Dual Antiplatelet Therapy for CV Risk Reduction


Recommendations for treating patients with coronary artery disease and type 2 diabetes with dual antiplatelet therapy based on data revealed by the THEMIS trial.

Manesh R. Patel, MD: It’s been a revolution of the things we have that we can treat our patients to prevent cardiovascular events. We talked some about the diabetic therapies, but there are certainly antiplatelet and antithrombotic therapies that work. Just to remind everyone that, the coagulation cascade has both an extrinsic and an intrinsic pathway. I often tell my patients, imagine that I’ve got a camera and I’m looking down any 1 of your blood vessels. There’s probably some cobblestone, which are the cells sitting on the line. As plaque builds up, it can build up. When plaque ruptures or a little disruption happens, the circulating platelets start to clot on the plaque. Additionally, you start clotting cascade with some tissue factor or other things being demonstrated to the cells. One of the strongest clotting-function factions happens along with some fibrin, thrombin leads to clotting at that cell level. 

The first action on the platelet side is that platelets come and aggregate. The antiplatelet agents aspirin, which works at the thromboxane level or, clopidogrel, ticagrelor, or prasugrel. They are P2RY12 inhibitors—a receptor on the platelets associated with aggregation. These oral agents work to inhibit platelet aggregation. We know that patients with diabetes have extra activated platelets…. They’ve been inflamed. They’ve been putting out fires all over the vascular bed for a while. They’re much more likely to aggregate than other patients. That’s partly how these agents work.

One of the most contentious places of care, in taking care of our patients, is how long do you use antiplatelet therapy on our patients with coronary artery disease and patients with diabetes? The most recent guidelines are from 2016, but there’s certainly a variety of data that have come out subsequently. In general, my general sense is, once somebody has had an acute coronary syndrome [ACS] in that first year after they’ve had a heart attack or an acute coronary syndrome, there’s broad agreement that dual antiplatelet therapy [DAPT] has been shown through several trials to be beneficial for up to a year. However, some of the more recent trials after the guidelines, such as TWILIGHT and other trials in which the aspirin was dropped after some period of time, have showed similar efficacy and less bleeding.

There’s some ongoing investigation to see in the acute coronary syndrome scenario if can we shorten the duration of dual antiplatelet therapy. Many have asked me, “What about after 1 year and the ACS? What about people chronically with coronary artery disease? After 1 year of an acute coronary syndrome, or after 1 year of an angioplasty PCI [percutaneous coronary intervention] event, we’ve had some other evidence: the dual antiplatelet trial, or the DAPT trial, and certainly trials associated with ticagrelor. In PEGASUS we studied patients with prolonged dual antiplatelet ticagrelor.

On top of aspirin, 2 different doses of ticagrelor were compared with aspirin. The DAPT trial showed us that prolonged dual antiplatelet therapy did not reduce mortality but did reduce EMI [electromagnetic interference], not always at the state level but other places. That came at the risk of an increase in bleeding. In fact, there’s a DAPT calculator for patients. And we make individualized decisions based on the patient’s risk of some of those thrombotic complications vs some of those bleeding complications. In fact, that’s what the guidelines do. The guidelines speak to determining the patient’s thrombotic risk vs their bleeding risk for prolonged dual antiplatelet therapy. But most recommend 1 year after ACS. After an angioplasty without ACS, based on some of the drug-coded data and others, the recommendations are in the 3- to 6-month time period.

Marc P. Bonaca, MD, MPH: Recently the results of the THEMIS trial were reported. They were originally reported at the European Society of Cardiology Congress, and there was a publication in the New England Journal of Medicine. This was a very large diabetes trial. Of patients with type 2 diabetes, 19,000 or so had coronary disease. There were patients who had a prior revascularization, but none of them had had a prior myocardial infarction. These were patients with stable chronic coronary disease and diabetes. And we saw that these patients were at very high risk of a myocardial infarction, stroke, and cardiovascular death and that the addition of a P2RY12 inhibitor, 1 called ticagrelor to aspirin vs aspirin alone reduced that risk. There was also an increase in bleeding. In the overall population, there was uncertain benefit, but in 1 of the analyses that was shown, there was a particular benefit with patients who had a prior history of coronary revascularization. From that trial we’ve learned that patients with diabetes and atherosclerotic cardiovascular disease [ASCVD] and coronary disease are at heightened risk of major adverse cardiovascular events and that a more potent antithrombotic therapy reduces that risk but increases bleeding. For P2RY12 inhibitors, the most benefited appears to be in those with coronary intervention.

When we think about dual antiplatelet therapy—the combination of aspirin and P2RY12 inhibitor—we think of it in the context of a procedure, most often a coronary procedure, like coronary stent. It’s often also used in peripheral artery stenting. It’s generally time limited with the notion that it provides some stent protection for a period of time, 1 month to several months. And then it’s stopped. There are a group of patients—for example, those with prior myocardial infarction or acute coronary syndrome, who may benefit from longer durations of dual antiplatelet therapy. For patients who don’t warrant long-term dual antiplatelet therapy, once their duration ends, once it’s safe to stop it from a stent protection perspective, those patients remain at heightened risk of atherothrombosis. In fact, we know patients with peripheral artery disease, polyvascular disease and coronary disease, particularly those with risk factors like comorbid diabetes, patients who have polyvascular disease or chronic kidney disease, are at long-term heightened risk of major adverse cardiovascular events. Even though their duration of DAPT has stopped, their risk remains and even increases over time. There’s significant residual risk of atherothrombosis in patients with ASCVD, particularly those with comorbid diabetes.

When we consider dual antiplatelet therapy, there are some contraindications. Certainly if a patient were to have an allergy to 1 or both of the agents, we wouldn’t use it, but primarily we worry about bleeding risk. For patients who are at very high risk of bleeding, patients who are on therapeutic anticoagulation, we may choose to use a single antiplatelet or even drop antiplatelet therapy after a period of time. For patients who had intracranial hemorrhage or prior stroke, we’d generally be more cautious about long-term dual antiplatelet therapy.

Transcript Edited for Clarity

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