Maintenance of Platelet Inhibition With Cangrelor After Discontinuation of Thienopyridines in Patients Undergoing Surgery - BRIDGE

Description:

The goal of the trial was to evaluate treatment with cangrelor, an intravenous P2Y12 inhibitor (plasma half-life of 3-6 minutes), compared with placebo among patients required to stop thienopyridine therapy due to need for cardiac surgery.

Hypothesis:

Cangrelor will decrease platelet reactivity throughout the preoperative period.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Stratified

Patient Populations:

  • Patients at least 18 years of age on thienopyridine therapy (ticlopidine, clopidogrel, or prasugrel) due to an acute coronary syndrome or treatment with a stent (drug-eluting or bare-metal)
  • Elective CABG, which required termination of thienopyridine therapy

    Number of enrollees: 210
    Duration of follow-up: Through hospital discharge
    Mean patient age: 65 years
    Percentage female: 25%

Exclusions:

  • Urgent need for CABG
  • Pregnancy
  • Stroke in the last year
  • Intracranial neoplasm or intracranial surgery
  • Bleeding disorder or coagulopathy
  • Thrombocytopenia
  • International normalized ratio >1.5
  • Need for dialysis or estimated glomerular filtration rate <30 ml/min
  • Glycoprotein IIb/IIIa inhibitor use in the last 12-24 hours
  • Plans to continue oral anticoagulation, thienopyridine, or glycoprotein IIb/IIIa inhibitor in the preoperative period
  • Refusal to receive blood transfusion
  • Fibrinolytic therapy in the last 12 hours
  • High likelihood of being unavailable for follow-up
  • Participation in another clinical study

Primary Endpoints:

  • Primary efficacy endpoint defined as proportion of patients with PRU <240 throughout the preoperative period
  • Primary safety endpoint, excessive CABG-related bleeding defined as surgical re-exploration, 24-hour chest tube output >1.5 liters, or a red blood cell transfusion >4 units

Secondary Endpoints:

  • Preoperative MACE
  • Postoperative MACE

Drug/Procedures Used:

Patients with an acute coronary syndrome or treatment with a stent (bare-metal or drug-eluting), and awaiting coronary artery bypass grafting (CABG), were randomized to preoperative intravenous cangrelor (n = 106) versus intravenous placebo (n = 104).

After thienopyridine therapy was stopped, cangrelor was administered within 3 days, maintained for 2-7 days, and stopped 1-6 hours prior to CABG.

The dose of cangrelor, 0.75 µg/kg/min, was determined by an initial open-label dose-finding phase.

Principal Findings:

Overall, 210 patients were randomized. The mean age was 65 years, 25% were women, 46% had diabetes, mean body mass index was 29 kg/m2, 15% had ST-elevation myocardial infarction, and 32% had non-ST-elevation myocardial infarction.

In the cangrelor group, the median time from thienopyridine discontinuation to study drug administration was 29 hours, the median duration of study drug infusion was 2.8 days, and the median time from study drug discontinuation to surgical incision was 3.2 hours.

The primary outcome, proportion of patients with P2Y12 reactivity units (PRUs) <240 throughout the preoperative period, was 98.8% in the cangrelor group versus 19.0% in the placebo group (p < 0.0001). PRU was similar in the two groups immediately before CABG: 280 versus 298 (p = 0.21), respectively.

Pre-procedure major adverse cardiac events (MACE): 2.8% versus 4.0%, and post-procedure MACE: 3.9% versus 4.2%, respectively.

The primary safety outcome, excessive CABG-related bleeding, was 11.8% in the cangrelor group versus 10.4% in the placebo group (p = 0.76). Surgical re-exploration: 2.0% versus 2.1% (p = 0.95), 24-hour chest tube output >1.5 liters: 7.8% versus 5.2% (p = 0.46), red blood cell transfusion >4 units: 5.9% versus 8.3% (p = 0.50), preoperative major bleeding (ACUITY): 2.8% versus 1.0%, preoperative major bleeding (GUSTO): 0 versus 0, preoperative major bleeding (TIMI): 0.9% versus 0, respectively.

Interpretation:

Among patients with prior acute coronary syndrome or percutaneous coronary intervention (PCI) with a bare-metal stent or drug-eluting stent who required discontinuation of thienopyridine therapy prior to CABG, the preoperative use of cangrelor reduced high platelet reactivity. Excessive CABG bleeding was similar between the two groups. Although the study was not powered to detect a difference in ischemic events, pre/postoperative adverse events were similar between the groups.

Despite this bridging strategy, platelet reactivity returned to baseline immediately prior to CABG and would be expected to remain at that level until thienopyridine therapy could be resumed postoperatively. The time from the index acute coronary syndrome and/or PCI was not reported, nor was the proportion/generation of drug-eluting stent use; therefore, the true risk profile of the study patients is unknown. Further studies are needed to determine if such a strategy is effective at reducing perioperative adverse events among high-risk patients.

References:

Angiolillo DJ, Firstenberg MS, Price MJ, et al., on behalf of the BRIDGE Investigators. Bridging Antiplatelet Therapy With Cangrelor in Patients Undergoing Cardiac Surgery: A Randomized Controlled Trial. JAMA 2012;307:265-74.

Presented by Dr. Dominick Angiolillo at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2011), San Francisco, CA, November 9, 2011.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery, Interventions and ACS

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Erythrocyte Transfusion, Drug-Eluting Stents, Ticlopidine, Piperazines, Blood Platelets, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Body Mass Index, Chest Tubes, Cardiac Surgical Procedures, Coronary Artery Bypass, Diabetes Mellitus, Preoperative Period


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