Seth Bilazarian, MD; Nikolaus Sarafoff, MD

Disclosures

October 22, 2014

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Seth Bilazarian, MD: Hi. Seth Bilazarian, from theheart.org on Medscape, at the TCT 2014 meeting in Washington, DC.

This is my blog, and I am very fortunate to be accompanied by Dr Nikolaus Sarafoff from the ISAR Study Group in Munich, who recently presented the ISAR-TRIPLE study.[1]

He is going to review the ISAR-TRIPLE study with us, but it helps to add some additional information. Managing the patient with both atrial fibrillation and either an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) is really a vexing problem for community practices. Do we use three drugs? Do we use two drugs? How long do we use them? I am very excited to have Dr Sarafoff share the summary of the data and then talk to him about what he does in practice. Thanks for joining me.

Nikolaus Sarafoff, MD: Thank you, Seth, for inviting me. I want to talk first about the ISAR-TRIPLE study. We started this trial because we wanted to evaluate the optimal duration of triple therapy in patients who have an indication for oral anticoagulation, mainly patients with atrial fibrillation but also patients with mechanical valves or deep vein thrombosis, pulmonary embolism.

We randomized patients with an indication for oral anticoagulation to either six weeks of clopidogrel therapy (a very short period) after drug-eluting stent placement or six month's of clopidogrel in the setting of aspirin and vitamin K antagonist therapy. The primary endpoint of our study was a net clinical outcome, which included the endpoints of death, myocardial infarction, stent thrombosis, stroke, and TIMI major bleeding.

In our study, the shorter duration (six weeks) was not superior to the six-month duration for the primary endpoint. We also had secondary endpoints, including the composite of ischemic complications (cardiac death, myocardial infarction, ischemic stroke, and stent thrombosis), and there was also no difference in those outcomes nor were there significant differences in the TIMI major bleedings between both groups.

When we analyzed results according to the more recent Bleeding Academic Research Consortium (BARC) criteria and included any BARC bleeding, the first thing we saw was very high bleeding rates: up to 40% after nine months, which is in line with the data from the WOEST trial.[2] In a post-hoc landmark analysis performed after the six-week clopidogrel therapy, we saw that there was a reduction in any BARC bleeding events in the six-week group (aspirin and oral anticoagulant [OAC]) compared with the six-month group (aspirin, clopidogrel, and OAC).

So these were the results of ISAR-TRIPLE.

Dr Bilazarian: Great. As your study was ending, of course, we have WOEST data. They went in a different direction in that they removed aspirin, whereas you removed clopidogrel early in your study. Tell me how this is going to impact your practice once you return home after presenting these data, in terms of the treatment of patients with atrial fibrillation and the need for antiplatelet therapy.

Dr Sarafoff: Managing patients with triple therapy is challenging for the treating physician because on the one hand we fear the bleeding risks, and on the other hand, when we de-escalate antithrombotic therapies, we fear an increase in ischemic events.

When we have a patient with a high bleeding risk who receives a drug-eluting stent, one might say that according to our study it is okay to reduce the duration of triple therapy to six weeks only. On the other hand, when we have a patient with a high thrombotic risk (eg, bifurcation lesions, a proximal left anterior descending, or a left main stem lesion), it is also okay to leave them on six-month duration of triple therapy, because we saw that although there might be some increase in BARC bleedings, the TIMI major bleedings—those which we fear—are not increased.

Dr Bilazarian: It seems like you have taken the information from ISAR-TRIPLE to allow use of either shorter or longer therapy at the physician's discretion, according to their fear of ischemic vs bleeding risk. Is that a correct summary?

Dr Sarafoff: Yes, because we could not show superiority for the six-week group as compared to the six-month group, so we cannot say that this is better. But we actually don't know the optimal duration of treatment after drug-eluting stent placement. In patients who don't have an indication for oral anticoagulation, there is a huge debate about whether to give six months, 12 months, or even shorter durations of three months or one month. In our population, the majority of patients had newer-generation drug-eluting stents. It is probably possible to give short durations of triple therapy.

Dr Bilazarian: We are practicing in a data-free zone, so to speak, in that we are not really sure whether we should use triple therapy of shorter or longer duration, as you have shown in ISAR-TRIPLE. Another variation is to switch to a novel oral anticoagulant (NOAC) and not use warfarin. There are so many different options here that it can be vexing for a physician to make the best decision. And as you said, the thing we fear most as interventionalists is stent thrombosis and the subsequent risks for death or myocardial infarction. Yet we know that our patients' greatest fear is the risk for stroke. Doing the best thing is very difficult. It is hard to have these conversations with the patient because how do you provide good counseling when you are not really sure?

How are you moving forward? Are you going to stick with triple therapy or will you at times also use two drugs rather than three drugs (more like WOEST) in certain subsets? How will you integrate this with the WOEST data while we wait for more data in the coming years?

Dr Sarafoff: This is a difficult question.

Dr Bilazarian: I asked you a difficult question on purpose because we are faced with it 5% of the time, actually.

Dr Sarafoff: These were two trials looking at the same thing from a different point of view. If a patient has a very high bleeding risk at the outset, where I'm even afraid of giving him any antiplatelet therapy, then I would be comfortable in omitting aspirin. However, in patients who have an acceptable bleeding risk, I would start with triple therapy and then adjust the duration of triple therapy according to the thrombotic risk.

Dr Bilazarian: That is very helpful. What about other drugs? You mention possibly omitting aspirin based on a higher bleeding risk, maybe formally using a HAS-BLED score greater than 2.0, which the European Society of Cardiology has suggested in the European Heart Journal[3] this year.

What about other therapies? Generally speaking, most of us have adopted use of NOACs because of their efficacy and safety benefits compared with warfarin when used as single therapy. How about using NOACs in this setting? Do you feel that this is an option right now or are you hesitant to use those with some antiplatelet therapy?

Dr Sarafoff: I think it is an option to use the NOACs in the setting of triple therapy, because from all NOAC studies we know that, compared with warfarin, they are either noninferior or have fewer bleeding events. However, we do not have much data on this type of triple therapy setting, except for one analysis from the RE-LY trial, where it was indeed shown that the lower bleeding rates with dabigatran as compared with warfarin were also seen in patients on triple therapy.[4] The bleeding rates were significantly lower with dabigatran 110 mg. This is minor bleeding events, not the major bleeding events. I want to emphasize that.

Currently there is no proven strategy for reducing major bleeding events. Neither the subgroups of the RE-LY trial nor the WOEST study could show reductions in TIMI major bleedings. ISAR-TRIPLE didn't show that either. Clearly, major bleedings are difficult to reduce in this setting.

I think the NOACs may be used, but you should use the lowest possible dosage, which would be dabigatran 110 mg, rivaroxaban 15 mg, or apixaban 2 x 2.5 mg.

Dr Bilazarian: For the American physicians, I should point out that that dabigatran dose is not available to us; we only have the 150-mg dose of dabigatran in the US.

Do you have a different approach in, say, the ACS patient vs an elective PCI patient? Are you more inclined to use two drugs or shorter duration with an elective PCI patient? Help us understand about that. Do those clinical factors make an impact on you?

Dr Sarafoff: Patients with an ACS, whether there are stents or not, have a higher thrombotic risk than a patient who receives a stent for stable coronary artery disease. Therefore, in ACS patients I would start with triple therapy. After one to three months, I am willing to de-escalate triple therapy and I would definitely continue with clopidogrel rather than with aspirin.

While I would probably discontinue clopidogrel in a stable patient, I would discontinue aspirin in the patients with ACS and leave them on dual therapy until one year.

Dr Bilazarian: Are there any things at this point while we wait for more data from large trials like RE-DUAL PCI[5] and PIONEER AF-PCI[6]? Those data are probably several years away.

Dr Sarafoff: I think the more potent P2Y12 inhibitors have shown reductions in thrombotic events but have also shown significant increases in bleeding events. So far we only have data from a retrospective study that we were able to publish last year, showing that prasugrel increased bleeding risk in patients with triple therapy.[7]

At the moment I wouldn't use agents such as prasugrel or ticagrelor in patients with triple therapy, unless the patient had a stent thrombosis while on clopidogrel or has an allergy to clopidogrel.

Dr Bilazarian: Okay. Would there be any patients in whom you would be more likely to use a NOAC? A higher CHADS2 score? Or a higher bleeding risk score rather than warfarin—would that sway you at all in regard to the NOAC data that we have?

Dr Sarafoff: Currently there is no good way to know whether to use a NOAC or a vitamin K antagonist. What is reasonable, and what is also written in the new European guidelines on this issue, is that in patients who are already on a vitamin K antagonist or a NOAC, leave them on that medication. When you start with oral anticoagulation, then you have to choose based on the patient's risks and preferences.

But current data do not allow us to recommend one over the other.

Dr Bilazarian: What a very difficult topic. Thank you for trying to clarify it for us. I don't think that we have any definitive answers on this topic, but your contribution has been fantastic and the ISAR-TRIPLE study gives us relative confidence in shorter-duration triple therapy. Going forward, we still have to rely largely on consensus opinion; some of it is formal consensus like that from the ESC, but it's also consensus from knowledgeable physicians like you.

I really appreciate you talking with me today and helping me understand how to best manage the 5% of patients who come to the cath lab for a coronary intervention and who also have atrial fibrillation. Thank you, Nikolaus Sarafoff, for joining me. Until next time, I'm signing off from the Washington, DC, meeting of the TCT 2014.

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