{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:39:49Z","timestamp":1789713589774,"version":"4.0.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Ibrutinib, a Bruton\u2019s tyrosine kinase (BTK) inhibitor, is authorized for the treatment of chronic lymphocytic leukemia (CLL). This study aims to explore the cardiac safety profile of ibrutinib in comparison with obinutuzumab.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A retrospective pharmacovigilance study was conducted on data retrieved from the European pharmacovigilance database (Eudravigilance) from 1 January 2014 to 30 September 2022. To compare the reporting frequency of cardiovascular events among ibrutinib, obinutuzumab, and the combination of both.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A total of 2 291 CV cases were retrieved, of which 1965 were related to ibrutinib, 312 to obinutuzumab, and 14 to the combination. Most cases referred to patients aged \u226565\u00a0years (<jats:italic>N<\/jats:italic> = 1,454; 63.47%) and male (<jats:italic>N<\/jats:italic> = 1,497; 65.34%). Most cases were serious (<jats:italic>N<\/jats:italic> = 2,131; 93.02%). The most reported events were: atrial fibrillation (<jats:italic>N<\/jats:italic> = 913; 31.31%) and haemorrhage (<jats:italic>N<\/jats:italic> = 201; 6.89%). A higher reporting frequency of CV events was found when ibrutinib was compared to obinutuzumab (ROR, 3.22; 95% CI, 2.89-3.60) or combination (ROR, 1.77; 95% CI, 1.11-2.83). A lower reporting was observed when obinutuzumab was compared to combination (ROR, 0.55; 95% CI, 0.34-0.88).<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> A higher reporting frequency of CV events in patients exposed to ibrutinib in comparison with obinutuzumab was found. Further studies are needed to better explore the safety of ibrutinib.<\/jats:p>","DOI":"10.3389\/fphar.2023.1229304","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T12:38:45Z","timestamp":1692275925000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Which is the top player for the cardiovascular safety? ibrutinib vs. obinutuzumab in CLL"],"prefix":"10.3389","volume":"14","author":[{"given":"Annamaria","family":"Mascolo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Di Napoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzia","family":"Balzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"D\u2019Alessio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imma","family":"Izzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Paolisso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Capuano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liberata","family":"Sportiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"769315","DOI":"10.3389\/FPHAR.2021.769315","article-title":"Safety profile of ibrutinib: an analysis of the WHO pharmacovigilance database","volume":"12","author":"Allouchery","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/S13045-023-01469-7","article-title":"Unresolved questions in selection of therapies for treatment-na\u00efve chronic lymphocytic leukemia","volume":"16","author":"Bennett","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1111\/J.1365-2125.2006.02746.X","article-title":"Patient reporting of suspected adverse drug reactions: a review of published literature and international experience","volume":"63","author":"Blenkinsopp","year":"2007","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"5845","DOI":"10.3390\/JCM10245845","article-title":"Long-term efficacy and safety of ibrutinib in the treatment of CLL patients: areal life experience","volume":"10","author":"Broccoli","year":"2021","journal-title":"J. Clin. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.3324\/HAEMATOL.2017.171041","article-title":"Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials","volume":"102","author":"Brown","year":"2017","journal-title":"Haematologica"},{"key":"B6","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1097\/PPO.0000000000000412","article-title":"Bruton tyrosine kinase inhibitors: present and future","volume":"25","author":"Burger","year":"2019","journal-title":"Cancer J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1182\/BLOOD-2018-10-879429","article-title":"Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia","volume":"133","author":"Burger","year":"2019","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e0211228","DOI":"10.1371\/JOURNAL.PONE.0211228","article-title":"Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis","volume":"14","author":"Caldeira","year":"2019","journal-title":"PLoS One"},{"key":"B9","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1080\/17474086.2022.2067526","article-title":"Cardiotoxicity of BTK inhibitors: ibrutinib and beyond","volume":"15","author":"Christensen","year":"2022","journal-title":"Expert Rev. Hematol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1182\/BLOOD.2019000840","article-title":"Hypertension and incident cardiovascular events following ibrutinib initiation","volume":"134","author":"Dickerson","year":"2019","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3225","DOI":"10.2147\/DDDT.S377697","article-title":"Ibrutinib-associated cardiotoxicity: from the pharmaceutical to the clinical","volume":"16","author":"Dong","year":"2022","journal-title":"Drug Des. devel. Ther."},{"key":"B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/J.ANNONC.2020.09.019","article-title":"Chronic lymphocytic leukaemia: eSMO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"32","author":"Eichhorst","year":"2021","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/S40545-021-00379-8","article-title":"Importance of medication reconciliation in cancer patients","volume":"14","author":"Elbeddini","year":"2021","journal-title":"J. Pharm. policy Pract."},{"key":"B14","article-title":"Directive 84\/2010\/EC","year":"2010","journal-title":"Off. J. Eur. Union"},{"key":"B15","unstructured":"Annex I summary of product characteristics (imbruvica)2019"},{"key":"B16","unstructured":"Imbruvica (ibrutinib): new risk minimisation measures, including dose modification recommendations, due to the increased risk for serious cardiac events | European Medicines Agency2022"},{"key":"B17","article-title":"European regulation 1235\/2010\/EC","year":"2010","journal-title":"Off. J. Eur. Union"},{"key":"B18","doi-asserted-by":"publisher","first-page":"370","DOI":"10.6004\/JADPRO.2015.6.4.7","article-title":"Obinutuzumab: a novel anti-CD20 monoclonal antibody for chronic lymphocytic leukemia","volume":"6","author":"Evans","year":"2015","journal-title":"J. Adv. Pract. Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1056\/NEJMOA1815281","article-title":"Venetoclax and obinutuzumab in patients with CLL and coexisting conditions","volume":"380","author":"Fischer","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B20","first-page":"24","article-title":"Nurse reporting of adverse events caused by medicines","volume":"99","author":"Hunt","year":"2003","journal-title":"Nurs. Times"},{"key":"B21","unstructured":"National report on medicines use in Italy - year 20212022"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1016\/J.HRTHM.2019.04.008","article-title":"Ibrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium","volume":"16","author":"Jiang","year":"2019","journal-title":"Hear. Rhythm"},{"key":"B23","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/J.PHRS.2017.11.003","article-title":"Hypertension and cardiovascular risk: general aspects","volume":"129","author":"Kjeldsen","year":"2018","journal-title":"Pharmacol. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.1182\/BLOOD-2016-10-742437","article-title":"Ventricular arrhythmias and sudden death in patients taking ibrutinib","volume":"129","author":"Lampson","year":"2017","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","first-page":"E255","DOI":"10.1002\/AJH.26558","article-title":"Cardiovascular disease in patients with chronic lymphocytic leukemia: a Swedish nationwide register study with matched comparators","volume":"97","author":"Larsson","year":"2022","journal-title":"Am. J. Hematol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1053\/J.SEMINONCOL.2016.02.008","article-title":"Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia","volume":"43","author":"Maddocks","year":"2016","journal-title":"Semin. Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1002\/JHA2.638","article-title":"A real-world study to assess the association of cardiovascular adverse events (CVAEs) with ibrutinib as first-line (1L) treatment for patients with chronic lymphocytic leukaemia (CLL) in the United States","volume":"4","author":"Mato","year":"2023","journal-title":"eJHaem"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3829","DOI":"10.1182\/BLOOD-2014-10-604272","article-title":"Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling","volume":"124","author":"McMullen","year":"2014","journal-title":"Blood"},{"key":"B29","unstructured":"Chronic lymphocytic leukemia \u2014 cancer stat facts2022"},{"key":"B30","doi-asserted-by":"publisher","first-page":"686768","DOI":"10.3389\/FIMMU.2021.686768","article-title":"BTK inhibitors in chronic lymphocytic leukemia: biological activity and immune effects","volume":"12","author":"Palma","year":"2021","journal-title":"Front. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"S21","DOI":"10.1517\/14740338.2014.939582","article-title":"Improvement of patient adverse drug reaction reporting through a community pharmacist-based intervention in the Campania region of Italy","volume":"13","author":"Parretta","year":"2014","journal-title":"Expert Opin. Drug Saf."},{"key":"B32","doi-asserted-by":"publisher","first-page":"998","DOI":"10.2353\/AJPATH.2009.090126","article-title":"Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation","volume":"175","author":"Pretorius","year":"2009","journal-title":"Am. J. Pathol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"349","DOI":"10.2165\/00128071-200102060-00001","article-title":"Do women have more adverse drug reactions?","volume":"2","author":"Rademaker","year":"2001","journal-title":"Am. J. Clin. Dermatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/14740338.2016.1229301","article-title":"Second generation antipsychotics in \u2018real-life\u2019 paediatric patients. Adverse drug reactions and clinical outcomes of drug switch","volume":"15","author":"Rafaniello","year":"2016","journal-title":"Expert Opin. Drug Saf."},{"key":"B35","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1001\/ARCHINTE.146.4.649","article-title":"Adverse drug reactions. The clinician\u2019s role in reporting","volume":"146","author":"Richard","year":"1986","journal-title":"Arch. Intern. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1016\/J.JACC.2019.07.056","article-title":"Cardiovascular toxicities associated with ibrutinib","volume":"74","author":"Salem","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1080\/14740338.2016.1221396","article-title":"New era in treatment options of chronic hepatitis C: focus on safety of new direct-acting antivirals (DAAs)","volume":"15","author":"Scavone","year":"2016","journal-title":"Expert Opin. Drug Saf."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e200","DOI":"10.1016\/S1470-2045(18)30099-8","article-title":"Medication overuse in oncology: current trends and future implications for patients and society","volume":"19","author":"Schleicher","year":"2018","journal-title":"Lancet. Oncol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1080\/14740338.2016.1221397","article-title":"Campania region (Italy) spontaneous reporting system and preventability assessment through a case-by-case approach: a pilot study on psychotropic drugs","volume":"15","author":"Sessa","year":"2016","journal-title":"Expert Opin. Drug Saf."},{"key":"B40","doi-asserted-by":"publisher","first-page":"305","DOI":"10.3389\/fphar.2017.00305","article-title":"Campania preventability assessment committee (Italy): a focus on the preventability of non-steroidal anti-inflammatory drugs\u2019 adverse drug reactions","volume":"8","author":"Sessa","year":"2017","journal-title":"Front. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1111\/JTH.13651","article-title":"Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies","volume":"15","author":"Shatzel","year":"2017","journal-title":"J. Thromb. Haemost."},{"key":"B42","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/s41408-020-00351-w","article-title":"Clinicopathological characterization of chronic lymphocytic leukemia with MYD88 mutations: l265P and non-l265P mutations are associated with different features","volume":"108","author":"Shuai","year":"2020","journal-title":"Blood Cancer J."},{"key":"B43","doi-asserted-by":"publisher","first-page":"81","DOI":"10.2147\/BLCTT.S326627","article-title":"Use of BTK inhibitors in chronic lymphocytic leukemia\/small lymphocytic lymphoma (CLL\/SLL): a practical guidance","volume":"12","author":"St-Pierre","year":"2022","journal-title":"Blood Lymphat. Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1111\/BJH.17788","article-title":"Management of cardiovascular complications of bruton tyrosine kinase inhibitors","volume":"196","author":"Tang","year":"2022","journal-title":"Br. J. Haematol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e610","DOI":"10.3747\/CO.26.4957","article-title":"Descriptive analysis of dosing and outcomes for patients with ibrutinib-treated relapsed or refractory chronic lymphocytic leukemia in a Canadian centre","volume":"26","author":"Uminski","year":"2019","journal-title":"Curr. Oncol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1517\/14740338.3.4.363","article-title":"Patients\u2019 role in reporting adverse drug reactions","volume":"3","author":"van Grootheest","year":"2004","journal-title":"Expert Opin. Drug Saf."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1033413","DOI":"10.3389\/FONC.2022.1033413","article-title":"Obinutuzumab plus chlorambucil versus ibrutinib in previously untreated chronic lymphocytic leukemia patients without TP53 disruptions: a real-life CLL campus study","volume":"12","author":"Visentin","year":"2022","journal-title":"Front. Oncol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.1161\/CIRCULATIONAHA.120.049210","article-title":"Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal src kinase","volume":"142","author":"Xiao","year":"2020","journal-title":"Circulation"},{"key":"B49","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/S12938-021-00973-6","article-title":"The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019","volume":"21","author":"Yao","year":"2022","journal-title":"Biomed. Eng. Online"},{"key":"B50","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3390\/PH16010098","article-title":"Cardiovascular toxicities of ibrutinib: a pharmacovigilance study based on the United States Food and drug administration adverse event reporting system database","volume":"16","author":"Zheng","year":"2023","journal-title":"Pharm. (Basel)."},{"key":"B51","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1007\/S00228-008-0494-6","article-title":"Women encounter ADRs more often than do men","volume":"64","author":"Zopf","year":"2008","journal-title":"Eur. J. Clin. Pharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1229304\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T12:38:49Z","timestamp":1692275929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1229304\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,16]]},"references-count":51,"alternative-id":["10.3389\/fphar.2023.1229304"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1229304","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,16]]},"article-number":"1229304"}}