Cardiology

Dual antiplatelet therapy with aspirin and an oral P2Y12 receptor inhibitor is the standard of care to prevent the recurrent atherothrombotic events in patients with ACS and those undergoing PCI. However, this occurs at the expense of an increased risk for bleeding, particularly in patients undergoing surgical procedures. For this reason, discontinuation of antiplatelet therapy for a time frame that allows recovery of platelet function is needed to minimize bleeding risk.

The public was made acutely aware of these issues in 2004 when former President Bill Clinton presented with unstable angina that required bypass surgery, but had to wait 6 days before surgery was performed because he had received a dose of a thienopyridine. However, premature discontinuation of antiplatelet therapy in these patients increases the risk for ischemic complications. These have been concerns, particularly in patients treated with drug-eluting stents in whom stent thrombosis occurring as a consequence of premature antiplatelet treatment discontinuation is associated with elevated morbidity and mortality. These considerations underscore the importance of identifying strategies of platelet inhibition that allow to safely “bridge” patients to their surgical procedure with minimal risk for ischemic events or bleeding complications.

Pharmaceutical Approaches

Various approaches using currently available IV antithrombotic drugs, such as heparin and glycoprotein IIb/IIIa inhibitors, have been considered for bridging therapy. However, these are associated with several limitations. Anticoagulants do not reduce the incidence of stent thrombosis, and heparin can actually increase platelet reactivity. Although glycoprotein IIb/IIIa inhibitors such as eptifibatide (Integrilin, Millennium/Schering) and tirofiban (Aggrastat, Merck) have potent and rapid onset of action, they require 4 to 6 hours to return to baseline platelet function. Further, these agents do not inhibit the P2Y12 receptor; they are used at dosing regimens recommended for ACS treatment and prolonged infusions can be associated with increased bleeding.

	Dominick J. Angiolillo

Cangrelor (The Medicines Company) is an IV investigational nonthienopyridine adenosine triphosphate analogue that inhibits the P2Y12 receptor and is characterized by rapid, potent, predictable and reversible platelet inhibition with very quick offset of effect. Therefore, this compound possesses desirable pharmacodynamic properties to be considered for bridging patients to surgery in whom discontinuation of antiplatelet therapy, particularly a P2Y12 receptor inhibitor, can lead to catastrophic consequences (eg, stent thrombosis), while preserving hemostasis at the time of surgery.

The BRIDGE Trial

Cangrelor was tested in the Maintenance of Platelet Inhibition with Cangrelor (BRIDGE) trial, which looked at patients who underwent surgery after discontinuation of thienopyridines and assessed the use of cangrelor for bridging patients with ACS or treated with a coronary stent on a thienopyridine awaiting CABG.

The BRIDGE trial consisted of two stages: Stage I was an open-label, dose-finding phase of the study aimed to identify the dose of cangrelor that achieved a desired antiplatelet effect after thienopyridine discontinuation, which was found to be 0.75 mcg/kg/min; and stage II was a multinational, prospective, randomized, double blind, placebo-controlled phase of the study aimed to demonstrate that a cangrelor IV infusion (at the dose determined in stage I) would maintain levels of platelet reactivity less than 240 P2Y12 Reaction Units (PRU) throughout the preoperative period as measured by a P2Y12 assay (VerifyNow, Accumetics). This level approximated the levels of platelet reactivity expected to be maintained if a thienopyridine had not been discontinued.

BRIDGE randomly assigned 210 patients to receive either cangrelor or placebo. Thienopyridines were stopped and patients were administered cangrelor or placebo for at least 48 hours and up to 7 days, which was discontinued 1 to 6 hours prior to CABG. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity, the study’s primary endpoint defined as a PRU less than 240, throughout the entire treatment period compared with placebo (98.8% vs. 19%; P,.001).

The rapid recovery of platelet function after discontinuing cangrelor infusion is shown by the similar levels of platelet inhibition compared with placebo before CABG and is consistent with the very short half-life of cangrelor (3-6 minutes). In turn, there was no excess in CABG-related bleeding with cangrelor, which occurred in 11.8% of patients in the cangrelor group vs. 10.4% of those in the placebo group (P=.763). There were also no significant differences in major bleeding before CABG, although minor bleeding was numerically higher with cangrelor, mainly attributed to ecchymosis at the site of venipuncture, which occurred daily.

In addition, there was no increased incidence of non-bleeding adverse events (including dyspnea) or laboratory abnormalities despite extended dosing. These observations support the hypothesis that cangrelor can safely provide consistent P2Y12 receptor inhibition during prolonged infusion in patients who must wait for cardiac surgery after thienopyridine discontinuation.

Conclusion

In summary, identifying antiplatelet treatment strategies that can safely and effectively bridge patients needing P2Y12 platelet inhibitors, such as those presenting with ACS or treated with stents, to surgery is an important unmet clinical need. In the BRIDGE trial, IV cangrelor consistently achieved and maintained target levels of platelet inhibition known to be associated with a low risk for thrombotic events compared with placebo, without any significant excess in bleeding complications in patients undergoing CABG. These findings support the hypothesis that IV cangrelor is a feasible management strategy in patients awaiting cardiac surgery who require prolonged P2Y12 platelet inhibition after thienopyridine discontinuation, making this a promising strategy to be further investigated for bridging patients to surgery, including non-cardiac surgery.

References:

• Angiolillo DJ. JAMA. 2012 (in press).

• Brilakis ES. J Am Coll Cardiol. 2007;49:2145-2150.

• Ferreiro JL. Expert Rev Cardiovasc Ther. 2009;7:1195-1201.

Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI, is the director of cardiovascular research and associate professor of medicine at the University of Florida College of Medicine-Jacksonville, and is on the Cardiology Today Intervention Editorial Board.

Disclosure: Dr. Angiolillo reports receiving honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo and Sanofi-Aventis; consulting fees from Abbott Vascular, Accumetrics, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Medicure, Novartis, Portola, Sanofi-Aventis and The Medicines Company; and research grants from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Otsuka, Portola, Sanofi-Aventis, Schering-Plough and The Medicines Company.