In this study, we evaluated and compared the effects of combination therapy of clopidogrel plus aspirin and aspirin monotherapy on laboratory parameters including creatinine, AST, ALT, hemoglobin level, hematocrit, WBC, RBC and PLT counts in a short-term administration period up to two months. We found that the reduction of WBC count in clopidogrel plus aspirin users was significantly greater than that in aspirin alone users. These results suggest that the hematological adverse effect on leukocytes is greater with combination therapy of clopidogrel plus aspirin than with aspirin monotherapy.
A variety of hematological adverse reactions, including leukopenia, agranulocytosis, and thrombocytopenia, have been reported in patients receiving clopidogrel or aspirin [24–27]. In the CAPRIE trial, the numbers of patients with a significant reduction in neutrophils were 0.10 percent and 0.17 percent in the clopidogrel and aspirin groups, respectively . In this study, the decrease in mean WBC count during the exposure period from baseline was significant both in clopidogrel plus aspirin users and in aspirin alone users (data are included in Additional file 3). Our findings support these previous studies suggesting that the use of these antiplatelet agents may be associated with leukopenia. Furthermore, our findings suggested the possibility that the addition of clopidogrel to aspirin may enhance the adverse effect of aspirin alone on WBC count, although the mechanism of myelotoxicity of these antiplatelet agents is not clear. Our study is expected to help physicians make decisions on drug selection because the adverse effect of an antiplatelet therapy on leukocytes may be of clinical concern, especially for patients with borderline low WBC count.
The nature of antiplatelet therapy involves an inherent risk of bleeding complications. Some trials reported that the addition of aspirin to clopidogrel increases the risk of hemorrhage [6, 11–13]. Our study showed that GI bleeding occurred more frequently in patients receiving clopidogrel plus aspirin than in patients receiving aspirin alone. Although patients who had increased risk of bleeding, including diagnosis of severe hepatic insufficiency, renal failure, current peptic ulceration or history of systemic bleeding, were excluded from the study population, there was a possibility that some covariates at baseline might impact on the results of hemorrhagic events. For instance, the risk of GI bleeding is increased by administration of NSAIDs, advanced age and liver disease, but is reduced by administration of PPI and H2 blockers. In this study, we used two adjustment methods to control for these potential confounding covariates, and thereby found that the risk of GI bleeding was increased with combination therapy of clopidogrel and aspirin compared with aspirin alone, with a relative risk ranging from 2.06 with the multivariate model and 2.61 for propensity adjustment. Our results were similar to the results of two large-scale randomized clinical trials reporting that dual antiplatelet therapy with clopidogrel and aspirin increased the risk of GI bleeding approximately 2-fold compared with aspirin alone [6, 13].
Our study has several limitations. It was a retrospective observational study, which has some issues with respect to the potential for selection bias and confounding factors. However, these problems caused by non-randomized data could be solved by combination with robust statistics; for example, propensity score method . We used rigorous statistical methods to control for potential confounding variables between clopidogrel plus aspirin and aspirin alone users, including propensity adjustment and a multivariate regression model. However, their ability to control for differences was limited to variables that were available or measurable. Second, this study was an investigation to compare the effects of clopidogrel plus aspirin and aspirin alone on laboratory tests focusing on a short-term administration period up to two months, but was not a long-term study that analyzed longitudinal data, including repeated measures of laboratory parameters. Whether the duration of treatment (especially, long-term treatment) is associated with the outcome is of interest because long-term maintenance of dual therapy (for about one year) is reasonable in patients with ST-elevation myocardial infarction according to the ACC/AHA guidelines . We will examine this theme in our next study. Third, we did fix the daily dosage in both treatment groups: clopidogrel (75 mg per day) plus aspirin (100 mg per day) users and aspirin alone users (100 mg per day), because these dosages are typically widely used to initiate antiplatelet therapy. This study was not designed to assess the effects of clopidogrel and aspirin at each dosage, because it is difficult to determine whether or not pharmacodynamics is dose-dependent in clinical settings. Furthermore, this study was undertaken to compare the effects of clopidogrel plus aspirin and aspirin alone on laboratory test results in a Japanese population; the cohorts identified for the study included only Japanese patients. There are genetic polymorphisms in several CYP450 enzymes involved in the metabolism of clopidogrel, such as variants in CYP2C19, particularly CYP2C19*2, which are associated with variability in clopidogrel active metabolite bioavailability, antiplatelet effects, and clinical outcomes [28, 29]. Because the frequency of genetic variability differs among ethnic groups, it cannot be concluded whether the present findings can be extended to people of other races. The findings of our study, based on a non-randomized design, call for further studies, such as similar analyses of larger international databases or randomized clinical trials for confirmation.