What is the prevalence of CVD associated with type 2 diabetes mellitus and coronary artery disease?

infarction. That's been appreciated for a

while. In fact, lots of data is supporting

ischemic stroke. So it's not just MI risk, it's ischemic stroke risk

bviously, this is known, they have a risk for

amputation, which while it may not be so high on an absolute level, in those that have peripheral artery disease and diabetes can be quite substantial—especially if they smoke, but even if they don't.

And the final risk that hasn't been as widely advertised is the risk of heart failure which is quite substantial and probably approximates the risk of MI. So a number of cardiovascular outcome trials have highlighted the fact that all these risks are present people with diabetes. And that's beyond the other risks that are well-known of microvascular complications—things like kidney failure, diabetes causing foot problems, which of course is tied into the amputation, but also things like neuropathy as well can be symptomatically quite problematic. And also, retinopathy and blindness.

So there obviously many bad things diabetes can do, but in terms of things that can lead to death, cardiovascular diseases is right at the top of that list.

What is the link between metabolic syndrome, diabetes, and CV-related morbidity and mortality?

It's sort of a continuous course. There's metabolic syndrome and diabetes, and eventually, if the diabetes isn't well controlled and treated—or sometimes even if it is&mdash;development of overt cardiovascular disease. So all these different conditions are quite interrelated and highlights the importance of identifying people with metabolic syndrome and diabetes early on, and getting them on treatment, diet, and exercise.

And weight loss being the first line of treatment, of course, but then oftentimes medical therapy focusing on glycemic control, on lipid control, and blood pressure control.

When should patients be screened for cardiovascular risks?

In terms of screening for cardiovascular risk, I think especially for any of the primary care physicians in the audience, it's really important to do every visit. For sure, you want to screen for things like cholesterol, blood pressure and glucose, the way the various societal guidelines recommended, in a formal sense.

But in an informal sense, in terms of asking patient's lifestyle habits and what they're doing with respect to diet and weight maintenance, or weight loss, if appropriate—in terms of daily exercise or daily physical activity.

Those are things that I would say every patient encounter should be emphasizing, because that can have a lot of impact on patients over the course of a lifetime, and can do a lot to prevent the development of things like metabolic syndrome and diabetes, or cardiovascular disease, or the combination.

Overview of Cardiovascular Disease in CAD, T2DM

Could you review the 2016 ACC/AHA guidelines focused update on duration of dual antiplatelet therapy in patients with CAD?

With respect to dual antiplatelet therapy guidelines, both sides of the Atlantic generally say six months of dual antiplatelet therapy for elective stenting, but for patients who have acute coronary syndromes treated with or without stenting in general, it’s 12 months. That's the anchor with a class 2b recommendation to continue longer, meaning it can be considered though but isn't obligated. And it should be considered, I think, but in patients that are at low bleeding risk only. If patients are at high bleeding risk, I think prolonged DAPT is a bad idea, beyond what the guideline recommendations that I just said were.

In particular, even if a patient's at high ischemic risk and high bleeding risk too, high bleeding risk trumps. So I wouldn't recommend prolonged DAPT, but again, antiplatelet monotherapy is the way to go there. Now, patients that are at high ischemic risk and a little bleeding risk, that's a different story. That's where I think protracted DAPT can be considered or should be considered in appropriately selected patients.

What is the mechanism of action of antiplatelet agents in the management of coronary artery disease?

The primary antiplatelet agents—at least on

commonly used, familiar, cheapest, antiplatelet agent, and for chronic

suggests that that might interfere in some patients with the

for chronic therapy. Of course, in an acute setting you want to load with about 62 or 325, but in general chronic therapy, 81. That reversibly inhibits the platelet for its lifespan of 7-10 days.

As far as the other broad category of oral antiplatelet, I refer to oral ATP receptor antagonists namely clopidogrel, which is now generic and most folks are familiar with, but also which is going into multiple generic forms these days. So the price is dropping there. And then ticagrelor, which is also an ATP receptor antagonist. Prasugrel and ticagrelor are more potent than clopidogrel, and clinical studies show that at least for patients with acute coronary syndromes, they may appear to be better.

Prasugrel, specifically, better applies to ACS treated with stents, and for ticagrelor, that better applies for ACS, where in the PLATO trial, ticagrelor was found to be superior to clopidogrel, and including lower cardiovascular mortality. So for that reason, some have favored ticagrelor as the preferred antiplatelet on top of aspirin in patients with ACS for a year, at least. In the PEGASUS trial, with ticagrelor, a lower dose than the ACS dose, 60 milligrams, the idea of ticagrelor 90 BID being the dose for that first after ACS. But in PEGASUS, patients with prior MI—1-3 years prior&mdash;there was a benefit of ticagrelor 60 PID when added to aspirin versus aspirin alone in reducing ischemic events in all cases.

Intensifying the regimen raises major bleeding risk, but in those populations, at least it seems to be worth it that there's a reduction in important ischemic events, even beyond the year after ACS. So in general, I'd say for ticagrelor, it's got the most data and in some respects, the most robust data. And the most recently we've added to that with THEMIS and THEMIS-PCI.

Antiplatelet Therapy in Coronary Artery Disease

Can you discuss the details of the THEMIS trial, looking at the effect of ticagrelor on health outcomes in patients with diabetes mellitus?

THEMIS is the largest trial of diabetes to date. I don't mean in antiplatelet therapy—I mean the entire field. 19,000 patients with diabetes and coronary artery disease defined angiographically, treated with a stent, treated with bypass surgery, treated medically&mdash;it turned out 15% of patients were treated with PCI in the past&mdash;that's the biggest subgroup so that and that's what PCI refers to.

But in the overall THEMIS, patients were randomized to ticagrelor versus placebo on top of aspirin, and the trial was a positive trial, with a 10% reduction in cardiovascular death, MI, or stroke, that was statistically significant. Now, that was the overall of the THEMIS trial for the classic intent-to-treat analysis. If we wanted to look at on-treatment analyses, the results are even stronger and more robust in terms of magnitude of benefit, statistical significance. The overall trial showed significant reductions in MI, and ischemic stroke and ST-elevation MI, in amputation and acute-limb ischemia. So really, the full spectrum of non-fatal ischemic events was significantly reduced with ticagrelor versus placebo on top of aspirin in THEMIS.

Now, THEMIS-PCI, looking at the 50% of patients with a history of prior PCI, largely stenting, there was an even larger reduction of 15% relative risk reduction—again, statistically significant, and therefore were willing to go into things like on-treatment analyses where the patients actually taking, adherent, not having side effects. There was even a reduction in all-cause mortality that was significant.

Now, there was a bleeding price to pay, as one would expect for ticagrelor versus placebo. It would be inconceivable that there not be an increase in bleeding. In the overall trial, there was over a doubling of rates of major bleeding. That was true both in THEMIS and THEMIS-PCI.

In THEMIS overall, really in the non-PCI patients, there was a signal toward more intercranial bleeding. In fact, it was significantly more intercranial bleeding. And that was largely due to subdural hematomas, largely due to falls, but still not a trivial thing to happen, intercranial bleeding. But the absolute rate in the overall trial is increased from 0.5 to 0.7 percent. So, small absolute increase, but statistically significant though.

That excess was really confined to the patients without a history of PCI. For that reason, the history of PCI patients within THEMIS and THEMIS-PCI had benefit. It didn't have the intercranial hemorrhage finding.

So, the net clinical benefit with respect to irreversible sorts of harms and outcomes seemed quite favorable in THEMIS-PCI—not so much in the no-PCI patient. So I think moving forward, where one would consider aspirin-ticagrelor extended-use would be of course in ACS patients, based on PLATO and PEGASUS, but also now in patients that have had elective stenting, save from stable angina, who it appears if they have diabetes would benefit from protracted aspirin and ticagrelor&mdash;assuming that there are low bleeding risk, assuming they have not bled while on dual antiplatelet therapy in the past. So that really sums up THEMIS and THEMIS-PCI.

Now, there’s one other trial that was just presented very recently, at least compared to the date of this taping, that a couple of days ago was the TWILIGHT trial—which examined high-risk PCI patients randomized to aspirin and ticagrelor. Everyone got it for 3 months, but then at randomization at that point, patients got ticagrelor monotherapy or a continuation of aspirin-ticagrelor for a year. And it transferred about a halving of the rates of major bleeding with ticagrelor monotherapy versus aspirin plus ticagrelor.

That's not surprising, obviously: ticagrelor plus a placebo will have less bleeding than ticagrelor plus aspirin—the aspirin could only increase bleeding. So that's interesting to see, but not at all unexpected. What was interesting and informed it from the trial was the rate of ischemic events were essentially similar in both of the arms.

So that's some support that, after 3 months—assuming the patients tolerated things well, not having problems with bleeding, with dyspnea, not having recurrent ischemic events there&mdash;that sort of patient who was randomized to the ticagrelor monotherapy or ticagrelor plus aspirin, ticagrelor monotherapy looks pretty good. So for some patients that might be an option, as well.

And potentially, even in THEMIS and THEMIS-PCI, especially what we saw there, the great efficacy may have been preserved with less bleeding if we dropped aspirin. In fact, we wanted to do that in an initial design of the study, but the FDA mandated aspirin. So you know potentially, there are areas where one might consider a DAPT and areas where one might consider ticagrelor monotherapy. In this rapidly-evolving field, what is the best anti-platelet cocktail for an individual patient?

Advances in the Treatment of CAD and T2DM

Overview of Cardiovascular Disease in CAD, T2DM

Antiplatelet Therapy in Coronary Artery Disease

THEMIS Trial Results