Evolocumab reduces aortic stenosis events in FOURIER
The FOURIER trial demonstrated significant reductions in LDL-cholesterol (LDL-C) level and cardiovascular (CV) risk with evolocumab vs placebo in patients with atherosclerotic CV disease on a background of statin therapy. New data from the trial, presented at the American College of Cardiology and World Congress of Cardiology 2020 virtual meeting (ACC.20/WCC), showed that the risk of aortic stenosis (AS) was significantly reduced with evolocumab used in combination with statin, through lowering lipoprotein(a) [Lp(a)] concentration.
Interrelationships between Lp(a) level, PCSK9 gene and AS
“For many years, it has been recognized that the pathophysiology of AS may be similar to that of vascular atherosclerosis, where there are overlaps in risk factors including Lp(a) and LDL-C levels,” said FOURIER investigator, Dr Brian Bergmark of the Harvard Medical School Teaching Hospital, Boston, US. [J Am Coll Cardiol 1997;29:630-634] “Apolipoproteins and chronic inflammatory cells have also been detected in early to end-stage lesions of AS.” [Arterioscler Thromb Vasc Biol 1996;16:523-532]
A genome-wide association study revealed genetic associations between Lp(a) variants and incident AS (hazard ratio [HR], 1.68 per risk allele; 95 percent confidence interval [Cl], 1.32 to 2.15; p=3x10-5), as well as between Lp(a) variants and incident AS plus aortic valve replacement (AVR) (HR, 1.54; 95 percent CI, 1.05 to 2.27; p=0.03). [N Engl J Med 2013;368:503-512]
“Consistent findings were demonstrated in the post hoc analysis of the ASTRONOMER trial, in which patients with Lp(a) concentration >140.4 nmol/L were found to have a significantly higher rate of AS progression [0.26 m/s/year vs 0.17 m/s/year; p=0.005] and twice the risk of AS-related events [ie, AVR and cardiac death] [HR, 2.0; 95 percent CI, 1.1 to 3.7; p=0.02] compared with those with Lp(a) concentration ≤140.4 nmol/L,” said Bergmark. [J Am Coll Cardiol 2015;66:1236-1246]
In a recent genetic study, lower median levels of Lp(a) (21.6 nmol/L for homozygotes and 19.2 nmol/dL for heterozygotes; p=0.02) and LDL-C (2.7 mmol/L and 2.5 mmol/dL; p=2x10-52), as well as a lower incidence of AS (p=0.06), were found among PCSK9R646L carriers, suggesting a potential role of proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors in AS. [J Clin Endocrinol Metab 2016;101:3281-3287]
“[At 48 weeks,] in addition to lowering mean LDL-C levels by 50–60 percent [compared with placebo; 95 percent Cl, 58 to 60; p<0.001], monoclonal antibodies against PCSK9 have also been shown to lower Lp(a) concentration from baseline by a median of 26.9 percent in the FOURIER trial, with the greatest absolute Lp(a) reduction seen in patients with higher baseline concentrations,” said Bergmark. [N Engl J Med 2017;376:1713-1722; Circulation 2019;139:1483-1492]
FOURIER trial: Evolocumab lowers Lp(a) and AS events
In the FOURIER trial, 27,564 high-risk, stable patients with established atherosclerotic CV disease, with a fasting LDL-C level of ≥70 mg/dL (1.8 mmol/L) or a non–HDL-cholesterol concentration of ≥100 mg/dL (2.6 mmol/L) who were receiving statin therapy (with or without ezetimibe), were randomized (1:1) to receive evolocumab (either 140 mg Q2W or 420 mg Q4W) or matching placebo subcutaneous injections. [N Engl J Med 2017;376:1713-1722; Circulation 2019;139:1483-1492; Am Heart J 2016;173:94-101]
Over a median of 2.2 years, there were 63 events related to new or worsening AS or AVR (18 events and 7 events of surgical and transcatheter aortic valve replacement, respectively; 1 event unspecified). [Bergmark B, et al, ACC/WCC 2020, abstract 914-08]
“In the post-hoc analysis, a significant association between 1 standard deviation increase in Lp(a) concentration and AS events [HRadj,1.55; 95 percent CI, 1.17 to 2.05; p=0.002] was observed after multivariable adjustment,” reported Bergmark. “There was also a robust association between achieved Lp[a] concentration and the harder endpoint of AVR [HRadj, 2.22; 95 percent CI, 1.38 to 3.58; p=0.001]. However, there was no significant association between LDL-C concentration and AVR.” (Figure 1)
“The overall HR of AS events with evolocumab vs placebo was 0.66 [95 percent CI, 0.40 to 1.09], with no apparent difference in the first 12 months of treatment [HR, 1.09; 95 percent CI, 0.48 to 2.47; p=0.84]. Nonetheless, a remarkable reduction in the risk of AS events was observed beyond 1 year of treatment with evolocumab [HR, 0.48; 95 percent CI, 0.25 to 0.93; p=0.026],” stated Bergmark. (Figure 2)
A sensitivity analysis of AS events risk, which removed patients with major adverse CV events prior to current AS event, showed no attenuation in the effect of evolocumab (HR, 0.35; 95 percent CI, 0.17 to 0.77). “The HR for all AS events beyond 12 months was almost identical to that for AVR beyond 12 months [HR, 0.49; 95 percent CI, 0.17 to 1.45],” Bergmark noted.
The current post hoc analysis of the FOURIER trial showed that achieved Lp(a) concentration was associated with future AS events, and the beneficial effect of evolocumab appeared to emerge after 1 year of treatment, providing a 52 percent reduction in risk of AS events. “These exploratory findings require validation in a dedicated randomized controlled trial,” said Bergmark.