Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Abstract

Background: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.

Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.

Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).

Results: In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (Pinteraction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43.

Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Keywords: PCSK9 inhibitor; acute coronary syndrome; lipoprotein(a); low-density lipoprotein cholesterol.

Conflict of interest statement

Funding Support and Author Disclosures ODYSSEY Outcomes (NCT01663402) was funded by Sanofi and Regeneron Pharmaceuticals. Dr Schwartz has received research support to the University of Colorado from AstraZeneca, Resverlogix, Roche, Sanofi, and The Medicines Company; and is a coinventor on pending US patent 62/806,313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. Dr Szarek has served as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, Lexicon, Sanofi, and Regeneron Pharmaceuticals. Dr Bittner has received grant support from Sanofi, AstraZeneca, DalCor, Esperion, Bayer, The Medicines Company, and Amgen (all paid direct to her institution); and has received personal fees from Sanofi. Dr Diaz has received research grants from Sanofi, DalCor Pharmaceuticals, the Population Health Research Institute, the Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit; and has received personal fees, as a member of the executive steering committee, from Amgen and Cirius. Dr Goodman has received research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker and consulting honoraria (eg, advisory boards) from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, and Valeo Pharma; and has received salary support and honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, the Canadian Heart Research Centre and MD Primer, the Canadian VIGOUR Centre, the Cleveland Clinic Coordinating Centre for Clinical Research, the Duke Clinical Research Institute, the New York University Clinical Coordinating Centre, and the PERFUSE Research Institute. Dr Jukema has received research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and has received research support from Amgen, Astellas, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr Landmesser has received research grants from Novartis, Bayer, and Amgen; and has received lecture or advisory honorary fees from Amgen, Sanofi, Novartis, Bayer, Pfizer, and The Medicines Company. Dr López-Jaramillo has received honoraria for lectures from Menarini, Abbott, and Merck. Drs Manvelian and Pordy are employees of Regeneron Pharmaceuticals. Dr Scemama is an employee of Sanofi. Dr Sinnaeve has received institutional grants from the Flemish government, AstraZeneca, and Daiichi Sankyo; is a corecipient of a named chair supported by Bayer; and has received advisory and speaker fees (all institutional) from Sanofi, Amgen, Idorsia, Bristol Myers Squibb/Pfizer, AstraZeneca, and Abbott. Dr White has received grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY Outcomes trial from Sanofi and Regeneron Pharmaceuticals, for the ACCELERATE study from Eli Lilly, for the STRENGTH trial from Omthera Pharmaceuticals, for the SPIRE trial from Pfizer, for the HEART-FID study from American Regent, for the CAMELLIA-TIMI study from Eisai, for the dal-GenE study from DalCor Pharma UK, for the AEGIS-II study from CSL Behring, for the SCORED trial and the SOLOIST-WHF trial from Sanofi Australia, and for the CLEAR Outcomes study from Esperion Therapeutics. Dr White has served on advisory boards for Actelion, Sirtex, and Genentech (an affiliate of F. Hoffmann-La Roche; Lytics Post-PCI Advisory Board at the European Society of Cardiology); and has received lecture fees from AstraZeneca. Dr. Steg has received grants and nonfinancial support (cochair of the ODYSSEY Outcomes trial; as such, he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (steering committee, MARINER, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (cochair of the ODYSSEY Outcomes trial; cochair of the SCORED trial; consulting and speaking), Servier (chair of the CLARIFY registry; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial; consulting); and has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Idorsia, Myokardia, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, and AstraZeneca. Dr Steg also has a European application number/patent number, issued on October 26, 2016 (15712241.7), for a method for reducing cardiovascular risk (all royalties assigned to Sanofi).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Baseline Lipoprotein (a) Distribution in Lower and Higher Baseline LDL-C Subgroups

(A) Lower low-density lipoprotein cholesterol (LDL-C) subgroup (n = 4,351) defined by a qualification or randomization LDL-C level <70 mg/dL. In this subgroup, median LDL-C was 69.4 mg/dL (interquartile range: 64.3–74.0 mg/dL). (B) Higher LDL-C subgroup (n = 14,573) defined by qualification and randomization LDL-C levels ≥70 mg/dL. In this subgroup, median LDL-C was 94.0 mg/dL (interquartile range: 83.2–111.0 mg/dL). The median value of lipoprotein(a) in the tower LDL-C subgroup (13.7 mg/dL) was used to dichotomize both LDL-C subgroups.

Figure 2. Cumulative Incidence of MACE by Baseline LDL-C Subgroup, Lipoprotein (a) Category, and Study Treatment

(A) Lower low-density lipoprotein cholesterol (LDL-C) subgroup. (B) Higher LDL-C subgroup. Subgroups and dichotomization of baseline lipoprotein(a) (Lp[a]) as defined in Figure 1. ALI = alirocumab; MACE = major adverse cardiovascular events; PBO = placebo.

Figure 2. Cumulative Incidence of MACE by Baseline LDL-C Subgroup, Lipoprotein (a) Category, and Study Treatment

(A) Lower low-density lipoprotein cholesterol (LDL-C) subgroup. (B) Higher LDL-C subgroup. Subgroups and dichotomization of baseline lipoprotein(a) (Lp[a]) as defined in Figure 1. ALI = alirocumab; MACE = major adverse cardiovascular events; PBO = placebo.

Figure 3. Spline Analysis of Probability of MACE by Baseline Lipoprotein(a) and Treatment Group

(A) Lower LDL-C subgroup. (B) Higher LDL-C subgroup. Red indicates alirocumab group; blue indicates placebo group. Shaded areas indicate 95% confidence intervals. Dashed lines indicate the median baseline lipoprotein(a) value (13.7 mg/dL) in the lower LDL-C subgroup. In each subgroup, the probability of MACE at the overall median follow-up of 2.7 years was estimated from a logistic regression model with a logit link function; logarithm of follow-up time was an offset variable. Models included adjustment for the baseline characteristics indicated in Figure 2, plus geographic region. Spline effect reflects a restricted cubic spline basis with knots at 4.9,13.6, and 40.3 mg/dL (ie, the spline was required to be linear for lipoprotein[a] <4.9 mg/dL and >40.3 mg/dL). Interaction of treatment and baseline lipoprotein(a) spline effect: Pinteraction = 0.031 and Pinteraction = 0.84 for lower and higher LDL-C subgroups, respectively. Subgroup definitions as in Figure 1. Abbreviations as in Figures 1 and 2.

CENTRAL ILLUSTRATION. Effect of Alirocumab on Major Adverse Cardiovascular Events by Baseline Low-Density Lipoprotein Cholesterol Subgroup and Lipoprotein(a) Category

The lower low-density lipoprotein cholesterol (LDL-C) subgroup (top) was defined by a qualification or randomization LDL-C level 2, history of heart failure, history of hypertension, and coronary artery bypass grafting or percutaneous coronary intervention prior to the qualifying acute coronary syndrome (ACS). In the higher LDL-C subgroup, adjustment variables were those in the lower LDL-C model plus history of chronic obstructive pulmonary disease, revascularization for the qualifying ACS, current smoking, and age.