Case 1: THEMIS Trial and Subgroup Analysis With Revascularization



Deepak Bhatt, MD, MPH: Marc Bonaca, maybe I’ll turn to you for more about dual antiplatelet [DAP] therapy. Last summer at ESC [European Society of Cardiology Congress], you presented the THEMIS-PAD study in which THEMIS was positive overall. You presented the outcomes of dual-antiplatelet therapy with aspirin and ticagrelor, and it looked pretty good, although that’s a population of angiographic CAD [coronary artery disease] in diabetes, not PAD [peripheral artery disease] per se as the entry criteria of the trial. Nonetheless, it looked as if there were good things happening to PAD end points. Marc, maybe you could summarize the findings and then contextualize the findings in light of what Manesh just said about single antiplatelet therapy with aspirin, with clopidogrel, with ticagrelor, dual-antiplatelet therapy with aspirin and clopidogrel, and now aspirin and ticagrelor in the THEMIS-PAD trial.

Marc Bonaca, MD, MPH: Thank you, Deepak. Starting at a high level, what we know is particularly for our polyvascular patients: Those with symptomatic coronary disease and PAD are at extreme risk, and I don’t think a single agent is sufficient for protection. Even if you’re addressing lipids, and you’re using the targeted diabetes agents, we know there are differing axes of risk, and you have to address all of them. The data from the THEMIS trial show us a more potent strategy: aspirin and ticagrelor vs aspirin alone reduces MACE [major adverse cardiovascular events] and reduces limb outcomes with the significant effect in that polyvascular population with diabetes. The PEGASUS-TIMI 54 trial showed a similar subgroup analysis where there’s a benefit for limb outcomes.

That is a population that overlaps, to some extent, with the population in the COMPASS trial. But it is distinct, as Manesh said, from the patient. With what we’re talking about, she doesn’t have any known coronary disease. She has only PAD, and we’re learning that there is some heterogeneity there. The data for monotherapy have always been debated in PAD alone. That goes back to some of the aspirin studies like the AAA trial and the POPADAD trial, in which people with marginally low ABI [ankle-brachial index] scores and no known atherosclerosis otherwise, aspirin didn’t show any benefit. The Antithrombotic Trialists’ Collaborative showed a benefit after revascularization or symptomatic PAD.

Clopidogrel was better in the CAPRIE trial. That being said, for the patient with only PAD, the data around DAP with a P2Y12 inhibitor and aspirin is less compelling. The CHARISMA trial showed some benefit for hospitalizations in that subgroup, but without coronary disease, I’m less convinced that the aspirin-P2Y12 combination is of benefit, particularly when you look at postrevascularization, like with the CASPAR trial, where we don’t see a benefit.

This patient, in terms of the strategy, stands out because she doesn’t have symptomatic coronary disease. That’s not to say she has normal coronaries, but she’s never ruptured a plaque in 70 years and 50 pack-years of smoking, so her biology is probably different. This is the kind of patient who did make it into the COMPASS trial and did make it into the VOYAGER trial, albeit postrevascularization. There is something about thrombin inhibition or thrombin as a particularly bad actor in this type of patient, particularly when it pertains to limb events, which we’ve clearly seen in the 2 trials. There are a lot of choices. Of all the things we’ve talked about with lipids and diabetes agents, the antithrombotic therapy is probably the most challenging for her. She probably needs more than a single agent, and as I look across the data from the trials, a combination therapy is probably best supported by the data for her.

Deepak Bhatt, MD, MPH: Before we move onto the next case, Kelley mentioned SGLT2 inhibitors, and that certainly seemed like a good idea. Marc Bonaca, do you have any thoughts about SGLT2 inhibitors and amputation risk? Is that something we need to worry about anymore? Of course, it came up in the CANVAS program, which had a statistically significant increase in amputation. Pretty much any way they sliced the data, it was impossible to eliminate that finding. Having said that, the FDA recently revised the wording around the labeling so that it’s not called out so much that there’s this type of black box amputation warning anymore for canagliflozin.

The other SGLT2 inhibitors out there haven’t been as clearly associated with amputation. You never know because the experiment may be altered by preexisting data, so it may be that, in the trials that came afterward, even if the protocol isn’t necessarily stipulated, the investigators might have been risk averse in terms of patients with very high-risk PAD getting in. This was most recently looked in the SOLOIST-WHF trial and the SCORED trial, and they didn’t find any significant amputation risk with that particular SGLT2/1 inhibitor.

In the end, what’s the bottom line? Somebody has PAD like this woman. She has diabetes. She may even have an issue with HFpEF [heart failure with preserved ejection fraction] or volume overload, and you’re wanting to start an SGLT2 inhibitor. Her glucose needs better control. Is it an issue if she has PAD? Is it an issue if she has PAD with a history of amputation? Do you think there is any concern there anymore?

Marc Bonaca, MD, MPH: Thanks, Deepak. It’s been an interesting evolution because, as you said, the data in the CANVAS trial were pretty strong no matter how you sliced it. The CREDENCE trial followed with the same compound, albeit with careful attention paid to foot hygiene, and it may have excluded some patients with extremely high risk who were in the throes of critical limb ischemia. There’s no signal there, nor have any other trials. There’s no signal with dapagliflozin. As you said, in the SCORED trial and the SOLOIST trial, there was no signal.

My takeaway is that these are important drugs. They have important, broad benefits. Particularly for heart failure and for renal function, we should not deny our patients with PAD access to these agents. If I have a patient who’s in the midst of an admission for critical limb ischemia with threatened tissue loss, I might not choose to start at that moment. I might stabilize them and start it as an outpatient when the limb is no longer threatened.

I don’t necessarily have a good basis to say that it would be harmful, but I might choose a more stable setting. Even if they have history of amputation, I would use them. Patients with PAD, in fact, are probably at higher risk of renal complications and heart failure. Even without these agents, those with diabetes are probably going to benefit in absolute terms, maybe even more than other patients would benefit. I use them, but I encourage careful foot hygiene, and I’m cautious with patients who are in the setting of a threatened limb.

Deepak Bhatt, MD, MPH: That’s good advice in general for patients with PAD. We hadn’t mentioned it before, but good foot hygiene, especially in this person with diabetes, at least an annual visit with the podiatrist, would probably be a good idea. With those precautions, SGLT2 inhibitors can be useful drugs in these patients. As you said, if somebody has critical limb ischemia or is otherwise critically ill, generally speaking, that’s not the time to start an SGLT2 inhibitor anyway. Of course, an adverse effect of these drugs is diabetic ketoacidosis [DK], and it can occur even at ranges of glucose where we don’t typically think of DK even through the 150 to 200 mg/dL range. Like every drug, there needs to be caution.

Transcript Edited for Clarity

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