Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.
Level 3 - non-randomized controlled study
Non-randomized observational follow-up cohort analysis nested within an open-label trial extension
PubMed 36779348 · doi:10.1161/CIRCULATIONAHA.122.063399
What was done
In a prespecified analysis of the FOURIER open-label extension study (FOURIER-OLE), researchers followed 6,559 patients with stable atherosclerotic cardiovascular disease who transitioned to open-label evolocumab (from the original 27,564 patients randomized in FOURIER) for an additional median of 5 years. Patients were categorized by achieved LDL-C levels (average of the first 2 measurements in OLE) into five strata: <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL. Multivariable modeling evaluated the association between achieved LDL-C and primary composite cardiovascular outcomes (CV death, myocardial infarction, stroke, unstable angina hospital admission, or coronary revascularization), key secondary cardiovascular outcomes (CV death, MI, or stroke), and safety outcomes over up to 8.6 years of total follow-up.
What was found
In FOURIER-OLE, 1,604 (24%), 2,627 (40%), 1,031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels—down to <20 mg/dL—and a lower risk of both the primary and key secondary cardiovascular composite end points after multivariable adjustment (adjusted P-trend <0.0001 for both). No statistically significant associations were found between lower achieved LDL-C levels and increased risk of safety outcomes, including serious adverse events, new/recurrent cancer, cataract-related events, hemorrhagic stroke, new-onset diabetes, neurocognitive events, muscle-related events, or noncardiovascular death.
Why it matters
This study shows that achieving very low LDL-C levels below 20 mg/dL with evolocumab is associated with continued incremental cardiovascular risk reduction without emerging safety concerns over extended follow-up.
Limits
Categorization by achieved LDL-C is an observational, non-randomized analysis subject to residual confounding despite multivariable adjustment. Only a subset (6,635 of 27,564) of the parent trial population entered the extension, introducing potential survival and selection biases. Specific effect estimates (hazard ratios and confidence intervals) were not provided in the abstract.
Cited by
- supports The FOURIER clinical trial demonstrated that reducing LDL cholesterol down into the 20s mg/dL appeared to be safe.