A 64-year-old anesthesiologist with a medical history of hypertension and high-risk chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (complex cytogenetics with 17pDEL) complicated by hyperviscosity from elevated monoclonal IgG managed on ibrutinib, rituximab, and bendamustine presented with recent onset of exertional angina. Following a positive exercise stress echocardiogram with stress-induced wall motion abnormalities, he was referred for a coronary angiogram. Angiogram revealed severe multivessel coronary artery disease (CAD): long 80% tandem stenosis of the proximal to mid left anterior descending artery (LAD), chronic total occlusion (CTO) of mid LAD after a small D2 branch with left-left collaterals, 80% mid right coronary artery stenosis, CTO of the mid circumflex with faint collaterals, and 80% stenosis in the obtuse marginal 1 branch. A thorough evaluation by cardiothoracic surgery and interventional cardiology was performed with consideration of his complex situation given his high-risk CLL and ongoing therapy with ibrutinib, which is associated with platelet dysfunction and an elevated risk of bleeding. Ultimately, the patient and team opted to proceed with percutaneous coronary intervention (PCI) with coronary stenting despite the requirement for dual antiplatelet therapy (DAPT). PCI with drug-eluting stents was successfully performed for the right coronary artery and circumflex stenoses but not for the LAD CTO. A transthoracic echocardiogram at the time showed a normal left ventricular systolic function with an estimated ejection fraction of 55% with no regional wall motion abnormalities and grade I diastolic dysfunction. He was started on optimal medical therapy including metoprolol, high-intensity statin, aspirin, and clopidogrel with significant improvement in his anginal symptoms. Furthermore, the patient's CLL remained stable with improvement in his hyperviscosity. The decision was made to defer further attempts to revascularize the LAD CTO unless clinically indicated due to an acute coronary syndrome or progressive angina despite medical therapy.
In follow-up, the patient is doing well with minimal exertional angina and no complaints of palpitations or reports of major bleeding. He does note mild nuisance bleeding and easy bruising. There have also been no findings of any atrial arrhythmias during subsequent clinic visits. His CLL is under control with daily ibrutinib, monthly rituximab, and bendamustine.
What is the most common cardiovascular side effect of the Bruton tyrosine kinase inhibitor ibrutinib?
The correct answer is: B. Atrial fibrillation (AF) or atrial flutter
Ibrutinib is generally well-tolerated but possesses two major and increasingly recognized adverse events: bleeding and AF.1-8 Ibrutinib-related AF is seen in 6-11% of patients receiving ibrutinib.1-5 It is not known whether initiation of anticoagulation after the development of ibrutinib-related AF will decrease thrombotic stroke risk without increasing hemorrhagic stroke risk. Ibrutinib alone is associated with increased risk of bleeding, and its interaction and bleeding risk with either anticoagulation or antiplatelet therapy is not well-studied.9 In one of the largests analyses to date evaluating risk of ibrutinib-related AF, among the 76 patients with AF, there were 8 major bleeds.10 Half of these bleeds were in the setting of aspirin use and none with anticoagulation therapy.10 Our patient has not experienced any documented AF or atrial flutter or bleeding episodes thus far, despite being treated with DAPT for his recent drug-eluting stents.
The mechanism of ibrutinib-related AF remains unclear. A preclinical mouse model suggests that AF may be induced by inhibition of phosphoinositide 3-kinase p110α in cardiac myocytes.11 This may have clinical and treatment implications but requires future investigation.
The bleeding risk associated with ibrutinib appears to be related to platelet dysfunction. In vitro, ibrutinib has been shown to inhibit Bruton tyrosine kinase and Tec kinase, leading to inhibition of glycoprotein VI and glycoprotein 1b-mediated platelet function and a subsequent inhibition of platelet aggregation, resulting in decreased platelet adhesion to von Willebrand factor and increased bleeding risk.8
As with all patients with AF, the CHA2DS2-VASc score to assess the risk of thromboembolic complications and the HAS-BLED score to estimate bleeding risk are the best available risk stratification tools clinically available to guide decide-making on anticoagulation management in patients who develop ibrutinib-related AF. However, neither of these scores take into account the diagnosis of cancer or the potential adverse bleeding effects of ibrutinib.12 Clinical trials and large-scale studies are needed to further delineate the utility of these risk scores in patients who take ibrutinib.
A major challenge in this patient population is the potential need for antiplatelet therapy and anticoagulation, such as in patients with AF and obstructive CAD requiring PCI. The addition of DAPT to oral anticoagulation increases the risk of bleeding by two-threefold irrespective of other factors.13,14 Furthermore, DAPT alone is inferior to warfarin for thromboembolic event prevention in patients with AF.13,14 The American College of Cardiology and the American Heart Association issued a focused update on duration of DAPT in patients with CAD, providing guidance to manage patients with AF undergoing PCI.15 However, there are no studies or consensus documents to provide guidance for managing patients needing DAPT in the setting of ibrutinib-related AF. Hence, this limits the ability to extrapolate shorter DAPT course in patients with ibrutinib-related AF needing anticoagulation.
Because our patient must be on DAPT if he develops AF or atrial flutter, we will likely avoid anticoagulants (CHA2DS2-VASc score of 2) and focus on a rate-control approach using beta-blockers, potentially followed by consideration of a left atrial appendage closure device. We recommend detailed discussions weighing risks and benefits of DAPT, anticoagulation, and ibrutinib-related increased bleeding risk with patients so we can try to personalize management plans until we have more evidence-based recommendations.
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32-42.
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.
Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497-506.
Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood 2015;126:739-45.
Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med 2015;372:1430-40.
Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med 2015;373:2425-37.
Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol 2016;17:200-11.
Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood 2014;124:3991-5.
Wiczer TE, Levine LB, Brumbaugh J, et al. Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib. Blood Adv 2017;1:1739-48.
Wiczer TE, Levine LB, Brumbaugh J, et al. Management and Outcomes of Atrial Fibrillation in Patients Receiving Ibrutinib for Hematologic Malignancies at a Single Center. Blood 2016;128:2040.
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.
Vrontikis A, Carey J, Gilreath JA, Halwani A, Stephens DM, Sweetenham JW. Proposed Algorithm for Managing Ibrutinib-Related Atrial Fibrillation. Oncology (Williston Park) 2016;30:970-4, 980-1, C3.
Capodanno D, Angiolillo DJ. Management of antiplatelet and anticoagulant therapy in patients with atrial fibrillation in the setting of acute coronary syndromes or percutaneous coronary interventions. Circ Cardiovasc Interv 2014;7:113-24.
Moser M, Olivier CB, Bode C. Triple antithrombotic therapy in cardiac patients: more questions than answers. Eur Heart J 2014;35:216-23.
Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082-115.