COMMENTARY

Antiplatelet Therapy Review: From Aspirin to Ticagrelor

Henry R. Black, MD

Disclosures

February 16, 2016

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Editor's Note: Dr Black interviews Jeffrey S. Berger, MD, associate professor of medicine, cardiology and hematology; associate professor of surgery, vascular surgery; and director of cardiovascular thrombosis at the New York University School of Medicine.

Henry R. Black, MD: Hi. I'm Dr Henry Black. I am an adjunct professor of medicine at the Langone New York University (NYU) School of Medicine, and I am here today with my friend and colleague, Dr Jeff Berger.

Jeffrey S. Berger, MD: Thanks for inviting me. As you know, I am an associate professor of medicine at the NYU School of Medicine, and it is really nice to be here.

Antiplatelet Therapy: In the Beginning, There Was Aspirin

Dr Black: When I was doing this, aspirin was all we had for platelet inhibitors. Now, it seems to me, the field has just exploded. Could you help me and others figure out where things are, what is new, and what is likely to be happening?

Dr Berger: The antiplatelet therapy world is really exciting right now. For a very long time, we have had one, maybe two, antiplatelet therapies—but over the past 5 years or so, it has really blossomed. It is really exciting because now, as a physician, you have a choice of different agents and they all have their benefits, and they all have their potential safety issues as well.

It is important to be familiar with them and to understand when one would use which agents. For example, you mentioned aspirin. Aspirin is probably one of the most interesting drugs we have had. If you go back to Hippocrates, he spoke about the willow and he spoke about the ingredient that was found in the willow: salicylic acid. Clearly, physicians, for hundreds, probably thousands, of years, have known some of the beneficial remedies of aspirin, and they have used it.

What I find extremely interesting is that Bayer, which really helped catapult aspirin and its use, had a large advertisement back in the beginning of the prior century (so around 100 years ago) that basically stated aspirin is great for rheumatism, for vertigo, for tinnitus, and the list went on. And then in bold letters in the middle, it said, "It does not affect the heart."

I found that really fascinating because a Nobel Prize has been won since then, demonstrating how [aspirin] does affect prostaglandins and how that ultimately does affect the heart, and ultimately affects clotting capability.

We are learning a lot, and we are still using aspirin. I still think aspirin is a very important drug in the prevention of cardiovascular events—and I think in certain populations it actually makes people live longer, as well.

Dr Black: I remember when I was doing it, we were talking 3000 mg/day, not 81 mg, and that seems to be a major change in how you use it. It is not surprising that a drug in a low dose is safe and a drug in a high dose is not.

P2Y12 Antagonists: Clopidogrel

Dr Black: What has happened since? Does clopidogrel belong in this scheme? Where does that fit in?

Dr Berger: In addition to blocking the thromboxane receptor, which is how aspirin works, you have the thienopyridines, or the P2Y12 antagonists, that block the P2Y12 receptor. It is also called the adenosine diphosphate (ADP) receptor. Clopidogrel is probably the most well known of these drugs. It was not the first, however. The first drug was ticlopidine, but ticlopidine lost a lot of its use because of its side effects of thrombotic thrombocytopenic purpura (TTP).[1,2] And clopidogrel came along, and it was really shown to be a blockbuster of a drug.

It was shown that in combination with aspirin,[3] [clopidogrel] prevented heart attack, stroke, and cardiovascular death in a variety of different populations. In patients who had an acute coronary syndrome, in patients who received a prior stent—the use of aspirin and clopidogrel really was the mainstay, probably, for the past 10 or 12 years.

TRITON-TIMI: Prasugrel

Dr Berger: Things have changed over the past 3 years to bring about some newer drugs. Probably the first one that came out that really changed things was a drug called prasugrel. Prasugrel is another P2Y12 antagonist, with a much faster effect. It does not require a two-stage metabolic conversion, which clopidogrel did. Basically, it affected people very quickly and it affected them in the same manner, so they all got very robust platelet inhibition.

The main trial of prasugrel was called the TRITON-TIMI trial,[4] and that showed that when you use prasugrel in addition to aspirin compared with clopidogrel in addition to aspirin, there was a very significant reduction in the composite of cardiovascular events.

The main drawback was that there was a lot of excess bleeding. When they looked at the drug, there was an increase in major bleeding but there was also an increase in life-threatening bleeding, and there was even an increase in fatal bleeding.

Because of that, we learned a few things. We learned, not unexpectedly, that when you inhibit platelets to a much greater degree, you get a decrease in thrombosis—but simultaneously, you get an increase in bleeding. That led to this idea of figuring out which patient should get which drug.

PLATO: Ticagrelor

Dr Berger: To further complicate [matters]—or to actually give us another potential option—along came another drug, called ticagrelor. Ticagrelor is interesting because it is actually not a thienopyridine, but it is a P2Y12 antagonist. And, similar to prasugrel, it also has a much quicker onset of action, and it also supplies a much more potent antiplatelet effect. It was studied in a large acute coronary syndrome trial called PLATO.[5]

In that trial, they looked at ticagrelor plus aspirin vs clopidogrel plus aspirin, and they showed that ticagrelor lowered the incidence of cardiovascular events. Now, very interestingly, in the PLATO trial they found that ticagrelor not only lowered the composite of cardiovascular events, but it also lowered the endpoint of cardiovascular death, and it lowered the endpoint of all cause death.

In today's era, when we are thinking about what drugs to use, I think it is important to think about what endpoints a certain drug lowers. But we can never forget that even ticagrelor, with its very beneficial effect, still increased the risk for major bleeding.

You don't get a free ride. When you inhibit platelets, you definitely get a lowering of the composite of cardiovascular events or thrombotic endpoints, but it definitely increases the risk for major bleeding.

Which Patient Populations?

Dr Black: Does it work in all populations, or is it specific for certain groups of people?

Dr Berger: Both of these trials, PLATO as well as TRITON, really looked at acute coronary syndrome patients—so within the early onset of an acute coronary syndrome, you give one of these drugs.

Now, there are small differences between the trials. In the TRITON trial, in the prasugrel trial, they actually gave them the prasugrel once their anatomy was known in the non–ST-segment elevation acute coronary syndrome group. In the ST-segment elevation myocardial infarction (STEMI) population, they were able to give it beforehand.

In the PLATO trial, they actually got [prasugrel] before they even went for a coronary angiogram, so it was a little bit more of an upfront strategy.

PEGASUS

Dr Berger: Since then, there have been a few other trials. There was a trial called PEGASUS,[6] which actually just came out a year ago or so, which looked at what to do a year out. Once you take your dual-antiplatelet therapy for a full 12 months, what should you do at that point? Do you drop the P2Y12 antagonist and just keep aspirin, or do you continue the P2Y12 antagonist?

Dr Black: I recall the information or the recommendation was that after 1 year you stop it, but that didn't seem to have any necessary sense. It was just all that had been studied.

Dr Berger: Exactly. If you read the guidelines, they were very careful in their wording. Depending on the stent type, depending on the acute coronary syndrome, they would say take it for up to 12 months or for at least 12 months.

But as you pointed out, the data were only up to 12 months, so it really left a dearth of information, and there was wide variation in how physicians treated their patients. There is definitely a group of doctors who believe that if [patients] were on it for the first 12 months, they should be on it forever. And there is clearly a group of people who believe, well, the data only state 12 months, so maybe we should stop then.

That is why the PEGASUS trial was really important. It asked the question, what do you do with the patient 1-3 years following their heart attack? And they found a not unexpected finding: They found that ticagrelor vs placebo on a background of aspirin lowered the risk for cardiovascular events. But there was a significant increased risk for major bleeding.

Dr Black: Even 3 years out?

Dr Berger: Even several years out. That really, in my opinion, reminded us why we all went to medical school. It is that you don't do the same thing for every patient, but it is the art of medicine. It is figuring out what each patient should get depending on their own inherent risk.

Personalized Medicine

Dr Berger: That is what we are moving toward. I think we are going to leave the era of "we have one drug or two drugs, and the whole population gets that." I think we are becoming much smarter. We are realizing there are more potent and less potent drugs, and there are individuals at greater or lesser risk for thrombosis and the same thing for bleeding. Then, on the basis of that individual, you would figure out which potential drug would be best for them.

Dr Black: I'm amused when people talk about personalized medicine as if you need DNA to tell you what to do. Epidemiology and trials have been saying that all along. We don't do the same thing for everybody. Is there anything on the horizon?

Dr Berger: I think that personalized medicine is a misunderstood notion, and I completely agree with you—I think that we have been using it for decades. For example, biomarkers, troponin elevations, creatine kinase MB (CKMB) [values]—that guided how we treated patients. That was a great example of personalized or "precision" medicine, as the President likes to say.

We have been using it. What we need to do, at the end of the day, is utilize all the data we have. There are a lot of excellent researchers out there, a lot of excellent clinicians. We need to bring everyone together, and we really need to figure out how we can utilize the data that we already have and treat patients in the best way we can.

Personally, I think we spend a lot of time thinking about newer drugs [and] different targets. I think we need to spend a little bit of time thinking about using what we already have. We have great drugs. We have great tests. We just need to make sure people use them. We need to make sure people know what is out there, and then educate them how they can really serve themselves best.

Dr Black: One of my biases, which a lot of people are angry about, is that I think the best way to do this is to have somebody see a specialist who really understands. I think even a general cardiologist, or someone with some experience in that, has got to be confused about what the options are. The person who doesn't in the case of platelet inhibition should be seeing you, or somebody like you.

A Role for Antiplatelet Therapy in Primary Prevention?

Dr Black: What is your recommendation now? How about for primary prevention, is there any role for any of these agents in primary prevention?

Dr Berger: Primary prevention of cardiovascular events is another very misunderstood area. There have been a lot of studies[7] that have shown that across the country, there is tremendous variation as to who uses or does not use antiplatelet therapy for the prevention of a first cardiovascular event.

Just to put things into perspective, there is really only one option right now of an antiplatelet therapy, and that is aspirin. Aspirin is the one drug that has been studied[8] for the primary prevention of cardiovascular events. There actually was a subset of another trial. There was a subset of the CHARISMA trial,[9] which looked at aspirin and clopidogrel vs aspirin alone. They included high-risk primary prevention patients, and in fact, those subjects who took dual-antiplatelet therapy did worse than with just aspirin alone.

People who have never had a cardiovascular event should not be taking dual-antiplatelet therapy.

What About Aspirin?

Dr Berger: Whether or not somebody should be taking aspirin is, I think, a fascinating area. The reason why I think it is so fascinating is because we have had 11 randomized trials for the primary prevention of cardiovascular events, and—surprisingly to some—not a single one of them met its primary endpoint.

Dr Black: There was a Physicians' Health Study,[10] which I was just old enough to be part of but didn't volunteer for, in which the group aged 40-59 years did not show benefit because [the study] was drastically underpowered to show that. The trend was there, and we have to face this issue when we have to use judgment, sometimes, when we don't have a trial that specifically answers the question.

Your recommendation for primary prevention, I would guess, on the basis of what you say, is not to use anything except maybe aspirin. What about aspirin?

Dr Berger: When you group all the trials together, you see a modest 10% reduction in the incidence of cardiovascular events. I think what is fascinating [is that] in the past several years, we have learned that aspirin for primary prevention may have a role in cancer prevention. I think that is where the interest really lies. Does aspirin have any other effects? Does it have any pleiotropic effects outside of just affecting the platelet?

I mean, clearly, it inhibits prostaglandin production, so it is silly to think that it just affects the platelet. It has a myriad of other effects. Don't forget that for thousands of years, it was used not for platelet inhibition but for the other anti-inflammatory effects—but obviously, that was at the much higher dose.

But at the low dose, there are some data that it actually prevents cancer metastasis,[11] specifically in the gastrointestinal (GI) [tract]. Understanding who would benefit is really of interest—you want to identify the people who are at highest risk for having a cardiovascular event and those at highest risk for having a GI cancer. If you can identify those patients, I think the benefit would probably outweigh the risk.

Dr Black: One of the ways to do that is to watch people get older. The most important risk factor for heart disease is age, and everybody will meet the Framingham score soon enough, if you live long enough. It is a very complicated issue.

I don't envy you trying to keep track of all this, but you are doing a great job. Thank you very much, Jeff—you have been a great help.

Dr Berger: Thanks a lot.

Disclosure: Jeffrey S. Berger, MD, has disclosed the following relevant financial relationships:
Received research grant from: AstraZeneca Pharmaceuticals LP

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