Effect of Alirocumab Added to High-Intensity Statin on Platelet Reactivity and Noncoding RNAs in Patients with AMI: A Substudy of the PACMAN-AMI Trial

Yasushi Ueki; Jonas D. Häner; Sylvain Losdat; Giuseppe Gargiulo; Hiroki Shibutani; Sarah Bär; Tatsuhiko Otsuka; Raminta Kavaliauskaite; Vera R. Mitter; Fabrice Temperli; David Spirk; Stefan Stortecky; George C. M. Siontis; Marco Valgimigli; Stephan Windecker; Clemens Gutmann; Konstantinos C. Koskinas; Manuel Mayr; Lorenz Räber

doi:10.1055/a-2156-7872

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2024; 124(06): 517-527
DOI: 10.1055/a-2156-7872

Cellular Haemostasis and Platelets

Effect of Alirocumab Added to High-Intensity Statin on Platelet Reactivity and Noncoding RNAs in Patients with AMI: A Substudy of the PACMAN-AMI Trial

Yasushi Ueki

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Jonas D. Häner

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Sylvain Losdat

²CTU Bern, University of Bern, Bern, Switzerland

,

Giuseppe Gargiulo

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

³Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy

,

Hiroki Shibutani

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Sarah Bär

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Tatsuhiko Otsuka

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Raminta Kavaliauskaite

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Vera R. Mitter

⁴Institute of Hospital Pharmacy, Bern University Hospital, Bern, Switzerland

,

Fabrice Temperli

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

David Spirk

⁵Department of Pharmacology, Bern University, Bern and Sanofi, Switzerland

,

Stefan Stortecky

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

George C. M. Siontis

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Marco Valgimigli

⁶Cardiocentro Ticino, Institute and Università della Svizzera Italiana (USI), Lugano, Switzerland

,

Stephan Windecker

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Clemens Gutmann

⁷King's British Heart Foundation Centre, King's College London, London, United Kingdom

⁸Division of Cardiology, Medical University of Vienna, Vienna, Austria

,

Konstantinos C. Koskinas

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

,

Manuel Mayr

⁶Cardiocentro Ticino, Institute and Università della Svizzera Italiana (USI), Lugano, Switzerland

⁷King's British Heart Foundation Centre, King's College London, London, United Kingdom

,

Lorenz Räber

¹Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland

› Institutsangaben

Abstract

Objective The effect of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown. We aimed to explore the effect of alirocumab added to high-intensity statin therapy on P2Y12 reaction unit (PRU) among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel). In addition, we assessed circulating platelet-derived noncoding RNAs (microRNAs and YRNAs).

Methods This was a prespecified, powered, pharmacodynamic substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Patients recruited at Bern University Hospital, receiving DAPT with a potent P2Y12 inhibitor, and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The primary endpoint was PRU at 4 weeks after study drug initiation as assessed by VerifyNow P2Y12 point-of-care assays.

Results Among 139 randomized patients, the majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] in the alirocumab group vs. 69 [94.5%] in the placebo group, p = 0.14). There were no significant differences in the primary endpoint PRU at 4 weeks between groups (12.5 [interquartile range, IQR: 27.0] vs. 19.0 [IQR: 30.0], p = 0.26). Consistent results were observed in 126 patients treated with ticagrelor (13.0 [IQR: 20.0] vs. 18.0 [IQR: 27.0], p = 0.28). Similarly, platelet-derived noncoding RNAs did not significantly differ between groups.

Conclusion Among AMI patients receiving DAPT with a potent P2Y12 inhibitor, alirocumab had no significant effect on platelet reactivity as assessed by PRU and platelet-derived noncoding RNAs.

Keywords

acute myocardial infarction - percutaneous coronary intervention - platelet reactivity - proprotein convertase subtilisin/kexin type 9 - microRNA

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References
1 Escaned J, Ryan N, Mejía-Rentería H. et al. Safety of the deferral of coronary revascularization on the basis of instantaneous wave-free ratio and fractional flow reserve measurements in stable coronary artery disease and acute coronary syndromes. JACC Cardiovasc Interv 2018; 11 (15) 1437-1449
2 Raal FJ, Giugliano RP, Sabatine MS. et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role. J Lipid Res 2016; 57 (06) 1086-1096
3 Wu NQ, Shi HW, Li JJ. Proprotein convertase subtilisin/kexin type 9 and inflammation: an updated review. Front Cardiovasc Med 2022; 9: 763516
4 Barale C, Melchionda E, Morotti A, Russo I. PCSK9 biology and its role in atherothrombosis. Int J Mol Sci 2021; 22 (11) 5880
5 Camera M, Rossetti L, Barbieri SS. et al. PCSK9 as a positive modulator of platelet activation. J Am Coll Cardiol 2018; 71 (08) 952-954
6 Qi Z, Hu L, Zhang J. et al. PCSK9 (proprotein convertase subtilisin/kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation 2021; 143 (01) 45-61
7 Navarese EP, Kolodziejczak M, Winter MP. et al. Association of PCSK9 with platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: the PCSK9-REACT study. Int J Cardiol 2017; 227: 644-649
8 Pastori D, Nocella C, Farcomeni A. et al; ATHERO-AF Study Group. Relationship of PCSK9 and urinary thromboxane excretion to cardiovascular events in patients with atrial fibrillation. J Am Coll Cardiol 2017; 70 (12) 1455-1462
9 Franchi F, Ortega-Paz L, Rollini F. et al. Impact of evolocumab on the pharmacodynamic profiles of clopidogrel in patients with atherosclerotic cardiovascular disease: a randomised, double-blind, placebo-controlled study. EuroIntervention 2023; 18 (15) 1254-1265
10 Gutmann C, Mayr M. Circulating microRNAs as biomarkers and mediators of platelet activation. Platelets 2022; 33 (04) 512-519
11 Zanchin C, Koskinas KC, Ueki Y. et al. Effects of the PCSK9 antibody alirocumab on coronary atherosclerosis in patients with acute myocardial infarction: a serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study-Rationale and design of the PACMAN-AMI trial. Am Heart J 2021; 238: 33-44
12 Räber L, Ueki Y, Otsuka T. et al; PACMAN-AMI collaborators. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. JAMA 2022; 327 (18) 1771-1781
13 Windecker S, Kolh P, Alfonso F. et al; Authors/Task Force members. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35 (37) 2541-2619
14 Neumann FJ, Sousa-Uva M, Ahlsson A. et al; ESC Scientific Document Group. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
15 Wijns W, Kolh P, Danchin N. et al; Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), European Association for Percutaneous Cardiovascular Interventions (EAPCI). Guidelines on myocardial revascularization. Eur Heart J 2010; 31 (20) 2501-2555
16 Gutmann C, Khamina K, Theofilatos K. et al. Association of cardiometabolic microRNAs with COVID-19 severity and mortality. Cardiovasc Res 2022; 118 (02) 461-474
17 Gutmann C, Takov K, Burnap SA. et al. SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care. Nat Commun 2021; 12 (01) 3406
18 Willeit P, Zampetaki A, Dudek K. et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ Res 2013; 112 (04) 595-600
19 Kaudewitz D, Skroblin P, Bender LH. et al. Association of MicroRNAs and YRNAs with platelet function. Circ Res 2016; 118 (03) 420-432
20 Franchi F, Faz GT, Rollini F. et al. Pharmacodynamic effects of switching from prasugrel to ticagrelor: results of the prospective, randomized SWAP-3 study. JACC Cardiovasc Interv 2016; 9 (11) 1089-1098
21 Ziogos E, Chelko SP, Harb T. et al. Platelet activation and endothelial dysfunction biomarkers in acute coronary syndrome: the impact of PCSK9 inhibition. Eur Heart J Cardiovasc Pharmacother 2023; 9 (07) 636-646
22 Thompson PD, Moyna NM, White CM, Weber KM, Giri S, Waters DD. The effects of hydroxy-methyl-glutaryl co-enzyme A reductase inhibitors on platelet thrombus formation. Atherosclerosis 2002; 161 (02) 301-306
23 Dangas G, Badimon JJ, Smith DA. et al. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 1999; 33 (05) 1294-1304
24 Leoncini M, Toso A, Maioli M. et al. High-dose atorvastatin on the pharmacodynamic effects of double-dose clopidogrel in patients undergoing percutaneous coronary interventions: the ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study. JACC Cardiovasc Interv 2013; 6 (02) 169-179
25 Koskinas KC, Siontis GCM, Piccolo R. et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J 2018; 39 (14) 1172-1180
26 Silverman MG, Ference BA, Im K. et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016; 316 (12) 1289-1297
27 Schwartz GG, Steg PG, Szarek M. et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379 (22) 2097-2107
28 Sabatine MS, Giugliano RP, Keech AC. et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376 (18) 1713-1722
29 Relou IA, Hackeng CM, Akkerman JW, Malle E. Low-density lipoprotein and its effect on human blood platelets. Cell Mol Life Sci 2003; 60 (05) 961-971
30 Olson EN. MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med 2014; 6 (239) 239ps3
31 Becker KC, Kwee LC, Neely ML. et al. Circulating MicroRNA profiling in non-ST elevated coronary artery syndrome highlights genomic associations with serial platelet reactivity measurements. Sci Rep 2020; 10 (01) 6169
32 Braza-Boïls A, Barwari T, Gutmann C. et al. Circulating MicroRNA levels indicate platelet and leukocyte activation in endotoxemia despite platelet P2Y₁₂ inhibition. Int J Mol Sci 2020; 21 (08) 2897
33 Zampetaki A, Willeit P, Tilling L. et al. Prospective study on circulating MicroRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012; 60 (04) 290-299
34 Bye A, Røsjø H, Nauman J. et al. Circulating microRNAs predict future fatal myocardial infarction in healthy individuals - the HUNT study. J Mol Cell Cardiol 2016; 97: 162-168
35 Carino A, De Rosa S, Sorrentino S. et al. Modulation of circulating MicroRNAs levels during the switch from clopidogrel to ticagrelor. BioMed Res Int 2016; 2016: 3968206
36 Bongiovanni D, Santamaria G, Klug M. et al. Transcriptome analysis of reticulated platelets reveals a prothrombotic profile. Thromb Haemost 2019; 119 (11) 1795-1806
37 de Boer HC, van Solingen C, Prins J. et al. Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease. Eur Heart J 2013; 34 (44) 3451-3457
38 Franchi F, Rollini F, Aggarwal N. et al. Pharmacodynamic comparison of prasugrel versus ticagrelor in patients with type 2 diabetes mellitus and coronary artery disease: the OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study. Circulation 2016; 134 (11) 780-792

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