BivaliRudin in Acute Myocardial Infarction vs. Glycoprotein IIb/IIIa and Heparin - BRIGHT

Description:

Although bivalirudin has been shown to be superior to heparin + glycoprotein (GP) IIb/IIIa use for bleeding endpoints in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), more recent data have raised concerns for increased stent thrombosis and no significant reduction in bleeding compared with heparin monotherapy. The current trial sought to compare outcomes with three different strategies for anticoagulation for patients undergoing PCI for ACS in China.

Hypothesis:

Bivalirudin would be superior to heparin monotherapy or heparin + tirofiban for the composite of ischemic and bleeding events in patients undergoing PCI for ACS.

Study Design

  • Randomized
  • Parallel

Patient Populations:

  • Age 18-80 years old
  • Plan to undergo PCI for ACS
  • No plan to perform nonculprit vessel PCI within 30 days of randomization
  • Appropriate use of antiplatelet therapy prior to PCI

    Number of enrollees: 2,194
    Duration of follow-up: 1 year
    Mean patient age: 58 years
    Percentage female: 18%

Exclusions:

  • Unsuitable for PCI, treatment by thrombolysis within 72 hours of acute STEMI, left main coronary artery disease, cardiogenic shock
  • Any anticoagulant agents were used 48 hours before randomization
  • Active bleeding or bleeding constitution, bleeding tendency, including recent retinal or vitreous hemorrhage (1 months), gastrointestinal or urinary tract hemorrhage (3 months), cerebral hemorrhage (6 months), or cerebral infarction history (3 months)
  • Secondary bleeding factors such as active gastric ulcer, active ulcerative colitis, intracranial aneurysm
  • Deep puncture or major surgery (including eye or brain surgery) within 1 month
  • Concern for aortic dissection, pericarditis, and subacute bacterial endocarditis
  • Untreated or uncontrolled hypertension >180/110 mm Hg
  • Hemoglobin <100 g/L or platelet count <100,000 cm3
  • Elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT) level higher than three times the normal upper limit
  • Severe renal insufficiency (estimated glomerular filtration rate <30 ml/min/1.73 m2)
  • Heparin-induced thrombocytopenia

Primary Endpoints:

  • NACE (MACCE + major bleeding) at 1 year

Secondary Endpoints:

  • MACCE at 1 year
  • Bleeding complications at 1 year

Drug/Procedures Used:

Patients were randomized in a 1:1:1 fashion to receive either bivalirudin alone, heparin alone, or heparin + tirofiban. Bivalirudin was administered as a 0.75 mg/kg bolus, with a 1.75 mg/kg/hr infusion (0.3 mg/kg bolus if activated clotting time [ACT] <225 seconds). Bailout GP IIb/IIIa use was permitted if necessary. The bivalirudin infusion was continued for at least 30 minutes post-PCI (median duration 234 minutes).

In the heparin monotherapy arm, heparin was given as an initial bolus of 100 U/kg with additional boluses as needed to keep the ACT >200. Bailout GP IIb/IIIa use was permitted. ACT goal was 250-300 seconds. In the heparin + tirofiban arm, heparin was administered as 60 U/kg bolus, and tirofiban as 10 μg/kg bolus, followed by 0.15 μg/kg/min infusion for 18-36 hours. The ACT goal was 200-250.

Principal Findings:

A total of 2,194 patients were randomized at 82 sites in China, 735 to bivalirudin, 729 to heparin monotherapy, and 730 to heparin + tirofiban. Baseline characteristics were fairly similar between the three arms. About 22% had diabetes mellitus, and the vast majority (89%) were patients presenting with ST-segment elevation myocardial infarction (STEMI) and undergoing primary PCI (median ischemic time, 6.9 hours; door-to-device time, 68 minutes). Bailout tirofiban use was noted in 5% of patients in the bivalirudin and heparin monotherapy arms. Nearly 79% patients underwent transradial access.

The composite 30-day net adverse clinical event (NACE) endpoint (major adverse cardiac and cerebrovascular event [MACCE] + bleeding) was lowest in the bivalirudin arm compared with the heparin monotherapy and heparin + tirofiban arms (8.8% vs. 13.2% vs. 17%, p < 0.001). This was driven predominantly by a reduction in the risk of Bleeding Academic Research Consortium (BARC) 3-5 (major) bleeding (0.5% vs. 1.5% vs. 2.1%, p = 0.04) and BARC 2-5 bleeding (1.2% vs. 3.6% vs. 5.1%, p < 0.001). Stent thrombosis rates at 30 days were similar (0.6% vs. 0.9% vs. 0.7%, p = 0.77). Similarly, at 1 year, NACE rates were lowest in the bivalirudin arm (12.8% vs. 16.5% vs. 20.5%, p < 0.001); MACCE rates were similar (6.7% vs. 7.3% vs. 6.8%, p = 0.9).

Interpretation:

The results of the BRIGHT trial indicate that the use of bivalirudin as choice of anticoagulant is superior to heparin monotherapy and heparin + tirofiban use in patients with ACS (predominantly STEMI) undergoing PCI. There was, however, no increase in the risk of stent thrombosis with bivalirudin monotherapy. It is important to note that more than three fourths of patients received transradial PCI, suggesting that the bleeding reduction was observed in nonaccess sites as well.

The use of bivalirudin during PCI has been a subject of much debate recently. The HEAT-PPCI trial results suggested that bivalirudin use during primary PCI was not associated with bleeding improvements compared with heparin monotherapy, but had a higher stent thrombosis risk. This was embellished in the results of a recent large meta-analysis as well. This trial adds to the controversy on this topic. One important point to note in this trial is that the heparin monotherapy arm received a 100 U/kg bolus, while the common clinically utilized dose is 70 U/kg. It is possible that the lower dose may have a better bleeding profile.

References:

Presented by Dr. Ya-Ling Han at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2014), Washington, DC, September 15, 2014.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Heart Failure and Cardiac Biomarkers, Interventions and ACS

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Heparin, Hirudins, Tyrosine, Platelet Membrane Glycoprotein IIb, Percutaneous Coronary Intervention, Stents, Thrombosis, Recombinant Proteins, Peptide Fragments, Diabetes Mellitus, Hot Temperature, Platelet Glycoprotein GPIIb-IIIa Complex, Transcatheter Cardiovascular Therapeutics


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