DR. FERDINAND: This is the first part of a two-part roundtable discussion series. The purpose of it is to reach out to clinical cardiologists, both invasive and non-invasive, to discuss the updated American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines on unstable angina and non-ST-segment-elevation myocardial infarction (NSTEMI)1 and the second group of guidelines of the ACCF/AHA ST-segment-elevation myocardial infarction (STEMI). We’re really interested in focusing on the implications for antiplatelet therapy. The guidelines, as you know, are very comprehensive and reach across a broad spectrum of medical and nonmedical interventions, but we’re not going to try to comprehensively cover all of those areas.
I’m Keith C. Ferdinand, MD. I’m a professor of clinical medicine at the Tulane University School of Medicine in New Orleans, Louisiana.
DR. LAVIE: This is Carl “Chip” Lavie. I’m a medical director of cardiac rehabilitation and preventive cardiology and director of the exercise laboratories at the John Ochsner Heart and Vascular Institute, Ochsner Clinical School, the University of Queensland School of Medicine in New Orleans, Louisiana.
DR. FOODY: This is JoAnne M. Foody, MD. I’m an associate professor at Harvard Medical School and I’m director of the cardiovascular wellness center at Brigham and Women’s Hospital in Boston, Massachusetts.
DR. BERGER: I’m Jeffrey Berger. I’m an assistant professor of medicine and surgery at NYU School of Medicine and director of cardiovascular thrombosis.
DR. FERDINAND: Thank you very much. For the purpose of the platform of this discussion, we’re going to be discussing acute coronary syndromes (ACS). As we know, it’s a constellation of clinical symptoms compatible with acute myocardial ischemia. It includes ST-segment-elevation myocardial infarction, or STEMI, and non-ST-segment-elevation myocardial infarction, or NSTEMI, which also includes unstable angina. ACS mainly is the disruption of a vulnerable high-risk plaque and consequently, disruption of blood flow through the affected artery. With unstable angina and NSTEMI, it is usually not a total occlusion vs STEMI. We’ll be discussing STEMI shortly, but at this time we’re going to focus mainly on unstable angina and NSTEMI in terms of the use of antiplatelet agents, and looking specifically at the recent updates to the ACCF/AHA guidelines for unstable angina and NSTEMI.
We’re also going to be focusing on the use of dual antiplatelet therapy. As you know, there is clopidogrel, which is time tested, but there are also two newer P2Y12 inhibitors which have been approved and have been included in the guidelines. Ticagrelor has been approved along with prasugrel.
So let’s do this as an open-ended discussion.
The first question is what do you see as the most significant changes in the guidelines?
DR. LAVIE: It seems like the biggest change in the guidelines is the addition of ticagrelor, or BRILINTA®. That is also a new antiplatelet therapy that has been shown to be effective in ACS. Actually, based on the Platelet Inhibition and Patient Outcomes (PLATO) trial and the current US Food and Drug Administration (FDA) rulings, it’s the only antiplatelet agent that is superior to clopidogrel for reducing cardiovascular death following ACS (4.0% vs 5.1% at 12 months; P < 0.001).2
DR. FERDINAND: How is that different, Dr. Lavie, from prasugrel?
DR. LAVIE: I do not think prasugrel has any data to show that it significantly reduces cardiovascular death compared to clopidogrel. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) there was reduced risk of myocardial infarction (7.4% in the prasugrel group vs 9.7% in the clopidogrel group; P < 0.001),3 but I do not think there was a substantially reduced risk of cardiovascular death. For every cardiovascular death that would have been prevented there was an equal fatal bleed.4 Prasugrel does not have FDA approval for reducing cardiovascular death compared to clopidogrel.
DR. FERDINAND: Does anyone else want to comment on that nuance that Dr. Lavie just mentioned, that it appears that in terms of the evidence, ticagrelor has some data supporting a decrease in cardiovascular death as compared to prasugrel?
DR. BERGER: I think that’s a very important point. I think that both trials, TRITON as well as PLATO, showed a reduction in cardiovascular events when looking at the composite endpoint,2,3 but when looking at the specific end points there was that important distinction. I think that the major bleeding piece is also really important. As potent antiplatelet therapies, ticagrelor and prasugrel increase the risk of bleeding, you have to be very careful with the major bleeding definition used in each publication such that in TRITON there was a significant increase in the risk of the primary safety end point, TIMI non-coronary artery bypass graft (CABG)-related major bleeding (2.4% in the prasugrel group vs 1.8% in the clopidogrel group: P = 0.03).3
In PLATO, there was no increase in the trial’s primary assessment of major bleeding which was the PLATO major bleeding definition,2 but when you look at the primary bleeding definition used in TRITON (the TIMI major non-CABG definition), there was a significantly increased risk (2.8% in the ticagrelor group vs 2.2% in the clopidogrel group: P = 0.03).5 Both drugs increase the risk of TIMI non-CABG related major bleeding, but prasugrel also increased fatal bleeding and life-threatening bleeding.2 So I think the excess bleeding risk that was seen with prasugrel in TRITON probably, most likely, counteracted or prevented the significant benefit in cardiovascular death as was seen in PLATO.
DR. FERDINAND: Dr. Foody, can you clarify—it appears that when you look at the guidelines for Class Ia evidence they’re talking on a platform of aspirin. All patients should get aspirin unless intolerant.
DR. FOODY: Correct.
DR. FERDINAND: Is that accurate?
DR. FOODY: Yes, and Keith, I just want to step back. I think your original question was really, “What did the new guidelines bring to light?” First and foremost, we have to step back and say that dual antiplatelet therapy is now without question recommended for all patients with ACS, and consists of a background of aspirin, as you mentioned, and any one of the three agents we’re talking about. In fact, as much as there are nuances between the three agents, the US guidelines do not specifically endorse one necessarily over the other. The real message is that all patients with unstable angina and NSTEMI should be considered candidates for dual antiplatelet therapy.
Now, there are subtleties within, and as we’ve moved from a simple aspirin-based strategy to clopidogrel and now moving to prasugrel and ticagrelor we continue to reduce ischemic events at the expense of bleeding. Again, many of these decisions need to be based on the risk of the given individual patient not only for ischemic events but also for their bleeding risk.
DR. FERDINAND: You know, one thing that is not really clear to me is why there are some nuances in the labeling for the drugs. I’m sure that someone can articulate how this is really based on evidence. It’s not new. It was in the older guidelines when they were first mentioning prasugrel, but they put this barrier of greater than or equal to 75 years of age not being recommended. What’s the benefit or harm of that?
DR. BERGER: Right. I think there are two very important points. One is when looking at the TRITON data there were three subgroups of patients with whom you have to be very careful when interpreting the data. One was in subjects who had a prior stroke or transient ischemic attack. The primary efficacy endpoint of death from cardiovascular causes, nonfatal MI and nonfatal stroke was higher with prasugrel vs clopidogrel treatment (19.1% vs 14.4% respectively), while the rate of TIMI non-CABG-related major bleeding was significantly higher (5.0% vs 2.9%, prasugrel vs clopidogrel respectively; P = 0.06).3 In fact, in that subgroup of patients, not only was there no net clinical benefit, there was actually net clinical harm. For that reason the FDA gave it a black box warning to avoid prasugrel in that group.
Then, they found two other subgroups. They found a group that was greater than or equal to 75 years of age or those with less than—I believe it was—60 kg.