What Should We Expect From Current and Future Oral Antiplatelet Drugs?





What Should We Expect from Current and Future Oral Antiplatelet Drugs?

Despite the development of several new oral antiplatelet agents, there exist none that can be used in all patients without some increased risk of bleeding over aspirin alone. This is as true for clopidogrel as it is for ticagrelor.  Obviously there are different degrees of bleeding and risk must always be balanced by benefit. We should expect of these drugs significant benefit without undue or excessive risk of bleeding. As in most therapies net clinical benefit defines the desired outcome.

What are the gaps in current knowledge?

There is a very large and expanding knowledge base regarding new drugs but really no comparisons between the newer agents. Following aspirin vs. placebo, clopidogrel has been the historical control which at this point seems inadequate going forward. It is unlikely that we will find the perfect potent drug that impacts clotting in a favorable way without some risk of bleeding but more robust comparisons between newer agents would inform the interventional community. The issues of genetic testing, for some and platelet function for others, remains an active area of research. That said, newer drugs might negate these concerns and the need for additional studies in these areas.

Summary and recommendations:

A new comparator drug to be used in subsequent studies is much desired. In addition, consistent enrollment criteria and definitions of outcomes are needed to better inform practitioners and allow more robust inferences to be made.  



Panel Discussion. What Should We Expect from Current and Future Oral Antiplatelet Drugs?


Speaker: Tarek Helmy

Moderator: Larry Dean Kereiakes

Panelists: Stefan Beyer-Enke, Bonnie Weiner


Larry Dean: I’ll be moderating the next session titled “What should we expect from current and future oral antiplatelet drugs.” Tarek is here, also Stefan and Bonnie. Tarek is going to lead off this session.

Tarek Helmy: Good morning everyone. It’s a pleasure and an honor to be here. We are going to follow up on the previous presentations regarding antiplatelet therapy in the setting of drug eluting stents. We all know that platelets play a pivotal role in the pathogenesis of acute coronary syndrome as well as in stent thrombosis. The P2 Y12 receptors have been targeted over the last few years with multiple agents, Clopidogrel, Prasugrel and more recently Ticagrelor. We know that cessation, Particularly early cessation of dual antiplatelet therapy can promote stent thrombosis. Very late stent thrombosis also remains a problem. Triton TIMI 38 looked at Prasugrel vs. Plavix and there was significant reduction in the primary efficacy composite endpoint of cardiovascular death, infarction and stroke which was mostly driven by myocardial infarction reduction decreased early revascularization and decreased stent thrombosis with Prasugrel compared to Plavix but there was a price to pay with increased bleeding events especially major bleeds. Ticagrelor is the most recent to be evaluated  and again it was superior to Plavix in the Plato trial. In this case there was a significant reduction in mortality which is a new finding for an antiplatelet agent of this era. Stent thrombosis of course was again reduced and this came at a pleasantly surprising no cost with respect to bleeding so there was no increase in risk of bleeding with the Ticagrelor compared to clopidogrel. So if you examine the major trials looking at antiplatelet drugs: the Cure trial, Triton TIMI 38 and Plato, the only agent that showed reduced mortality was the Ticagrelor, they all reduced myocardial infarction and Prasugrel and Ticagrelor reduced stent thrombosis. Major bleeding was increased in the Cure trial compared to aspirin alone. Prasugrel had increased bleeding compared to Plavix but Ticagrelor did not have increased bleeding compared to Plavix. Interestingly enough with the trials that have been done the indication for withdrawal before major surgery mostly CABG has all been 5-7 days despite the fact the Ticagrelor is a reversible drug with a fairly short half-life. So the challenges with all the agents is determining how they fit into current practice. Issues include cost, and the risk of bleeding. What we need to better understand are the factors that are going to affect your choice, whether it be factors related to the patient, the lesion, the location of stent and the risk of bleeding for a specific patient. I would now like to open discussion for the panel and attendees.

Larry Dean: Thanks very much, Tarek. So I will throw out something to the panel: knowing what we know about Plato and Triton TIMI 38, why are we using Clopidogrel at all?

Bonnie Weiner: Because it is cheap and we have the most long-term experience with it.

Larry Dean: We were just shown that Ticagrelor decreases mortality, that is a pretty strong endpoint compared to how much something costs. We are not talking about bleeding which is certainly important, we are not talking about restenosis, now we are talking about mortality, so my question remains: why should we be using Clopidogrel at all?

Stefan Beyar-Enke: My question is do we have to look only at the early effects up to 10 days or should we look at longer information risk up to six weeks or longer?

Bonnie Weiner: I think that is an important point because the real reason that we are talking about 12 months or more of dual antiplatelet agents isn’t really because of in-stent thrombosis it is really because most of the patients we treat have acute coronary syndromes, they are being treated for acute coronary syndromes and that is where the data for a year or more actually comes from, it has nothing to do with the fact that we are putting stents in them. So to just look at short-term results even if it is a mortality endpoint I think is problematic if we are talking about keeping people on these drugs for a year or more.

Larry Dean: You are right in that we are treating a chronic disease but irrespective of that I come back to Ticagrelor again, it has less bleeding and it has a mortality benefit: so, why are we using Clopidogrel or for that matter, Prasugrel.

Kirk Garratt: Can I just offer one point of clarification here?

Larry Dean: Yes.

Kirk Garratt: There is less bleeding with ticagrelor in the Plato trial only because Plato used its own definition. If you use the more generally accepted definition of TIMI major and minor bleeding not related to bypass surgery the bleeding rates between the clopidogrel and the ticagrelor arm were exactly the same. Furthermore the mortal bleeding, that is bleeding that lead to death was .3% for both ticagrelor and clopidogrel treated patients in the Plato trial. Interestingly in the Triton Trial which got all kinds of headlines because lethal bleeding was .3% when patients got prasugrel and .1% of the time when they got clopidogrel. My read is this, considering the Plato data with clopidogrel is that it was just a fluke, that there was for whatever reason fewer lethal bleeds in the clopidogrel-treated patients in that trial than you would have otherwise expected. I think we have to keep this in mind because we are about to make very big decisions about clinical practice based on information that I personally believe is being widely misinterpreted.

Larry Dean: Finally, Kirk has started the discussion about bleeding risk -- buried in the Plato trial is the fact that the bleeding risk was higher with ticagrelor than clopidogrel in the non-CABG bleeding. They are more efficacious but by their very nature they would be expected to cause more bleeding than clopidogrel, the older agent. My concern is mortality reduction. So that is the thing I keep coming back to. The bleeding issue can start a big conversation about whether it is really true or not. On the other hand, mortality reduction is the thing I think we have to really need to think about.

Tarek Helmy:  The definition and the TIMI definition of bleeding are examined and you are right: non-CABG related bleeding was higher for ticagrelor, by both definitions.

Larry Dean: The other thing is if you go back and look at Triton TIMI 38 the incidence of bleeding with clopidogrel was also higher in the older age and the smaller patients as well. So right now we don’t have a silver bullet and maybe that is what this conversation is supposed to be about, what information do we need to really change practice?

There is one other issue with the ticagrelor that we personally struggle with at my site and that is the lower aspirin dose. I am curious to hear from everyone here: are you comfortable with 81 mg right off the bat or are you still using 2 weeks or 4 weeks of full dose aspirin?

So, Bonnie or Stefan, what do you think about the aspirin dose?

Tarek Helmy: It is recommended that with ticagrelor you do not use aspirin dose higher than 100 mg.

Bonnie Weiner: I think the new guidelines would suggest that it is reasonable now to drop down and to use a lower dose from the beginning. I think a lot of us will still use 325 for maybe the first 24-48 hours but that is about it. I think more and more people are dropping down to 81 very quickly and that I think is a change of practice and will change the bleeding profile.

Stefan: I am working in the periphery and mostly use aspirin in a dose of 300 to 500 mg.

Larry Dean: So just going back to the question that we are supposed to be trying to answer is, what is it going to take to get to the next step from the standpoint of antiplatelet drugs?

Audience member: So I would like to raise another point and that is using large clinical trials to guide the absolute use of a drug, so TIMI 38 is an example. They happen on a dose of Prasugrel of 10 mg a day mainly for efficacy reasons, clearly it was not the dose to give for safety reasons, but we are held hostage and give 10 mg a day for 450 days if we really follow the trial. It is absurd to think that the degree of platelet inhibition that we need at 30 days is the same longer term. It is actually probably different than what we need at 60 days, 90 days, 180 days.  And tomorrow we could ratchet that degree of platelet inhibition down and likely lessen the bleeding rate. So I think we need to rethink things. The active moiety for prasugrel is identical to the active moiety for clopidogrel, yet one has a warning and one doesn’t have a warning for stroke, it makes no sense.

Larry Dean: There actually is a warning around increased bleeding in the package insert for ticagrelor. So to get back to this question about clopidogrel, prasugrel and ticagrelor: would we want to see a trial comparing the newer agents to each other?

Tarek Helmy: So a point to make with the Triton TIMI 38 -- all the patients included were acute coronary syndrome patients who were planned for intervention. So almost, everybody ….

Larry Dean: 99% got intervention.

Tarek Helmy: Plato included all ACS patients including ST elevations and only 65% of those patients ended up getting PCI on the initial hospitalization.

Larry Dean: Another good point. Which brings back the question I just posed: do we really need a head to head comparison with the same kind of patient population to answer the question?

Mike Cowley: I think it depends on your goal, if you ask AstraZeneca, who has ticagrelor and not so much market penetration, if they would like to have a trial to get people to be more likely to use their drug, they might be interested. However, I don’t think you are going to get a head-to-head trial because nobody wins.

Larry Dean: Somebody might win.

Mike Cowley: I am sure Lilly won’t do a trial because they don’t need to. And, you know if you want to get better market share you may want to do the trial…but it is going to be huge and very expensive. So I am not sure we are going to get it….

Larry Dean: So, what do you think is going to happen to market share? I think there has been a relatively slow adoption of prasugrel.

Mike Cowley: You know clopidogrel is like an old friend, well maybe not that good a friend, but it is like an old friend. People are comfortable.

Larry Dean: It kills people Mike, come on.

Mike Cowley: People are comfortable with it, they have used it for years and they don’t see a problem with it. A lot of people just don’t see that  prasugrel is worth the difference. They are comfortable with Plavix, they say we have never had a problem with it and they just stick with it. So I think even before it becomes generic there is still an awful lot of Plavix being used. If you look just at the trials, prasugrel is far superior, ticagrelor is superior in terms of mortality and in terms of other important endpoints but yet most physicians don’t perceive  that it is enough of a difference to change practice.

Larry Dean: So it goes back again to the same question that we were talking about, to a degree, with the bioabsorbable stents and that is: if I am a company and I have to go to the next step, what is going to make you change when we have two new drugs, one of which supposedly has a mortality benefit, and people aren’t running to it, to the newest and greatest drug. …..

Gary Roubin: It is worth saying that bioabsorbable stents, if we had them available and we could get them in just as safely and as quickly, and they were no more expensive, we would all use bioabsorbable stents. What we should realize in this group is that it takes time for the market to adjust to new things, including these drugs.  

Larry Dean: And it is hard to change from clopidogrel to another drug.

Gary Roubin:…..after a while they become commodities, stents or drugs. What we should focus on is what is really best for patients and work at how to get there and I think some of the dual antiplatelet agents definitely are better for patients.

Larry Dean: What you are saying is very true. It does take some time because we spoiled the companies when we initially adopted DES from BMS, it was a pretty rapid ramp up. But I think the return on investment now is going to have to be over a longer period of time.

Tim Henry: A couple of things to follow up on Gary’s thoughts. Another challenge is the insurance companies. Often we are aware of the data and want to use the preferred drug. For example, prasugrel is currently actually cheaper until clopidogrel goes generic. But when you prescribe it and patients return back saying that they won’t fill the script or it cost too much money, it is negative feedback. So you have to get the whole system to adapt more rapidly. The other point I want to touch on is on average what do we do for patients on Coumadin? And the even more potent new antithombin agents. Unfortunately, there are no data with prasugrel or ticagrelor in those patients.

They were completely excluded from the trials and yet this group represents a large segment of the population which we don’t really know how to manage.

Larry Dean: We put these devices into older patients as well, and as I said, patients older than 75 years in Triton TIMI 38 had a higher incidence of bleeding with clopidogrel as well, so if you add warfarin, absolutely, bleeding  is going to be an issue.

Bill O’Neill: Larry, do you think, or does the panel think, that platelet reactivity monitoring is going to play a role at all in this? because we are kind of flying blind. You have three different drugs and all sorts of varieties of settings and how much antiplatelet therapy do you really need? It would be just like giving somebody 10 mg of a pill for blood pressure and say okay that is enough the trial shows that you never measure the blood pressure you just give them the drug and on faith assume that a 40-year-old man and a 90-year-old woman are going to have the same biologic response.

Larry Dean: That is a great comment. Actually it goes back to what someone mentioned earlier: you probably don’t need the same antiplatelet therapy initially as what you need long term. Comments from Bonnie or others?

Bonnie Weiner: I think the problem lies in properly identifying your goal. If your goal is to prevent people from subsequent events, then the need and the threshold for antiplatelet agents may be very different than if your goal is looking at just stent thrombosis. The data about the relationship between testing values and late stent and very late stent thrombosis are not very good. That is why I think we are not using them routinely. I don’t think we have the total answer and my bias right now is still not to use the newer agents routinely.

Gary Roubin: So who has been getting letters from health insurance companies? I received one for the first time this last week saying “your patient that you prescribed Plavix for is having to be tested for reactivity…”

Larry Dean: I haven’t gotten that one yet.

Gary Roubin: And what do you want to do about the request? Do you want to go ahead and test or not test? Do you want to change your prescription, is that the right thing to do?

Tim Henry: In an ongoing registry at our institution, about 25% of the clopidogrel patients are low responders and 10% are at 0 platelet response. So it’s like taking a placebo. On the other hand there are about 15% of patients who are high responders and actually may have increased bleeding. So there are things we can learn from platelet testing.

Larry Dean: So as the moderator I am getting the sign we are out of time, but the next presentation will probably get back into this.. We are not done with platelets yet.

Kirk Garratt: So the next topic is part two of the platelet discussion and we are going to deal with optimal duration. Skip Anderson is going to tee it up.