DR. STONE: Welcome to this roundtable discussion. Today, we’ll be focusing on some of the advantages, disadvantages, and nuances of drug-eluting and bare-metal stents in the practice of interventional cardiology. My name is Gregg W. Stone; I’m an interventional cardiologist and Professor of Medicine at Columbia University Medical Center and the Cardiovascular Research Foundation in New York City. I’m very pleased to have a distinguished panel who will be leading us through this discussion; I’d like my colleagues to introduce themselves.
DR. COLOMBO: I’m Antonio Colombo, interventional cardiologist and Director of Interventions at San Raffaele Scientific Institute and Columbus Hospital in Milan, Italy.
DR. KEREIAKES: I’m Dean Kereiakes, an interventional cardiologist and Medical Director of The Christ Hospital Heart and Vascular Center and the Lindner Clinical Research Center at The Christ Hospital in Cincinnati, Ohio, and Clinical Professor of Medicine at Ohio State University.
DR. KIRTANE: I’m Ajay J. Kirtane, an interventional cardiologist and Chief Academic Officer of the Center for Interventional Vascular Therapy at Columbia University Medical Center/New York-Presbyterian Hospital in New York City, and I am also affiliated with the Cardiovascular Research Foundation.
DR. STONE: When I look back and think about the field of interventional cardiology, specifically percutaneous coronary intervention, I realize that we always describe its evolution in terms of 3 transformative or revolutionary phases. First, of course, was the introduction of balloon angioplasty by Andreas Gruentzig in 1977, followed by the bare-metal stent period beginning in the mid-1990s, and the current drug-eluting stent era (since 2003 in the US). Bare-metal stents were introduced to overcome some of the limitations of balloon angioplasty, specifically acute coronary occlusion that would occur during and shortly after the interventional procedure as well as late recoil and restenosis. Drug-eluting stents were then introduced principally to overcome the problem of late restenosis that was still occurring at an excessively high rate with bare-metal stents.
Today, stents (both drug-eluting and bare-metal) are the dominant revascularization modality for the treatment of most patients with obstructive coronary artery disease. Drug-eluting stents are used in the majority of patients in most geographies, although bare-metal stents are still widely utilized in certain institutions in certain countries and for certain specific types of patients and indications, which we will be discussing today.
The principal reason why stents are so dominant (compared to balloon angioplasty) is that they prevent acute occlusion. However, today, we’re going to focus mainly on restenosis. So, I would like to ask my panelists—I will start with Dr. Kirtane—to describe the pathophysiology and clinical manifestations of coronary restenosis.
DR. KIRTANE: When you put a foreign body such as a stent into the bloodstream, there’s a normal response that involves not only healing but also a pathologic response. Smooth muscle cells undergo hyperplasia, which causes neointima formation within the stented area itself.
If the neointimal proliferation is severe, that essentially causes constriction of the lumen, which can then lead to an obstruction of flow beyond a certain point. If the growth of the tissue is such that it decreases flow, then patients can present with either angina in a stable form or even acute coronary syndromes if the neointimal proliferation becomes even more occlusive.
DR. STONE: Dr. Kereiakes, how common is restenosis with bare-metal stents? Here, we have to differentiate clinical from angiographic restenosis because not all patients with anatomic narrowing within the stent become symptomatic.
DR. KEREIAKES: Following bare-metal stent deployment, the development of restenosis is dependent on the substrate being treated. The major determinants are postprocedure minimum lumen diameter, which is the platform upon which restenosis occurs, and stent length. An additional important factor that shifts the curve for restenosis is the presence of diabetes. Diabetic patients have a more exuberant, more aggressive restenotic process. The incidence of clinical restenosis is about half that of angiographic restenosis, and following bare-metal stenting, it is not uncommon to see angiographic restenosis rates of 30% to 40% and clinical restenosis rates that are roughly half of that.
DR. STONE: The ability to differentiate complex from noncomplex anatomy is essential if we want to stratify the likelihood of restenosis, which is also modulated by increases in smooth muscle cell hyperplasia and extracellular matrix production that occur in diabetic patients. Therefore, to summarize, in the bare-metal stent era, restenosis rates varied anywhere from 10% to 50% depending on whether treatment was restricted to simple short lesions in large vessels (mostly seen in nondiabetic patients) or very complex lesions in diffusely diseased small vessels (often seen in diabetic patients). Dr. Colombo and all of us on this panel routinely treat these complex lesions at our referral centers. Typically, when using bare-metal stents in these complex cases, the initial result would be good; however, we would frequently be plagued by restenosis, for example, after opening up long chronic total occlusions or treating complex bifurcations, 4 to 6 lesions, small vessels, diffuse disease, etc.
So Dr. Colombo, if drug-eluting stents reduce restenosis by approximately 50% to 60%, which is what most of the larger studies have shown, do all patients benefit from drug-eluting stents or bare-metal stents in terms of reduction in restenosis? Alternatively, should drug-eluting stents be reserved only for complex patients and lesions and bare-metal stents be reserved for short lesions in large vessels or perhaps thrombotic lesions?
DR. COLOMBO: The answer is yes and no. In general, I would say yes: all patients benefit from a drug-eluting stent in terms of reduction of restenosis. The difference is the number needed to treat. If you are dealing with high-risk subgroups, the benefit is more relevant and the number needed to treat is low. In vessels smaller than 3.5 mm, the benefit is clear. If you compare bare-metal stents placed on a short lesion in a vessel that is 3.5 mm or larger, the benefit is more limited. The difference is smaller, and that’s why some centers reserve drug-eluting stent implantation for so-called “higher risk” lesions where the number needed to treat is relatively small.
DR. STONE: To summarize, a 50% or 60% reduction in restenosis is realized in essentially all patients and lesions; however, if your baseline clinical restenosis rate with bare-metal stents is 5%, then you’re only going to see an advantage in 1 or 2 of 100 patients (1% to 2%), whereas if your baseline clinical restenosis rate is 20%, you would see a clinical benefit in more than 1 of 10 patients (~10%).
So, Dr. Kirtane, how do we factor the cost into clinical decision making? Some people believe that, as a society, we should primarily be making therapeutic decisions on a population basis. In this regard, there have been papers describing theoretical models suggesting that if we treat only those patients who are at high risk for restenosis with drug-eluting stents, we could preserve substantial resources and not lose that much clinically in terms of greater rates of adverse outcomes. So, in addition to addressing your perspectives on the needs of the individual patient vs society, please also describe just how meaningful the clinical benefits of preventing angiographic restenosis are to the patient. Is this a major factor that substantially affects quality of life, freedom from angina, freedom from medication use, and freedom from subsequent revascularization procedures, or is this really a fairly minor endpoint?
DR. KIRTANE: Not all patients will experience angiographic restenosis. Only a certain proportion of patients who have angiographic restenosis actually have clinical restenosis. If a patient has clinical restenosis, it usually results in another procedure—either a repeat angioplasty and stent procedure or, in some cases, bypass surgery. These things are clearly relevant to patients. You would want to avoid having these additional procedures, if possible. I think that brings us, ultimately, to the issue of making decisions with the individual patient in mind, because some of the modeling that you talked about occurs on the population level. These models are important in a cost-constrained environment; however, when you’re looking at an individual patient, it is very difficult for a clinician to predict whether that patient is going to experience restenosis. So, if there is a way to avoid restenosis, or at least mitigate how frequently it occurs, and there’s no disadvantage to using the drug-eluting stent, as a provider, you would always try to pick the more efficacious therapy for your patient. However, I’m curious to hear what the other panelists have to say about that.
DR. STONE: Dr. Kereiakes, you stated earlier that approximately 50% of patients with angiographic restenosis develop “clinical” restenosis. However, we tend to measure clinical restenosis in terms of the rate of ischemia-driven repeat revascularization procedures: either another percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. This occurs 1 or more times in 50% of patients with angiographic restenosis. However, we haven’t done a good job of characterizing what portion of the other 50% have actually developed recurrent angina or are limiting their lifestyle because of exertional dyspnea or other manifestations of ischemia. So, how essential are nonobstructive coronary arteries for quality of life, and conversely, how critical is the development of restenosis for quality of life impairment?
DR. KEREIAKES: I think you’re touching upon an important topic now. The topic is not revascularization to improve survival or symptoms, but revascularization to improve ischemia and the use of ischemia guidance in revascularization. I don’t think there’s a more important topic right now, and whether it involves ischemia guidance with myocardial perfusion single-photon emission computed tomography as in the recent ASAN multivessel registry, which showed improved outcomes in patients who underwent multivessel revascularization following PCI compared to coronary artery bypass graft surgery, or the use of fractional flow reserve, as described in the Fractional Flow Reserve vs Angiography for Multivessel Evaluation (FAME) study,1 where in-lab ischemia guidance using fractional flow reserve maximized the benefit relative to the risk of PCI revascularization. So, the more I think about criteria for coronary revascularization, the more I’m driven to allow the presence and magnitude of ischemia to dictate therapeutic strategy in my practice.
DR. STONE: Before we make a choice between drug-eluting and bare-metal stents, we should examine why we are performing PCI (or any revascularization procedure). Revascularization with stents improves survival and prevents myocardial infarction (MI) in patients with ST-segment elevation MI (STEMI) and most patients with non-STEMI. However, in patients with stable coronary artery disease, most studies suggest that revascularization (for most patients at least) does not prolong life or prevent future MIs. If this is true, then the rationale for PCI would be to improve quality of life, decrease the occurrence of angina, decrease the requirement for antianginal medications, and decrease the need for hospitalization for subsequent revascularization procedures.
On the other hand, emerging data suggest that PCI may prevent death and/or MI in some patients. Specifically, a strong relationship between ischemia and subsequent rates of death and MI have been reported in numerous studies, leading to the hypothesis that reducing ischemia by revascularization will prolong life and reduce MI rates. This is currently being tested in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial (unpublished). Dr. Colombo, acknowledging the fact that all 4 of us are interventional cardiologists, when you are treating somebody with severe double vessel or triple vessel disease including high-grade stenosis in the proximal left anterior descending (LAD) and/or left main coronary artery, do you believe that you are prolonging that patient’s life or preventing MI (assuming it’s stable coronary artery disease)? This is a difficult question without concrete data.