Finishing the Picture: Clopidogrel Is Indeed the Most Common Drug Associated with Thrombotic Thrombocytopenic Purpura (TTP) In FDA Databases: Its Mechanism, Laboratory Findings, Clinical Features, and Epidemiology Differ From That Associated with Ticlopidine

In 1998, 60 persons developed TTP between two and 12 weeks after initiation of ticlopidine therapy. We predicted that a newer thienopyridine, clopidogrel, upon FDA approval in 1999, would be associated with TTP. Cleveland Clinic physicians predicted that because of different metabolites, TTP following clopidogrel would not occur. We initiated an intensive 11-year multifaceted prospective pharmacovigilance program to characterize all clopidogrel-associated TTP instances and to evaluate epidemiologic, clinical and laboratory findings. In 1999, 11 cases of TTP occurred within 0 to 14 days following clopidogrel-initiation from queries of medical directors of plasma exchange centers in Houston, Chicago, Boston, Indiana, North Carolina, Baltimore, and Cincinnati- none of which were reported to the FDA. Since then, FDA's MedWatch database identified clopidogrel as the most common drug associated with reported TTP cases (n=197). (Table 1) Case reporting to the FDA decreased by 90% following toxicity description in Direct-To-Consumer advertisements beginning in 2006. Epidemiologic estimates suggest that 1 TTP occurs among 15,000 to 80,000 clopidogrel-treated persons (estimation efforts), versus rates of 1 TTP per 1,600 to 5,000 ticlopidine users (based on data obtained from interventional cardiology laboratories and plasmapheresis centers). Antibodies to ADAMTS-13 were evaluated for two of the first 11 patients with clopidogrel-associated TTP- both had antibodies to ADAMTS13- and developed spontaneous TTP relapses. After evaluating an additional 24 clopidogrel-associated TTP cases, these cases were recharacterized as idiopathic TTP patients (they were the only clopidogrel-associated TTP individuals exposed to a thienopyridine who had spontaneous relapses and the only clopidogrel-associated TTP patients to have detectable antibodies to ADAMTS13 and severe ADAMTS13 deficiency). Epidemiologic studies funded by clopidogrel's manufacturer reported that TTP occurrence rates did not increase following 1999 FDA approval of clopidogrel and there was no statistical association of clopidogrel with TTP. Pharmacovigilance studies of plasmaphersis centers and national referral laboratories in Japan and Canada identified 20 individuals who developed TTP within two weeks of clopidogrel initiation. Several clinicians reported again that the association of clopidogrel with TTP likely represented an epi-phenomenon. Five published case reports described TTP developing shortly after clopidogrel initiation- none had ADAMTS13 antibodies or deficient ADAMTS13 activity levels. Laboratory studies reported that antibodies to ADAMTS-13 were identified in 100% of 30 ticlopidine-associated TTP patients and 0% of eight clopidogrel-associated TTP patients and severe ADAMTS13-deficiency occurred in 80% of ticlopidine patients and 0% of clopidogrel patients (p<0.05 for each). These laboratory findings for clopidogrel-associated TTP supported the hypothesis that the association of clopidogrel with TTP represented a causal relationship. Clinical studies indicated that ticlopidine- versus clopidogrel-associated TTP differed with respect to platelet counts < 20,000/mm³ (84% versus 60%; p< 0.05) and onset within two to 12 weeks of drug initiation (90% versus 26%, p<0.05). We conclude that: instances of TTP following clopidogrel therapy occurred; clinical and laboratory characteristics of TTP following clopidogrel initiation differed from those reported with ticlopidine; and clopidogrel is the most common drug currently associated with TTP in the MedWatch database. Without this pharmacovigilance effort, the association of clopidogrel with TTP would have gone unnoticed. With this effort, we identified clopidogrel as the most common drug associated with TTP, as a proximate cause of TTP in rare instances, and reported that clinical and laboratory findings, prognosis, and therapeutic approaches differed between clopidogrel- and ticlopidine-associated TTP.

Figure 1 FDA reports of Thienopyridine-associated TTP by year

Figure 2 Following Ticlopidine and Clopidogrel over time

Bennett:Pfizer: Consultancy.