Bennett had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. em Study concept and design /em : Bennett em Acquisition of data /em : Jacob, Dunn, Qureshi, Raisch, Chen, Chen, Bennett em Interpretation of data /em : all authors em Drafting of the manuscript /em : all authors em Essential revision of the manuscript for important intellectual content material /em : all authors em Administrative, technical, or material support /em : Bennett em Study supervision /em : Bennett . Disclosure Preliminary findings of these study results were offered like a poster in the 53rd American Society of Hematology annual meeting and exposition, San Diego, December 10 to 13, 2011. TTP. TTP is usually associated with use of each of the three thienopyridines, even though mechanistic pathways may differ. = 93 patients); 86% survival with therapeutic plasma exchange, 46% withoutOnset within 2 weeks, 74% (= 35 patients); 72% survival with therapeutic plasma exchange, 67% withoutNo cases reported experienced onset beyond 2 weeks of drug initiationPlasma samples from your SERF-TTP study (2003C2007); ADAMTS-13 deficiency80% (30 patients)0% (8 patients)Not availablePlasma samples from your SERF-TTP study (2003C2007); neutralizing antibodies to ADAMTS-13100% (30 patients)0% (8 patients)Not available Open in a separate windows Abbreviations: ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1motif,member 13; EMA, Western Medicines Agency; FDA, U.S. Food and Drug Administration; SERF-TTP, Surveillance Epidemiology and Risk Factor cIAP1 Ligand-Linker Conjugates 11 for TTP; TTP, thrombotic thrombocytopenic purpura. Adverse event case information sources included U.S. Food and Drug Administration (FDA) databases and physician surveys. The FDA database, FDA Adverse Event Reporting System (AERS), was interrogated for the years 1998 to 2011. Information on cases of ticlopidine- and clopidogrel-associated TTP was obtained from surveys of therapeutic cIAP1 Ligand-Linker Conjugates 11 plasma exchange Rabbit polyclonal to PLS3 centers and TTP referral practices in eight cities.8,13 Causality was assessed with the validated World Health Business (WHO) level. Using this level, a causal relationship is categorized as certain if the clinical event of interest occurs in a plausible time relationship to drug administration, cannot be explained by concurrent disease or other drugs or cIAP1 Ligand-Linker Conjugates 11 chemicals, the event enhances with dechallenge cIAP1 Ligand-Linker Conjugates 11 and recurs with rechallenge, the response to drug withdrawal is usually clinically plausible, and the event is usually definitive pharmacologically or phenomenologically. This analysis has not been reported in previous reviews of thienopyridine-associated TTP. Thienopyridine-associated TTP rates were derived from one survey of directors of six therapeutic plasma exchange centers reported by our group and a second survey of nine interventional cardiology centers reported by Steinhubl et al,9,14 phase III clinical trial reports,15C22 and analyses of insurance claim files and group practice databases.23,24 As reported in our 2007 and 2009 reviews,8,13 plasma samples obtained from patients with thienopyridine-associated TTP included in the Surveillance Epidemiology and Risk Factor for TTP (SERF-TTP) project were evaluated for ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, as measured with standard assays.25 The inhibitory activity of the autoantibodies was determined by mixing TTP plasma samples at various dilutions with normal plasma and measuring proteinase activity of the mixture, as previously reported and described.26 Results FDA Adverse Event Reports Database and FDA-Approved Case Information Disseminated by Product Manufacturers A literature review of all drugs associated with TTP, conducted in 2001, estimated that clopidogrel accounted for 8% of all drug-induced TTP cases reported to the FDA, second only to ticlopidine at the time (Table 2).27 Only one published abstract includes information of prasugrel-associated TTP cases.28 Updated review of FDA safety databases (1998C2011) recognized clopidogrel as the most common drug associated with TTP (= 197 cases) and ticlopidine cIAP1 Ligand-Linker Conjugates 11 as the fifth-most common drug (= 97 cases) associated with TTP (Fig. 2). Between 1998 and 2001, 57 cases of clopidogrel-associated and 87 cases of ticlopidine-associated TTP were reported to the FDA. Since 2002, 140 cases of clopidogrel-associated TTP, 10 cases of ticlopidine-associated TTP, and 14 cases of prasugrel-associated TTP cases were reported to the FDA (Table 2). Based on the WHO criteria, more than 95% of reported ticlopidine-associated TTP cases are likely to have a causal relationship with TTP.29 For 74% of reported clopidogrel and prasugrel-associated TTP cases where onset information was available, onset occurred within 2 weeks of drug initiation. However, causal associations in these cases are considered uncertain because of the presence of comorbid illnesses and concomitant medications. Open in a separate windows Fig. 2 A, Cases per year of thienopyridine-associated thrombotic thrombocytopenic purpura (TTP) reported to the U.S. Food and Drug Administration (FDA) (1998C2011). B, Drugs and number of cases reported to the FDAs Adverse Event Reporting System in association with thrombotic thrombocytopenic purpura (1998C2011). In the first year of marketing of each agent, the FDA received reports of 4 ticlopidine-associated-cases, 11 clopidogrel-associated cases, and 11 prasugrel-associated TTP cases. In 1989, a package place for ticlopidine explained rare instances of TTP in the post-marketing setting. In 1998, following our publication describing 60 cases of ticlopidine-associated TTP, this information was described as a Boxedwarning indicating that TTP onset occurred frequently between 2 and 12 weeks after drug initiation and at an estimated rate of one TTP case per 5,000 ticlopidine-treated patients. In 2000, following our publication of 11 cases of clopidogrel-associated TTP, a warning was first.
Bennett had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis