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From MedscapeCME Cardiology

Differentiating Antiplatelet Therapy in ACS CME

Deepak L. Bhatt, MD; Christopher P. Cannon, MD; Paul A. Gurbel, MD; Robert F. Storey, MD CME Released: 03/31/2010; Valid for credit through 03/31/2011

Slide 1.

Deepak Bhatt, MD: Hello. I'm Deepak Bhatt from Boston. Welcome to our Spotlight entitled, "Differentiating Antiplatelet Therapy in Acute Coronary Syndromes." Joining me today at the American College of Cardiology's annual meeting in Atlanta, Georgia, are Paul Gurbel, Director of the Sinai Center for Thrombosis Research at the Sinai Hospital of Baltimore and Associate Professor of Medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome, Paul. Paul Gurbel, MD: Thanks, Deepak. Dr. Bhatt: Rob Storey, Reader and Honorary Consultant in Cardiology at the Department of Cardiovascular Science at the University of Sheffield in Sheffield, United Kingdom; and Chris Cannon, Associate Professor of Medicine at Harvard Medical School and Senior Investigator in the TIMI study group. Welcome. Christopher P. Cannon, MD: Thanks very much.

Slide 2.

Dr. Bhatt: We've got an exciting series of topics that we had planned to discuss, but let me go off the board instead and start off with a topic that's relatively new. Just a couple of days ago, the US Food and Drug Administration (FDA) came out with some revised labeling for clopidogrel. Chris, I saw you had some comments on that in the Wall Street Journal. What do you think of that label change? What's a doctor supposed to do with that information? Dr. Cannon: Well, interestingly this is a pharmacogenetic warning of where the FDA made a reference to "poor metabolizers," which would be the homozygote *2 of the 2C19 allele, in that they're at increased risk in patients getting clopidogrel. They go on to say that one should consider higher doses or alternate treatments for these patients. The warning is reasonable. We've heard this. We've seen more data with the heterozygotes, which are a larger percentage. The homozygotes are in the range of 2%-4% of people. They are higher in Asians upwards of 14%, but the heterozygotes can be more like 30% in Caucasians and higher in other groups. It's worthy to make note of this. The problem is that the implications are pretty broad, so we need to do testing. How do we do this? We've had emails flying at our hospital asking if we offer this and, of course, then what? What alternate therapies do we do now? So a lot of questions have been raised that are unanswered, and there are not much data to help guide. Dr. Bhatt: Paul, what do you think? What are you going to do differently in your practice, if anything, based on this black box warning?

Slide 3.

Dr. Gurbel: Well, the point that's confusing is does it mandate that we genotype? How do we interpret the message from the FDA? Is it incumbent upon us to determine the genetic profile with respect to the *2 status in all patients in whom we consider clopidogrel? For the homozygotes to determine homozygosity presence, that's a reasonable recommendation. I don't think that I'll be genotyping all of my patients, but we need more prospective work in this area to see whether we can overcome the high platelet reactivity in the *2 with a different drug or with more clopidogrel because that's still an area of controversy. What do you do with the *2 homozygous patient with the current therapeutic agents that we have right now? We need more study there. Dr. Bhatt: That's what I think too. It's definitely interesting, but I would say there is a need for more research. It's hard to know exactly what to do with all this information, especially because the response currently to any sort of genotype information would be off-label use of therapies in many cases. Dr. Gurbel: Right. Dr. Bhatt: So I'm not really sure what the message is. How about on the other side of the Atlantic, Rob? Robert F. Storey, MD: The clinical situation is the key, isn't it, and what the alternative drugs are, and that really depends on the practice. So if you're already using an alternative agent type, at the moment prasugrel for percutaneous coronary intervention (PCI) in the acute coronary syndrome (ACS) setting, then the issue of genotype for clopidogrel is obviously irrelevant. If you're using clopidogrel in the ACS PCI setting, then it would seem appropriate. If you need a reason to switch to prasugrel in the event of PCI or in the future perhaps as alternatives, then I think

genotyping does become important because it doesn't seem appropriate to continue clopidogrel without assessing its response and doing genotyping in a complementary way if there's an alternative licensed drug, which we know works more reliably. Dr. Bhatt: Chris, what other developments have there been recently in antiplatelet therapy? Let's start off with high dosing of clopidogrel. What are your thoughts about that?

Slide 4.

Dr. Cannon: Well, that's certainly the next step we immediately think of. At the European Society of Cardiology, we saw data presented from the CURRENT-OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes) trial of 1 week of 150 mg. Longer durations really haven't been done for very long, maybe for 2-week or 30day platelet-based studies.

Slide 5.

There is an ongoing study called GRAVITAS (Gauging Responsiveness with A VerifyNow Assayimpact on Thrombosis And Safety) that is looking at platelet testing for nonresponders not genetically defined, but by the VerifyNow assay, and randomizing them to 6 months of 75 mg of clopidogrel or 150 mg. That's an ongoing study, so it doesn't help us today in terms of can we extend high-dose treatment. There are alternatives like that of platelet testing using prasugrel and some recent data just published that Paul did with ticagrelor -- an agent that's not available. However, it did look like a good alternative approach in the low-responder group. Dr. Bhatt: As far as other new developments in antiplatelet therapy, Paul, what do you think about cilostazol? There have been a lot of data that have come out about that. When I had initially heard about cilostazol as an antiplatelet, I was a little bit skeptical, but there have been a number of studies in different therapeutic areas supporting some sort of antiplatelet effect.

Slide 6.

Slide 7.

Dr. Gurbel: Just recently, there are data on the superior effect compared with aspirin for secondary prevention of stroke. Also, when added to dual antiplatelet therapy, there was an effect on myocardial infarction (MI) reduction as shown in large numbers of patients studied from Korea. There were also

effects on target lesion revascularization and restenosis, perhaps because of its effects beyond the platelet on other cells and its effect on smooth muscle cell proliferation. It's an interesting drug that has effects on phosphodiesterase inhibition associated with a rise in intraplatelet cyclic adenosine monophosphate (AMP). Also interesting is its effect on adenosine reuptake. So in the local microenvironment where there is adenosine, this drug can potentiate the cardioprotective effects of adenosine to its adenosine reuptake blockade effects, which is similar to the effect of dipyridamole and also ticagrelor. So it has interesting effects beyond the platelet. Dr. Bhatt: It seems like there's really something going on there though. It does have a bit of an issue with side effects. Not a trivial number of patients do have side effects, such as headache from cilostazol. Rob, what about prasugrel? You mentioned that before. What's new with prasugrel?

Slide 8.

Dr. Storey: Well, there are a bit more pharmacodynamic data now suggesting how one may need to swap patients who are on clopidogrel, perhaps they're poor responders, and they swap them onto prasugrel. You need to give a loading dose of prasugrel to achieve a rapid effect that will protect from stent thrombosis in the first few days after switching. Dr. Bhatt: So you're saying if you're on clopidogrel 75 mg today, and you want to switch to prasugrel tomorrow, that it would be 60 mg of prasugrel tomorrow and then what? Dr. Storey: That's a bit of an unknown at the moment because you need to check what the response is to clopidogrel in terms of deciding how much prasugrel you will need to put them on to get an effect. Sure, if someone is a poor responder to clopidogrel, then probably 60 mg of prasugrel would be appropriate. But we don't really know at this stage what the safety implications are from that. Further work is needed to test that.

Dr. Bhatt: It's tough from a clinician's perspective though, because with 3 experts if it's all "probably," "maybe," or "we can consider it," then when you have a real patient in front of you, what's a clinician supposed to do 60 mg, 30 mg, don't switch; this is really challenging for clinicians. New data have come out on ticagrelor as well, Chris, including at this meeting. Do you want to summarize some of the highlights of these data?

Slide 9.

Dr. Cannon: Sure. Some platelet responses that Paul did on the clinical side included one of the latebreaking trials, which was a subset analysis looking at those patients who needed coronary artery bypass graft surgery (CABG). It's a preliminary analysis and looked at those who required or came off of drug within 7 days, then had their CABG; it is sort of that key group that we worry about in-house. If you've gotten clopidogrel, do you wait or do you hold off etc? A striking finding there was the finding of lower mortality in patients who had been treated with ticagrelor as compared with clopidogrel.

Slide 10.

Consistent with the trial as a whole, there was a reduction in the overall MI and cardiovascular death, MI, stroke, and no difference in bleeding. So these preliminary findings stack up nicely with a standout finding of reduction in mortality. Dr. Bhatt: Did the reduction in mortality in the CABG patients explain away the reduction in the overall trial? Or was it across the board? Dr. Cannon: The number of deaths overall is about one quarter. The deaths prevented were in those who had had CABG on a rough calculation. So it's a substantial explanation that we're still working. Part of that is to understand exactly how this is and applying different bleeding definitions looking at different cohorts. The adenosine story looks like it's emerging from various things. That's been observed to have adenosine reuptake blocked by ticagrelor, and that's a possible explanation of something. However, it's really conjecture at this point. Dr. Bhatt: Paul, what are your thoughts about some of the other ticagrelor data that's come out, ONSET/OFFSET, RESPOND?

Slide 11.

Dr. Gurbel: Well, from the ONSET/OFFSET study, we learned that the drug has a very rapid onset. The near maximal antiplatelet effect observed was in 1 hour. Then it's sustained during the maintenance period. With offset, it has a steeper slope of offset than clopidogrel such that at 72 hours, it's significantly lower and associated with lower platelet inhibition than in a patient who's stopped clopidogrel for 72 hours. This may explain some of what we observed in the CABG patients with respect to bleeding and the timing of stopping the therapy. Ticagrelor was stopped at 48-72 hours as compared with clopidogrel which was 5-7 days, if I'm not mistaken. So we observed numerically less bleeding in those CABG patients. The pharmacodynamic data from ONSET/OFFSET sort of go hand in hand. They showed higher platelet inhibition, and they showed more rapid offset, and that goes along with the results of the clinical trial.

Slide 12.

Slide 13.

Dr Gurbel: In the RESPOND study, we looked at patients who were nonresponsive to clopidogrel. We treated those patients with clopidogrel and ticagrelor and then switched therapy, and showed that you could convert clopidogrel nonresponders to responders. All patients responded to ticagrelor.

Slide 13.

The final important point of the RESPOND study, when you look at the frequency of high platelet reactivity, the cutpoint of high platelet reactivity has been associated with ischemic events post-PCI, the VAST method, VerifyNow method, and the light transmit and segregation cutpoints. All of those patients, when they're on ticagrelor in the maintenance phase, they're all below that high platelet reactivity cutpoint. Dr. Bhatt: Do you think if clopidogrel were achieving that same level of platelet inhibition, the benefit seen in PLATO (PLATelet inhibition and patient Outcomes) would still have been better? Dr. Gurbel: That's a fabulous question, and that leads to the off-target question. It may not be that if you have the same level of platelet function on ticagrelor or on clopidogrel that it means that you'll have the same outcomes. I think the adenosine story is very intriguing. The effect of the drug on adenosine reuptake may be an important explanation for the mortality benefit. Dr. Bhatt: So you think it's more than just platelets? Dr. Gurbel: I would bet that it is, yes. Dr. Bhatt: Chris, you were about to say something. Dr. Cannon: I was going to ask you, one thing that has come up often on ticagrelor is it's a BID drug. Everyone is worrying about compliance in general, that we're not so good on and patients struggle with. What would you say from the various studies in terms of if you miss 1 dose or you miss 2 doses, is that dangerous with ticagrelor?

Dr. Bhatt: That's a really good question. I'm going to say from the antihypertensive literature, it's pretty clear that when you go from QD to BID there's a pretty sharp drop-off in compliance. Dr. Storey: Well, I've been thinking about this in terms of relation to the ONSET/OFFSET data, ticagrelor doesn't wear off that quickly. At 48 hours, they've still got a reasonable amount of inhibition.

Slide 14.

Dr. Storey: One of the important issues is if you miss a few days of ticagrelor or you miss a few days of clopidogrel, you won't be at that different a level of inhibition. When you take 1 maintenance dose of ticagrelor 90 mg, we showed in DISPERSE-2 that within 2 hours, you're near steady state level of inhibition with ticagrelor; whereas, if you took a maintenance level dose of clopidogrel, it would take you several days to get back to steady state. So that is a clear advantage. Dr. Bhatt: That's a good point. I never thought of it that way. Dr. Cannon: It's a great point. Dr. Bhatt: What if you are just a patient that's supposed to be taking BID ticagrelor but, in fact, they're taking it QD? Do you not drop down, though towards the end of the day, below 75 of clopidogrel? Dr. Storey: So certainly by 24 hours you have dipped a bit, but your level of inhibition is similar to the main level of inhibition with clopidogrel. Dr. Bhatt: So it's not worse than that. Dr. Storey: There's a fairly good level of protection, in fact.

Dr. Bhatt: So in terms of platelets, you wouldn't actually be worse off than if you were taking QD ticagrelor vs just 75 mg a day of clopidogrel. Is that true? Dr. Storey: It was not really done; we've got a lot of data looking at just 1 daily dosing of 90 mg of ticagrelor over time and there we know -- if you missed 1 dose by 24 hours-- the level of inhibition. But it's unclear what level of variability it would be if you consistently took it QD. Dr. Bhatt: I guess it makes compliance even more important for patients on ticagrelor with its BID nature. Rob, you've done a lot of work on cangrelor. I think you've been with it right from the start. What do you think of the state of cangrelor right now after the 2 phase III trials? Dr. Storey: Well, cangrelor is still a very promising drug. However, there are issues related to its use. One of the key issues perhaps is the interaction with clopidogrel. When cangrelor is bound to a P2Y12 receptor, the clopidogrel active metabolite can't get on. What that means is you have to give clopidogrel after the cangrelor. The infusion is switched off, and you get a window where the antiplatelet effect has worn off. That potentially could offset the benefit that you achieved during an infusion, as clearly the patient population trial design impacts on what level of efficacy you would see with a short infusion.

Slide 15.

Dr. Storey: The mortality reduction that was seen in CHAMPION-PLATFORM (Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition) is probably a real phenomenon and tells us the importance of P2Y12 inhibition at the time of PCI, particularly in high-risk patients. It's still got a lot of promise.

Slide 16.

Dr. Storey: The BRIDGE study -- looking at the bridging between stopping an oral antiplatelet and continuing antiplatelet effect up until the time of surgery -- is a promising niche that could be useful. Dr. Bhatt: Chris, there's lots of interesting stuff going on with clopidogrel in regards to higher dosing and maybe a genetic platelet function testing in the future. The prasugrel and ticagrelor stories continue to evolve. Beyond that, what's next in the world of antiplatelet therapy?

Slide 17.

Dr. Cannon: Another class of drugs is being studied with the thrombin receptor antagonist (TRA). There is a pair of studies: David Morrow is leading the TRA2p for secondary prevention, the biggest of the TIMIs (Thrombolysis in Myocardial Infarction), so that's 26,000 plus patients in the post MI population, but also peripheral artery disease and post-stroke, so it's a broad group.

Slide 18.

That's ongoing. There is a parallel ACS study called TRA-CER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) that Duke Clinical Research Institute is leading. So that's a novel class of drugs that's added on top of all of the different P2Y12 and aspirin therapies that exist. That's coming soon. We do have to just simply wait and see what these large trials show. Dr. Bhatt: What else is coming out, Rob, that you think is interesting in the next couple of years beyond what we discussed?

Slide 19.

Dr. Storey: Just extending what Chris has said about the TRA, that is an interesting class in terms of the limited effects on hemostasis that is seen in the preclinical studies and the clinical data to date, which is different to targeting P2Y12 where you see a clear effect on hemostasis, again which is well borne out by the clinical and preclinical studies. What we're looking for beyond effective P2Y12 inhibition is how we might achieve that similar level of inhibition of thrombosis without affecting hemostasis so much. There are some promising targets within platelets and the coagulation system, but we need a lot of studies to see which might actually be the promising ones. Dr. Bhatt: Right. Paul, what do you think is next on the horizon? Dr. Gurbel: Well, I would go along and finish what Rob was saying in respect to understanding the importance of thrombin, thrombin platelet interaction, and the role that unchecked thrombin has in treatment failure. It may be that with the TRA on board, you don't need as potent P2Y12 blockade. Maybe you can even have less P2Y12 inhibition, but equivalent antithrombotic effect when you add TRA and have overall less bleeding, which is an intriguing possibility. Also the investigations of the Xa inhibitors in ACS patients again will test the role of these drugs to get at the treatment failure and the role that thrombin plays here. Dr. Bhatt: Potentially also, the direct thrombin inhibitors. Dr. Gurbel: Yes, exactly. So that's the next avenue. With P2Y12 blockade, we've exhaustedly studied these agents. But, of course, there's one other one. Dr. Bhatt: Do we seem to keep learning more?

Dr. Gurbel: Yes. Dr. Bhatt: I mean there's clopidogrel. It's going to be generic soon. Dr. Gurbel: Right. Dr. Bhatt: But we're still learning lots. Dr. Gurbel: The research has focused on P2Y12 for so many years. Now we're moving towards thrombin. We forgot to mention one other P2Y12 blocker, elinogrel -- another direct acting, more rapidly reversible agent than ticagrelor that will be entering a phase III trial. So we'll wait to see about elinogrel. Dr. Storey: That is an interesting compound in its binding to P2Y12. So we've had the thienopyridines, which bind irreversibly. We've got ticagrelor, which binds and blocks the action of adenosine diphosphate (ADP) in a noncompetitive way. Elinogrel competes with ADP at the P2Y12 receptor. A different type of binding may lead to different efficacy and safety profiles. That was an interesting hypothesis that we need to study further. Dr. Bhatt: So it sounds like research on the P2Y12 receptor and its antagonists is still going to be a fertile area for many years to come. Well, I'd like to thank the audience for joining us. Hopefully this was interesting and educational. I certainly learned a lot from the distinguished faculty here. Thank you so much for joining. This educational activity is supported by an independent educational grant from AstraZeneca.

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As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Any use of trade names in this program is for reference purposes only. No promotion of particular products or devices should be inferred.

Deepak L. Bhatt, MD

Chief of Cardiology, VA Boston Healthcare System, Director, Integrated Interventional Cardiovascular Program, Brigham and Women's Hospital and the VA Boston Healthcare System, Boston, Massachusetts Disclosure: Dr. Deepak L. Bhatt has disclosed the following relevant financial relationships: Received grants for clinical research from: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Eisai Inc.; Ethicon Inc.; sanofi-aventis; The Medicines Company; Heartscape Technologies, Inc. Dr. Bhatt does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the US Food and Drug Administration (FDA) for use in the United States. Dr. Bhatt does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Christopher P. Cannon, MD

Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts Disclosure: Dr. Christopher P. Cannon has disclosed the following relevant financial relationships: Received grants for clinical research from: Accumetrics, Inc.; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; sanofi-aventis; GlaxoSmithKline; Intekrin Therapeutics; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Takeda Pharmaceuticals North America, Inc. Has equity in: Automedics Medical Systems Dr. Cannon does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Dr. Cannon does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.
Paul A. Gurbel, MD

Director, Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Associate Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Disclosure: Dr. Paul A. Gurbel has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Bayer HealthCare Pharmaceuticals; Portola Pharmaceuticals, Inc.; Eli Lilly and Company; Haemonetics; POZEN, Inc.; Medtronic, Inc.; Accumetrics, Inc. Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Bayer HealthCare Pharmaceuticals; Portola Pharmaceuticals, Inc.; Eli Lilly and Company; Haemonetics; POZEN, Inc; Medtronic, Inc.; Accumetrics, Inc. Received grants for clinical research from: AstraZeneca Pharmaceuticals LP; Bayer HealthCare Pharmaceuticals; Portola Pharmaceuticals, Inc.; Eli Lilly and Company; POZEN, Inc.; Haemonetics. Owns stock, stock options, or bonds from: Medtronic, Inc.; Merck & Co., Inc.

Dr. Gurbel does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Dr. Gurbel does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.
Robert F. Storey, MD

Senior Lecturer and Honorary Consultant in Cardiology, The Cardiovascular Research Unit, University of Sheffield, Sheffield, United Kingdom Disclosure: Dr. Robert F. Storey has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Eli Lilly and Company; Daiichi Sankyo, Inc.; Teva Pharmaceuticals USA; Schering-Plough Corporation; Novartis Pharmaceuticals Corporation; The Medicines Company. Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceutical LP; Eli Lilly and Company; Daiichi Sankyo, Inc. Received grants for clinical research from: AstraZeneca Pharmaceuticals LP; Eli Lilly and Company; Daiichi Sankyo, Inc.; Schering-Plough Corporation; Dynabyte. Dr. Storey does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Dr. Storey does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Caroline M. Fisher, B.Pharm

Senior Scientific Director, Medscape/ Disclosure: Caroline M. Fisher has disclosed no relevant financial relationships.

CME Reviewer(s)
Laurie E. Scudder, MS, NP

Accreditation Coordinator, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland Disclosure: Laurie E. Scudder, MS, NP, has disclosed no relevant financial relationships.
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CME Information
CME Released: 03/31/2010; Valid for credit through 03/31/2011

Target Audience
This program is intended for cardiologists, interventionalists, and other healthcare providers involved in the management of patients with ACS.

The purpose of this activity is to update physicians regarding new data on antiplatelet agents used in the treatment of patients with ACS.

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At the conclusion of this program, participants will be able to: 1. 2. Compare/contrast different antiplatelet mechanisms of action Discuss the impact of recent randomized clinical trial data involving antiplatelet therapy on the management of patients with ACS

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