LAUSR

Similarities and differences in two contemporary post-randomization on-treatment analyses from the FOURIER and CANTOS trials may provide insight into what factors drive reductions in cardiovascular mortality and all-cause mortality among atherosclerosis patients already treated with high intensity statins. In the first paper, the FOURIER investigators elegantly demonstrate that lower is better for low-density lipoprotein cholesterol (LDLC) after adjunctive therapy with the PCSK9 inhibitor evolocumab1 For the FOURIER primary endpoint (a composite of myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death), there was a highly significant monotonic relationship between sequentially lower achieved LDLC concentrations and lower cardiovascular risk, extending even to those with on-treatment LDLC below 20 mg/dL. This benefit was largely driven by statistically significant reductions in the trial composite endpoint among those with LDLC levels below the approximate on-treatment median of 50mg/dL (where hazard ratios ranged between 0.76 and 0.85). By contrast, marginal and non-significant reductions were observed among those in FOURIER with on-treatment LDLC levels above 50mg/dL (where hazard ratios ranged from 0.94 to 0.97). These PCSK9 data are important since evolocumab has powerful effects on LDLC, but no effect on high-sensitivity C-reactive protein (hsCRP).