The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

Leong, Darryl P.; Caron, François; Hillis, Christopher; Duan, Annie; Healey, Jeff S.; Fraser, Graeme; Siegal, Deborah

doi:10.1182/blood-2016-05-712828

Cited by 206 publications

(135 citation statements)

References 24 publications

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“…[1][2][3][4][5] An increased rate of atrial fibrillation has been observed in clinical trials of ibrutinib. 37,38 While there is net benefit from anticoagulation in individuals from the general population with atrial fibrillation and additional stroke risk factors, the increased bleeding risk in ibrutinib-treated patients may alter the risk-benefit ratio of anticoagulant therapy for the prevention of stroke and systemic embolism. To our knowledge, there is no evidence regarding the stroke risk in ibrutinib-treated patients with atrial fibrillation or whether [39][40][41] Patients with an indication for warfarin were excluded from the later trials after high rates of bleeding were noticed in earlier studies.…”

Section: Discussionmentioning

confidence: 99%

Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis

Caron

Leong

Hillis³

et al. 2017

Blood Advances

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Ibrutinib therapy was associated with an increased risk of bleeding in previous trials. In this systematic review and meta-analysis of published trials including patients treated with ibrutinib, the relative risk (95% confidence interval [CI]) of overall bleeding was significantly higher in ibrutinib recipients (2.72 [1.62-6.58]), but major bleeding did not show a significant difference (1.66 [0.96-2.85]). The incidences (95% CI) of major bleeding and any bleeding were 3.0 (2.3-3.7) and 20.8 (19.1-22.1) per 100 patient-years, respectively. This analysis is limited by reporting bias from variable ascertainment of bleeding and lack of allocation concealment in some studies and differing exposures between groups, leading to potential overestimation of event rates in the ibrutinib group. CaseA 65-year-old man with chronic lymphocytic leukemia (CLL) with 17p deletion on first-line ibrutinib 420 mg daily for 8 weeks presented with a 2-week history of easy bruising and epistaxis. He was previously healthy with no personal or family history of a bleeding disorder and no regular antithrombotic drug use. Laboratory testing revealed a hemoglobin concentration of 8 g/dL, lymphocyte count of 13 3 10 9 /L, and normal platelet count, international normalized ratio, and activated partial thromboplastin time. What is the role of ibrutinib in this patient's bleeding symptoms?

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Section: Discussionmentioning

confidence: 99%

Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis

Caron

Leong

Hillis³

et al. 2017

Blood Advances

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“…[1][2][3][4][5] Ibrutinib use is associated with atrial fibrillation (AF), with an incidence of 5% to 6% after 18 months on therapy [4][5][6] and up to 16% with longer follow-up. 2,7 Prompted by an episode of unexplained ventricular tachycardia (VT) in a patient taking ibrutinib, we hypothesized that ibrutinib use may be associated with ventricular arrhythmias (VAs).…”

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confidence: 99%

“…Cytogenetic analysis was available in 26 (96%) and 147 patients (91%) with PEL and AEL, respectively, and revealed higher frequency of complex karyotype among patients with PEL (96% vs 61%; P , .001). Among patients with PEL, median number of cytogenetic abnormalities was 20 (range, 9-47), and median number of cytogenetic clones was 2 (range, [1][2][3][4][5][6] Targeted sequencing was performed in 12 patients (44%) with PEL. The most frequently mutated gene was TP53, detected in 11 (92%) of 12 patients, followed by ASXL1 (G646fs*), PTPN11 (G503R) and DNMT3A (L798P), each present in 1 patient (8%).…”

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confidence: 99%

Ventricular arrhythmias and sudden death in patients taking ibrutinib

Lampson

Glynn

et al. 2017

Blood

179

101

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Ibrutinib, approved by the US Food and Drug Administration (FDA), is an inhibitor of Bruton tyrosine kinase (BTK). [1][2][3][4][5] Ibrutinib use is associated with atrial fibrillation (AF), with an incidence of 5% to 6% after 18 months on therapy [4][5][6] and up to 16% with longer follow-up. 2,7Prompted by an episode of unexplained ventricular tachycardia (VT) in a patient taking ibrutinib, we hypothesized that ibrutinib use may be associated with ventricular arrhythmias (VAs). To further investigate, we gathered 4 cases of VAs in ibrutinib-treated patients, mined the FDA Adverse Event Reporting System (FAERS) for additional reports of VAs in patients receiving ibrutinib, and estimated incidence rates of VAs in clinical trials of ibrutinib. Individual patients were enrolled on data collection protocols approved by institutional review boards or collected from publicly available data. We obtained adverse events (AEs) for ibrutinib reported to the FAERS from the fourth quarter of 2013 (ibrutinib was approved by the FDA in November 2013) to the fourth quarter of 2015. Additional details were requested for AE reports with the following preferred search terms: ventricular arrhythmia, ventricular fibrillation (VF), Brugada syndrome, right bundle branch block, cardiac arrest, cardiac death, cardiac fibrillation, cardiorespiratory arrest, conduction disorder, sudden death, sudden cardiac death, ventricular extrasystoles, and ventricular tachycardia. If dates of ibrutinib discontinuation, cardiac events, or death were redacted, we used the date when the patient was last seen alive or when the event was filed. Patients for whom there was not enough information to determine the timing of ibrutinib administration or for whom ibrutinib was discontinued before the event were excluded. Clinical trial data were drawn from published results. Median time on therapy was assumed to be mean time on therapy to calculate total time on therapy for the group of interest. Statistical analysis was performed by using STATA 14 (STATA, College Station, TX).Our index patient was a 60-year-old man who had chronic lymphocytic leukemia (CLL) and no prior cardiac history. He was a vigorous exerciser with resting sinus bradycardia. Two months after beginning ibrutinib, he reported new palpitations. He experienced syncope 86 days after initiating ibrutinib. Frequent premature ventricular contractions (PVCs) and nonsustained VT were identified ( Figure 1A). An exercise stress test was negative for ischemic changes, but polymorphic VT occurred when he transferred from stretcher to treadmill ( Figure 1B). Cardiac catheterization and echocardiogram were normal. Electrophysiologic studies induced PVCs originating from the moderator band but could not ablate the focus; therefore, he was started on antiarrhythmics and a cardioverter-defibrillator was implanted. Ibrutinib was resumed at discharge. Attempted downtitration of his quinidine later resulted in an increase in PVCs. He has since been maintained on ibrutinib, quinidine, and metoprolol for 28 mont...

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“…Generally the latter should be avoided given evidence of increased major bleeding with this combination, without ibrutinib 25 . A recent meta-analysis of published trial data on ibrutinib and bleeding demonstrates a 2.72 relative risk of any bleeding, and a trend toward increased major bleeding at 1.66 relative risk, despite being underpowered for this outcome 26 .…”

Section: Bleeding Diathesis And/or Need For Full Dose Anticoagulationmentioning

confidence: 99%

“…The best studied cardiac side effect of ibrutinib is AF, which occurs initially in about 6% of patients 2,3,26 , increasing to 10-15% over two years 29 . An analysis from four randomized registration trials identified risk factors for AF on ibrutinib as age > 65 and a prior AF history.…”

Section: Cardiac Effects Of Ibrutinibmentioning

confidence: 99%

How I treat CLL patients with ibrutinib

Brown

2018

Blood

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Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.

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The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

Cited by 206 publications

References 24 publications

Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis

Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis

Ventricular arrhythmias and sudden death in patients taking ibrutinib

How I treat CLL patients with ibrutinib

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