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In patients who need to stop antiplatelet therapy in anticipation of coronary artery bypass graft (CABG) surgery, cangrelor can maintain levels of platelet inhibition associated with a low risk of thrombotic events without increasing CABG-related bleeding, according to results of the BRIDGE study published in the January 18, 2012, issue of the Journal of the American Medical Association. The findings suggest that cangrelor is a feasible management strategy for this common scenario.

The findings were initially presented in November 2011 at the annual Transcatheter Cardiovascular Therapeutics scientific symposium in San Francisco, CA.

For the prospective, randomized, double blind, multicenter trial, investigators led by Eric J. Topol, MD, of Scripps Translational Science Institute (La Jolla, CA), enrolled 210 patients with ACS or treated with a coronary stent (BMS or DES) who discontinued thienopyridine therapy and were awaiting CABG. After thienopyridine therapy was stopped, patients were randomized to cangrelor (n = 106) or placebo (n = 104) for between 48 hours and 7 days. Bridging therapy was discontinued 1 to 6 hours prior to surgery.

Effectiveness and Safety Demonstrated

A greater proportion of patients treated with intravenous cangrelor met the primary efficacy endpoint of a P2Y12 reaction unit (PRU) level, measured by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA), of less than 240 throughout the treatment period compared with those treated with placebo (98.8% vs. 19.0%; adjusted RR 5.2; 95% CI 3.3-8.0; P < 0.001). These reactivity levels were achieved regardless of prior thienopyridine dose and time of discontinuation (RR 4.3; 95% CI 2.8-6.6).

Rates of the main safety endpoint, study-defined excessive CABG-related bleeding, which occurred in 22 patients, were similar between the cangrelor and placebo groups (11.8% vs. 10.4%; RR 1.1; 95% CI 0.5-2.5; P = 0.763). In addition, there were no differences between the 2 groups in individual bleeding components, such as surgical re-exploration, transfusions of more than 4 units of packed red blood cells, and reoperation for bleeding. However, a nonsignificant increase in minor pre-CABG bleeding was seen with cangrelor.

Ischemic events were minimal in both cangrelor and placebo (2.8% vs. 4.0%) groups prior to surgery.

A ‘More Natural’ Strategy

According to Dr. Topol, a motivator for this study was the fact that there are currently no validated therapies for stented patients undergoing cardiac surgery. “There has never been a treatment to protect people from stent thrombosis in this setting, and it’s a very common clinical circumstance,” he told TCTMD in a telephone interview.

Dr. Topol and colleagues write that other approaches are currently used for this clinical scenario, such as intravenous heparin and glycoprotein IIb/IIIa inhibitors. However, they point out, these have significant drawbacks, such as minimal protection against stent thrombosis with anticoagulants and platelet reactivity enhancement with heparin, adding that cangrelor may be a “more natural bridging strategy because it selectively targets the P2Y12 receptor.”

In a telephone interview with TCTMD, Neal S. Kleiman, MD, of the Methodist DeBakey Heart and Vascular Center (Houston, TX), put the potential risk of increased bleeding with cangrelor in context.

“If you give somebody antiplatelet drugs versus none, they are going to be more likely to bleed,” he said. “The real question is if you do this in enough patients who are having enough serious operations, is that increment in minor bleeding going to be enough to be of clinical consequence or not?”

Dr. Topol agreed, noting that bleeding is always a concern with a “potent” drug like cangrelor but the lack of significance seen in this trial is “very encouraging.”

BRIDGE Strategy Far from Proven

While not discounting the implications of the BRIDGE trial, David P. Faxon, MD, of Harvard Medical School (Boston, MA), said that it is “way too premature” to conclude that cangrelor is the best bridging strategy available.

“We don’t actually have a [standard] bridging therapy for discontinuation of antiplatelet therapy before surgery,” he told TCTMD in a telephone interview. “This trial was a very important pilot trial. It doesn’t actually demonstrate that this is a strategy that’s useful in managing patients for cardiac surgery. What it demonstrated was that if you use cangrelor, you can maintain adequate platelet function inhibition during the interval period while somebody comes off clopidogrel.”

Drs. Topol and Faxon agreed that a larger, randomized trial is needed to conclusively confirm the efficacy and safety of cangrelor as the optimal bridging therapy for this patient group.

“I think [BRIDGE is] the right first step to a larger, major clinical trial,” Dr. Faxon said. “And if [cangrelor] is effective in a larger trial, it would be a great advance, and it would give us a great option for these patients.”

Dr. Kleiman added that the trial confirmed a commonly held hypothesis regarding cangrelor as an effective platelet inhibitor. “We assumed this was true. Now we know it’s true. The next step is to see what this means in practical and clinical terms,” he concluded.

Study Details

Cangrelor was administered to cohorts of 5 patients at a time in a step-wise fashion at predetermined doses (0.5 μg/kg, 0.75 μg/kg, 1.0 μg/kg, and 1.5 μg/kg per minute) until percent platelet inhibition as measured by VerifyNow was greater than 60% in 80% of daily samples or a dose of 2.0 μg/kg per minute was reached.

The treatment groups were similar in terms of baseline characteristics, though about 75% of the overall group were men. The average age was 65 years for the cangrelor group and 62 for the placebo group. In the cangrelor group, 15.1% of patients presented with STEMI and 32.1% with NSTEMI, whereas these percentages in the placebo group were 11.9% and 44.5%, respectively. The remaining patients were enrolled in a nonacute setting. CABG was performed in 96% of patients in the cangrelor group and 95% of patients in the placebo group.

Related Stories:

• BRIDGE: Cangrelor Provides Effective Maintenance of Platelet Inhibition Without Major Bleeding
• Meta-analysis: New P2Y12 Antagonists Show Mortality Benefit vs. Clopidogrel