Atrial Fibrillation and Ibrutinib

We often fear what we do not understand. I fear oncology.

Call it bad experiences, call it the realities of pharmacy school, but oncology has always been an area I’ve actively avoided. I’ve taken detours around the subject so much so that it was a key component that a made sure to not be a core rotation in the PGY1 programs I considered.

But the time has come for me to sit down and really begin to understand these drugs in the only way I know how: writing a bunch of blog posts. So please forgive me if these topics or this content is “old news.” It’s actually really interesting and exciting to see so much advancement and drug development I was completely naive to. What’s even more surprising is there exists a whole new population of patients that could be visiting an ED near you from ADRs or immune-related adverse events (irAEs)!

But first, I want to explore a class of drugs that were completely new to me: Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib

How they work

BTK or Burton Tyrosine Kinase belongs to a family of kinases that regulate lymphocyte function. While ITK largely affects NK cells, Tec regulates T cells, and BTK plays a large role in B cell function and proliferation.

BTKs important role in B cell receptor pathway influences development, function, and survival can become unregulated in cancer cells. While in healthy cells, BTK’s secondary messaging activity is only intermittently activated, persistent activation that can occur in cancer may lead to unchecked cell growth and/or function in tissues like bone marrow, lymph nodes or in peripheral blood.

However, decreasing BTK overexpression or hyperactivity can regulate growth, promote cell survival signaling and prevent malignant B cells from proliferating and migrating.

Ibrutinib and Acalabrutinib

The two available BTK inhibitors on the market today include ibrutinib and acalabrutinib. Ibrutinib can be thought of as a first-generation BTK inhibitor, whereas acalabrutinib a second generation. The main difference lies in their respective selectivity to BTK. Acalabrutinib was developed to mitigate some of the “off-target” effects observed with ibrutinib. Which begs the question, what are these “off-target” effects?

Adverse events like arthralgias and infection are common among “conventional” chemotherapeutics these associated events for ibrutinib specifically can include new-onset atrial fibrillation and bleeding. For those of us in the ED, this translates to BTK inhibitors becoming need-to-know drugs.

Ibrutinib and Atrial fibrillation

A fundamental difference between BTK inhibitors and other chemotherapeutics you may be familiar with is that these drugs must be continued indefinitely to maintain their therapeutic benefits. So if a BTK inhibitor possesses an ADR that causes up to 51% of the population taking it to stop, it means that these toxicities are significant.

Although this population taking ibrutinib is often over 65 and (obviously) has cancer, their risk of developing atrial fibrillation is higher than a similarly matched cancer-free cohort. This risk of new-onset atrial fibrillation has been reported to be as high as 4-10% of patients taking ibrutinib and appears to increase in incidence the longer a patient takes it.

Mechanism

Of course, the mechanism of ibrutinib-induced atrial fibrillation is “not fully elucidated.” However, the proposed mechanism relates to something referred to as “off-target” effects. These off-target effects of ibrutinib appear to affect other kinases than BTK including cardiac phosphoinositide 3-kinase. It has been suggested that this inhibition of PI3K leads to prolonged cardiac action potentials and increased cardiac late sodium currents.

Incidence

So how big of a problem is this? Well, to answer that question, we must also discuss the “Common Terminology Criteria for Adverse Events” grade system published by the US HHS. Adverse events (AE) of chemotherapeutic agents undergo safety analysis and the incidence and severity of adverse events. The incidence of a given adverse event is categorized into grades 1 through 5 and can be broken down in the following format:

Grade 1Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL).
Grade 3Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling;
limiting self-care ADL.
Grade 4Life-threatening consequences; urgent intervention indicated
Grade 5Death related to AE

In the major clinical studies of ibrutinib, the RESONATE1, and RESONATE2, atrial fibrillation was observed to occur more often in the ibrutinib groups compared to control groups. Atrial fibrillation also occurs with more frequency as time went on.

While atrial fibrillation of any grade was observed in 5-10% of these populations, patients with Grade 3, 4 or 5 atrial fibrillation occurred in roughly 4% of the study population receiving ibrutinib.

A separate pooled analysis of 4 randomized controlled studies of ibrutinib vs comparator agents saw similar trends in new-onset atrial fibrillation. This pooled data suggested that atrial fibrillation commonly occurs during the first 3 months of therapy. However, among the patients who develop atrial fibrillation, almost 70% have complete resolution of atrial fibrillation and causes about 1% of patients to discontinue treatment with ibrutinib. Although real-world patient experience suggests higher rates of atrial fibrillation and drug discontinuation.

Problems in Atrial Fibrillation Management

If a patient develops atrial fibrillation from ibrutinib, it’s not as simple as a typical patient in the ED where we would start diltiazem for rate control and discuss an anticoagulant strategy likely involving apixaban. The reason being is that a separate AE of ibrutinib is bleeding AND there are pharmacokinetic drug interactions with commonly used rate and rhythm control drugs used in the ED including diltiazem, amiodarone, and digoxin.

Ibrutinib is a potent P-glycoprotein inhibitor which complicates the use of digoxin or dabigatran (no problem, since it’s rarely used anyway). However, ibrutinib is also a substrate of CYP 3A4 and CYP 2D6 (SSRI’s anyone?), so inhibitors such as amiodarone, diltiazem or verapamil could decrease ibrutinib elimination and increase risks of AEs. So rate control strategies are limited to beta-blockers (metoprolol and esmolol), and rhythm control strategies are of an Edisonian nature.

While we consider controlling the arrhythmia, we often must consider reducing the risk of stroke in these patients using antithrombotic agents. CHA2DS2-VASc and HAS-BLED risk categorizations were obviously not developed with ibrutinib in mind, thus have a limited role. For anyone with a CHA2DS2-VASc score of 2 or higher, anticoagulation is recommended.

We can navigate the pharmacokinetic interactions of warfarin by simply not using it, DOACs such as apixaban appear to be reasonable options. However, it’s controversial what dose should be used. Some have recommended empirically lowering doses of DOACs in this population with therapeutic monitoring. However, DOAC therapeutic monitoring is not widely available and titration options are limited.

Complicating matters further is another risk we have yet to discuss: the risk of hemorrhage associated with ibrutinib. In the RESONATE trial, 44% of patients had a bleeding event, of which 1% were Grade 3 or higher. As research experience continued, the incidence of clinically significant bleeding (Grade 3 or higher) continued to increase to approximately 6%. In the real world setting, this is likely higher.

Ibrutinib’s action leading to bleeding is thought to be related to platelet aggregation via glycoprotein VI signalings. It’s been proposed that this effect is short-lived and dependent on the presence of ibrutinib. So with a 4-6 hour half-life, some have suggested platelet infusions can help to restore hemostasis.

But in the setting of ibrutinib-induced atrial fibrillation, this complicates matters. The general consensus at this time is to not try to maintain these spinning plates. For patients developing atrial fibrillation and a CHA2DS2-VASc 2 or higher, it’s recommended to stop ibrutinib and manage atrial fibrillation with beta-blockers and anticoagulation or a rhythm control strategy.

If these patients taking ibrutinib to develop atrial fibrillation that goes un-noticed or not treated and subsequently develop an ischemic stroke is another problem. Quite simply put, until someone can prove otherwise, I would not consider these patients candidates for fibrinolytics.

Acalabrutinib may be a different story
We’ve yet to discuss the other agent in this drug class. Acalabrutinib is a selective BTK inhibitor that was developed to mitigate some of these “off-target” effects observed. As far as I can tell, acalabrutinib successfully mitigates the risk of treatment-related atrial fibrillation. But approximately 10% of patients who developed intolerances to irutinib and were subsequently moved to acalabrutinib therapy still developed arrhythmias. But since there is limited experience with acalabrutinib, it’s still unclear if it has actually mitigated this safety concern or we have yet to observe it.

Needless to say, in the next new-onset atrial fibrillation patient rolling into the ED, ibrutinib, and acalabrutinib should be in your mind when scanning their home medications.