Association of Non‐Cytochrome P450 3A4‐Metabolized Statins Versus Atorvastatin With Major Adverse Cardiovascular Events in Patients With Cancer Receiving Tyrosine Kinase Inhibitors: A Propensity Score–Matched Target Trial Emulation

Background Tyrosine kinase inhibitors (TKIs) often undergo CYP3A4 (cytochrome P450 3A4) metabolism. Atorvastatin is a CYP3A4 substrate, whereas rosuvastatin and pitavastatin largely bypass this pathway. We evaluated whether statin choice was associated with major adverse cardiovascular events in TKI‐treated patients with cancer. Methods Using TriNetX, we conducted an active‐comparator, new‐user target trial emulation among adults with cancer receiving their first TKI. The index date was the first statin dispensation; outcome ascertainment began on Day 30 and continued up to 3 years. Separate 1:1 propensity score‐matched comparisons included rosuvastatin versus atorvastatin (primary; 2215 per group), pitavastatin comparisons, and a pooled non‐CYP3A4 statin comparison. Results Among 10 843 eligible patients (mean age, 66.7 years; 60.7% male), rosuvastatin was associated with a lower major adverse cardiovascular events rate than atorvastatin (624 versus 769 events; hazard ratio [HR], 0.84 [95% CI, 0.76–0.93]). The proportional‐hazards assumption was violated ( P =0.042), so the HR was interpreted as a time‐averaged association. The pooled comparison was concordant (HR, 0.87 [95% CI, 0.78–0.96]). The early‐persistence Day‐180 estimate was imprecise (HR, 0.90 [95% CI, 0.73–1.09]). Conclusions Rosuvastatin use was associated with lower major adverse cardiovascular events than atorvastatin in TKI‐treated patients with cancer. This observational finding is compatible with, but does not establish, a CYP3A4‐mediated interaction. Residual confounding, nonaligned TKI and statin timing in part of the primary cohort, and lack of individual‐level event‐time data require prospective confirmation.