Multiplex Apolipoprotein Panel Improves Cardiovascular Event Prediction and Cardiovascular Outcome by Identifying Patients Who Benefit From Targeted PCSK9 Inhibitor Therapy

Arteriosclerosis Thrombosis and Vascular Biology, vol. 45, pp. 2111–2123

Abstract

BACKGROUND: Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine. METHODS: Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial ( https://www.clinicaltrials.gov ; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed. RESULTS: The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626–0.670), compared with 0.579 (0.557–0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664–0.733), while the lipid panel had an AUC of 0.599 (0.564–0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel ( P <0.0001): AUC, 0.659 (0.637–0.681) for MACE and 0.724 (0.691–0.756) for all-cause death. Higher risk for MACE based on the baseline apolipoprotein panel was found to predict greater treatment benefit with alirocumab. CONCLUSIONS: A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future.

Authors 17

1. Esther Reijnders Aachen Department of Clinical Chemistry Laboratory Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Chemistry and Laboratory Medicine (E.R., L.R.R., F. P.H.T.M.R., C.M.C.), Leiden University Medical Center, the Netherlands

   Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, the Netherlands. (E.R., L.R.R., F.R., C.C.)

2. Patrick M. Bossuyt

   Amsterdam University Medical Centers

   Affiliation as printed

   Department of Epidemiology and Data Science, Amsterdam UMC, The Netherlands (P.M.B.)

   Department of Epidemiology and Data Science, Amsterdam UMC, The Netherlands (P.B.)

3. J. Wouter Jukema Aachen Department of Cardiology, Leiden University Medical Center

   Leiden University Medical Center · Netherlands Heart Institute

   Affiliation as printed

   Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands

   Department of Cardiology, Netherlands Heart Institute, Utrecht (J.W.J.)

   Department of Cardiology, Leiden University Medical Center, the Netherlands. (J.W.J.)

   Netherlands Heart Institute, Utrecht (J.W.J.)

4. L. Renee Ruhaak Aachen Department of Clinical Chemistry Laboratory Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Chemistry and Laboratory Medicine (E.R., L.R.R., F. P.H.T.M.R., C.M.C.), Leiden University Medical Center, the Netherlands

   Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, the Netherlands. (E.R., L.R.R., F.R., C.C.)

5. Fred P.H.T.M. Romijn Aachen Department of Clinical Chemistry Laboratory Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Chemistry and Laboratory Medicine (E.R., L.R.R., F. P.H.T.M.R., C.M.C.), Leiden University Medical Center, the Netherlands

   Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, the Netherlands. (E.R., L.R.R., F.R., C.C.)

6. Michael J. Szarek

   SUNY Downstate Health Sciences University · University of Colorado Anschutz

   Affiliation as printed

   CPC Clinical Research, Aurora, CO (M.S.)

   Division of Cardiology, University of Colorado School of Medicine, Aurora (M.S., G.G.S.)

   State University of New York, Downstate Health Sciences University, Brooklyn (M.S.)

   Division of Cardiology, University of Colorado School of Medicine, Aurora (M.S., G.S.)

7. Stella Trompet Aachen Department of Internal Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (S.T.), Leiden University Medical Center, the Netherlands

   Department of Internal Medicine, Leiden University Medical Center, the Netherlands. (S.T.)

8. Deepak L. Bhatt

   Icahn School of Medicine at Mount Sinai

   Affiliation as printed

   Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY (D.L.B.)

   Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY (D.B.)

9. Vera Bittner

   University of Alabama at Birmingham

   Affiliation as printed

   Division of Cardiovascular Disease, University of Alabama at Birmingham (V.A.B.)

   Division of Cardiovascular Disease, University of Alabama at Birmingham (V.B.)

10. Sergio Fazio

    Regeneron (United States)

    Affiliation as printed

    Regeneron Pharmaceuticals, Tarrytown, NY (S.F.)

11. Irena Stevanovic

    Sanofi (France)

    Affiliation as printed

    Sanofi, Paris, France (I.S.)

12. Shaun G. Goodman

    St. Michael's Hospital · University of Alberta · University of Toronto · Canadian VIGOUR Centre

    Affiliation as printed

    Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada (S.G.G.)

    St Michael’s Hospital, University of Toronto, Ontario, Canada (S.G.G.)

    Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada (S.G.)

    St Michael's Hospital, University of Toronto, Ontario, Canada (S.G.)

13. Robert A. Harrington

    Weill Cornell Medicine

    Affiliation as printed

    Weill Cornell Medicine, New York, NY (R.A.H.)

    Weill Cornell Medicine, New York, NY (R.H.)

14. Harvey Douglas White

    University of Auckland · Health New Zealand

    Affiliation as printed

    Green Lane Cardiovascular Research Unit, Te Whatu Ora–Health New Zealand, Te Toka Tumai, and University of Auckland (H.D.W.)

    Green Lane Cardiovascular Research Unit, Te Whatu Ora–Health New Zealand, Te Toka Tumai, and University of Auckland (H.W.)

15. Philippe Gabríel Steg

    Inserm · Institut Universitaire de France · Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Hôpital Bichat-Claude-Bernard

    Affiliation as printed

    Université Paris-Cité, INSERM-UMR1148, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, French Alliance for Cardiovascular Trials, and Institut Universitaire de France (P.G.S.)

16. Gregory G. Schwartz

    University of Colorado Anschutz

    Affiliation as printed

    Division of Cardiology, University of Colorado School of Medicine, Aurora (M.S., G.G.S.)

    Division of Cardiology, University of Colorado School of Medicine, Aurora (M.S., G.S.)

17. Christa M. Cobbaert Aachen Department of Clinical Chemistry Laboratory Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Chemistry and Laboratory Medicine (E.R., L.R.R., F. P.H.T.M.R., C.M.C.), Leiden University Medical Center, the Netherlands

    Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, the Netherlands. (E.R., L.R.R., F.R., C.C.)