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The Editor's Roundtable: Bare-Metal Stents Versus Drug-Eluting Stents—Indications and Complications
The Editor’s Roundtable: Bare-Metal Stents Versus Drug-Eluting Stents—Indications and Complications Vincent E. Friedewald, Jr., MDa,*, Adnan Kastrati, MDb, William C. Roberts, MDc, George W. Vetrovec, MDd, and Stephan Windecker, MDe Acknowledgment
Objectives
This CME activity is supported by an educational grant from Cordis Cardiology, Miami Lakes, Florida.
Upon completion of the activity, the physician should be able to:
Disclosure Dr. Friedewald has received honoraria from Novartis, East Hanover, New Jersey. Dr. Kastrati has received honoraria from Astra-Zeneca, Wilmington, Delaware; Bristol-Myers Squibb, Plainsboro, New Jersey; Cordis, Miami Lakes, Florida; and Eli Lilly, Indianapolis, Indianapolis. Dr. Roberts has received honoraria from Merck, Whitehouse Station, New Jersey; Schering Plough, Kenilworth, New Jersey; Pfizer, New York, New York; AstraZeneca; and Novartis. Dr. Vetrovec is a member of the speaker’s bureaus of Pfizer; CV Therapeutics, Palo Alto, California; Eli Lilly; Cordis; and Stereotaxis, St. Louis, Missouri. Dr. Vetrovec has received education or research grants from Cordis; Eli Lilly; and The Medicines Company, Parsippany, New Jersey. Dr. Vetrovec has received end point committee contracts from Merck; Pfizer; Boston Scientific, Natick, Massachusetts; and Abbott Laboratories, Abbott Park, Illinois. Dr. Vetrovec has received consulting fees from Cordis and the United States Food and Drug Administration, Rockville, Maryland. Dr. Vetrovec owns stock in Merck; Pfizer; Medtronic, Minneapolis, Minnesota; Boston Scientific; and Johnson & Johnson, Piscataway, New Jersey. Dr. Windecker has received honoraria from Biotronik, Berlin, Germany; Boston Scientific; Biosensors, Victoria, Australia; Cordis; Medtronic; and Abbott Laboratories.
a
Assistant Editor, The American Journal of Cardiology, Clinical Professor, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, and Adjunct Research Professor, College of Science, University of Notre Dame, Notre Dame, Indiana; b Professor of Cardiology, Technische Universität, and Director of Interventional Cardiology, Deutsches Herzzentrum, Munich, Germany; cEditorin-Chief, The American Journal of Cardiology and Baylor University Medical Center Proceedings, Executive Director, Baylor Heart and Vascular Institute, Baylor University Medical Center, and Dean, A. Webb Roberts Center for Continuing Medical Education of Baylor Health Care System, Dallas, Texas; dKimmerly Professor of Medicine and Chairman of Cardiology, VCU Pauley Health Center, Virginia Commonwealth University, Richmond, Virginia; and eDirector, Invasive Cardiology, Department of Cardiology, University Hospital, Bern, Switzerland. Manuscript received and accepted March 28, 2008. This discussion took place at Baylor University Medical Center, Dallas, Texas, on September 6, 2007. *Corresponding author: Tel: 512-264-1611; fax: 512-264-7034. E-mail address: [email protected] (V.E. Friedewald). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.03.051
1. Describe the components of drug-eluting stents (DES). 2. Select patients who are appropriate candidates for the implantation of DES. 3. Recognize the importance of increasing patient adherence to antiplatelet therapy after stent implantation. 4. Recognize the clinical features of stent thrombosis and in-stent restenosis and initiate appropriate treatment. Needs Assessment: The need for this activity for cardiologists and other health care specialists in cardiovascular medicine is based on the following premises1– 6: 1. Stent implantation is a routine part of percutaneous transluminal coronary angioplasty (PTCA). 2. Bare-metal stents (BMS) are particularly associated with coronary artery restenosis. 3. DES are particularly associated with acute coronary thrombosis. 4. There is currently controversy concerning the use of BMS versus DES. 5. Better medication compliance with dual-antiplatelet therapy is needed after stent implantation. Target Audience: This activity is designed for cardiologists and all other health care specialists caring for patients with acute and chronic coronary heart disease. CME Credit: The A. Webb Roberts Center for Continuing Medical Education of Baylor Health Care System, Dallas, Texas, designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. The A. Webb Roberts Center for Continuing Medical Education for Baylor Health Care System, Dallas, Texas, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME Instructions: After reading this article, go online at www.AJConline.org to register, complete a post-test with a minimum score of 80%, complete an evaluation, and print a certificate. Combination of Media: Print and Internet Computer Requirements: Windows 2000, Pentium 3 or greater, 512 ram, 80 gigabytes storage Estimated Time to Complete: 1 hour www.AJConline.org
Roundtable Discussion/BMS and DES: Indications and Complications
Release Date: July 2008 Termination Date: July 2009 Introduction The first reported series of intracoronary stent implantations for the prevention of recurrent occlusion after PTCA was in 1987.1 BMS and DES are now routinely implanted as part of PTCA, with 6 million patients worldwide receiving stents as of 2007, at an annual cost of $4 billion to $5 billion.2 Despite their ubiquitous use in treating patients with coronary artery disease, there are numerous questions about stent selection and safety, indications, long-term efficacy, and the treatment and prevention of complications, especially in-stent restenosis (ISR) after BMS placement and acute thrombosis after DES placement. Dr. Friedewald: Dr. Roberts, what have been your observations of coronary stents at autopsy? Dr. Roberts: I have little experience with stent thrombosis at autopsy because the number of autopsies has dropped dramatically, and in many patients who die after receiving stents, the thrombus has already lysed or has been removed at cardiac catheterization. Furthermore, the only way to examine a coronary artery with a stent in place is to cut it with a diamond knife. Dr. Renu Virmani is the only pathologist I know who is doing this. The heart can be x-rayed, however, to determine coronary stent location, followed by excision separation of the major coronary arteries and then re-x-raying them apart from the myocardium. This allows identification of the length of the stent within the artery but does not determine stent contents such as thrombi. Dr. Windecker: For nonhuman animal research, we also use a diamond knife and leave the stent within the artery to examine the entire coronary artery. I do not have experience with human specimens. Dr. Friedewald: What is the mechanism of ISR following coronary stent placement? Dr. Vetrovec: ISR is caused by injury to the coronary artery from dilatation and persistent stretching—with the well-apposed stent—leading to an inflammatory local response. ISR is the formation of a scar as a response to injury of the stented coronary artery. Dr. Friedewald: Are you saying that inflammation contributes to ISR? Dr. Vetrovec: Yes, inflammation is an important component. Dr. Roberts: In atherosclerosis in native coronary arteries, inflammatory cells are very uncommon. Atherosclerosis from a morphologic standpoint is not an inflammatory problem. With coronary stents, however, there is intentional injury to the artery, so ISR in that setting appears to be a very different process in which inflammation might play a role. Since I cannot cut the artery to examine ISR, however, I cannot comment on the role of inflammation based on personal observations. Dr. Vetrovec: I believe that ISR injures the coronary artery, causing an inflammatory response and scar formation like the body’s normal response to other types of injury.
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Dr. Kastrati: ISR is comprised of a series of events leading to neointimal formation, initially triggered by arterial injury that varies with stent structural design and chemical composition. These events include plasma cell deposition, leukocyte migration and activation, smooth muscle cell proliferation, and collagen matrix formation. The exact contribution of inflammation to this process is unknown, but the fact that local use of anti-inflammatory drugs—such as rapamycin used in DESs—suppresses ISR implies that inflammation plays a significant role. Dr. Roberts: Stents are placed in areas of coronary arteries containing large quantities of plaque. They “burrow” into these plaques, burying themselves in plaque. It is reasonable to assume that the DES, because it contains a polymer, also might produce an inflammatory reaction in the plaque. The BMS also produces an inflammatory reaction, I understand. Dr. Kastrati: Yes, and with gold-coated stents there is much more inflammatory reaction and neointimal formation. Such surface contact seems to be very important in addition to the physical injury caused by the stent struts. Dr. Vetrovec: I agree that ISR is a foreign-body reaction. There is evidence that thinner forms of BMSs cause less restenosis than stents with thicker struts, suggesting that the amount of foreign material impacts the amount of reaction. This is consistent with the concept of the stent’s acting as a foreign body to stimulate an inflammatory response. Dr. Windecker: One could also argue, however, that the thicker struts simply cause more physical arterial injury than thinner struts. With intentional arterial overstretch there is increased neointimal proliferation. In the era of balloon coronary angioplasty before the use of stents, no extraneous matter was left in the coronary artery following angioplasty, but ISR did occur, perhaps due to vessel wall elastic recoil. Thus, direct injury to the coronary artery is probably the principal cause of ISR following stent implantation. Dr. Roberts: With balloon angioplasty, there is no inflammatory reaction to the crack in the plaque created by the procedure. It fills up with a neointimal combination of smooth muscle and fibrous tissue. This is a very uniform type of material, distinctive from underlying plaque, but there are no inflammatory cells. Dr. Friedewald: Let’s discuss stent construction. Dr. Kastrati: The DES has 3 components: the stent platform, the polymer, and the drug coating. Most stent platforms are constructed of stainless steel or cobalt-chromium. The drug and the polymer differ among different types of DESs, and they account for differences in efficacy and safety among the various DESs. Dr. Vetrovec: Although difficult to access, the DES polymers and drugs have different effects and different clinical outcomes. An ongoing discussion among experts in this area concerns the amount of endothelialization, which is associated with ISR, that should be allowed by the stent design, and this has not been resolved. Dr. Kastrati: We once believed that BMSs and DESs had similar clinical efficacy. Now we know there are important differences between them. Dr. Friedewald: Are the stents used in the USA the same as those used in Western Europe?
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Dr. Vetrovec: Yes. Dr. Friedewald: What are the risk factors for ISR? Dr. Vetrovec: There are patient-related factors and there are anatomical factors. Aside from features of the stents themselves, anatomical factors such as longer lesions and small coronary arteries have greater risks of ISR than patients without these coronary findings. The more complex “Y” lesions (branched atheromatous lesions) also increase the risk of ISR. Significant patient factors for ISR are diabetes mellitus and acute and chronic renal failure. Dr. Friedewald: What do you mean by “longer lesions”? Dr. Vetrovec: By “longer lesions,” I am referring to the length of the stent, which is determined by the length of the atherosclerotic plaque causing the blockage. Dr. Friedewald: Is elevated C-reactive protein (CRP) a risk factor for ISR? Dr. Vetrovec: Following PTCA and stent placement, the CRP rises and then falls, peaking around 48 hours. This increase is probably a response to injury to the coronary artery, but I do not know if that represents an inflammatory reaction. Patients with large CRP increases after stenting are more likely to have a recurrent cardiovascular event of some type—not necessarily ISR— during the following year. Dr. Kastrati: We found that the baseline CRP was predictive of mortality but not ISR, and the delta change of CRP after stent intervention was predictive of ISR. Dr. Roberts: Does the procedure itself—such as trauma to the groin— elevate the CRP? Dr. Kastrati: Yes, it could, as well as other factors. For example, complex coronary artery lesions require longer procedures, which may further raise the CRP. Dr. Vetrovec: Elevated CRP predicts adverse cardiovascular events in general. Patients having longer procedures also receive more image contrast agents, which may be another risk factor. Dr. Friedewald: What is the clinical relevance of ISR? Is it always bad? Dr. Kastrati: There is debate about the clinical significance of ISR. There are, however, studies showing that ISR is not necessarily a benign event. A study reported in The American Journal of Cardiology in 2006 showed that ⬎50% of patients admitted for ISR present with acute coronary syndrome.3 Many patients with acute coronary syndrome have a worse outcome after reintervention. There appears to be higher 4-year mortality in patients presenting with angiographic evidence of ISR within 6 months following stent placement. Thus, ISR is a clinically relevant complication in that it may be associated with severe cardiac symptoms and increased risk of death. Dr. Friedewald: What type of acute coronary syndrome usually occurs with ISR or in-stent thrombosis? Dr. Kastrati: Most acute coronary syndromes due to ISR are non–ST-segment elevation myocardial infarction or unstable angina pectoris with ischemic electrocardiographic changes without ST-segment elevation.3 We do not know whether unexpected deaths after stenting are due to thrombosis or progressive ISR. I believe in-stent thrombosis is more common in sudden cardiac events,
however, because ISR has a more gradual, progressive course, allowing warning symptoms to occur before complete occlusion and its catastrophic consequences. Dr. Friedewald: When is the peak time following stent placement for the occurrence of acute coronary syndrome secondary to ISR? Dr. Kastrati: Most cases of acute coronary syndrome secondary to ISR present within 2 or 3 months after stent placement, indicating a very quick progression of neointimal formation. There are studies of BMSs showing that most cases of ISR have occurred by 6 months poststenting, although some occur much later. There are no comparable data for ISR with DESs. Dr. Roberts: Is ISR the superimposition of thrombus on isolated neointimal proliferation? Dr. Kastrati: We do not know. The specific contributions of thrombus and neointimal formation are difficult to distinguish. I believe both may contribute, especially in cases of acute coronary syndrome. Dr. Vetrovec: Heightened concerns about intrastent thrombosis with DESs may in part be due more to perception than reality. The ISR rate is moderately high for BMSs, and some of these cases are associated with acute coronary syndromes—mostly non-Q-wave myocardial infarction. With DESs, however, the ISR rate is so low that when intrastent thrombosis occurs, it stands out. Some patients definitely have late stent thrombosis with BMSs years after they are implanted and late thrombosis also occurs with DESs. Dr. Friedewald: Are there subsets of patients who do not benefit from DESs in terms of reduced ISR incidence, and are they identifiable? Dr. Kastrati: The risk of ISR is higher in certain patient groups, such as patients with diabetes mellitus, those with small coronary arteries, and patients with complex coronary artery lesions. The problem is that we cannot predict the risk of ISR for individual patients. I would not, however, selectively limit the use of DESs if there were no financial restrictions. The only reason that I do not use DESs in all patients is insufficient financial resources for their universal use. Dr. Vetrovec: A 4-mm-diameter coronary artery with obstructive atherosclerotic plaque ⬍10 mm in length in a patient without diabetes mellitus can be treated with a short stent, and the probability of subsequent ISR (for patients in that group) is about 3%. With a longer narrowing—for example, 25 mm—in a patient who has diabetes mellitus, the ISR rate is much higher. The BMS, compared to balloon angioplasty alone, sequentially lowered the risk of ISR, but the relative risk variability of ISR was unchanged and driven by coronary artery size, the length of the stent, and whether diabetes mellitus was present. The DESs reduced ISR by a relatively similar degree across the overall risk, with the same amount of reduction in patients with and without diabetes mellitus. Dr. Kastrati: A low rate of ISR for certain patient subsets makes it difficult for studies with relatively small numbers of patients to show significantly different ISR risk. Large numbers of patients with less complex lesions are needed to prove a significant reduction of ISR with DESs. Dr. Windecker: We must be careful in balancing the
Roundtable Discussion/BMS and DES: Indications and Complications
benefits and risks of DESs in individual patients. While DESs are very effective in procedures involving small coronary arteries, the incremental value in using DESs in large arteries requiring stent diameters ⬎3.5 cm is minimal. I would not agree with the position of using DESs in all patients receiving coronary stents if cost is not a consideration. Consider, for example, patients with ST elevation myocardial infarction (STEMI). The obstruction in STEMI typically is in a proximal, large coronary artery, in which the DES has less advantage over the BMS. In STEMI, there is less viability of the myocardium supplied by the obstructed coronary artery, so ISR has less adverse effect if it occurs. Thus, while I am in general agreement with using DESs in most types of patients, I would be cautious in advocating them for their use in STEMI or in other instances of large coronary artery obstruction. Dr. Vetrovec: In patients with acute myocardial infarction (AMI), patients in whom I suspect will not be compliant with medications after implanting the stent, and patients I do not know well enough to judge their likelihood for poststent drug adherence, I use BMSs. Coronary artery size may be difficult to evaluate in the acute setting because there may be arterial vasoconstriction with superimposed thrombus, making it hard to assess the actual size of the artery. Using inappropriate-sized stents is a risk factor for late stent thrombosis using DESs in patients with AMI. Dr. Roberts: Are there any clinical situations in which you perform PTCA alone without stent placement? Dr. Kastrati: No, not in my practice. Dr. Vetrovec: I use stents 95% of the time with PTCA, but I still perform PTCA alone in very select types of blockages, such as a moderate-sized coronary artery branch coming out of a stent. Performing PTCA for obstructive atherosclerotic disease involving very small coronary arteries, putting in a stent is no better and no worse than performing PTCA alone. Dr. Roberts: George, if you had to have percutaneous coronary intervention today, would you want a BMS or a DES? Dr. Vetrovec: I would prefer the DES provided it was unlikely I would need to stop antiplatelet agents within the following year. Dr. Friedewald: What is your belief about on-label versus off-label indications for coronary artery stents? Dr. Kastrati: On-label indications are based on studies performed for initial device approval. All initial studies have included only simple, short lesions involving coronary arteries from 2.5 to 3.5 cm in diameter, no chronically occluded arteries, and in patients without AMI or prior coronary artery bypass grafting (CABG). All other situations that were not included in these initial studies are considered as off-label uses of DESs. Thus, many of us pay little attention to what is off label and what is on label. Dr. Windecker: Few patients have only on-label coronary narrowing. Rather, most patients have mixtures of narrowing, so labeling has little applicability to actual practice. Dr. Vetrovec: I sat on the Food and Drug Administration (FDA) panel that reviewed labeling for the DES and found that this is a very bureaucratic issue unique to the USA.
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Dr. Friedewald: Device labeling, however, raises important legal issues for clinicians who must decide which stents to use. Dr. Vetrovec: The FDA says that it does not dictate the practice of medicine. However, it approves drugs or devices based on the studies, and the manufacturers promote the use of the devices for those populations in which they are likely to be effective. It remains up to the practicing physician to decide whether to use devices off label. To the credit of the FDA, which generally looks only at on-label issues, it did discuss the issue of off-label uses of coronary stents. DESs are used in 60% of cases in the USA, so many patients are receiving them off-label, because most patients’ clinical situations and coronary artery obstructive lesions do not fit the label criteria. Dr. Friedewald: What are the contraindications for using DESs? Dr. Vetrovec: Patients should not receive DESs when, for any reason, they cannot take dual-antiplatelet therapy for 1 year. Dr. Friedewald: Who are those patients? Dr. Vetrovec: A good example would be a patient with recurrent colon polyps who needs colonoscopy in 3 months for cancer surveillance, and it is believed that delaying this for 1 year would carry excess risk for cancer recurrence. Another example would be a patient contemplating hip surgery who has a positive exercise test for myocardial ischemia, and it is decided that PTCA and stent implantation are indicated prior to hip surgery. The patient may prefer a BMS to have the hip surgery as soon as possible or may elect to have a DES and wait a year before having hip surgery. Dr. Friedewald: Let’s discuss stent thrombosis, beginning with its definition. Dr. Vetrovec: The original definition of stent thrombosis has been changed, which changes the reported relative incidence of this complication. The initial definition of stent thrombosis stated that it was acute coronary syndrome of some type plus angiographic or pathologic confirmation of coronary artery thrombosis or occlusion occurring in a patient who had received a coronary stent. The stent manufacturers created the ARC (Academic Research Consortium) standard definitions,4 which added a “probable” category for stent thrombosis that included unexplained death within 30 days after stent implantation or a target coronary artery AMI without visible thrombus. This definition assumed that thrombi go away, so it would be appropriate to call that a “probable” stent thrombosis. A “possible” thrombosis category involved patients with unexplained death occurring within 30 days following stent implant. Most experts, however, believe that this “possible” category using a very broad death definition was too extreme and includes too many deaths unrelated to the stent. Dr. Kastrati: I am glad the original definition of “definite” stent thrombosis remains. Nothing is gained, however, by adding definitions of “probable” and “possible” thrombosis, and having 3 categories of definitions is confusing. Dr. Windecker: The principal reason for redefining stent thrombosis was that there were differing definitions in different trials. For example, some trials used sudden death
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during the first 30 days following stent implantation, some looked only at angiographically proven stent thrombosis, and others included AMI up to 30 days after implant. There has been much heterogeneity in the definition of stent thrombosis. One goal of the new definitions is to achieve standardization for defining “thrombosis” in future trials. The most useful of the 3 definitions is the “definite” stent thrombosis because it is a distinct clinical syndrome that is easy to recognize and can be clearly attributed to the stent. I do not know whether the “probable” and “possible” definitions are useful. Dr. Kastrati: I agree. Dr. Friedewald: Sudden, unexplained cardiac death within 30 days of implantation of a stent is probably due to stent thrombosis, according to the new definitions? Dr. Vetrovec: Yes. It should be pointed out that these new definitions change the data of prior trials. With the expanded definitions the incidence of stent thrombosis is decreased to about 1/2 the incidence stated in the original reports. Dr. Kastrati: ARC also eliminates the censoring of patients from stent thrombosis analysis after having coronary artery reintervention. Dr. Windecker: It is important to count both primary and secondary stent thrombosis, because studies otherwise violate the intention-to-treat principle that does not count stent thrombosis when there was a prior event. Dr. Friedewald: What factors contribute to early stent thrombosis? Dr. Windecker: Up to 30 days following stent implantation, mechanical factors are most important, with residual coronary artery dissections as the leading cause for thrombosis with both BMSs and DESs. Another important contribution in the early phase is inadequate antiplatelet therapy because many patients do not receive sufficient antiplatelet drugs or they are resistant to them. Diabetes mellitus is another important factor for early thrombosis of BMSs and DESs. Dr. Friedewald: What factors contribute to late stent thrombosis, defined as occurring ⬎1 month after implantation? Dr. Windecker: The cause of late stent thrombosis is a much more complex issue than early thrombosis. The only independent predictor for late stent thrombosis is acute coronary syndrome at the time of the initial stent placement. Dr. Friedewald: Is renal disease a risk factor for stent thrombosis? Dr. Kastrati: Yes, there is a correlation between renal failure and the risk of stent thrombosis, at least for the BMS. Dr. Vetrovec: The quality of stent deployment is also probably an important risk factor for DES thrombosis, because the presence of polymer on the stent seems to change the expansion relation of the stent to the balloon inflation pressure. It appears that the higher the inflation pressure, the lower the risk of late stent thrombosis, which suggests that when the stent is appropriately sized, it still needs to be well expanded for optimal placement in the coronary arterial wall. At least part of late stent thrombosis is due to inadequate initial stent expansion. Dr. Kastrati: There have been studies, however, showing that malapposition was not predictive of stent thrombo-
sis or any other outcome following placement of DESs. Other important factors may be residual dissection and uncovered coronary artery lesions. Central to all risk factors for thrombosis is the role of platelets, and for that reason, premature discontinuation of dual-antiplatelet therapy is highly predictive of stent thrombosis. Patients who are nonresponsive to clopidogrel are also at high risk. Dr. Friedewald: How is stent thrombosis diagnosed? Dr. Vetrovec: Stent thrombosis is often manifest as an AMI in the coronary arterial distribution of a prior stent placement. This occurrence strongly correlates with patient failure to take the antiplatelet drugs. Dr. Friedewald: How is stent thrombosis treated? Dr. Kastrati: The most frequent form of treatment for stent thrombosis is early percutaneous intervention of the occluded coronary arteries. Most interventional cardiologists use plain angiography, with or without thrombus aspiration devices, and try to avoid implanting a new stent into the affected coronary artery. Many cardiologists perform the procedure under the protection of glycoprotein IIb/IIIa inhibitors. After a successful procedure for correcting stent thrombosis, the most important issue then becomes subsequent antiplatelet treatment. If stent thrombosis occurred after the patient stopped taking clopidogrel, the decision to simply restart clopidogrel is the logical course, and administration of clopidogrel for a prolonged period of time—at least 1 year—is the recommended strategy. If stent thrombosis occurred despite the patient’s taking the recommended doses of clopidogrel, however, the correct course to recommend is much less certain. I suggest that the next step should be to reexamine the initial stent implant to see whether there were any suboptimal results to explain stent thrombosis, and fix those with a second procedure. When stent thrombosis is not explained by an abnormality at the time of the initial procedure, it becomes very puzzling. One possibility is that something is inherently abnormal with the way some such patients respond to clopidogrel, and some investigators are assessing platelet responsiveness to clopidogrel. Both the methodology and the clinical relevance of tests for abnormal clopidogrel response, however, are yet to be defined. Some simply advocate doubling the dose of clopidogrel. New drugs in development, such as prasugrel, may offer more effective alternatives to clopidogrel, but we are awaiting studies to see if they will be safe and effective. Finally, CABG may be considered depending on the coronary artery anatomy and the patient’s clinical condition. Dr. Windecker: I agree with that approach. Coronary angiography should definitely be performed to make the diagnosis. There should be a very low threshold for studying a patient who has an acute onset of chest pain and has had previous stent placement to confirm or exclude stent thrombosis. I also agree that the main strategy should be thrombus aspiration and balloon angioplasty, unless there is residual coronary arterial dissection, which should be treated with new stent placement. Another diagnostic consideration is intravascular ultrasound, which returns us to the issue of incomplete stent apposition with the coronary arterial wall. Incomplete stent apposition, however, is not completely predictive of adverse events and depends on the exact nature of the incomplete apposition. The definition of incomplete
Roundtable Discussion/BMS and DES: Indications and Complications
stent apposition is the failure of only 1 strut to be in contact with the coronary arterial wall. I believe that small areas of incomplete stent apposition probably do not play a role in causing adverse events, but large areas of incomplete stent apposition due to positive arterial remodeling or coronary arterial aneurysmal formation are causes of adverse events. When managing the patient who has a coronary stent and who is too far from cardiac catheterization facilities to be treated quickly, I recommend thrombolytic therapy. Dr. Vetrovec: A patient with a coronary stent and chest pain— especially with acute ST-segment elevation on the electrocardiogram—should have immediate coronary angiography. When stent thrombosis occurs, there is almost always some stent-edge coronary artery dissection that can be seen on the original coronary angiogram, especially in patients who have been taking clopidogrel. In such patients, I often implant an additional stent to cover that area of dissection. I also try to better deploy the stent by using higher pressure. Quite often, I implant secondary stents with the goal of achieving the best possible result by correcting any stent-edge abnormalities. I find that when I perform this procedure “blindly,” I sometimes balloon beyond the location of the previous stent, so 1 reason I often put in another stent is to correct for any damage I may have caused in this area of the artery. Dr. Friedewald: Let’s discuss antiplatelet therapy. Dr. Vetrovec: It is possible that the risk of stopping clopidogrel and aspirin may be greater than the relative benefit of taking them, because of a prothrombotic rebound effect when they are discontinued. Dr. Roberts: How long do you keep your patients on clopidogrel after receiving coronary stents? Dr. Vetrovec: I keep most patients on clopidogrel for 1 year, based on a BMS trial in which patients were first randomized to clopidogrel pretreatment before stent placement versus beginning clopidogrel at the time of or after the intervention.5 This study found an advantage for pretreatment with clopidogrel. One month after stenting, they rerandomized the patients to long-term clopidogrel versus aspirin alone (clopidogrel plus aspirin versus just aspirin). The patients at the end of 1 year who were continued on clopidogrel plus aspirin versus those on aspirin alone had a 23% relative reduction in coronary events and an absolute reduction of 4%, which is statistically significant. A comparable study has never been performed for DESs. Why not take clopidogrel forever? There are 2 reasons not to. First, 25% of patients with late sent thrombosis are already taking clopidogrel. Second, patients do worse late on long-term clopidogrel, mostly due to increased bleeding episodes. Thus, dual-antiplatelet therapy has not been shown to improve late outcomes. Dr. Roberts: What dose of aspirin do you prescribe for use in conjunction with clopidogrel? Dr. Vetrovec: I prescribe 81 mg once daily for longterm treatment. Dr. Kastrati: The optimal dose of aspirin is not known. Our practice is to prescribe 200 mg/day, but this is not based on any data, just tradition. We also prescribe clopidogrel for 1 year for all patients receiving DESs, although there is no evidence to support this duration of treatment. We need randomized trials that determine the
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optimal length of dual antiplatelet therapy, because prolonged therapy also prolongs the time for bleeding complications. We are also concerned with the potential for rebound thrombosis when stopping clopidogrel, which may be attenuated by tapering the drug to every other day for 2 weeks before stopping it completely. Dr. Vetrovec: I have not seen a case of stent thrombosis when both aspirin and clopidogrel had not been stopped at the same time. As long the clopidogrel is discontinued first and then the aspirin is discontinued a week later, it does not seem to be a problem. Stopping both drugs together, however, carries increased risk for stent thrombosis. Dr. Kastrati: I have seen patients stop only clopidogrel and then develop stent thrombosis. Dr. Vetrovec: Many cases of very late stent thrombosis seem to happen when stopping the agents is coupled with another unrelated surgical procedure. Maybe increased systemic inflammation caused by another procedure can trigger stent thrombosis. Dr. Windecker: I usually give 100 mg of aspirin daily and I recommend clopidogrel for 1 year. I believe that we overestimate the compliance of our patients with the recommended therapy. In the CREDO (Clopidogrel for the Reduction of Events During Observation) trial,5 in which patients were randomized to 1 month versus 12 months of clopidogrel, only 60% adhered to the long-term administration of clopidogrel. Patients are very compliant for the first 30 days, and up to 90% comply for 6 months, but after that, it declines to 70% at 9 months and even less at 12 months. Alerting patients to the danger of premature antiplatelet discontinuation is extremely important. Dr. Friedewald: How do you treat patients whom you believe will not be compliant in taking aspirin and clopidogrel? Dr. Vetrovec: I refer patients with multivessel coronary artery disease whom I do not believe will be compliant with medications to CABG. Deciding whether a specific patient will be compliant, however, is very difficult. Dr. Windecker: Medication compliance failure also contributes to saphenous vein graft closure following CABG. CABG is probably safer than stent implantation for noncompliant patients, but those patients are also at increased risk of AMI due to medication noncompliance. Dr. Vetrovec: The prevalence of not complying with long-term use of cardiac medications is poor. With so much communication technology in modern society, we could at least better notify patients about taking their medications and improve our awareness of whether patients are taking their drugs. This is an area that is understudied and underdeveloped. Dr. Friedewald: Do you prescribe statins for patients with coronary stents? Dr. Vetrovec: I believe in placing all patients having coronary interventions on statins at the time of the procedure. I believe statins lower the risks of the procedure. Whether statins impact the occurrence of late stent thrombosis is unknown. Dr. Friedewald: Could each of you summarize how you decide between using BMSs and DESs? Dr. Vetrovec: I prefer DESs for patients whose coronary artery size is appropriate and who can take clopidogrel and
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aspirin, especially clopidogrel, for 1 year. I also believe that in very high risk patients, such as those with poor left ventricular function, it is better to implant DESs because late myocardial ischemia. which may not be recognized as being caused by ISR, may cause an even greater number of adverse outcomes in such high-risk populations. For patients whom I know are not going to take antiplatelet drugs BMSs are favored. Dr. Windecker: I also advise a thorough risk-benefit analysis of each individual patient. The first issues I address are whether the patient is likely to adhere to long-term antiplatelet therapy and whether there are any unrelated surgical procedures contemplated. Next, I carefully look at coronary artery size, favoring DESs when treating reference arteries with a diameter ⬍3.5 mm. I also favor DESs in treating narrowings of more complex morphology, because the risk of ISR is much higher with BMSs than with DESs. The 1 situation in which I am cautious in preferring DESs over BMSs is in patients with STEMI. Dr. Kastrati: For patients who can take dual-antiplatelet therapy for 6 to 12 months, I do not see any indication for BMSs. There is no evidence that DESs increase the risk of stent thrombosis compared to the risk of thrombosis with BMSs. We are now treating much more complex narrowings, so a higher thrombosis rate is found when comparing outcomes of DESs today with studies performed several years ago with BMSs. Dr. Friedewald: Are there new stents on the horizon and new drugs to go with them, beyond clopidogrel and aspirin? What additional studies do we need? Dr. Kastrati: There is a lot of research in their early phases of testing with new types of DESs. I expect that the major changes in new stents will involve the polymer, with a trend toward biodegradable polymers rather than permanent polymers, because permanent polymers are not needed after the drug has been released. It is also possible that future stents themselves will be degradable, but this is further in the future because attempts to develop them have so far been unsuccessful. There has been an increase in the risk of ISR with such temporary types of stents. Future stent designs will also have improvements in the release kinetics of the drugs. With respect to the drugs, there are ongoing studies of other platelet adenosine diphosphate (ADP) receptor antagonists such as prasugrel. Another development may be the synthesis of short-acting ADP or reversible ADP receptor antagonists. This approach may offer a solution for patients going to surgery by substituting for clopidogrel a shortacting ADP receptor antagonist that is totally reversible within minutes. We also need more trials focused on additional, untested indications for DESs. For example, left main coronary artery stenting is an important application in which we may see some trial results in the next year. There are other trials comparing DESs with CABG in patients with diabetes mellitus. Dr. Windecker: There will be an interesting period ahead in the development of new DES platforms. The limus family of stents, in particular, will be enhanced by new additions, such as everolimus-, zotarolimus-, and biolimuseluting stents. We will eventually have a variety of stents to choose from in the limus family, probably with similar
efficacy profiles. Two other agents, pimecrolimus and tacrolimus, require additional study but may cause less smooth muscle cell proliferation because they appear to have more anti-inflammatory properties than current agents. There is a lot of effort in the development of bioabsorbable polymers, with the idea that these stents resemble more BMSs after the drug and the polymer have been released. The most promising technology is a truly and fully biodegradable DES platform, because stents or metal structures within the arterial wall are foreign bodies, and they do not allow the coronary arteries in which they are implanted to function normally. Dr. Vetrovec: I anticipate that better antiplatelet agents will make a big difference in preventing restenosis. I am hopeful that new stents and polymers will improve their deliverability and inflation characteristics. I also would like to see the development of stents that are easier to implant into the coronary artery. Because there may be differences in patients with AMI or even thrombotic lesions in terms of the late risks of coronary stents, there may even be drug combinations that work better in some patient subsets. We are trying to treat every patient the same, but neither the biology of all of these underlying pathological processes is the same, nor are their responses to coronary artery stent implantation the same. While randomized long-term trials are a wonderful goal, time waiting for their results is excessive. We need to organize a registry where we can go back and study those patients whom we have already treated with stents to determine what works and what does not work. Such a registry could provide a quicker fix than a 5-year randomized trial, which is the ideal, but we need to know what to do in the next 5 years while we are conducting these trials. Finally, we need to individualize patients according to disease severity. We are treating patients with small AMIs the same as patients with severe left ventricular dysfunction, but late restenosis may be far more important in sicker patients, who do not tolerate late myocardial ischemia as well. We need to start looking at some of these specialized populations in terms of what are the relative benefits of 1 type of stent versus another type. Dr. Roberts: I am glad that there are both BMSs and DESs available, because there are some patients who cannot or will not take antiplatelet drugs. At this moment, if I had to have a stent, I would prefer to receive a DES for many of the reasons you have mentioned. I am counting on not having to have a stent in my life, however, because I am trying very hard to keep my low-density lipoprotein cholesterol level ⬍70 mg/dl and try to not eat cows, pigs, sheep, goats, and chickens, so I hope that I will never have to see any of you from a therapeutic standpoint. There needs to be a stronger pulpit to get people interested in controlling their lipid levels and their blood pressure levels so we will not have so many “wrecks” for you cardiac interventionalists to fix. The automobile industry has decreased the number of accidents in the last 10 years, primarily by improvements in the vehicles they build. If we take the magical drugs that have been provided by the pharmaceutical industry— especially the statins and the antihypertensives—we
Roundtable Discussion/BMS and DES: Indications and Complications
could put many of you out of work. But since I am a bit cynical about how many people do and will adequately care for their health, I think you will be busy for decades. Dr. Friedewald: Thank you. 1. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987;316:701–706. 2. Kaul S, Shah PK, Diamond GA. As time goes by. J Am Coll Cardiol 2007;50:128 –137. 3. Assali AR, Moustapha A, Sdringola S, Denktas AE, Willerson JT, Holmes DR, Smalling RW. Acute coronary syndrome may occur with
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in-stent restenosis and is associated with adverse outcomes (the PRESTO trial). Am J Cardiol 2006;98:729 –733. 4. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es G-A, Steg PG, Morel M, Mauri L, Vranckx P, et al, on behalf of the Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –2351. 5. Steinhubl SR, Berger PB, Mann JT, for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA 2002;288: 2411–2420. 6. United States Food and Drug Administration. FDA statement on coronary drug-eluting stents (September 14, 2006). Available at: http://www.fda.gov/cdrh/news/091406.html. Accessed November 10, 2007.
Objectives
This CME activity is supported by an educational grant from Cordis Cardiology, Miami Lakes, Florida.
Upon completion of the activity, the physician should be able to:
Disclosure Dr. Friedewald has received honoraria from Novartis, East Hanover, New Jersey. Dr. Kastrati has received honoraria from Astra-Zeneca, Wilmington, Delaware; Bristol-Myers Squibb, Plainsboro, New Jersey; Cordis, Miami Lakes, Florida; and Eli Lilly, Indianapolis, Indianapolis. Dr. Roberts has received honoraria from Merck, Whitehouse Station, New Jersey; Schering Plough, Kenilworth, New Jersey; Pfizer, New York, New York; AstraZeneca; and Novartis. Dr. Vetrovec is a member of the speaker’s bureaus of Pfizer; CV Therapeutics, Palo Alto, California; Eli Lilly; Cordis; and Stereotaxis, St. Louis, Missouri. Dr. Vetrovec has received education or research grants from Cordis; Eli Lilly; and The Medicines Company, Parsippany, New Jersey. Dr. Vetrovec has received end point committee contracts from Merck; Pfizer; Boston Scientific, Natick, Massachusetts; and Abbott Laboratories, Abbott Park, Illinois. Dr. Vetrovec has received consulting fees from Cordis and the United States Food and Drug Administration, Rockville, Maryland. Dr. Vetrovec owns stock in Merck; Pfizer; Medtronic, Minneapolis, Minnesota; Boston Scientific; and Johnson & Johnson, Piscataway, New Jersey. Dr. Windecker has received honoraria from Biotronik, Berlin, Germany; Boston Scientific; Biosensors, Victoria, Australia; Cordis; Medtronic; and Abbott Laboratories.
a
Assistant Editor, The American Journal of Cardiology, Clinical Professor, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, and Adjunct Research Professor, College of Science, University of Notre Dame, Notre Dame, Indiana; b Professor of Cardiology, Technische Universität, and Director of Interventional Cardiology, Deutsches Herzzentrum, Munich, Germany; cEditorin-Chief, The American Journal of Cardiology and Baylor University Medical Center Proceedings, Executive Director, Baylor Heart and Vascular Institute, Baylor University Medical Center, and Dean, A. Webb Roberts Center for Continuing Medical Education of Baylor Health Care System, Dallas, Texas; dKimmerly Professor of Medicine and Chairman of Cardiology, VCU Pauley Health Center, Virginia Commonwealth University, Richmond, Virginia; and eDirector, Invasive Cardiology, Department of Cardiology, University Hospital, Bern, Switzerland. Manuscript received and accepted March 28, 2008. This discussion took place at Baylor University Medical Center, Dallas, Texas, on September 6, 2007. *Corresponding author: Tel: 512-264-1611; fax: 512-264-7034. E-mail address: [email protected] (V.E. Friedewald). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.03.051
1. Describe the components of drug-eluting stents (DES). 2. Select patients who are appropriate candidates for the implantation of DES. 3. Recognize the importance of increasing patient adherence to antiplatelet therapy after stent implantation. 4. Recognize the clinical features of stent thrombosis and in-stent restenosis and initiate appropriate treatment. Needs Assessment: The need for this activity for cardiologists and other health care specialists in cardiovascular medicine is based on the following premises1– 6: 1. Stent implantation is a routine part of percutaneous transluminal coronary angioplasty (PTCA). 2. Bare-metal stents (BMS) are particularly associated with coronary artery restenosis. 3. DES are particularly associated with acute coronary thrombosis. 4. There is currently controversy concerning the use of BMS versus DES. 5. Better medication compliance with dual-antiplatelet therapy is needed after stent implantation. Target Audience: This activity is designed for cardiologists and all other health care specialists caring for patients with acute and chronic coronary heart disease. CME Credit: The A. Webb Roberts Center for Continuing Medical Education of Baylor Health Care System, Dallas, Texas, designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. The A. Webb Roberts Center for Continuing Medical Education for Baylor Health Care System, Dallas, Texas, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME Instructions: After reading this article, go online at www.AJConline.org to register, complete a post-test with a minimum score of 80%, complete an evaluation, and print a certificate. Combination of Media: Print and Internet Computer Requirements: Windows 2000, Pentium 3 or greater, 512 ram, 80 gigabytes storage Estimated Time to Complete: 1 hour www.AJConline.org
Roundtable Discussion/BMS and DES: Indications and Complications
Release Date: July 2008 Termination Date: July 2009 Introduction The first reported series of intracoronary stent implantations for the prevention of recurrent occlusion after PTCA was in 1987.1 BMS and DES are now routinely implanted as part of PTCA, with 6 million patients worldwide receiving stents as of 2007, at an annual cost of $4 billion to $5 billion.2 Despite their ubiquitous use in treating patients with coronary artery disease, there are numerous questions about stent selection and safety, indications, long-term efficacy, and the treatment and prevention of complications, especially in-stent restenosis (ISR) after BMS placement and acute thrombosis after DES placement. Dr. Friedewald: Dr. Roberts, what have been your observations of coronary stents at autopsy? Dr. Roberts: I have little experience with stent thrombosis at autopsy because the number of autopsies has dropped dramatically, and in many patients who die after receiving stents, the thrombus has already lysed or has been removed at cardiac catheterization. Furthermore, the only way to examine a coronary artery with a stent in place is to cut it with a diamond knife. Dr. Renu Virmani is the only pathologist I know who is doing this. The heart can be x-rayed, however, to determine coronary stent location, followed by excision separation of the major coronary arteries and then re-x-raying them apart from the myocardium. This allows identification of the length of the stent within the artery but does not determine stent contents such as thrombi. Dr. Windecker: For nonhuman animal research, we also use a diamond knife and leave the stent within the artery to examine the entire coronary artery. I do not have experience with human specimens. Dr. Friedewald: What is the mechanism of ISR following coronary stent placement? Dr. Vetrovec: ISR is caused by injury to the coronary artery from dilatation and persistent stretching—with the well-apposed stent—leading to an inflammatory local response. ISR is the formation of a scar as a response to injury of the stented coronary artery. Dr. Friedewald: Are you saying that inflammation contributes to ISR? Dr. Vetrovec: Yes, inflammation is an important component. Dr. Roberts: In atherosclerosis in native coronary arteries, inflammatory cells are very uncommon. Atherosclerosis from a morphologic standpoint is not an inflammatory problem. With coronary stents, however, there is intentional injury to the artery, so ISR in that setting appears to be a very different process in which inflammation might play a role. Since I cannot cut the artery to examine ISR, however, I cannot comment on the role of inflammation based on personal observations. Dr. Vetrovec: I believe that ISR injures the coronary artery, causing an inflammatory response and scar formation like the body’s normal response to other types of injury.
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Dr. Kastrati: ISR is comprised of a series of events leading to neointimal formation, initially triggered by arterial injury that varies with stent structural design and chemical composition. These events include plasma cell deposition, leukocyte migration and activation, smooth muscle cell proliferation, and collagen matrix formation. The exact contribution of inflammation to this process is unknown, but the fact that local use of anti-inflammatory drugs—such as rapamycin used in DESs—suppresses ISR implies that inflammation plays a significant role. Dr. Roberts: Stents are placed in areas of coronary arteries containing large quantities of plaque. They “burrow” into these plaques, burying themselves in plaque. It is reasonable to assume that the DES, because it contains a polymer, also might produce an inflammatory reaction in the plaque. The BMS also produces an inflammatory reaction, I understand. Dr. Kastrati: Yes, and with gold-coated stents there is much more inflammatory reaction and neointimal formation. Such surface contact seems to be very important in addition to the physical injury caused by the stent struts. Dr. Vetrovec: I agree that ISR is a foreign-body reaction. There is evidence that thinner forms of BMSs cause less restenosis than stents with thicker struts, suggesting that the amount of foreign material impacts the amount of reaction. This is consistent with the concept of the stent’s acting as a foreign body to stimulate an inflammatory response. Dr. Windecker: One could also argue, however, that the thicker struts simply cause more physical arterial injury than thinner struts. With intentional arterial overstretch there is increased neointimal proliferation. In the era of balloon coronary angioplasty before the use of stents, no extraneous matter was left in the coronary artery following angioplasty, but ISR did occur, perhaps due to vessel wall elastic recoil. Thus, direct injury to the coronary artery is probably the principal cause of ISR following stent implantation. Dr. Roberts: With balloon angioplasty, there is no inflammatory reaction to the crack in the plaque created by the procedure. It fills up with a neointimal combination of smooth muscle and fibrous tissue. This is a very uniform type of material, distinctive from underlying plaque, but there are no inflammatory cells. Dr. Friedewald: Let’s discuss stent construction. Dr. Kastrati: The DES has 3 components: the stent platform, the polymer, and the drug coating. Most stent platforms are constructed of stainless steel or cobalt-chromium. The drug and the polymer differ among different types of DESs, and they account for differences in efficacy and safety among the various DESs. Dr. Vetrovec: Although difficult to access, the DES polymers and drugs have different effects and different clinical outcomes. An ongoing discussion among experts in this area concerns the amount of endothelialization, which is associated with ISR, that should be allowed by the stent design, and this has not been resolved. Dr. Kastrati: We once believed that BMSs and DESs had similar clinical efficacy. Now we know there are important differences between them. Dr. Friedewald: Are the stents used in the USA the same as those used in Western Europe?
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Dr. Vetrovec: Yes. Dr. Friedewald: What are the risk factors for ISR? Dr. Vetrovec: There are patient-related factors and there are anatomical factors. Aside from features of the stents themselves, anatomical factors such as longer lesions and small coronary arteries have greater risks of ISR than patients without these coronary findings. The more complex “Y” lesions (branched atheromatous lesions) also increase the risk of ISR. Significant patient factors for ISR are diabetes mellitus and acute and chronic renal failure. Dr. Friedewald: What do you mean by “longer lesions”? Dr. Vetrovec: By “longer lesions,” I am referring to the length of the stent, which is determined by the length of the atherosclerotic plaque causing the blockage. Dr. Friedewald: Is elevated C-reactive protein (CRP) a risk factor for ISR? Dr. Vetrovec: Following PTCA and stent placement, the CRP rises and then falls, peaking around 48 hours. This increase is probably a response to injury to the coronary artery, but I do not know if that represents an inflammatory reaction. Patients with large CRP increases after stenting are more likely to have a recurrent cardiovascular event of some type—not necessarily ISR— during the following year. Dr. Kastrati: We found that the baseline CRP was predictive of mortality but not ISR, and the delta change of CRP after stent intervention was predictive of ISR. Dr. Roberts: Does the procedure itself—such as trauma to the groin— elevate the CRP? Dr. Kastrati: Yes, it could, as well as other factors. For example, complex coronary artery lesions require longer procedures, which may further raise the CRP. Dr. Vetrovec: Elevated CRP predicts adverse cardiovascular events in general. Patients having longer procedures also receive more image contrast agents, which may be another risk factor. Dr. Friedewald: What is the clinical relevance of ISR? Is it always bad? Dr. Kastrati: There is debate about the clinical significance of ISR. There are, however, studies showing that ISR is not necessarily a benign event. A study reported in The American Journal of Cardiology in 2006 showed that ⬎50% of patients admitted for ISR present with acute coronary syndrome.3 Many patients with acute coronary syndrome have a worse outcome after reintervention. There appears to be higher 4-year mortality in patients presenting with angiographic evidence of ISR within 6 months following stent placement. Thus, ISR is a clinically relevant complication in that it may be associated with severe cardiac symptoms and increased risk of death. Dr. Friedewald: What type of acute coronary syndrome usually occurs with ISR or in-stent thrombosis? Dr. Kastrati: Most acute coronary syndromes due to ISR are non–ST-segment elevation myocardial infarction or unstable angina pectoris with ischemic electrocardiographic changes without ST-segment elevation.3 We do not know whether unexpected deaths after stenting are due to thrombosis or progressive ISR. I believe in-stent thrombosis is more common in sudden cardiac events,
however, because ISR has a more gradual, progressive course, allowing warning symptoms to occur before complete occlusion and its catastrophic consequences. Dr. Friedewald: When is the peak time following stent placement for the occurrence of acute coronary syndrome secondary to ISR? Dr. Kastrati: Most cases of acute coronary syndrome secondary to ISR present within 2 or 3 months after stent placement, indicating a very quick progression of neointimal formation. There are studies of BMSs showing that most cases of ISR have occurred by 6 months poststenting, although some occur much later. There are no comparable data for ISR with DESs. Dr. Roberts: Is ISR the superimposition of thrombus on isolated neointimal proliferation? Dr. Kastrati: We do not know. The specific contributions of thrombus and neointimal formation are difficult to distinguish. I believe both may contribute, especially in cases of acute coronary syndrome. Dr. Vetrovec: Heightened concerns about intrastent thrombosis with DESs may in part be due more to perception than reality. The ISR rate is moderately high for BMSs, and some of these cases are associated with acute coronary syndromes—mostly non-Q-wave myocardial infarction. With DESs, however, the ISR rate is so low that when intrastent thrombosis occurs, it stands out. Some patients definitely have late stent thrombosis with BMSs years after they are implanted and late thrombosis also occurs with DESs. Dr. Friedewald: Are there subsets of patients who do not benefit from DESs in terms of reduced ISR incidence, and are they identifiable? Dr. Kastrati: The risk of ISR is higher in certain patient groups, such as patients with diabetes mellitus, those with small coronary arteries, and patients with complex coronary artery lesions. The problem is that we cannot predict the risk of ISR for individual patients. I would not, however, selectively limit the use of DESs if there were no financial restrictions. The only reason that I do not use DESs in all patients is insufficient financial resources for their universal use. Dr. Vetrovec: A 4-mm-diameter coronary artery with obstructive atherosclerotic plaque ⬍10 mm in length in a patient without diabetes mellitus can be treated with a short stent, and the probability of subsequent ISR (for patients in that group) is about 3%. With a longer narrowing—for example, 25 mm—in a patient who has diabetes mellitus, the ISR rate is much higher. The BMS, compared to balloon angioplasty alone, sequentially lowered the risk of ISR, but the relative risk variability of ISR was unchanged and driven by coronary artery size, the length of the stent, and whether diabetes mellitus was present. The DESs reduced ISR by a relatively similar degree across the overall risk, with the same amount of reduction in patients with and without diabetes mellitus. Dr. Kastrati: A low rate of ISR for certain patient subsets makes it difficult for studies with relatively small numbers of patients to show significantly different ISR risk. Large numbers of patients with less complex lesions are needed to prove a significant reduction of ISR with DESs. Dr. Windecker: We must be careful in balancing the
Roundtable Discussion/BMS and DES: Indications and Complications
benefits and risks of DESs in individual patients. While DESs are very effective in procedures involving small coronary arteries, the incremental value in using DESs in large arteries requiring stent diameters ⬎3.5 cm is minimal. I would not agree with the position of using DESs in all patients receiving coronary stents if cost is not a consideration. Consider, for example, patients with ST elevation myocardial infarction (STEMI). The obstruction in STEMI typically is in a proximal, large coronary artery, in which the DES has less advantage over the BMS. In STEMI, there is less viability of the myocardium supplied by the obstructed coronary artery, so ISR has less adverse effect if it occurs. Thus, while I am in general agreement with using DESs in most types of patients, I would be cautious in advocating them for their use in STEMI or in other instances of large coronary artery obstruction. Dr. Vetrovec: In patients with acute myocardial infarction (AMI), patients in whom I suspect will not be compliant with medications after implanting the stent, and patients I do not know well enough to judge their likelihood for poststent drug adherence, I use BMSs. Coronary artery size may be difficult to evaluate in the acute setting because there may be arterial vasoconstriction with superimposed thrombus, making it hard to assess the actual size of the artery. Using inappropriate-sized stents is a risk factor for late stent thrombosis using DESs in patients with AMI. Dr. Roberts: Are there any clinical situations in which you perform PTCA alone without stent placement? Dr. Kastrati: No, not in my practice. Dr. Vetrovec: I use stents 95% of the time with PTCA, but I still perform PTCA alone in very select types of blockages, such as a moderate-sized coronary artery branch coming out of a stent. Performing PTCA for obstructive atherosclerotic disease involving very small coronary arteries, putting in a stent is no better and no worse than performing PTCA alone. Dr. Roberts: George, if you had to have percutaneous coronary intervention today, would you want a BMS or a DES? Dr. Vetrovec: I would prefer the DES provided it was unlikely I would need to stop antiplatelet agents within the following year. Dr. Friedewald: What is your belief about on-label versus off-label indications for coronary artery stents? Dr. Kastrati: On-label indications are based on studies performed for initial device approval. All initial studies have included only simple, short lesions involving coronary arteries from 2.5 to 3.5 cm in diameter, no chronically occluded arteries, and in patients without AMI or prior coronary artery bypass grafting (CABG). All other situations that were not included in these initial studies are considered as off-label uses of DESs. Thus, many of us pay little attention to what is off label and what is on label. Dr. Windecker: Few patients have only on-label coronary narrowing. Rather, most patients have mixtures of narrowing, so labeling has little applicability to actual practice. Dr. Vetrovec: I sat on the Food and Drug Administration (FDA) panel that reviewed labeling for the DES and found that this is a very bureaucratic issue unique to the USA.
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Dr. Friedewald: Device labeling, however, raises important legal issues for clinicians who must decide which stents to use. Dr. Vetrovec: The FDA says that it does not dictate the practice of medicine. However, it approves drugs or devices based on the studies, and the manufacturers promote the use of the devices for those populations in which they are likely to be effective. It remains up to the practicing physician to decide whether to use devices off label. To the credit of the FDA, which generally looks only at on-label issues, it did discuss the issue of off-label uses of coronary stents. DESs are used in 60% of cases in the USA, so many patients are receiving them off-label, because most patients’ clinical situations and coronary artery obstructive lesions do not fit the label criteria. Dr. Friedewald: What are the contraindications for using DESs? Dr. Vetrovec: Patients should not receive DESs when, for any reason, they cannot take dual-antiplatelet therapy for 1 year. Dr. Friedewald: Who are those patients? Dr. Vetrovec: A good example would be a patient with recurrent colon polyps who needs colonoscopy in 3 months for cancer surveillance, and it is believed that delaying this for 1 year would carry excess risk for cancer recurrence. Another example would be a patient contemplating hip surgery who has a positive exercise test for myocardial ischemia, and it is decided that PTCA and stent implantation are indicated prior to hip surgery. The patient may prefer a BMS to have the hip surgery as soon as possible or may elect to have a DES and wait a year before having hip surgery. Dr. Friedewald: Let’s discuss stent thrombosis, beginning with its definition. Dr. Vetrovec: The original definition of stent thrombosis has been changed, which changes the reported relative incidence of this complication. The initial definition of stent thrombosis stated that it was acute coronary syndrome of some type plus angiographic or pathologic confirmation of coronary artery thrombosis or occlusion occurring in a patient who had received a coronary stent. The stent manufacturers created the ARC (Academic Research Consortium) standard definitions,4 which added a “probable” category for stent thrombosis that included unexplained death within 30 days after stent implantation or a target coronary artery AMI without visible thrombus. This definition assumed that thrombi go away, so it would be appropriate to call that a “probable” stent thrombosis. A “possible” thrombosis category involved patients with unexplained death occurring within 30 days following stent implant. Most experts, however, believe that this “possible” category using a very broad death definition was too extreme and includes too many deaths unrelated to the stent. Dr. Kastrati: I am glad the original definition of “definite” stent thrombosis remains. Nothing is gained, however, by adding definitions of “probable” and “possible” thrombosis, and having 3 categories of definitions is confusing. Dr. Windecker: The principal reason for redefining stent thrombosis was that there were differing definitions in different trials. For example, some trials used sudden death
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during the first 30 days following stent implantation, some looked only at angiographically proven stent thrombosis, and others included AMI up to 30 days after implant. There has been much heterogeneity in the definition of stent thrombosis. One goal of the new definitions is to achieve standardization for defining “thrombosis” in future trials. The most useful of the 3 definitions is the “definite” stent thrombosis because it is a distinct clinical syndrome that is easy to recognize and can be clearly attributed to the stent. I do not know whether the “probable” and “possible” definitions are useful. Dr. Kastrati: I agree. Dr. Friedewald: Sudden, unexplained cardiac death within 30 days of implantation of a stent is probably due to stent thrombosis, according to the new definitions? Dr. Vetrovec: Yes. It should be pointed out that these new definitions change the data of prior trials. With the expanded definitions the incidence of stent thrombosis is decreased to about 1/2 the incidence stated in the original reports. Dr. Kastrati: ARC also eliminates the censoring of patients from stent thrombosis analysis after having coronary artery reintervention. Dr. Windecker: It is important to count both primary and secondary stent thrombosis, because studies otherwise violate the intention-to-treat principle that does not count stent thrombosis when there was a prior event. Dr. Friedewald: What factors contribute to early stent thrombosis? Dr. Windecker: Up to 30 days following stent implantation, mechanical factors are most important, with residual coronary artery dissections as the leading cause for thrombosis with both BMSs and DESs. Another important contribution in the early phase is inadequate antiplatelet therapy because many patients do not receive sufficient antiplatelet drugs or they are resistant to them. Diabetes mellitus is another important factor for early thrombosis of BMSs and DESs. Dr. Friedewald: What factors contribute to late stent thrombosis, defined as occurring ⬎1 month after implantation? Dr. Windecker: The cause of late stent thrombosis is a much more complex issue than early thrombosis. The only independent predictor for late stent thrombosis is acute coronary syndrome at the time of the initial stent placement. Dr. Friedewald: Is renal disease a risk factor for stent thrombosis? Dr. Kastrati: Yes, there is a correlation between renal failure and the risk of stent thrombosis, at least for the BMS. Dr. Vetrovec: The quality of stent deployment is also probably an important risk factor for DES thrombosis, because the presence of polymer on the stent seems to change the expansion relation of the stent to the balloon inflation pressure. It appears that the higher the inflation pressure, the lower the risk of late stent thrombosis, which suggests that when the stent is appropriately sized, it still needs to be well expanded for optimal placement in the coronary arterial wall. At least part of late stent thrombosis is due to inadequate initial stent expansion. Dr. Kastrati: There have been studies, however, showing that malapposition was not predictive of stent thrombo-
sis or any other outcome following placement of DESs. Other important factors may be residual dissection and uncovered coronary artery lesions. Central to all risk factors for thrombosis is the role of platelets, and for that reason, premature discontinuation of dual-antiplatelet therapy is highly predictive of stent thrombosis. Patients who are nonresponsive to clopidogrel are also at high risk. Dr. Friedewald: How is stent thrombosis diagnosed? Dr. Vetrovec: Stent thrombosis is often manifest as an AMI in the coronary arterial distribution of a prior stent placement. This occurrence strongly correlates with patient failure to take the antiplatelet drugs. Dr. Friedewald: How is stent thrombosis treated? Dr. Kastrati: The most frequent form of treatment for stent thrombosis is early percutaneous intervention of the occluded coronary arteries. Most interventional cardiologists use plain angiography, with or without thrombus aspiration devices, and try to avoid implanting a new stent into the affected coronary artery. Many cardiologists perform the procedure under the protection of glycoprotein IIb/IIIa inhibitors. After a successful procedure for correcting stent thrombosis, the most important issue then becomes subsequent antiplatelet treatment. If stent thrombosis occurred after the patient stopped taking clopidogrel, the decision to simply restart clopidogrel is the logical course, and administration of clopidogrel for a prolonged period of time—at least 1 year—is the recommended strategy. If stent thrombosis occurred despite the patient’s taking the recommended doses of clopidogrel, however, the correct course to recommend is much less certain. I suggest that the next step should be to reexamine the initial stent implant to see whether there were any suboptimal results to explain stent thrombosis, and fix those with a second procedure. When stent thrombosis is not explained by an abnormality at the time of the initial procedure, it becomes very puzzling. One possibility is that something is inherently abnormal with the way some such patients respond to clopidogrel, and some investigators are assessing platelet responsiveness to clopidogrel. Both the methodology and the clinical relevance of tests for abnormal clopidogrel response, however, are yet to be defined. Some simply advocate doubling the dose of clopidogrel. New drugs in development, such as prasugrel, may offer more effective alternatives to clopidogrel, but we are awaiting studies to see if they will be safe and effective. Finally, CABG may be considered depending on the coronary artery anatomy and the patient’s clinical condition. Dr. Windecker: I agree with that approach. Coronary angiography should definitely be performed to make the diagnosis. There should be a very low threshold for studying a patient who has an acute onset of chest pain and has had previous stent placement to confirm or exclude stent thrombosis. I also agree that the main strategy should be thrombus aspiration and balloon angioplasty, unless there is residual coronary arterial dissection, which should be treated with new stent placement. Another diagnostic consideration is intravascular ultrasound, which returns us to the issue of incomplete stent apposition with the coronary arterial wall. Incomplete stent apposition, however, is not completely predictive of adverse events and depends on the exact nature of the incomplete apposition. The definition of incomplete
Roundtable Discussion/BMS and DES: Indications and Complications
stent apposition is the failure of only 1 strut to be in contact with the coronary arterial wall. I believe that small areas of incomplete stent apposition probably do not play a role in causing adverse events, but large areas of incomplete stent apposition due to positive arterial remodeling or coronary arterial aneurysmal formation are causes of adverse events. When managing the patient who has a coronary stent and who is too far from cardiac catheterization facilities to be treated quickly, I recommend thrombolytic therapy. Dr. Vetrovec: A patient with a coronary stent and chest pain— especially with acute ST-segment elevation on the electrocardiogram—should have immediate coronary angiography. When stent thrombosis occurs, there is almost always some stent-edge coronary artery dissection that can be seen on the original coronary angiogram, especially in patients who have been taking clopidogrel. In such patients, I often implant an additional stent to cover that area of dissection. I also try to better deploy the stent by using higher pressure. Quite often, I implant secondary stents with the goal of achieving the best possible result by correcting any stent-edge abnormalities. I find that when I perform this procedure “blindly,” I sometimes balloon beyond the location of the previous stent, so 1 reason I often put in another stent is to correct for any damage I may have caused in this area of the artery. Dr. Friedewald: Let’s discuss antiplatelet therapy. Dr. Vetrovec: It is possible that the risk of stopping clopidogrel and aspirin may be greater than the relative benefit of taking them, because of a prothrombotic rebound effect when they are discontinued. Dr. Roberts: How long do you keep your patients on clopidogrel after receiving coronary stents? Dr. Vetrovec: I keep most patients on clopidogrel for 1 year, based on a BMS trial in which patients were first randomized to clopidogrel pretreatment before stent placement versus beginning clopidogrel at the time of or after the intervention.5 This study found an advantage for pretreatment with clopidogrel. One month after stenting, they rerandomized the patients to long-term clopidogrel versus aspirin alone (clopidogrel plus aspirin versus just aspirin). The patients at the end of 1 year who were continued on clopidogrel plus aspirin versus those on aspirin alone had a 23% relative reduction in coronary events and an absolute reduction of 4%, which is statistically significant. A comparable study has never been performed for DESs. Why not take clopidogrel forever? There are 2 reasons not to. First, 25% of patients with late sent thrombosis are already taking clopidogrel. Second, patients do worse late on long-term clopidogrel, mostly due to increased bleeding episodes. Thus, dual-antiplatelet therapy has not been shown to improve late outcomes. Dr. Roberts: What dose of aspirin do you prescribe for use in conjunction with clopidogrel? Dr. Vetrovec: I prescribe 81 mg once daily for longterm treatment. Dr. Kastrati: The optimal dose of aspirin is not known. Our practice is to prescribe 200 mg/day, but this is not based on any data, just tradition. We also prescribe clopidogrel for 1 year for all patients receiving DESs, although there is no evidence to support this duration of treatment. We need randomized trials that determine the
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optimal length of dual antiplatelet therapy, because prolonged therapy also prolongs the time for bleeding complications. We are also concerned with the potential for rebound thrombosis when stopping clopidogrel, which may be attenuated by tapering the drug to every other day for 2 weeks before stopping it completely. Dr. Vetrovec: I have not seen a case of stent thrombosis when both aspirin and clopidogrel had not been stopped at the same time. As long the clopidogrel is discontinued first and then the aspirin is discontinued a week later, it does not seem to be a problem. Stopping both drugs together, however, carries increased risk for stent thrombosis. Dr. Kastrati: I have seen patients stop only clopidogrel and then develop stent thrombosis. Dr. Vetrovec: Many cases of very late stent thrombosis seem to happen when stopping the agents is coupled with another unrelated surgical procedure. Maybe increased systemic inflammation caused by another procedure can trigger stent thrombosis. Dr. Windecker: I usually give 100 mg of aspirin daily and I recommend clopidogrel for 1 year. I believe that we overestimate the compliance of our patients with the recommended therapy. In the CREDO (Clopidogrel for the Reduction of Events During Observation) trial,5 in which patients were randomized to 1 month versus 12 months of clopidogrel, only 60% adhered to the long-term administration of clopidogrel. Patients are very compliant for the first 30 days, and up to 90% comply for 6 months, but after that, it declines to 70% at 9 months and even less at 12 months. Alerting patients to the danger of premature antiplatelet discontinuation is extremely important. Dr. Friedewald: How do you treat patients whom you believe will not be compliant in taking aspirin and clopidogrel? Dr. Vetrovec: I refer patients with multivessel coronary artery disease whom I do not believe will be compliant with medications to CABG. Deciding whether a specific patient will be compliant, however, is very difficult. Dr. Windecker: Medication compliance failure also contributes to saphenous vein graft closure following CABG. CABG is probably safer than stent implantation for noncompliant patients, but those patients are also at increased risk of AMI due to medication noncompliance. Dr. Vetrovec: The prevalence of not complying with long-term use of cardiac medications is poor. With so much communication technology in modern society, we could at least better notify patients about taking their medications and improve our awareness of whether patients are taking their drugs. This is an area that is understudied and underdeveloped. Dr. Friedewald: Do you prescribe statins for patients with coronary stents? Dr. Vetrovec: I believe in placing all patients having coronary interventions on statins at the time of the procedure. I believe statins lower the risks of the procedure. Whether statins impact the occurrence of late stent thrombosis is unknown. Dr. Friedewald: Could each of you summarize how you decide between using BMSs and DESs? Dr. Vetrovec: I prefer DESs for patients whose coronary artery size is appropriate and who can take clopidogrel and
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aspirin, especially clopidogrel, for 1 year. I also believe that in very high risk patients, such as those with poor left ventricular function, it is better to implant DESs because late myocardial ischemia. which may not be recognized as being caused by ISR, may cause an even greater number of adverse outcomes in such high-risk populations. For patients whom I know are not going to take antiplatelet drugs BMSs are favored. Dr. Windecker: I also advise a thorough risk-benefit analysis of each individual patient. The first issues I address are whether the patient is likely to adhere to long-term antiplatelet therapy and whether there are any unrelated surgical procedures contemplated. Next, I carefully look at coronary artery size, favoring DESs when treating reference arteries with a diameter ⬍3.5 mm. I also favor DESs in treating narrowings of more complex morphology, because the risk of ISR is much higher with BMSs than with DESs. The 1 situation in which I am cautious in preferring DESs over BMSs is in patients with STEMI. Dr. Kastrati: For patients who can take dual-antiplatelet therapy for 6 to 12 months, I do not see any indication for BMSs. There is no evidence that DESs increase the risk of stent thrombosis compared to the risk of thrombosis with BMSs. We are now treating much more complex narrowings, so a higher thrombosis rate is found when comparing outcomes of DESs today with studies performed several years ago with BMSs. Dr. Friedewald: Are there new stents on the horizon and new drugs to go with them, beyond clopidogrel and aspirin? What additional studies do we need? Dr. Kastrati: There is a lot of research in their early phases of testing with new types of DESs. I expect that the major changes in new stents will involve the polymer, with a trend toward biodegradable polymers rather than permanent polymers, because permanent polymers are not needed after the drug has been released. It is also possible that future stents themselves will be degradable, but this is further in the future because attempts to develop them have so far been unsuccessful. There has been an increase in the risk of ISR with such temporary types of stents. Future stent designs will also have improvements in the release kinetics of the drugs. With respect to the drugs, there are ongoing studies of other platelet adenosine diphosphate (ADP) receptor antagonists such as prasugrel. Another development may be the synthesis of short-acting ADP or reversible ADP receptor antagonists. This approach may offer a solution for patients going to surgery by substituting for clopidogrel a shortacting ADP receptor antagonist that is totally reversible within minutes. We also need more trials focused on additional, untested indications for DESs. For example, left main coronary artery stenting is an important application in which we may see some trial results in the next year. There are other trials comparing DESs with CABG in patients with diabetes mellitus. Dr. Windecker: There will be an interesting period ahead in the development of new DES platforms. The limus family of stents, in particular, will be enhanced by new additions, such as everolimus-, zotarolimus-, and biolimuseluting stents. We will eventually have a variety of stents to choose from in the limus family, probably with similar
efficacy profiles. Two other agents, pimecrolimus and tacrolimus, require additional study but may cause less smooth muscle cell proliferation because they appear to have more anti-inflammatory properties than current agents. There is a lot of effort in the development of bioabsorbable polymers, with the idea that these stents resemble more BMSs after the drug and the polymer have been released. The most promising technology is a truly and fully biodegradable DES platform, because stents or metal structures within the arterial wall are foreign bodies, and they do not allow the coronary arteries in which they are implanted to function normally. Dr. Vetrovec: I anticipate that better antiplatelet agents will make a big difference in preventing restenosis. I am hopeful that new stents and polymers will improve their deliverability and inflation characteristics. I also would like to see the development of stents that are easier to implant into the coronary artery. Because there may be differences in patients with AMI or even thrombotic lesions in terms of the late risks of coronary stents, there may even be drug combinations that work better in some patient subsets. We are trying to treat every patient the same, but neither the biology of all of these underlying pathological processes is the same, nor are their responses to coronary artery stent implantation the same. While randomized long-term trials are a wonderful goal, time waiting for their results is excessive. We need to organize a registry where we can go back and study those patients whom we have already treated with stents to determine what works and what does not work. Such a registry could provide a quicker fix than a 5-year randomized trial, which is the ideal, but we need to know what to do in the next 5 years while we are conducting these trials. Finally, we need to individualize patients according to disease severity. We are treating patients with small AMIs the same as patients with severe left ventricular dysfunction, but late restenosis may be far more important in sicker patients, who do not tolerate late myocardial ischemia as well. We need to start looking at some of these specialized populations in terms of what are the relative benefits of 1 type of stent versus another type. Dr. Roberts: I am glad that there are both BMSs and DESs available, because there are some patients who cannot or will not take antiplatelet drugs. At this moment, if I had to have a stent, I would prefer to receive a DES for many of the reasons you have mentioned. I am counting on not having to have a stent in my life, however, because I am trying very hard to keep my low-density lipoprotein cholesterol level ⬍70 mg/dl and try to not eat cows, pigs, sheep, goats, and chickens, so I hope that I will never have to see any of you from a therapeutic standpoint. There needs to be a stronger pulpit to get people interested in controlling their lipid levels and their blood pressure levels so we will not have so many “wrecks” for you cardiac interventionalists to fix. The automobile industry has decreased the number of accidents in the last 10 years, primarily by improvements in the vehicles they build. If we take the magical drugs that have been provided by the pharmaceutical industry— especially the statins and the antihypertensives—we
Roundtable Discussion/BMS and DES: Indications and Complications
could put many of you out of work. But since I am a bit cynical about how many people do and will adequately care for their health, I think you will be busy for decades. Dr. Friedewald: Thank you. 1. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987;316:701–706. 2. Kaul S, Shah PK, Diamond GA. As time goes by. J Am Coll Cardiol 2007;50:128 –137. 3. Assali AR, Moustapha A, Sdringola S, Denktas AE, Willerson JT, Holmes DR, Smalling RW. Acute coronary syndrome may occur with
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in-stent restenosis and is associated with adverse outcomes (the PRESTO trial). Am J Cardiol 2006;98:729 –733. 4. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es G-A, Steg PG, Morel M, Mauri L, Vranckx P, et al, on behalf of the Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –2351. 5. Steinhubl SR, Berger PB, Mann JT, for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA 2002;288: 2411–2420. 6. United States Food and Drug Administration. FDA statement on coronary drug-eluting stents (September 14, 2006). Available at: http://www.fda.gov/cdrh/news/091406.html. Accessed November 10, 2007.