In this study, we evaluated and compared the effects of combination therapy of clopidogrel plus aspirin and aspirin monotherapy on hematological parameters, including creatinine, aspartate transaminase, alanine aminotransferase, hemoglobin level, hematocrit, and white blood cell, red blood cell, and platelet counts during a short-term administration period of up to 2 months. We found that the reductions in white blood cell and red blood cell counts, hemoglobin level, and hematocrit in users of clopidogrel plus aspirin were significantly greater than those in users of aspirin alone. These results suggest that adverse hematological effects are greater with combination therapy of clopidogrel plus aspirin than with aspirin monotherapy.
A variety of adverse hematological reactions, including leukopenia, agranulocytosis, and thrombocytopenia, have been reported in patients receiving clopidogrel or aspirin.16
In the CAPRIE trial, the numbers of patients with a significant reduction in neutrophils were 0.10% and 0.17% in the clopidogrel and aspirin groups, respectively.16
Our findings support those of previous studies suggesting that use of these antiplatelet agents may be associated with leukopenia.
Furthermore, our findings suggest the possibility that addition of clopidogrel to aspirin may enhance the adverse effect of aspirin alone on white blood cell count, although it is not clear whether or not the effects of these antiplatelet agents are dose-dependent. Our study may help physicians to make decisions on drug selection, especially when treating patients with a borderline low white blood cell count.
In this study, we used propensity score matching to balance the population of users of covariate, a potential confounding variable, between users of clopidogrel plus aspirin and users of aspirin alone, and found significant adverse effects on red blood cell count, hemoglobin level, and hematocrit in users of clopidogrel plus aspirin compared with users of aspirin alone. The nature of antiplatelet therapy involves an inherent risk of bleeding complications. Some trials have reported that addition of aspirin to clopidogrel increases the risk of hemorrhage.2
Supporting this, our study showed that hemorrhagic events occurred more frequently in patients receiving clopidogrel plus aspirin than in patients receiving aspirin alone (). These patients may have impacted on our hematological results. Therefore, we reanalyzed the data without patients who had hemorrhagic events, and found that the reductions in red blood cell and white blood cell counts in users of clopidogrel plus aspirin remained significant in comparison with those in users of aspirin alone (data not shown). Our findings, combined with previous reports, suggest that regular checks of hematological parameters should be performed, especially within the 2 months after initiating therapy.
Our study has several limitations. First, the retrospective design with nonrandomized assignment involved inherent issues of selection bias and confounding. We used rigorous statistical methods to balance potential confounding variables between users of clopidogrel plus aspirin and users of aspirin alone, including propensity score matching and a multivariate regression model. However, their ability to control for differences was limited to variables that were available and measurable. Second, there is also the possibility of inaccuracy of information in the database (eg, misclassification of exposure and outcome, ie, ascertainment bias). Prescription claims data and medical records are considered by many to be the gold standard for measuring drug exposure and for capturing intermediate and final outcomes, respectively.20
However, the Nihon University School of Medicine Clinical Data Warehouse used in this study may combine the best of both worlds by linking a prescription database to detailed medical information, and is suitable for pharmacoepidemiological research. Third, this study was undertaken to compare the effects of clopidogrel plus aspirin and aspirin alone on laboratory test results in a Japanese population, so the cohorts identified for the study included only Japanese patients. Therefore, it cannot be concluded that the present findings can be extended to people of other races, such as Caucasians. The findings of our study, based on a nonrandomized design, call for further studies, such as similar analyses of larger international databases or randomized clinical trials for confirmation.