RE-DUAL PCI: Testing Triple and Dual Therapy Regimens

RE-DUAL PCI

Samuel Z. Goldhaber, MD: Hello. This is Dr Sam Goldhaber for the Clot Blog at theheart.org on Medscape speaking to you from the American Heart Association Scientific Sessions in Chicago. We are very fortunate to have Dr Chris Cannon from Brigham and Women's Hospital and Harvard Medical School with us today. I have asked Chris to talk about a new trial on which he is principal investigator called RE-DUAL PCI.^[1] Do you want to tell our Clot Blog audience what RE-DUAL PCI is all about?

Christopher P. Cannon, MD: We are studying how to manage antithrombotic therapy in patients who have both atrial fibrillation and need to undergo percutaneous coronary intervention (PCI). The issue is that they have two different types of clots. First, there is the arterial clot in the artery, the reason that they need the PCI. Dual antiplatelet therapy has been shown to be more beneficial than aspirin in this situation. With atrial fibrillation, there is more of a low shear stress clot, for which anticoagulation has been shown to be better than antiplatelet therapy. So for the patients who have both at the same time, they have needed so-called triple therapy. We all know the bleeding risk that comes with triple therapy, so it has been a difficult conundrum. How do we adjust therapy for these patients? This trial is looking at different regimens to try to see whether we could find a new approach.

Following WOEST: Dropping Aspirin

Dr Goldhaber: What are the regimens in RE-DUAL PCI?

Dr Cannon: The backdrop was the recent WOEST trial,^[2] which captured everyone's attention and made it into guidelines. They looked at triple therapy and compared it with double therapy, dropping aspirin. None of us had dared to drop the aspirin in any of our previous trials, but they found both lower bleeding rates (not surprisingly), and lower thrombotic rates. The problem is that it was just a 600-patient study, so we are adopting the concept of double therapy (without aspirin) vs a control arm in which we use three drugs.

We are looking at patients with nonvalvular atrial fibrillation undergoing PCI (for either acute coronary syndrome or an elective indication), and the patients will have the PCI under whatever therapy (aspirin, etc.) that they are on. After the PCI, they will be randomly assigned to one of two doses of dabigatran ([Pradaxa®]; 150 mg or 110 mg twice daily) with a P2Y12 inhibitor and no aspirin, so we are adopting the full WOEST approach.

No Prasugrel Allowed

Dr Goldhaber: So they can receive clopidogrel [Plavix®] or ticagrelor [Brilinta®]?

Dr Cannon: Right. We aren't allowing prasugrel [Effient®]. There was a recent publication^[3] that reported a fourfold higher risk of bleeding in the triple-therapy setting with prasugrel. It is not well-defined with ticagrelor, and we know of the bleeding risk with clopidogrel.

Dr Goldhaber: Does everyone receive mandatory aspirin for some period of time?

Dr Cannon: For the PCI, they would receive aspirin. In those two arms, it would immediately be stopped, so they have about a week's worth of aspirin.

The control arm is a warfarin arm. It's currently the standard therapy arm, so it will be triple therapy. But we have done two things to enhance the triple therapy and keep it current. We have shortened the duration of dual antiplatelet therapy to 1 month for the bare metal stent and 3 months for the drug eluting stent, and we are dropping the aspirin in those arms so they soon become a double therapy group.

Dr Goldhaber: That is why it's called RE-DUAL PCI?

Dr Cannon: I think that's true. We never quite know with these acronyms. Of interest, there are about 40 different combinations that you could try with the three different novel agents and three different antiplatelet agents (the P2Y12 inhibitors and aspirin) and different doses, so there is a dizzying number of potential regimens, none of which has evidence. We are studying a few of them. Some other trials are ongoing.

Dr Goldhaber: Is the primary endpoint in RE-DUAL PCI an efficacy endpoint or a major bleeding safety endpoint?

Dr Cannon: Both.

Dr Goldhaber: It's a co-primary endpoint?

Dr Cannon: That's an interesting statistical issue -- how do we balance it? We are actually testing for noninferiority of both of these regimens separately, and our hypothesis is that it would meet both noninferiority for thrombotic events and for bleeding events. If that is shown, we can test for superiority, and we hypothesize that the 110-mg dose of dabigatran would have a lower rate of major bleeding. It's not the typical net benefit combined endpoint but rather separate evaluations as we do clinically. It was planned to be a very large trial, about 8500 patients.

Dr Goldhaber: Is it a global trial?

Dr Cannon: Yes, it is a global trial, in 40 plus countries. It's just getting underway, and we are very excited. Everyone wants evidence in this field.

A Daring Study?

Dr Goldhaber: It's a daring study, isn't it? Novel oral anticoagulants have been tried before in acute coronary syndrome, and they have been stopped because of bleeding complications, haven't they?

Dr Cannon: In the non-atrial fibrillation patients, not surprisingly, triple therapy with novel agents has had high bleeding rates, and that's why I think we have all been so encouraged with this idea of dropping aspirin out of the regimen. You would have a strong antiplatelet and a good anticoagulant as a regimen, and that may be one that finds that balance of efficacy and safety.

Dr Goldhaber: How long do you think this trial will go to enroll this large number of patients?

Dr Cannon: Roughly a year and a half to 2 years of enrollment, and then we have a minimum of 6 months of follow-up. But it's event driven, and so we will not see exactly how long it will take.

Dr Goldhaber: Every patient is randomized either to dabigatran 150 mg twice a day or dabigatran 110 mg twice a day?

Dr Cannon: Or warfarin.

Dr Goldhaber: There is a 1:1:1 allocation ratio.

Dr Cannon: Exactly. One adaptation for the elderly outside of the United States is that the 150-mg dose is not recommended for those over the age of 80. For elderly patients outside the United States, it will be 1:1 randomization, 110 mg dabigatran vs warfarin.

Dr Goldhaber: It sounds like a very exciting trial, and we are going to learn a lot more on how to lower ischemic events and also improve safety in this very challenging population with atrial fibrillation and multivessel coronary disease.

Dr Cannon: Yes.

Dr Goldhaber: Thank you for sharing this preview of RE-DUAL PCI. This is Dr Sam Goldhaber signing off for the Clot Blog.

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Cite this: RE-DUAL PCI: Testing Triple and Dual Therapy Regimens - Medscape - Mar 05, 2015.