shown in the GISE-SICI study by Palmerini et al. in their study involving 773 patients with distal LM disease undergoing PCI. A single-stent strategy (group 1) was compared to a two-stent strategy (group 2) and at two years the propensity-adjusted hazard ratio for the risk of two-year MACE in patients in group 1 versus group 2 was 0.53 (95 % CI, 0.37–0.76). The propensity-adjusted hazard ratio for the risk of two-year cardiac mortality and myocardial infarction in patients in group 1 versus group 2 was 0.38 (95 % CI, 0.17–0.85). In a more recent study by the same group of investigators,46 outcomes of patients with distal LM bifurcation disease was compared to those with ostial/mid-shaft lesions with the use of DES. They documented that patients with LM bifurcation disease treated with a single-stent strategy had similar outcomes compared to those with ostial and mid-shaft lesions whereas those with bifurcation disease treated with a two-stent strategy had increased adverse outcomes.46 Similarly, there was a 10–fold increase in the rates of stent thrombosis in the treatment of distal LM lesion in the French LM Taxus registry in which a two-stent strategy was utilised.47

There are clearly situations in which a two-stent strategy is the optimal approach, but there is little guideline on the optimal two-stent technique. Situations in which a two-stent technique would be favoured would include disease involving the daughter vessels with similar size, dissection of the side branch after predilation and a large side branch with disease extending more than 5 mm from its ostium. There are a variety of two-stent techniques available, among which are the culotte, crush, simultaneous kissing stents, T- or V-stenting techniques.48 Anatomical factors and operator experience and familiarity with the technique would determine the two-stent technique. There has been no reported differences in outcomes regardless of which two-stent technique was utilised. This has been confirmed in the GISE-SICI study where 317 patients were treated with two stents for distal LM bifurcation. There was no difference in outcomes among patients treated with the T-stenting, V-stenting or crush techniques.49

Post-procedure Surveillance

The appropriate strategy for follow-up of these patients after the procedure remains unclear. Previously routine surveillance angiography was mandated after 3–6 months after LM PCI. Recent data has revealed that this practice does not add any benefit to patient care and results in unnecessary invasive procedures. This is based on the low rates of stent thrombosis and restenosis seen in patients undergoing LM PCI with DES. For example, in the LE MANS substudy of the SYNTAX trial involving 145 patients, angiographic restenosis was found in 2 % of patients with ostial/mid-shaft lesions and 10 % of patients with bifurcation lesion after 15 months of follow-up. Similarly in a study by Biondi-Zoccai et al., it was found that there was no difference in mortality between patients undergoing clinically driven follow-up compared with those undergoing routine angiographic follow-up.50 Based on the lack of benefit from routine angiographic follow-up in these patients, the 2009 ACC/AHA-focused PCI guidelines no longer recommends routine angiographic follow-up after LM PCI.1 The use of CT coronary angiography and non-invasive imaging stress tests may be viable alternatives for this patient subset but there is no data supporting these options.

Treatment of LM stent restenosis is also challenging. It should be clearly established by the use of FFR and/or IVUS that the restenotic lesion is significant. The use of IVUS also helps determine the mechanism of restenosis and helps differentiate restenosis secondary to neointimal hyperplasia from that due to stent under expansion. Options for management include balloon angioplasty in cases of stent under expansion, repeat stenting with DES, medical therapy and CABG. The incidence of LM restenosis and the different treatment modalities was evaluated in a study by Sheiban et al.51 In their study 70 out of 718 (9.7 %) patients who underwent LM PCI had restenosis; the majority (84 %) had repeat PCI with BES, POBA and atherectomy; 10 % underwent bypass surgery; and 5.7 % were treated medically. Over a follow-up period of 35 months, MACE occurred cumulatively in 18 (25.7 %) patients, with death in four (5.7 %), MI in two (2.9 %) and TLR in 15 (21.4 %). Patients treated with medical, interventional and surgical therapy had the following MACE rates, respectively: 50, 25.4 and 14.3 %.

Future Directions

The use of newer imaging tools, such as optical coherence tomography for assessment of the LM coronary artery pre- and post-stenting will help shed more light on our current approach to the LM. The emergence of dedicated bifurcation stents and bioabsorbable stents will also play a major role in advancing the field.

Conclusion

CABG remains the standard of care for the majority of patients with LM coronary artery disease. However, in the past few years there have been emerging indications and a growing trend in favour of PCI for LM disease. This has been supported by a large body of data ranging from single centre retrospective studies to large randomised trials. This has been made possible by tools and techniques described above. Operators who wish to undertake PCI of the LM coronary artery must work within the context of a heart team which includes cardiac surgeons and must be competent using the tools, techniques and strategies as outlined above. In the next few years the indications for LM PCI will probably expand as further data is garnered in this rapidly evolving field.

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