Triple Therapy: When AF and Stents Collide

Bernard J. Gersh, MB, ChB, DPhil; Robert D. McBane, MD


July 18, 2014

Editorial Collaboration

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Who Needs Triple Oral Antithrombotic Therapy?

Bernard J Gersh, MB, ChB, DPhil: This is Bernard Gersh from the Mayo Clinic, and with me, a colleague and friend Rob McBane, professor of medicine at the Mayo Clinic and head of the vascular section within the division of cardiovascular diseases. Rob is a world expert in many aspects of thrombogenesis, both from an etiological and basic-science perspective and a clinical perspective.

We are going to talk about a very controversial subject, and that is triple oral antithrombotic therapy. We are talking specifically about the combination of aspirin, clopidogrel, and warfarin, and we will also talk about the novel oral anticoagulants. First, what patients are we talking about? Who needs triple therapy?

Robert D McBane, MD: First, we should underscore the magnitude of this issue. We might think that triple oral antithrombotic therapy is not a very common scenario, but, in fact, it's extremely common. There are probably four to six million individuals in our country with atrial fibrillation and 16 million with coronary disease. We do more than a million catheterizations with an intervention each year, and most of those interventions, 70%, are with a drug-eluting stent.

Dr Gersh: Do nearly all of these patients have atrial fibrillation, plus other indications for dual antiplatelet therapy?

Dr McBane: Exactly right. They have the indication for dual antiplatelet therapy for their coronary stents, but they might also have atrial fibrillation. They might have had a venous thrombotic event, which then forces us to at least consider an anticoagulant. This is a large number of patients, 250 000 by my calculation.

Dr Gersh: You mentioned the coronary stents, but what about patients who simply have had an acute coronary syndrome and don't have a drug-eluting stent, but are on warfarin because they have atrial fibrillation. Isn't that an indication for dual antiplatelet therapy?

Dr McBane: It would be another indication. My back-of-the-card estimate of 250 000 is probably very low. Many patients in our country and across the world have at least a theoretical indication for triple therapy, so this is a big deal and cardiologists need to know about this.

Triple Therapy and Bleeding Risk

Dr Gersh: It is a big deal, and the risks are substantial. Can you give us an idea of the magnitude of risk? What bleeding rates are we talking about over a year's time with triple therapy?

Dr McBane: This has been studied in large cohort trials with many thousands of patients, from Denmark[1] and other countries.[2] In fact, a fair amount of data has assessed this. In general, the risk for major bleeding (however you want to define major bleeding), is 10% to 15% annually if a patient is given triple therapy. Triple therapy doubles the rate of major bleeding compared with dual antiplatelet therapy, and it essentially triples the rate of major bleeding compared with monotherapy with aspirin, clopidogrel, or warfarin. A quick way to remember it, is "triple therapy doubles the risk compared with dual therapy and triples the risk compared with monotherapy."

Dr Gersh: That's a very important rule to remember, and it is a very sobering figure. Whichever way you look at it, these are high-risk patients. There is a potential reward, but there is also significant risk.

Dr McBane: As cardiologists, we tend to want to do anything we can to prevent a clot, but we have to keep in mind that a major bleed can be a life-threatening event. That is the conundrum.

Dr Gersh: There seems to be a paradox. In patients with drug-eluting stents who have had an acute ischemic event (an acute coronary syndrome), we tend to focus on preventing recurrent ischemic events, and we don't focus as much on the risk for bleeding.

A very good study was done in Canada by Devereaux several years ago and published in the BMJ.[3] Devereaux conducted a survey of physicians and patients with atrial fibrillation and asked what bothered them most. Patients were very worried about stroke, and physicians were very worried about bleeding, a near reversal of attitudes. In the setting of an acute coronary syndrome and drug-eluting stents, it is the specter of late stent thrombosis that worries us. We focus primarily on the ischemic event and less on bleeding events.

Dr McBane: What do you think of the new generation of stents? What's your sense of these devices and the risk for stent thrombosis? Everything hinges on that.

Dr Gersh: A network meta-analysis was just published in the BMJ by Stephan Windecker from Switzerland and his colleagues.[4] They looked at several trials involving approximately 100 000 patients, and it looks as though the third-generation stents are associated with a lower rate of stent thrombosis and probably a lower event rate. This is a very important meta-analysis. How this will play out in our approach to dual and triple antithrombotic therapy in the next few years is going to be exciting.

WOEST: Drop Aspirin?

Dr Gersh: Given the high risk for bleeding, several smaller trials have looked at alternative approaches. One is the WOEST trial.[5] Can you tell us about trial and your thoughts about it?

Dr McBane: The WOEST trial is fascinating. It has about 570 high-risk patients, who underwent a coronary intervention and were then randomly assigned to receive either triple therapy or dual therapy with warfarin and clopidogrel.

One would anticipate that the rate of bleeding would be reduced in dual therapy vs triple therapy. But what was fascinating was that the rate of ischemic events didn't worsen. Patients receiving dual therapy did better in terms of ischemic events compared with triple therapy, which doesn't correspond with what we believe but is nonetheless provocative.

Dr Gersh: This was a hypothesis-generating study. The question is—and the guidelines wrestle with this—that WOEST would suggest that we could get away from triple antithrombotic therapy by treating patients with warfarin and clopidogrel, but are we ready to do that in practice? Do we actually have the data? Ongoing trials are looking at this and at using such drugs as ticagrelor [Brilinta, AstraZeneca] in this setting. It's a changing backdrop.

However, if you had a high-risk patient right now and you were worried, or you had your patient on triple therapy and he bled, what would you do?

Dr McBane: There is certainly reason to consider dual therapy in that circumstance. Part of the process in my decision making would be to assess the atrial fibrillation risk, and if the patient had a low CHADS2 score or a CHA2DS2-VASc, I might consider either dual therapy with warfarin or even dual antiplatelet therapy. If the patient had a CHADS2 score of 1 and needed this therapy, I might consider withholding the anticoagulant for a period of time.

Many of our patients won't have a CHADS2 score of 1, or they may have a higher CHA2DS2-VASc score, and then the issue is what to do.

Dr Gersh: These patients are not going to have a CHA2DS2-VASc score of 1. They have coronary disease, and they are going to have other risk factors. The problem is that the WOEST trial, although interesting, was underpowered, so we don't really know.

What Place for Aspirin in AFib?

Dr Gersh: Before we move on to the novel oral anticoagulants (NOACs), may I make a statement and ask you a direct question? It has been said that the major cause of bleeding on warfarin is aspirin, and now we also have new data from the NICE UK recommendations that said there is no place for aspirin in atrial fibrillation other than in people with coronary disease. Would you agree with that?

Dr McBane: The aspirin aspect is really evolving, isn't it? We would stand firmly on aspirin a few years ago, and now it seems to be shaky ground.

Dr Gersh: We are talking about atrial fibrillation alone.

Dr McBane: If it's atrial fibrillation alone without acute coronary syndrome or a drug-eluting stent, apixaban [Eliquis, Bristol-Myers Squibb/Pfizer] is a wonderful option. For example, if the patient has a low CHADS2 score or a low CHA2DS2-VASc score and I wasn't sure whether to use warfarin or aspirin, apixaban is the game-changer because it has now been shown to be superior in AVERROES,[6] and it has a very low bleeding rate, similar to aspirin. That low-CHADS2-score-risk patient is probably best served with a novel agent. Would you agree with that?

Dr Gersh: I have a conflict of interest in that I have been involved with the ARISTOTLE trial[7] from the beginning and still am. I want to be very specific. The WOEST approach of warfarin and clopidogrel is promising but unproven. It is perhaps something one would use clinically in a patient who has already bled, but we need more data.

Furthermore, the duration of dual antiplatelet therapy, which clearly influences the duration of triple therapy, remains to be determined. A number of trials are ongoing. The expectation is that the duration of dual antiplatelet therapy will become shorter, and, therefore, the exposure to triple therapy will be less.

NOACs in Triple Therapy

Dr Gersh: Now we come to the NOACs—apixaban, rivaroxaban [Xarelto, Bayer Pharma/Janssen Pharmaceuticals], and dabigatran [Pradaxa, Boehringer Ingelheim]. We haven't tested them in this situation. That would be a very good trial—warfarin vs a novel agent in people on dual antiplatelet therapy or even in people on clopidogrel. We haven't tested them yet in this setting.

Dr McBane: We haven't, but hypothesis-generating trials include the APPRAISE-2[8] trial with apixaban, which looked at high-risk coronary patients, randomizing them to apixaban plus dual antiplatelet therapy or dual antiplatelet therapy alone. APPRAISE-2 was a negative trial with respect to ischemic outcomes.

Dr Gersh: Yes, they had to stop prematurely.

Dr McBane: However, if you look at the major bleeding rates, they were about 2% to 2.5% in the patients receiving apixaban.

Dr Gersh: There was a high rate of ischemic events.

Dr McBane: Right, and that is a very important point. However, if you were concerned about bleeding, at least the APPRAISE-2 trial suggests that if you extrapolated that to atrial fibrillation (which needs to be done in a trial, as you pointed out), one would hope that the bleeding rates would be low. The nice part about APPRAISE-2 was that the apixaban arm was 5 mg, twice a day.

Dr Gersh: The APPRAISE trial failed in terms of recurrent ischemic events.

Dr McBane: Apixaban did not improve outcomes relative to placebo, both groups having dual antiplatelet therapy. So it was a negative trial from an ischemia standpoint but reassuring from a bleeding standpoint [Editor’s Note: In APPRAISE-2, TIMI major bleeding was significantly higher in patients who received apixaban vs placebo].

Dr Gersh: So are you suggesting atrial fibrillation is an area where we perhaps could justify a trial?

Dr McBane: Absolutely.

Dr Gersh: In ATLAS,[9] which was a positive trial for rivaroxaban, how many ischemic events occurred in patients with atrial fibrillation?

Dr McBane: I don't remember, but it would be a low number. ATLAS was very interesting, as well. The difference between ATLAS and APPRAISE-2, however, was that the dose of rivaroxaban in ATLAS was not high enough to be used for atrial fibrillation alone. They used an abbreviated dose—2.5 mg and 5 mg in the active arm. On the other hand, maybe 2.5 to 5 mg could be reasonable if you are already using antiplatelet therapy.

Predicting the Future of Anticoagulation

Dr Gersh: This remains an extremely difficult area. In terms of triple therapy, it would be very interesting to see trials of the NOACs. I'm sure you don’t want to predict the future, but what are we going to be doing in two years' time for a patient who has a drug-eluting stent for an acute coronary syndrome and is in atrial fibrillation? Just a quick guess. We won't hold you to it.

Dr McBane: If I had to guess, my prediction would be that dual therapy with an anticoagulant plus an antiplatelet agent will be the mode of the future. Whether that anticoagulant is warfarin or one of the NOACs is hard to say, but I am very concerned about this risk for bleeding. The antiplatelet will be clopidogrel, or at least a thienopyridine.

Dr Gersh: Good-bye, aspirin.

Dr McBane: It will be very interesting to see.

Dr Gersh: And the duration of therapy will probably be less with the newer stents?

Dr McBane: Six months. Some people say even less, but we'll have to see.

Dr Gersh: This is an area for more trials with the new anticoagulants.


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