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Abstract
Background: Several randomized clinical trials (RCTs) have shown the efficacy of the association of ticlopidine and aspirin as an antithrombotic treatment after coronary stenting. As a result, this association is now the standard treatment for this condition. Recently, several case-series have suggested that ticlopidine plus aspirin treatment might be associated with an increased incidence of a potentially fatal complication, such as thrombotic thrombocytopenic purpura (TTP). While case-series cannot firmly establish the causal relationship between ticlopidine plus aspirin and TTP, RCTs cannot evaluate the incidence of rare adverse drug events (ADRs) because their sample size is too small and calculated on the basis of the expected frequency of the primary outcomes for efficacy. Post-marketing surveillance systems might address this issue. Aim of the study: to estimate the incidence of a rare ADR, such as TTP, during ticlopidine plus aspirin treatment after coronary stenting.
Methods: Medline, Embase, Cochrane Controlled Trials Register were searched from 1991 to 1999 and primary authors were contacted to identify: 1. RCTs evaluating ticlopidine plus aspirin treatment after coronary stenting 2. prospective or retrospective observational studies evaluating ADRs during ticlopidine plus aspirin treatment after coronary stenting; 3. the total number of case-reports of TTP after ticlopidine plus aspirin for coronary stenting. The WHO Monitoring Centre in Uppsala was also contacted to identify reports of TTP associated with ticlopidine plus aspirin treatment after coronary stenting.
Results: None of the identified 10 RCTs reported cases of TTP. Among the seven observational studies retrieved, only one study reported 9 cases of TTP after the retrospective evaluation of 43322 patients who were treated with ticlopidine plus aspirin after coronary stenting in the USA. The incidence of TTP resulted 0.02% (95% confidence intervals: 0.04%-0.009%) with 2 fatal cases. Case reports or series were found for a total of 72 cases of TTP. The WHO Monitoring Centre did not hold any cases of TTP related to ticlopidine plus aspirin after coronary stenting.
Conclusions: The incidence of rare but potentially fatal ADRs cannot be reliably estimated by RCTs or small observational studies. Rare ADRs are usually underreported in post-marketing surveillance systems. Only observational studies of a large number of patients can estimate the incidence of rare ADRs.
Methods: Medline, Embase, Cochrane Controlled Trials Register were searched from 1991 to 1999 and primary authors were contacted to identify: 1. RCTs evaluating ticlopidine plus aspirin treatment after coronary stenting 2. prospective or retrospective observational studies evaluating ADRs during ticlopidine plus aspirin treatment after coronary stenting; 3. the total number of case-reports of TTP after ticlopidine plus aspirin for coronary stenting. The WHO Monitoring Centre in Uppsala was also contacted to identify reports of TTP associated with ticlopidine plus aspirin treatment after coronary stenting.
Results: None of the identified 10 RCTs reported cases of TTP. Among the seven observational studies retrieved, only one study reported 9 cases of TTP after the retrospective evaluation of 43322 patients who were treated with ticlopidine plus aspirin after coronary stenting in the USA. The incidence of TTP resulted 0.02% (95% confidence intervals: 0.04%-0.009%) with 2 fatal cases. Case reports or series were found for a total of 72 cases of TTP. The WHO Monitoring Centre did not hold any cases of TTP related to ticlopidine plus aspirin after coronary stenting.
Conclusions: The incidence of rare but potentially fatal ADRs cannot be reliably estimated by RCTs or small observational studies. Rare ADRs are usually underreported in post-marketing surveillance systems. Only observational studies of a large number of patients can estimate the incidence of rare ADRs.