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      Ibrutinib increases the risk of hypertension and atrial fibrillation: Systematic review and meta-analysis

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          Abstract

          Introduction

          Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm’s macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction.

          Methods

          We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach.

          Results

          There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52–5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17–7.64) with high quality evidence.

          Conclusions

          Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.

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          Most cited references24

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          Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.

          Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.
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            Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling.

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              Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia

              Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Funding acquisitionRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 February 2019
                2019
                : 14
                : 2
                : e0211228
                Affiliations
                [1 ] Serviço de Cardiologia, Hospital Universitário de Santa Maria (CHLN), CAML, Centro Cardiovascular da Universidade de Lisboa—CCUL, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa, Portugal
                [2 ] Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa, Portugal
                [3 ] Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa, Portugal
                [4 ] Hematology Department, Faculdade de Medicina, Universidade de Lisboa, Santa Maria University Hospital (CHLN), Lisbon, Portugal
                Institute for Quality and Efficienty in Health Care (IQWiG), GERMANY
                Author notes

                Competing Interests: DC has participated in educational meetings and/or attended a conferences or symposia with Bristol-Myers Squibb, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck Serono, Ferrer, Pfizer, Novartis and Roche. DA received speaker fees from Janssen, Roche, Gillead and Takeda. JJF had speaker and consultant fees with GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Abbott, Bial, Merck-Serono, Grunenthal, and Merck Sharp and Dohme; FJP had consultant and speaker fees with Astra Zeneca, Bayer, BMS, Boehringer Ingelheim and Daiichi Sankyo. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-2520-5673
                Article
                PONE-D-18-25537
                10.1371/journal.pone.0211228
                6382095
                30785921
                5e1e19fb-ca8f-4934-9a22-5070c3a1c648
                © 2019 Caldeira et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 September 2018
                : 9 January 2019
                Page count
                Figures: 5, Tables: 2, Pages: 15
                Funding
                Funded by: FEDER, POR Lisboa 2020, Portugal 2020, FCT
                Award ID: LISBOA-01-0145-FEDER-007391
                UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Cardiology
                Arrhythmia
                Atrial Fibrillation
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Hypertension
                Research and Analysis Methods
                Research Design
                Clinical Research Design
                Adverse Events
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Metaanalysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Metaanalysis
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Hematologic Cancers and Related Disorders
                Leukemias
                Lymphoblastic Leukemia
                Chronic Lymphoblastic Leukemia
                Medicine and Health Sciences
                Hematology
                Hematologic Cancers and Related Disorders
                Leukemias
                Lymphoblastic Leukemia
                Chronic Lymphoblastic Leukemia
                Research and Analysis Methods
                Research Assessment
                Systematic Reviews
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Trials
                Randomized Controlled Trials
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Clinical Trials
                Randomized Controlled Trials
                Research and Analysis Methods
                Clinical Trials
                Randomized Controlled Trials
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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                Uncategorized

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