PEGASUS–TIMI 54: Ticagrelor linked with better outcomes in patients at least 1 year after MI

John Gordon Harold, MD, MACC

This study demonstrated that long-term use of an antiplatelet agent improves outcomes. We knew it at least up to 12 months, but this longer-term trial did show a significant difference. The issue is, will the same be true with a generic drug such as clopidogrel? But this will give clinicians something to think about when they have discussions with their patients about the use of maintenance medications to reduce risk. I think the data are very powerful and the trial was very well-done. Ticagrelor has not been used aggressively across the country, but I think this will give physicians another option to look at, though the downside of bleeding risk will need to be considered. The findings are going to stimulate physicians to think about the issue of maintenance therapy with DAPT in a different light. Each patient will need to be individualized with this new body of knowledge.

Farouc A. Jaffer, MD, PhD, FACC

This study found that extended ticagrelor treatment was associated with a net CV benefit. There was about a 15% reduction in the primary efficacy endpoint, driven by a reduction in MI. As with all antiplatelet agents, there is a chance of bleeding, but there was a reassuring finding that there was no difference in the life-threatening complication of intracerebral hemorrhage. However, there was a risk for increased significant bleeding of about 2.5-fold, and about a threefold increase in transfusion. Therefore, these are factors that have to be balanced in terms of how we apply extended ticagrelor dual antiplatelet therapy to patients who have had events.

The PEGASUS–TIMI 54 study was a little bit different than the DAPT study, in that the PEGASUS researchers did not specify that patients had to be on DAPT at the time of randomization. They enrolled patients who had an MI 1 to 3 years earlier, but did not specify their DAPT history or status. Patients in PEGASUS were randomized at a mean of 1.7 years after the index event. In contrast, in the DAPT study, patients were randomized right after completing 12 months of DAPT with clopidogrel. Both studies excluded patients with recent bleeding or stroke. So these are not our highest-risk bleeders. And yet, there was an increase in bleeding associated with ticagrelor (as well as with clopidogrel in the DAPT study).

It shows that the potential for extended DAPT could be as another form of secondary prevention, such as aspirin, statins and optimal diet and exercise. But it has to be very carefully applied because of the bleeding risk.

A fascinating question is whether extended ticagrelor improves outcomes compared with extended clopidogrel. That study has not been performed. The advantages of clopidogrel are lower cost and less bleeding, as we know from pivotal trials. It varies by center and by doctor, but many patients felt to be low-risk bleeders may be recommended extended DAPT. I think what we’ll see from PEGASUS is that for patients who were on ticagrelor after their index event, there may be a natural inclination to continue on ticagrelor for another 1 to 3 years if they are doing fine on it. Another point of interest is that the rates of dyspnea on ticagrelor were higher than expected. That is another factor to consider because clopidogrel does not have that side effect.

Ticagrelor is only available in a 90-mg dose in the United States. For extended therapy, it might make sense to make the 60-mg dose available. To show a benefit of 60 mg during the initial 1 year post-MI, one would have to reproduce the PLATO study, and I don’t think that will be done. But making a 60-mg dose available after 1 year may make sense to mitigate some of the bleeding risk and still get the extended DAPT benefit.

Gregg W. Stone, MD

PEGASUS was a very important study. Building on the DAPT trial, PEGASUS looked at long-term antiplatelet therapy with ticagrelor in patients with prior MI. I believe that overall, it was a neutral to slightly negative study showing somewhat more harm than benefit with prolonged ticagrelor. What was seen in prior studies with clopidogrel was that longer DAPT did have efficacy compared with shorter DAPT in reducing MI and stent thrombosis, but also substantially increased major bleeding, with a net effect of increasing all-cause mortality. Those were the findings of a recently published meta-analysis that I contributed to (Palmerini T, et al. Lancet. 2015;doi:10.1016/S0140-6736(15)60263-X). Building on that in PEGASUS, we see at least there was not an increase in mortality with ticagrelor 90 mg twice a day and 60 mg twice a day, although the reduction in MI was more than offset by twice-as-high occurrence of TIMI major or minor bleeding.

When these risks are considered, along with the considerable cost of yearly (or lifelong) ticagrelor, most patients with ACS need not be treated with this agent beyond 1 year. Selected patients in whom the risk of recurrent ischemic events is very high and the risk of bleeding is very low may benefit, however. Further research is required to determine the balance of risk factors that characterize these patients.