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Brief Report
April 29, 2020

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

Author Affiliations
  • 1TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
  • 2National Medical Research Center of Cardiology, Moscow, Russia
  • 3Third Internal Medicine Clinic, Center for Preventive Cardiology, University General Hospital, First Medical Faculty, Charles University, Prague, Czech Republic
  • 4Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
  • 5Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  • 6Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark
  • 7Department of Cardiology, Hacettepe University, Ankara, Turkey
  • 8Cardiology Division, Geneva University Hospitals, Geneva, Switzerland
  • 9Cardiology and Intensive Care Medicine, Wilhelminenhospital, Third Department of Medicine, Sigmund Freud University, Medical Faculty, Vienna, Austria
  • 10Department of Internal Medicine, Hypertension and Vascular Disease, the Medical University of Warsaw, Warsaw, Poland
  • 11The Ruth and Bruce Rappaport School of Medicine, Lady Davis Carmel Medical Center, Technion-IIT, Haifa, Israel
  • 12University Hospital Center Besançon, Besançon, France
  • 13Department of Cardiology, Leiden University Medical Center, the Netherlands
  • 14Netherlands Heart Institute, Utrecht, the Netherlands
  • 15Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway
JAMA Cardiol. Published online April 29, 2020. doi:10.1001/jamacardio.2020.0728
Key Points

Question  What is the association between lipoprotein(a) and low-density lipoprotein–cholesterol concentrations and aortic stenosis events, and does proprotein convertase subtilisin/kexin type 9 inhibition reduce the risk of aortic stenosis events?

Findings  In this secondary analysis of 63 patients in a randomized clinical trial, elevated lipoprotein(a) concentrations were associated with higher rates of aortic stenosis events, including aortic valve replacement. The overall hazard ratio for aortic stenosis 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.

Meaning  Long-term therapy with evolocumab may reduce the risk of aortic stenosis events, although these findings require validation in a dedicated randomized clinical 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

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