Treatment effect of PCSK9-inhibitor on major coronary events by baseline Lp(a) level in ASCVD
Lipoprotein(a), PCSK9 Inhibition and Cardiovascular Risk: Insights from the FOURIER TrialLiterature - O’Donoghue ML, Fazio S, Giugliano RP et al. - Circulation 2018: published online ahead of print
Introduction and methods
Higher plasma lipoprotein(a) (Lp[a]) levels are associated with the development of CAD [1-2]. However, there are only few treatments that can reduce Lp(a) levels and it remains unknown whether reducing Lp(a) levels will translate into improved CV outcomes [3-5]. Although proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce plasma Lp(a) concentrations by ~25-30% [6-8], it remains unknown whether the effect of evolocumab on risk of coronary events is dependent on baseline Lp(a) levels. This analysis of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial therefore investigated the relationship between Lp(a) levels, PCSK9 inhibition with evolocumab, and CV risk reduction.
The randomized, double-blind, placebo-controlled FOURIER trial randomized 25.096 patients aged 40-85 years with established atherosclerotic CVD (ASCVD), fasting LDL-c levels ≥70 mg/dl (1.8 nmol/L) or non-HDL-c levels ≥100mg/dl (2.6 nmol/L), who were on optimized lipid-lowering therapy, to receive either evolocumab or placebo. Participants were followed for a median of 2.2 years and stratified into quartiles based on baseline Lp(a) levels. Event rates were estimated at 3 years using the Kaplan-Meier method.
The outcome was major coronary events, consisting of coronary heart disease (CHD) death, myocardial infarction (MI) and urgent coronary revascularization.
Treatment effect of evolocumab on Lp(a) levels after 48 weeks
- In the evolocumab group, Lp(a) levels were decreased by a median of 26.9% (IQR: 6.2-46.7%) or 11 (IQR: 1-32) nmol/L (P<0.001) at week 48, compared to placebo, with greater absolute reduction in Lp(a) for those with higher baseline Lp(a) levels (P-trend <0.001).
- In the evolocumab group, the percent change in Lp(a) and LDL-c at week 48 was moderately positively correlated (r=0.37, 95%CI: 0.36-0.39, P<0.001).
Treatment effect of evolocumab on major coronary events by baseline Lp(a) level
- At year 3, the absolute risk reduction of major coronary events was non-significantly greater (0.95% vs. 2.49%) and the number needed to treat were lower (40 vs. 105) in patients with baseline Lp(a) levels above the median than in those below the median ( after treatment with evolocumab (P-interaction=0.07).
- After adjustment for LDL-c, an absolute reduction in Lp(a) of 25 nmol/L was significantly related to a 15% relative risk reduction (95%CI: 2-26%, P=0.0199) in major coronary events, whereas the percent change in Lp(a) was not significantly associated, after 48 weeks.
Risk of CHD events by achieved Lp(a) and LDL-c levels at week 12
- Compared with patients above the median achieved level for both Lp(a) and LDL-c, patients with at least one level below the median had a 15% lower risk of major coronary events (HRadj: 0.85, 95%CI: 0.75-0.97, P=0.01) and those with both levels below the respective medians had a 29% lower risk of major coronary events (HRadj: 0.72, 95%CI: 0.62-0.83, P<0.0001).
Results of a subanalysis of the FOURIER trial showed that evolocumab significantly reduced Lp(a) levels compared to placebo. Moreover, patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) levels and non-significant greater coronary benefit from PCSK9 inhibition, compared to those with low baseline Lp(a) levels.