{"\ufeffANTIPLATELETS GUIDELINES IN ENDOVASCULAR TREATMENT OF INTRACRANIAL ANEURYSMS: RECOMMENDATIONS FROM MALAYSIAN NEUROINTERVENTIONAL SOCIETY (MyNIS)\n\nM.F.A. Kamis, I.A. Zainal": null, " on behalf of the Malaysian Neurointerventional Society.\n\nDOI: https://doi.org/10.32896/tij.v4n2.11-17\nSubmitted: 23.06.2024\nAccepted: 28.06.2024\nPublished: 30.06.2024\n \n\nINTRODUCTION\nThe landscape of periprocedural antiplatelet therapy has witnessed significant evolution alongside advancements in the endovascular management of intracranial aneurysms. This includes the introduction of flow-diverting stents, intracranial stents, intrasaccular devices, and stent-assisted coiling. Traditionally, a dual antiplatelet therapy (DAPT) regimen involving Aspirin and Clopidogrel has been widely adopted due to its established safety and efficacy. However, recent studies have identified alternative antiplatelet agents such as Ticagrelor, Tirofiban, or Prasugrel, which have demonstrated comparable efficacy and safety profiles. Endorsed by the Malaysian Society of Interventional Neuroradiology (MYNIS), this guideline aims to assist Interventional Neuroradiologists (INRs) and other physicians involved in treatment in selecting the most appropriate antiplatelet therapy for patients undergoing interventional procedures.\n\nCOX-1 INHIBITORS\n\nAspirin\nAspirin, also known as acetylsalicylic acid (ASA), functions as an irreversible inhibitor of cyclooxygenase-1 (COX-1), thereby impeding the production of thromboxane A2. Even with daily doses as low as 75 mg, Aspirin achieves complete inactivation of COX-1 within platelets due to its irreversible binding and the fact that platelets do not synthesize new proteins during their 7- to 10-day lifespan. This characteristic renders Aspirin an ideal antiplatelet agent, characterized by a stable half-life and predictable therapeutic response, particularly in preventing thromboembolism in the treatment of unruptured intracranial aneurysms. Its onset of action typically occurs within 15\u201330 minutes, and the plasma half-life of Aspirin is approximately 15\u201320 minutes.\nOriginal trials involving intracranial flow diverters utilized daily maintenance doses ranging from 100 mg to 325 mg of Aspirin, while a standard dosage of 325 mg per day is commonly employed for intracranial stents and flow-diverting devices. Research suggests that Aspirin may contribute to the reduction of aneurysmal degradation and inflammation of the aneurysmal wall, in addition to promoting endothelial progenitor cell mobilization. Common side effects of Aspirin administration include gastritis and ulceration attributed to its non-selective COX blockade.\n\nP2Y12 INHIBITORS\n\nClopidogrel\nClopidogrel, a thienopyridine compound, functions by irreversibly inhibiting the platelet P2Y12 adenosine diphosphate receptor, thereby reducing platelet aggregation. Additionally, it impedes platelet aggregation by other platelet agonists such as thromboxane A2 and thrombin by diminishing the amplification effect of ADP released from platelet-dense granules. With a half-life spanning 7\u20138 hours and an onset of action typically ranging from 2 to 4 hours, Clopidogrel is commonly administered in a loading dose of 300 to 600 mg, complemented by a daily dosage of 75 mg.\nThe combination of Clopidogrel with Aspirin as part of dual antiplatelet therapy (DAPT) is a widely adopted practice in endovascular aneurysm treatment. However, a major concern with Clopidogrel is its nature as a prodrug, necessitating enzymatic conversion to active metabolites for its antiplatelet effects to manifest. Consequently, loading doses are often required to achieve rapid efficacy. Various factors, including drug interactions, polymorphisms within the CYP450 enzyme family, and smoking status, can contribute to a significant proportion of individuals showing an inadequate response to Clopidogrel treatment.\n\nPrasugrel\nPrasugrel is a newer generation thienopyridine, functions by inhibiting the P2Y12 receptor and has a half-life ranging from 2 to 15 hours. In comparison to Clopidogrel, it offers a faster onset of action and increased efficacy. Prasugrel undergoes more efficient conversion to its active metabolites and exhibits reduced dependence on CYP enzymes compared to Clopidogrel. Prasugrel is primarily used for patients undergoing intracranial flow diversion, especially when Clopidogrel fails to produce an adequate response due to altered hepatic metabolism. The duration of action of Prasugrel is similar to other thienopyridines, involving irreversible binding to ADP receptors. The standard dosing regimen is a 60 mg loading dose followed by a once-daily maintenance dose of 10 mg (or 5 mg if the patient weighs less than 60 kg). Prasugrel is associated with an increased risk of major bleeding and is contraindicated in patients with acute stroke due to the increased risk of hemorrhagic transformation.\n\nTicagrelor\nTicagrelor is a reversible inhibitor of P2Y12 receptors, belonging to the thienopyridine class, similar to Clopidogrel and Prasugrel. It has a median onset of action of 1.3\u20132 hours, a half-life of 4.6\u20136.3 hours, and becomes undetectable in plasma after 20 hours. Unlike Clopidogrel, Ticagrelor does not require hepatic metabolism for activation, making it effective for patients with genetic resistance to Clopidogrel due to CYP2C19 enzyme alterations. Ticagrelor is considered a safe and efficacious alternative to Clopidogrel, typically administered with a loading dose of 180 mg and a maintenance dose of 90 mg twice daily for 3\u20136 months.\n\nGLYCOPROTEIN IIB/IIIA AGENTS\n\nTirofiban\nTirofiban, a glycoprotein IIb/IIIa receptor antagonist, binds reversibly to the GPIIb/IIIa receptor and has a plasma half-life of 2.5 hours. It is helpful in preventing platelet aggregation and thrombosis, particularly in acute ischemic stroke and during endovascular treatments. Administered intravenously, Tirofiban achieves more than 90% inhibition of ADP-induced platelet aggregation within 10\u201340 minutes with a 0.4 \u03bcg/kg loading infusion, followed by a maintenance infusion of 0.1 \u03bcg/kg/min. Platelet function returns to near baseline in 90% of patients within 4\u20138 hours after discontinuing the infusion. Similar to Eptifibatide, Tirofiban is renally cleared and requires dose adjustment in patients with impaired renal function": null, " however, it can be effectively cleared by hemodialysis.\n\nEptifibatide\nEptifibatide, a cyclic heptapeptide derived from rattlesnake venom, reversibly binds to the GPIIb/IIIa receptor and has a plasma half-life of 1.5\u20132.5 hours. A bolus dose of 180 \u03bcg/kg achieves over 80% inhibition of platelet function within 15 minutes. An infusion of 0.5\u20130.75 \u03bcg/kg/min decreases platelet function after 4\u20136 hours, the time required to reach a steady state. This delay can be mitigated by administering a second 180 \u03bcg/kg bolus within 10 minutes after the first. Less than 50% of platelet aggregation inhibition remains 4 hours after stopping the infusion. Eptifibatide is renally cleared and requires dosage adjustment in patients with a creatinine clearance of less than 50 ml/min. It is particularly useful for proximal thrombus or in-stent occlusions during aneurysm coil embolization, with no reported hemorrhagic complications or worsening of pre-existing subarachnoid hemorrhage, although it may be less effective for distal thrombi.\n\nCLINICAL SCENARIO\n\nCASE 1\nElective procedure with no intra-operative complication, e.g unruptured intracranial aneurysm for flow diverter stent placement\nPre-procedure:\nOral Aspirin 300-325mg and Clopidogrel 300-600mg given 5-7 days prior to the procedure\n\nPost-procedure:\nOral Aspirin 75-100mg daily for 12 months and Clopidogrel 75mg daily for 3-6 months": null, " or\nOral Aspirin 75-100mg daily for 12 months and Ticagrelor 90mg BD for 3-6 months\nCASE 2\nEmergency procedure with no intra-operative complication, e.g ruptured intracranial aneurysm for flow diverter stent or stent and coiling placement\nPre-procedure:\nOral Aspirin 300-325mg or IV Aspirin 500mg, and Clopidogrel 300-600mg prior to the procedure\n\nPost-procedure:\nOral Aspirin 75-100mg daily for 12 months and Clopidogrel 75mg daily for 3-6 months": null, " or\nOral Aspirin 75-100mg daily for 12 months and Ticagrelor 90mg BD for 3-6 months\nCASE 3\nElective procedure with intra-operative thrombosis, e.g placement of flow diverter in unruptured intracranial aneurysm complicated with thrombosis.\nPre-procedure:\nOral Aspirin 300-325mg and Clopidogrel 300-600mg given 5-7 days prior to the procedure\n\nIntra-procedure:\nTirofiban 12\u03bcg/kg loading infusion over 30 minutes\n\nPost-procedure:\nIV infusion of Tirofiban 0.1\u03bcg/kg/min for 12-24 hours": null, " and\nOral Aspirin 75-100mg daily for 12 months and Clopidogrel 75mg daily for 3-6 months": null, " or\nOral Aspirin 75-100mg daily for 12 months and Ticagrelor 90mg BD for 3-6 months\n\nREFERENCES:\n    1. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D. The pipeline embolization device for the intracranial treatment of aneurysms trial. Am J Neuroradiol. 2011 Jan": null, "32(1):34-40. \n\n    2. Tonetti DA, Jankowitz BT, Gross BA. Antiplatelet Therapy in Flow Diversion. Neurosurgery. 2020 Jan 1": null, "86(Suppl 1):S47-S52. \n\n    3. Soize S, Foussier C, Manceau PF, Litr\u00e9 CF, Backchine S, Gawlitza M, Pierot L. Comparison of two preventive dual antiplatelet regimens for unruptured intracranial aneurysm embolization with flow diverter/disrupter: A matched-cohort study comparing clopidogrel with ticagrelor. J Neuroradiol. 2019 Nov": null, "46(6):378-383. \n\n    4. Farrokh S, Owusu K, Lara LR, Nault K, Hui F, Spoelhof B. Neuro-Interventional Use of Oral Antiplatelets: A Survey of Neuro-Endovascular Centers in the United States and Review of the Literature. J Pharm Pract. 2021 Apr": null, "34(2):207-215. \n\n    5. Podlasek A, Al Sultan AA, Assis Z, Kashani N, Goyal M, Almekhlafi MA. Outcome of intracranial flow diversion according to the antiplatelet regimen used: a systematic review and meta-analysis. J Neurointerv Surg. 2020 Feb": null, "12(2):148-155. \n\n    6. Pearce S, Maingard JT, Li K, Kok HK, Barras CD, Russell JH, Hirsch JA, Chandra RV, Jhamb A, Thijs V, Brooks M, Asadi H. Antiplatelet Drugs for Neurointerventions: Part\u00a01 Clinical Pharmacology. Clin Neuroradiol. 2020 Sep": null, "30(3):425-433. \n\n    7. Goyal M, Orlov K, Jensen ME, Taylor A, Majoie C, Jayaraman M, Liu J, Milot G, Brouwer P, Yoshimura S, Albuquerque F, Arthur A, Kallmes D, Sakai N, Fraser JF, Nogueira R, Yang P, Dorn F, Thibault L, Fiehler J, Chapot R, Ospel JM. A DELPHI consensus statement on antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of mechanical thrombectomy. Neuroradiology. 2021 Apr": null, "63(4):627-632. \n\n    8. Pearce S, Maingard JT, Kuan Kok H, Barras CD, Russell JH, Hirsch JA, Chandra RV, Jhamb A, Thijs V, Brooks M, Asadi H. Antiplatelet Drugs for Neurointerventions: Part\u00a02 Clinical Applications. Clin Neuroradiol. 2021 Sep": null, "31(3):545-558. \n\n    9. Li W, Zhu W, Wang A, Zhang G, Zhang Y, Wang K, Zhang Y, Wang C, Zhang L, Zhao H, Wang P, Chen K, Liu J, Yang X. Effect of Adjusted Antiplatelet Therapy on Preventing Ischemic Events After Stenting for Intracranial Aneurysms. Stroke. 2021 Dec": null, "52(12):3815-3825. \n\n    10. Schirmer CM, Bulsara KR, Al-Mufti F, Haranhalli N, Thibault L, Hetts SW": null, " SNIS Standards and Guidelines Committee. Antiplatelets and antithrombotics in neurointerventional procedures: Guideline update. J Neurointerv Surg. 2023 Nov": null, "15(11):1155-1162. \n\n    11. Papaxanthos J, Cagnazzo F, Collemiche FL, Barreau X, Radu RA, Gariel F, Derraz I, Gascou G, Riquelme C, Ferreira I, Lefevre PH, Berge J, Costalat V, Dargazanli C, Marnat G. Ticagrelor versus clopidogrel dual antiplatelet therapy for unruptured intracranial aneurysms treated with flow diverter. J Neuroradiol. 2023 May": null, "50(3):346-351. \n\n    12. Meyer BM, Campos JK, Collard de Beaufort JC, Chen I, Khan MW, Amin G, Zarrin DA, Lien BV, Coon AL. Trends in Dual Antiplatelet Therapy Use for Neurointerventional Procedures for the Management of Intracranial Aneurysms. Biomedicines. 2023 Aug 9": null, "11(8):2234. \nTABLE LEGENDS:\n\nTable 1: Summary of pharmacokinetic and pharmacodynamics of commonly used antiplatelet agents.\n\nAntiplatelet Agents\nMechanism of action\nHalf-life\nOnset of action\nConsideration\nSide effects\nAspirin\nCOX-1 inhibitor\n15\u201320min\nin plasma\n\n15-30min\nEffect on platelets 8\u201310 days given irreversibility\nof COX inhibition\nBleeding. Gastrointestinal upset\nClopidogrel\nIrreversible P2Y12\ninhibitor\n7-8h\n2-4h\nRequires hepatic metabolism, potential genetic resistance (CYP2C19 variations)\nBleeding. Marrow suppression.\nThrombotic thrombocytopenic purpura\nPrasugrel\nIrreversible P2Y12\ninhibitor\n2-15h\n30min\nEffects last 8\u201310 days. Rapid onset of action due to fast conversion to active metabolites\nBleeding\n\nTicagrelor\nReversible P2Y12\ninhibitor\n4.6-6.3h\n1.3-2h\nNot affected by CYP polymorphisms\nBleeding. Respiratory discomfort\nTirofiban\nReversible GPIIb/IIIa receptor antagonist\n2.5h\n10-40min\nGiven IV or IA. Needs renal adjustment\nBleeding. Thrombocytopenia\nEptifibatide\nReversible GPIIb/IIIa receptor antagonist\n1.5-2.5h\n15min\nGiven IV or IA. Needs renal adjustment\nBleeding. Thrombocytopenia\n\n\nTable 2: Recommended antiplatelet regimes and dosage.\n\n\nAntiplatelet\nAgents\nDosage\nDuration\n\nLoading\nMaintenance\n\nElective\nAspirin\n300-325mg\n75-100mg daily\n\n5-7 days prior, then continue minimum for 12 months\nClopidogrel\n300-600mg\n75mg daily\n5-7 days prior, then continue for 3-6 months\nPrasugrel\n30-60mg\n5-10mg daily\n3-6 months\nTicagrelor\n180mg\n90mg twice daily\n3-6 months\nEmergency\nAspirin\nOral: 75-325mg\nIV: 500mg\nRectal: 120-300mg\n75-100mg daily\n\nSTAT, then continue minimum for 12 months\nClopidogrel\n300-600mg\n75mg daily\nSTAT, then continue for 3-6 months\nPrasugrel\n30-60mg\n5-10mg daily\n3-6 months\nTicagrelor\n180mg\n90mg twice daily\n3-6 months\nRescue Therapy\nTirofiban\n12\u03bcg/kg for 30 min\n0.1\u03bcg/kg/min\nIV or IA bolus, followed by infusion 12-24 hours\nEptifibatide\n180\u03bcg/kg for 1-2 min\n1-2\u03bcg/kg/min\nIV or IA bolus, followed by infusion 12-24 hours": null}