Current percutaneous coronary intervention and coronary artery bypass grafting practices for three-vessel and left main coronary artery disease.☆Insights from the SYNTAX run-in phase

Coronary bypass surgery remains the standard of care for patients with three-vessel disease (3VD) and left main (LM) coronary artery disease [1,2]. However, percutaneous coronary intervention (PCI) has progressed through simple balloon angioplasty, to bare metal coronary stents, and then drug-eluting stents, and is now challenging coronary artery bypass graft surgery (CABG) as an alternative for revascularization of these patients with multivessel coronary artery disease (CAD) or left main disease. Traditionally, the increased, symptom-driven need for subsequent revascularization, as a result of restenosis, has been a major disadvantage of choosing PCI. In patients with left main disease this may result in a potential fatal complication. With the advent of drug-eluting stents, restenosis has become less of a concern [3] although the data mainly support use in more simple anatomy. Published data on the use of drug-eluting stents in the treatment of three-vessel disease and left main disease are relatively limited [4–6]. Additionally, while PCI has improved, CABG has also progressed with better perioperative management, a higher use of arterial grafting, and improved techniques with minimally invasive and off-pump surgery as options [7,8]. Due to these recent improvements in both PCI and CABG, determining the best revascularization strategy for 3VD and LM disease patients may not be straightforward. SYNTAX (Synergy between PCI with TAXUS drug-eluting stent and Cardiac Surgery) is a prospective, randomized, multicenter trial designed to compare revascularization with either CABG or PCI with TAXUS paclitaxel-eluting stents for the treatment of de novo 3VD or left main disease (isolated or in association with one-, two-, or three-vessel disease). The primary objective of the SYNTAX trial is to compare the 12-month major adverse cardiac and cerebral events (MACCE) rates including death, stroke, documented nonfatal myocardial infarction, and repeat revascularization by either percutaneous intervention or bypass surgery. The SYNTAX trial has an ‘all comers’ design to address the criticism of previous trials that did not capture the real world of clinical practice. The trial includes a randomized arm of 1500 patients: 750 assigned to PCI with a TAXUS drug-eluting stent versus 750 to coronary artery bypass graft surgery. In addition to the randomized arm, there are two nested registries, one that includes patients undergoing coronary artery bypass graft surgery who are deemed ineligible for PCI, and the other includes patients treated with PCI who are deemed ineligible for coronary artery bypass graft surgery. As a requirement for participation in SYNTAX, all interested investigators were asked to provide anonymous information on each LM or three-vessel disease procedure performed at their site during a 3-month period. These data were used to make decisions for site entry based on case volume, case complexity, and technique. The purpose of this manuscript is to describe the findings from this unique roll in database reflecting current surgical and percutaneous revascularization patterns in Europe and North America. The SYNTAX trial Steering Committee identified recruiting sites for this trial in Europe, United States, and Canada based on procedural volume and expertise, participation in prior scientific trials, and personal knowledge of the specific centers and operators. To project expected enrolment, a ‘run-in phase’ was performed to gather anonymous information on patients treated at the potential sites during a 3-month period between January and March 2004. Parameters evaluated included the number of three-vessel disease and left main disease patients undergoing revascularization with either coronary artery bypass graft surgery or PCI. Additional information was collected to identify isolated left main coronary artery disease, left main disease in conjunction with one-, two-, or three-vessel disease, and protected or unprotected left main coronary artery disease. Information was also gathered to determine whether CABG procedures utilized arterial grafts only, venous grafts only, or a combination of both. This survey included 104 sites, with 77 in Europe and 27 in North America. Detailed information on CABG patients was missing from one North American site. Data summaries primarily consisted of descriptive tabulations of overall and subgroup procedural data collected. Descriptive statistics included sample size (N), mean, median, standard deviation, and minimum and maximum values for continuous variables. Sample size (N), number of subjects, and percent of subjects were used to summarize the categorical variables. A total of 12,072 patients were entered in the database (Table 1). There were 8895 patients (74%) who underwent CABG and 3177 patients (26%) who underwent PCI. Three-vessel disease patients predominated with 8532 (71%) versus 3540 (29%) left main patients. A total of 6215 (70%) patients in the CABG group and 2317 (73%) patients in the PCI group had three-vessel disease. The mean number of left main disease patients treated per center with PCI was 8.3 and with CABG was 26.0. The ratio of PCI to CABG for both three-vessel disease and left main disease was 1:3. Overall results Of the 3540 patients treated for LM coronary artery disease, 459 (13%) had isolated left main disease (Table 2). In these cases, PCI was performed more often (274, 60%) than CABG (185, 40%). However, among the 1645 patients with both LM coronary artery disease and three-vessel disease, CABG was used 10 times more frequently than PCI (1492, 91% vs 153, 9%). PCI and CABG treatment for left main coronary artery disease There were important differences between the European and North American sites (Table 3). In all three-vessel and left main disease patients, PCI was performed more often in Europe than in North America (2638, 29% vs 539, 18%). This difference was more pronounced for three-vessel disease (1990, 30% in Europe vs 327, 17% in North America) than for left main disease (648, 26% in Europe vs 212, 21% in North America). With respect to PCI treatments of left main disease, unprotected left main coronary artery interventions were performed three times more often in Europe (429, 66%) than in North America (48, 23%). PCI for left main stenosis in conjunction with three-vessel disease was also performed more often in Europe with a mean number of patients per site of 1.8 versus 0.7 in North America. Differences between Europe and North America for treatment of left main and three-vessel disease Differences in CABG and PCI practice patterns were observed between individual European countries (Figs. 1 and 2). CABG revascularization for either three-vessel or left main disease ranged from 50% in France to 87% in the United Kingdom. For LM coronary artery disease as a whole, CABG revascularization was lowest in the Netherlands at 59% and highest in Belgium at 87%. The Netherlands (85%) was more likely to perform unprotected left main PCI procedures than the rest of Europe (66%), while Germany was less likely (55%). For three-vessel disease, CABG revascularization was lowest in France at 42% and highest in the United Kingdom at 90%. Procedures by region or country for three-vessel disease. Procedure by region or country for left main disease. Revascularization, with arterial grafts only, was performed in 12% of the CABG procedures while 7% were treated with venous grafts only. The majority (81%) was treated with a combination of venous and arterial grafts. There were no differences in graft use between Europe and North America. However, within Europe, France (39%), the Netherlands (15%), and Germany (14%) had a higher rate of total arterial grafting compared to the rest of Europe (mean 12%). PCI and CABG have both proven to be effective in improving symptoms from myocardial ischemia; however, the two techniques were initially used in very different populations. Technical challenges limited PCI applicability to chronic totally occluded vessels and there was concern in treating complex anatomical subsets because of the high risk of restenosis. With the advent of drug-eluting stents the practice of interventional cardiology has changed dramatically and also, to a lesser extent, there have been parallel improvements in cardiac surgery. The progress in both specialties not only depends on major advances in technique and equipment, such as the introduction of drug-eluting stents for PCI and off-pump or minimally invasive surgery, but also on the implementation of more aggressive adjunctive pharmacology such as aspirin, clopidogrel, IIb/IIIa inhibitors and statins, better control of risk factors, and improving operator experience. The contribution of each of these factors to changing practice patterns may vary between institutions, regions, and countries. As documented in this study, there is substantial variability in the selection of specific revascularization strategies chosen for patients with multivessel and left main coronary artery disease. With technical advances, more challenging anatomical subsets become amenable to treatment with PCI. Patients with three-vessel disease and left main coronary artery disease are being treated with increasing frequency with PCI, due to findings that in selected patients who could have either procedure, both survival and survival free of myocardial infarction are equivalent between PCI and CABG [1,2]. The introduction of drug-eluting stents may also have a major impact on the need for repeat revascularization in diabetic patients, and the difference between PCI and coronary surgery may also narrow considerably in this higher risk patient population [9]. Despite the increasing age and concomitant increased co-morbidity of patients presenting for CABG, clinical outcomes have continued to improve [8]. This trend was evident from the 5-year results of the ARTS study [2] with a lower mortality seen in the CABG arm compared with older studies. The off-pump coronary bypass technique, developed to minimize the invasiveness of CABG, has demonstrated a reduction in morbidity and mortality in several large, retrospective studies when compared with CABG [10,11]. Conversely, aside from improvements in atrial fibrillation, randomized, controlled trials did not show the same statistically significant reductions in short-term mortality or morbidity that were demonstrated by observational studies [12]. These discrepancies might be due to differing patient-selection and study methodologies. Larger randomized trials focusing on long-term outcomes are necessary to definitively address this issue [13]. Despite the growing evidence in the literature that arterial-only grafts in CABG achieve significantly better long-term survival than the combined use of arterial and vein grafts [7,14], the 12% rate of total arterial grafting in this study was low. In comparison with PCI, the strength of coronary surgery may ultimately lie in better long-term outcomes, and therefore, the use of arterial grafts should be further advocated. In this current run-in phase, patients with multivessel disease are frequently treated with PCI. Of interest is the fact that PCI is performed 1.5 times more often in these selected centers in Europe as compared with North America. When isolated three-vessel disease patients are considered, the frequency of PCI performance is 1.8 times higher in Europe compared to North American centers. PCI for unprotected left main coronary artery disease showed the most striking difference with three times as many procedures in Europe. There was also a considerable variability within Europe with the United Kingdom using CABG for three-vessel disease almost twice as often as France. There was less variability between North American and European centers for left main coronary artery disease. However, there were noticeable differences between European countries, with 60% CABG revascularization for left main disease in the Netherlands compared to 87% CABG revascularization in Belgium. This regional variability may reflect differences in reimbursement policies, local practice guidelines, or more conservative approaches to novel technologies due to a lack of evidence-based medicine. Earlier data from randomized trials indicated an advantage of CABG over PCI for left main and three-vessel coronary artery disease, and surgery remained the standard of care for these patients. However, as the data from this run-in phase show, the introduction of drug-eluting stents has changed practice patterns, and many patients are now being treated with PCI. Nevertheless, drug-eluting stents may also be associated with complications, particularly stent thrombosis [15–17], and it has yet to be proven in a randomized trial that the hard end points of death, repeat revascularization, cerebrovascular accidents and myocardial infarction are the same with both revascularization techniques. The SYNTAX trial will provide a solid dataset to assess the various issues in left main and multivessel disease and will set new guidelines for our patients in the future. Also on behalf of the Steering committee members Antonio Colombo, Elisabeth Stahle, David Holmes, Marcel van den Brand and Jorg Koglin. We are grateful to Jeroen Kleijne, Blessie Concepcion, Nic van Dijck, and Luc Verhees for their outstanding continuous support and management of the SYNTAX trial. We thank Dr Leslie E. Stolz for her careful review of the manuscript and for her constructive suggestions. This study is financially supported by Boston Scientific, Natick, MA, USA. Centers that participated in the roll in phase of the SYNTAX trial are as follows: Univ. Klinik für Herzchirurgie Landeskliniken, Salzburg, Austria; Allgemeines Krankenhaus AKH, Vienna, Austria; Onze-Lieve-Vrouw Ziekenhuis, Aalst, Belgium; AZ Middelheim Antwerp, Belgium; UZ gent, Gent, Belgium; CHU Sart Tilman, L ìege, Belgium; Hôpital de la Citadelle, Lìege, Belgium; University of Calgary, Calgary, Canada; Vancouver General Hospital, Vancouver, Canada; St. Paul's Hospital, Vancouver, Canada; Sunnybrook & Women's College Health Sciences Centre, Toronto, Canada; St. Michael's Hospital, Toronto, Canada; Faculty Hospital Kralovske, Prague, Czech Republic; Prague University Hospital, Prague, Czech Republic; Skejby Sygehus, Aarhus, Denmark; Rigshospitalet Copenhagen, Copenhagen, Denmark; Helsinki University Hospital, Helsinki, Finland; Tampere University Hospital, Tampere, Finland; CHU C ôté de Nacre, Caen, France; Institut Hospitalier Jacques Cartier, Massy, France; CHU Rouen, Rouen, France; Clinique St Hilaire, Rouen, France; CCN St. Denis, St. Denis, France; CHU Toulouse, Toulouse, France; Clinique Pasteur, Toulouse, France; Clinique St. Augustin, Bordeaux, France; Hospital Henri Mondor, Creteil, France; Universitätsklinikum Rudolf Virchow, Berlin, Germany; Ludwigs-University Freiburg, Freiburg, Germany; Universittsklinikum Eppendorf, Hamburg, Germany; Christian Albrechts University, Kieäl, Germany; Herzzentrum Leipzig, Leipzig, Germany; Medizinische Universität Lübeck, Lubeck, Germany; Klinikum Grosshadern, Munich, Germany; Krankenhaus der Barmherziger Bruder, Trier, Germany; Herz- und Diabetes zentrum Nordrhein Westfalen, Bad Oeyenhausen, Germany; National Health Institute, Budapest, Hungary; University of Debrecen, Debrecen, Hungary; Heart Institute Medical School of University PECS, Pécs, Hungary; Ospedali Riuniti di Bergamo, Bergamo, Italy; Spedali civili di Brescia, Brescia, Italy; G. Pasquinucci Hospital, Massa, Italy; Fondazione San Raffaele de Monte, Milano, Italy; Ospedale di Mirano, Mirano, Italy; Instituto di Ricovero e Cura, Pavia, Italy; Azienda Ospedaliera Pisana, Pisa, Italy; Universita Cattolica del Sacro Cuore, Roma, Italy; Instituto Clinico Humanitas, Rosano, Italy; AZIENDA TREVISO, Treviso, Italy; P Stradins University Hospital, Riga, Latvia; Amphia Ziekenhuis Klokkenberg, Breda, Netherlands; Catharina Ziekenhuis, Eindhoven, Netherlands; AZ Groningen, Groningen, Netherlands; Sint Antonius Ziekenhuis, Nieuwegein, Netherlands; Erasmus MC, Thoraxcenter, Rotterdam, Netherlands; Ziekenhuis De Weezenlanden, Zwolle, Netherlands; Rikshospitalet, Oslo, Norway; SPSK Nr 7 Silesian School of Medecine, Katowice, Poland; Jagellionian University, John Paul II Hospital, Krakow, Poland; National Institute of Cardiology, Warsaw, Poland; Central Hospital Int Affairs, Warsaw, Poland; Hospital de Santa Marta, Lisboa, Portugal; H. de Alicante, Alicante, Spain; Hospital Clínico I Provencial, Barcelona, Spain; Hospital del Mar, Barcelona, Spain; Hospital Clínico San Carlos, Madrid, Spain; Hospital Salamanca, Salamanca, Spain; Sahlgrenska Universitetssjukhus, Göteborg, Sweden; Universitetssjukhuset Lund, Lund, Sweden; Karolinska, Stockholm, Sweden; Akademiska Sjukhuset, Uppsala, Sweden; Hôpital Cantonal Universitaire, Service Cardiologie, Geneva, Switzerland; University Hospital, Zurich, Switzerland; Western Infirmary, Glasgow, UK; Glenfield General Hospital, Leicester, UK; King's College Hospital, London, UK; London Chest, London, UK; St Thomas and Guys, London, UK; James Cook, Middlesbrough, UK; John Radcliffe Hospital, Oxford, UK; Southampton University Hospital, Southampton, UK; Royal Sussex County hospital, Brighton, UK; Mayo Clinic, Rochester, MN, USA; Birmingham Heart Clinic, Birmingham, AL, USA; Abbott Northwestern, Minneapolis, MN, USA; Mercy General Hospital, Sacramento, CA, USA; Florida Hospital Orlando, Orlando, FL, USA; Cannon Cardiac & Vascualr Research Ctr, Petoskey, MI, USA; Maine Medical Center, Portland, ME, USA; Ocala Heart Institute, Ocala, FL, USA; St. Luke's Medical Center, Milwaukee, WI, USA; Medical City Hospital, Dallas, TX, USA; Wakemed Wake Heart Research, Raleigh, NC, USA; Evanston Hospital, Evanston, IL, USA; Oklahoma Heart Hospital, Oklahoma, OK, USA; Sentara Norfollk, Norfolk, VA, USA; Moses Cone Memorial,Greensboro, NC, USA; St. Joseph's Hospital, Syracuse, NY, USA; Tufts New England, Boston, MA, USA; Spectrum Health Hospital, Detroit, MI, USA; Northwestern Memorial Hosp, Chicago, IL, USA; University of Virginia, Charlottesville, VA, USA; Washington Hospital Centre, Washington DC, USA; Scripps Clinic, La Jolla, CA, USA. Conference discussion Dr P. Kolh (Liege, Belgium) As you know, we are participating in the trial and happy to do so. I would like to ask you a couple of questions. First, do you have any idea why PCI is less used in the US as compared to Europe? I understand why there could be regional differences within Europe but I don’t see why there would be a between-continent difference. The second is that most of us should be surprised by the rather low use of full arterial revascularization. Do you think that because of this trial and because of the long-term importance of arterial revascularization, the surgeons would change their practice during the trial are we to to do Dr important you I think that an important why there is a difference in PCI rate between Europe and North America is that because PCI treatment for three-vessel disease and left main is not evidence-based the interventional in the United are more to perform PCI for this because might be for a you at the difference between the United Kingdom and the rest of Europe, it might be due to the that drug-eluting stents in the are not is not that the interventional are not as in the rest of Europe. to arterial grafting, we think it is very We have seen a of in the literature that arterial grafting is in the patient we the surgeons who in the trial to perform as arterial grafting as increasing the risk for the are used to perform arterial grafting we to do so. we will be to the whether arterial grafting is I have as you know, cardiac surgeons at the long-term while interventional at a The primary end of this trial will be at one and the end at and then it will the might be Dr is the of study and do you make that it is an Dr I in the trials only of the patients were included in the we to have this design to be that we capture the real practice. we asked the to capture all patients that their hospital, when the trial. When think that the patient is for PCI and coronary bypass surgery, the patient will be When think that coronary bypass surgery is not because the patient has a of the patient will be entered a we the PCI and when the interventional I do a PCI on this patient because has two chronic total and has a very left main then the patient will be to surgery and will be entered in a CABG In this the and the are to to the the and the whether the patient is or whether has to one of the

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