TCT: Cangrelor may fill unmet need for some patients undergoing surgery
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SAN FRANCISCO—When used as a bridging strategy to CABG after thienopyridine discontinuation, cangrelor achieves levels of platelet inhibition known to be associated with a low risk of thrombotic events, without increased risk of bleeding before or during CABG, according to the BRIDGE late-breaking clinical trial presented Nov. 9 at the 23rd annual Transcatheter Cardiovascular Therapeutics (TCT) conference.

Thienopyridines use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines five to seven days prior to surgery to minimize bleeding. However, during the press conference, the moderator Ajay J. Kirtane, MD, of New York-Presbyterian Hospital in New York City, noted that there are indications that surgeons will recommend the discontinuation of the medication as much as 10 days in advance.

Surgery is frequent in patients presenting with acute coronary syndrome (ACS) or treated with stents, with 10 to 15 percent of patients presenting with ACS having to undergo CABG and 5 to 25 percent of patients having to undergo non-cardiac surgery, the study’s lead author Dominick J. Angiolillo, MD, PhD, director of cardiovascular research at the University of Florida College of Medicine in Jacksonville, said during a press conference.

There are pros and cons with the decision to continue or stop theinopyridine use through surgery, according to Angiolillo. Continuation puts patients at about 35 percent incidence of bleeding, and bleeding and transfusion are associated with increased risk of mortality. However, preoperative discontinuation of anti-platelet therapy is associated with an approximate 20 percent incidence of ischemic events.

"No proven and efficacious alternative solution for bridging to surgery is currently available,” he added.

In the BRIDGE trial, researchers sought to determine whether the investigational drug cangrelor could be used as a “bridge” between discontinuing thienopyridines and surgery.

BRIDGE is a prospective, randomized double-blind, placebo-controlled, multicenter trial in 210 patients with ACS or treated with a coronary stent (either bare-metal stent or drug-eluting stent) on a thienopyridine awaiting CABG to receive either cangrelor or placebo after an initial open-label, dose-finding phase.

After thienopyridine discontinuation (less than 72 hours), 210 patients were administered cangrelor or placebo for at least 48 hours and up to seven days, which was discontinued one to six hours prior to CABG. The dose of cangrelor determined in the open-label stage was 0.75 µg/kg/min.

The objective was to demonstrate that cangrelor would maintain levels of platelet reactivity <240 P2Y12 Reaction Units (PRU) throughout the pre-operative period as measured by the VerifyNow P2Y12 test (Accumetrics).

In the randomized phase, Angiolillo reported that a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo, with the PRU primary endpoint of <240 at 98.8 percent vs. 19 percent. Excessive CABG-related bleeding occurred in 11.8 percent vs. 10.4 percent in the cangrelor and placebo groups, respectively.

There were no significant differences in major bleeding prior to CABG, although minor bleeding was numerically higher with cangrelor, according to Angiolillo. Also, there was no increased incidence of adverse events (e.g. dyspnea) or laboratory abnormalities despite extended dosing.

The findings indicate that in patients on thienopyridines who undergo cardiac surgery, “cangrelor provides effective maintenance of platelet inhibition with no apparent increase in major bleeding, despite numerically higher rates of minor bleeding prior to surgery, which were mostly attributed to ecchymosis at the site of venipuncture,” he concluded. “Larger patient samples are needed to more definitively assert the safety and effectiveness of cangrelor bridging therapy to surgery.”

The press conference panelists, after listening to the results expressed excitement this drug’s potential in this patient population. “Based on these results, this drug may provide a great alternative to fill the gap of those post-PCI patients who are forced to stop DAPT due to a planned surgical procedure, which is a tremendous unmet [need],” according to Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Weiner Cardiovascular Institute at Mount Sinai School of Medicine in New York City.

In fact, Kirtane referenced a recent survey in which 50 percent of interventional cardiologists felt a bridge treatment was needed.

Cangrelor is an investigational IV antiplatelet agent, manufactured by The Medicines Company, which funded the BRIDGE trial.