Lower achieved LDL-c levels associated with lower CV risk in ASCVD
Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE
Introduction and methods
Elevated LDL-c levels are a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD) . The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and the FOURIER-OLE (FOURIER Open-Label Extension) trials demonstrated that PCSK9i evolocumab reduced LDL-c and lowered the short and long-term risk of CV events [2-3]. However, it remains uncertain what the optimal long-term LDL-c levels are with regards to cardiovascular and safety outcomes.
Aim of the study
The authors investigated the relationship between achieved LDL-c levels with evolocumab and the occurrence of long-term adverse cardiovascular and safety outcomes.
The FOURIER trial was a randomized, double-blind, placebo-controlled trial, with 27,564 patients with stable ASCVD. Patients had baseline LDL-c concentrations of ≥70 mg/dL or non-HDL-c levels ≥100 mg/dL while on optimized lipid-lowering therapy, including a high- or moderate-intensity statin with or without ezetimibe. Patients were randomized to subcutaneous evolocumab (either 140 mg every 2 weeks or 420 mg once per month) or matching placebo. The median follow-up was 2.2 years.
6635 patients of the FOURIER trial were enrolled in the FOURIER-OLE trial. Patients received subcutaneous evolocumab (either 140 mg every 2 weeks or 420 mg once per month), regardless of initial allocation in the parent trial. For this prespecified secondary analysis, data of 6559 patients with achieved LDL-c levels (average of the first 2 LDL-c measurements at weeks 12, 24, or 48) were available. Patients were categorized in 5 different categories based on the achieved LDL-c levels: <20 mg/dL, 20 to <40 mg/dL, 40 to <55 mg/dL, 55 to <70 mg/dL, or ≥70 mg/dL. The median follow-up was 4.8 years. The maximum follow-up was 8.6 years in the entire FOURIER and FOURIER-OLE cohort.
The primary efficacy outcome was the composite of CV death, MI, stroke, coronary revascularization, or hospital admission for unstable angina. The key secondary efficacy outcome was the composite of cardiovascular death, MI, or stroke.
- The median achieved LDL-c level was 32 mg/dL (IQR: 20 to 40 mg/dL). The distribution of achieved LDL-c level was as follows: 1604 patients (24%) achieved <20 mg/dL, 2627 patients (40%) achieved 20 to <40 mg/dL, 1031 patients (16%) achieved 40 to <55 mg/dL, 486 patients (7%) achieved 55 to <70 mg/dL, and 811 patients (12%) achieved ≥70 mg/dL.
- The annualized incidence rate of the primary and secondary efficacy outcomes was lower in the lower achieved LDL-c categories. The indicate rate of the primary efficacy outcome was 3.42 (95%CI: 2.67-4.39), 4.09 (95%CI: 3.26-5.14), 3.88 (95%CI: 3.00-5.03), 5.12 (95%CI: 3.85-6.80), and 5.76 (95%CI: 4.52-7.35) for <20 mg/dL, 20 to <40 mg/dL, 40 to <55 mg/dL, 55 to <70 mg/dL, and ≥70 mg/dL, respectively (adjusted P trend<0.0001). The indicate rate of the secondary efficacy outcome was 2.37 (95%CI: 1.75-3.21), 2.77 (95%CI: 2.10-3.65), 3.05 (95%CI: 2.24-4.14), 3.63 (95%CI: 2.56-5.13), and 4.24 (95%CI: 3.17-5.68) for <20 mg/dL, 20 to <40 mg/dL, 40 to <55 mg/dL, 55 to <70 mg/dL, and ≥70 mg/dL, respectively (adjusted P trend<0.0001).
- The risk of the primary outcomes was monotonically lower with lower achieved LDL-c levels when analyzing LDL-c levels as a continuous variable: 18% lower risk per 1.0 mmol/L (38.7 mg/dL) lower achieved LDL-c level (HR: 0.82; 95%CI: 0.75-0.90; adjusted P<0.0001). Similarly, the risk of the secondary CV outcomes was monotonically lower with lower LDL-c levels: 21% lower risk per 1.0 mmol/L (38.7 mg/dL) lower achieved LDL-c level (HR: 0.79; 95%CI: 0.71-0.88; adjusted P<0.0001).
- The incidence rate of all-cause mortality was lower in the lower achieved LDL-c categories (adjusted P trend=0.0001). There was no monotonic relationship between lower achieved LDL-c level and the risk of other safety events (such serious adverse events, neurocognitive events, cataract-related adverse events, new or progressive malignancy, new-onset diabetes, hemorrhagic stroke, muscle-related events, or noncardiovascular death).
The authors demonstrate that achievement of lower LDL-c levels in patients with ASCVD is associated with a reduced long-term risk of cardiovascular outcomes, without any serious safety concerns.