Principal Findings:

The primary outcome, incidence of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, occurred in 12.6% of the evolocumab group versus 14.6% of the placebo group (p < 0.0001). This finding was consistent among all tested subgroups. Benefit was enhanced among higher-risk subgroups (those with recent MI, multiple prior MIs, and residual multivessel coronary artery disease) compared to those without such characteristics.

Evolocumab reduced total cardiovascular events (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.75-0.90, p < 0.001), first cardiovascular events (HR 0.85, 95% CI 0.79-0.92, p < 0.001), and subsequent events (HR 0.74, 95% CI 0.65-0.85).

Secondary outcomes:

• Absolute reduction in LDL-C was 56 mg/dl with evolocumab versus placebo (median LDL-C = 30 mg/dl)
• Any serious adverse event: 24.8% with evolocumab versus 24.7% with placebo
• Complex coronary revascularization (>1 of: multivessel percutaneous coronary intervention [PCI], ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG): evolocumab vs. placebo (HR 0.71, 95% CI 0.61-0.84, p < 0.001)

A proportion of patients underwent cognitive testing (n = 1,204). Among this cohort, there was no difference between evolocumab versus placebo for a battery of cognitive tests, patient-reported everyday cognition, and physician-reported adverse cognitive events.

As the proportion of LDL-C lowering below 40 mg/dl increased, there was no evidence of attenuation in treatment effect (p value for treatment interaction = 0.78). Ten percent of participants had LDL-C <20 mg/dl, while 31% had LDL-C between 20 and 50 mg/dl. There was a linear relationship between LDL-C and adverse cardiovascular events, such that adverse events continued to decline to the lowest levels of LDL-C (p = 0.0012). There was no notable increase in any safety events, including cancer and cognition, with very low LDL-C levels.

Among those with baseline LDL-C <70 mg/dl, evolocumab reduced the primary endpoint (HR 0.80, 95% CI 0.60-1.07) to a similar degree as those with baseline LDL-C ≥70 mg/dl (HR 0.86, 95% CI 0.79-0.92; p = 0.65 for interaction).

PAD subset: A total of 13.2% of patients had established PAD. Patients with PAD had an 81% higher risk of cardiovascular disease/MI/stroke compared with those without (p < 0.001). There was a significant reduction in cardiovascular disease/MI/stroke with evolocumab versus placebo among patients with PAD (9.5% vs. 13.0%, p = 0.004) and those without (6.2% vs. 7.6%, p < 0.001) (p for interaction = 0.41). The absolute risk reduction was greater among PAD patients due to the higher event rates. There was a significant reduction in the incidence of major adverse limb events with evolocumab (0.27% vs. 0.45%, p = 0.0093), with greater net reductions among patients with PAD (1.5% vs. 2.4%). There appeared to be a monotonic relationship between reduction in LDL-C and reduction in adverse limb events (p = 0.026).

Outcomes according to inflammatory risk: Among those with high-sensitivity C-reactive protein <1 mg/dl, 1-3 mg/dl, and >3 mg/dl, there was an absolute reduction in the primary outcome of 1.6%, 1.8%, and 2.7%, respectively.

Genetic risk score: A 27–single-nucleotide polymorphism (SNP) genetic risk score was created to categorize subjects into low-risk, intermediate-risk, and high-risk categories. Major vascular events were increased 14% for those categorized as intermediate-risk vs. low-risk and increased 37% for those categorized as high-risk vs. low-risk.

Major vascular events: Among those without multiple clinical risk factors or genetic high-risk, evolocumab vs. placebo was not associated with risk reduction. Among those with multiple clinical risk factors but without genetic high-risk, evolocumab vs. placebo was associated with a 1.4% absolute risk reduction. Among those with genetic high-risk (irrespective of clinical risk), evolocumab vs. placebo was associated with a 4.0% absolute risk reduction (p for trend = 0.04).

Prevention of stroke: The incidence of any stroke was 1.5% for evolocumab vs. 1.9% for placebo (p = 0.01), the incidence of ischemic stroke was 1.2% for evolocumab vs. 1.6% for placebo (p = 0.005), and the incidence of ischemic stroke or transient ischemic attack (TIA) was 1.7% for evolocumab vs. 2.1% for placebo (p = 0.003).

The association between evolocumab vs. placebo on the primary outcome among subjects with prior stroke (HR 0.85, 95% CI 0.72-1.00) and among subjects with no prior stroke (HR 0.85, 95% CI 0.79-0.93) was similar (p for interaction = 0.91).

Open-label extension (median follow-up, 5 years):

• Primary outcome of cardiovascular death, MI, stroke, unstable angina, or coronary revascularization: HR 0.85 (95% CI 0.75-0.96, p = 0.008)
• Serious adverse events: 10% with long-term use of evolocumab