TCT 2002 Proceedings: The Glycoprotein IIb/IIIa Inhibitors in PCI: A Record of Success

Current Status of Antithrombotics and Antiplatelets in PCI A. Michael Lincoff, MD Dr. Michael Lincoff stated that despite the advent of stents, which are clearly effective in reducing restenosis, we continue to have ischemic complications following coronary intervention that are thrombosis mediated. Existing PCI trials demonstrate decreased target vessel revascularization rates; however, the rates of death, MI and the combined triple endpoint have not declined. So, while we continue to gain ground on restenosis, thrombosis continues, and serves as the rationale for continued development and optimizing of antithrombotics and antiplatelets as adjunct for coronary intervention. The goal of reducing myocardial infarction (MI) is an important one, despite the controversy associated with whether or not these events in fact are clinically relevant. Cardiologists may never be in a position to decisively work out whether or not the occurrences of microinfarctions are a marker for a diffuse disease or a separate mechanism of long-term complications. The bottom line is that these are infarctions and have been demonstrated in a number of different methods, including the microinfarction studies using MRI. According to Dr. Lincoff, one class of agents that has made the biggest impact in the last decade from the antithrombotic standpoint is the glycoprotein (GP) IIb/IIIa receptor inhibitors. Placebo controlled trials have been performed in the setting of coronary intervention, and clearly show a reduction in clinical events with the GP IIb/IIIa receptor inhibitors, regardless of the means of interventional procedure. Dr. Lincoff stated the unified field theory is that GP IIb/IIIa receptor inhibitors reduce events in coronary intervention. He stated that all patients seem to benefit. Patients that do not benefit have yet to be identified. Cardiologists cannot predict by any criteria which group of patients will be low risk or low benefit, or at higher risk or higher benefit. The benefit is multi-factorial. There is evidence of an improvement in microvascular perfusion as measured by peak flow velocity in study patients who have been randomized to abciximab. One of the most interesting findings with GP IIb/IIIa blockade is the fact that there is a long-term improvement in mortality. This was not necessarily expected, particularly given the low rates of mortality seen in the population of patients. Multivariate analyses using a risk model which predicts mortality on the basis of criteria indicates the benefit from GP IIb/IIIa blockade to be an absolute 2.7 lives saved per 100 patients treated at 3 years. This reduction is based upon the data presented by Dr. Lincoff from the EPIC, EPILOG, and EPISTENT trials. Provided the wealth of data, it is easy to formulate this is valid for abciximab. However, what about the other GP IIb/IIIa agents? The ESPRIT trial demonstrated that eptifibatide also reduced clinical events at 30 days and 6 months. Nevertheless, when Dr. Lincoff presented data from the EPISTENT and ESPRIT trials side by side, there were differences in the magnitude of the benefit (51% vs. 35% relative risk reduction at 30 days for the triple endpoint of death, UR, and MI, or 5.5 vs. 3.7 events at 30 days). Similarly, when examining 1-year mortality, the difference was not significant in ESPRIT, but clearly significant with EPISTENT. There has been one comparative trial, the TARGET study, comparing tirofiban to abciximab with the intent of showing non-inferiority. To the contrary of demonstrating noninferiority, the results actually favored abciximab upon examination of the triple endpoint at 30 days, according to Dr. Lincoff. Finally, Dr. Lincoff stated that not only does the data from these comparisons favor abciximab, but from a point of view of cost-effectiveness, both abciximab and stenting fit very nicely with other measurements of cost-effectiveness in medical therapy and in society as a whole. Cost-effectiveness benchmarks indicate that stents cost $5,219/life-year and abciximab $6,213/life-year (as compared to automobile airbags at a cost of $1.7M/life-year and a heart transplant at $54,000/life-year). Appropriate Drug Therapy for Patients with Unstable Angina Shamir Mehta, MD Dr. Shamir Mehta presented a concise review of the therapies currently used in patients with unstable angina (UA)/NSTEMI. The most appropriate use of these therapies involves an assessment of their tangible benefits and risks, the practice pattern of the institution, and patient characteristics. Dr. Mehta focused primarily on antithrombotic therapies in UA/NSTEMI. He presented data from the CURE trial, which evaluated the use of clopidogrel in addition to aspirin in patients with UA/NSTEMI. The results demonstrated a highly significant 20% relative risk reduction with clopidogrel and aspirin over aspirin alone (p Drug-Eluting Stents and Higher Risk PCI Martin B. Leon, MD Dr. Martin Leon noted that 2002 marked the 25th anniversary of the first balloon angioplasty by Andreas Gruentzig. The dream of Dr. Gruentzig of a catheter-based percutaneous treatment in alert and awake patients has become the obsession of many. The goal of interventionalists has become to make this procedure safe, complication-free, predictable, widely applicable, and “definitive — no restenosis”. Dr. Leon elaborated that restenosis has always been “an emotional problem, because even though it may not be the cause of patients’ death or myocardial infarction, it represents a failure of the procedure.” Restenosis has been the focus of cardiologists for 20 of the last 25 years. Yet, “for the first time”, said Dr. Leon, we have a substantive advance on the impact on 1 parameter: restenosis. This has been an evolutionary process. Practitioners began with balloon angioplasty, and then went through an interim period of new device angioplasty with lasers, atherectomy devices, and other kinds of techniques to improve the revascularization of the coronary arteries. Interventionalists began to focus on stents, which did fulfill some of the requirements of an improved therapy. That launched an era of “stent frenzy,” between 1993 and 2002. Approximately 85% of patients in the U.S. last year received stents upon presentation in the cath labs. This year, the number will be 90%, and Dr. Leon predicted that it will be 95% next year. Interventionalists are beginning to understand how to improve device-based therapy with adjunctive pharmacology. Drug-eluting stents have entered the scene. In fact, "I’ve never been involved in any field that is growing so rapidly, almost frenetically," stated Dr. Leon. Dr. Leon presented data from double-blinded randomized clinical trials including RAVEL, and most recently, the SIRIUS trial (presented at this year’s TCT annual meeting). Dr. Leon cautioned the audience that this almost euphoric frenzy around drug-eluting stents should not be confused with a cure for restenosis. However, he stated that it is reasonable to expect a rapid transition of practice patterns over a relatively short period of time, based upon the data. Dr. Leon advised against trivializing the complexity of developing a drug-eluting stent because it represents advanced biotechnology. A drug-eluting stent requires a stent that has very special design characteristics that permits homogeneity of drug delivery and deliverability of the device. The pharmacologic agent must be given at the right time, at the right doses, with the right kinetics and dynamics, to elicit very specific biologic effects on the vessel wall. This is not easy, and it’s not going to be easy for people to simply duplicate some of the early very, very good results observed with RAVEL and SIRIUS. Dr. Leon presented the path for the development of the Bx VELOCITY stent, which was used in the SIRIUS trial. This drug-eluting stent has 2 acrylate copolymers that have been used in orthopedics for decades with Sirolimus, or rapamycin, blended in a fixed ratio. It possesses a matrix-release formulation in the form of a thin coating over the stent, which encapsulates it and is invisible to the eye. The slow-release of the pharmacologic agent is documented — about 50% of the drug is released in a week and 80–90% in a month. There are many different drugs used in drug-eluting stents: anti-proliferative agents, anti-inflammatory agents, metalloproteinase inhibitors, anti-sclerosing agents, pro-healing drugs, statins, mast cell inhibitors and molecular approaches using anti-sense gene cells. Sirolimus affects the cell cycle in the G1S phase before the cell commits to actually dividing. Other drugs, like paclitaxel, work further downstream at the microtubular phase, and actinomycin D and radiation have more global effects — perhaps being a bit too toxic. By December 2002, three years of experience in the first cohort of drug-eluting stent patients, said Dr. Leon. The portfolio of studies includes RAVEL, SIRIUS, several registries, a newer trial called FREEDOM, and SIROCCO. The FREEDOM Trial is an important study focusing on diabetics with multi-vessel disease. Dr. Leon reviewed the basis and design of this trial. There is good evidence-based medicine to suggest that patients benefit from the standpoint of death and MI from a surgical versus an interventional approach, so this involves just that cohort of patients: diabetics with multi-vessel disease. FREEDOM is a 2,300-patient randomized trial comparing modern surgery versus Sirolimus-eluting stents. The primary endpoint of FREEDOM is 5-year mortality. Importantly, abciximab therapy is mandated for patients who receive PCI. There will be 100 centers from North America involved in FREEDOM with initiation in the third quarter of 2003. Dr. Leon concluded by stating that the drug-eluting stent approach works and “will transform the landscape of interventional vascular medicine.” Furthermore, “it needs to be used wisely in conjunction with other therapies to get optimal effects…but it is having a disruptive influence on the way we think about how to manage patients.” Inflammation in PCI Pascal Goldschmidt, MD Interventionalists are well aware that atherosclerosis, the process that damages the coronary vessel, results from a series of injuries to the vessel wall that eventually results in symptomatic disease. One of the complex problems, according to Dr. Goldschmidt, is understanding why this inflammatory process takes place and what are the mechanisms that permit the extension of this etiology. Dr. Goldschmidt stated that there is actually a new dimension to understanding atherosclerosis, a dimension that cardiologists had not previously anticipated: the fact there is a third component to atherosclerosis. This third component is what is happening in the bone marrow of the patient. So, as the patient experiences insults linked to risk factors (i.e., elevated cholesterol, cigarette smoking), there is an accelerated death of vessel wall cells. As a consequence, the vessel wall loses its confluence. This produces a response of the vessel wall, including the production of molecules (cytokines, growth factors), which stimulate the bone marrow to produce vascular progenitive cells or stem cells, which may repair the vessel. Unfortunately, according to Dr. Goldschmidt, this process is not infinite. The time when atherosclerosis starts to develop is when the vascular progenitive cells, the bone marrow undergoes some degree of senescence, and consequently, the vessel wall is unable to repair itself. This process starts to develop very rapidly as evidenced from mouse models of atherosclerosis and ApoE studies. Dr. Goldschmidt presented data from mouse model studies, which demonstrated a marked reduction of atherosclerosis with stem cell therapy. Stem cells (from either the bone marrow or exogenously administered) go to where the vessel needs to be repaired. That is the reason why atherosclerosis is prevented in the mouse models. He stated that these studies are interesting because they constitute a model of atherosclerosis with vessel injury triggering the production of cytokines. This is the reason why cytokines and growth factors like C-reactive protein and IL-6 are so efficient at predicting the degree of illness in a patient. When an individual loses vascular progenitive cells, the cytokines continue to increase. These cytokines recruit cells to the vessel wall, such as macrophages, and as a consequence, increases the vessel injury. According to Dr. Goldschmidt, percutaneous coronary intervention (PCI) procedures actually induce damage to a vessel wall that may be already damaged. The additional insult to the vessel wall can be associated with increases in C-reactive protein and IL-6. Furthermore, the elevation of IL-6 is nearly eliminated by the administration of a GP IIb/IIIa receptor inhibitor — suggesting the repair process may be more efficient in such patients. Therefore, it is important to actually try to normalize the inflammatory markers in these patients; otherwise the risk of having an event substantially increases. Dr. Goldschmidt reviewed the classic process of acute events in the injured coronary vessel including the delivery of von Willebrand factor and collagen, which activates platelets and produces a conformational change that leads to the binding of additional platelets. Further accumulation of platelets and the activation of GP IIb/IIIa receptor agonists allow for the binding of fibrinogen-bridged platelets. Logically, GP IIb/IIIa receptor inhibitors can hinder this reaction. However, there are other cells that are attracted to the vessel wall, according to Dr. Goldschmidt. These cells can be good cells, including vascular progenitive cells and cells responsible for the repair process, or “bad” cells such as macrophages, which can potentially worsen the condition at the vessel wall. If a patient is in the “lucky category”, they will be able to produce a lot of repair cells, the vascular progenitive cells, and the vessel will repair and everything will go back to normal. However, if the patient is in the “unlucky category”, where they do not have enough repair cells, macrophages are recruited and induces further vessel destruction leading to a poorer outcome. Of particular interest, according to Dr. Goldschmidt, for abciximab there is an additional potential benefit. There is an opportunity for abciximab, as recently published in Circulation, to actually prevent the damaging effects of macrophages on the vessel wall. If the macrophage attacks smooth muscle cells, it induces a lot of smooth muscle cell death. Abciximab appears to be able to block this reaction because it cross-reacts with other receptors important in the smooth muscle cell killing by the macrophage. This may explain why, according to Dr. Goldschmidt, that in the TARGET trial data that abciximab turned out to be the major, most efficient drug. Diabetes — Current Perspectives Eric Van Belle, MD, PhD, FESC, FACC It is well known that the population of diabetics is large, consisting of approximately 16 million in the United States, with 15–25% undergoing myocardial revascularization (PTCA or CABG). Dr. Eric Van Belle presented insight on why this group of patients has typically displayed very poor outcomes and how outcomes with current techniques and medications may be improved. Dr. Van Belle reviewed data from the BARI trial, which was the first demonstration there was some interaction between diabetes and poor outcomes following revascularization procedures. He presented data that the risk of death at 5 years in the diabetic population was higher than that in the non-diabetic population. This data also showed that in diabetics referred to angioplasty there was a much higher mortality rate than those referred to bypass surgery. Finally, the increase in mortality rate observed in diabetics treated by PTCA was almost exclusively related to an increase in cardiovascular death. So what is the potential explanation for this poor outcome? asked Dr. Van Belle. A comparison of baseline characteristics (previous MI, 3-vessel disease, LV ejection fraction) demonstrated that baseline characteristics are not the explanation. Neither was the occurrence of peri-procedural complications or in-hospital complications according to the data. Follow-up data from the BARI trial also indicated that the difference accounting for the poor outcomes in diabetics was not due to an increase in coronary artery disease. Dr. Van Belle explored the biological viewpoint, that the diabetic patients may be considered at a prothrombotic milieu with increased vessel abnormalities, endothelial dysfunction, increased PAI-1, increased thrombotic risk, increased procoagulant factors, and decreased fibrinolysis. He set the stage that these abnormalities may translate into clinical issues. Dr. Van Belle presented data from a series of patients treated by coronary balloon angioplasty in the early 1990s for restenosis in diabetics to non-diabetic patients to illustrate several points. In addition to finding a higher risk of restenosis, there was a specific feature called occlusive restenosis. Patients with coronary occlusions at 6 months had a lower survival. With multivariate analyses in these populations, it was determined that in addition to expected risk factors (age, changes in LVEF, multi-vessel disease, baseline LVEF, hypertension, diabetes-related complications), occlusive restenosis and occlusion at untreated sites were associated with higher mortality rates. Several improvements have been made in the areas of revascularization, said Dr. Van Belle. The use of stents can lead to some reduction in restenosis, and maybe more importantly some reduction in occlusive restenosis (from 13% to 4% for each treated lesion), and this may be associated with improvements in clinical outcomes (40% reduction in the rates of cardiovascular death and MI by 4 years). According to Dr. Van Belle, this led to new trials comparing the use of stents to bypass surgery. The ARTS trial presented the outcome of approximately 200 diabetic patients. This study showed that the mortality rate at 3 years was 4.2% in the bypass group, compared to 7.1% in the stent group, and a slightly higher risk of stroke in patients treated by bypass surgery. The impact of coated stents on death and MI is being explored at the present time commented Dr. Van Belle. Data presented from RAVEL trial follow-up data at 1 year did not show that the rate of death and MI was significantly modified by the use of Sirolimus-coated stents. The use of glycoprotein IIb/IIIa receptor inhibitors in diabetic patients has significant application. Data presented by Dr. Van Belle for the meta-analysis of the EPIC, EPILOG and EPISTENT trials compared the outcome of diabetic and non-diabetic patients. The reduction in 1-year mortality observed in the overall population (3.1% to 2.0%, N = 6,534) was in large part due to the improvement of mortality observed with the use of abciximab in the population of diabetic patients (4.5% to 2.5%, N = 1,462). The EPISTENT trial shows that the use of stents plus abciximab produced a 65% reduction in the rate of death and large MI at 1 year compared to stent alone. Perhaps, more importantly, the rate of events in this group of diabetic patients is almost similar to the rate of events at 1 year in the group of non-diabetic patients treated with the same technique, posed Dr. Van Belle. He concluded by stating that the use of stents and glycoprotein IIb/IIIa receptor inhibitors may prevent thrombosis. However, it is too early to know exactly what will be the effect of coated stents; even though these stents may reduce the risk of restenosis, it is unclear what their impact will be on thrombosis.