Dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor such as clopidogrel, ticagrelor, or prasugrel is recommended post percutaneous coronary intervention (PCI) for 6-12 months, depending on stent type and patient-specific factors.¹ In patients requiring temporary interruption of DAPT for procedures or surgeries, periprocedural 'bridge' therapy with a short acting parenteral antithrombotic such as cangrelor or eptifibatide may be considered, especially within the first 3 months post PCI, to prevent stent thrombosis.²

Cangrelor is a selective, reversible intravenous (IV) P2Y12 receptor inhibitor that is approved for use during PCI with stent placement to decrease the risk of periprocedural myocardial infarction, need for repeat coronary revascularization, and stent thrombosis.³ Cangrelor's pharmacokinetic and pharmacodynamic properties are ideal for periprocedural use, including rapid-onset, short plasma half-life of approximately 3 to 5 minutes, and reversible platelet inhibition with restoration of platelet function within 1 hour of cessation.⁴ Although the European Society of Cardiology guidelines advocate for a bridge strategy if DAPT needs to be temporarily held in the periprocedural time-frame, no IV antiplatelet strategy is approved or preferred for this indication.⁵ In the BRIDGE trial, thienopyridines were stopped and patients were administered IV cangrelor or placebo for at least 48 hours, which was discontinued 1 to 6 hours before coronary artery bypass surgery (CABG).⁶ Platelet function testing before, during, and after study drug infusion using the VerifyNOW P2Y12 (Accumetrics) assay was checked to target platelet reactivity units (PRU) of < 240.⁶ Cangrelor, at an infusion dose of 0.75mcg/kg/min achieved platelet inhibition in 98.8% compared to 19% in those on placebo; (RR) 5.2 (95% confidence interval [CI], 3.3-8.1) p <0.001, without increasing the risk of major bleeding prior to CABG, 11.8% versus 10.4% in cangrelor and placebo groups, respectively.⁶

Eptifibatide and tirofiban make up the glycoprotein IIb/IIa (GP IIb/IIIa) inhibitor class that are  alternative parenteral antiplatelet agents. However, cangrelor inhibits platelet activation, while the GP llb/IIIa inhibitors  reversibly compete with von Willebrand factor and fibrinogen at the GP IIb/IIIa receptor site, thereby inhibiting the final pathway of platelet aggregation. The plasma half-life of both GP IIb/IIIa inhibitors is approximately 2 hours and both undergo renal elimination, with eptifibatide having a contraindication for use in patients on hemodialysis.⁷ The GP IIb/IIIa inhibitors have been evaluated in small cohorts as bridge therapy in situations requiring temporary discontinuation of DAPT. Tirofiban, initiated 3 days preoperatively, compared to holding DAPT with no bridge, found lower 30-day major adverse cardiac events (MACE) (OR) 0.3 (95% CI 0.13-0.39) p <0.01, particularly in patients who were <60 days from their stent implantation.⁸ In one systematic review of five observational retrospective studies, tirofiban was used as bridge at a dose of 0.1mcg/kg/min or 0.05mcg/kg/min in those with a creatinine clearance (CrCl) < 30mL/min for 3-5 days pre non-cardiac surgery and found decreased stent thrombosis, with low occurrences of bleeding events in those that received the bridge protocol.⁹ In contrast, data evaluating eptifibatide for perioperative bridging has focused on safety, mainly the need for blood transfusion perioperatively, though the overall reported incidence of MACE was low.^10-11 In a smaller, single-arm, analyses of case reports and retrospective studies with eptifibatide, bleeding was increased in patients with preoperative hold times of <4 hours; stent thrombosis was, however, prevented in these cohorts.¹²

Although data comparing parenteral antiplatelets for periprocedural bridging is lacking, one retrospective analysis suggested that eptifibatide may potentially be a more cost-effective agent, especially in patients without renal impariment.¹³ In this analysis, patients who were deemed low bleeding risk, patients who did not require rapid reversal, and those with "normal" renal function were allocated to eptifibatide at PCI dosing. All others were given cangrelor. The authors identified similar incidences of GUSTO bleeding with both bridge strategies, though there was more intraoperative bleeding with eptifibatide ([32% vs. 12%] p < 0.05).¹³ A potential cost savings of $5,824 per patient was calculated for those who received eptifibatide compared to cangrelor.¹³ Though the potential of cost savings is attractive when comparing GP IIb/IIIa inhibitors to cangrelor, careful consideration regarding patient selection should be undertaken in order to minimize bleeding risk. Given the  short half-life of cangrelor, elimination independent of renal function, and prospective data for use in periprocedural bridging, cangrelor should be considered the preferred parenteral antiplatelet to use in those with impaired renal function. GP IIb/IIIa inhibitors may be considered in patients without renal impairment who have planned procedures and are deemed to be low bleeding risk based on clinician discretion. Selection of parenteral antiplatelet therapy should be discussed at a multidisciplinary level, to include the managing cardiologists, surgeons, and clinical pharmacists.

Table 1: Comparison of Parenteral Antiplatelet Therapies and Periprocedural Management

Medication	Class	Half-life	Bridge Dose	Periprocedural Management
Cangrelor (Kengreal®)	P2Y12 Antagonist	3 – 5 minutes	0.75 mcg/kg/min following enteral P2Y12 inhibitor discontinuation for up to 7 days prior to procedure Ω	Hold 1 – 6 hours preoperatively and resume enteral P2Y12 inhibitor once hemostasis achieved. Re-load with enteral P2Y12 inhibitor in most cases.
Tirofiban (Aggrastat)	GP IIb/IIIa inhibitor	1.5 – 2 hours*	0.1 mcg/kg/min (CrCl < 30 mL/min use 0.05 mcg/kg/min) following enteral P2Y12 inhibitor discontinuation Ω	Hold 4 hours preoperatively* and resume enteral P2Y12 inhibitor once hemostasis achieved. Re-load with enteral P2Y12 inhibitor in most cases.
Eptifibatide (Integrilin)	GP IIb/IIIa inhibitor	2 – 3 hours*	2 mcg/kg/min (CrCl < 50 mL/min use 1 mcg/kg/min) following enteral P2Y12 inhibitor discontinuation Ω	Hold 6 – 12 hours preoperatively* and resume enteral P2Y12 inhibitor once hemostasis achieved. Re-load with enteral P2Y12 inhibitor in most cases.
Table 1: Courtesy of Ahuja T, Simone P. Ω The effects of enteral agents persist with meaningful levels of P2Y12 inhibition after discontinuation. It is reasonable to wait to start cangrelor bridging for up to 3-4 days after prasugrel discontinuation and 2-3 days after clopidogrel or ticagrelor discontinuation. P2Y12 testing may help determine appropriate timing of cangrelor initiation. *Longer in patients with renal impairment

References

1. Khan SU, Singh M, Valavoor S, et al. Dual antiplatelet therapy after percutaneous coronary intervention and drug-eluting stents. Circulation 2020;142:1425-36.
2. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur J Cardiothorac Surg 2018;53:34-78.
3. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368:1303-13.
4. Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55.
5. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213-60.
6. Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 2012;307:265-74.
7. Schrör K, Weber AA. Comparative pharmacology of GP IIb/IIIa antagonists. J Thromb Thrombolysis 2003;15:71-80.  
8. De Servi S, Morici N, Boschetti E, et al. Bridge therapy or standard treatment for urgent surgery sfter coronary stent implantation: analysis of 314 patients. Vascul Pharmacol 2016;80:85-90.  
9. Riscado LVS, de Pinho JHS, de Carvalho Lobato A. Efficacy and safety of tirofiban bridge as an alternative to suspension of dual antiplatelet therapy in patients undergoing surgery: a systematic review. J Vasc Bras 2021;20:e20210113.
10. Rassi AN, Blackstone E, Militello MA, et al. Safety of "bridging" with eptifibatide for patients with coronary stents before cardiac and non-cardiac surgery. Am J Cardiol 2012;110:485-90.
11. Waldron NH, Dallas T, Erhunmwunsee L, Wang TY, Berry MF, Welsby IJ. Bleeding risk associated with eptifibatide (Integrelin) bridging in thoracic surgery patients. J Thromb Thrombolysis 2017;43:194-202.
12. Van Tuyl JS, Newsome AS, Hollis IB. Perioperative bridging with glycoprotein IIb/IIIa inhibitors versus cangrelor: balancing efficacy and safety. Ann Pharmacother 2019;53:726-37.
13. Yun AN, Toyoda AY, Solomon EJ, Roberts RJ, Ji CS. Safety and efficacy of periprocedural bridging with cangrelor versus eptifibatide. J Cardiovasc Pharmaco 2022;79:383-89.

Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery

Keywords: Purinergic P2Y Receptor Antagonists, Platelet Aggregation Inhibitors, Ticagrelor, Clopidogrel, Percutaneous Coronary Intervention, Eptifibatide, Fibrinolytic Agents, Prasugrel Hydrochloride, Confidence Intervals, Half-Life, Myocardial Infarction, Coronary Artery Bypass, Hemorrhage, Aspirin, Thrombosis, Tirofiban, Stents, Platelet Aggregation, Incidence, Creatinine, Retrospective Studies, Platelet Membrane Glycoprotein IIb, von Willebrand Factor, Patient Selection, Cost Savings, Cost-Benefit Analysis, Pharmacists, Prospective Studies, Blood Transfusion, Contraindications, Kidney, Renal Dialysis, Surgeons, Fibrinogen, Observational Studies as Topic

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