An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial

Abstract

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%.

Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease.

Interventions: Patients were randomized 1:1 to evolocumab or placebo.

Design, setting, and participants: Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020.

Main outcomes and measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model.

Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment.

Conclusions and relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial.

Trial registration: ClinicalTrials.gov Identifier: NCT01764633.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Bergmark, O'Donoghue, Giugliano, and Sabatine and Mss Murphy and Kuder are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr Bergmark reports grant support from MedImmune, Amgen, AstraZeneca, and Abbott Vascular and consulting fees from Quark Pharmaceuticals, Abbott Vascular, Philips, Daiichi Sankyo, and Janssen Pharmaceuticals. Dr O’Donoghue reports institutional research grants from Amgen, Janssen, the Medicines Company, Eisai, GlaxoSmithKline, Merck, and AstraZeneca and personal fees from AstraZeneca, Amgen, Janssen, and Novartis. Ms Murphy reports institutional grant support from Amgen and personal fees from Amgen. Ms Kuder reported institutional grant support from Amgen during the conduct of the study. Dr Ezhov has served as a consultant for Amgen and Sanofi and reports lecture fees from Amgen, AstraZeneca, Berlin Chemie, Egis, KRKA, Mylan Pharma, Novo Nordisk, Pfizer, Recordati, and Sanofi. Dr Češka has received consulting fees and personal fees from Amgen and consulting fees from Sanofi, Akcea, Merck Sharp & Dohme, and Boehringer Ingelheim. Dr Gouni-Berthold reports personal fees, nonfinancial support, and/or honoraria for consulting from Amgen, Akcea, Sanofi, Regeneron, Aegereon, and Daiichi Sankyo. Dr Jensen is supported by a grant from the Novo Nordisk Foundation, Denmark (grant NNF18OC0031258) and has received lecture fees from AstraZeneca and Merck Sharp & Dohme. Dr Tokgozoglu reports consulting fees from Bayer, Merck Sharp & Dohme, Mylan, and Sanofi; speaker honoraria from Abbott, Actelion (Jansen), Amgen, Astra, Bayer, Daiichi Sankyo, Merck Sharp & Dohme, Mylan, Novartis, Novo Nordisk, Sanofi, Servier, Pfizer, and Recordati; and trial participation from Amgen. Dr Mach received research grants to his institution from Amgen, AstraZeneca, BMS, Eli Lilly, MSD, Sanofi, and Pfizer. Dr Huber reports lecture fees from Amgen, AstraZeneca, Pfizer, and Sanofi Aventis. Dr Jensen is supported by the Novo Nordisk Foundation (grant NNF18OC0031258); reports lecture fees from Amgen, Pfizer, and Sanofi; and has received research grants from Amgen, Pfizer, and Sanofi. Dr Gaciong reports personal fees from Amgen. Dr Lewis reports research support and honoraria from Amgen, Pfizer, Bayer Healthcare, Merck Sharp & Dohme, and Kowa pharmaceuticals and grants from Resverlogix. Dr Schiele reports consulting fees from Amgen, Sanofi, Bayer, Merck Sharp & Dohme, Servier, Novonordisk, AstraZeneca, and Lilly. Dr Jukema reports that he and/or his department have received research grants from and/or was speaker (with or without lecture fees) at (continuing medical education–accredited) meetings sponsored by Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, the Medicines Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme. Dr Pedersen reported grants and personal fees from Amgen during the conduct of the study and personal fees from Merck outside the submitted work. Dr Giugliano reports grants from Amgen; grants, personal fees, and/or honoraria from Amgen, Daiichi Sankyo, and Merck; and consultant fees from Amgen, Akcea, Amarin, Boehringer-Ingelheim, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Lexicon, Merck, Portola, Pfizer, and Servier. Dr Sabatine reports research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Janssen Research and Development, Jazz Pharmaceuticals, the Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda (all >$10 000 per year), and consulting for Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, the Medicines Company, MedImmune, Merck, and Novartis (all ≤$10 000 per year except Amgen). No other disclosures were reported.

Figures

Figure 1.. Adjusted Risk for Aortic Stenosis (AS) Events by 1-SD Increase in Lipoprotein(a) (Lp[a]) and Corrected Low-Density Lipoprotein Cholesterol Concentrations

There was a significant association between week-12 Lp(a) concentration and AS events as well as aortic valve replacement (AVR) specifically. In addition to lipoprotein (Lp[a]) and corrected low-density lipoprotein cholesterol (LDL-C) level, the multivariable model included terms for age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. HR indicates hazard ratio.

Figure 2.. Association of Evolocumab With Aortic Stenosis (AS) Events

The overall hazard ratio for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (hazard ratio, 1.09 [95% CI, 0.48-2.47]) but a hazard ratio of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. EVO indicates evolocumab; HR, hazard ratio; PBO, placebo.