Managing Afib in Cancer Patients Taking BTK Inhibitors

Today we are speaking to Leon M. Ptaszek, MD, PhD, about managing cancer patients who have atrial fibrillation and are being treated with Bruton's tyrosine kinase (BTK) inhibitors. Dr. Ptaszek is a cardiologist at the Massachusetts General Hospital in Boston whose practice includes the care of cancer patients with cardiology comorbidities and cancer patients with new-onset cardiac issues.

-Interviewed by Anna Azvolinsky

Cancer Network: First, what is atrial fibrillation?

Dr. Ptaszek: Atrial fibrillation is caused by rapid, irregular electrical firings within the upper chambers of the heart. Although the pulmonary veins are classically described as the origin of atrial fibrillation it should be noted that atrial fibrillation and the closely related atrial flutter can emanate from any part of the upper heart chambers.

The presence of atrial fibrillation has several physiological consequences. While in atrial fibrillation the heart rate can be frequently elevated. In addition, while in atrial fibrillation, the ventricles do not contract as vigorously as they do in sinus rhythm. The absence of a regular contraction can lead to a less efficient ventricular filling and this can lead potentially, to a lesser cardiac output.

In additional, statis of blood in the atria in the context of atrial fibrillation can increase the risk of intracardiac thrombus formation. These thrombi can embolize into the systemic circulation. Although embolic events can occur in any organ, the event with which we are particularly concerned is thromboembolic stroke.

Atrial fibrillation is the most common sustained arrhythmia in adults and therefore is encountered very frequently. More than 2 million Americans and more than 33 million people worldwide are affected. The population-wide prevalence of atrial fibrillation is approximately 1%. The incidence of atrial fibrillation increases with age and about 70% of affected patients are 65 years and older.

Prevalence of atrial fibrillation is increasing as a result of the aging population and it is estimated that the number of people affected by atrial fibrillation will rise to 5 million by 2050. The prevalence of atrial fibrillation is slightly higher in men, approximately 1.1%, than in women, approximately 0.8%. There is also some data suggesting that the prevalence of atrial fibrillation is slightly higher in whites than in non-whites.

The critical consequences of atrial fibrillation include symptoms associated with [an] irregular heart rhythm, symptoms associated with elevated heart rate, and the increased risk of stroke, by 500%. It has been estimated that atrial fibrillation is responsible for up to 25% of all strokes.

A number of clinical conditions including hypertension, coronary artery disease, and heart failure are associated with atrial fibrillation. The presence of these conditions in a patient can increase the risk of atrial fibrillation related stroke.

Atrial fibrillation is frequently diagnosed in the setting of cancer but epidemiological data is limited in this setting. One study reported that 2.4% of patients with a newly diagnosed malignancy had pre-existing atrial fibrillation. In the same study, an additional 1.8% [of patients] developed atrial fibrillation after their malignancy was discovered. The higher prevalence of atrial fibrillation in patients diagnosed with cancer is likely driven by age. For example, the average age of patients with cancer and atrial fibrillation in the study was greater than 72 years and the average age of patients with a malignancy but no atrial fibrillation was 60 years.

Cancer Network: How is atrial fibrillation generally treated?

Dr. Ptaszek: There are two pillars of atrial fibrillation management. The first is limiting atrial fibrillation related stroke through the use of anti-coagulation therapy. The type of anticoagulant utilized depends on the calculated risk of stroke for an individual patient. Several atrial fibrillation stroke risk calculators are available but perhaps the most common one used is the CHADSVASC score.

This score assigns one point for each of the following conditions: heart failure, hypertension, age greater than 65 years, diabetes, vascular disease, or female gender at birth. The score also assigns two points for age greater than 75 years and history of stroke.

According to the guidelines set forth by the American Heart Association and the American College of Cardiology and the Heart Rhythm Society, patients with atrial fibrillation and a CHADSVASC score of zero do not require anti-coagulation. Patients with a CHADSVASC score of 1 can either be treated with an aspirin or an oral anticoagulant such as [warfarin] or a novel oral anticoagulant. Patients with a CHADSVASC score of 2 or higher should be treated with an oral anticoagulant unless there is a contra-indication.

The second pillar of atrial fibrillation management involves minimization of the hemodynamic consequences of atrial fibrillation. This can involve one of two strategies. The first is a rate-control strategy which involves medication such as beta blockers and calcium channel blockers that reduce the heart rate. These medications may restore sinus rhythm, but recurrence of atrial fibrillation with use of these medications is common. The second strategy is the rhythm-control strategy, which involves restoring sinus rhythm, which involves a number of tools, antiarrhythmic drugs, and catheter ablation procedures.

Restoration of sinus rhythm with a rhythm-control strategy has not been shown to produce clear mortality benefits over the rate-control strategy but even so, a rhythm-control strategy is frequently implemented to treat symptoms associated with atrial fibrillation.

Cancer Network: BTK inhibitors such as ibrutinib have been shown to contribute to the development of atrial fibrillation in some cancer patients. What do we know about this link between these targeted cancer agents and this cardiovascular condition?

Dr. Ptaszek: In the RESONATE and RESONATE-2 trials, studying the use of ibrutinib in patients with CLL [chronic lymphocytic leukemia], 3% of patients with relapsed or refractory CLL presented with severe atrial fibrillation as compared with 0% of patients treated in the control group with ofatumumab. Six percent of patients who were given ibrutinib as a frontline therapy were found to develop atrial fibrillation.

Similar observations were made in subsequent open-label trials of ibrutinib in combination with rituximab for refractory mantle cell lymphoma. A subsequent international, retrospective study demonstrated that patients treated with ibrutinib typically developed atrial fibrillation within 3 to 8 months after the start of their therapy.

There is demonstrated crosstalk between the BTK and the PI3K kinase pathways and this has been implicated as the molecular mechanism for atrial fibrillation in patients treated with BTK inhibitors including ibrutinib. Inhibition of the PI3K pathway has been shown to be associated with prolonged action potentials and myocyte models and this is thought to be the molecular mechanism responsible for atrial fibrillation. Therefore, BTK inhibitors that demonstrate less crosstalk between the PI3 kinase and BTK pathways are thought to be associated with a comparatively lower risk of atrial fibrillation.

Cancer Network: Are there ways to lessen the chance that a cancer patient who begins BTK inhibitor therapy would develop atrial fibrillation?

Dr. Ptaszek: Yes. Careful management of other co-morbidities that could precipitate episodes of atrial fibrillation can reduce the likelihood that a patient has episodes of atrial fibrillation and can also reduce the symptomatic burden of atrial fibrillation. These medical co-morbidities include hypertension, thyroid disease, thyroid disease, heart failure, and sleep apnea. In addition, alternative BTK inhibitors with fewer off-target effects such as acalabrutinib may reduce the likelihood of atrial fibrillation.

Cancer Network: How is this condition generally managed in cancer patients who are taking these targeted therapies and what are the challenges of managing these patients?

Dr. Ptaszek: The two pillars of atrial fibrillation management I mentioned earlier apply whether the patient has cancer or not. However, the presence of cancer and associated treatments may limit our ability to treat the atrial fibrillation so I will go in the order of the pillars I mentioned earlier.

Patients with cancer often have a number of issues that may increase the risk of bleeding on an anti-coagulant. These include thrombocytopenia and the presence of metastases, which may be associated with an unacceptably high-risk of bleeding. In addition, the use of particular of anticoagulants may be limited, for example, the vitamin K antagonist such as [warfarin] can be challenging to administer in patients with a variety of gastrointestinal absorption issues and renal insufficiency.

In addition, utilization of novel, oral anticoagulants may not be advisable in conjunction with BTK inhibitors due to possible increase in CNS [central nervous system] levels of the drug, which may lead to an increase in intracranial bleeding risk. This is thought to be secondary to a P-glycoprotein interaction. Without the ability to anti-coagulate safely, it’s not possible to use a rhythm-control strategy.

Cardioversion either by antiarrhythmic drug use or DC cardioversion can only be performed safely for those patients on an anti-coagulant therapy. And even in those patients that can be anti-coagulated despite the issues I mentioned, antiarrhythmic drug utilization may be challenging. For example, certain drugs cannot be administered with ibrutinib. In addition, QT prolongation has been noted for multiple BTK inhibitors and may make it difficult to administer antiarrhythmic drugs, many of which are associated with QT prolongation. In addition, renal insufficiency in the context of cancer and cancer treatment may limit the ability to use other antiarrhythmic drugs.