A study published in the Journal of the American Medical Association (JAMA) shows that the novel drug cangrelor (The Medicines Company) is associated with a higher rate of platelet inhibition, compared with placebo, in patients who have discontinued thienopyridine therapy prior to cardiac surgery.
Lead investigator Eric Topol, Scripps Translational Science Institute, La Jolla, California, USA, and his co-authors (for the BRIDGE trial investigators) report in the JAMA paper that although thienopyridines are used to reduce the risk of thrombosis in high-risk patients (ie, those with acute coronary syndrome and those undergoing percutaneous coronary intervention), their use is discontinued in such patients five to seven days prior to surgery to reduce the risk of bleeding.
However, according to Topol et al, discontinuing thienopyridine therapy in this setting is associated with an increased risk of ischaemic complications – particularly in patients with drug-eluting stents. Topol et al wrote: “These findings underscore the need to define strategies of platelet inhibition that allow to safely ‘bridge’ patients to their surgical procedure with minimum risk of ischaemic events or bleeding.”
Therefore, the aim of the BRIDGE study was to determine if cangrelor (a non-thienopyridine adenosine triphosphate analogue) was a safe and effective treatment to “bridge” patients from irreversible P2Y12 inhibitors to open heart surgery.
In the first part (an open-label stage) of the two-part study, Topol et al found that 0.75ug/kg per minute was the optimum dose to investigate the drug’s effects for maintaining platelet inhibition. Therefore, in the second part, prior to having coronary artery bypass grafting (CAB) surgery and after thienopyridine therapy was discontinued, 210 patients were randomised to receive 0.75ug/kg per minute cangrelor (106) or placebo (104) for at least 48 hours (which was then discontinued one to six hours before CABG surgery). As the first 24 patients had to be excluded from the efficacy analyses because of the unblinding requirement of the DSM, the intention-to-treat efficacy population consisted of 183 patients (93 in the cangrelor group and 90 in the placebo group). The percentage of patients with platelet reactivity of less than 240 P2Y12 reactive units (PRUs), which indicates a low risk of thrombotic events, throughout the infusion of the study drug was higher in the cangrelor group compared with the placebo group (thus meeting the primary endpoint): 98.8% vs. 19% (p<.001). Also, the percentage of overall samples displaying platelet reactivity less than 240 PRU, patients with all samples with baseline PRU valve, and total patient samples that maintained higher than 60% platelet inhibition during study drug infusion were all higher in the cangrelor group than in the placebo group (all P<.001). After the study drugs were discontinued, the active treatment group and placebo group had similar PRU levels and similar percentages of patients with platelet reactivity lower than 240PRU.
As well as meeting the study’s efficacy endpoint, cangrelor also met the safety endpoint: there were no significant differences between the cangrelor group and the placebo group in the number of excessive CABG-surgery related bleeding events (11.8 vs. 10.4%) and there were no significant differences in Bleeding Academic Research Consortium (BARC) defined CABG-surgery related bleeding occurring during surgery until patient discharge (9.8% vs. 10.4%).
However, there were numerical more (but not significantly more) minor bleeding events in the cangrelor group.
About their observations, Topol et al wrote: “These observations support the hypothesis that intravenous cangrelor is a feasible management strategy, providing prolonged P2Y12 inhibition in patients who must wait for cardiac surgery after thienopyridine discontinuation.”
They added that various approaches have already been used as bridging strategies, but these have been problematic. For example antithrombotic therapies such as heparin and glycoprotein IIb/IIa inhibitors, have been proposed, but anticoagulants do not reduce the incidence of stent thrombosis and heparin can enhance platelet reactivity. They concluded: “Ultimately, cangrelor may represent a more natural bridging strategy because it selectively targets the P2Y12 receptor.
Although the drug is not yet commercially available, it has been extensively studied in large-scale trials of patients with coronary artery disease.”
Topol told Cardiovascular News: “The patients who would benefit most from this strategy are those with a recent stent and high-risk anatomy – either due to a major territory supplied by the stented artery or decreased left ventricular function.”