THEMIS Trial Results

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

Bhatt: 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—it turned out 15% of patients were treated with PCI in the past—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—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—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?