Deepak Bhatt, MD, MPH: Manesh, something a doctor might think of when looking at this patient is to switch her from aspirin to clopidogrel based on the CAPRIE study of patients with peripheral artery disease [PAD] who are symptomatic. That is certainly a CAPRIE trial-like patient as well. There are also patients with polyvascular disease who seemed to fare particularly well. What do you think is the role of clopidogrel monotherapy vs dual antiplatelet therapy, which you studied with aspirin and ticagrelor in the EUCLID trial as well as the COMPASS trial regimen. How do those 3 approaches stack up in this type of patient in your mind?
Manesh Patel, MD: Thanks, Deepak. As you said, this patient is typical of who we see in our clinical practice. A 70-year-old woman reminds me, unfortunately, of a lot of our people in North Carolina with a 50 pack-year history of smoking. As Kelley said, with her history and the multisystem, diabetic disease, she is polyvascular. I know we’re being brief on our cases, but I’ll bet her ABI [ankle-brachial index] score is abnormal. I’ll bet her pulses aren’t normal, and I’ll bet she’s got claudication from actual vascular disease in the limbs.
With that assumption, the point you’re making is about what we know about our patients with chronic PAD, and this is an interesting patient, as Marc was saying. We’re learning more about patients who are able to get to age 70 with PAD but haven’t had a heart event. She’s got diabetes and cardiovascular events. She is a patient with PAD who is represented in some of the COMPASS trial data; a lot of the EUCLID trial data, which we’ll talk about in a second; and certainly in the VOYAGER PAD trial if she has had a revascularization.
Right now, she’s a claudicant. What we know from the CAPRIE trial is that the comparison of aspirin to clopidogrel is from some 20 years ago in patients with PAD, but overall the trial showed a reduction in cardiovascular events. It was an 8% relative-risk reduction. I believe the absolute event rates were around 5.5% or 5.58%, so this is not a huge change for absolute reduction, but there was a relative risk reduction in the overall trial, which was significant in 19,000 patients. I would say that a stronger antiplatelet clopidogrel was demonstrated to be somewhat beneficial in patients with PAD in the subgroup but also overall in the vascular population.
In the EUCLID trial, we [at Duke University School of Medicine] studied monotherapy ticagrelor vs monotherapy clopidogrel, and this is 1 of the reasons I’ve come to respect this population differently. If you would have said to me at the start of that trial—14,000 patients with claudication and prior lower-extremity revascularization and PAD—that if you give them a stronger antiplatelet agent, almost everyone would say ticagrelor is compared with clopidogrel, we should have reduced their cardiovascular events but didn’t. That trial informed me to say that for those stable patients with PAD who haven’t had a cardiovascular event, haven’t had a stent, haven’t had ACS [acute coronary syndrome] so much, a stronger antiplatelet agent did not reduce their cardiovascular events or their limb events.
That brings me to the COMPASS trial, and it makes me think about our dual-pathway therapy, if you will, with the COMPASS trial regimen of low-dose rivaroxaban, 2.5 mg plus aspirin. I would think that she’s a patient who fits some of the things Kelley mentioned with Sonia Anand’s paper: She’s a patient with diabetes and PAD, and she has a tobacco history. We haven’t fully examined all of her, but I suspect that she would be someone for whom I would potentially lean toward thinking that way.
The last thought somebody might ask me is this: “Manesh, what about aspirin and clopidogrel compared with aspirin alone?” You studied that in the CHARISMA trial and others. In a chronic vascular population, although numerically there were patients with diabetes and patients with PAD, there was a reduction around 8% or 9%. It didn’t quite meet statistical significance. It’s certainly not as robust as the finding in the COMPASS trial, so I would lean toward that.
Deepak Bhatt, MD, MPH: I was going to ask you that. It’s interesting that clopidogrel beat aspirin in the CAPRIE trial. In the EUCLID trial, ticagrelor couldn’t beat clopidogrel, at least not in the overall trial for the primary end point. There may be some signals in ischemic stroke or other things, but overall it’s not a clear win. In the CHARISMA trial, dual-antiplatelet therapy looked like it was heading in the right direction, but it does not have the statistical significance or robustness seen in the COMPASS trial.
Transcript Edited for Clarity