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CARDIOVASCULAR COMPLICATIONS OF IBRUTINIB: A SYSTEMATIC REVIEW AND META-ANALYSIS
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Canadian Journal of Cardiology Volume 32 2016
357 CARDIOVASCULAR COMPLICATIONS OF IBRUTINIB: A SYSTEMATIC REVIEW AND META-ANALYSIS F Caron, DM Siegal, CM Hillis, GA Fraser, DP Leong Hamilton, Ontario BACKGROUND:
Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signalling pathway. Ibrutinib has recently been shown to be highly effective in the treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma and other B-cell lymphoproliferative diseases and is likely to become a paradigm-shifting therapy. Early clinical trials reported increased incidence of atrial fibrillation (AF) and bleeding in patients on ibrutinib when compared with alternative therapies. The objectives of this systematic review are 1) to characterize the incidence rate of AF and bleeding in clinical trials of ibrutinib, and 2) to estimate the risk of atrial fibrillation and bleeding among patients treated with ibrutinib compared with alternative treatments. METHODS: We conducted a systematic search of MEDLINE and EMBASE for articles and conference abstracts of studies of patients on ibrutinib that report either AF or bleeding events. The search yielded 1871 abstracts, from which we identified 26 studies, including 2940 patients on ibrutinib. RESULTS: In the four randomized controlled trials identified, pooled relative risks (95% confidence interval [CI]) of AF, any bleeding and major bleeding for ibrutinib recipients compared with alternative therapies were 3.9 (2.07.7, p<0.0001), 2.47 (1.95-3.14, p<0.0001), and 1.70 (0.96, 3.00, p¼0.07), respectively. Pooled incidence of AF, any bleeding and major bleeding for patients receiving ibrutinib were 3.0 (2.3-3.8), 16.4 (14.9-18.0) and 3.0 (2.3-3.8) per 100 patient-years, respectively. The pooled incidence (95% CI) of AF among patients receiving an alternative therapy in the four randomized trials was 0.8 (0.3-1.6) per 100 patient-years, and the pooled incidence of major bleeding in the same patients was 1.9 (1.1-2.8). The definition of major bleeding in most studies was grade 3, which corresponds to blood loss requiring a transfusion or surgical intervention. CONCLUSION: Ibrutinib increases the risk of incident AF and bleeding compared with alternative therapies. The incidence of AF in ibrutinib recipients exceeds the incidence rate reported in the general population while the major bleeding rate in ibrutinib recipients is similar to the major bleeding rate seen in clinical trials of direct oral anticoagulants. The numbers for AF could be underestimated in this study, as none of the trials used systematic ascertainment of rhythm. Further research is needed to determine the incidence of AF and bleeding in “real-world” ibrutinib recipients, the mechanism and implications for therapy of these complications.
Canadian Society of Atherosclerosis, Thrombosis and Vascular Biology (CSATVB) ePoster ATHEROSCLEROSIS EPOSTERS Monday, October 24, 2016 358 ROLE OF P2Y2R-SRC-FILAMIN A PATHWAY DURING MECHANICAL STRESS-INDUCED MINERALIZATION OF VALVE INTERSTITIAL CELLS: IMPLICATION FOR BICUSPIDE AORTIC VALVE R Bouchareb, M Boulanger, P Pibarot, P Mathieu, Y Bossé Québec, Québec INTRODUCTION:
Calcific aortic valve stenosis (CVAS) is the most common valvular heart disease in Western countries. Bicuspid aortic valve (BAV) is a strong risk factor for the development of CAVS. Valve interstitial cells (VICs) in BAV are exposed to high mechanical constraint. Previous studies in our laboratory have shown that P2Y2 purinergic receptor (P2Y2R) exerts an important control over the osteogenic transition of VICs. Mechanical stress is known to increase the expression of ectonucleotidases in VICs, but whether mechanical constraint affects P2Y2R and its downstream signalling is unknown. Filamin A (FLNA) and the tyrosine kinase Src bind to the SH3 domain of P2Y2R. In this study, we hypothesized that mechanical stress could act as an important regulator of VIC mineralization through P2Y2R-Src-FLNA pathway. METHODS: VICs were subjected to mechanical stress by using the Flexcell-5000 system and the functional relevance of P2Y2R-Src-FLNA on mineralization of VICs was examined. RESULTS: Mechanical stress increased the mineralization of VICs P2Y2R-/- by 4 fold compared to control VICs (P2Y2R+/+). Furthermore, in response to mechanical stress the expression of RUNX2, a transcription factor involved in osteogenesis, was increased in P2Y2R-/- VICs. In rescue experiments, the transfection of VICs P2Y2R-/- with a vector encoding for P2Y2R reduced the level of mineralization induced by mechanical stress. This effect was enhanced by a co-transfection with a vector encoding for Src. Also, overexpression of FLNA and Src abolished the pro-mineralizing effect of mechanical stress in the VICs. Analysis by
Canadian Journal of Cardiology Volume 32 2016
357 CARDIOVASCULAR COMPLICATIONS OF IBRUTINIB: A SYSTEMATIC REVIEW AND META-ANALYSIS F Caron, DM Siegal, CM Hillis, GA Fraser, DP Leong Hamilton, Ontario BACKGROUND:
Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signalling pathway. Ibrutinib has recently been shown to be highly effective in the treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma and other B-cell lymphoproliferative diseases and is likely to become a paradigm-shifting therapy. Early clinical trials reported increased incidence of atrial fibrillation (AF) and bleeding in patients on ibrutinib when compared with alternative therapies. The objectives of this systematic review are 1) to characterize the incidence rate of AF and bleeding in clinical trials of ibrutinib, and 2) to estimate the risk of atrial fibrillation and bleeding among patients treated with ibrutinib compared with alternative treatments. METHODS: We conducted a systematic search of MEDLINE and EMBASE for articles and conference abstracts of studies of patients on ibrutinib that report either AF or bleeding events. The search yielded 1871 abstracts, from which we identified 26 studies, including 2940 patients on ibrutinib. RESULTS: In the four randomized controlled trials identified, pooled relative risks (95% confidence interval [CI]) of AF, any bleeding and major bleeding for ibrutinib recipients compared with alternative therapies were 3.9 (2.07.7, p<0.0001), 2.47 (1.95-3.14, p<0.0001), and 1.70 (0.96, 3.00, p¼0.07), respectively. Pooled incidence of AF, any bleeding and major bleeding for patients receiving ibrutinib were 3.0 (2.3-3.8), 16.4 (14.9-18.0) and 3.0 (2.3-3.8) per 100 patient-years, respectively. The pooled incidence (95% CI) of AF among patients receiving an alternative therapy in the four randomized trials was 0.8 (0.3-1.6) per 100 patient-years, and the pooled incidence of major bleeding in the same patients was 1.9 (1.1-2.8). The definition of major bleeding in most studies was grade 3, which corresponds to blood loss requiring a transfusion or surgical intervention. CONCLUSION: Ibrutinib increases the risk of incident AF and bleeding compared with alternative therapies. The incidence of AF in ibrutinib recipients exceeds the incidence rate reported in the general population while the major bleeding rate in ibrutinib recipients is similar to the major bleeding rate seen in clinical trials of direct oral anticoagulants. The numbers for AF could be underestimated in this study, as none of the trials used systematic ascertainment of rhythm. Further research is needed to determine the incidence of AF and bleeding in “real-world” ibrutinib recipients, the mechanism and implications for therapy of these complications.
Canadian Society of Atherosclerosis, Thrombosis and Vascular Biology (CSATVB) ePoster ATHEROSCLEROSIS EPOSTERS Monday, October 24, 2016 358 ROLE OF P2Y2R-SRC-FILAMIN A PATHWAY DURING MECHANICAL STRESS-INDUCED MINERALIZATION OF VALVE INTERSTITIAL CELLS: IMPLICATION FOR BICUSPIDE AORTIC VALVE R Bouchareb, M Boulanger, P Pibarot, P Mathieu, Y Bossé Québec, Québec INTRODUCTION:
Calcific aortic valve stenosis (CVAS) is the most common valvular heart disease in Western countries. Bicuspid aortic valve (BAV) is a strong risk factor for the development of CAVS. Valve interstitial cells (VICs) in BAV are exposed to high mechanical constraint. Previous studies in our laboratory have shown that P2Y2 purinergic receptor (P2Y2R) exerts an important control over the osteogenic transition of VICs. Mechanical stress is known to increase the expression of ectonucleotidases in VICs, but whether mechanical constraint affects P2Y2R and its downstream signalling is unknown. Filamin A (FLNA) and the tyrosine kinase Src bind to the SH3 domain of P2Y2R. In this study, we hypothesized that mechanical stress could act as an important regulator of VIC mineralization through P2Y2R-Src-FLNA pathway. METHODS: VICs were subjected to mechanical stress by using the Flexcell-5000 system and the functional relevance of P2Y2R-Src-FLNA on mineralization of VICs was examined. RESULTS: Mechanical stress increased the mineralization of VICs P2Y2R-/- by 4 fold compared to control VICs (P2Y2R+/+). Furthermore, in response to mechanical stress the expression of RUNX2, a transcription factor involved in osteogenesis, was increased in P2Y2R-/- VICs. In rescue experiments, the transfection of VICs P2Y2R-/- with a vector encoding for P2Y2R reduced the level of mineralization induced by mechanical stress. This effect was enhanced by a co-transfection with a vector encoding for Src. Also, overexpression of FLNA and Src abolished the pro-mineralizing effect of mechanical stress in the VICs. Analysis by