Expert Perspectives on Managing Polyvascular Disease and Coronary Artery Disease - Episode 9

Dual Pathway Inhibition in Coronary Artery Disease

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Expert cardiologists provide an overview of dual pathway inhibition, modulation of thrombotic risk and treatment of CAD.

Deepak Bhatt, MD, MPH: Marc, since we’re sort of pivoting now to talk a little bit about dual pathway inhibition, do you want to just remind the audience specifically what that term refers to? Dual antiplatelet therapy [DAPT], of course, refers to aspirin plus clopidogrel or aspirin plus prasugrel or aspirin plus ticagrelor. Dual pathway inhibition is a little bit more specific.

Marc P. Bonaca, MD, MPH: That’s a great question, Deepak. Thank you for the opportunity. And I know Manesh Patel spoke a little bit about the different trials in DAPT, but there’s a different way of interrupting the thrombin-mediated risk that these patients face. And that is through interrupting the generation of thrombin, either with a factor Xa inhibitor. Some people have looked at warfarin or vitamin K antagonists, and there are other agents as well. And I will remind folks that actually before DAPT came on the scene, there were data for warfarin for reducing recurrent myocardial infarction. In fact, President Eisenhower, when he was at the at University of Colorado, they still have the sweep, but Dr Paul Dudley White [Massachusetts General Hospital] flew out there. It was the first human to get warfarin to prevent a recurrent myocardial infarction. Now, when there were questions about stent safety, there were questions about how to prevent short-term stent thrombosis, and warfarin did not look as good as DAPT for that pothole problem. But there was clearly un-residual risk. And I think part of is that it was completely platelet focused. And we’ve learned that thrombin is a particularly bad actor in the vasculature and that not only does it work in the coagulation cascade, and we know about that from atrial fibrillation and other things, but it is a most potent activator for platelets, and there’s crosstalk between the platelets and the coagulation cascade.

And thus, then the question is, how do you interrupt that crosstalk in a way that has a net benefit, as Amy Pollak spoke about? There was a program to understand how factor Xa inhibitors might be utilized in a way that could have a better efficacy versus safety profile than vitamin K antagonists. And this was a surprise, where in the ATLAS [Antiretroviral Therapy as Long Acting Suppression] studies, we learned that lower is better; that a dose that was 25% of the daily dose of a therapeutic factor Xa inhibitor, rivaroxaban [Xarelto] actually was the sweet spot of modulating antiplatelet with aspirin in thrombin generation through factor Xa inhibition. And the ATLAS trial that came from that with just, per C. Mike Gibson, MD, [Beth Israel Deaconess Medical Center] had dramatic reductions in mortality and CV [cardiovascular] mortality. We actually observed in small numbers, about a 50% reduction in acute limb ischemia, and then that was carried forward into the COMPASS [Cardiovascular Outcomes for People using Anticoagulation Strategies] trial that Amy Pollak spoke about in chronic PAD [peripheral artery disease], CAD [coronary artery disease], and polyvascular disease. And the trial halted early for overwhelming efficacy for mortality benefit, and then also studied in the periprocedural, postprocedural setting and VOYAGER, and so there are very consistent benefits. And as Amy Pollak said, we don’t think necessarily about anticoagulants for vascular disease, but that’s because we haven’t had many tools in the toolkit. But I do think that data have shown thrombin is a core bad actor. Maybe not for the stent, but for the patient, and that we need to modulate that risk and antiplatelets don’t do that. Thus, the dual pathway approach of interrupting thrombin generation along with a single antiplatelet now has multiple, robust studies that we can talk about that have shown really overwhelming benefit.

Transcript Edited for Clarity