PDF herunterladen
Thromb Haemost 2023; 123(02): 166-176
DOI: 10.1055/s-0042-1758654
Theme Issue Article

Drug–Drug Interaction between Antiplatelet Therapy and Lipid-Lowering Agents (Statins and PCSK9 Inhibitors)

Karsten Schrör‡   *
1   Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Düsseldorf, Germany
,
Freek W. A. Verheugt 
2   Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, The Netherlands
,
Dietmar Trenk  ‡   *
3   Department Universitäts-Herzzentrum, Klinik für Kardiologie und Angiologie Bad Krozingen, Klinische Pharmakologie, Universitätsklinikum Freiburg, Bad Krozingen, Germany
› Institutsangaben
› Weitere Informationen
    Lizenzen und Reprints

Abstract

Lipid-lowering agents and antiplatelet drugs are guideline-recommended standard treatment for secondary prevention of acute thrombotic events in patients with increased cardiovascular risk. Aspirin is the most frequently used antiplatelet drug, either alone or in combination with other antiplatelet agents (P2Y12 inhibitors), while statins are first-line treatment of hypercholesterolemia. The well-established mode of action of aspirin is inhibition of platelet-dependent thromboxane formation. In addition, aspirin also improves endothelial oxygen defense via enhanced NO formation and inhibits thrombin formation. Low-dose aspirin exerts in addition anti-inflammatory effects, mainly via inhibition of platelet-initiated activation of white cells.

Statins inhibit platelet function via reduction of circulating low-density lipoprotein-cholesterol (LDL-C) levels and a more direct inhibition of platelet function. This comprises inhibition of thromboxane formation via inhibition of platelet phospholipase A2 and inhibition of (ox)LDL-C-mediated increases in platelet reactivity via the (ox)LDL-C receptor (CD36). Furthermore, statins upregulate endothelial NO-synthase and improve endothelial oxygen defense by inhibition of NADPH-oxidase. PCSK9 antibodies target a serine protease (PCSK9), which promotes the degradation of the LDL-C receptor impacting on LDL-C plasma levels and (ox)LDL-C-receptor-mediated signaling in platelets similar to but more potent than statins.

These functionally synergistic actions are the basis for numerous interactions between antiplatelet and these lipid-lowering drugs, which may, in summary, reduce the incidence of atherothrombotic vascular events.

Keywords

antiplatelet drugs - aspirin - PCSK9 - statins

* Authors contributed equally to the manuscript (shared main authorship)




Publikationsverlauf

Eingereicht: 01. März 2022

Angenommen: 23. September 2022

Artikel online veröffentlicht:
15. Dezember 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357 (24) 2482-2494
    CrossrefPubMedGoogle Scholar
  • 2 Lordan R, Tsoupras A, Zabetakis I. Platelet activation and prothrombotic mediators at the nexus of inflammation and atherosclerosis: potential role of antiplatelet agents. Blood Rev 2021; 45: 100694
    CrossrefPubMedGoogle Scholar
  • 3 Hohlfeld T, Schrör K. Antiinflammatory effects of aspirin in ACS: relevant to its cardiocoronary actions?. Thromb Haemost 2015; 114 (03) 469-477
    PubMedGoogle Scholar
  • 4 Manson JE, Grobbee DE, Stampfer MJ. et al. Aspirin in the primary prevention of angina pectoris in a randomized trial of United States physicians. Am J Med 1990; 89 (06) 772-776
    CrossrefPubMedGoogle Scholar
  • 5 Ridker PM, Cook NR, Lee IM. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352 (13) 1293-1304
    CrossrefPubMedGoogle Scholar
  • 6 Ridker PM, Manson JE, Buring JE, Goldhaber SZ, Hennekens CH. The effect of chronic platelet inhibition with low-dose aspirin on atherosclerotic progression and acute thrombosis: clinical evidence from the Physicians' Health Study. Am Heart J 1991; 122 (06) 1588-1592
    CrossrefPubMedGoogle Scholar
  • 7 Goldhaber SZ, Manson JE, Stampfer MJ. et al. Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians' Health Study. Lancet 1992; 340 (8812): 143-145
    CrossrefPubMedGoogle Scholar
  • 8 West LE, Steiner T, Judge HM, Francis SE, Storey RF. Vessel wall, not platelet, P2Y12 potentiates early atherogenesis. Cardiovasc Res 2014; 102 (03) 429-435
    CrossrefPubMedGoogle Scholar
  • 9 Yourman LC, Cenzer IS, Boscardin WJ. et al. Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years: a meta-analysis. JAMA Intern Med 2021; 181 (02) 179-185
    CrossrefPubMedGoogle Scholar
  • 10 Byrne P, Cullinan J, Smith A, Smith SM. Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews. BMJ Open 2019; 9 (04) e023085
    CrossrefPubMedGoogle Scholar
  • 11 Cai T, Abel L, Langford O. et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. BMJ 2021; 374 (1537): n1537
    CrossrefPubMedGoogle Scholar
  • 12 Hennekens CH, Sacks FM, Tonkin A. et al. Additive benefits of pravastatin and aspirin to decrease risks of cardiovascular disease: randomized and observational comparisons of secondary prevention trials and their meta-analyses. Arch Intern Med 2004; 164 (01) 40-44
    CrossrefPubMedGoogle Scholar
  • 13 Gallone G, Baldetti L, Pagnesi M. et al. Medical therapy for long-term prevention of atherothrombosis following an acute coronary syndrome: JACC state-of-the-art review. J Am Coll Cardiol 2018; 72 (23, Pt A): 2886-2903
    CrossrefPubMedGoogle Scholar
  • 14 Arnett DK, Blumenthal RS, Albert MA. et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019; 74 (10) e177-e232
    PubMedGoogle Scholar
  • 15 Sanz-Cuesta BE, Saver JL. Lipid-lowering therapy and hemorrhagic stroke risk: comparative meta-analysis of statins and PCSK9 inhibitors. Stroke 2021; 52 (10) 3142-3150
    CrossrefPubMedGoogle Scholar
  • 16 Nenna A, Nappi F, Lusini M. et al. Effect of statins on platelet activation and function: from molecular pathways to clinical effects. BioMed Res Int 2021; 2021: 6661847
    CrossrefPubMedGoogle Scholar
  • 17 Shapiro MD, Fazio S. PCSK9 and atherosclerosis - lipids and beyond. J Atheroscler Thromb 2017; 24 (05) 462-472
    CrossrefPubMedGoogle Scholar
  • 18 Paciullo F, Momi S, Gresele P. PCSK9 in haemostasis and thrombosis: possible pleiotropic effects of PCSK9 inhibitors in cardiovascular prevention. Thromb Haemost 2019; 119 (03) 359-367
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Ragusa R, Basta G, Neglia D, De Caterina R, Del Turco S, Caselli C. PCSK9 and atherosclerosis: Looking beyond LDL regulation. Eur J Clin Invest 2021; 51 (04) e13459
    CrossrefPubMedGoogle Scholar
  • 20 Barale C, Melchionda E, Morotti A, Russo I. PCSK9 biology and its role in atherothrombosis. Int J Mol Sci 2021; 22 (11) 5880
    CrossrefPubMedGoogle Scholar
  • 21 Pęczek P, Leśniewski M, Mazurek T, Szarpak L, Filipiak KJ, Gąsecka A. Antiplatelet effects of PCSK9 inhibitors in primary hypercholesterolemia. Life (Basel) 2021; 11 (06) 466
    PubMedGoogle Scholar
  • 22 Puccini M, Landmesser U, Rauch U. Pleiotropic effects of PCSK9: focus on thrombosis and haemostasis. Metabolites 2022; 12 (03) 226
    CrossrefPubMedGoogle Scholar
  • 23 Camera M, Rossetti L, Barbieri SS. et al. PCSK9 as positive modulator of platelet activation. J Am Coll Cardiol 2018; 71 (08) 952-954
    CrossrefPubMedGoogle Scholar
  • 24 Petersen-Uribe Á, Kremser M, Rohlfing AK. et al. Platelet-derived PCSK9 is associated with LDL metabolism and modulates atherothrombotic mechanisms in coronary artery disease. Int J Mol Sci 2021; 22 (20) 11179
    CrossrefPubMedGoogle Scholar
  • 25 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
    CrossrefPubMedGoogle Scholar
  • 26 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 28 Schrör K, Löbel P, Steinhagen-Thiessen E. Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia. Eicosanoids 1989; 2 (01) 39-45
    PubMedGoogle Scholar
  • 29 Kaczmarek D, Hohlfeld T, Wambach G, Schrör K. The actions of lovastatin on platelet function and platelet eicosanoid receptors in type II hypercholesterolaemia. A double-blind, placebo-controlled, prospective study. Eur J Clin Pharmacol 1993; 45 (05) 451-457
    CrossrefPubMedGoogle Scholar
  • 30 Luzak B, Boncler M, Rywaniak J. et al. The effect of a platelet cholesterol modulation on the acetylsalicylic acid-mediated blood platelet inhibition in hypercholesterolemic patients. Eur J Pharmacol 2011; 658 (2–3): 91-97
    CrossrefPubMedGoogle Scholar
  • 31 Zhao Q, Li M, Chen M. et al. Lovastatin induces platelet apoptosis. Environ Toxicol Pharmacol 2016; 42: 69-75
    CrossrefPubMedGoogle Scholar
  • 32 Tacconelli S, Dovizio M, Di Francesco L. et al. Reduced variability to aspirin antiplatelet effect by the coadministration of statins in high-risk patients for cardiovascular disease. Clin Pharmacol Ther 2018; 104 (01) 111-119
    CrossrefPubMedGoogle Scholar
  • 33 Sexton TR, Wallace EL, Macaulay TE. et al. The effect of rosuvastatin on platelet-leukocyte interactions in the setting of acute coronary syndrome. J Am Coll Cardiol 2015; 65 (03) 306-307
    CrossrefPubMedGoogle Scholar
  • 34 Moscardó A, Vallés J, Latorre A, Madrid I, Santos MT. Reduction of platelet cytosolic phospholipase A2 activity by atorvastatin and simvastatin: biochemical regulatory mechanisms. Thromb Res 2013; 131 (04) e154-e159
    CrossrefPubMedGoogle Scholar
  • 35 Mattiello T, Guerriero R, Lotti LV. et al. Aspirin extrusion from human platelets through multidrug resistance protein-4-mediated transport: evidence of a reduced drug action in patients after coronary artery bypass grafting. J Am Coll Cardiol 2011; 58 (07) 752-761
    CrossrefPubMedGoogle Scholar
  • 36 Santos MT, Fuset MP, Ruano M, Moscardó A, Valles J. Effect of atorvastatin on platelet thromboxane A(2) synthesis in aspirin-treated patients with acute myocardial infarction. Am J Cardiol 2009; 104 (12) 1618-1623
    CrossrefPubMedGoogle Scholar
  • 37 Bliden KP, Singla A, Gesheff MG. et al. Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin. Thromb Haemost 2014; 112 (02) 323-331
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 38 Chaudhary R, Bliden KP, Garg J. et al. Statin therapy and inflammation in patients with diabetes treated with high dose aspirin. J Diabetes Complications 2016; 30 (07) 1365-1370
    CrossrefPubMedGoogle Scholar
  • 39 Konishi T, Funayama N, Yamamoto T. et al. Stabilization of symptomatic carotid atherosclerotic plaques by statins: a clinico-pathological analysis. Heart Vessels 2018; 33 (11) 1311-1324
    CrossrefPubMedGoogle Scholar
  • 40 Sexton T, Wallace EL, Smyth SS. Anti-thrombotic effects of statins in acute coronary syndromes: at the intersection of thrombosis, inflammation, and platelet-leukocyte interactions. Curr Cardiol Rev 2016; 12 (04) 324-329
    CrossrefPubMedGoogle Scholar
  • 41 Puccetti L, Pasqui AL, Pastorelli M. et al. Platelet hyperactivity after statin treatment discontinuation. Thromb Haemost 2003; 90 (03) 476-482
    PubMedGoogle Scholar
  • 42 Heeschen C, Hamm CW, Laufs U, Snapinn S, Böhm M, White HD. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002; 105 (12) 1446-1452
    CrossrefPubMedGoogle Scholar
  • 43 Sundström J, Hedberg J, Thuresson M, Aarskog P, Johannesen KM, Oldgren J. Low-dose aspirin discontinuation and risk of cardiovascular events: a Swedish nationwide, population-based cohort study. Circulation 2017; 136 (13) 1183-1192
    CrossrefPubMedGoogle Scholar
  • 44 Atar S, Cannon CP, Murphy SA, Rosanio S, Uretsky BF, Birnbaum Y. Statins are associated with lower risk of gastrointestinal bleeding in patients with unstable coronary syndromes: analysis of the Orbofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction 16 (OPUS-TIMI 16) trial. Am Heart J 2006; 151 (05) 976.e1-976.e6
    CrossrefPubMedGoogle Scholar
  • 45 Quinn KL, Macdonald EM, Mamdani MM, Diong C, Juurlink DN. Canadian Drug Safety and Effectiveness Research Network (CDSERN). Lipophilic statins and the risk of intracranial hemorrhage following ischemic stroke: a population-based study. Drug Saf 2017; 40 (10) 887-893
    CrossrefPubMedGoogle Scholar
  • 46 Valdes V, Nardi MA, Elbaum L, Berger JS. Reproducibility over time and effect of low-dose aspirin on soluble P-selectin and soluble CD40 ligand. J Thromb Thrombolysis 2015; 40 (01) 83-87
    CrossrefPubMedGoogle Scholar
  • 47 Jayaram P, Yeh P, Patel SJ. et al. Effects of aspirin on growth factor release from freshly isolated leukocyte-rich platelet-rich plasma in healthy men: a prospective fixed-sequence controlled laboratory study. Am J Sports Med 2019; 47 (05) 1223-1229
    CrossrefPubMedGoogle Scholar
  • 48 Polzin A, Rassaf T, Böhm A. et al. Aspirin inhibits release of platelet-derived sphingosine-1-phosphate in acute myocardial infarction. Int J Cardiol 2013; 170 (02) e23-e24
    CrossrefPubMedGoogle Scholar
  • 49 Ulrych T, Böhm A, Polzin A. et al. Release of sphingosine-1-phosphate from human platelets is dependent on thromboxane formation. J Thromb Haemost 2011; 9 (04) 790-798
    CrossrefPubMedGoogle Scholar
  • 50 Nomura S, Fujita S, Ozasa R. et al. The correlation between platelet activation markers and HMGB1 in patients with disseminated intravascular coagulation and hematologic malignancy. Platelets 2011; 22 (05) 396-397
    CrossrefPubMedGoogle Scholar
  • 51 Kang R, Chen R, Zhang Q. et al. HMGB1 in health and disease. Mol Aspects Med 2014; 40: 1-116
    CrossrefPubMedGoogle Scholar
  • 52 Mardente S, Mari E, Massimi I. et al. From human megakaryocytes to platelets: effects of aspirin on high-mobility group box 1/receptor for advanced glycation end products axis. Front Immunol 2018; 8: 1946
    CrossrefPubMedGoogle Scholar
  • 53 Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol 1971; 231 (25) 235-237
    CrossrefPubMedGoogle Scholar
  • 54 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22 (09) 1381-1389
    CrossrefPubMedGoogle Scholar
  • 55 Tarantino E, Amadio P, Squellerio I. et al. Role of thromboxane-dependent platelet activation in venous thrombosis: Aspirin effects in mouse model. Pharmacol Res 2016; 107: 415-425
    CrossrefPubMedGoogle Scholar
  • 56 Kyrle PA, Westwick J, Scully MF, Kakkar VV, Lewis GP. Investigation of the interaction of blood platelets with the coagulation system at the site of plug formation in vivo in man–effect of low-dose aspirin. Thromb Haemost 1987; 57 (01) 62-66
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 57 Undas A, Brummel-Ziedins K, Mann KG. Why does aspirin decrease the risk of venous thromboembolism? On old and novel antithrombotic effects of acetyl salicylic acid. J Thromb Haemost 2014; 12 (11) 1776-1787
    CrossrefPubMedGoogle Scholar
  • 58 Szczeklik A, Krzanowski M, Góra P, Radwan J. Antiplatelet drugs and generation of thrombin in clotting blood. Blood 1992; 80 (08) 2006-2011
    CrossrefPubMedGoogle Scholar
  • 59 Szczeklik A, Musial J, Undas A. et al. Inhibition of thrombin generation by aspirin is blunted in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1996; 16 (08) 948-954
    CrossrefPubMedGoogle Scholar
  • 60 Sanguigni V, Pignatelli P, Lenti L. et al. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation 2005; 111 (04) 412-419
    CrossrefPubMedGoogle Scholar
  • 61 Khattab AA, Ndrepepa G, Schulz S. et al. Statin effect on thrombin inhibitor effectiveness during percutaneous coronary intervention: a post-hoc analysis from the ISAR-REACT 3 trial. Clin Res Cardiol 2011; 100 (07) 579-585
    CrossrefPubMedGoogle Scholar
  • 62 Serebruany VL, Miller M, Pokov AN. et al. Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study). Am J Cardiol 2006; 97 (09) 1332-1336
    CrossrefPubMedGoogle Scholar
  • 63 Schrör K. Acetylsalicylic Acid. 3rd ed.. Berlin: de Gruyter; 2022
    CrossrefGoogle Scholar
  • 64 McClelland S, Gawaz M, Kennerknecht E. et al. Contribution of cyclooxygenase-1 to thromboxane formation, platelet-vessel wall interactions and atherosclerosis in the ApoE null mouse. Atherosclerosis 2009; 202 (01) 84-91
    CrossrefPubMedGoogle Scholar
  • 65 Praticò D, Smyth EM, Violi F, FitzGerald GA. Local amplification of platelet function by 8-Epi prostaglandin F2alpha is not mediated by thromboxane receptor isoforms. J Biol Chem 1996; 271 (25) 14916-14924
    CrossrefPubMedGoogle Scholar
  • 66 Audoly LP, Rocca B, Fabre JE. et al. Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo. Circulation 2000; 101 (24) 2833-2840
    CrossrefPubMedGoogle Scholar
  • 67 Schwedhelm E, Bierend A, Maas R. et al. Redox-generated isoprostanes are associated with residual platelet activity in aspirin-treated patients with stable coronary heart disease. J Thromb Haemost 2010; 8 (12) 2662-2670
    CrossrefPubMedGoogle Scholar
  • 68 Violi F, Pignatelli P. Statins as regulators of redox signaling in platelets. Antioxid Redox Signal 2014; 20 (08) 1300-1312
    CrossrefPubMedGoogle Scholar
  • 69 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336 (14) 973-979
    CrossrefPubMedGoogle Scholar
  • 70 Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98 (08) 731-733
    CrossrefPubMedGoogle Scholar
  • 71 Ridker PM, Danielson E, Fonseca FA. et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21) 2195-2207
    CrossrefPubMedGoogle Scholar
  • 72 Eisenhardt SU, Habersberger J, Murphy A. et al. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res 2009; 105 (02) 128-137
    CrossrefPubMedGoogle Scholar
  • 73 Puccetti L, Santilli F, Pasqui AL. et al. Effects of atorvastatin and rosuvastatin on thromboxane-dependent platelet activation and oxidative stress in hypercholesterolemia. Atherosclerosis 2011; 214 (01) 122-128
    CrossrefPubMedGoogle Scholar
  • 74 Fisher M, Cushman M, Knappertz V, Howard G. An assessment of the joint associations of aspirin and statin use with C-reactive protein concentration. Am Heart J 2008; 156 (01) 106-111
    CrossrefPubMedGoogle Scholar
  • 75 Taubert D, Berkels R, Grosser N, Schröder H, Gründemann D, Schömig E. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol 2004; 143 (01) 159-165
    CrossrefPubMedGoogle Scholar
  • 76 O'Kane P, Xie L, Liu Z. et al. Aspirin acetylates nitric oxide synthase type 3 in platelets thereby increasing its activity. Cardiovasc Res 2009; 83 (01) 123-130
    CrossrefPubMedGoogle Scholar
  • 77 Grosser N, Abate A, Oberle S. et al. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun 2003; 308 (04) 956-960
    CrossrefPubMedGoogle Scholar
  • 78 Grosser N, Schröder H. Aspirin protects endothelial cells from oxidant damage via the nitric oxide-cGMP pathway. Arterioscler Thromb Vasc Biol 2003; 23 (08) 1345-1351
    CrossrefPubMedGoogle Scholar
  • 79 Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Villela CG, Fierro IM. Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells. Am J Physiol Cell Physiol 2005; 289 (03) C557-C563
    CrossrefPubMedGoogle Scholar
  • 80 Hennekens CH, Schneider WR, Pokov A. et al. A randomized trial of aspirin at clinically relevant doses and nitric oxide formation in humans. J Cardiovasc Pharmacol Ther 2010; 15 (04) 344-348
    CrossrefPubMedGoogle Scholar
  • 81 Hetzel S, DeMets D, Schneider R. et al. Aspirin increases nitric oxide formation in chronic stable coronary disease. J Cardiovasc Pharmacol Ther 2013; 18 (03) 217-221
    CrossrefPubMedGoogle Scholar
  • 82 Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J Exp Med 2004; 200 (01) 69-78
    CrossrefPubMedGoogle Scholar
  • 83 Laufs U, Gertz K, Huang P. et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000; 31 (10) 2442-2449
    CrossrefPubMedGoogle Scholar
  • 84 Loboda A, Jazwa A, Grochot-Przeczek A. et al. Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2008; 10 (10) 1767-1812
    CrossrefPubMedGoogle Scholar
  • 85 Violi F, Carnevale R, Pastori D, Pignatelli P. Antioxidant and antiplatelet effects of atorvastatin by Nox2 inhibition. Trends Cardiovasc Med 2014; 24 (04) 142-148
    CrossrefPubMedGoogle Scholar
  • 86 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
    CrossrefPubMedGoogle Scholar
  • 87 Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354 (12) 1264-1272
    CrossrefPubMedGoogle Scholar
  • 88 Leander K, Mälarstig A, Van't Hooft FM. et al. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future risk of cardiovascular events independently of established risk factors. Circulation 2016; 133 (13) 1230-1239
    CrossrefPubMedGoogle Scholar
  • 89 Gurbel PA, Navarese EP, Tantry US. Exploration of PCSK9 as a cardiovascular risk factor: is there a link to the platelet?. J Am Coll Cardiol 2017; 70 (12) 1463-1466
    CrossrefPubMedGoogle Scholar
  • 90 Kasichayanula S, Grover A, Emery MG. et al. Clinical Pharmacokinetics and pharmacodynamics of evolocumab, a PCSK9 inhibitor. Clin Pharmacokinet 2018; 57 (07) 769-779
    CrossrefPubMedGoogle Scholar
  • 91 Sahebkar A, Simental-Mendía LE, Guerrero-Romero F, Golledge J, Watts GF. Effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) concentrations: a systematic review and meta-analysis of clinical trials. Diabetes Obes Metab 2015; 17 (11) 1042-1055
    CrossrefPubMedGoogle Scholar
  • 92 Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009; 50 (Suppl): S172-S177
    CrossrefPubMedGoogle Scholar
  • 93 Zhang DW, Lagace TA, Garuti R. et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007; 282 (25) 18602-18612
    CrossrefPubMedGoogle Scholar
  • 94 Barale C, Bonomo K, Frascaroli C. et al. Platelet function and activation markers in primary hypercholesterolemia treated with anti-PCSK9 monoclonal antibody: a 12-month follow-up. Nutr Metab Cardiovasc Dis 2020; 30 (02) 282-291
    CrossrefPubMedGoogle Scholar
  • 95 Ding Z, Wang X, Liu S. et al. PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy. Cardiovasc Res 2018; 114 (13) 1738-1751
    CrossrefPubMedGoogle Scholar
  • 96 Momtazi-Borojeni AA, Sabouri-Rad S, Gotto AM. et al. PCSK9 and inflammation: a review of experimental and clinical evidence. Eur Heart J Cardiovasc Pharmacother 2019; 5 (04) 237-245
    CrossrefPubMedGoogle Scholar
  • 97 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
    CrossrefPubMedGoogle Scholar
  • 98 Werner C, Hoffmann MM, Winkler K, Böhm M, Laufs U. Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment. Vascul Pharmacol 2014; 62 (02) 94-102
    CrossrefPubMedGoogle Scholar
  • 99 Cammisotto V, Pastori D, Nocella C. et al. PCSK9 regulates Nox2-mediated platelet activation via CD36 receptor in patients with atrial fibrillation. Antioxidants 2020; 9 (04) 296
    CrossrefPubMedGoogle Scholar
  • 100 Podrez EA, Byzova TV, Febbraio M. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med 2007; 13 (09) 1086-1095
    CrossrefPubMedGoogle Scholar
  • 101 Giugliano RP, Pedersen TR, Park JG. et al; FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017; 390 (10106): 1962-1971
    CrossrefPubMedGoogle Scholar
  • 102 Fitzgerald K, White S, Borodovsky A. et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017; 376 (01) 41-51
    CrossrefPubMedGoogle Scholar
  • 103 German CA, Shapiro MD. Small interfering RNA therapeutic inclisiran: a new approach to targeting PCSK9. BioDrugs 2020; 34 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 104 Musunuru K. Treating coronary artery disease: beyond statins, ezetimibe, and PCSK9 inhibition. Annu Rev Med 2021; 72: 447-458
    CrossrefPubMedGoogle Scholar