title: Risk of Atrial Fibrillation and Bleeding Diathesis Associated With Ibrutinib Treatment: A Systematic Review and Pooled Analysis of Four Randomized Controlled Trials.
abstract: Clinical trials raised concern that ibrutinib may increase the risk of atrial fibrillation/flutter (Afib/Aflutter) and major bleeding. However, the association has not been statistically validated, and there is no consensus regarding optimal management of anticoagulation among patients receiving ibrutinib who develop Afib/Aflutter. We performed a systematic review and pooled analysis to precisely assess the risk of Afib/Aflutter and bleeding associated with ibrutinib treatment in patients with hematologic malignancies.
  
  
  
  We searched PubMed, EMBASE, Cochrane Database, and meeting abstracts up to May 15, 2016, for randomized controlled trials comparing ibrutinib to chemotherapy, monoclonal antibody, or a combination. Primary outcomes were serious Afib/Aflutter and major bleeding. Secondary outcomes were all-grade Afib/Aflutter and bleeding. We calculated the Mantel-Haenszel risk ratio (RR) and estimated the effect of the treatments using a fixed-effects model.
  
  
  
  Ibrutinib treatment was associated with a significantly higher incidence of serious Afib/Aflutter (3.03% vs. 0.80%, RR = 3.80, 95% confidence interval [CI] = 1.56-9.29, P = .003), all-grade Afib/Aflutter (8.18% vs. 0.93%, RR = 8.81, 95% CI = 2.70-28.75, P = .0003), and all-grade bleeding (4.85% vs. 1.55%, RR = 2.93, 95% CI = 1.14-7.52, P = .03) compared to control treatments. The observed between-treatment difference in major bleeding rates was not statistically significant (3.69% vs. 2.13%, RR = 1.72, 95% CI = 0.95-3.11, P = .07). The risk of these adverse events was not different between subgroups on the basis of pathology, treatment setting, dose, and duration of ibrutinib exposure.
  
  
  
  The risks of Afib/Aflutter and all-grade bleeding were significantly higher in the ibrutinib group. These results indicate the need for vigilant monitoring while the patient is receiving ibrutinib therapy, and careful assessment of the risks and benefits of anticoagulation is required.
authors: Department of Hematology and Oncology, H. Lee Moffitt Cancer Center, Tampa, FL; Department of Medicine, University of Arizona, Tucson, AZ. Electronic address: Seongseok.yun@moffitt.org.
authors: Seongseok
authors: S
authors: Yun
authors: Department of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, FL; Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
authors: Nicole D
authors: ND
authors: Vincelette
authors: Division of Hematology and Oncology, Internal Medicine, Ohio State University, Columbus, OH.
authors: Utkarsh
authors: U
authors: Acharya
authors: Arizona Cancer Center, University of Arizona, Tucson, AZ; Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, AZ.
authors: Ivo
authors: I
authors: Abraham
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000225:Adenine / Q000031:analogs & derivatives; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000139:chemically induced; D004198:Disease Susceptibility / Q000139:chemically induced; D006470:Hemorrhage / Q000139:chemically induced; D010880:Piperidines; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012306:Risk
chemical_list: D000225:Adenine; D000911:Antibodies, Monoclonal; C551803:ibrutinib; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines
keywords: Anticoagulation; Atrial flutter; Chronic lymphocytic leukemia; Mantle cell lymphoma; Waldenstrom macroglobulinemia