by Dominick J. Angiolillo, MD, PhD
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.
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
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
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
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
studys 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.
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
Angiolillo DJ. JAMA. 2012 (in press).
Brilakis ES. J Am Coll Cardiol.
Ferreiro JL. Expert Rev Cardiovasc
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.