Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial

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 to 7 days prior to surgery to minimize bleeding.

Objective: To evaluate the use of cangrelor, an intravenous, reversible P2Y(12) platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG) surgery.

Design, setting, and patients: Prospective, randomized, double-blind, placebo-controlled, multicenter trial, involving 210 patients with an acute coronary syndrome (ACS) or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery 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 were administered cangrelor or placebo for at least 48 hours, which was discontinued 1 to 6 hours before CABG surgery.

Main outcome measures: The primary efficacy end point was platelet reactivity (measured in P2Y(12) reaction units [PRUs]), assessed daily. The main safety end point was excessive CABG surgery-related bleeding.

Results: The dose of cangrelor determined in 10 patients in the open-label stage was 0.75 μg/kg per minute. 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 end point, PRU <240; 98.8% (83 of 84) vs 19.0% (16 of 84); relative risk [RR], 5.2 [95% CI, 3.3-8.1] P < .001). Excessive CABG surgery-related bleeding occurred in 11.8% (12 of 102) vs 10.4% (10 of 96) in the cangrelor and placebo groups, respectively (RR, 1.1 [95% CI, 0.5-2.5] P = .763). There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor.

Conclusions: Among patients who discontinue thienopyridine therapy prior to cardiac surgery, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition.

Trial registration: clinicaltrials.gov Identifier: NCT00767507.

Figure 1. BRIDGE CONSORT diagram

CABG indicates coronary artery bypass grafting. ITT indicates intention to treat

Figure 2. Distribution of platelet reactivity during the overall study time course

Platelet reactivity as assessed by PRU using the VerifyNow P2Y12 assay during the study time course (at baseline and up to 7 days of study drug infusion) (Figure 2A) and at last on-infusion sample and prior to CABG (Figure 2B). Data are presented as mean and standard deviations. Blue box: cangrelor. Red circle: placebo. PRU indicates P2Y12 Reactivity Units. N indicates number of patients with valid samples in the intention to treat population. CABG indicates coronary artery bypass grafting.