COMMENTARY

PEGASUS: Ticagrelor Post MI and Precision Medicine

Seth Bilazarian, MD; Marc S. Sabatine, MD, MPH

Disclosures

March 23, 2015

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A Plethora of DAPT Trials

Seth Bilazarian, MD: This is Seth Bilazarian with theheart.org on Medscape, at the American College of Cardiology (ACC) meeting in San Diego. I am very excited to sit down with Dr Marc Sabatine, chairman of the TIMI Study Group and senior physician at the Brigham and Women's Hospital. He has presented the PEGASUS-TIMI 54 trial,[1,2] a study looking at long-term dual antiplatelet therapy (DAPT) with ticagrelor (Brilinta®) in patients who have had a myocardial infarction (MI) more than 1 year earlier.

For purposes of disclosure, I was an investigator on this trial; but despite being an investigator I have a lot of questions, and I'm excited to try to drill down on what we learned from the PEGASUS trial, and get some sense about what I should be doing for my patients when I return home tomorrow.

We all know that there are a lot of trials. The last meeting of the American Heart Association was the "long-term DAPT meeting" because we heard about all of these trials that asked the question: Is there a benefit of DAPT after MI stenting? The DAPT study[3] was the largest of the DAPT trials. There is a take-home message for clinicians: that there is ischemic benefit but there is also more bleeding. That is the background. Before we get to the PEGASUS trial, was that a reasonable summary of where we were?

Marc S. Sabatine, MD, MPH: For patients who have been stented, that is absolutely right. It's a related but somewhat distinct question for patients who have had a previous MI. For them, we look at data from the 1-year ACS [acute coronary syndrome] trials of the P2Y12 inhibitors[4,5] in which, in landmark analysis, it looked like the curves continued to separate out over time. In those trials, we treated patients only for 1 year; therefore, the guidelines[6] said to treat for only 1 year and then stop the P2Y12 inhibitor, but there was a tantalizing signal that we might see additional benefit if we were to continue the P2Y12 inhibitor.

TIMI-54 PEGASUS Enters the Fray

Dr Bilazarian: Give us a very brief top line of what the take-home message should be from PEGASUS presentation.

Dr Sabatine: We looked at more than 21,000 patients who had an MI 1-3 years earlier. On average, these patients were close to 2 years out from their qualifying MI. We randomly assigned them to one of three arms. All patients received background low-dose aspirin. The first group received ticagrelor dosed at 90 mg twice a day, which is the standard dose that was studied and approved in the ACS trials. We also studied a lower dose, 60 mg twice daily, that was designed to achieve a little bit less but still quite robust platelet inhibition. And the third group received placebo. We found that both doses of ticagrelor, each compared with placebo, significantly reduced the risk for cardiovascular death, MI, or stroke, with a 15% reduction with the 90-mg dose and a 16% reduction with the 60-mg dose.

Dr Bilazarian: One thing that I would want to emphasize is that these weren't just any MI patients; these were patients who also had other risk factors. Can you talk more about that?

Dr Sabatine: Commonly in clinical trials, to help achieve a higher event rate to allow the trial to conclude in a more reasonable timeframe, we will enrich for certain risk factors. In this case we wanted patients to have at least one additional atherothrombosis risk factor: more advanced age, diabetes, multivessel disease, a second previous MI, or chronic kidney disease. When we looked at the subgroups, there was a consistent benefit regardless of the presence or absence of any of those individual risk factors.

Dr Bilazarian: There was a 3% event rate in the arm with aspirin alone and a 9% rate over 3 years. What did we get by adding ticagrelor?

Dr Sabatine: In the control arm, the event rate was about 9% over the course of 3 years, so a 15% or 16% reduction resulted in event rates that were around 7.5% in the two ticagrelor arms.

What Can We Take Home From PEGASUS?

Dr Bilazarian: We are here in San Diego but soon you and I will be back in Massachusetts. I will be taking care of patients. How do I apply these data? We have the US guidelines that say that after MI and a drug-eluting stent placement, 1 year of DAPT is the current recommendation. We are not certain about that, but it is a different question—whether shorter is safer for patients who need surgery or have an emergency issue. How long should we treat patients? That's the real question. Yesterday in your presentation, Dr Bob Harrington (Stanford) made the comment as a discussant that maybe patients should be on DAPT forever after MI. Give us your thoughts about that.

Dr Sabatine: It's important to know that we followed patients for just under 3 years on average. If you consider the time from their qualifying MI to the end of follow-up as we approached the end of PEGASUS-TIMI 54, more than one fourth of the patients were more than half a decade out from their qualifying MI, and the event curves continued to diverge over time.

What would I do in practice? Because we didn't have the data, the current guidelines say to stop the P2Y12 inhibitor at the end of 12 months. On the basis of these data, I think we should continue. The guidelines give the recommendation of ticagrelor over clopidogrel, given the benefits seen in the PLATO trial,[4] so for my patients with ACS coming in, I would start them on ticagrelor and at the 12-month mark I wouldn't stop. I would keep it going.

Dr Bilazarian: We are all trying to think more about personalizing and individualizing care for our patients. Would you continue the therapy for all patients with MI or, based on the data, only do so in those who were enriched with one of those risk factors? Or is that not important?

Dr Sabatine: I would continue it for all of the patients. Obviously, the decision to continue depends on how well the patient tolerated the drug over the 12 months. You are absolutely right. We need to think about it for each individual patient. We didn't enroll patients at particularly high risk of bleeding. We excluded patients with ischemic stroke or intracranial hemorrhage, so naturally I wouldn't give this therapy to those patients.

Alternative DAPT

Dr Bilazarian: Here is a more mundane question. Medical practice is often criticized in the newspapers for costs and value. We should be thinking seriously as stewards of healthcare about good value. Obviously there is a generic alternative—clopidogrel. How would that play into treatment for our patients? If the patient says, "The copay is different," how would I discuss that with a patient?

Dr Sabatine: We need to be mindful of those factors. At the top level we know now from both PEGASUS-TIMI 54 as well as the DAPT trial that there is a consistent message that more prolonged, more intensive antiplatelet therapy reduces ischemic events in our patients. I would follow the evidence base and start my patients on ticagrelor when they came in, and I would continue it long-term. If a patient can't take ticagrelor for some reason, there is evidence that they benefit from more intensive therapy, so I would go with the best therapy that we have prospective data to support. If the patient is unable to do that, then I would rather give that patient something that might have less platelet inhibition than nothing at all. Keep in mind that both doses we studied (90 mg and 60 mg) achieved more platelet inhibition that clopidogrel 75 mg, so we can't be sure that we would see the same efficacy with clopidogrel.

Dr Bilazarian: Thinking about efficacy and hazard, rather than cost, you showed about a 1.2% absolute risk reduction in ischemic events and about a 1.2% moderate or major bleeding risk—almost exactly the same numbers. You made the compelling argument, in my view, that we have on the benefit side irreversible problems, whereas most of the bleeding is a reversible problem. You weren't saying that bleeding is unimportant but it's reversible, and that rates of irreversible bleeding, such as intracranial hemorrhage and fatal bleeding, were not different. As you said, "You are trading a bleeding event for a MACE [major adverse cardiac event] benefit" is not a fair comparison. Thinking more specifically about individual patients, we don't have a tool such as HAS-BLED for atrial fibrillation to help us figure out in which patients we should avoid or think seriously about not using these therapies. Do you have any insights about trying to parse out who is at risk and in whom the risk-benefit ratio may tip in favor of not using therapy?

Dr Sabatine: One thing to keep in mind is that if you look at just the math, you have to do the analysis in the same way. If you want to look at benefit and risk, you have to analyze both as intention-to-treat or both on-treatment. Typically, the convention in these papers is that the efficacy data are done as intent-to-treat and the safety as on-treatment, but once you do net benefit, you have to use the same analytic approach. When you do that, it shows that you prevent one third more MACE events than you cause TIMI major bleeds, so at a straight count level, you are preventing more events. Those events are of very different clinical import. I would value a cardiovascular death, an MI, or a stroke far above a nonfatal bleed. That being said, we are certainly going to look in the database and see whether we can, through a variety of risk scores (clinical, biochemical, and genetic), identify those individuals in whom therapy will maximize the ischemic benefit and minimize the bleeding risk.

Personalizing Antiplatelet Therapy

Dr Bilazarian: Despite your many hats as the TIMI leader and as a physician at the Brigham and Women's Hospital, one of your real interests is in genetic testing. You have authored several papers on genetic testing for antiplatelet therapy.[7,8] The President announced a signature initiative in his recent State of the Union Address, calling on the National Institutes of Health to lead a precision medicine initiative. Dr Francis Collins and Dr Harold Varmus have written in the New England Journal of Medicine[9] in greater detail about this. They specifically talk about diabetes and cancer as areas of precision medicine, but I'm sure that cardiologists are not being intentionally left out. How might that play a role in this—not in the near term, but will that be something that we are going to be able to use in our patients in the community?

Dr Sabatine: When we think about pharmacogenetics, it comes out in a couple of different flavors in precision medicine. One is an oncology example: Are there individuals who have a tumor with a specific genetic mutation that can be targeted with a drug? There is very elegant biology for that. Cardiology is more complex in the sense that it's multifactorial. There, the benefits of genetics come in two different domains. First, you can find a genetic variance that predisposes patients to risk. We had an article published in the Lancet[10] recently using a composite risk score to identify patients at increased risk for cardiovascular events, and the risk score had previously been shown to predict incident events. We looked at it in patients who already had an MI and we showed that it predicted recurrent events. You can start to envision using those risk scores to decide who will enjoy a larger benefit for the same 20% relative risk reduction. Of course, it depends on the absolute risk. We did that in four statin trials that we analyzed in that study, showing that the absolute risk reduction was greater in patients with a higher genetic burden, and therefore the number needed to treat went down.

The other arena is in pure pharmacogenetics, where you find variants that predict the efficacy or safety of the drug. We published another paper in the Lancet[11] looking at warfarin and different genetic variants that predispose patients to bleeding on warfarin, and we were able to look at that in another TIMI trial, (ENGAGE AF-TIMI 48[12]) which compared warfarin with edoxaban. It showed that although edoxaban was safer overall, it was particularly safer and better in patients who were predisposed to bleeding with warfarin. Those are the two areas where genetics were the most useful. As you point out, the technology is advancing rapidly so that our patients will be coming to us already genotyped. It's going to be up to us to figure out what to do with that information.

Dr Bilazarian: That's a good handicap. When might that happen? When will I be able to test for a warfarin genotype that predicts a poorer outcome?

Dr Sabatine: You already can do it. It's already in the FDA label for warfarin. As the costs go down to do that, it's going to become more common to do that. I suspect that over the next 5 years we are going to see an increasing prevalence of patients saying, "I've tested myself, I have these genetic data. Is this a problem? I've read about it; Doc, what should I do?" and that is going to force all of us to become quite facile with that literature.

Dr Bilazarian: Marc, thank you very much for your leadership of this important PEGASUS trial. Thank you for sitting down with me and helping clarify your views on how this should be implemented by community-based physicians. You send the message that we now have good safety and efficacy data showing that potentially using DAPT indefinitely for our post-MI patients is the right way to go, and hopefully guidelines will catch up.

I'm Seth Bilazarian. Thanks for joining us here at the ACC in San Diego, reviewing the PEGASUS trial.

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