Thomas Cuisset, MD, PhD; Roxana Mehran, MD


July 10, 2014

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No Benefit From Prasugrel Pretreatment

Thomas Cuisset, MD, PhD: Hello. I am Dr. Cuisset, an interventional cardiologist from Marseille, France. I am here at EuroPCR with Roxana Mehran. Roxana, you just came from the Hot Line session. What can you tell us about the session?

Roxana Mehran, MD: This is a very exciting EuroPCR, with a lot of enthusiasm and excitement all around the convention center. I want to congratulate the meeting organizers for a great meeting.

I just came back from the Hot Line session on adjunct pharmacology. There were some subset analyses of the major trials that we all know about. The first was the subanalysis of the ACCOAST trial[1] -- the non-ST-segment elevation myocardial infarction (NSTEMI) patient population undergoing percutaneous coronary intervention (PCI). You can imagine that those are the patients whom we most want to pretreat. This prespecified subgroup might benefit from pretreatment. What do you think they showed?

Dr. Cuisset: I am aware of the data. Even patients with thrombotic lesions did not have any benefit from pretreatment with 30 mg of prasugrel.

Dr. Mehran: That was incredible to me. First of all, pretreatment made no difference in the overall population in any of the ischemic events, and it was associated with much more bleeding. It is basically saying that pretreatment with prasugrel is not worth it, and that you should find the anatomy and then give the drug. Even if you are going to proceed with PCI, you can give it on the table. You will have less bleeding and no difference in your ischemic complications.

It was unbelievable to me that they showed very clearly that patients with thrombus-containing lesions had a much worse outcome, with more myocardial infarctions (usually more periprocedural myocardial infarctions). Even in that subgroup, the P interaction was negative for pretreatment vs no pretreatment. You might think that pretreatment would work for that population, but it doesn't.

That raises a very important question about the fast-acting intravenous treatments, such as cangrelor. What do you think about that now? Do you think that is why we need cangrelor?

How Many Antiplatelet Drugs Do We Need?

Dr. Cuisset: We need something more than an oral drug in these high-risk NSTEMI patients, and it is probably the same in the STEMI population. There, we need intravenous antiplatelet drugs. Today we only have one option. We have the glycoprotein (GP) IIb/IIIa inhibitors, but clearly cangrelor would be a very good option for this specific population.

It is interesting to see that after the original ACCOAST study, a lot of physicians did not change their daily practice, and they still pretreat patients with NSTEMI with either clopidogrel or ticagrelor. The main question about ACCOAST is whether this is about a pretreatment strategy, or a pretreatment strategy with one specific drug.

Dr. Mehran: That is a good question. We have so much data now on pretreatment. Mark Sabatine's meta-analysis[2] from CLARITY PCI showed that pretreatment with clopidogrel was better than not treating at all.

Is it that prasugrel is so strong that when you give it at the time of PCI, it is just as good as if you gave it before? Or do we still have a hole in the window of treating patients, such that even the best drug -- prasugrel or ticagrelor -- may not work if you give it before the procedure because you still need time for these drugs to work? We can't answer these questions.

Dr. Cuisset: The evidence supporting pretreatment with clopidogrel was probably weak. We also have had a huge evolution in the devices we put in the patients. The timing of action of prasugrel is 30 minutes to 1 hour -- much faster than what we had with clopidogrel. The new generation of drug-eluting stents, with a very low rate of stent thrombosis, has also changed the global picture in non-STEMI patients who undergo PCI.

Dr. Mehran: I would agree. Even though we saw no effect from pretreatment on thrombus-containing lesions, the numbers were small. We could have been underpowered. We still have a lot of unanswered questions in this area.

Dr. Cuisset: A lot of people are pretreating patients with ticagrelor, which probably provides the same amount of platelet inhibition as prasugrel and thus led to a higher risk for bleeding in ACCOAST. Is it safer to pretreat the patient with ticagrelor or prasugrel, on the basis of the ACCOAST study?

Dr. Mehran: We don't know that, because they weren't compared in a head-to-head fashion. We do know from PLATO[3] that almost everyone was pretreated, because they received ticagrelor in the ticagrelor arm, or clopidogrel at the time of first presentation of acute coronary syndrome.

Dr. Cuisset: Was this before the cath lab?

Dr. Mehran: Yes, before the cath lab.

There were also a couple of interesting pharmacodynamic studies.[4,5] These studies show the pharmacodynamic variability among ticagrelor, prasugrel, and clopidogrel, but all were underpowered for clinical events, so we could not tell much from those studies: TRIPLETE[4] and BLESS.[5]

Bivalirudin in the Ambulance

Dr. Mehran: Finally, we heard a very interesting substudy of EUROMAX.[6] It was on a prespecified endpoint of the EUROMAX study.

EUROMAX was a European study for patients with STEMI who received early administration of bivalirudin vs heparin, with or without a GP IIb/IIIa inhibitor. All patients went to the cath lab, and primary PCI was performed. Many patients received the potent novel P2Y12 inhibitors. The big question was the early administration in the ambulance of bivalirudin and these agents.

The data have been published in the New England Journal of Medicine,[7] showing a reduction in death and bleeding in the overall population in favor of bivalirudin. They did a prespecified analysis (which, by the way, is now online in the European Heart Journal[8] as a simultaneous fast-track publication).

Of the 2100 patients who were enrolled, about 1000 had bivalirudin alone. with a provisional GP IIb/IIIa inhibitor in about 7%. In the other arm, one half of the patients who were in the heparin therapy group received routine GP IIb/IIIa drugs, but 460 of those patients had only bailout GP IIb/IIIa inhibitor therapy -- thus, a strategy of heparin alone with bailout GP IIb/IIIa inhibitor therapy. It was a little bit like HEAT-PPCI, but not randomized to that exact strategy.

This study had one half as many patients, but at least it gave an important analytical way of looking at it. The primary endpoints of death and major bleeding were in favor of bivalirudin alone, mostly driven by the reduction in bleeding complications, there was no reduction in death. Stent thrombosis was numerically higher at 30 days; it did not reach statistical significance, but the noise was there. The study was underpowered.

It is very interesting that the bailout rate of GP IIb/IIIa inhibitor use in the heparin alone group was 25% vs 7% in the bivalirudin arm. That is an important observation -- more bailout GP IIb/IIIa inhibitor therapy in patients who received heparin. Obviously, this is an open-label study, so it is open to bias. There are many issues there, but the results were different from what we saw with HEAT-PPCI.[9]

Dr. Cuisset: With HEAT-PPCI, we had the same rate of bailout use of GP IIb/IIIa inhibitors, which was about 15% in both groups. The final result in HEAT-PPCI showed no difference in terms of bleeding. Do you think the difference of practice among HORIZONS-AMI,[10] EUROMAX, and HEAT-PPCI concerning the rate of GP IIb/IIIa inhibitor use or the rate of radial access might have also affected the results of the different studies?

Dr. Mehran: There is no question when you look at HEAT-PPCI. It is a contemporary primary PCI, especially if you are doing 90% through radial access, and about 80% of these patients receive novel P2Y12 inhibitors. This was a single-center, well-done study. They prospectively randomized these patients and included everyone -- an all-comers STEMI study.

Putting all of the ethical issues aside, this is a wake-up call for us. We need to revaluate this. Is this real? Are those bleeding events right? Were they correctly ascertained? I would call the reinfarctions "reocclusions," because it is hard to adjudicate reinfarction in the setting of a STEMI. These were acute stent thromboses, but we have seen stent thromboses in EUROMAX and HORIZONS (with bivalirudin). The only things we did not see that we have always seen in the past are the bleeding rate, which was exactly the same, and the bailout rate, which was also exactly the same. It needs to be explored further, and if it is true, then we need to reexamine that strategy.

DAPT Disruption More Common in Women

Dr. Mehran: Finally, I presented a subanalysis[11] of the PARIS registry data by sex. We looked at men and women, and at the modes of discontinuation, interruption, and disruption of dual-antiplatelet therapies. Of interest, discontinuation and interruption, both guided by a physician, were very similar between men and women, but women had significantly higher disruption.

Dr. Cuisset: Was it because of bleeding?

Dr. Mehran: There was more bleeding, because they also had more major adverse cardiac events and more cardiac death; but when we looked, we wondered whether the impact of disruption was much worse on women, because they have more comorbid conditions. The P for interaction was negative.

Disruption is bad, whether you are a man or a woman. It is more frequent in women. That was the bottom line of the sex analysis of the PARIS data.

Dr. Cuisset: Thank you for this update on the Hot Line session.

Dr. Mehran: Thank you.


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