{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:34:29Z","timestamp":1790883269379,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Arianna Anticoagulation Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients\u2019 demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2\u20132.0), major bleedings (RR 1.8; 95% CI 1.3\u20131.7), and mortality (RR 2.8; 95% CI 1.9\u20134.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight &lt;60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events.<\/jats:p>","DOI":"10.3390\/jcm13072009","type":"journal-article","created":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T13:32:56Z","timestamp":1711891976000},"page":"2009","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Inappropriate Underdosing of Direct Oral Anticoagulants in Atrial Fibrillation Patients: Results from the START2-AF Registry"],"prefix":"10.3390","volume":"13","author":[{"given":"Daniela","family":"Poli","sequence":"first","affiliation":[{"name":"Center of Atherothrombotic Disease, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9185-2046","authenticated-orcid":false,"given":"Emilia","family":"Antonucci","sequence":"additional","affiliation":[{"name":"Fondazione Arianna Anticoagulazione, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Ageno","sequence":"additional","affiliation":[{"name":"SSD Degenza Breve Internistica, Dipartimento di Medicina Interna, Ospedale di Circolo e Fondazione Macchi, ASST Sette Laghi, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8281-4734","authenticated-orcid":false,"given":"Martina","family":"Berteotti","sequence":"additional","affiliation":[{"name":"Center of Atherothrombotic Disease, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5007-3457","authenticated-orcid":false,"given":"Anna","family":"Falanga","sequence":"additional","affiliation":[{"name":"School of Medicine, Universit\u00e0 di Milano Bicocca, 20126 Milano, Italy"},{"name":"Immunoematologia e Medicina Trasfusionale ASST Papa Giovanni XXIIIo, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2064-6071","authenticated-orcid":false,"given":"Vittorio","family":"Pengo","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Cardio-Toraco-Vascolari, AOU Padova, 35121 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Chiarugi","sequence":"additional","affiliation":[{"name":"UO di Analisi Chimico Cliniche, Azienda Ospedaliero Universitaria Pisana, 56100 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0606-6038","authenticated-orcid":false,"given":"Benilde","family":"Cosmi","sequence":"additional","affiliation":[{"name":"Division of Angiology and Blood Coagulation, IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"Paparo","sequence":"additional","affiliation":[{"name":"Laboratorio Analisi, Ospedale Maggiore, 10023 Chieri, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2593-1376","authenticated-orcid":false,"given":"Antonio","family":"Chistolini","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Universit\u00e0 di Roma, 00185 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Insana","sequence":"additional","affiliation":[{"name":"SC Laboratorio Analisi Chimico-Cliniche e Microbiologia, A.O. Ordine Mauriziano, 10128 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Lione","sequence":"additional","affiliation":[{"name":"UOC di Patologia Clinica, Ospedale A Perrino, 72100 Brindisi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Malcangi","sequence":"additional","affiliation":[{"name":"U.O. Medicina Trasfusionale, Azienda Ospedaliero-Universitaria Policlinico di Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Martini","sequence":"additional","affiliation":[{"name":"Centro Emostasi, Spedali Civili Di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucilla","family":"Masciocco","sequence":"additional","affiliation":[{"name":"UOC Medicina Interna, Ospedale Lastaria, 71036 Lucera, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Pedrini","sequence":"additional","affiliation":[{"name":"Servizio di Laboratorio, Istituto Ospedaliero Fondazione Poliambulanza, 25124 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Bucherini","sequence":"additional","affiliation":[{"name":"Medicina Interna, Ambulatorio Emostasi Trombosi, Faenza (Ra) AUSL Romagna, 48018 Faenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6357-5213","authenticated-orcid":false,"given":"Daniele","family":"Pastori","sequence":"additional","affiliation":[{"name":"Emergency Medicine Unit, Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2265-7455","authenticated-orcid":false,"given":"Pasquale","family":"Pignatelli","sequence":"additional","affiliation":[{"name":"Emergency Medicine Unit, Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8582-4077","authenticated-orcid":false,"given":"Andrea","family":"Toma","sequence":"additional","affiliation":[{"name":"UOC di Patologia Clinica, Ambulatorio Terapia Anticoagulante Orale, O.C. \u201cL. Cazzavillan\u201d, 36071 Arzignano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Testa","sequence":"additional","affiliation":[{"name":"Haemostasis and Thrombosis Centre, Laboratory Medicine Department, ASST Cremona, 26100 Cremona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4327-9561","authenticated-orcid":false,"given":"Gualtiero","family":"Palareti","sequence":"additional","affiliation":[{"name":"Fondazione Arianna Anticoagulazione, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"START AF Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/S0140-6736(13)62343-0","article-title":"Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials","volume":"383","author":"Ruff","year":"2014","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1056\/NEJMoa0905561","article-title":"Dabigatran versus warfarin in patients with atrial fibrillation","volume":"361","author":"Connolly","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1056\/NEJMoa1107039","article-title":"Apixaban versus warfarin in patients with atrial fibrillation","volume":"365","author":"Granger","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJMoa1009638","article-title":"Rivaroxaban versus warfarin in nonvalvular atrial fibrillation","volume":"365","author":"Patel","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1310907","article-title":"Edoxaban versus warfarin in patients with atrial fibrillation","volume":"369","author":"Giugliano","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_6","first-page":"1467","article-title":"Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation","volume":"17","author":"Heidbuchel","year":"2015","journal-title":"EP Eur."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.jacc.2020.07.045","article-title":"Mortality in Patients With Atrial Fibrillation Receiving Nonrecommended Doses of Direct Oral Anticoagulants","volume":"76","author":"Camm","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1007\/s11606-020-05777-3","article-title":"Comparative Safety and Effectiveness of Direct-Acting Oral Anticoagulants Versus Warfarin: A National Cohort Study of Nursing Home Residents","volume":"35","author":"Alcusky","year":"2020","journal-title":"J. Gen. Intern. Med."},{"key":"ref_9","first-page":"1577","article-title":"Inappropriate doses of direct oral anticoagulants in real-world clinical practice: Prevalence and associated factors. A subanalysis of the FANTASIIA Registry","volume":"20","author":"Muniz","year":"2018","journal-title":"EP Eur."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.amjmed.2019.01.025","article-title":"Effectiveness and Safety of Off-Label Dose-Reduced Direct Oral Anticoagulants in Atrial Fibrillation","volume":"132","author":"Arbel","year":"2019","journal-title":"Am. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.jacc.2016.11.061","article-title":"The Changing Landscape for Stroke Prevention in AF: Findings From the GLORIA-AF Registry Phase 2","volume":"69","author":"Huisman","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1016\/j.jacc.2016.09.966","article-title":"Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes: The ORBIT-AF II Registry","volume":"68","author":"Steinberg","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Antonucci, E., Poli, D., Tosetto, A., Pengo, V., Tripodi, A., Magrini, N., Marongiu, F., Palareti, G., and Register, S. (2015). The Italian START-Register on Anticoagulation with Focus on Atrial Fibrillation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124719"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1159\/000180580","article-title":"Prediction of creatinine clearance from serum creatinine","volume":"16","author":"Cockcroft","year":"1976","journal-title":"Nephron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1378\/chest.09-1584","article-title":"Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation","volume":"137","author":"Lip","year":"2010","journal-title":"Chest"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1378\/chest.10-0134","article-title":"A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey","volume":"138","author":"Pisters","year":"2010","journal-title":"Chest"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/j.1538-7836.2005.01204.x","article-title":"Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients","volume":"3","author":"Schulman","year":"2005","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1111\/jth.13140","article-title":"Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: Communication from the SSC of the ISTH","volume":"13","author":"Kaatz","year":"2015","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e007633","DOI":"10.1161\/JAHA.117.007633","article-title":"Frequency and Outcomes of Reduced Dose Non-Vitamin K Antagonist Anticoagulants: Results from ORBIT-AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II)","volume":"7","author":"Steinberg","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/bcp.14127","article-title":"Impact of direct oral anticoagulant off-label doses on clinical outcomes of atrial fibrillation patients: A systematic review","volume":"86","author":"Santos","year":"2020","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1177\/1060028017726795","article-title":"Assessment of Apixaban Prescribing Patterns for Nonvalvular Atrial Fibrillation in Hospitalized Patients","volume":"52","author":"Gibson","year":"2018","journal-title":"Ann. Pharmacother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1093\/ehjcvp\/pvaa103","article-title":"Off-label use of reduced dose direct oral factor Xa inhibitors in subjects with atrial fibrillation: A review of clinical evidence","volume":"7","author":"Bo","year":"2021","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1182\/bloodadvances.2020003560","article-title":"Bleeding and related mortality with NOACs and VKAs in newly diagnosed atrial fibrillation: Results from the GARFIELD-AF registry","volume":"5","author":"Bassand","year":"2021","journal-title":"Blood Adv."},{"key":"ref_24","first-page":"6","article-title":"Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: Primary results of the PREvention oF thromboemolic events\u2014European Registry in Atrial Fibrillation (PREFER in AF)","volume":"16","author":"Kirchhof","year":"2014","journal-title":"EP Eur."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1136\/heartjnl-2022-321114","article-title":"Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: A systematic review and meta-analysis","volume":"109","author":"Caso","year":"2023","journal-title":"Heart"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ahj.2021.09.003","article-title":"The importance of the design of observational studies in comparative effectiveness research: Lessons from the GARFIELD-AF and ORBIT-AF registries","volume":"243","author":"Farjat","year":"2022","journal-title":"Am. Heart J."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/7\/2009\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:21:10Z","timestamp":1760106070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/7\/2009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,29]]},"references-count":26,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["jcm13072009"],"URL":"https:\/\/doi.org\/10.3390\/jcm13072009","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,29]]}}}