IVUS measurements were evaluated as least squares means. Comparison of treatment groups was conducted using analysis of covariance on rank transformed data that accounted for baseline value and geographic location. Investigators used a step-down statistical procedure to evaluate primary and secondary endpoints. The statistical model accounted for confounders such as baseline LDL-C, baseline PAV, intensity of statin therapy, geographic region, age, and sex.
Main results. 484 participants were randomized to the evolocumab group and 484 to the placebo group, and 423 participants in both groups completed both baseline and follow-up IVUS imaging. Treatment and control groups contained participants matched for age, gender, ethnicity, cardiovascular risk factors, and baseline medication use, including lipid-lowering agents, ACE inhibitors, ARBs, beta-blockers, and antiplatelet therapies. Both groups consisted of a majority of white (93.4% in placebo and 94.2% in treatment) males (72.3% in placebo and 72.1% in treatment). Approximately 80% of participants had hypertension (83.7% in placebo and 82.2% in treatment), about 35% had prior MIs (35.3% in placebo and 34.9% in treatment), and roughly a fifth of participants had diabetes (21.5% in placebo and 20.2% in treatment). At baseline 98.6% of participants were treated with statins, with 58.9% on high-intensity therapy and 39.4% on moderate-intensity. Mean LDL-C level at baseline was 92.5 (SD, 27.2) mg/dL.
After 76 weeks of treatment, mean LDL-C level in the placebo group was 93.0 mg/dL and 36.6 mg/dL in the treatment group, which corresponds to a 0.2 mg/dL increase in the placebo group and a 56.3 mg/dL reduction in the treatment group. The change in LDL-C level was statistically significant ( P < 0.001).
Placebo group participants had no significant change in PAV (0.05%, P = 0.78), but the evolocumab group experienced a 0.95% decrease from baseline ( P < 0.001). Similarly, the placebo group had no change in TAV from baseline (–0.9 mm 3, P = 0.45), but the treatment group had a 5.8 mm 3 reduction in TAV from baseline ( P < 0.001). The treatment group had a greater proportion of patients who experienced PAV regression (64.3% vs. 47.3%, P < 0.001) and TAV regression (61.5% vs. 48.9%, P < 0.001).
Subgroup analysis did not demonstrate a significant association between change in PAV and specific study participant characteristics (eg, age, gender, ethnicity).
Post-hoc analysis using local regression (LOESS) curve revealed a linear relationship between achieved LDL-C level and change in PAV for LDL-C levels from 110 mg/dL to 20 mg/dL.
The treatment group did not exhibit a significant increase in adverse drug events, which included injection site reactions, myalgias, neurocognitive events, and incidence of diabetes. There was no significant difference in adverse cardiovascular outcomes between groups; however, there were numerically fewer nonfatal MIs and coronary revascularizations in the treatment group.
Conclusion. The use of evolocumab in statin-treated patients resulted in greater reduction of PAV than use of statins alone.
Commentary
Evolocumab is a monoclonal antibody that inhibits pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is involved in LDL-C receptor recycling. By reducing removal of LDL-C receptors, evolocumab amplifies LDL-C clearance and has been shown to reduce LDL-C levels by approximately 61% from baseline with 12 weeks oftreatment [2]. Studies have shown that the lipid-lowering potential of evolocumab is superior to statins alone and to combination therapy with statins and ezetimibe [2]. Furthermore, PCSK9 inhibitors have been effective at LDL-lowering in patients who failed or could not tolerate standard of care therapy with statins and ezetimibe [3,4]. PCSK9 inhibitors hold great promise for reducing morbidity and mortality of cardiovascular disease; however, LDL-lowering is not equivalent to improved clinical outcomes.