Aspirin in the Food and Drug Administration Adverse Event Reporting System: Missing Demographics and Underreporting
30 August 2017 (online)
Background The U.S. Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (FAERS) is a global passive surveillance repository requiring mandatory updates by pharmaceutical manufacturers. Oral antiplatelet agents (OAAs) including aspirin (acetylsalicylic acid [ASA]) are broadly used to prevent thrombosis, at the expense of extra bleeding risks. However, the OAA filing quality and their comparative patterns in FAERS are unknown. We assessed completeness of original annual FAERS reports for OAA with special attention on ASA.
Methods We extracted AE cases co-reported with OAA including ASA, clopidogrel, prasugrel, ticagrelor, vorapaxar, or their combination. The 2015 FAERS cases were examined based on OAA distribution, suspected causative role, missing gender or age, and most common AEs after ASA.
Results A total of 1,187,729 reports qualified the inclusion criteria. The majority (n = 1,121,989) of the reports contain no reference of OAA, while 65,730 reports contain reference of at least one OAA, including 47,900 ASA cases. Therapy with ASA was heavily (>50%) underreported when used with prasugrel or ticagrelor, but still dominant (72.8%) among OAAs, followed by clopidogrel (18.7%), prasugrel (4.1%), ticagrelor (3.6%), and anecdotal vorapaxar (0.05%). Despite current recommendations, some (0.73%) reports contain multi-OAAs. The primary role of ASA in AE reporting was seldom (<1%), followed by clopidogrel (2.9%), prasugrel (3.7%), and highest for ticagrelor (9.3%). Missing gender after OAA was not common (<10%), but age was missing in approximately 25% of reports. Bleeding was the most frequent AE associated with ASA.
Conclusion The quality of reporting for OAA in general and ASA in particular can be improved by stricter FDA rules, better surveillance, and enforcements. Heavy ASA underreporting during dual antiplatelet therapy and missed demographic variables challenge outcome research capacities for establishing drug interactions in FAERS.
- 1 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324 (7329): 71-86
- 2 Pilgrim T, Windecker S. Antiplatelet therapy for secondary prevention of coronary artery disease. Heart 2014; 100 (22) 1750-1756
- 3 Eidelman RS, Hebert PR, Weisman SM, Hennekens CH. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med 2003; 163 (17) 2006-2010
- 4 Mora S, Manson JE. Aspirin for primary prevention of atherosclerotic cardiovascular disease: advances in diagnosis and treatment. JAMA Intern Med 2016; 176 (08) 1195-1204
- 5 Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006; 295 (03) 306-313
- 6 Serebruany VL, Steinhubl SR, Berger PB. , et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol 2005; 95 (10) 1218-1222
- 7 Adverse Event Reporting System (AERS). Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm . Assessed May 4, 2017
- 8 Duggirala HJ, Tonning JM, Smith E. , et al. Use of data mining at the Food and Drug Administration. J Am Med Inform Assoc 2016; 23 (02) 428-434
- 9 Böhm R, von Hehn L, Herdegen T. , et al. OpenVigil FDA - Inspection of U.S. American Adverse Drug Events Pharmacovigilance Data and Novel Clinical Applications. PLoS One 2016; 11 (06) e0157753
- 10 Patrono C. The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol 2015; 66 (01) 74-85
- 11 Angiolillo DJ. The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs 2012; 72 (16) 2087-2116
- 12 Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006; 116 (01) 4-15
- 13 Serebruany VL, Kim M-H, Marciniak TA. Worldwide reporting of fatal outcomes after ticagrelor to the US Food and Drug Administration. Eur Heart J Cardiovasc Pharmacother 2017; DOI: 10.1093/ehjcvp/pvx024.
- 14 Expedited Safety Reporting Requirements for Human Drug and Biological Products. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm120262.htm . Assessed May 5, 2016