Left Main Coronary Artery Percutaneous Coronary Intervention in High-Risk Patients: Hopes for Improvement and Limitations of Randomized Trials

Abstract

Obstructive coronary artery disease involving the left main coronary artery (LMCA) is found during cardiac catheterization in 4%-6% of patients.1Ragosta M. Dee S. Sarembock I.J. et al.Prevalence of unfavorable angiographic characteristics for percutaneous intervention in patients with unprotected left main coronary artery disease.Catheter Cardiovasc Interv. 2006; 68: 357-362Crossref PubMed Scopus (106) Google Scholar Randomized trials performed in the 1970s included small subgroups of patients with unprotected LMCA (ULMCA) and demonstrated the superiority of coronary artery bypass grafting (CABG) compared with medical management, which led to recommending CABG for those patients.2European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina pectoris.Lancet. 1982; 2: 1173-1180PubMed Google Scholar, 3The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-year survival in the Veterans Administration randomized trial of coronary artery bypass surgery for stable angina.N Engl J Med. 1984; 311: 1333-1339Crossref PubMed Scopus (645) Google Scholar Although technically, LMCA percutaneous coronary intervention (PCI) is often feasible, the outcome with balloon angioplasty or bare metal stenting was initially disappointing. In fact, the first patient who underwent PCI to the LMCA by Andreas Gruentzig in 1978, died within a year.4Rahimtoola S.H. First percutaneous catheter intervention for left main coronary artery disease: 30 years ago.J Am Coll Cardiol Intv. 2008; 1: 108Abstract Full Text Full Text PDF Scopus (4) Google Scholar CABG remained the preferred approach for this subset of patients. Advances in the realm of interventional cardiology, including the advent of the drug-eluting stent (DES), have made the treatment of ULMCA disease with PCI a more acceptable treatment as an alternative to CABG. There is a growing body of evidence to support the treatment of ULMCA disease with PCI as opposed to CABG. However, because of the common assumption that withholding surgery is unethical, patients have usually been excluded from randomized clinical trials (RCTs) comparing PCI and CABG. Only a few RCTs to date have compared the efficacy of CABG and PCI in this setting, and even then most did not specifically target this population but reported subgroup results. The Synergy Between Percutaneous Coronary Intervention with TAXus and Cardiac Surgery (SYNTAX) trial randomized 1800 patients with 3-vessel or ULMCA disease, or both, to CABG or PCI using a first-generation DES. Among the 750 patients in the ULMCA disease subgroup, 1-year major adverse cardiovascular and cerebrovascular event (MACCE) rates were similar for PCI and CABG (15.8% vs 13.7%; P = 0.48), with the caveat of increased need for repeated revascularization with PCI and increased risk of stroke with CABG. In patients with isolated ULMCA disease, there was even a numerically nonsignificant decrease in events with PCI.5Morice M.C. Serruys P.W. Kappetein A.P. Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial.Circulation. 2010; 121: 2645-2653Crossref PubMed Scopus (490) Google Scholar, 6Serruys P.W. Morice M.C. Kappetein A.P. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.N Engl J Med. 2009; 360: 961-972Crossref PubMed Scopus (3179) Google Scholar Recently, the 5-year outcomes of this study were published and confirmed the long-term advantages and drawbacks of PCI and CABG in this setting.7Morice M.C. Serruys P.W. Kappetein A.P. et al.Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial.Circulation. 2014; 129: 2388-2394Crossref PubMed Scopus (368) Google Scholar The SYNTAX trial is also renowned for formulating the now widely used SYNTAX score, a scoring system used to quantify the extent and complexity of coronary disease. Boudriot et al.8Boudriot E. Thiele H. Walther T. 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: 538-545Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar evaluated the efficacy of PCI vs CABG in a dedicated ULMCA disease population with a lower SYNTAX score and euroSCORE than patients in the SYNTAX trial. As shown previously, PCI produced MACCE rates comparable to those of CABG, again at the cost of higher repeated revascularization rates. In the Premier of Randomized Comparison of Bypass Surgery Versus AngioplasTy Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease (PRECOMBAT) trial, in which 600 patients with LMCA disease were randomized to PCI or CABG, PCI was found to be noninferior to CABG.9Park S.J. Kim Y.H. Park D.W. Randomized trial of stents versus bypass surgery for left main coronary artery disease.N Engl J Med. 2011; 364: 1718-1727Crossref PubMed Scopus (485) Google Scholar Limitations of these studies include the use of older generation stents and insufficient power. A recent meta-analysis that included the preceding trials demonstrated that the risk of mortality and myocardial infarction (MI) in patients with ULMCA disease is similar with PCI and CABG and reiterated the lower rate of repeated revascularization and higher risk of stroke with CABG.10Al Ali J. Franck C. Filion K.B. Eisenberg M.J. Coronary artery bypass graft surgery versus percutaneous coronary intervention with first-generation drug-eluting stents: a meta-analysis of randomized controlled trials.J Am Coll Cardiol Interv. 2014; 7: 497-506Crossref Scopus (37) Google Scholar The joint American and joint European guidelines have incorporated anatomic risk stratification according to SYNTAX score and general surgical risk with class II recommendations for PCI as an alternative to CABG in patients with less complex anatomy, as defined by a low-range (< 23) to intermediate-range (23-32) SYNTAX score or a more proximal LMCA disease location.11Levine G.N. Bates E.R. Blankenship J.C. et al.2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention.J Am Coll Cardiol. 2011; 58: e44-e122Abstract Full Text Full Text PDF PubMed Scopus (1896) Google Scholar, 12Wijns W. Kolh P. Danchin N. Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).Eur Heart J. 2010; 31: 2501-2555Crossref PubMed Scopus (27) Google Scholar However, the evidence supporting the current guidelines have mainly been derived from a limited number of studies, which largely excluded patients with active or recent acute coronary syndrome or hemodynamic instability.5Morice M.C. Serruys P.W. Kappetein A.P. Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial.Circulation. 2010; 121: 2645-2653Crossref PubMed Scopus (490) Google Scholar, 6Serruys P.W. Morice M.C. Kappetein A.P. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.N Engl J Med. 2009; 360: 961-972Crossref PubMed Scopus (3179) Google Scholar, 7Morice M.C. Serruys P.W. Kappetein A.P. et al.Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial.Circulation. 2014; 129: 2388-2394Crossref PubMed Scopus (368) Google Scholar, 8Boudriot E. Thiele H. Walther T. 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: 538-545Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, 9Park S.J. Kim Y.H. Park D.W. Randomized trial of stents versus bypass surgery for left main coronary artery disease.N Engl J Med. 2011; 364: 1718-1727Crossref PubMed Scopus (485) Google Scholar, 10Al Ali J. Franck C. Filion K.B. Eisenberg M.J. Coronary artery bypass graft surgery versus percutaneous coronary intervention with first-generation drug-eluting stents: a meta-analysis of randomized controlled trials.J Am Coll Cardiol Interv. 2014; 7: 497-506Crossref Scopus (37) Google Scholar As such, there is no strong evidence and thus no clear guidelines regarding the acute management of this very high-risk population. In their article entitled “Long-Term Outcome of Unprotected Left Main Stenting: A Canadian Tertiary Care Experience” in this issue of the Canadian Journal of Cardiology, Sibbald et al.13Sibbald M, Chan W, Daly P, et al. Long-term outcome of unprotected left main stenting: a Canadian tertiary care experience. Can J Cardiol 2014;30:1407-14.Google Scholar report a retrospective analysis evaluating the experience with ULMCA PCI in a heterogeneous population at Toronto General Hospital over an 11-year period. Long-term outcomes were assessed with linkage to the provincial Institute for Clinical Evaluative Sciences, an effective and economical approach in outcome research. In this largest Canadian report to date, most of the 221 patients analyzed would have almost uniformly been excluded from the previously cited and other similar trials. More than half of the patients (53.5%) had a recent MI, with significant left ventricular systolic dysfunction (ejection fraction < 40%) in 29%. Moreover, many patients in the analysis would generally be considered very high risk, including 12% who presented in cardiogenic shock and 4.5% who underwent primary ULMCA PCI. Most patients also had complex anatomy, with an average intermediate SYNTAX score of 28. Although a formalized risk predictor such as the euroSCORE was not explicitly used, it is evident that a significant proportion of the patients were high risk and were not candidates for surgery. Indeed, the institutional practice during this period was to refer patients with ULMCA disease for surgery if eligible. As expected, the in-hospital event rates, including mortality of 13%, were higher than those seen in trials with more stable patients. During an average follow-up of 3.1 years, the primary end point (a composite of death from any cause, MI, and repeated revascularization) occurred in 68% of patients, and all-cause mortality was 49%. The high mortality rate over time underscores the poor outcomes of patients with complex coronary anatomy and acute presentation, regardless of revascularization. Not surprisingly, death, MI, and MACCE rates were higher among patients in higher SYNTAX score tertiles. Interestingly, no difference was seen in in-hospital outcomes between ostial and bifurcation lesion location. The use of a DES vs a bare metal stent was associated with better in-hospital and long-term outcomes, although it is recognized that selection bias likely exists between these 2 subgroups. Although at first glance these event rates appear high, given that the majority of patients in the study were at high risk, the reported outcomes are quite acceptable compared with other registries.14Pappalardo A. Mamas M.A. Imola F. Percutaneous coronary intervention of unprotected left main coronary artery disease as culprit lesion in patients with acute myocardial infarction.J Am Coll Cardiol Interv. 2011; 4: 618-626Abstract Full Text Full Text PDF Scopus (48) Google Scholar, 15Puricel S. Adorjan P. Oberhansli M. et al.Clinical outcomes after PCI for acute coronary syndrome in unprotected left main coronary artery disease: insights from the Swiss Acute Left Main Coronary Vessel Percutaneous Management (SALVage) study.EuroIntervention. 2011; 7: 697-704Crossref PubMed Scopus (24) Google Scholar Furthermore, because the study period spans > 10 years, the majority of patients received older generation stents. In fact, only 37 patients (17%) received a second-generation DES. Current stent platforms have thinner struts and more compatible polymers, with a corresponding lower risk of stent thrombosis. Unfortunately, these higher risk patients are normally subject to the risk/treatment paradox whereby the high-risk patients who stand to gain the most from aggressive treatment are the least likely to receive it.16Bagnall A.J. Goodman S.G. Fox K.A. et al.Influence of age on use of cardiac catheterization and associated outcomes in patients with non-ST-elevation acute coronary syndromes.Am J Cardiol. 2009; 103: 1530-1536Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Similarly, RCTs tend to focus their attention on low-risk populations while routinely excluding high-risk patients. Therefore, the authors should be commended not only for performing these high-risk procedures but also for reporting their outcomes. The observational study by the group at Toronto General Hospital is an important demonstration of ULMCA PCI in a real-world setting, with greater applicability to patients at high risk. These results support the concept of performing PCI in ULMCAs for patients at high risk and reassure us that we can expect reasonable, albeit not excellent, in-hospital outcomes. However, the poor long-term outcome of these patients mandate aggressive medical management and close follow-up. One of the largest RCTs comparing LMCA PCI and CABG, the Evaluation of Xience Prime vs Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL trial), recently completed enrollment of approximately 1900 randomized patients and is expected to provide new information on LMCA PCI using contemporary technology in a broader population of patients who are candidates for CABG. Still, the Achilles' heel of RCTs is that their findings often cannot be generalized, and therefore it is our mandate to perform RCTs with as broad inclusion criteria as possible. Observational outcome studies are vital and complementary. Many of the limitations of single-centre registries can be overcome through collaboration and the creation of provincial and national registries, the benefits of which were seen in this registry in which almost all patients were included, with outcome data in 100%. Reporting provincial outcome of ULMCA PCI would be welcome. Although there have been many developments since Gruentzig's work > 35 years ago, there is still much room for progress in this increasingly prevalent treatment strategy. It is anticipated that with further enhancements in equipment, medications, and techniques, patient outcomes will continue to improve in these higher risk settings and make ULMCA PCI an even more appealing treatment option. The authors have no conflicts of interest to disclose. Long-term Outcome of Unprotected Left Main Stenting: A Canadian Tertiary Care ExperienceCanadian Journal of CardiologyVol. 30Issue 11PreviewCoronary stenting is increasingly used to treat unprotected left main disease in selected patients. However, there is a paucity of data on the long-term outcome of these patients in a Canadian context outside of clinical trials. Full-Text PDF