{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T17:14:22Z","timestamp":1765041262194,"version":"3.37.3"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Clin Pharmacol"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>The aim of this study was to analyze the clinical characteristics of fatal adverse events (AEs) of rivaroxaban combined with aspirin and to underline the importance of the rational use of drugs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The WHO global database of reported potential side effects of medicinal products (VigiBase) was searched for fatal AEs in the combined use of rivaroxaban and aspirin, and the clinical characteristics of those cases with sufficient information (vigiGrade completeness score\u2009\u2265\u20090.80) were analyzed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>By January 19, 2020, 2309 fatal adverse event reports of rivaroxaban combined with aspirin from 21 countries were entered in VigiBase. One hundred and twenty cases contained further information, of which 42 were female (35%) and 78 were male (65%). The median age was 75 (range 34 to 93) years, and 109 cases (91%) were elderly patients (\u2265\u200965\u00a0years). The AEs listed in the fatal case reports included bleeding in 114 cases (mainly intracranial hemorrhage and gastrointestinal hemorrhage, 59 and 46 respectively, accounting for 88%) and ischemic events in six cases (ischemic stroke in three, acute myocardial infarction in two, myocardial infarction combined with acute liver failure in one). Among the patients with bleeding events, 108 (95%) had existing risk factors for bleeding or for interacting with aspirin or rivaroxaban. These may be divided into the following: diseases (hypertension, renal impairment, history of stroke, peptic ulcer, or previous bleeding), drugs (high dose aspirin, antiplatelet drugs, anticoagulants, P-gp inhibitors\/CYP3A4 inhibitors, non-steroidal anti-inflammatory drugs, steroids, and selective serotonin reuptake inhibitors), or other factors (e.g., elderly, low body weight, or excessive intake of ginger, fish oil, or alcohol). There were 45 cases with two or more of these risk factors in addition to rivaroxaban and aspirin. Patients with ischemic events are often in very high-risk groups of atherosclerotic cardiovascular disease (ASCVD) or self-discontinuation of treated drugs. Medication errors occurred in 24 patients (20%): excessive treatment in 17 cases, contraindication in three, frequency error in two, excessive treatment combined with contraindication in one, and self-discontinuation in one.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Fatal AEs related to rivaroxaban combined with aspirin, including bleeding and ischemic events, have been reported mostly in the elderly, and sometimes involved medication errors. The fatal AEs mainly manifested as serious bleeding, and most of them occurred in patients with concurrent multiple risk factors. Monitoring coagulation during rivaroxaban treatment is recommended in very high-risk ASCVD populations, and attention should be paid to prevention of medication errors.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00228-022-03357-4","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T11:02:34Z","timestamp":1656673354000},"page":"1521-1526","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Fatal adverse events of rivaroxaban combined with aspirin: an analysis using data from VigiBase"],"prefix":"10.1007","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3843-8767","authenticated-orcid":false,"given":"Qingxia","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5323-9996","authenticated-orcid":false,"given":"Qian","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suying","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2475-2621","authenticated-orcid":false,"given":"Qun-Ying","family":"Yue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,7,1]]},"reference":[{"issue":"9","key":"3357_CR1","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1093\/eurheartj\/ehn579","volume":"30","author":"J Schmitt","year":"2009","unstructured":"Schmitt J, Duray G, Gersh BJ et al (2009) Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 30(9):1038\u20131045","journal-title":"Eur Heart J"},{"issue":"9","key":"3357_CR2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024964","volume":"6","author":"S Kralev","year":"2011","unstructured":"Kralev S, Schneider K, Lang S et al (2011) Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography. PLoS One 6(9):e24964","journal-title":"PLoS ONE"},{"issue":"22","key":"3357_CR3","doi-asserted-by":"publisher","first-page":"2422","DOI":"10.1093\/eurheartj\/ehi505","volume":"26","author":"R Nieuwlaat","year":"2005","unstructured":"Nieuwlaat R, Capucci A, Camm AJ et al (2005) Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 26(22):2422\u20132434","journal-title":"Eur Heart J"},{"issue":"4","key":"3357_CR4","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1093\/europace\/eun369","volume":"11","author":"M Nabauer","year":"2009","unstructured":"Nabauer M, Gerth A, Limbourg T et al (2009) The registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace 11(4):423\u2013434","journal-title":"Europace"},{"issue":"10","key":"3357_CR5","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1093\/europace\/euab065","volume":"23","author":"J Steffel","year":"2021","unstructured":"Steffel J, Collins R, Antz M et al (2021) 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace 23(10):1612\u20131676","journal-title":"Europace"},{"issue":"19","key":"3357_CR6","doi-asserted-by":"publisher","first-page":"4693","DOI":"10.1182\/bloodadvances.2020001830","volume":"4","author":"TL Ortel","year":"2020","unstructured":"Ortel TL, Neumann I, Ageno W et al (2020) American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 4(19):4693\u20134738","journal-title":"Blood Adv"},{"key":"3357_CR7","doi-asserted-by":"crossref","unstructured":"Bibbins-Domingo K (2016) US Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med 164(12):836\u201345","DOI":"10.7326\/M16-0577"},{"issue":"5","key":"3357_CR8","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.jacc.2020.09.011","volume":"77","author":"DJ Kumbhani","year":"2021","unstructured":"Kumbhani DJ, Cannon CP, Beavers CJ et al (2021) 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atherosclerotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 77(5):629\u2013658","journal-title":"J Am Coll Cardiol"},{"key":"3357_CR9","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.ijcard.2020.06.032","volume":"320","author":"T Akhtar","year":"2020","unstructured":"Akhtar T, Fratti JDC, Mattumpuram J et al (2020) Factors associated with bleeding events in patients on rivaroxaban for non-valvular atrial fibrillation: a real-world experience. Int J Cardiol 320:78\u201382","journal-title":"Int J Cardiol"},{"key":"3357_CR10","unstructured":"Banerjee A (2018) There may be a role for addition of rivaroxaban to aspirin in patients with stable coronary artery disease. BMJ Evid Based Med: bmjebm-2018-110900."},{"key":"3357_CR11","unstructured":"https:\/\/admin.ich.org\/sites\/default\/files\/inline-files\/Understanding_MedDRA_2013.pdf Accessed 5th April 2022"},{"key":"3357_CR12","doi-asserted-by":"crossref","unstructured":"Bergvall T, Nor\u00e9n GN, Lindquist M (2014)\u00a0vigiGrade: a tool to identify well-documented individual case reports and highlight systematic data quality issues. Drug Saf\u00a037(1):65\u201377","DOI":"10.1007\/s40264-013-0131-x"},{"key":"3357_CR13","unstructured":"https:\/\/www.medicines.org.uk\/emc\/product\/2408\/smpc Accessed 7th February 2022"},{"key":"3357_CR14","unstructured":"https:\/\/www.medicines.org.uk\/emc\/product\/6402\/smpc Accessed 7th February 2022"},{"issue":"5","key":"3357_CR15","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1093\/eurheartj\/ehaa612","volume":"42","author":"G Hindricks","year":"2021","unstructured":"Hindricks G, Potpara T, Dagres N et al (2021) 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 42(5):373\u2013498","journal-title":"Eur Heart J"},{"issue":"2","key":"3357_CR16","doi-asserted-by":"publisher","first-page":"e125","DOI":"10.1161\/CIR.0000000000000665","volume":"140","author":"CT January","year":"2019","unstructured":"January CT, Wann LS, Calkins H et al (2019) 2019 AHA\/ACC\/HRS focused update of the 2014 AHA\/ACC\/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation 140(2):e125\u2013e151","journal-title":"Circulation"},{"key":"3357_CR17","doi-asserted-by":"crossref","unstructured":"Jiang HY, Chen HZ, Hu XJ\u00a0et al (2015) Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis.\u00a0Clin Gastroenterol Hepatol\u00a013(1)","DOI":"10.1016\/j.cgh.2014.06.021"},{"issue":"2","key":"3357_CR18","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/0002-9343(94)90131-7","volume":"96","author":"KG Saag","year":"1994","unstructured":"Saag KG, Koehnke R, Caldwell JR et al (1994) Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med 96(2):115\u2013123","journal-title":"Am J Med"},{"key":"3357_CR19","unstructured":"https:\/\/consumermedsafety.org\/medication-safety-articles\/item\/847-teaching-sheets Accessed 7th February 2022"},{"issue":"1","key":"3357_CR20","first-page":"95","volume":"30","author":"P Gressenberger","year":"2019","unstructured":"Gressenberger P, Rief P, Jud P et al (2019) Increased bleeding risk in a patient with oral anticoagulant therapy and concomitant herbal intake - a case report. EJIFCC 30(1):95\u201398","journal-title":"EJIFCC"},{"key":"3357_CR21","unstructured":"https:\/\/www.uptodate.com\/contents\/rivaroxaban-drug-information?search=Rivaroxaban&source=panel_search_result&selectedTitle=2~149&usage_type=panel&kp_tab=drug_foreign&display_rank=1 Accessed 7th February 2022"},{"issue":"5","key":"3357_CR22","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1378\/chest.10-0134","volume":"138","author":"R Pisters","year":"2010","unstructured":"Pisters R, Lane DA, Nieuwlaat R et al (2010) A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 138(5):1093\u20131100","journal-title":"Chest"},{"issue":"7","key":"3357_CR23","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1007\/s11739-018-1858-2","volume":"13","author":"D Arioli","year":"2018","unstructured":"Arioli D, Donelli D, Morini L et al (2018) Drug plasma level measurement in management of severe bleeding during direct oral anticoagulant treatment: case report and perspective. Intern Emerg Med 13(7):1093\u20131096","journal-title":"Intern Emerg Med"},{"key":"3357_CR24","unstructured":"National Institute for Health and Care Excellence (2021) Clinical Guidelines. Atrial fibrillation: diagnosis and management. London; National Institute for Health and Care Excellence (NICE) Copyright\u00a9 NICE 2021"},{"key":"3357_CR25","doi-asserted-by":"crossref","unstructured":"Proietti M, Romiti GF, Vitolo M et al (2021) Comparison of HAS-BLED and ORBIT bleeding risk scores in AF patients treated with NOACs: a report from the ESC-EHRA EORP-AF general long-term registry. Eur Heart J Qual Care Clin Outcomes","DOI":"10.1093\/ehjqcco\/qcab069"},{"issue":"10","key":"3357_CR26","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1056\/NEJMoa1009638","volume":"365","author":"MR Patel","year":"2011","unstructured":"Patel MR, Mahaffey KW, Garg J et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883\u2013891","journal-title":"N Engl J Med"},{"issue":"3","key":"3357_CR27","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1093\/europace\/euz361","volume":"22","author":"AH Malik","year":"2020","unstructured":"Malik AH, Yandrapalli S, Shetty S et al (2020) Impact of weight on the efficacy and safety of direct-acting oral anticoagulants in patients with non-valvular atrial fibrillation: a meta-analysis. Europace 22(3):361\u2013367","journal-title":"Europace"},{"key":"3357_CR28","doi-asserted-by":"crossref","unstructured":"Lee SR, Choi EK, Park CS et al (2019) Direct oral anticoagulants in patients with nonvalvular atrial fibrillation and low body weight. J Am Coll Cardiol 73(8):919\u201331","DOI":"10.1016\/j.jacc.2018.11.051"},{"issue":"8","key":"3357_CR29","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1007\/s00392-017-1102-5","volume":"106","author":"R de Caterina","year":"2017","unstructured":"De Caterina R, Lip GY (2017) The non-vitamin K antagonist oral anticoagulants (NOACs) and extremes of body weight-a systematic literature review. Clinical research in cardiology\u202f: official journal of the German Cardiac Society 106(8):565\u2013572","journal-title":"Clinical research in cardiology : official journal of the German Cardiac Society"},{"key":"3357_CR30","unstructured":"Liang Ting HS, Wu J et al (2021) Analysis and prediction of bleeding risk factors caused by rivaroxaban.\u00a0Chinese J Pharmacol Toxicol\u00a0(3):277\u201381"},{"issue":"9921","key":"3357_CR31","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/S0140-6736(13)62343-0","volume":"383","author":"CT Ruff","year":"2014","unstructured":"Ruff CT, Giugliano RP, Braunwald E et al (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921):955\u2013962","journal-title":"Lancet"},{"issue":"3","key":"3357_CR32","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1055\/s-0038-1627480","volume":"118","author":"RC Gosselin","year":"2018","unstructured":"Gosselin RC, Adcock DM, Bates SM et al (2018) International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 118(3):437\u2013450","journal-title":"Thromb Haemost"},{"key":"3357_CR33","doi-asserted-by":"crossref","unstructured":"W\u00fcrtz M, Olesen KK, Mortensen MB\u00a0et al (2022) Dual antithrombotic treatment in chronic coronary syndrome: European Society of Cardiology criteria vs. CHADS-P2A2RC score.\u00a0Eur Heart J\u00a043(10):996\u20131004","DOI":"10.1093\/eurheartj\/ehab785"},{"key":"3357_CR34","unstructured":"http:\/\/www.jcpcarchives.org\/full\/spontaneous-reporting-in-pharmacovigilance--strengths-49.php Accessed 7th February 2022"}],"container-title":["European Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-022-03357-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00228-022-03357-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-022-03357-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T07:08:30Z","timestamp":1660115310000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00228-022-03357-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,1]]},"references-count":34,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["3357"],"URL":"https:\/\/doi.org\/10.1007\/s00228-022-03357-4","relation":{},"ISSN":["0031-6970","1432-1041"],"issn-type":[{"type":"print","value":"0031-6970"},{"type":"electronic","value":"1432-1041"}],"subject":[],"published":{"date-parts":[[2022,7,1]]},"assertion":[{"value":"14 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}