Interview: Ticagrelor as Long-term Secondary Prevention in Patients with PAD and Prior MI | An Interview with Marc P. Bonaca, MD

CardioSource WorldNews | Investigators for two separate sub-analyses of PEGASUS-TIMI 54 presented their results at ACC.16 in Chicago, IL, looking specifically at the long-term use of ticagrelor in patients with a history of myocardial infarction (MI) and at least one additional risk factor for thrombotic cardiovascular events. The first sub-analysis included patients with peripheral artery disease (PAD), and the second looked at patients with diabetes. Marc Bonaca, MD, of Brigham and Women’s Hospital in Boston, MA, is lead investigator for the PAD sub-analysis of PEGASUS.

CSWN: Why did you focus on this population of patients with PAD?

Marc P. Bonaca, MD: We know that patients with PAD are at a heightened ischemic risk, as well as for MI, stroke and cardiovascular death. We also know that patients with prior MI and PAD (so-called “polyvascular” disease) are at even higher risk. So this is a very high-risk population. The PEGASUS-TIMI 54 study overall showed that ticagrelor reduced cardiovascular risk over the long term. There was some increased bleeding. We felt this was a cohort that might derive particularly robust benefit from more intensive anti-thrombotic strategy as long-term secondary prevention.

How many patients were analyzed?

Just over 1,000 patients were in the PAD subgroup. They were analyzed as the primary group for this study. All the patients were randomized 1 to 3 years after MI. These 1,100 patients or so had symptomatic PAD or abnormal ankle-brachial index, and they were followed for 3 years of therapy.

What did you find?

First, we found that when you look at patients that have PAD and prior MI versus patients with prior MI alone, those that have PAD are much higher risk of major adverse cardiovascular events. The event rate at 3 years was 20%, meaning one in five patients had CV death, MI, or stroke, versus a much lower rate of patients without PAD. And when you look at the individual events, they’re at higher risk of cardiovascular death, all-cause mortality, and of course limb events. We saw that it was a much higher-risk population than those without PAD, and also that that relationship remained even after we adjusted for all of the imbalances at baseline, so that they have more diabetes, more smoking, etc. Even after you adjust for that, they’re at higher risk.

Is that appreciated among the cardiovascular community?

Yes. I think that people understand that patients with PAD are at higher risk for ischemic events, not necessarily beyond prior MI. And so I think this does add to the fact that polyvascular disease, as others have described, is a much higher-risk population. And then the second part of the analysis, of course, was looking at how they responded to therapy.

For the second analysis you did a sub-analysis of almost 6,800 patients with a prior MI and diabetes. What went on in that study?

Similar to PAD, diabetes indicated a higher-risk population within the trial cohort (more aggressive atherosclerotic phenotype, worse outcomes, etc). In both of these populations, by nature of their higher risk, that translated into a greater absolute risk reduction with ticagrelor. For the PAD population, the absolute risk reduction was more than 4% over 3 years for a number needed-to-treat of about 25. That is very attractive. Then the 60 mg dose that is approved for use actually had a very attractive efficacy profile with reductions in CV death and all-cause mortality. So I think this really underscores that high-risk populations derive greater benefit. We saw the same thing in diabetes: a greater absolute risk reduction.

Similar to non-diabetic patients, there was an increase in TIMI major bleeding with ticagrelor, but it did not offset the advantages.

Yes, and so you raise a very important point. One of the themes at this conference has been the struggle that we’re all grappling with in terms of applying the dual antiplatelet therapy (DAPT) and the PEGASUS-TIMI 54 data in clinical practice. These are very broad populations with coronary disease getting stents or who have had prior MI. People have said, “Well, in order to take on this bleeding risk, there needs to be a robust risk reduction; it needs to be offset.” So part of [the reason for] these subgroup analyses is to illustrate to the clinical community that there are subgroups of patients that are very high risk who derive a great absolute risk reduction. We’ve seen that now with the PAD population and the diabetes population. Importantly, the most sophisticated way to integrate all these factors is through risk scores. Robert Yeh, MD, and the DAPT team have put out a risk-score for post-PCI patients, and there is another one for long-term secondary prevention. I think these type of subgroup analyses help inform the need for those type of risk scores which add all these factors together and say, “This patient’s gonna get a robust benefit that’s worth the risk.”

At the 2016 meeting, the ACC put out an updated guidelines focusing on DAPT use, and have you had a chance to look at those yet? Does it help?

Well, I think it really tresses the need for individualization of care. There is no one-size-fits-all, and I think that comes out loud and clear in the guidelines and is appropriate. They do talk about things like the DAPT risk score and there are other risk scores that have been published—the one by Erin Bohula, MD, that I mentioned. And I think to me that’s what the takeaway is, that we can’t make this an algorithmic decision. We have to really select patients based on their risk, their tolerability or their ability to tolerate drug, and their bleeding profile, and hopefully these sub-analyses, this PAD subgroup where one in five have a bad event at 3 years and you can have greater than 4% absolute risk reduction. I think that may be meaningful to clinicians as a subgroup that derives particular benefit.

Read the full July issue of CardioSource WorldNews at

Clinical Topics: Vascular Medicine, Atherosclerotic Disease (CAD/PAD)

Keywords: CardioSource WorldNews, Adenosine, Diabetes Mellitus, Myocardial Infarction, Peripheral Arterial Disease, Thrombosis

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