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Featured Clinical Topic - Use of Cangrelor for bridging in patients that require discontinuation of dual antiplatelet therapy (DAPT)

20 Sep 2017 12:52 PM | Anonymous

Authors:

Fangzheng Yuan, PharmD Candidate 2018: St. Louis College of Pharmacy
Hannah Pope, PharmD, BCPS: Barnes-Jewish Hospital

Dual antiplatelet therapy (DAPT) is the mainstay of treatment in acute coronary syndromes (ACS). The use of DAPT is crucial in those who undergo percutaneous coronary intervention (PCI) and coronary artery stent implantation.1 DAPT consists of low-dose aspirin and an oral P2Y12 receptor inhibitor such as clopidogrel, prasugrel, or ticagrelor.2 Premature discontinuation of DAPT has been associated with an increased risk of adverse events, including stent thrombosis and mortality.2 Mortality rates of 19-30 % have been observed in patients who had DAPT discontinued early for a surgical procedure.3-5 Studies have shown that over 4% of patients on DAPT will require non-cardiac surgery within one year after stent implantation.6 The optimal approach for managing the risk of potential catastrophic perioperative stent thrombosis and bleeding in patients requiring surgery during the recommended duration of DAPT remains uncertain.

In non-emergent cases, American College of Cardiology/American Heart Association recommended that DAPT be discontinued 5-7 days prior to surgical intervention. Current guidelines recommend that all elective surgeries be postponed until DAPT is complete.1 Per these recommendations, non-cardiovascular, elective surgeries should be delayed for at least 30 days after bare metal stent (BMS) and 6 months after drug eluting stents (DES).2 However, this is not always feasible and temporary administration of a short-acting antiplatelet agent, also known as bridging anti-platelet therapy, is warranted to minimize ischemic and bleeding events. 

An ideal bridging agent should achieve platelet inhibition similar to the oral P2Y12 receptor inhibitors, with a rapid onset and short duration of action.7 Off-label use of the GPIIb/IIIa inhibitors, tirofiban and eptifibatide, as bridging agents has been advocated as an alternative to oral DAPT therapies, due to their pharmacokinetic profiles (Table 1).7-10 Current evidence for this indication is limited and the optimal duration of therapy is unknown.

Cangrelor is an intravenous, non-thienopyridine adenosine triphosphate analogue that directly and reversibly binds to the P2Y12 receptor.8 This differs from oral thienopyridines such as clopidogrel and prasugrel that require metabolic activation and bind irreversibly. Although not FDA approved for bridging therapy, the pharmacokinetic profile of cangrelor makes it an ideal bridging agent. It has a faster onset and offset than other agents considered for bridging (Table 1).8-10 Due to its rapid inactivation in the circulation via dephosphorylation, cangrelor is less likely to accumulate and does not require renal dosing when compared to GPIIb/IIIa anti-platelet agents, which are eliminated as unchanged drug or partial metabolites.8-10

Table 1. Pharmacokinetic profiles of bridging agents8-10

Cangrelor

Tirofiban

Eptifibatide

Administration

IV

IV

IV

Onset of action

Immediate

Immediate

Immediate

Mechanism of action

P2Y12 inhibition

GPIIb/IIIa inhibition

GPIIb/IIIa inhibition

Plasma t ½

3-5 min

2 hours

2.5 hours

Offset of action

1 hour

4-8 hours

4-6 hours

Renal dosing

No

Yes

Yes

To date, cangrelor is FDA approved as an adjunct to PCI. However, the phase II randomized, double-blind trial, Bridging anti-platelet therapy with cangrelor in patients undergoing cardiac surgery (BRIDGE trial), evaluated the hypothesis that cangrelor may be a safe and effective option to bridge patients from irreversible platelet P2Y12 inhibitors to cardiac surgery.11 Patients were randomized to cangrelor or placebo after an initial open-label, dose-finding phase that determined the dose of 0.75 mcg/kg/minute was necessary to achieve appropriate platelet inhibition in 10 patients. In stage 2 of the study, a greater proportion of patients (98.8%) treated with cangrelor achieved the goal of platelet reactivity units (PRU) <240 throughout the entire treatment period compared with placebo (RR=5.2, 95% CI 3.3-8.1, P<0.001). In addition, no significant differences were found in excessive coronary artery bypass grafting (CABG) surgery-related bleeding or major bleeding prior to surgery. However, minor bleeding episodes were numerically higher with the cangrelor group. Angiolio, et al. concluded that the cangrelor group had a higher rate of maintenance of platelet inhibition than the control group.11

Firstenberg, et al. assessed the effects of preoperative cangrelor on the incidence of perioperative complications in the BRIDGE trial.12 All patients received 2-7 days of therapy (cangrelor or control) and the therapy was discontinued 1-6 hours before the planned CABG. Pre- and post-operative outcomes, bleeding values, and transfusion rates were compared between the cangrelor and placebo groups. A multivariable logistic model was used to quantify bleeding risks. No significant difference was found in the rate of CABG-related bleeding (P=0.763) or in serious post-operative adverse events (p=0.454) between the cangrelor group and placebo group. Bridging patients with cangrelor prior to CABG effectively maintained platelet inhibition at <240 P2Y12 PRU without increasing post-CABG bleeding or infusion needs. This analysis further suggests that cangrelor treatment is a potential strategy for bridging patients to a procedure and surgery.12

Overall, the pharmacokinetic profile and data from the BRIDGE trial suggest that cangrelor is a potential treatment option in patients that require DAPT discontinuation prior to a procedure or surgery. Cangrelor can be initiated at the dose of 0.75 mcg/kg/minute through IV administration until 1-6 hours before surgery. Signs and symptoms of bleeding should be monitored during therapy and the procedure. DAPT with an oral antiplatelet agent should be resumed as soon as possible post-surgery.

References

  1. Levine GN, Bates ER, Bittl JA et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Thorac Cardiovasc Surg. 2016; 152(5):1243-1275. 
  2. Song JW, Soh S, Shim J-K. Dual antiplatelet therapy and non-cardiac surgery: evolving issues and anesthetic implications. Korean Journal of Anesthesiology. 2017; 70(1):13-21.
  3. Wilson SH, Fasseas P, Orford JL, et al. Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol. 2003; 42(2):234-240.
  4. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007; 297(2):159-168.
  5. Ferrari E, Benhamou M, Cerboni P, Marcel B. Coronary syndromes following aspirin withdrawal: A special risk for late stent thrombosis. J Am Coll Cardiol. 2005; 45(3):456-459.
  6. Berger PB, Kleiman NS, Pencina MJ et al. Frequency of major noncardiac surgery and subsequent adverse events in the year after drug-eluting stent placement results from the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) Registry. JACC Cardiovasc Interv. 2010; 3(9):920-927.
  7. Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac Surgery. Circulation. 2013; 128:2785-2798.
  8. Cangrelor. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
  9. Tirofiban. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
  10. Eptifibatide. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
  11. Angiolio DJ, Firstenberg MS, Price MJ, et al. Bridging anti-platelet therapy with the intravenous agent cangrelor in patients undergoing cardiac surgery. JAMA. 2012; 307(3):265-274. Firstenberg MS, Dyke CM, Angiolillo DJ, et al. Safety and efficacy of cangrelor, an intravenous, short-acting platelet inhibitor in patients requiring coronary artery bypass surgery. Heart Surg Forum. 2013.


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