November 10, 2011

November 9, 2011 (San Francisco, California) — A continuous infusion of cangrelor, an investigational P2Y12 platelet inhibitor, allowed patients with acute coronary syndromes or coronary stents to go off oral dual-antiplatelet therapy safely in advance of CABG surgery in a modest-sized placebo-controlled phase 2 study.

In the Maintenance of Platelet Inhibition with Cangrelor after Discontinuation of Thienopyridines in Patients Undergoing Surgery (BRIDGE) study, cangrelor (the Medicines Company) given IV after withdrawal of oral thienopyridines kept platelet reactivity at levels that seemed to keep the risks of major bleeding and ischemic complications down in the week leading up to surgery. But the short-acting agent's antiplatelet effects fell off quickly, allowing safe surgery, once the infusion was withdrawn.

Cangrelor wasn't associated with the dyspnea or hepatic-enzyme abnormalities sometimes seen with antithrombotics; it did seem to slightly increase the risk of minor bleeding, although the effect wasn't significant in the 210-patient trial, Dr Dominick Angiolillo (University of Florida College of Medicine, Jacksonville) told heartwire . He presented the BRIDGE results today at here at TCT 2011.

The antiplatelet effects of available oral thienopyridines take several days to a week to fall off adequately for the patient to have surgery without an untoward risk of bleeding, but in the meantime patients are exposed to an increased risk of thrombotic events, Angiolillo observed.

"This is the first time we have a trial assessing, in a prospective, randomized, double-blind fashion, the use of a novel [antiplatelet] agent that has the ideal properties for bridging. And the trial clearly shows that we are able to achieve and sustain adequate levels of P2Y12 inhibition during the preoperative stage, with overall favorable safety signals." Angiolillo cautioned that BRIDGE was powered for assessing platelet reactivity and safety, not hard clinical outcomes, so cangrelor's usefulness in weaning patients off oral thienopyridines before CABG requires further study in larger trials.

A two-hour infusion of cangrelor had previously been compared with an oral loading dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in patients with planned PCI who for the most part had ACS. In neither the CHAMPION-PCI and CHAMPION-PLATFORM trials, as reported by heartwire , was there a difference between the two agents in a primary end point of death, MI, or ischemic-driven revascularization within 48 hours of the procedure.

But as an IV drug, cangrelor had been envisioned all along for the niche application explored in BRIDGE. Currently, cangrelor's primary description on the Medicine Company's website is "an investigational antiplatelet agent undergoing testing to enable safe bridging of patients undergoing surgery" [1].

In the trial, 210 patients with ACS or coronary stents on ticlopidine, clopidogrel, or prasugrel (Effient, Lilly/Daiichi) awaiting CABG were randomized to receive continuous infusions of cangrelor or placebo. The trial was conducted at 125 centers in the US, 55 in the Czech Republic, 12 in the UK, 11 in the Netherlands, and seven in Austria.

Within 72 hours of going off the oral antiplatelets, patients went on either cangrelor or placebo for at least 48 hours, and the infusion was withdrawn one to six hours before CABG. Platelet function was monitored using the VerifyNow P2Y12 assay (Accumetrics). Cangrelor was given at 0.75 µg/kg/min, a rate selected based on a preceding open-label dose-ranging phase.

Significantly more patients on cangrelor than placebo had low levels of platelet reactivity throughout the entire infusion, according to Angiolillo. Mean reactivity levels were comparable at baseline and after infusion withdrawal, but significantly reduced in the cangrelor patients during infusion. The rate of achieving platelet reactivity units (PRU) <240 on the VerifyNow assay during the infusion, the study's primary end point, was 98.8% for cangrelor and 19.0% among controls (p<0.0001).

Platelet Reactivity at Baseline and During and After Randomized Infusion, in PRU on the VerifyNow System

End point: Mean PRU Cangrelor, n=93 Placebo, n=90 p
Baseline 210.9 214.1 0.817
During infusion 68.9 263.7 <0.001
After end of infusion 279.7 297.8 0.212

PRU=platelet reactivity units on the VerifyNow assay.

The primary safety end point, excessive CABG-related bleeding during the procedure or subsequent hospitalization, didn't differ significantly between the two groups (p=0.763).

Excessive CABG-Related Bleeding (During the Procedure or After Until Discharge), the Primary Safety End Point

End point* Cangrelor, n=106 (%) Placebo, n=101, (%) OR (95% CI)
Total CABG-related bleeding 11.8 10.4 1.15 (0.47–2.79)
Surgical reexploration 2.0 2.1 0.94 (0.13–6.81)
24-hour chest-tube output >1.5 L 7.8 5.2 1.55 (0.49–4.91)
Incidence of packed RBCs >4 U 5.9 8.3 0.69 (0.23–2.06)

*Defined as occurrence of one or more of the following events during CABG or the postoperative hospitalization: Surgical reexploration, 24-hour chest-tube output >1.5 L, packed RBC transfusion >4 units)

There was a "numerical increase" in minor bleeding complications (about 18% vs 10%) among cangrelor recipients, "which were mostly attributable to ecchymoses at the site of venous puncture," according to Angiolillo. "We need to consider that these patients were on prolonged infusions of the drug, so minor bleeding at the site of venous puncture, I would say, would be expected."

Incidence of Ischemic Events (%) Preprocedure (From Randomization to Surgery) and Postsurgery (Out to 30 Days)

Endpoint Cangrelor presurgery Placebo presurgery Cangrelor postsurgery Placebo postsurgery
Death/MI/ ischemia-driven revascularization/stroke 2.8 4.0 3.9 4.2
Death 0.9 3.0 1.0 2.1
MI 1.9 0 2.0 1.0
Ischemia-driven revascularization 0.9 0 2.5 0

Rates of ischemic events from randomization to the postsurgical period were not significantly different. And the patient groups were comparable with respect to CABG procedural details, including number of grafts and prevalence of arterial conduits used, Angiolillo said.

"Five to twenty-five percent of patients who have been treated with a stent will need some form of surgery," and for them, he noted, cangrelor might ultimately prove a good option for minimizing risk as they go off oral thienopyridines.

Angiolillo discloses receiving honoraria for lectures from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, and Daiichi Sankyo; honoraria for consulting/advisory board membership from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, the Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Evolva, and Abbott Vascular; and research grants (paid to his institution) from GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly, Daiichi Sankyo, the Medicines Company, Portola Pharmaceuticals, Schering-Plough, AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, and Sanofi-Aventis.

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