Intravenous cangrelor may prove to be a useful "bridge" in patients awaiting nonemergency CABG who must first discontinue their regular antiplatelet therapy, according to the results of the Maintenance of Platelet Inhibition With Cangrelor (BRIDGE) trial reported in the Jan. 18 issue of JAMA.
The practice of discontinuation of antiplatelet therapy is associated with significant morbidity and mortality; in patients who have coronary stents, it raises the risk of stent thrombosis that often leads to myocardial infarction and death.
Dr. Dominick J. Angiolillo
"Cessation of thienopyridine treatment for nearly a week before surgery, with patients not hospitalized or monitored but carrying an excess risk of major ischemic events, has been a troubling and not infrequent problem for clinicians, because it is estimated that approximately 5% of patients will require some type of surgery within the first 12 months after stent implant or [acute coronary syndrome] diagnosis," said Dr. Dominick J. Angiolillo of the department of cardiology, University of Florida, Jacksonville, and his associates.
In this multicenter clinical trial sponsored by the drug’s maker, cangrelor "achieved and maintained target levels of platelet inhibition known to be associated with a low risk of thrombotic events compared with placebo, without a significant excess in bleeding complications," the investigators noted.
Cangrelor is an investigational nonthienopyridine adenosine triphosphate analogue that acts as an antagonist of the P2Y12 receptor. It is characterized by "rapid, potent, predictable, and reversible platelet inhibition," and its extremely short half-life (3-6 minutes) allows "rapid offset of effect."
The investigators hypothesized that cangrelor would allow patients who must discontinue antiplatelet therapy prior to cardiac surgery, especially if they’re taking a P2Y12 inhibitor such as ticlopidine, clopidogrel, or prasugrel, to go off their usual drug without raising their risk for thrombotic events. They tested this hypothesis in a two-part trial.
The first part was an open-label dose-finding study involving 11 adults, which concluded that the optimal intravenous dose needed to maintain antiplatelet activity without raising bleeding risks was 0.75 mcg/kg per minute.
In the second part of the trial, 210 patients awaiting CABG at 34 medical centers around the world were randomly assigned to receive either cangrelor (106 subjects) or placebo (104 subjects) after thienopyridines were discontinued and throughout the preoperative period – that is, until 1-6 hours before surgical incision. Platelet function was assessed before, during, and after the infusion.
The mean interval between discontinuation of thienopyridines and infusion of the study drug was 29 hours, and the mean duration of the infusion was approximately 3 days.
The primary end point was the percentage of patients who showed platelet reactivity of less than 240 P2Y12 Reaction Units (PRUs) throughout the infusion of the study drug. "This level approximated the levels of platelet reactivity expected to be maintained if a thienopyridine had not been discontinued," the investigators explained.
This end point was met by 99% of the cangrelor group but only 19% of the placebo group. It was achieved independently of patients’ usual dose of thienopyridines and independently of the length of time since thienopyridines were discontinued, Dr. Angiolillo and his colleagues said (JAMA 2012;307:265-74).
Moreover, cangrelor did not raise the rate of excessive bleeding related to CABG surgery. This safety end point occurred in 22 patients: 11.8% of the cangrelor group and 10.4% of the placebo group, a nonsignificant difference.
The number of minor bleeding events was numerically higher with cangrelor but did not reach statistical significance. Other adverse events, including dyspnea and laboratory abnormalities, also were comparable between the two groups. This favorable safety profile, even with prolonged infusion of up to 7 days, was "reassuring," the researchers noted.
Ischemic end points prior to surgery were low in both groups, occurring in 2.8% (3 of 106) and 4.0% (4 of 101) of patients in the cangrelor and placebo groups.
"These observations support the hypothesis that intravenous cangrelor is a feasible management strategy, providing prolonged platelet P2Y12 inhibition in patients who must wait for cardiac surgery after thienopyridine discontinuation," they said.
This study was sponsored by the Medicines Company. Dr. Angiolillo reported ties to Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, Evolva, and Abbott Vascular, and his associates reported ties to numerous other industry sources.