title: Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions.
abstract: Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase.
  
  
  
  Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant.
  
  
  
  We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously.
  
  
  
  As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred.
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Monaco
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Biagi
authors.affiliation: Pharmacovigilance Regional Centre of Lombardy, Via Taramelli 26, 20124, Milan, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Conti
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Melis
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Donati
authors.affiliation: Pharmacovigilance Regional Centre of Lombardy, Via Taramelli 26, 20124, Milan, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Venegoni
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Vaccheri
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Motola
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D001281:Atrial Fibrillation / Q000150:complications*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000453:epidemiology*; D002648:Child; D002675:Child, Preschool; D000069604:Dabigatran / Q000009:adverse effects; D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000453:epidemiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000009:adverse effects; D011728:Pyridones / Q000009:adverse effects; D012307:Risk Factors; D000069552:Rivaroxaban / Q000009:adverse effects; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D014859:Warfarin / Q000009:adverse effects; D014944:World Health Organization; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D000069552:Rivaroxaban; D000069604:Dabigatran
keywords: adverse drug reaction; apixaban; dabigatran; pharmacovigilance; rivaroxaban; warfarin