Similarities and differences in 2 contemporary postrandomization on-treatment analyses from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) may provide insight into what factors drive reductions in cardiovascular mortality and all-cause mortality among patients with atherosclerosis already treated with high-intensity statins.

In the first article, the FOURIER Investigators elegantly demonstrate that lower is better for low-density lipoprotein cholesterol (LDLC) after adjunctive therapy with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab. For the FOURIER primary end point (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 <20 mg/dL. This benefit was driven largely by statistically significant reductions in the trial composite end point among those with LDLC levels below the approximate on-treatment median of 50 mg/dL (for which hazard ratios ranged between 0.76 and 0.85). In contrast, marginal and nonsignificant reductions were observed among those in FOURIER with on-treatment LDLC levels >50 mg/dL (for which hazard ratios ranged from 0.94–0.97). These PCSK9 data are important because evolocumab has powerful effects on LDLC but no effect on high-sensitivity C-reactive protein (hs-CRP).

In the second article, the CANTOS Investigators similarly demonstrate that lower is better for inflammation reduction, at least with the interleukin-1β inhibitor canakinumab.2 For the CANTOS primary end point (a composite of myocardial infarction, stroke, or cardiovascular death), there was a highly significant 25% reduction among those with on-treatment hs-CRP levels below the approximate on-treatment median of 2 mg/L. In contrast, marginal and nonsignificant reductions …