Clopidogrel Treatment Is Associated with a Decrease in Cancer Incidence
Authors: Leader Avi , Zelikson-Saporta Ravit , Rozovski Uri , Pereg David , Raanani Pia , Spectre Galia , Lishner Michael , Hermoni Doron 
Published: October 2019

Abstract
Introduction: Multiple studies have shown an association between aspirin treatment and a reduced incidence of cancer. An antiplatelet effect is one of the hypotheses explaining these results. Whether the antiplatelet thienopyridine drug, clopidogrel, influences the incidence of cancer is unknown.
Objective: To assess the effect of clopidogrel on the incidence of cancer.
Methods: A population-based historical cohort study within the HMO-Clalit Health Services population was performed. Members living in the Sharon-Shomron district ≥ 50 years were included in this cohort between January 2000 and January 2012, and followed until December 2014. We excluded patients treated with prasugrel or ticagrelor, and those diagnosed with cancer prior to or within 1 year of study inclusion. The study population was divided into 4 groups based on antiplatelet treatment with aspirin, clopidogrel, both (defined as ≥ 1 monthly prescription at any stage) or neither.
To determine whether long-term antiplatelet treatment (i.e. follow-up for ≥ 5 years since the first antiplatelet dose) is associated with decreased rates of cancer (defined by ICD-9 codes), we applied a logistic regression model. With this model, the Exp(ß) was used to calculate the odds ratio (OR) and the 95% confidence interval (CI) of each type of antiplatelet treatment compared to the reference group of patients who did not receive treatment. Cox proportional hazards regression models were fitted to assess the association between the duration of time until cancer developed and the different anti-platelet treatments.
Results: The study cohort included 184,781 patients with a median age of 54.9 years (range: 50-100.1), 53.7% female, 19.6% past or current smokers, and mean BMI of 31±8.3 kg/m2. Patients receiving antiplatelet drugs were older, had higher BMI and were more likely to be men and smokers, compared to patients receiving no treatment (p<0.001 for all). Long-term (≥5 years) follow up from antiplatelet treatment with clopidogrel, aspirin or both was associated with a lower risk of cancer, compared to no antiplatelet treatment (median follow up: 155 months (range, 12-179)), before and after adjustment for baseline variables (Table 1).
Any duration of treatment with clopidogrel (HR 0.42, 95% CI: 0.33-0.53), aspirin (HR 0.76, 95% CI: 0.74-0.78) or both (HR 0.49, 95% CI: 0.47-0.52) was also associated with a lower risk of incident cancer (p<0.001), compared to patients who received no treatment, in multivariate analysis. The reduction in cancer incidence with clopidogrel alone was maintained in a subgroup analysis of solid cancers (OR 0.53, p=0.001) as well as gastrointestinal (GI; OR 0.45, p=0.02) and non-GI malignancies (OR 0.43, p<0.01). In an exploratory secondary analysis after adjustment for baseline variables and duration of antiplatelet treatment, patients receiving clopidogrel only, had a lower risk of cancer than the aspirin only group (HR 0.57, 95% CI: 0.36-0.91, p=0.018), on long term follow-up.
Conclusions: Clopidogrel treatment, with or without aspirin, was associated with a lower risk of cancer when compared to no antiplatelet treatment. The risk of cancer was reduced with aspirin only, similar to prior studies. The effect of clopidogrel alone was at least comparable to that of aspirin, despite shorter median exposure to clopidogrel (Table 1). Our results supports the antiplatelet role in reducing the risk of cancer.
Table 1. The long-term risk of cancer* in subjects treated with aspirin, clopidogrel or both, compared with no antiplatelet treatment Long-term follow-up Study Groups (N) No anti-platelet (75,624) Clopidogrel only (271) Aspirin only (64,362) Combined anti-platelet (15,103) Incidence of cancer, % (n) 11.7 (8816) 6.6 (18) 8.8 (5692) 8.5 (1286) No. of cancer cases / 1000 patient years 12.8 5.6 7.6 7.0 Median duration of follow up (range), months 119 (12-179) 179 (24-179) 179 (12-179) 179 (12-179) Median duration of antiplatelet treatment (range), months NA 43 (1-168) 87 (1-172) Aspirin: 117 (1-170); Clopidogrel 13 (1-170) Risk of cancer, HR (95% CI) Unadjusted 1 (ref.) 0.32 (0.20-0.51)** 0.48 (0.46-0.49)** 0.40 (0.37-0.42)** adjusted for: age, gender, BMI, smoking status 1 (ref.) 0.37 (0.23-0.58)** 0.54 (0.52-0.56)** 0.46 (0.44-0.49)** *More than 5 years follow up from first anti platelet prescription. **p<0.001 NA, not applicable

Disclosures
Leader: Novartis: Research Funding.