Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Paul P. Dobesh, PharmD, FCCP, BCPS, and Daniel M. Kolansky, MD. This program is available as read only and with accompanying audio.
*Scroll to read lecture and/or follow along with audio.
Slide 1:
Slide 2: Dr. Dobesh: Welcome to Antiplatelet Therapy in Percutaneous Coronary Intervention: An Educational Initiative for Clinical and Managed Care Pharmacists. This activity is sponsored by Princeton CME and is supported through an educational grant from Daiichi Sankyo and Eli Lilly and Company.
Slide 3: I am Paul Dobesh, Associate Professor of Pharmacy Practice for the College of Pharmacy at the University of Nebraska Medical Center in Omaha, Nebraska. I will be one of your presenters, along with Dr. Daniel Kolansky. He’s the Director of the Cardiac Care Unit and Associate Professor of Medicine for the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania.
Please remember, to receive continuing education credit, following the conclusion of this activity each participant must complete the post-test and evaluation form. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Thank you again for joining us. And now, let’s start by going through our case.
Slide 4: Now, in this case, we have KM who is a 61-year-old male. He’s about 5’9”, 90 kg. He developed substernal chest pain about 5 out of 10 while taking his shower earlier in the morning at about 6:30. He decided it wasn’t too bad, so he would go ahead and eat some breakfast but this pain persisted. It now got much worse, where it’s now 8 out of 10, and it is now radiating to his left shoulder.
He decides to call his local physician when their office opened at 9 o’clock and they instructed him to call 911. He was told to take 2 to 4 baby aspirin, which he already has at home, and he also received 3 sublingual nitroglycerin in the ambulance with very mild relief. He arrived in the emergency department at about 10:00 in the morning.
Slide 5: If we look at his history, we can see he has a fairly typical medical history for a person presenting with chest pain, a number of risk factors, hypertension, diabetes, he has lipid issues. He is a long-time smoker, as you can see, occasionally drinks alcohol. His medications are fairly appropriate for his medical history, but still, obviously presenting with chest pain.
Slide 6: His vital signs, you can see, present hypertensive. He is tachycardic. His O2 saturation is 90% on room air. His laboratory chemistries are relatively normal, except for an elevated blood sugar which could be, of course, from the acute event. And he also has positive cardiac markers with a troponin level of 5.8. His electrocardiogram shows that he has sinus tachycardia and ST-segment depression in his anterior leads.
Slide 7: So there are several things we need to consider, as we listen to the presentation that is about to come: are we going to manage this patient’s antiplatelet therapies? And how will he be treated?
One of the things we may consider is, will he undergo an invasive or a conservative approach? In the United States, as we know, an invasive approach is much more common and becoming much more popular, but that would be a question to answer. Obviously, since this is a presentation on percutaneous intervention, our patient will undergo that invasive approach. The question we have to ask ourselves then, is well, how soon will it be before this is done, before he undergoes angiography and PCI? And what would be the appropriate antiplatelet agents based on that timing, because as we will see, the timing does matter about what drugs we are going to use and what doses we may use.
Another thing we have to consider in chronic management is, you know, will the patient get stented? And nowadays about 90% of these patients do get stented, but will it be a bare-metal stent or a drug-eluting stent? And that will impact, basically several things such as how long they get multiple antiplatelet therapy, which drugs they get, the doses and things like that. So, there are a number of things for us to consider as we listen to the upcoming presentation.
Slide 8: So, now what I would like to do is welcome Dr. Kolanksy for his presentation on antiplatelet therapy in percutaneous coronary intervention. Dr. Kolanksy.
Dr. Kolansky: Thank you, Dr. Dobesh. This is an important topic for both clinical and managed care pharmacists because of the increasing prevalence of acute coronary syndromes and the complexity of the therapeutic options for this illness.
Slide 9: Turning to the slides, what we are going to do during this presentation is to review the available guidelines related to acute coronary syndrome and spend a few minutes on the background of acute coronary syndrome and percutaneous coronary intervention or PCI.
PCI is often performed in acute coronary syndrome and therefore it will be appropriate to understand the rationale for performing this procedure and some background about coronary intervention and coronary stenting. We will talk about the current treatment strategies related to this and then spend a good portion of the program on the pharmacologic strategies for platelet inhibition which is critical to the treatment of acute coronary syndromes and critical for the optimal performance of percutaneous coronary intervention. We will then review some of the emerging data on some of the newer antiplatelet agents which are not yet in routine use.
Slide 10: There are generally accepted guidelines for the treatment of ACS and for the performance of percutaneous coronary intervention available from the major cardiovascular societies.
For example, the American College of Cardiology and the American Heart Association have guidelines for the management of patients with unstable angina, non-ST elevation MI most recently updated in 2007. In addition there are guidelines which were published in 2005 and then updated in 2007 related to the performance of percutaneous coronary intervention.
Both of these topics are intertwined and there are areas of overlap within the guidelines. These guidelines are extensive. I will mention selective guidelines throughout this presentation and they are available in more detail on the web sites of the societies as noted on the slide.
Slide 11: Beginning with acute coronary syndrome there are more than 1.5 million hospital discharges each year with the diagnosis of acute coronary syndrome the United States. Almost 900,000 are for myocardial infarction and almost 700,000 for unstable angina.
The estimated direct and indirect costs related to coronary heart disease in the United States are staggering and for 2007 are estimated at about $150 billion.
Slide 12: Turning to percutaneous coronary intervention it is the most common revascularization treatment for CAD. More than 1.2 million PCI procedures were performed in the United States in the year 2002 as compared to about 360,000 coronary bypass procedures in the same year.
This is a costly therapy with revascularization cost estimates as high as $20 billion yearly. Increasingly, PCI is being used in many different subsets of this illness. Interestingly, it may be cost saving as compared to CABG in selective subsets, in particular, in high-risk patients and of some elderly patients, and we will review that in a subsequent slide.
Slide 13: On the next slide it simply demonstrates the continued growth of coronary intervention as compared to coronary bypass surgery based on New York State data. You can see that from the year 1995 to the year 2004 PCI continued to grow at a steady rate, whereas coronary bypass surgical volume was stable or slightly reduced.
Slide 14: On the next slide is demonstrated an example of coronary intervention versus coronary bypass surgery in 1 subset. In this particular case being a subset of high-risk patients and looking at the mean economic cost over a 5-year follow-up time. In this example, it was shown that PCI was cost saving as compared to coronary bypass surgery. Clearly, there are many different subgroups and the relative costs may differ, but this is part of the reason that PCI has become increasingly popular.
Slide 15: On the next slide we will review some current PCI outcome data. This comes from a registry published by Dr. David Williams in Circulation in 2006. This registry looked at both bare-metal stents and drug-eluting stents, and we will cover some of the differences between these 2 stent types subsequently in this program. The main point of this slide is to look at the outcomes at 1 year in the stented groups. For example, the overall death rate in the drug-eluting stent group was only 3%, and death or myocardial infarction in this group was about 5.2% over 1 year. In addition it points out that stent thrombosis is relatively low at well under 1% in either group, and that target vessel revascularization (TVR) is also under 10% in both groups. The take-home message from this slide is that, increasingly, the outcomes for PCI are very acceptable with good, long-term data and with relatively low rates of revascularization.
It has therefore become a well-accepted therapy in the treatment of acute coronary syndromes and in coronary disease in general.
Slide 16: Let us turn on the next slide to a brief review of the full spectrum of acute coronary syndrome as part of the background needed to understand the pharmacologic approaches to this.
As outlined in this diagram, we generally divide acute coronary syndrome according to the EKG criteria of ST elevation or no ST elevation at the presentation. On the left, we have patients presenting without ST elevation on the EKG. Some of these present simply as unstable angina. Others present with positive cardiac biomarkers or positive enzymes and are classified as a non-ST elevation MI or a NSTEMI.
Some of the older literature also refers to this as a non-Q-wave acute myocardial infarction. On the right side of the diagram are those patients presenting with ST-segment elevation on their ECG. In general, these patients go on to have what has been referred to as a Q-wave acute myocardial infarction.
These are patients in whom prompt revascularization, either with thrombolytic therapy to restore flow, or with PCI or even CABG are indicated to reduce myocardial damage. On the next slide we will review the pathophysiology of acute coronary syndrome.
Slide 17: ACS typically results from the rupture of an atherosclerotic coronary plaque followed by a sequence of platelet adhesion, platelet activation, and thrombus formation with obstruction of the coronary vessel.
The thrombosis that ensues may be partial with reduced or intermittent blood flow, or complete as occurs with an ST-segment elevation myocardial infarction. The consequences of obstruction to coronary flow are decreased flow with resultant cardiac ischemia. The symptoms may include chest pain, shortness of breath, or cardiac arhythmias.
Slide 18: This is diagrammed on the next slide which again highlights the presence of an atherosclerotic plaque within the coronary vessel. This plaque is made up of a lipid-rich pool which also contains macrophages, and then the presence of either internal stress or external shear forces will lead to the development of a fissure within the plaque or a plaque rupture as shown in the middle portion of this diagram.
This plaque rupture then results in either acute closure with thrombus formation and complete obstruction of flow as seen in the top panel, or a mural thrombus with partial obstruction and intermittent blood flow down the vessel. Typically, the totally occlusive thrombus results in an ST-segment elevation myocardial infarction, whereas a partial thrombosis results in either unstable angina or non-ST elevation MI.
It should be noted that there is considerable overlap among these presentations but it is helpful to view them in this dichotomous way as a means of understanding and approaching therapy. Let us go on the next slide to the initial evaluation of patients who present with acute coronary syndrome.
Slide 19: The initial approach must include a full assessment of the clinical situation including the patient characteristics such as age, gender, medical history, presence of diabetes, or concomitant medication use, a physical examination with particular attention paid to the vital signs, and the presence or absence of congestive heart failure, and a laboratory evaluation which should include the ECG, cardiac biomarkers, and a basic metabolic panel.
Slide 20: On the next slide is some information related to the TIMI risk score. As part of the initial evaluation it can be useful to risk-stratify a patient as to their risk of continuing on to adverse cardiovascular events, and this TIMI risk score is one such model which may be a predictor of these adverse outcomes.
This risk score is comprised of the sum of 7 variables which would be present at admission, and 1 point is given for each of these 7 variables. They are listed on the slide and they include the following: age >65 years, the presence of at least 3 risk factors for coronary artery disease, the existence of prior coronary artery disease, ST-segment deviation on the electrocardiogram, at least 2 recurrent angina events in the 24 hours preceding presentation, the use of aspirin already within the past 7 days, and perhaps most importantly, elevated cardiac biomarkers. These variables are summed up and the higher the TIMI risk score, the greater the risk of adverse cardiac events.
Slide 21: Now, let us look on the next slide at what happens to adverse events with increasing TIMI risk score. As you can see on the left, TIMI risk score of only 0 or 1 results on the right side of the slide in about a 4.7% risk over 14 days of adverse cardiac events which include all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring revascularization. In contrast, as the TIMI score rises with a score of 5 there is about a 26% risk of adverse events and with a score of 6 or 7 there is a 40% risk. Therefore, the TIMI risk score can be a very useful model which will help us determine the risk of events and the urgency and type of treatment provided.
Slide 22: Now let us turn to the treatment approaches specific for acute coronary syndrome. After initial evaluation, initial medical therapy will be introduced typically in the emergency department or the coronary care unit.
Patients are stratified into an early invasive or an early initial conservative therapy. We will review that momentarily. Patients with higher-risk TIMI scores or high-risk features should undergo early invasive therapy as you will see.
Slide 23: The next slide describes one of a number of randomized trials of invasive versus conservative therapy. This is the TACTICS-TIMI 18 trial presented in the New England Journal of Medicine in 2001. In this trial, 2200 patients were evaluated who presented with unstable angina or non-ST elevation MI.
All patients were treated with standard therapies including aspirin, heparin and with a glycoprotein IIb/IIIa inhibitor, tirofiban. Randomization was performed to either early catheterization in this study performed within 4 to 48 hours or to conservative therapy, meaning initiation of medical therapy and only shifting to catheterization if recurrent ischemia occurred
Slide 24: The next slide shows the results of the TACTICS-TIMI 18 trial looking at the primary endpoint of death, nonfatal myocardial infarction, or rehospitalization for ACS at 6 months, and as you can see the invasive strategy led to a reduction in the occurrence of the primary endpoint as compared to the conservative strategy.
Slide 25: The next slide shows the results of a meta-analysis of 7 separate studies comparing early invasive therapy to conservative therapy with a mean follow-up of 2 years. These studies which included the FRISC-II trial, the RITA-3 trial, ISAR-COOL, and several others, all demonstrated a benefit to the early invasive therapy as compared to conservative therapy in the treatment of acute coronary syndrome.
Slide 26: The next slide describes the names of the 7 trials included in this meta-analysis looking at all-cause mortality for the early invasive versus the conservative approaches to therapy in ACS.
Slide 27: So, turning to the next slide we can summarize and say that the selection of the initial strategy in ACS should be an early invasive approach.
In other words, cardio catheterization in patients with recurrent angina or ischemia at rest or those with elevated biomarkers, new ST-segment depression or other high-risk features. In contrast, a conservative strategy is preferred in patients with a low-risk TIMI score.
Early percutaneous coronary intervention in such patients with appropriate lesions is supported in the latest PCI guidelines. This is reviewed in the article cited here as a reference.
Slide 28: Let’s turn now more specifically to the treatment of acute coronary syndromes.
Slide 29: The initial pharmacologic therapy for ACS should include medications from several different classes. Anti-ischemic therapy is always initiated and may include supplemental oxygen, the use of IV nitroglycerin, the use of oral beta-blockers and of ACE inhibitors. Anticoagulation therapy is also important. This may include either unfractionated heparin or low-molecular-weight heparin or the use of the direct thrombin inhibitor bivalirudin.
Antiplatelet therapy is also a cornerstone to the management. Antiplatelet agents include aspirin, it may include clopidogrel, and it may include the use of intravenous glycoprotein IIb/IIIa inhibitors, and we will spend some time reviewing each of these in detail. So, this initial treatment approach is outlined on a diagram on the following slide.
Slide 30: And just to review, on the left we have those patients presenting without ST elevation on their EKG and on the right those with ST elevation on their EKG. In both groups of patients, it is appropriate to use anti-platelet, anti-ischemic, and anti-coagulant therapy.
For those patients who have non-ST elevation MI with high-risk features, they will typically go on to early invasive assessment and then to percutaneous coronary intervention or perhaps coronary bypass surgery.
Importantly, this will then be followed with long-term medical management. In the patients on the right who present with ST elevation myocardial infarction after initial therapy is given in the emergency department they are treated most commonly in the United States with percutaneous coronary intervention.
Other options would include thrombolytic therapy or perhaps coronary bypass surgery. And again they go on to long-term medical management. The trend in the United States has clearly been for those patients who present with ST elevation MI to be treated with primary coronary intervention in the cardiac catheterization laboratory.
Slide 31: Let us focus on the antiplatelet therapies used in acute coronary syndrome and in particular in percutaneous coronary intervention in this syndrome. In addition to anti-ischemic therapy and antithrombotics, antiplatelet therapy is critical. Aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitors all play a role, and some newer agents are becoming available which may improve platelet inhibition.
Slide 32: This reviews the use of aspirin. Aspirin inhibits the cyclooxygenase pathway blocking the production of thromboxane A2 and diminishing platelet aggregation. Aspirin in the dose of 162 to 325 mg is given orally to all patients and it is continued at 325 mg daily after presenting with ACS.
At some point it may be able to be reduced to 81 mg. Clopidogrel is indicated in patients who are intolerant of aspirin.
Slide 33: Clopidogrel is an oral thienopyrodine which inhibits the ADP P2Y12 receptor resulting in decreased platelet aggregation. It is a more potent antiplatelet agent than aspirin and it is used along with aspirin in the treatment of ACS and following PCI.
Slide 34: The next slide demonstrates the use of clopidogrel in acute coronary syndrome and one of the key trials that was useful in understanding the role of clopidogrel. The CURE study in acute coronary syndrome confirmed the benefit of adding clopidogrel to aspirin therapy. This study involved patients who presented with unstable angina or non-ST elevation MI. A 300-mg oral loading dose was given followed by 75 mg daily and it was continued for 9 to12 months.
Slide 35: The next slide demonstrates the use of clopidogrel in acute coronary syndrome and highlights one of the major trials demonstrating the importance of clopidogrel. In this trial known as the CURE study patients were randomized to receive aspirin alone or clopidogrel in addition to aspirin when they presented with acute coronary syndrome. Those patients in the clopidogrel arm of the study receive a 300-mg oral loading dose followed by 75 mg daily and this dose was continued for 9 to 12 months. Patients in the aspirin arm of the study receive aspirin only, and a placebo. This study involved both medically treated and PCI-treated patients, and there is a benefit in both groups of patients who were in the clopidogrel arm.
There was a slight excess in major bleeding of about 3.7% versus 2.7% in the clopidogrel versus aspirin arm, but this was not life-threatening bleeding. It should be noted that the clopidogrel was stopped 5 to 7 days before coronary bypass surgery in this trial.
The results are demonstrated graphically on the following slide.
Slide 36: The placebo group represents patients who received aspirin and standard therapies but did not receive clopidogrel. The clopidogrel group received clopidogrel in addition to aspirin and standard therapies. This shows the primary end point consisting of MI, stroke, or cardiovascular death in this trial and demonstrates a substantial reduction in the clopidogrel-treated patients.
Notice that this reduction in adverse events started very early and was persistent for up to 12 months. The study was published in the New England Journal of Medicine in 2001.
Slide 37: This shows the plasma concentrations of the active metabolite of clopidogrel before and serially after the administration of either 300, 600, or 900 mg of clopidogrel. The graph shows that the 600-mg dose led to substantially higher concentration of the active metabolite by 60 minutes as compared to the 300-mg dose with only a small incremental advantage to the 900-mg dose. This has become common practice. Therefore, although the approved dose remains 300 mg for loading the 600-mg loading dose has become common practice in many cardio catheterization laboratories prior to percutaneous coronary intervention.
Slide 38: In addition there have been studies looking at the effects of a higher loading dose on the occurrence of periprocedural myocardial infarction during PCI. The ARMYDA-II study is one such study which looked at a 600-mg loading dose of clopidogrel as compared to a 300-mg loading dose prior to PCI, and this in fact demonstrated a reduced periprocedural infarct rate with the higher dose.
Slide 39: This is demonstrated graphically in the following slide which looks at the primary study endpoint from the ARMYDA-II study which was the 30 day occurrence of death, MI, or target vessel revascularization in patients receiving the 2 different dosages. You can see that the composite primary endpoint is reduced with a 600-mg dose.
Slide 40: On the next slide, we show some information related to the CREDO trial. The CREDO trial examined a 300-mg loading dose and 1-year extended treatment with clopidogrel. The results indicated that pretreatment of greater than 6 hours before percutaneous coronary intervention reduced adverse cardiac outcomes at 8 days.
A similar pattern was seen among all the sub-groups studied including those receiving glycoprotein IIb/IIIa inhibitors. Other studies have suggested that with a 600-mg loading dose, 2 hours of pretreatment may be sufficient. There are ongoing studies looking at these time points.
Slide 41: Let us review the use of glycoprotein IIb/IIIa inhibitors in PCI in patients presenting with acute coronary syndrome. Aspirin is only a partial inhibitor of platelet aggregation acting through the cyclooxygenase pathway. In contrast, glycoprotein IIb/IIIa antagonists block the final common pathway of platelet thrombus formation.
There are 3 agents currently available, abciximab, integrilin, and tirofiban. There have been a number of studies performed confirming the efficacy of these agents in PCI. Most of them performed confirming the efficacy of these agents in PCI; most of them performed in the pre-clopidogrel era.
Slide 42: The cumulative evidence indicates that the use of glycoprotein IIb/IIIa inhibitors results in the reduction in adverse cardiac events in patients with ACS, specifically those with higher-risk features and those with positive cardiac biomarkers.
Slide 43: What about the question of glycoprotein IIb/IIIa inhibitors in lower-risk PCI patients? This was studied in the ISAR-REACT trial. This trial took low- or intermediate-risk PCI patients. All patients received clopidogrel 600 mg at least 2 hours before their percutaneous coronary intervention and all received aspirin. They were randomized to receive abciximab or placebo. Abciximab had no additional benefits in such patients and there was a small increase in thrombocytopenia noted in the abciximab group.
Slide 44: The data for this are shown on the following slide where you can see the 30-day cumulative incidents of death, MI, or urgent target vessel revascularization in the 2 groups, and notice that there was no significant reduction when adding abciximab to this patient population.
The conclusion is that in the lower- or intermediate-risk PCI patients who are adequately treated with clopidogrel at least 2 hours prior to PCI and who also receive aspirin that there does not appear to be a benefit from adding abciximab. This should not be confused with data related to higher-risk patients or those presenting with acute coronary syndrome and positive cardio biomarkers in which IIb/IIIa inhibitors may still be of additional benefit.
Slide 45: Let us go on to the next slide which is a somewhat complicated table making an effort to summarize all these treatments, and this table is adapted from the New England Journal of Medicine from 2004.
The table divides the agents into aspirin and clopidogrel versus glycoprotein IIb/IIIa inhibitors, and looks at patients undergoing PCI, or patients with acute coronary syndrome. The dosages for each of the agents are given and some comments are made regarding the timing of loading doses. A notation is also present about the cost. More details about this can be found in the New England Journal of Medicine paper, but it is a reasonable summary of some of the current practices.
Slide 46: So, in summary the guidelines related to the use of antiplatelet agents for PCI and acute coronary syndrome are shown here. The guidelines are complex, and there are multiple variations based on the situation at hand.
In general, all patients should receive aspirin. Patients not having coronary bypass surgery should receive clopidogrel either before diagnostic angiography or before percutaneous coronary intervention.
Higher-risk patients should receive glycoprotein IIb/IIIa inhibitors upstream, meaning while still in the emergency department or in the CCU if they are unstable, or at the time of percutaneous coronary intervention.
Slide 47: Let us talk for a moment about antiplatelet agents as related to coronary stenting. As a review, coronary stents are placed during PCI procedures. They result in a decrease in the acute complications and a reduction in coronary restenosis.
Antiplatelet agents are required to reduce the occurrence of stent thrombosis in the post procedure time period. The duration of anti-platelet therapy differs according to the type of stent used.
Slide 48: As you are aware, we generally divide stents into 2 classes, bare-metal stents or drug-eluting stents. For bare-metal stents, the risk of subacute stent thrombosis occurs over approximately 30 days; therefore, aspirin and clopidogrel are indicated for 30 days.
For drug-eluting stents, there is a longer-term risk of sub-acute thrombosis which likely extends out to at least a year. Therefore, the current recommendations are that aspirin and clopidogrel be continued for a minimum of 1 year after drug-eluting stent placement. It is important to note that in both groups of patients aspirin is recommended indefinitely because of the presence of coronary artery disease.
Slide 49: Let us turn to a review of some newer antiplatelet agents which are going to be coming to clinical practice in the next few years. Why should newer antiplatelet agents be developed? Well, some patients have poor antiplatelet responses to clopidogrel, which has been labeled so-called clopidogrel resistance in the literature.
Increasing the dosage of clopidogrel may overcome this. In addition, a number of new potent antiplatelet agents are under development, including cangrelor, which is a short acting intravenous agent, and prasugrel, which is a more potent oral thienopyridine agent.
Slide 50: Cangrelor has been developed as an IV P2Y12 platelet antagonist. It has a rapid onset and offset with a half-life of about 2.6 minutes. It does not require metabolic conversion for its activity. One potential advantage for cangrelor will be intravenous use at the time of percutaneous coronary intervention without the need for pretreatment. Preliminary studies have shown that cangrelor can be safely used without excess bleeding as compared to clopidogrel.
Slide 51: One phase 2 clinical trial in which patients were treated with heparin and aspirin, and then were given cangrelor looked at a primary end point of major and minor bleeding and a secondary end point of the 30-day major adverse cardiovascular events.
In part 1 of this trial, cangrelor versus placebo was given for PCI at 3 different cangrelor doses. 200 patients were enrolled with an 18- to 24-hour intravenous infusion and no significant difference was seen in bleeding.
In part 2 of this trial, cangrelor was compared to the glycoprotein IIb/IIIa inhibitor abciximab. 199 patients were studied. There was no significant difference in bleeding and the 30-day major adverse cardiovascular event rate also showed no significant difference. Subsequent to this, a phase 3 clinical trial was developed and is now well under way in a number of hospitals.
Slide 52: Another new agent which is coming on the scene is prasugrel. This has been studied in the PRINCIPLE-TIMI 44 study. The rational for this is that higher doses of clopidogrel are being studied in ACS to achieve more complete inhibition of platelet aggregation known as IPA.
The PRINCIPLE-TIMI 44 study compared prasugrel with higher doses of clopidogrel with the end point being the assessment of IPA following the use of these medications.
Slide 53: The following slide describes the trial. Patients were undergoing catheterization with planned percutaneous coronary intervention. An oral loading dose of 60 mg prasugrel was given or an oral loading dose of 600 mg clopidogrel was given.
In the second phase of the study, a maintenance dose of 10 mg/day of prasugrel was given versus 150 mg/day of clopidogrel. The primary end point was the IPA measured at 6 hours, and then IPA measured after 14 days of maintenance with either drug.
Slide 54: The results are shown in the following slide, and in the left panel you see the measured IPA after the loading-dose phase of the drug demonstrating a substantial increase in inhibition of platelet activity using prasugrel as compared to clopidogrel.
On the right panel is shown the vasodilator-stimulated phosphoprotein platelet reactivity index a measure of the effectiveness of the agent in inhibiting platelets, and you can again see in the loading-dose phase that the platelet reactivity index was markedly reduced with the administration of prasugrel.
Slide 55: Well, these studies then led to the clinical trial known as TRITON-TIMI 38, comparing prasugrel to clopidogrel in moderate- to high-risk ACS patients. More than 13,000 patients with ACS who were scheduled for PCI were entered into the trial and were randomized to either a prasugrel arm or a clopidogrel arm.
The prasugrel arm used a 60-mg loading dose and a daily maintenance dose of 10 mg, and the clopidogrel arm used the standard 300-mg loading dose and daily maintenance of 75 mg.
Slide 56: Efficacy and safety outcomes were reviewed. These are shown on the following slide which looks at the cumulative Kaplan-Meier estimates of the rates of the study end points during the follow-up period.
The primary efficacy end point is shown in the top portion of this slide and shows a reduction in end point events using prasugrel as compared to clopidogrel. However, the key safety end point of bleeding shows that there was a slight increase in bleeding events with prasugrel as compared to clopidogrel.
Slide 57: The next slide looks at some of the details of the end points in the overall cohort at 15 months comparing prasugrel and clopidogrel. It is a busy slide, but I will simply point out in the first line, death from cardiovascular causes, non-fatal MI, or nonfatal stroke, which was the primary end point, was statistically significantly reduced using prasugrel as compared to clopidogrel.
In addition there was a reduction in stent thrombosis shown in the last line of the table in the prasugrel group as compared to the clopidogrel group.
Slide 58: However, in looking at the bleeding endpoints there was an excess amount of bleeding in the prasugrel-treated patients, as compared to the clopidogrel-treated patients as shown in the first line.
Slide 59: Therefore, we can make the following general conclusions related to the TRITON-TIMI 38 data, that prasugrel therapy was associated with a reduction in ischemic events including stent thrombosis. However, prasugrel therapy was associated with an increased risk of major bleeding including fatal bleeding. There was no difference between the groups in the overall mortality. Thus, it is a promising therapy but further evaluations and studies are needed and are ongoing.
Slide 60: Let us take a moment and mention secondary prevention of coronary events after presentation with acute coronary syndrome. Following initial medical or invasive treatment, patients with ACS require ongoing medical therapy at the time of hospital discharge. Aspirin should be continued indefinitely at 75 to160 mg daily.
Aspirin can be continued indefinitely and clopidogrel for 1 month and ideally up to 1 year for those medically treated patients and for those who have received bare-metal stents. Again, aspirin should be continued indefinitely and clopidogrel for 1 year for those who have received drug-eluting stents.
Slide 61: In addition to antiplatelet therapy, the following are also indicated in most patients who are recovering from acute coronary syndrome—the use of ACE inhibitors, the use of beta-blockers, and the use of statins for treatment of hyperlipidemia. In addition, attention to risk factor modification is indicated including the treatment of hypertension and diabetes as well as smoking cessation counseling.
Slide 62: In summary then, antiplatelet therapy is a key aspect to the treatment of acute coronary syndrome in general and in PCI specifically. Oral agents such as aspirin and clopidogrel are critical in the treatment algorithm and reduced cardiovascular adverse events.
Intravenous glycoprotein IIb/IIIa inhibitors are added in higher-risk patients with ACS and in higher-risk PCI patients. The assessment of patient risk is an important component of antiplatelet therapy selection. Continued therapy and risk reduction after the acute event are important and guidelines from the major societies are readily available for review for these details.
Slide 63: We will now turn back to Dr. Dobesh for discussion of the case presented at the beginning of this program. Dr. Dobesh.
Dr. Dobesh: Thank you, Dr. Kolanksy. Now, let’s go back to our case.
Slide 64: You will remember, we had a 61-year-old male who presented to the emergency department with about 3 and a half hours of substernal chest pain. He had a fairly extensive medical history with a number of risk factors. He presented hypertensive and tachycardic. His cardiac markers were positive and his EKG showed ST-segment depression in his anterior leads.
Slide 65: When we look at his treatment plan, we know that we’ll probably give this patient oxygen. He is going to obviously need antiplatelet therapy, but how extensive? He will get aspirin, yes. He will get clopidogrel, but how much, and when? Will this patient need a glycoprotein IIb/IIIa inhibitor? These are all things we have to consider. The patient will get anticoagulant therapy and that could be a variety of different options being unfractionated heparin, low-molecular-weight heparin, fondaparinux or bivalirudin.
And he would probably get IV nitroglycerin, IV beta-blocker metoprolol and IV morphine.
Slide 66: When we look at the antiplatelet therapy from an acute setting, we know that everyone gets aspirin, obviously, unless they have an allergy. That first dose being a larger dose, 162 to 325 mg if they have never had aspirin, even if they have been previously exposed to aspirin, even that day, we would still give them an additional bolus dose of aspirin but maybe not quite as much.
The patient is going to PCI, now, and we’re going to use the dual antiplatelet therapy by adding an ADP antagonist like clopidogrel. One of the things we have to ask ourselves is when, because that will affect, like we talked about earlier, dosing and timing and issues. If the PCI is going to be more than 6 hours away, we could probably get away with a clopidogrel loading dose of 300 mg. As mentioned in the literature, it usually takes, at least 6 hours to get adequate antiplatelet activity with the 300-mg loading dose of clopidogrel, while still some people may still choose to use a higher dose of 600 mg. If we do not have that 6 hours though, then we really are pushed into a situation where we have to use the larger dose of clopidogrel, such as 600 mg to get the adequate antiplatelet activity in that shorter period of time.
But, even using that higher dose of clopidogrel, we still have complications and things to consider, because even with that higher dose, it is still going to take at least 2 hours. And, what if you don’t have 2 hours? What if the patient is going to go immediate PCI? We would still probably give clopidogrel, but probably do not need as high of a dose, because we are going to really probably need a glycoprotein IIb/IIIa inhibitor if we have a very short time span to get an adequate amount of antiplatelet activity. And once again, should we use the IIb/IIIa inhibitor or not, and how does that impact the rest of our strategy? Obviously, we are still going to be giving aspirin, but if we are not going to be using a IIb/IIa inhibitor, probably we might consider the larger dose of clopidogrel, such as 600 mg. If a IIb/IIIa inhibitor is being used, there is not much advantage to adding a larger dose, and the 300-mg dose of clopidogrel would be sufficient.
Slide 67: Now, when the patient goes home, discharge therapy, obviously, once again, is going to be antiplatelet therapy: beta-blockers, statins, ACE inhibitors. Smoking cessation is very important for these patients.
Slide 68: But, when we think about the chronic use of antiplatelet therapy what will they get? Well, once again, this may depend upon whether or not they get a bare-metal stent or a drug-eluting stent.
If they get a bare-metal stent placed, their aspirin dose should be 162 to 325 mg daily, for about a month, and then a lower dose of that continued indefinitely. For clopidogrel, or ADP antagonist, for a bare-metal stent, it would be 75 mg/day for at least a month, and ideally, up to 12 months is basically the way that the guidelines suggest that the clopidogrel be used with bare-metal stent placement.
Now, with the drug-eluting stent, once again, we are going to start out with the higher doses of aspirin but for a longer period of time. If it is a sirolimus-eluting stent it would be 3 months of this higher dose of aspirin. And if it’s a paclitaxel-eluting stent, the guidelines state that it should be 6 months of this higher dose of aspirin, and then reduced to the lower dose indefinitely after that.
The use of ADP antagonist clopidogrel with drug-eluting stent placement is 75 mg daily, for at least 12 months, and some evidence showing that, possibly even longer duration of therapy of clopidogrel after that may be warranted.
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