ABSTRACT
Title
Torsade de Pointes and QT prolongation with antipsychotics: a disproportionality analysis in the FDA Adverse Event Reporting System (FDA_AERS)
Authors
E. Raschi1, E. Poluzzi1, A. Koci1 and F. De Ponti1
1 Dept. of Pharmacology, University of Bologna, Bologna, Italy
1 Dept. of Pharmacology, University of Bologna, Bologna, Italy
Abstract
Introduction. The risk of arrhythmias with antipsychotics (APs) is often viewed as a class effect, especially for “conventional” APs, although clinical evidence is available only for some compounds. We comprehensively assessed the strength of the association between APs and the reporting of Torsade de Pointes (TdP) and QT prolongation.
Methods. The FDA Adverse Event Reporting System (AERS) database was used (January 2004-December 2009) to conduct a case-non case analysis (Moore et al., 1997). Cases were defined as reports of TdP or QT prolongation (without co-reported TdP) according to the Medical Dictionary for Regulatory Activities (MedDRA) system. Non cases were represented by all other reports. The analysis was restricted to cases where APs were the suspect drugs. Reports including Class III antiarrhythmic drugs (known for TdP potential) were a priori removed to minimize the effect of “competition bias” (Pariente et al., 2010). Disproportionality analysis was performed by calculating Reporting Odds Ratios (RORs) with corresponding 95%CI.Significant disproportionality (i.e. disproportionality signal) was formally defined when the lower limit of the 95%CI was >1. The lists of drugs with TdP risk provided by the Arizona Centre of Education and Research on Therapeutics was used as reference to distinguish expected from unexpected signals (www.azcert.org).
Results. Over the 6-year period, APs were reported in 151 cases of TdP (approximately 10% of the overall 1486 TdP cases) and in 957 cases of QT prolongation (approximately 27% of the overall 3519 cases of QT prolongation). APs more frequently reported in TdP cases were haloperidol (40), ziprasidone (31) and risperidone (25), whereas olanzapine (167), ziprasidone (166) and clozapine (154) received the highest number of reports for QT prolongation. Significant disproportionality was found for 16 APs, including conventional and atypical agents. Concerning TdP, unexpected disproportionality was generated by amisulpiride (ROR=20.35; 95%CI=7.57-54.72). Concerning QT prolongation, signals found for aripiprazole (1.79; 1.30-2.46), chlorpromazine (9.80; 5.53-17.37), clozapine (7.99; 6.79-9.41), cyamemazine (15.67, 8.59-28.59), fluphenazine (10.60; 4.72-23.71) and olanzapine (6.30; 5.39-7.37) were considered unexpected.
Conclusion. Conventional and atypical APs were frequently reported in cases of TdP and QT prolongation and generated signals. Unexpected signals deserve further investigation, especially for atypical APs, which are often claimed to be safer as regards cardiotoxicity.
Moore et al. (1997). Br J Clin Pharmacol. 44, 513-518.
Pariente et al. (2010). Pharmacoepidemiol Drug Saf. 19, 1166-1171.
Methods. The FDA Adverse Event Reporting System (AERS) database was used (January 2004-December 2009) to conduct a case-non case analysis (Moore et al., 1997). Cases were defined as reports of TdP or QT prolongation (without co-reported TdP) according to the Medical Dictionary for Regulatory Activities (MedDRA) system. Non cases were represented by all other reports. The analysis was restricted to cases where APs were the suspect drugs. Reports including Class III antiarrhythmic drugs (known for TdP potential) were a priori removed to minimize the effect of “competition bias” (Pariente et al., 2010). Disproportionality analysis was performed by calculating Reporting Odds Ratios (RORs) with corresponding 95%CI.Significant disproportionality (i.e. disproportionality signal) was formally defined when the lower limit of the 95%CI was >1. The lists of drugs with TdP risk provided by the Arizona Centre of Education and Research on Therapeutics was used as reference to distinguish expected from unexpected signals (www.azcert.org).
Results. Over the 6-year period, APs were reported in 151 cases of TdP (approximately 10% of the overall 1486 TdP cases) and in 957 cases of QT prolongation (approximately 27% of the overall 3519 cases of QT prolongation). APs more frequently reported in TdP cases were haloperidol (40), ziprasidone (31) and risperidone (25), whereas olanzapine (167), ziprasidone (166) and clozapine (154) received the highest number of reports for QT prolongation. Significant disproportionality was found for 16 APs, including conventional and atypical agents. Concerning TdP, unexpected disproportionality was generated by amisulpiride (ROR=20.35; 95%CI=7.57-54.72). Concerning QT prolongation, signals found for aripiprazole (1.79; 1.30-2.46), chlorpromazine (9.80; 5.53-17.37), clozapine (7.99; 6.79-9.41), cyamemazine (15.67, 8.59-28.59), fluphenazine (10.60; 4.72-23.71) and olanzapine (6.30; 5.39-7.37) were considered unexpected.
Conclusion. Conventional and atypical APs were frequently reported in cases of TdP and QT prolongation and generated signals. Unexpected signals deserve further investigation, especially for atypical APs, which are often claimed to be safer as regards cardiotoxicity.
Moore et al. (1997). Br J Clin Pharmacol. 44, 513-518.
Pariente et al. (2010). Pharmacoepidemiol Drug Saf. 19, 1166-1171.