Bridging Antiplatelet Therapy With Cangrelor in Patients Undergoing Cardiac Surgery

Abstract

Context Thienopyridines are among the most widely prescribed medications, but their use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines 5–7 days prior to surgery to minimize bleeding. Objective To evaluate the use of cangrelor, an intravenous, reversible P2Y12 platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG). Design, Setting, and Patients Prospective, randomized double-blind, placebo-controlled, multicenter trial, in patients (n=210) with an acute coronary syndrome (ACS) or treated with a coronary stent on a thienopyridine awaiting CABG to receive either cangrelor or placebo after an initial open-label, dose-finding phase (n=11) conducted between January 2009 and April 2011. Interventions Thienopyridines were stopped and patients administered cangrelor or placebo for at least 48 hours, which was discontinued 1–6 hours prior to CABG. Main outcome measures The primary efficacy endpoint was platelet reactivity (measured in P2Y12 Reaction Units [PRU]), assessed daily with the VerifyNow™ P2Y12 assay. The main safety endpoint was excessive CABG-related bleeding. Results The dose of cangrelor determined in the open-label stage was 0.75 µg/kg/min. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary endpoint, PRU<240: 98.8% (83/84) vs. 19.0% (16/84); relative risk [RR]: 5.2, 95% confidence interval [CI]:3.3–8.1, p<0.001). Excessive CABG-related bleeding occurred in 11.8% (12/102) vs. 10.4% (10/96) in the cangrelor and placebo groups, respectively (RR=1.1, 95% CI: 0.5–2.5, p=0.763). There were no significant differences in major bleeding prior to CABG, although minor bleeding was numerically higher with cangrelor. Conclusions Among patients who must wait for cardiac surgery after thienopyridine discontinuation, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition.

Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and Beyond

“…The excess dyspnea rates after cangrelor were reported in all 4 randomized trials (BRIDGE [22], CHAMPION-PCI [23], CHAMPION-PLATFORM [24], and finally the largest, CHAMPION-PHOENIX [11]). Each trial consistently revealed two- to three-fold excess rates of dyspnea after cangrelor when compared to placebo, or background clopidogrel.…”

Management of Antiplatelet Therapy in Patients With Coronary Artery Disease Requiring Cardiac and Noncardiac Surgery

“…Importantly, bridging with a prolonged infusion of cangrelor did not increase major bleeding before surgery, although minor bleedings, largely attributed to ecchymosis at the site of venous puncture, were more commonly documented with cangrelor. 106 The BRIDGE trial therefore supports the hypothesis that bridging with intravenous cangrelor may be a successful strategy to provide adequate platelet P2Y 12 inhibition after thienopyridine discontinuation in patients referred to cardiac surgery. Although this approach has the potential to also be valid in noncardiac surgery, this possibility has still to be proven, given that different noncardiac operations have variable bleeding risk.…”

“…This hypothesis has been recently tested in the phase II prospective, randomized, double-blind Maintenance of Platelet inhibition With cangrelor After discontinuation of Thienopyridines in Patients Undergoing surgery (BRIDGE) trial, in which 210 patients with an ACS or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery were randomly assigned to receive either cangrelor (0.75 μg·kg -1 min -1 ) or placebo for at least 48 hours. 106 The study drug was discontinued 1 to 6 hours before CABG surgery. Aspirin therapy was maintained throughout perioperative period.…”

“…Cangrelor is still not approved for clinical use, but may become a treatment option in the future. The dosing regimen and bridging scheme should reflect how cangrelor was tested in the BRIDGE trial, 106 in which a tailored dose to achieve "thienopyridine-like" platelet inhibition (0.75 μg·kg -1 ·min -1 ) was identified. In particular, this dose was one-fifth of that used in the PCI trial 110 and without a loading bolus.…”

To Pretreat or Not to Pretreat (With Oral P2Y12 Antagonists)? That is the Question

“…For example, platelet inhibition with clopidogrel is irreversible and platelet reactivity is only regained with regeneration of new platelets, which occurs at a rate of ≈10% to 15% per day 16. Conversely, given its very short half‐life, cangrelor can safely be administered up to 1 to 6 hours pre‐CABG without an increase in bleeding, compared with placebo therapy,17 and offers an alternative P2Y12 treatment strategy that avoids the issues of pretreatment with an oral agent.…”