Balancing the Risk and Benefit of Anticoagulation in Patients on BTKi


Carrie Lenneman, MD, MSCI, and Farrukh Awan, MD, review the risk versus benefit of anticoagulation strategies in patients on BTKi.

Farrukh Awan, MD: We’ll keep talking about specific things. I’ll tell you a few specific issues that I deal with. I’m sure a lot of people in the audience might have to deal with these issues. I’ve had problems, and I’ve had discussions, arguments, and fights with various cardiologists. With the cardio-oncology group, as we keep working with them, we have a very nice equation and we’re thinking the same thing. But initially, at least when we weren’t sure how this would pan out and what the issues are, there was always a debate about balancing the risk of bleeding vs the risk of stroke with AFib [atrial fibrillation]. The argument was that if you had ibrutinib—because that was the first 1, so we had the most experience with it and probably similar risks with the other 2—then your risk of major bleeding in the real-world setting is probably 8% to 10%, maybe lower, maybe higher. The risk of minor bleedings could be as high as 30%.

My understanding is even with a high CHADS-VASc [CHA2DS2-VASc] score, the risk of stroke is still 6% to 7%. So major bleeding is a pretty drastic life event; it can be catastrophic. A major stroke can be catastrophic. But is there a cutoff for anticoagulation? Initially, when we started treating these patients, we categorically said, I’m not going to anticoagulate those patients. We’ve published our results, and we had 1200 patient-years of follow-up. We followed more than 600 patients treated with ibrutinib. Of the 1200 patient-years of follow up, we had 0 strokes. That was important because only 30% of those patients had AFib—around 70 patients, so roughly 10% to 15% had AFib. Of those 10% to 15% of patients with atrial fibrillation, we anticoagulated less than 30%, and 70% were not anticoagulated despite the AFib. Cardiologists early on were saying, “You guys are crazy.” I wasn’t willing to risk it when I saw a huge hemothorax or hemoperitoneum. I was scared; I didn’t want to risk it. I saw the hematomas and all those things. A bunch of us decided not to anticoagulate those guys. As luck would have it, none of those patients had a stroke, so we feel comfortable anticoagulating those patients even though this is the kind of question that will probably never have a randomized study to address it. I’ve always wondered, if it’s a person who has a cardiac or mitral valve or something and they need to be on warfarin, that’s a completely different beast. If somebody has a PE [pulmonary embolism] and needs to be on anticoagulation, I understand. But for these patients with irregular AFib without valvular heart disease or prosthetic valves, who have a low to moderate CHADS-VASc score, is it safe to omit anticoagulation? That’s difficult to answer.

Carrie Lenneman, MD, MSCI: You’re right. We’re in a space where there aren’t a ton of clinical data. This population on BTK inhibitors may be similar to our patients with chronic kidney disease. Ironically, our dialysis patients who get AFib don’t tend to have a lot of strokes from a cardioembolic standpoint, which is weird. There are some cases where we don’t anticoagulate those individuals. We’ve seen a relatively low incidence of strokes with those patients, so I think there are different entities. Obviously we already know that people on BTK inhibitors will bleed because their platelets don’t work normally. We do know they probably have some protective benefit in general.

I’ll tell you my personal bias. In a person who has a really high CHADS-VASc score, we’re looking at not just a CHADS-VASc of 1 or 0, where in a real-world population if I had a patient with a CHADS-VASc of 0, 1, I always anticoagulate. But if you’re a CLL [chronic lymphocytic leukemia] patient on a BTK inhibitor with a CHADS-VASc of 2 or more, I will have that patient-centered discussion about the risks and benefits of being on anticoagulants. And I tend to start with Eliquis, but at a low dosage, 2.5 mg twice a day. So it’s, how do I balance these 2 things? Where are the data? There aren’t great data. This is where we’re at. We’re acting in a waiting room trying to use common sense. This maybe is the art of medicine: how do we balance these 2 things? I do think with the increased use of left atrial appendage occluder devices, this may become less of an issue. Once we find A-fib, we can put in an occluder device, put them on anticoagulants for a very short period of time. Usually it’s aspirin and Plavix. Have aspirin and Plavix for 45 days, then go on aspirin alone. This may become less of an issue. I hope it will be because these therapies are helpful for sure for patients with CLL.

Farrukh Awan, MD: I completely agree with you. I’ll tell you my funny anecdote. I guess you live and learn. A few years ago, when we started using ibrutinib, we didn’t know what was going to happen. On the early phase 1 studies and even before it was approved, we had to put a patient on an anticoagulation that was allowed. I remember distinctly. This is why I use apixaban rather than rivaroxaban. Its once a day. It’s so much easier. We use a once-a-day drug vs a twice-a-day drug. Initially we had used Xarelto or rivaroxaban. Nothing against the drug. It’s a beautiful drug. But I was seeing more blood blisters, and I was seeing a lot more bruising, and a very annoying minor bleed. Fortunately, there was no major bleed. As a result, because of these issues, I saw a bunch of patients back-to-back. My theory was that maybe it’s once a day, so the compliance is better and the drug is effective much more than possibly Eliquis. Maybe the compliance is not as good with Eliquis than it is with a once-a-day drug. That’s why I switched to Eliquis. Since then, I have not had any problems with apixaban. The question that gets asked is exactly the 1 you addressed. Can I use a low dose? Can I use edoxaban? Can I use all the newer DOACs [direct oral anticoagulants]? Because they have theoretically a lower incidence of bleeding, are those any safer? What I’ve been telling people is that with low-dose anticoagulation, my preferred drug is apixaban. But it’s probably not wrong to use the other DOACs. What do you think?

Carrie Lenneman, MD, MSCI: I totally agree. My go-to is obviously using apixaban. That’s 2.5 mg twice a day. But you bring up a good point. It’s not as easy for compliance. I will say head-to-head that taking CLL out of the picture, looking at all comers for AFib—the data bear true that of all them that you compare—head-to-head apixaban, edoxaban, and rivaroxaban—apixaban still has a lower bleeding risk. The next in line would be edoxaban, and then that little higher bleeding risk would be rivaroxaban. It’s just a percentage or so, but that percentage—especially in a patient with CLL—is a big deal. That’s another reason why I reach for apixaban even over edoxaban, although I use edoxaban for a lot of other clotting issues in patients cancer. It’s been well studied. Those are just some real-world things that I find helpful.

This transcript has been edited for clarity.

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