LAUSR

Question What is the association between treatment with aspirin plus clopidogrel compared with aspirin alone or no antiplatelet use and risk for cancer? Methods Setting Sharon-Shomron district, Israel. Patients 184781 adults 50 years of age (mean age 60 y, 54% women) who were members of the Clalit Health Services health maintenance organization. Exclusion criteria were use of prasugrel or ticagrelor or cancer diagnosed before, or within 1 year of, study entry. Risk factors Prescription for aspirin (1 monthly prescription for 75 to 100 mg/d), clopidogrel (1 monthly prescription for 75 mg/d), or both (not necessarily simultaneously). Analysis was adjusted for sex, age, body mass index (BMI), and smoking status and stratified by duration of follow-up. Too few patients received a prescription for clopidogrel alone (n =869), so this group was excluded from the analysis. Outcomes New cases of cancer (excluding melanoma skin cancers) identified through diagnostic codes. Main results There were 21974 cases of newly diagnosed cancer. The main results are in the Table. Conclusion Aspirin plus clopidogrel was not associated with increased risk for cancer compared with aspirin alone or no antiplatelet use. Association between aspirin plus clopidogrel or aspirin alone and risk for cancer* Treatment N Duration of follow-up Cancer cases/1000 patient-y Adjusted HR (95% CI) No antiplatelet 75624 All 12.8 1.0 (reference) Aspirin alone 91615 All 12.0 0.76 (0.74 to 0.78) Aspirin + clopidogrel 17673 All 8.5 0.49 (0.47 to 0.52) Aspirin alone 64362 Long-term 7.6 0.54 (0.52 to 0.56) Aspirin + clopidogrel 15103 Long-term 7.0 0.46 (0.44 to 0.49) Aspirin alone 64362 Long-term 7.6 1.0 (reference) Aspirin + clopidogrel 15103 Long-term 7.0 0.92 (0.86 to 0.97) *Abbreviations defined in Glossary. No antiplatelet (all durations) served as the reference for aspirin alone and aspirin plus clopidogrel, all durations, and long-term follow-up (>5 y from first antiplatelet prescription or cohort entry). Adjusted for sex, age, body mass index, and smoking status. For long-term follow-up, aspirin plus clopidogrel was also compared with aspirin alone as the reference. Commentary Controversy exists concerning whether antiplatelet drugs increase or decrease cancer risk or have no effect, and nondefinitive evidence exists for each possibility (1). The observational cohort study by Leader and colleagues addresses the effects of antiplatelet therapy on risk for cancer. The results show a reduction in cancer, both with aspirin and aspirin plus clopidogrel, compared with no antiplatelet therapy. Although this seems to be good news, the study results should be interpreted with caution. Cohort studies can be vulnerable to both confounding and detection bias. The authors have adjusted for such potential confounders as age, sex, BMI, and smoking status, but they cannot correct for unknown or unmeasurable potential confounders. The risk for detection bias in this study seems to be low given that cancer is not a particularly subtle or subjective diagnosis and that this diagnosis was only included if it occurred >1 year after inclusion into the study. The magnitude of the effect is mildly reassuring, because bias may account for small observed effects but is less likely to account for the full 50% reduction in risk that was observed in the combined treatment group. These results apply to men and women older than 50 years of age. The inference regarding cancer risk is limited to 2 agentslow-dose aspirin and clopidogrelbecause users of ticagrelor and prasugrel were excluded. Only aspirin and the combination of aspirin with clopidogrel could be compared with the reference standard of no treatment because the study had insufficient power to assess the effect of clopidogrel alone. Given the methodological limitations of this study, one should not attribute a cancer-lowering benefit to dual-antiplatelet therapy. However, clinicians prescribing such therapy after an acute coronary syndrome event can be reassured that the combination of aspirin and clopidogrel is unlikely to increase the risk for cancer.