PCI in Left Main Disease: Are We There Yet?

Transcription

1 PCI in Left Main Disease: Are We There Yet? Moderator Mark A. Turco, MD Director Center for Cardiac & Vascular Research Washington Adventist Hospital Takoma Park, Maryland Panelists David E. Kandzari, MD Director Interventional Cardiology Research Scripps Clinic La Jolla, California Panelists Seung Jung Park, MD, PhD Chief of Cardiology Division of Cardiology Asan Medical Center Seoul, Korea Joseph F. Sabik, III, MD Chairman Department of Thoracic & Cardiovascular Surgery Cleveland Clinic Cleveland, Ohio Slide 1 Mark Turco, MD: Hello. I'm Dr. Mark Turco, Director of the Center for Cardiac and Vascular Research at Washington Adventist Hospital. I'd like to welcome you today to our Spotlight entitled, "" I'm very pleased and honored to have a distinguished panel of guests today to speak on this particular topic. I'm joined today with Dr. David Kandzari, Director of Interventional Cardiology Research at Scripps Clinic in La Jolla, California. David, welcome. David Kandzari, MD: Thank you. Dr. Turco: Our second panelist is Dr. Seung-Jung Park. Dr. Park is well known to many of you. He is an Interventional Cardiologist and Chief of Cardiology at the Asan Medical Center in South Korea. He and his colleagues have been very well published in this field of left main coronary intervention. Dr. Joe Sabik is Chairman of the Department of Thoracic and Cardiac Surgery at the Cleveland Clinic. Very pleased and honored to have you with us today. Gentlemen, we have a very complex topic to discuss, and that's angioplasty and PCI [percutaneous coronary intervention] in the left main coronary artery subgroup. There have been a lot of data published, but there also remains a lot of controversy in this area. We specifically have one of our esteemed surgical colleagues here today to keep us all honest from the same point of intervention. What I'd like to do is start with Dr. Park, as Dr. Park has been very well published. His MAIN-

2 COMPARE [revascularization for unprotected left MAIN coronary artery stenosis: COMparison of Percutaneous coronary Angioplasty versus surgical REvascularization] publication is one of the landmark articles in regards to left main PCI. Dr. Park, can you give our audience a bit of an update in regards to some of the data that you found? MAIN COMPARE: Outcomes at 3 Years (%) Death, Myocardial Infarction (MI), Stroke HR: 1.10 ( ) (%) Target Vessel Revascularization (TVR) HR: 4.76 ( ) P =.61 P <.001 N = 542 propensity matched pairs from 2240 patients with unprotected left main (LM) January 2000 June 2006 CABG = coronary artery bypass graft surgery Slide 2 Seung KB, et al. N Engl J Med. 2008;358: Seung-Jung Park, MD, PhD: Yes. The MAIN-COMPARE study was basically a registry study, a multicenter prospective registry, we included 2240 patients (the patients who had received bypass surgery and PCI), to compare propensity-matched patients. The number was 542 wellmatched pairs. We clearly demonstrated that hard endpoints, death, and composite hard endpoint, death, MI, stroke are clearly the same between the PCI vs the surgery. The only difference was actually TVR, target vessel revascularization rate. Rates with either drug-eluting stent [DES] or bare metal stent [BMS] are clearly higher than that of surgery. These are our main data from the MAIN-COMPARE registry.

3 MAIN COMPARE: DES and BMS at 3 Years Death or MI HR: 0.83 ( ) Target Lesion Revascularization (TLR) HR: 0.40 ( ) (%) (%) P =.479 P =.003 N = 864 N = 353 N = 864 N = 353 DES = drug eluting stent BMS = bare metal stent Slide 3 Kim YH, et al. Circulation. 2009;120: Actually, we published subgroup analyses of the MAIN-COMPARE registries, for example, the comparison of DES vs BMS. Again, we don't have any hard endpoint differences. However, the frequency of TVR is greater in the group with BMS compared to the DES group. In other papers, we compared different types of DES, Cypher [Cordis Coporation] vs Taxus [Boston Scientific]. There was clearly no difference between these different commercial DES.

4 MAIN COMPARE: IVUS Guided Mortality Analysis 3 Year Mortality (%) All Stents HR: 0.54 ( ) P =.061 IVUS guided N = 756 N = Year Mortality (%) Angiography guided HR: 0.39 ( ) P =.055 DES vs BMS HR: 0.59 ( ) P = propensity matched pairs IVUS = intravascular ultrasound 145 propensity matched pairs Slide 4 Park SJ, et al. Circ Cardiovasc Intervent. 2009;2: Another point is, for the procedure itself, we strongly recommended IVUS [intravascular ultrasound]-guided procedures. The number is relatively small; however, we analyzed a subgroup, a propensity-matched group. We clearly demonstrated that IVUS-guided procedures have better survival compared with the angiography-guided procedures. Actually, we cannot explain the reason why exactly; however, it may be a small difference during the procedures, for example, good apposition of a stent, bigger stent cross-sectional areas. Those kinds of things may influence good long-term outcomes. Another point is that late stent thrombosis occurs at a relatively small frequency with IVUS guidance -- which may be the reason why we have even better survival in the group with IVUSguided procedure. Personally, I strongly recommend IVUS-guided procedure for the left main DES intervention.

5 MAIN COMPARE: Extent of Disease Analysis Death, Q MI, or Stroke Total BMS DES Isolated LM LM + 1 VD LM + 2 VD LM + 3 VD Isolated LM LM + 1 VD LM + 2 VD LM + 3 VD Isolated LM LM + 1 VD LM + 2 VD LM + 3 VD P int =.660 P int =.717 P int = PCI Better CABG Better Slide 5 Park SJ. TCT; September 2009; San Francisco, CA. In another publication of the data from the MAIN-COMPARE registry, we analyzed the extent of disease. For example, left main with single-vessel, two-vessel, three-vessel disease. Actually, no group with for isolated left main disease results are is quite the same with PCI vs surgery. However, patients who had left main disease combined with two vessels, three vessels, those patients have a higher frequency of composite endpoints with PCI. For example, the hard endpoint plus TVR, those composite endpoints are clearly better in the bypass surgery group.

6 MAIN COMPARE: Multivariate Predictors of Death, MI, Stroke Variable HR (95% CI) P value Overall EuroSCORE 1.25 ( ) <.001 Chronic lung disease 2.14 ( ).032 Chronic renal failure 2.67 ( ) <.001 Atrial fibrillation 2.21 ( ).024 Percutaneous coronary intervention (PCI) patients EuroSCORE 1.17 ( ).004 Prior congestive heart failure 3.86 ( ).003 Chronic renal failure 6.15 ( ) <.001 CABG patients EuroSCORE 1.27 ( ) <.001 Diabetes 1.76 ( ).013 Chronic lung disease 4.03 ( ) <.001 Prior cerebrovascular disease 2.36 ( ).005 Hyperlipidemia 0.60 ( ).043 Slide 6 Park SJ. TCT; September 2009; San Francisco, CA. Ultimately, we found predictors for late outcomes in terms of hard endpoints. These were mainly clinical variables, including the EuroSCORES [European System for Cardiac Operative Risk Evaluation] and the frequency comorbidities such as chronic lung disease, peripheral disease, and previous history of a stroke, previous history of an MI [myocardial infarction], previous history of renal disease. Many clinical variables are related with long-term outcomes. Dr. Turco: Thank you. That's a great introduction, and certainly a lot to discuss there and some great work by you and your Korean colleagues. David, let me turn to you, if I can. There was a Makkar meta-analysis that was published. I wonder if you could just give us a brief update, in your perspective, as to where we are with some of the evidence.

7 Current Guidelines LM ACC/AHA/SCAI 2007 PCI Update 1 Significant left main coronary artery disease (CAD) and candidacy for CABG (Class III LoE: B) Use of PCI is reasonable in patients with UA/NSTEMI with significant LM CAD who are candidates for revascularization but are not eligible for CABG or who require emergency intervention at angiography for hemodynamic instability (Class Iia LoE: B) ESC 2005 PCI Guideline 2 Unprotected LM in the absence of other revascularization options (Class IIb LoE: C) Slide 7 1. King SB, et al. Circulation. 2008;117: Silber S, et al. Eur Heart J. 2005;26: Dr. Kandzari: That's a great segue from SJ's experience because I think SJ's contribution to this particular treatment lesion subset has been remarkable. When we think about different geographies of the world performing left main PCI, I would say in many countries, perhaps it's almost a routine alternative to bypass surgery. In the United States and in many countries within Europe, alternatively, it's been considered taboo, at least certainly in the area of balloon angioplasty and BMS treatment. Perhaps, in part, that was because of patient selection, lesion selection, the risks for restenosis in the left main indication itself contributing to sudden death. But altogether, as we know well, our current guidelines -- at least, while perhaps under revision for the left main indication -- recommend this as a class III indication, perhaps class IIb in patients who are considered unsuitable for bypass surgery. Yet, the guidelines, while again, currently under consideration for revision, also reflect in some ways older sources of data in comparison to the evidence basis we have now.

8 Stent Thrombosis* in LM Studies *ARC definite/probable (%) 3 Year P = Year Year Slide 8 N = 669 N = 189 MAIN COMPARE 1 1. Lee JY, et al. J Am Coll Cardiol. 2009;54: Meliga E, et al J Am Coll Cardiol. 2008;51: Mehilli J, et al. J Am Coll Cardiol. 2009;53: DELFT ISAR LM3 2 3 PES = paclitaxel eluting stent SES = sirolimus eluting stent Ultimately, most of our evidence to support left main PCI, while demonstrating overall no major differences in the composite endpoints of death, of MI, of stroke, still show even in a DES era, especially with increasing patient complexity, that PCI falls short in regard to repeat revascularization. More often than not, however, we have to be reminded that this is probably related to lesions other than the index left main lesion itself, that restenosis [of the left main] is relatively uncommon. As SJ describes, the rates of stent thrombosis in these large caliber vessels is exceptionally uncommon.

9 Meta analysis of PCI vs CABG in LM (N = 3773) Death, MI, Stroke Slide 9 Naik H. et al. J Am Coll Cardiol. 2009;2: Reproduced with permission. Collectively, whether it's through individual trials, more recently through meta-analysis -- as you suggested, one recently published of almost 3700 patients -- again, these studies highlight an overall homogeneity across them of no major differences in the hard safety endpoints, but more disparate results in regard to repeat revascularization compared with surgery. Ultimately, however, we have to remember that whether its propensity score matching or other means most of our data are predicated on nonrandomized clinical trial data. We do have the left main subset of the SYNTAX [Synergy between PCI with TAXus and cardiac surgery] trial now through 2 years of follow-up, and I'm sure Joe will speak on this as well. But aside from that, we only have 2 small randomized trials with populations of 150 patients or less, so we can't make meaningful conclusions to that. We're very hopeful that we're working near term to the initiation of a large global randomized trial comparing bypass surgery vs PCI. I think the details of this still need to be fully worked out, but this is really what needs to take us beyond; what I would say we now have is a level of clinical equipoise, at least for selected patients with left main disease. As we go on to higher lesion complexity, this is where Joe would come in and some of the findings might be more favorable for CABG. Dr. Turco: It's a great segue, and we do need to hear from our surgical colleagues. We would all agree at this table that where we have come in the field of intervention is really a collaborative effort between the surgeons and the interventional cardiologists. Whether it be in the field of purcutaneous valve therapies or complex multivessel intervention, we will all get

10 better results for our patients if we collaborate with our cardiac surgical colleagues. The centers that do it the best have the best collaboration, that's for sure. Joe, David's put some data out there for you. We, as interventionalists, are always taught that from a surgical standpoint, we do not have mortality evidence for some of these higher-risk multivessel left main interventions, and we certainly fall short in regards to target lesion and TVR rates. Can you give us your thoughts on the SYNTAX trial, specifically about the left main subset groups, and how you approach things with your interventional colleagues, and how you approach it from a surgical standpoint? NY Registry: CABG vs PCI in LM (2 Years) Patients (n) HR: 0.32 ( ) P =.005 N = 135 N = 135 HR: 0.15 ( ) P <.001 Patients (n) HR: 0.73 ( ) P =.69 N = 56 N = 56 HR: 0.10 ( ) P =.03 N = 56 N = 135 N = 135 N = 56 Mortality Revascularization Mortality Revascularization 01/01/ /31/ /01/ /31/2004 Slide 10 Wu C, et al. Ann Thorac Surg. 2008;86: Joseph Sabik, MD: Sure. I'd also like to talk just a little bit about the meta-analysis and a little bit of a word of caution. The meta-analysis increases the number of patients we have to analyze, but we have to realize it does nothing about the selection bias of the patients that got originally entered into the individual studies or publication bias. Even though we have a metaanalysis of greater than 3700 patients, this is pretty much a very select group of patients. As you know, it's 10 studies, 9 of which came from very experienced centers, and 30% of the patients came from 1 Korean center. It's really not reflective of what's happening out there. One of the studies was a New York registry study. That, you could argue, was probably the most reflective of what is really happening with left main stenting. That study had the opposite finding of the overall meta-analysis in that stenting had worse outcomes in some of the hard endpoints that we're talking about. We have to be very careful not to read too much into this.

11 SYNTAX: LM Cohort Findings 1 Year MACCE by Syntax Score CABG DES 2 Year Findings (N = 705) P =.008 P =.27 Patients % P = N=118 N=103 Low (0 22) P = N=195 N=92 Intermediate (23 32) N=135 N=150 High ( 33) P = P = Death/CVA/MI Revasc MACCE MACCE = death, MI, stroke, revascularization Slide 11 Serruys P, et al. TCT; October 2008; Washington DC. Kappetein AP, et al. TCT; September 2009; San Francisco, CA. If we look at SYNTAX, obviously a very, very important study, and we look at the 1200 patients with left main disease that were either in the registry or in the randomized part of the study, first of all, 500 of them were in the registry, so not appropriate for PCI. An additional 300 were in that very high-complexity coronary artery disease group. That's the group that clearly seems to benefit from bypass surgery. So we have two thirds of these patients considered not really appropriate for PCI. We have this other third, which again, is this group of patients that are in those lower 2 tertiles of coronary complexity. We have to be very careful when we look at that group, that subgroup analysis of subgroups. We all know now it's just an observational study looking at univariate outcomes. Because of the numbers getting smaller, a few events going either way could really change those outcomes. Although, I think it is very interesting and important for us to pay attention to, you can't read too much into it. I agree, we do need to study this in a randomized fashion. Dr. Kandzari: To your point Joe too, I totally agree about the patient selection bias. That's a very important point when we're talking about trials like SYNTAX. There was a general agreement between a surgeon and an interventionalist that there was an uncertainty and that this patient would be suitable for randomization. As you say, many patients were not. It's a two-way street, though, too because when we look at the registries, and we look at poor outcomes with unprotected left main PCI, in most institutions in the United States at least, I think many of these patients are selected because of their comorbidities because they would

12 fall into that class IIb indication and perhaps have other associated comorbidities that might not make them suitable for PCI but make them less suitable for bypass surgery selection. We just don't know. Dr. Turco: We don't know. We have a lot still to discuss, and our time is getting short. I want to be sure to get to many of these other topics because they're very important. Let me start with David and go down the line here. David, how do you choose what patient should undergo PCI for left main intervention or be referred to surgery? Then for you, how do you get consent from your patients, given the fact that we do have class III recommendation in the guidelines? What do you tell your patients from an informed perspective? Dr. Kandzari: As you know, we perform a great deal of unprotected left main PCI at Scripps Clinic. You raise several issues. To begin with, for patient selection, I believe that in many instances, some of the more recent data -- again, with all the limitations that Joe and SJ and I and you agree upon -- have still helped refine our patient selection issues. We've learned from more recent studies too that these high-complexity patients -- that is, those with either high SYNTAX scores or high Parsonnet or EuroSCOREs, whatever metric we want to apply for it -- these are patients with left main disease, in addition to significant multiple other lesions who will fare better with bypass surgery. On the other hand, patients withan intermediate or a low SYNTAX score, certainly isolated and ostial and shaft disease, which I would go back to say many of us, as interventionalists, would even further advance those guidelines to arguably, IIa just given the outcomes with nonbifurcation left main disease. This is also factoring heavily into the issue. Not to take time, though, beyond issues of patient selection, I would also say that in regard to consent, this is highly variable across countries and across the United States as well for left main PCI. But I think the best opportunity for informed consent is after the diagnostic catheterization, to have this patient be evaluated and informed by discussion with one of my surgical colleagues, independently of me, as well as an interventional cardiologist. Dr. Turco: I think that's a great point, David. As opposed to doing ad-hoc left main intervention, really take that patient off the table and give them some time. SJ, I guess I should ask you, what patients do you send to surgery? You're not allowed to say none.

13 Left Main Stenting Not suitable for PCI High EuroSCORE/SYNTAX score/parsonnet score Significant comorbidities Significant MVD Amenable to PCI Low intermediate SYNTAX score (< 33) Isolated LM LM + 1VD Ostial/shaft lesions Slide 12 Dr. Park: In terms of guidelines, it's a little bit of a different situation in Korea. We've changed our guidelines, actually, from the Class III to Class IIb for the general practice. The reason why is we have lots of experience with the procedure, we have to have more data. Based on the current data, the good candidates for PCI are patients who have ostial and shaft lesions. Based on the SYNTAX and the MAIN-COMPARE data, patients with isolated left main and left main with single-vessel disease -- if we actually use SYNTAX scores less than 33, the lower 2 tertiles had relatively comparable results with PCI or surgery. In summary, I'd define a candidate for PCI as isolated ostial, shaft lesions, left main with a single vessel, and SYNTAX score less than 33. That would be okay. Dr. Turco: Perfect, thank you. Joe, in your mind, which patients should be referred to surgery that have left main disease? Dr. Sabik: Obviously, it's very difficult for us to turn anyone down with left main disease. The 2 things that surgery's been shown to be beneficial in terms of survival are aortic stenosis and left main, the strongest indicator. It's very, very rare for us to turn a patient down. Obviously, you might say if a patient has an awful lot of comorbidities, and maybe this is a lesion that wouldn't be too difficult to handle in PCI, that's something to reasonably talk about with your interventional cardiologist.

14 SYNTAX Score Website supported by Cardialysis and Boston Scientific Slide 13 Dr. Turco: That's great. Very briefly because we're running out of time, but the SYNTAX score does not take into account left ventricular [LV] dysfunction. When you are performing left main intervention, does LV dysfunction and what your starting ejection fraction is change your opinions as to whether you want to proceed with PCI vs referring those patients for surgery? Just very briefly, in those patients, are you using supportive devices, such as the Impella catheter [ABIOMED, Inc.] or intra-aortic balloon pump to give you a little edge there to support those patients? Very briefly, David? Dr. Kandzari: It certainly factors into our decision making because SYNTAX, as you say, is just exclusively based on angiographic measures alone. For patients with LV dysfunction, we have some general guidelines that we use either the Impella device or intra-aortic balloon pump. For patients with acute coronary syndromes, patients with severe LV dysfunction, patients with relative hypotension, those that have very calcified bifurcation lesions as well, those are our own personal experience base. That's the art, not the science of medicine.

15 ISAR Left Main: Characteristics PES (n = 302) SES (n = 305) P value LVEF (% ± SD) 53.4 ± ± Localization LM lesion Ostium 37 (12) 33 (11) Midshaft 74 (25) 79 (26) Distal 191 (63) 193 (63).82 Intra aortic balloon pump 4 (1) 4 (1).99 IVUS 0 0 N/A LVEF = left ventricular ejection fraction Slide 14 Mehilli J, et al. J Am Coll Cardiol. 2009;53: Then you look at trials like ISAR-LEFT-MAIN [Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions], a 607 patient randomized trial that used less than 1% balloon pump and virtually no IVUS. There's this wide disparity of what we know to now advance the procedure and what would be a nice to have. Dr. Turco: That's great. Before we close, I want to go down the line again and really try to get at the issue of what we need to do to advance the field further. How do we get to understand some of the clinical evidence that we need and what trials are on the horizon to help answer some of our questions that we've laid out here today. Let me start, Joe? Dr. Sabik: Sure. There appears to be some equipoise in some patients with left main disease, particularly if we look at coronary complexity, that patients with less complex disease, there may be equal outcomes. I don't think we know that, but there appears to be some equipoise. It seems to me that a trial of those patients is very important. Dr. Turco: Thank you. SJ? Dr. Park: Yes, I agree there. We need more globalized, large-scale multicenter studies. Actually, my thinking is on an all-comer basis to see if the interventionist can do the PCI in feasible patients who had adequate lesions by angiograms, we could include these in randomized studies.

16 Dr. Turco: David, I know you're working on a trial. What are your thoughts? ACC Interventional Scientific Council Position Paper Slide 15 Kandzari DE, et al. J Am Coll Cardiol. 2009;54: Dr. Kandzari: I agree with SJ and Joe completely. I think that in addition to those comments, the ACC [American College of Cardilogy] Interventional Council is coming forward with a manuscript soon in publication to address many of these issues of what are the outstanding issues to move this beyond its existing indication. In addition, to the trial that Joe mentioned and the issues SJ has mentioned, we also need to include technique. We know that there's an evolution in PCI technique with a 1-stent technique being favored over 2 stents and with, perhaps, better outcomes when feasible in the left main indication.

17 Issues to Resolve Ideal technique Number and type of stent Restenosis risks lower vs other vessels Hemodynamic support Appropriate follow up? Angiography Computed tomography angiogram Clinical Slide 16 We talked about the hemodynamic support. We don't know also issues regarding the role of dual antiplatelet therapy, although stent thrombosis in the left main seems to be a very uncommon occurrence. There's also some recent evidence that suggests maybe the type of stent is not as relevant in the left main indication, given that the restenosis risks are relatively low. I think the other issue for us is, how do we follow these patients after left main PCI? It is a very common, but nonstandardized practice to perform follow-up angiography, follow-up CT [computed tomography] angiography, but then again, we know that in trials like SYNTAX, these patients were simply followed clinically and did exceptionally well. I think these are some of the unknowns that hopefully could be answered, perhaps as part of a trial. Dr. Turco: Great comments. David, yes or no, are we going to see a change in guidelines here in the United States? Dr. Kandzari: I have no insight to that at all, but I think that given the more recent evidence that we're seeing from studies like SYNTAX and long-term follow-up from MAIN-COMPARE, we should see some advancement. But certainly, without a prospective, dedicated and wellpowered randomized trial, we won't see it go to something like a class I indication. Dr. Turco: Thank you. Today, we've had an opportunity to have 3 distinguished panelists with

18 us, all that have very good perspectives. I think the take-home message from this program should be patient selection is truly the key, and that we need to follow the evidence-based medicine that we have available to us: SYNTAX, Dr. Park's work, and others in this field. There are still many unanswered questions that we will learn as the new clinical trials move forward. I think with newer dual antiplatelet therapies, we may improve on our safety margin. I think the final take-home is to stress the importance of a collaborative effort in the cardiac catheterization lab and in your institution with your cardiac surgical colleagues. That's only going to lead to safer patient care, and sharing of information is going to lead us to answer some of these questions in a much, much better way. I want to thank Dr. Sabik, Dr. Park, and Dr. Kandzari for joining us. I'm Dr. Mark Turco. Thank you.