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Accepted Date : 03-Feb-2014 Article type : Review

Revascularization strategies for patients with stable coronary artery disease

Javaid Iqbal1, 2 & Patrick W. Serruys2,3

From the 1South Yorkshire Cardiothoracic Centre, Northern General Hospital, Sheffield, UK; 2

Thorax Centre, Erasmus MC, Rotterdam, the Netherlands; and 3Department of Cardiology,

Imperial College London, London, UK

Running title: Revascularization strategy

Correspondence: Professor Patrick Serruys Department of Interventional Cardiology, Thorax Centre, Erasmus Medical Centre, Rotterdam, the Netherlands Tel: +31 107035260 Fax: +31 107039154 E-mail: [email protected]

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/joim.12243 This article is protected by copyright. All rights reserved.

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ABSTRACT Patients with coronary artery disease who have prognostically significant lesions or symptoms despite optimum medical therapy require mechanical revascularization with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) or both. In this review we will evaluate the evidence-based use of the two revascularization approaches in treating patients with coronary artery disease. CABG has been the predominant mode of revascularization for more than half a century and is the preferred strategy for patients with multivessel disease, especially those with diabetes mellitus, left ventricular systolic dysfunction or complex lesions. There have been significant technical and technological advances in PCI over recent years and this is now the preferred revascularization modality in patients with single-vessel or low-risk multivessel disease. PCI can also be considered to treat complex multivessel disease in patients with increased risk of adverse surgical outcomes including frail patients and those with chronic obstructive pulmonary disease. Improvements in both CABG (including total arterial revascularization, off-pump CABG and ‘no-touch’ graft harvesting) and PCI (including newer-generation stents, adjunctive pharmacotherapy and intracoronary imaging) mean that they will continue to challenge each other in the future. A ‘heart team’ approach is strongly recommended to select an evidence-based, yet individualized, revascularization strategy for all patients with complex coronary artery disease. Finally, optimal medical therapy is important for all patients with coronary artery disease, regardless of the mode of revascularization.

Keywords: coronary artery bypass grafting, coronary artery disease, percutaneous coronary intervention, revascularization.

INTRODUCTION

Coronary artery disease (CAD) remains the single most important cause of morbidity and mortality worldwide. There have been substantial advances in medical therapy to prevent and treat CAD. However, patients with prognostically significant disease or symptoms of angina despite optimal medical therapy (OMT) require mechanical revascularization: either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). CABG has remained the predominant mode of revascularization during the second half of 20th century.

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PCI has become the preferred method of revascularization in patients with single- or doublevessel disease without left main stem (LMS) involvement. However, the optimal strategy in patients with multivessel disease and/or unprotected LMS disease has remained controversial and the subject of many clinical trials in recent years. In this review we discuss the current status and the evidence-based use of these two revascularization strategies in the treatment of patients with stable CAD.

OMT The main focus of this review is revascularization; however, it is essential to first highlight the importance of OMT, which encompasses pharmacotherapy for CAD, good control of cardiovascular disease risk factors and lifestyle modifications (Table 1).

OMT as first-line treatment of CAD The Medical, Angioplasty, or Surgery Study-II (MASS-II) trial (n = 611), though underpowered for outcomes, has shown no difference in survival between OMT and revascularization (OMT 69%, CABG 74.9%, PCI 75.1%, P = 0.089) at the 10-year followup, despite differences in the rates of myocardial infarction (MI) and repeat revascularization [1]. In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial (n = 2287) it was shown that, among patients with significant one-, twoand three-vessel CAD without left main stem (LMS) involvement randomly assigned to receive OMT either alone or plus PCI, there was no significant difference in the composite endpoint of death or non-fatal MI at a median follow-up of 4.6 years [hazard ratio (HR) for the PCI group 1.05, 95% confidence interval (CI) 0.87–1.27, P = 0.62] [2]. Despite frequent crossover to revascularization, the majority (67%) of patients remained on OMT alone for the duration of the trial. Both groups were also equivalent in terms of freedom from angina at 5 years [2]. Other studies comparing OMT with PCI have also reported no mortality benefit, increased non-fatal periprocedural MI and reduced need for urgent revascularization with PCI compared with OMT [3]. Therefore, OMT is the recommended initial choice for patients with stable CAD without significant disease of the LMS or proximal left anterior descending artery (LAD) [4].

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OMT for all patients undergoing revascularization OMT is important and complementary to revascularization therapy, whether PCI [2] or CABG [5]. Progression of atherosclerosis continues after revascularization and is associated with deterioration of left ventricular function. However, appropriate use of secondary prevention medications reduces mortality and the incidence of MI after revascularization [6].

INDICATIONS FOR REVASCULARIZATION Careful evaluation is needed before a decision is made to embark on surgical or percutaneous revascularization. This decision is usually based on the patient’s symptoms or ischaemic burden in the presence of significant obstructive coronary artery stenosis.

Resistant symptoms Patients with significant CAD and symptoms despite OMT should be considered for revascularization [4]. Use of standardized questionnaires (e.g. the Seattle Angina Questionnaire) or objective assessment with exercise testing can be helpful. If the significance of a lesion is uncertain, assessment of the fractional flow reserve (FFR) is strongly recommended [7].

Large ischaemic burden A large ischaemic burden has an adverse impact on clinical outcomes. In patients with a moderate or large degree of inducible ischaemia, the survival benefit (absolute and relative) was greater when treated with revascularization, as compared with OMT [8]. The nuclear substudy of the COURAGE trial has also shown that the degree of reduction in ischaemic myocardium was significantly greater with PCI than with OMT (2.7% vs. 1.6%, P < 0.0001) [9].

Left ventricular dysfunction Revascularization therapy is of benefit in patients with left ventricular systolic dysfunction and angina due to significant CAD [4]. However, among patients with ischaemic heart failure

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but no angina, revascularization therapy should be limited to those who have ischaemic but viable myocardium on non-invasive testing as revascularization in these patients has been shown to improve left ventricular function and survival [10].

REVASCULARIZATION TECHNIQUES Revascularization can be achieved surgically (CABG) or percutaneously (PCI), or by a hybrid approach.

CABG Vasilii Kolesov is believed to have been the first surgeon to perform an anastomosis between the left internal mammary artery (LIMA) and the left circumflex artery in man in 1962. Rene Favaloro used a saphenous vein graft (SVG) as a bypass conduit in 1967. Reed was the first surgeon to perform the operation using cardiopulmonary bypass. Carpentier used radial artery graft for CABG in 1973. The history of CABG has been reviewed in detail elsewhere [11].

The superiority of CABG over OMT has been demonstrated in multiple studies and metaanalyses. CABG confers a survival benefit in patients with unprotected LMS or three-vessel CAD, particularly in those with severe symptoms, early positive exercise tests and/or impaired left ventricular function [12].

PCI Balloon angioplasty was first performed by Andreas Grüentzig in 1977. Coronary stents were developed subsequently to overcome the problems of dissection, elastic recoil and constrictive remodelling with angioplasty [13, 14]. However, the medium- and longer-term outcome using these bare metal stents (BMSs) was compromised by a high incidence of in-stent restenosis, and the drug-eluting stents (DESs) were therefore developed to reduce restenosis and the need for target vessel revascularization (TVR) [15, 16]. The concern of stent thrombosis with the first-generation DESs [17] led to the development of novel polymers, antiplatelet agents and the ‘newer generation’ of DESs [18]. The newer-generation DESs have been shown to reduce major adverse cardiac events (MACEs) [19, 20]. The historical development of coronary stents

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is reviewed elsewhere [18].

Hybrid revascularization The concept of hybrid revascularization is to combine the prognostic benefits of the LIMA-toLAD graft with minimal invasiveness and PCI of non-LAD significant lesions. This approach has largely been used for patients with limited conduit availability or predicted healing problems after sternotomy, or following primary PCI of a non-LAD culprit lesion. However, hybrid revascularization may provide a minimally invasive alternative to traditional CABG. In a single-centre study of 300 consecutive patients, hybrid revascularization resulted in reasonably good outcomes: 30-day mortality, stroke and non-fatal MI were observed in four (1.3%), three (1.0%), and four (1.3%) patients, respectively [21]. In a propensity matched study, consecutive patients undergoing one-stop hybrid revascularization (n = 141) were compared with patients who underwent isolated CABG or PCI (n = 141) After stratification by EuroSCORE or Syntax score, the cumulative major adverse cardiac and cerebrovascular event (MACCE) rates were similar in the low and medium tertiles among the three groups. However in the top EuroSCORE tertile, the hybrid group had a lower MACCE rate than the CABG (P = 0.030) and PCI (P = 0.006) groups. Additionally, among patients with a high Syntax score, in the hybrid group the MACCE rate was lower than in the PCI group (P = 0.002), but similar to that of the CABG group (P = 0.36) [22].

The limited available data on hybrid revascularization appear promising. However, little progress has been made in this field over recent years and, without an appropriately powered randomized trial of hybrid versus traditional revascularization, the uptake of this approach is unlikely to increase.

SELECTION OF REVASCULARIZATION TECHNIQUE The choice between CABG and PCI should be based on a careful evaluation of the extent of CAD, the expected completeness of revascularization, the presence of comorbidities and any associated significant valvular disease [4].

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Extent of CAD The anatomical extent and complexity of CAD plays an important role in decision-making regarding revascularization strategy (Fig. 1).

One- to two-vessel disease without LMS involvement. Patients with one- or two-vessel disease not involving the LMS can be treated with PCI, if technically feasible to achieve complete revascularization. PCI can provide good outcomes in such patients and may be the preferred revascularization strategy [4]. PCI and CABG can provide similar levels of long-term improvement in quality of life in this group of patients [23].

Historically, proximal LAD disease has been treated with CABG. However, recent studies have shown that PCI using DESs is non-inferior to CABG [24, 25]. Therefore international guidelines have accepted PCI as a reasonable alternative to surgery for the treatment of isolated proximal LAD disease [4].

Complex or triple vessel disease. The historical data showing clear superiority of CABG over balloon angioplasty or PCI with BMS for patients with multivessel disease have limited applicability in contemporary practice [26].

With the advent of DESs, indirect comparison with CABG was attempted by the addition of DES arms to the original PCI with BMS versus CABG trials, for example in the Arterial Revascularization Therapies Study II (ARTS-II) and Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI-III) studies. In the ARTS-II study, higher rates of repeat revascularization were observed in the PCI arm (20.8% vs. 9.0%, P < 0.001) but there was no difference in survival between PCI with DES and CABG (94.5% vs. 92.6%, respectively) at the 5-year follow-up [27]. In the ERACI-III study, similar event rates were also observed in the CABG and PCI with DES groups after follow-up for 3 years (5.7% vs. 9.8%; Relative Risk 0.59, 95% CI 0.31–1.14) [28]. The comparison between CABG and PCI with DES in various registries has produced mixed results: the Asan Medical Center-Multivessel Revascularization Registry found no difference in mortality at 5 years [29]; the New York State registry reported similar

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unadjusted survival (PCI 93.7% vs. CABG 93.4%) but different risk-adjusted survival for the two techniques (PCI 94.0% vs. CABG 92.7%, P = 0.03) at 18 months [30]; and ASCERT (the ACCF-STS Database Collaboration on the Comparative Effectiveness of Revascularization Strategies) demonstrated no mortality difference at 1 year (PCI 6.55% vs. CABG 6.24%; HR 0.95, 95% CI 0.90–1.0) but lower mortality with CABG at 4 years (PCI 20.8% vs. CABG 16.4%; HR 0.79, 95% CI 0.76–0.82) [31].

The SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) trial is the largest (n = 1800) contemporary ‘all-comers’ study of patients with complex CAD. At the 5-year follow-up, CABG was superior to PCI with a firstgeneration DES: MACCE (PCI 37.3% vs. CABG 26.9%, P < 0.001), all-cause death (PCI 13.9% vs. CABG 11.4%, P = 0.10), MI (PCI 9.7% vs. CABG 3.8%, P < 0.001), stroke (PCI 2.4% vs. CABG 3.7%, P = 0.09) and repeat revascularization (PCI 25.9% vs. CABG 13.7%, P < 0.001) [32]. The subgroup analysis of this trial showed that in the tertile of patients with the lowest Syntax scores (0–22) there was no significant difference in the MACCE rate between the two groups (PCI 32.1% vs. CABG 28.6%, P = 0.43). However, CABG outperformed PCI in the intermediate (23–32 score) (PCI 36.0% vs. CABG 25.8%, P = 0.008) and top (≥33 score) tertiles (PCI 44.0% vs. CABG 26.8%, P < 0.001) for MACCE rate at 5 years [32]. These outcomes are also consistent with findings of several other studies [31, 33]. It has been shown that combining anatomical Syntax score with clinical characteristics (Syntax score II) is useful for selecting a favourable revascularization strategy [34]. Although prospective validation of the Syntax score II is needed, we would advocate using this score for decision-making in a multidisciplinary setting (Fig. 1).

Unprotected LMS disease. LMS disease has remained a class III indication for PCI (i.e. the procedure is generally not effective and may even be harmful) according to international guidelines, due to historical data showing high rates of complications and modest outcomes [35]. However, recent data from multiple registries have shown that PCI using DESs in patients with LMS disease has similar mortality and safety outcomes, but a higher rate of TVR, compared with CABG [36–38]. Several randomized trials, including LEMANS [39], SYNTAX left main [32], Boudriot [40] and PRECOMBAT [41], have compared PCI with DES against CABG for the treatment of LMS stenosis (Table 2). In a recent meta-analysis of four

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randomized trials including 1611 patients it was shown that PCI, as compared to CABG, was associated with a lower risk of stroke, increased risk of repeat revascularization and similar risk of mortality or MI, resulting in a higher risk of MACEs but a similar risk of MACCEs [42]. Based on these recent data, PCI for LMS has been upgraded to a class IIb indication in current guidelines, and may be considered for patients with coronary anatomy that is associated with a low risk of procedural complication if treated by PCI and/or clinical conditions that predict an increased risk of adverse surgical outcomes [43]. Therefore we recommend that patients with LMS disease and Syntax scores between 0 and 32 can be treated with PCI using DESs when technically feasible, whereas CABG surgery should remain the standard treatment in patients with Syntax scores ≥33.

Expected completeness of revascularization Complete revascularization of complex CAD has been shown to improve clinical outcomes in patients with multivessel disease [44]. A recent meta-analysis has demonstrated that complete revascularization is associated with better outcomes [45]. It is, therefore, important to evaluate whether a given technique can achieve complete revascularization.

Patient comorbidities Older age, frailty and the presence of multiple comorbidities including chronic obstructive pulmonary disease generally increase surgical risk, and PCI may be the preferred mode of revascularization in elderly, frail and/or comorbid patients [34, 46].

Diabetes mellitus is a risk factor for both revascularization strategies. There have been some conflicting reports on the effect of diabetes on outcome of revascularization [29, 47–50]. However, the Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) study, the largest dedicated contemporary trial in patients with diabetes and multivessel CAD randomly assigned to either PCI with DES or CABG, has clearly shown the superiority of CABG in treating these patients [51]. Therefore, CABG should,be the revascularization option of choice for patients with multivessel CAD and diabetes mellitus. However, diabetic patients with less complex CAD can be treated with PCI.

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There are conflicting data on revascularization in patients with chronic heart failure; the Asan Medical Center-Multivessel Revascularization Registry found no difference between PCI with DES and CABG in patients with or without abnormal ventricular function [29], whereas data from an Australian registry have shown that heart failure is an independent predictor of 30day mortality after PCI but not after CABG [50]. The findings of the SYNTAX trial also suggest that patients with multivessel disease and heart failure with low ejection fraction may derive more benefit from surgical revascularization [34].

A ‘heart team’ approach for individualized risk stratification The selection of revascularization strategy for patients with complex coronary disease remains challenging, and adopting a multidisciplinary ‘heart team’ approach for decisionmaking after careful consideration of the relevant data is strongly recommended (Fig. 2) [52]. It is best to avoid ad hoc PCI in stable patients with complex CAD and each case should be discussed by the heart team before a deferred revascularization (PCI or CABG) procedure [4]. There are various tools available to help the heart team in selecting the optimal strategy. The EuroSCORE and the Syntax score have been shown to predict adverse outcomes in studies containing both PCI and CABG arms [32, 53]. The recently proposed SYNTAX score II, combining anatomical and clinical factors, may provide an evidence-based approach for decision-making [34]. It is important to acknowledge that all risk models have their limitations; informed patient consent and clinical judgement of the heart team remain vital.

FACTORS TO CONSIDER IN PATIENTS UNDERGOING CABG Selection of conduit The choice of conduits for surgical revascularization may influence the long-term outcome. Reduced mortality and morbidity have been demonstrated for the LIMA graft compared to other conduits [54]. It is therefore common practice to offer LIMA to LAD graft and supplemental SVG to other arteries. It is arguable that total arterial revascularization using the bilateral internal mammary arteries (BIMAs) or radial artery may offer additive benefits [55]. The radial artery has been shown to offer better long-term graft and patient survival [56]; however, concerns regarding vasospasm and neointimal hyperplasia remain. Use of the right This article is protected by copyright. All rights reserved.

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internal mammary artery appears to be more attractive with patency rates equal to those of LIMA and better than those of the radial artery and SVG [57]. Use of the BIMAs has been shown to offer a survival advantage [58]. However, due to concerns about the risk of infection and impaired sternotomy healing, caution is warranted in the use of the BIMAs for patients with chronic obstructive lung disease and diabetes mellitus.

On-pump or off-pump surgery Surgical revascularization on the beating heart (off-pump CABG) has a potential to reduce the detrimental effects of cardiopulmonary bypass. In the Surgical Management of Arterial Revascularization Therapies (SMART) trial, patients (n = 197) randomly assigned to either offpump or conventional CABG had similar rates of death, stroke, MI, angina, reintervention and graft patency, and similar quality of life, at 30 days and 1 year [59]. In another trial (n = 308), off-pump CABG was associated with fewer grafts and a higher incidence of atrial fibrillation but reduced intensive care unit and hospital length of stay. However, after 5 years of follow-up, there was no difference in MACCE rate between the two groups (HR 0.71, 95% CI 0.41–1.22, P = 0.21) [60]. These small studies providing the proof of concept for off-pump CABG led to two large-scale trials. The Randomized On/Off Bypass (ROOBY) trial (n = 2203) showed lower graft patency rates with off-pump CABG, suggesting that this technique may not completely revascularize all major coronary arteries [61]. The CABG Off or On Pump Revascularization Study (CORONARY) is the largest (n = 4752) multicentre trial comparing off-pump versus on-pump procedures. No significant differences between the two techniques in the rate of the primary composite endpoint (death, non-fatal stroke, non-fatal MI or new renal failure requiring dialysis) (9.8% vs. 10.3%; HR 0.95, 95% CI 0.79–1.14, P = 0.59) or in any individual component of the primary endpoint were shown in this study at 30 days after randomization. However, the use of off-pump CABG significantly reduced the need for blood transfusion (50.7% vs. 63.3%, P < 0.001), reoperation due to perioperative bleeding (1.4% vs. 2.4%, P = 0.02), acute kidney injury (28.0% vs. 32.1%, P = 0.01) and respiratory complications (5.9% vs. 7.5%, P = 0.03) but increased the rate of early repeat revascularization (0.7% vs. 0.2%, P = 0.01) [62]. A recent meta-analysis has shown a reduction in the incidence of stroke with off-pump CABG [63].

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In summary, it may be reasonable to consider off-pump CABG in patients at increased risk of perioperative complications, especially those attributed to cardiopulmonary bypass (inflammation, infection, kidney injury, atrial fibrillation) and aortic manipulation (stroke), if a surgeon experienced in performing off-pump CABG is available. If off-pump CABG is performed, the degree of aortic manipulation should be reduced to a minimum to decrease the risk of neurological complications [64].

Minimally invasive direct CABG Minimally invasive direct coronary artery bypass (MIDCAB) uses a small anterior left thoracotomy incision to harvest the LIMA and perform an anastomosis to the LAD with or without cardiopulmonary bypass. It is a safe procedure with good short- and long-term results [65]. However, in a small trial in patients (n = 130) with isolated proximal LAD disease, MIDCAB was not superior to PCI with DES (in terms of MACE rate at 12 months), although TVR was higher in the PCI arm [25]. Therefore, MIDCAB is primarily performed for LAD lesions unsuitable for PCI or for repeat CABG when sternotomy or cardiopulmonary bypass could be high risk, or for diffuse aortic calcification. MIDCAB to the LAD in conjunction with PCI of other vessels i.e. hybrid revascularization, as discussed above, remains an attractive option, but further data to support this approach are needed.

FACTORS TO CONSIDER IN PATIENTS UNDERGOING PCI Selection of a stent Although a variety of stents are available for clinical use, the main choice is between BMSs and DESs. BMSs have higher incidence of in-stent restenosis, whereas DESs are expensive and healing may be delayed leading to late stent thrombosis [18].

A meta-analysis of clinical trials comparing DESs with BMSs reported similar rates of allcause death, cardiac death and non-fatal MI, but a significant reduction in TVR with DESs [66]. By contrast, an unadjusted analysis of 182,901 patients in 34 observational studies of BMSs and DESs demonstrated a significant reduction in mortality (HR 0.78, 95% CI 0.71– 0.86) and MI (HR 0.87, 95% CI 0.78–0.97) with DESs [67]. After multivariable adjustment,

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the benefits of DESs were significantly attenuated. A recent Cochrane review has shown that patients have similar rates of death and MI with BMSs and DESs [68].

It could be argued that all patients without bleeding problems should receive DESs. However, it is also acceptable that shorter lesions (≤15 mm) in bigger vessels (≥3 mm diameter) in nondiabetic patients may be treated with BMSs [69, 70]. BMSs could also be the preferred choice for patients unwilling to take or unlikely to adhere to dual antiplatelet therapy (DAPT). Diabetes mellitus is an independent predictor of in-stent restenosis and diabetic patients treated with DESs have significantly lower rates of death, acute MI and repeat revascularization than those treated with BMSs [71].

If DESs are to be used, then the ‘newer-generation’ DESs are highly preferable, compared to the ‘first-generation’ stents, as they may reduce cardiovascular complications and TVR [19, 20, 72]; however there is no clear effect on mortality between the older and newer versions [73].

Selection of antiplatelet regimen Unless contraindicated, all patients undergoing PCI with stents should receive DAPT to reduce the risk of stent thrombosis. For patients undergoing PCI for acute coronary syndromes, DAPT is recommended for 12 months. However, the duration and choice of antiplatelet agents for patients undergoing PCI for stable angina remains debatable and may depend on the choice of stent (BMS or DES). DAPT for a minimum of 1 month with BMSs and 6 months with DESs is generally recommended. However, 3 months of treatment with DAPT for the newer-generation DESs (e.g. Xience stents from Abbot Vascular Ltd, Santa Clara, USA) has also been approved in Europe, based on data suggesting a low incidence of stent thrombosis with these stents [72].

Aspirin should be continued indefinitely and a low dose (75–100 mg daily) is preferred over higher doses. Clopidogrel is still the most commonly used P2Y12 inhibitor; however, it is a prodrug that requires hepatic activation by the cytochrome P450 system and consequently some patients are resistant to clopidogrel or respond poorly [74]. Therefore, the newer P2Y12 inhibitors prasugrel and ticagrelor have been developed in recent years [74]. These agents have

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proven benefits for patients with acute coronary syndromes [75, 76]. Currently, there is limited evidence to support the use of these potent antiplatelet agents in patient with stable angina undergoing PCI.

Patients receiving coronary stents who require warfarin are at high risk of bleeding if they also receive DAPT. Omission of aspirin may be advantageous in such patients [77]. Routine platelet function or genetic testing is currently not recommended to tailor antiplatelet therapy after PCI [78].

Adjunctive intracoronary imaging Adjunctive intracoronary imaging during PCI can be used to guide appropriate sizing and deployment of stents and to exclude any local complication (e.g. dissection). Intravascular ultrasound-guided PCI has been shown to reduce the incidence of adverse outcomes [79]. Optical coherence tomography, which offers considerably higher resolution at the expense of limited penetration, is also a promising tool to optimize stent deployment [80], although further data are needed to establish its precise role in clinical practice.

FUTURE OF REVASCULARIZATION STRATEGIES Advances in surgical techniques Robotic surgery. MIDCAB can also be performed with computer-assisted (robotic) surgery; the surgeon, seated at a computer console, introduces instruments through small incisions in the chest and manipulates them with robotic arms. Early results of robotic coronary surgery are promising and it may play an important role in the coming years [81].

‘No-touch’ SVG harvest. The poor outcome with SVG can partially be due to trauma during harvesting. ‘No-touch’ harvesting can potentially eliminate this problem. The PATENT-SVG study compared markers of vascular injury in 17 patients who had SVGs harvested with the notouch technique from one leg and using the conventional method from the other leg. SVG segments harvested using the no-touch technique exhibited preserved intimal, medial and adventitial architecture. Furthermore, vascular smooth muscle cell expression of key

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transcriptional genes involved in aberrant differentiation and phenotypic modulation was significantly reduced in the no-touch harvesting group [82]. Larger studies are required to determine whether no-touch vein harvesting can reduce the incidence of SVG blockage and improve clinical outcomes.

Advances in PCI Novel DESs. DESs either with biodegradable polymer or with no polymer at all eliminate the long-term undesirable effects of the presence of polymer. These polymer-free DESs contain drugs incorporated into a microporous or nanoporous surface of the metallic stent. These stents are described in detail elsewhere [83]. A short summary is provided in Table 3.

Pro-healing stents. The antiproliferative drugs used in DESs not only inhibit proliferation of vascular smooth muscle cells underlying neointimal formation, but also compromise endothelial regeneration and, hence, increase the risk of stent thrombosis. Different agents to promote endotheial healing have been investigated. Vascular endothelial growth factor-eluting stents were tested; they not only failed to promote endothelialization but also increased neointimal proliferation [84]. The GENOUS (OrbusNeich, Wanchai, Hong Kong) is a stainless steel stent coated with anti-CD34 antibodies to capture endothelial progenitor cells (EPC). A new-generation Combo (OrbusNeich) stent combines EPC-capturing anti-CD34 antibodies on the luminal surface and a sirolimus-eluting biodegradable polymer on the abluminal surface. The Combo stent has been compared in the Randomized Evaluation of an Abluminal sirolimus coated Bio-Engineered Stent (REMEDEE) trial with the first-generation TAXUS Liberté (Boston Scientific Corporation, Natick, USA) stent and was found to be non-inferior for angiographic in-stent late lumen loss at 9 months and MACE rates at 12 months [85].

Bioresorbable scaffolds. The bioresorbable stents (scaffolds) provide initial scaffolding similar to that of the metallic stents but undergo gradual bioresorption, so that after a predefined period the vessel will be free of the metallic cage and could regain its normal function. The absence of any residual foreign material and restoration of endothelial coverage would also reduce the risk of stent thrombosis and the requirement for long-term treatment with DAPT [86]. The current scaffolds are composed of either magnesium alloys or polymers of poly-lactic acids [86]. The ABSORB BVS (bioresorbable vascular scaffold) (Abbott Vascular Ltd, Santa Clara, USA) and This article is protected by copyright. All rights reserved.

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DESolve (Elixir Medical corporation, Sunnyvale, USA) devices have achieved CE marking. An example of a complex PCI case with the use of intracoronary imaging is shown in Fig. 3. A number of bioresorbable devices are currently undergoing clinical and preclinical evaluation (Fig. 4).

Novel revascularization approaches Various novel revascularization approaches, mechanical and pharmacological, are currently being investigated. Transmyocardial revascularization is based on creating small (1-mm diameter) channels mechanically or using a laser along the left ventricular free wall. Although some studies have shown no effect [87], others have demonstrated an improvement in angina pectoris and functional capacity [88, 89]. This procedure is currently indicated only if PCI and CABG are not possible and the patient has resistant symptoms on maximal therapy. Further studies of transmyocardal revascularization via a minimally invasive or endocardial approach are needed. Additionally, interest is increasing in the concept of pharmacological revascularization using local or systemic cell-, gene- or drug-based therapy to promote angiogenesis. This approach may prove to be useful for patients with diffuse disease not amenable to PCI or CABG. It is possible that expansion of the microvascular bed may also induce enlargement of upstream collateral arteries via gap junction-mediated retrograde signalling and increased shear stress, resulting in effective perfusion downstream of the occlusion and hence providing a ‘biological bypass’ [90]. Several agents have shown promising results in preclinical or first-in-man studies, and further clinical studies and randomized trials are warranted [91, 92].

Ongoing and planned clinical trials EXCEL trial. The debate on the optimal revascularization strategy for LMS disease is not yet over. A large dedicated LMS study, the Evaluation of Xience Prime Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial, with planned enrolment of 2600 patients to revascularization with either a newer-generation everolimuseluting stent (Xience V/PRIME, Abbott Vascular Ltd., Santa Clara, USA) or CABG is currently underway (NCT 01205776). The results are awaited with great interest.

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BEST trial. The purpose of the BEST (Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease; NCT 00997828) study is to determine that the safety and efficacy of PCI with everolimus-eluting stents is non-inferior to CABG for the treatment of patient with multivessel CAD. It is planned that 1776 patients will be enrolled, and the primary endpoint is the composite of all-cause death, non-fatal MI and ischaemiadriven TVR.

ISCHEMIA trial. In the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches; NCT 01471522) trial, patients are randomly assigned, before coronary angiography, to a conservative OMT strategy or to an invasive strategy if they have documented myocardial ischaemia. The primary endpoint is death or MI.

REVIVED-BCIS2 trial. Revascularization for Ischaemic Ventricular Dysfunction (REVIVEDBCIS2; NCT 01920048) is a multicentre, randomized, open, controlled trial to evaluate the efficacy and safety of PCI compared to OMT alone for ischaemic left ventricular dysfunction. The trial has just started with the intention of recruiting 700 patients, and the primary endpoint is all-cause death or hospitalization due to heart failure.

Clinical trials of bioresorbable scaffolds The second-generation magnesium scaffold (DREAMS, Biotronik, Berlin, Deutschland) is being tested in the BIOSOLVE-II study. ReZolve2 (REVA Medical, San Diego, CA, USA), a desaminotyrosine polycarbonate scaffold, is being tested in the RESTORE-II study. ABSORB EXTEND is an international prospective, single-arm study that will recruit more than 800 patients with more complex coronary disease than previously studied in the ABSORB cohort A and B. ABSORB-II (NCT 01425281) is a prospective, randomized, controlled trial to compare the safety and efficacy of the Absorb BVS versus the Xience stent in 501 patients with stable angina and one- to two-vessel disease. The primary endpoints are the superiority of Absorb BVS for vasomotion of the treated segment and non-inferiority for angiographic minimum lumen diameter at 2 years. There are a number of other ongoing studies with Absorb BVS, including ABSORB Japan (NCT 01844284), ABSORB-STEMI (NCT 01986803) and ABSORB-III (NCT 01751906). The potential advantages of

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bioresorbable scaffolds need to be proven in adequately powered trials with long-term follow-up to establish the role of this device in routine practice [86].

SUMMARY The optimal treatment strategy for patients with complex CAD will continue to be debated in the coming years. Recent studies including SYNTAX and FREEDOM have helped to improve therapeutic decision-making and also provided tools to identify the appropriate treatment for individual patients. EXCEL will further inform treatment decisions. Generally, as the anatomical complexity increases, surgical revascularization appears to be more beneficial; however, comorbidities in certain subset of patients are likely to make PCI a more attractive and practical choice. It remains reasonable to suggest that an open dialogue between members of the heart team and the individual patient is the key to deciding the OMT. Both surgeons and interventional cardiologists should note that OMT and management of risk factors are essential for the best prognosis after either PCI or CABG.

Conflict of interest statement No conflict of interest was declared. References 1 Hueb W, Lopes N, Gersh BJ, et al. Ten-year follow-up survival of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2010; 122: 949-57. 2 Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356: 1503-16. 3 Katritsis DG, Ioannidis JP. Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease: a meta-analysis. Circulation 2005; 111: 290612. 4 Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010; 31: 2501-55. 5 Chaitman BR, Hardison RM, Adler D, et al. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation 2009; 120: 2529-40. 6 Piepoli MF, Corra U, Benzer W, et al. Secondary prevention through cardiac rehabilitation: from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. European journal of cardiovascular prevention and rehabilitation : official

This article is protected by copyright. All rights reserved.

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journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 2010; 17: 1-17. 7 De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012; 367: 991-1001. 8 Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003; 107: 2900-7. 9 Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008; 117: 1283-91. 10 Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002; 39: 1151-8. 11 Head SJ, Kieser TM, Falk V, Huysmans HA, Kappetein AP. Coronary artery bypass grafting: Part 1--the evolution over the first 50 years. Eur Heart J 2013; 34: 2862-72. 12 Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994; 344: 563-70. 13 Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandablestent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994; 331: 489-95. 14 Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994; 331: 496-501. 15 Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimuseluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773-80. 16 Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004; 350: 221-31. 17 McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004; 364: 1519-21. 18 Iqbal J, Gunn J, Serruys PW. Coronary stents: historical development, current status and future directions. Br Med Bull 2013; 106: 193-211. 19 Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA 2008; 299: 1903-13. 20 Serruys PW, Silber S, Garg S, et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med 2010; 363: 136-46. 21 Halkos ME, Walker PF, Vassiliades TA, et al. Clinical and Angiographic Results After Hybrid Coronary Revascularization. Ann Thorac Surg 2013. 22 Shen L, Hu S, Wang H, et al. One-stop hybrid coronary revascularization versus coronary artery bypass grafting and percutaneous coronary intervention for the treatment of multivessel coronary artery disease: 3-year follow-up results from a single institution. J Am Coll Cardiol 2013; 61: 2525-33. 23 Brorsson B, Bernstein SJ, Brook RH, Werko L. Quality of life of chronic stable angina patients 4 years after coronary angioplasty or coronary artery bypass surgery. J Intern Med 2001; 249: 47-57.

This article is protected by copyright. All rights reserved.

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24 Kukreja N, Serruys PW, De Bruyne B, et al. Sirolimus-eluting stents, bare metal stents or coronary artery bypass grafting for patients with multivessel disease including involvement of the proximal left anterior descending artery: analysis of the Arterial Revascularization Therapies study part 2 (ARTS-II). Heart 2009; 95: 1061-6. 25 Thiele H, Neumann-Schniedewind P, Jacobs S, et al. Randomized comparison of minimally invasive direct coronary artery bypass surgery versus sirolimus-eluting stenting in isolated proximal left anterior descending coronary artery stenosis. J Am Coll Cardiol 2009; 53: 2324-31. 26 Hoffman SN, TenBrook JA, Wolf MP, Pauker SG, Salem DN, Wong JB. A metaanalysis of randomized controlled trials comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty: one- to eight-year outcomes. J Am Coll Cardiol 2003; 41: 1293-304. 27 Serruys PW, Onuma Y, Garg S, et al. 5-year clinical outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions. J Am Coll Cardiol 2010; 55: 1093-101. 28 Rodriguez AE, Maree AO, Mieres J, et al. Late loss of early benefit from drug-eluting stents when compared with bare-metal stents and coronary artery bypass surgery: 3 years follow-up of the ERACI III registry. Eur Heart J 2007; 28: 2118-25. 29 Park DW, Kim YH, Song HG, et al. Long-term comparison of drug-eluting stents and coronary artery bypass grafting for multivessel coronary revascularization: 5-year outcomes from the Asan Medical Center-Multivessel Revascularization Registry. J Am Coll Cardiol 2011; 57: 128-37. 30 Hannan EL, Wu C, Walford G, et al. Drug-Eluting Stents vs. Coronary-Artery Bypass Grafting in Multivessel Coronary Disease. New England Journal of Medicine 2008; 358: 331-41. 31 Weintraub WS, Grau-Sepulveda MV, Weiss JM, et al. Comparative effectiveness of revascularization strategies. N Engl J Med 2012; 366: 1467-76. 32 Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013; 381: 629-38. 33 Hannan EL, Wu C, Walford G, et al. Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease. N Engl J Med 2008; 358: 331-41. 34 Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet 2013; 381: 639-50. 35 Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005; 26: 804-47. 36 Palmerini T, Marzocchi A, Marrozzini C, et al. Comparison between coronary angioplasty and coronary artery bypass surgery for the treatment of unprotected left main coronary artery stenosis (the Bologna Registry). Am J Cardiol 2006; 98: 54-9. 37 Chieffo A, Meliga E, Latib A, et al. Drug-Eluting Stent for Left Main Coronary Artery DiseaseThe DELTA Registry: A Multicenter Registry Evaluating Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Left Main Treatment. JACC: Cardiovascular Interventions 2012; 5: 718-27. 38 Park DW, Seung KB, Kim YH, et al. Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year

This article is protected by copyright. All rights reserved.

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results from the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry. J Am Coll Cardiol 2010; 56: 117-24. 39 Buszman PE, Kiesz SR, Bochenek A, et al. Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization. J Am Coll Cardiol 2008; 51: 538-45. 40 Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011; 57: 538-45. 41 Park SJ, Kim YH, Park DW, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med 2011; 364: 1718-27. 42 Ferrante G, Presbitero P, Valgimigli M, et al. Percutaneous coronary intervention versus bypass surgery for left main coronary artery disease: a meta-analysis of randomised trials. EuroIntervention 2011; 7: 738-46, 1. 43 Kushner FG, Hand M, Smith SC, Jr., et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120: 2271-306. 44 Farooq V, Serruys PW, Garcia-Garcia HM, et al. The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol 2013; 61: 282-94. 45 Aggarwal V, Rajpathak S, Singh M, Romick B, Srinivas VS. Clinical outcomes based on completeness of revascularisation in patients undergoing percutaneous coronary intervention: a meta-analysis of multivessel coronary artery disease studies. EuroIntervention 2012; 7: 1095-102. 46 Iqbal J, Denvir M, Gunn J. Frailty assessment in elderly people. Lancet 2013; 381: 1985-6. 47 Kapur A, Hall RJ, Malik IS, et al. Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients. 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial. J Am Coll Cardiol 2010; 55: 432-40. 48 Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents. J Am Coll Cardiol 2010; 55: 1067-75. 49 Kappetein AP, Head SJ, Morice MC, et al. Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial. European journal of cardiothoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2013. 50 Yan BP, Clark DJ, Buxton B, et al. Clinical characteristics and early mortality of patients undergoing coronary artery bypass grafting compared to percutaneous coronary intervention: insights from the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) and the Melbourne Interventional Group (MIG) Registries. Heart, lung & circulation 2009; 18: 184-90. 51 Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for Multivessel Revascularization in Patients with Diabetes. N Engl J Med 2012; 367: 2375-84.

This article is protected by copyright. All rights reserved.

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52 Head SJ, Kaul S, Mack MJ, et al. The rationale for Heart Team decision-making for patients with stable complex coronary artery disease. Eur Heart J 2013. 53 Rodes-Cabau J, Deblois J, Bertrand OF, et al. Nonrandomized comparison of coronary artery bypass surgery and percutaneous coronary intervention for the treatment of unprotected left main coronary artery disease in octogenarians. Circulation 2008; 118: 237481. 54 Cameron A, Davis KB, Green G, Schaff HV. Coronary bypass surgery with internalthoracic-artery grafts--effects on survival over a 15-year period. N Engl J Med 1996; 334: 216-9. 55 Nasso G, Coppola R, Bonifazi R, Piancone F, Bozzetti G, Speziale G. Arterial revascularization in primary coronary artery bypass grafting: Direct comparison of 4 strategies--results of the Stand-in-Y Mammary Study. J Thorac Cardiovasc Surg 2009; 137: 1093-100. 56 Cao C, Manganas C, Horton M, Bannon P, Munkholm-Larsen S, Ang SC, Yan TD. Angiographic outcomes of radial artery versus saphenous vein in coronary artery bypass graft surgery: A meta-analysis of randomized controlled trials. J Thorac Cardiovasc Surg 2012. 57 Tatoulis J, Buxton BF, Fuller JA. The right internal thoracic artery: the forgotten conduit--5,766 patients and 991 angiograms. Ann Thorac Surg 2011; 92: 9-15; discussion -7. 58 Grau JB, Ferrari G, Mak AW, et al. Propensity matched analysis of bilateral internal mammary artery versus single left internal mammary artery grafting at 17-year follow-up: validation of a contemporary surgical experience. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2012; 41: 770-5; discussion 6. 59 Puskas JD, Williams WH, Mahoney EM, et al. Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost, and quality-of-life outcomes: a randomized trial. JAMA 2004; 291: 1841-9. 60 Hueb W, Lopes NH, Pereira AC, et al. Five-year follow-up of a randomized comparison between off-pump and on-pump stable multivessel coronary artery bypass grafting. The MASS III Trial. Circulation 2010; 122: S48-52. 61 Hattler B, Messenger JC, Shroyer AL, et al. Off-Pump coronary artery bypass surgery is associated with worse arterial and saphenous vein graft patency and less effective revascularization: Results from the Veterans Affairs Randomized On/Off Bypass (ROOBY) trial. Circulation 2012; 125: 2827-35. 62 Lamy A, Devereaux PJ, Prabhakaran D, et al. Off-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med 2012; 366: 1489-97. 63 Afilalo J, Rasti M, Ohayon SM, Shimony A, Eisenberg MJ. Off-pump vs. on-pump coronary artery bypass surgery: an updated meta-analysis and meta-regression of randomized trials. Eur Heart J 2012; 33: 1257-67. 64 Misfeld M, Brereton RJ, Sweetman EA, Doig GS. Neurologic complications after offpump coronary artery bypass grafting with and without aortic manipulation: meta-analysis of 11,398 cases from 8 studies. J Thorac Cardiovasc Surg 2011; 142: e11-7. 65 Holzhey DM, Cornely JP, Rastan AJ, Davierwala P, Mohr FW. Review of a 13-year single-center experience with minimally invasive direct coronary artery bypass as the primary surgical treatment of coronary artery disease. The heart surgery forum 2012; 15: E61-8. 66 Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007; 370: 937-48. 67 Kirtane AJ, Gupta A, Iyengar S, et al. Safety and efficacy of drug-eluting and bare metal stents: comprehensive meta-analysis of randomized trials and observational studies. Circulation 2009; 119: 3198-206.

This article is protected by copyright. All rights reserved.

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68 Greenhalgh J, Hockenhull J, Rao N, Dundar Y, Dickson RC, Bagust A. Drug-eluting stents versus bare metal stents for angina or acute coronary syndromes. Cochrane Database Syst Rev 2010: CD004587. 69 Pfisterer M, Brunner-La Rocca HP, Rickenbacher P, et al. Long-term benefit-risk balance of drug-eluting vs. bare-metal stents in daily practice: does stent diameter matter? Three-year follow-up of BASKET. Eur Heart J 2009; 30: 16-24. 70 Tu JV, Bowen J, Chiu M, et al. Effectiveness and safety of drug-eluting stents in Ontario. N Engl J Med 2007; 357: 1393-402. 71 Bangalore S, Kumar S, Fusaro M, et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22,844 patient years of follow-up from randomised trials. BMJ 2012; 345: e5170. 72 Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012; 379: 1393-402. 73 Navarese EP, Tandjung K, Claessen B, et al. Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis. BMJ 2013; 347. 74 Storey RF. New P2Y12 inhibitors. Heart 2011; 97: 1262-7. 75 Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-15. 76 Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-57. 77 Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381: 1107-15. 78 Brilakis ES, Patel VG, Banerjee S. Medical management after coronary stent implantation: a review. JAMA 2013; 310: 189-98. 79 Zhang Y, Farooq V, Garcia-Garcia HM, et al. Comparison of intravascular ultrasound versus angiography-guided drug-eluting stent implantation: a meta-analysis of one randomised trial and ten observational studies involving 19,619 patients. EuroIntervention 2012; 8: 855-65. 80 Prati F, Di Vito L, Biondi-Zoccai G, et al. Angiography alone versus angiography plus optical coherence tomography to guide decision-making during percutaneous coronary intervention: the Centro per la Lotta contro l'Infarto-Optimisation of Percutaneous Coronary Intervention (CLI-OPCI) study. EuroIntervention 2012; 8: 823-9. 81 Mohr FW, Falk V, Diegeler A, et al. Computer-enhanced "robotic" cardiac surgery: experience in 148 patients. J Thorac Cardiovasc Surg 2001; 121: 842-53. 82 Verma S, Lovren F, Pan Y, et al. Pedicled no-touch saphenous vein graft harvest limits vascular smooth muscle cell activation: the PATENT saphenous vein graft study. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2013. 83 Abizaid A, Costa JR, Jr. New drug-eluting stents: an overview on biodegradable and polymer-free next-generation stent systems. Circ Cardiovasc Interv 2010; 3: 384-93. 84 Swanson N, Hogrefe K, Javed Q, Malik N, Gershlick AH. Vascular endothelial growth factor (VEGF)-eluting stents: in vivo effects on thrombosis, endothelialization and intimal hyperplasia. J Invasive Cardiol 2003; 15: 688-92. 85 Haude M, Lee SW, Worthley SG, et al. The REMEDEE trial: a randomized comparison of a combination sirolimus-eluting endothelial progenitor cell capture stent with a paclitaxel-eluting stent. JACC Cardiovasc Interv 2013; 6: 334-43.

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86 Iqbal J, Onuma Y, Ormiston J, Abizaid A, Waksman R, Serruys P. Bioresorbable scaffolds: rationale, current status, challenges, and future. Eur Heart J 2013: [Epub 23 Dec 2013]. 87 Stone GW, Teirstein PS, Rubenstein R, et al. A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions. J Am Coll Cardiol 2002; 39: 1581-7. 88 Oesterle SN, Sanborn TA, Ali N, et al. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial. Potential Class Improvement From Intramyocardial Channels. Lancet 2000; 356: 1705-10. 89 Babin-Ebell J, Sievers HH, Charitos EI, et al. Transmyocardial laser revascularization combined with intramyocardial endothelial progenitor cell transplantation in patients with intractable ischemic heart disease ineligible for conventional revascularization: preliminary results in a highly selected small patient cohort. Thorac Cardiovasc Surg 2010; 58: 11-6. 90 Rissanen TT, Korpisalo P, Markkanen JE, et al. Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis. Circulation 2005; 112: 3937-46. 91 Freedman SB, Isner JM. Therapeutic angiogenesis for coronary artery disease. Ann Intern Med 2002; 136: 54-71. 92 Simons M, Bonow RO, Chronos NA, et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary. Circulation 2000; 102: E73-86. Figure legends Fig. 1 A potential revascularization pathway for patients with stable angina pectoris. OMT, optimal medical therapy; FFR, fractional flow reserve; CAD, coronary artery disease; LMS, left main stem; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.

Fig. 2 Factors influencing decision-making for coronary revascularization. CAD, coronary artery disease.

Fig. 3 Percutaneous coronary intervention of a chronically occluded left anterior descending artery (LAD) using the Absorb bioresorbable vascular scaffold (BVS). Coronary angiography revealed a chronically occluded LAD (A), which was successfully opened using the Absorb BVS (B). Illustrative images using intravascular ultrasound (C) and optical coherence tomography (D) in a patient who underwent revascularization using the Absorb BVS (in Absorb cohort B study) are shown at various follow-up timepoints.

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Fig. 4 Design of clinically tested bioresorbable scaffolds

Table 1 Optimal medical treatment for patients with stable coronary artery disease Lifestyle modification

Smoking cessation Healthy diet

Advice, encouragement and pharmacological aid with nicotine-replacement therapy Limit saturated fats, five servings of fruit/vegetables daily and fish twice per week Physical activity Moderate-intensity aerobic exercise for 30 min at least three times per week Control of risk Obesity Aim for BMI