Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.
Level 2 - randomized trial
Prespecified secondary analysis of a large randomized controlled trial.
PubMed 28859947 · doi:10.1016/S0140-6736(17)32290-0
What was done
In a prespecified secondary analysis of the randomized FOURIER trial (NCT01764633), investigators evaluated 25,982 patients with atherosclerotic cardiovascular disease who received evolocumab (n=13,013) or placebo (n=12,969) and had LDL cholesterol measured at 4 weeks without prior events. Patients were stratified into five categories of achieved LDL cholesterol at week 4 (<0.5, 0.5 to <1.3, 1.3 to <1.8, 1.8 to <2.6, and ≥2.6 mmol/L). The association between achieved LDL cholesterol and subsequent cardiovascular outcomes (primary composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary composite of cardiovascular death, myocardial infarction, or stroke) along with ten prespecified safety events was analyzed over a median follow-up of 2.2 years using multivariable adjustment.
What was found
At 4 weeks, 2,669 (10%) patients achieved LDL cholesterol <0.5 mmol/L, 8,003 (31%) achieved 0.5 to <1.3 mmol/L, 3,444 (13%) achieved 1.3 to <1.8 mmol/L, 7,471 (29%) achieved 1.8 to <2.6 mmol/L, and 4,395 (17%) achieved ≥2.6 mmol/L. There was a significant monotonic relationship between lower achieved LDL cholesterol and lower incidence of both the primary (p=0.0012) and secondary (p=0.0001) composite endpoints, extending down to concentrations <0.2 mmol/L. There was no significant association between achieved LDL cholesterol and overall serious adverse events or any of the other nine prespecified safety events.
Why it matters
These data demonstrate that cardiovascular risk reduction continues down to extremely low LDL-cholesterol concentrations (below 0.2 mmol/L) without an apparent efficacy plateau or emergent safety signal over medium-term follow-up.
Limits
Categorization by achieved LDL cholesterol is non-randomized, introducing potential confounding despite multivariable adjustment. Median follow-up was 2.2 years, which cannot rule out very long-term safety risks of profound LDL lowering. Hazard ratios and exact risk estimates per stratum 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.