Cardiovascular Risks of BTK Inhibitors: What Pharmacists Need to Know

At the ACC 2025 Scientific Sessions, Pharmacy Times® spoke with Sarah Spinler, PharmD, FCCP, FAHA, FASHP, AACC, professor at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University, about her presentation on the increased risk of atrial fibrillation (AF) in patients with cancer. She shares key insights about AF risk and management, as well as key drug-drug interactions pharmacists should be aware of when treating patients for cancer and AF.

Pharmacy Times: What types of cancers and cancer treatments are most commonly associated with AF?

Sarah Spinler, PharmD, FCCP, FAHA, FASHP, AACC: So, [AF] is most commonly associated with breast cancer, lung cancer, prostate cancer, colon cancer. There's an increased risk of stroke in patients who have AF and breast cancer or prostate cancer.

Pharmacy Times: How do cancer treatments impact stroke risk stratification in AF patients?

Spinler: So, for the session that we talked about today, the primary classes that we talked about were the BTK [Bruton tyrosine kinase] inhibitors. I remember doing a session here at ACC maybe 5 years ago when those were relatively new, and there was only one drug in the class.

Ibrutinib [Imbruvica, Janssen Biotech, inc] has probably had the most experience and is the one that's most commonly associated with [AF]. It probably increases your risk up to maybe 25% to 30% in patients that have [AF], and it tends to happen within the first, say, 5 months. But the patient in the case that we discussed today—that was presented—that happened within a week. So, not that uncommon.

Currently, because of some of the cardiovascular risks, some of the second- and third-generation ones may be preferred but may not necessarily always be available for patients to use. In head-to-head trials, acalabrutinib probably has less, and the third-generation agent zanubrutinib [Brukinsa; BeuGene] has less, but it hasn't been studied head-to-head with the second-generation one that I'm aware of. They have less in terms of [AF], but it's still not insignificant. So, the risk is still higher with all of the agents in the class compared to not being treated.

Pharmacy Times: What are the key drug-drug interactions that clinicians need to be aware of when managing AF in oncology patients?

When you think about managing AF, we talk about rhythm control, rate control, and anticoagulation. The BTK inhibitors have a risk of bleeding, so they all carry that as an adverse event when you're combining it with anticoagulants. The DOACs are preferred anticoagulants for those patients. Ibrutinib and zanubrutinib are PGP inhibitors, so they probably are not a good combination with dabigatran [Pradaxa; Boehringer Ingelheim], for example. Some of the drugs interact with CYP3A4, but not to a significant extent to be labeled a drug interaction with apixaban [Eliquis; Bristol-Myers Squibb Co] or rivaroxaban [Xarelto; Janssen CarePath].

When we think about zanubrutinib, it has a labeled interaction with moderate CYP3A4 inhibitors. The other scenario we think about is for rate control. So, a drug like diltiazem [Tiazac; Bausch Health] would have a significant drug interaction—it would increase levels and would require a reduced dose for those patients. Oftentimes, an option like ablation or left atrial appendage occlusion may be preferred in some patients on these therapies if they can't tolerate them. But again, for the most part, all of the side effects must be managed—that's essentially how you're managing it.

One of the other presentations in the program today was a patient with CLL [chronic lymphocytic leukemia]. They were talking about some of the drug interactions that may happen after a stem cell transplant. In that case, with agents like tacrolimus [Prograf; Astellas Pharma Philippines Inc] that's taken by transplant patients, those patients—when treated for [AF]—have an increased risk of a drug interaction with amiodarone [Pacerone; Upsher-Smith]. Tacrolimus can also cause hyperkalemia and prolong the QT interval. So that was also one of the key drug-drug interactions that was mentioned in the program.

Pharmacy Times: How do you see the management of AF in oncology patients evolving in the next few years?

I think the management that was mentioned today was that much of what goes on is monitoring patients. Monitoring can happen with the patient's own devices—for instance, a smartwatch could alert a patient, so that gives a better chance that the patient could receive care. Right now, there's not a good risk stratification tool to identify patients at risk—perhaps like we have for some high-risk oncology patients. For instance, a pancreatic cancer patient who undergoes chemotherapy will likely get some type of almost prophylactic anticoagulation, but we don't necessarily have those treatments for patients who are in sinus rhythm and starting cancer therapies.

So perhaps there's going to be more of a role for smartwatches or self-monitoring devices in that regard. Also, perhaps fine-tuning whether or not you need full-dose anticoagulation in these patients. The drugs themselves that I mentioned—BTK inhibitors—also have antiplatelet effects, so perhaps you don't need as high of a dose of an anticoagulant as you would have initially thought.