Dual Antiplatelet and Glycoprotein Inhibitors in Emergency PCI

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1 Dual Antiplatelet and Glycoprotein Inhibitors in Emergency PCI 8 Alan Yean Yip Fong and Hwei Sung Ling 8.1 Introduction Platelet inhibition remains the core pharmacotherapy component in patients undergoing emergency or primary percutaneous coronary interventions (PCI). This can be achieved using a number of intravenous and oral preparations. Intravenous (iv) antiplatelets include various glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors and the only available intravenous P 2 Y 12 inhibitor, cangrelor. Available oral agents include aspirin and various P 2 Y 12 inhibitors or their analogues. These are usually used in combination with the intention to maintain dual antiplatelet therapy (DAPT) for a period of time (generally up to 12 months) after the index PCI procedure. Understanding and appropriate use of antiplatelet agents are vital in optimizing clinical outcomes of patients with acute coronary syndromes, particularly in the emergency setting where the patient may be naïve to all pharmacological agents. In this review, an overview on antiplatelet therapy for patient needing emergency PCI is described, including evidence from important clinical trials and suggested antiplatelet therapy regimens by published clinical practice guidelines. 8.2 Aspirin Aspirin (acetylsalicylic acid) ( 75 mg daily) permanently inhibits plateletdependent cyclooxygenase 1 (COX-1) enzyme and consequently preventing synthesis of and thromboxane A 2 (TXA 2 ), which is a powerful promoter of platelet aggregation [1]. At higher doses, aspirin inhibits COX-2 which offers analgesic and A. Y. Y. Fong (*) Sarawak Heart Centre, Kota Samarahan, Malaysia alanfong@crc.gov.my H. S. Ling Sarawak General Hospital, Kuching, Malaysia The Author(s) 2018 T. J. Watson et al. (eds.), Primary Angioplasty, 99

2 100 A. Y. Y. Fong and H. S. Ling antipyretic effects by blocking production of prostaglandin. Aspirin in a broad range of patients has been shown to offer clinically important benefits on protection from coronary artery disease (CAD). This predominantly appears related to antiplatelet effects, although the drug may also play a role in reducing atherosclerosis by blocking COX-dependent vasoconstrictors and prevent oxidation of low density lipoprotein. Importantly, aspirin has become a central component of the antiplatelet regimen both for patients with established CAD and those undergoing PCI procedures Evidence of Aspirin in Myocardial Infarction and PCI Major studies indicating a central role for aspirin in patients with acute MI and undergoing emergency revascularization include: International Study of Infarct Survival (ISIS-2) [2] This study was performed in the thrombolysis era but demonstrated a headline 23% reduction of mortality rate among patients with MI with a near to 50% reduction of nonfatal reinfarction or stroke. Meta-analysis of aspirin usage for prevention of stroke, myocardial infarction, and death among high-risk patients [3] This study from the Antithrombotic Trialists Collaboration showed a 53% reduction of death and vascular events in those underwent coronary angioplasty. Aspirin in prevention of restenosis after PCI [4] This study showed that in addition to protection from stent thrombosis, aspirin offered a significant reduction of stent restenosis rate after PCI Aspirin Dosing Consensus with regard to dosing of aspirin before and after PCI (including primary PCI) has been established and recommended as follows [5]: Loading (prior to PCI) Tablet mg stat dose if not on chronic aspirin therapy, at least 2 h before PCI Tablet mg stat dose if already on chronic aspirin therapy Maintenance therapy (post PCI) Tablet mg OD to continue indefinitely 8.3 P 2 Y 12 Inhibitors The P 2 Y 12 receptor plays a key role in the platelet activation process. Adenosine diphosphate (ADP) interacts with the platelet P 2 Y 12 receptor stimulating activation of the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor. In turn, activation of the GP2b3a

3 8 Dual Antiplatelet and Glycoprotein Inhibitors in Emergency PCI 101 receptor results in enhanced platelet degranulation and thromboxane production, driving platelet aggregation [6]. Various P 2 Y 12 inhibitors are available. Clopidogrel and prasugrel are thienopyridine prodrugs that must undergo cytochrome P450-mediated conversion to the active metabolite which then covalently bond to the P 2 Y 12 receptor, thus inhibiting platelet activation. In contrast, ticagrelor and cangrelor are direct-acting platelet inhibitors which do not need activation. These agents are thus more potent and have more rapid onset of action Evidence for P 2 Y 12 Inhibitor in MI and PCI CURE (PCI-CURE) [7] This trial showed a significant reduction of cardiovascular death and myocardial infarction post PCI using clopidogrel. TRITON-TIMI 38 [8] This trial showed a significant reduction of cardiovascular death, nonfatal myocardial infarction, and stroke using prasugrel among patients with high-risk ACS undergoing PCI. Of note, patients with prior stroke, transient ischemic attack (TIA), age > 75, and weight < 60 kg had no net benefit. PLATO [9] This trial showed a reduction of composite death from vascular causes, MI, and stroke with use of ticagrelor. Of note, patients with prior stroke, TIA which led to net harm, age > 75, and weight < 60 kg had no net benefit P 2 Y 12 Inhibitor Dosing Clopidogrel Loading (prior to PCI) Tablet mg stat dose Maintenance therapy Tablet mg OD Prasugrel Loading (prior to PCI) Tablet 60 mg stat dose Maintenance therapy Tablet 10 mg OD Tablet 5 mg OD (if body weight < 60 kg) Ticagrelor Loading (prior to PCI). Tablet 180 mg stat dose Maintenance therapy Tablet 90 mg BD

4 102 A. Y. Y. Fong and H. S. Ling 8.4 Glycoprotein IIb/IIIa Inhibitors GPIIb/IIIa inhibitors directly target the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor. This receptor is the most abundant integrin found on the surface of platelets and is composed of two separate subunits, α IIb (GPIIb) and β 3 (GPIIIa). GPIIb/ IIIa inhibitors prevent binding of primarily fibrinogen, but various other ligands also, hence, inhibit the aggregation of platelets [10]. Various agents are available: Abciximab is a monoclonal antibody. Eptifibatide is a synthetic cyclic heptapeptide. Tirofiban is a nonpeptidal antagonist to glycoprotein IIb/IIIa receptor Evidence for GPIIb/IIIa Inhibitors in MI and PCI Guidance on the Use of Glycoprotein IIb/IIIa Inhibitors in the Treatment of Acute Coronary Syndrome [10] Review of multiple trials showed statistically significant benefit in GPIIb/IIIa treatment groups in terms of composite outcome of death, subsequent MI, and revascularization. Evaluation of 7e3 for Prevention of Ischemic Complication (EPIC) [11] Usage of abciximab during coronary angioplasty after presentation with highrisk unstable angina showed significant reduction in composite death, nonfatal MI, repeat coronary artery bypass grafting (CABG), repeat PCI for recurrent ischemia, or requirement for a coronary stent after balloon angioplasty. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) [12] Usage of eptifibatide in patient with ST changes and MI (but not persistent ST elevation) together with aspirin and intravenous heparin, via infusion for up to 96 h, significantly reduces composite of death and nonfatal myocardial infarction within 30 days from index event. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM PLUS) [13] Usage of tirofiban with heparin infusion in patient with acute myocardial infarction for up to 72 h showed significant decrease of 7 days to 30 days composite death, recurrent myocardial infarction Dosing Abciximab Bolus of 0.25 mg/kg intravenous Infusion at μg/kg/min (maximum 10ug/min) for 12 h

5 8 Dual Antiplatelet and Glycoprotein Inhibitors in Emergency PCI 103 Eptifibatide Double bolus of 180 μg/kg intravenous (given at 10-min interval) Infusion 2.0 μg/kg/min for up to 18 h Tirofiban Bolus of 25 μg/kg over 3 min Infusion at 0.15 μg/kg/min for up to 18 h DAPT and glycoprotein IIb/IIIa inhibitor in emergency PCI 8.5 Recommended Treatment Algorithms from Consensus Guidelines [14, 15] 1. A potent, faster onset and superior clinical efficacy P 2 Y 12 inhibitor (prasugrel or ticagrelor) is recommended ideally prior to (or at least at the time of) PCI. 2. Ticagrelor is recommended as P 2 Y 12 inhibitor of choice on top of aspirin in patients with ACS. 3. Ticagrelor should not be used in patient with previous intracranial hemorrhage or ongoing bleeds or on oral anticoagulants. 4. Prasugrel should not be used in patient with previous intracranial hemorrhage, previous ischemic stroke or transient ischemic attack, or ongoing bleeds or on oral anticoagulants. Prasugrel is generally not recommended in patient >75 years old or weighing <60 kg. 5. In cases prasugrel is used for patient >75 years old or weighing <60 kg, a dose of 5 mg OD should be used. 6. When none of the ticagrelor or prasugrel can be used, clopidogrel can be the choice of P 2 Y 12 inhibitor. 7. Switching from clopidogrel to either ticagrelor or prasugrel in acute setting need not consider prior clopidogrel timing and dosing (Fig. 8.1). Time of use DAPT duration strategies assessed PRECISE-DAPT score 18 At the time of coronary stenting Short DAPT (3-6 months) vs. Standard/long DAPT (12-24 months) DAPT score 15 After 12 months of uneventful DAPT Standard DAPT (12 months) vs. Long DAPT (30 months) Score calculation 2 Score range Decision making cut-of suggested HB Age WBC to < <65 Age Cigarette smoking Diabetes mellitus CrCI MI at presentation Prior PCI or prior MI Prior Paclitaxel-eluting stent Yes No Bleeding Stent diameter <3 mm Score CHF or LVEF <30% points Vein graft stent 0 to 100 points Score 25 Short DAPT Score <25 Standard/long DAPT 2 to 10 points Score 2 Long DAPT Score <2 Standard DAPT 2 pt 1 pt 0 pt +2 pt +2 pt Calculator Fig. 8.1 Switching of P 2 Y 12 inhibitor product in acute setting [13]

6 104 A. Y. Y. Fong and H. S. Ling 8. Switching in between ticagrelor and prasugrel or from either one to clopidogrel in acute setting requires 24-h lapse since the last dose (Fig. 8.1). 9. Bleeding risk can be assessed using risk model, e.g., PRECISE-DAPT and DAPT score. Bleeding risk decides duration of DAPT (Fig. 8.2). 10. Suggested duration of DAPT (Fig. 8.3): (a) Acute coronary syndrome receiving PCI At least 12 months of DAPT (aspirin and a P 2 Y 12 inhibitor) is recommended. Six months of DAPT should be considered if there is high bleeding risk; with emerging data for abbreviated DAPT with certain stents, even earlier cessation may be possible. Extension of DAPT >12 months may be considered if no bleeding complication during initial treatment. Percutaneous Coronary Intervention Treatment indication Stable Coronary Artery Disease Acute Coronary Syndrome Device used DES/BMS or DCB BRS DES/BMS or DCB High Bleeding Risk High Bleeding Risk Time I mo. 3 mo. 6 mo. 12 mo. 30 mo. No A C 6 mo. DAPT Class I A A C Continue DAPT Class IIb A Yes No Yes A C 1 mo. DAPT Class IIb C 3 mo. DAPT Class IIa B A P A T A P A T A C OR A T OR 2 A C 12 mo. DAPT Class IIa C OR 3 A C 12 mo. DAPT Class II A A T OR 4 4 A P A C Continue DAPT >12 mo. in pts with prior MI Class IIa B 6 mo. DAPT Class IIa B A = Aspirin C = Clopidogrel P = Prasugrel T = Ticagrelor Fig. 8.2 Bleeding risk assessment before deciding duration of dual antiplatelet therapy [14]

7 8 Dual Antiplatelet and Glycoprotein Inhibitors in Emergency PCI 105 CLOPIDOGREL Prasugrel LD (60 mg) irrespective of prior Clopidogrel timing and dosing Clopidogrel LD (600 mg) 24h after last Prasugrel dose ACUTE SETTING ALWAYS RELOAD Ticagrelor LD (180 mg) irrespective of prior Clopidogrel timing and dosing Clopidogrel LD (600 mg) 24h after last Ticagrelor dose PRASUGREL Ticagrelor LD (180 mg) 24h after last Prasugrel dose TICAGRELOR Prasugrel LD (60 mg) 24h after last Ticagrelor dose Fig. 8.3 Recommended duration of DAPT in patient undergoing PCI [14] (b) Benefits and risks of extended DAPT (18 36 months) Absolute decrease in risk of instent thrombosis, myocardial infarction, and major adverse cardiac events by 1 2%. Absolute increase in bleeding complications by 1%. More benefits are seen in patient with ACS rather stable IHD. 11. Types of stent and its duration: (a) Shorter duration (3 6 months) may be reasonable in patients treated with newer-generation stents as compared to first generation. Emerging data may permit even shorter duration; trials are awaited. 12. DAPT dose in chronic kidney disease: (a) Stages 1 3 EGFR >30 ml/min/1.73 m 2 Aspirin: Loading at mg orally, followed by maintenance 75 mg 100 mg/day Clopidogrel: Loading at mg orally, followed by 75 mg/day Ticagrelor: Loading at 180 mg orally, followed by 90 mg BD/day Prasugrel: Loading at 60 mg orally, followed by 10 mg/day (b) Stage 4 EGFR ml/min/1.73 m 2 No dose adjustment (c) Stage 5 EGFR <15 ml/min/1.73 m 2 Aspirin: No dose adjustment Clopidogrel: No information available Ticagrelor and prasugrel: NOT recommended

8 106 A. Y. Y. Fong and H. S. Ling 13. Glycoprotein IIb/IIIa inhibitor usage in prehospital or upstream settings has not shown extra benefits on efficacy of treatment. 14. Selective downstream usage of GPIIb/IIIa inhibitors reduces cost of treatment and bleeding risk [15]. 15. Usage of glycoprotein IIb/IIIa inhibitor during coronary catheterization as a bailout therapy can be considered. This includes large thrombus, slow or no reflow, or other findings of thrombotic complications during coronary angiogram [16]. 16. Special patient subgroup. In patients on oral anticoagulation who present with STEMI and are undergoing emergency PCI, these patients should: (a) Loading of aspirin and clopidogrel (the P 2 Y 12 inhibitor of choice, 600 mg loading dose) should be done. (b) Also receive additional parenteral anticoagulation. (c) Chronic oral anticoagulation therapy should not be stopped during admission. (d) Gastric protection with a proton pump inhibitor is recommended. (e) Triple therapy (oral anticoagulation, aspirin, and clopidogrel) should be considered for 6 months after STEMI. (f) Oral anticoagulation plus aspirin or clopidogrel should be considered for an additional 6 months; after which, it is then indicated to maintain oral anticoagulation. (g) For patients with atrial fibrillation as the indication for anticoagulation, rivaroxaban in combination with clopidogrel and without aspirin may be a reasonable choice. (h) The use of ticagrelor or prasugrel is not recommended as part of a triple therapy regimen with aspirin and oral anticoagulation. 8.6 Summary DAPT is an important periprocedural pharmacotherapy in patient receiving PCI. DAPT, aspirin, and a P 2 Y 12 inhibitor are to be loaded orally as soon as diagnosis of ACS was made. Choice of P 2 Y 12 inhibitor includes prasugrel, ticagrelor, and clopidogrel. Duration of DAPT treatment after emergency PCI depends on bleeding risk assessment and types of stents used. Extra attention in cases with bioresorbable vascular scaffold, which requires at least 12 months of DAPT regardless of bleeding risk. Glycoprotein IIb/IIIa inhibitor usage depends on treating physician justification as no conclusive evidence of its routine use in emergency PCI.

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