A 69-year-old male patient with history of hypertension and chronic lymphocytic lymphoma, refractory to first-line chemotherapy, was started on ibrutinib. Three weeks after initiation of this medication, he presented with palpitations and lightheadedness. He was noted to be in atrial fibrillation (AF) with rapid ventricular response. He was hospitalized, and heart rate was controlled with diltiazem. He was also initiated intravenous heparin infusion initially and then was transitioned to rivaroxaban for systemic anticoagulation. He underwent transesophageal echocardiography-guided direct current cardioversion. Echocardiogram showed normal biventricular systolic function without any valvular heart disease. He was discharged home the following day with improvement in his symptoms. Three days later, he presented again with palpitations and lightheadedness. His current medications were ibrutinib 420 mg daily, diltiazem extended release 120 mg daily, and rivaroxaban 20 mg daily.
His physical examination was notable for hypotension with blood pressure of 78/42 mmHg and a heart rate of 127 bpm. Cardiac examination revealed distant heart sounds and an irregularly irregular heart rhythm. Electrocardiogram again revealed AF with rapid ventricular response. Bedside echocardiogram demonstrated a large pericardial effusion with associated right ventricular diastolic collapse consistent with pericardial tamponade. He underwent emergent pericardiocentesis, and 850 cc of hemorrhagic fluid was drained.
Ibrutinib is associated with all of the following EXCEPT:
Show Answer
The correct answer is: D. Major drug interaction with warfarin
Ibrutinib is a novel Bruton's tyrosine kinase inhibitor approved for treatment of B-cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.1-3 It is associated with an increased risk of AF due to inhibitory effect on cardiac Bruton's tyrosine kinase as well as Tec protein tyrosine kinase. One of the pathways regulated by Bruton's tyrosine kinase and TEC is the phosphoinositide 3-kinase-Akt pathway, which is a critical regulator of cardiac protection under stress conditions, and lower phosphoinositide 3-kinase-Akt activity has been noted in patients with AF.4 In clinical trials, ibrutinib was associated with up to 15% increased incidence of AF. Ibrutinib is also associated with increased risk of bleeding, with up -to 4% risk of major hemorrhage noted in clinical trials. Ibrutinib interacts with several medications commonly used to manage AF, which further complicates the management of these patients (See Table 1).5
Table 1
Medication
Level of Interaction
Effect
Mechanism of Interaction
Diltiazem/Verapamil
Major
Increases plasma level of ibrutinib (six- to ninefold)
CYP450 3A4 inhibition by Diltiazem/Verapamil
Digoxin
Moderate
Increases plasma level of digoxin
P-glycoprotein inhibition by ibrutinib
Amiodarone /Dronedarone
Major
Increases plasma level of ibrutinib (six- to ninefold)
CYP450 3A4 inhibition by Amiodarone/Dronedarone
Factor Xa Inhibitor (Rivaroxaban, Apixaban, Edoxaban)
Major
Increases plasma level of Factor Xa inhibitors
P-glycoprotein inhibition by ibrutinib
Direct Thrombin Inhibitor (Dabigatran)
Major
Increases plasma level of dabigatran
P-glycoprotein inhibition by ibrutinib
This patient received diltiazem initially, which likely increased the level of ibrutinib via CYP450 3A4 inhibition, further potentiating the risk of AF and bleeding. He also received rivaroxaban along with ibrutinib; due to P-glycoprotein inhibition by ibrutinib, it likely increased the plasma level of this Factor Xa inhibitor despite receiving usual dose and in turn further increasing the risk of bleeding. As a result of this multifold increase in ibrutinib and rivaroxaban plasma levels, he suffered from hemorrhagic pericardial effusion and recurrence of AF.
The myriad of interactions with drugs commonly used to manage AF pose a unique clinical challenge. Although optimal strategy for AF management has not been established for patients on ibrutinib, drugs with moderate to major levels of interaction should be avoided, and rate control strategy with the use of beta-blocker seems to be the safer option. A decision regarding anticoagulation for stroke prevention needs to be individualized with the understanding of the inherent increased risk of bleeding with the use of ibrutinib. Factor Xa inhibitors and direct thrombin inhibitor should be avoided. Although concomitant use of ibrutinib and warfarin increases the risk of bleeding, one does not potentiate the other, and there is no known drug interaction between the two drugs. In turn, warfarin is likely the optimal choice for anticoagulation. A multidisciplinary approach with involvement of cardio-oncology should be considered in this high-risk subset.
References
Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213-23.
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507-16.
Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med 2015;372:1430-40.
McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood 2014;124:3829-30.
Ganatra S, Majithia A, Shah S. Challenges in Ibrutinib Associated Atrial Fibrillation. J Am Coll Cardiol 2017;11:2308.
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