Novel Approaches in Preventing or Limiting Events III | Clinical Trial - NAPLES III

Description:

Bivalirudin has been shown to be superior to unfractionated heparin (UFH) for anticoagulation in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). The current trial sought to compare outcomes between UFH and bivalirudin in patients undergoing elective PCI via the femoral approach, and who were at high-risk for bleeding.

Contribution to the Literature: In mostly elective patients undergoing PCI via the transfemoral approach, UFH had similar ischemic and bleeding event rates as bivalirudin.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age ≥18 years
  • Bleeding risk score ≥10
  • Procedure planned through the femoral approach
  • Angiographic evidence of de novo or restenotic lesions requiring revascularization
  • Stable or unstable angina or documented silent ischemia
  • Negative biomarkers of myocardial injury
  • Double antiplatelet therapy
  • Stable hemodynamic conditions
  • Number screened: 1,859
  • Number of enrollees: 837
  • Duration of follow-up: In-hospital
  • Mean patient age: 78 years
  • Percentage female: 48%
  • Left ventricular ejection fraction: 50%

Exclusions:

  • Bleeding risk score <10
  • Pregnancy
  • Ongoing or recent (<48 hours) episode of ST-segment elevation MI (STEMI) or non-STEMI
  • Negative biomarkers of myocardial injury
  • Chronic dialysis and/or history or previous dialysis
  • Hemodynamic instability requiring inotropic support or intra-aortic balloon pump
  • Ongoing or recent (<7 days) treatment with GP IIb/IIIa inhibitors
  • Ongoing or recent (6 months) bleeding or bleeding diathesis
  • Recent (within 6 months) stroke
  • History of heparin-induced thrombocytopenia
  • Platelet count <100.000/mm3

Primary Endpoints:

  • Rate of in-hospital major bleeding, defined according the REPLACE 2 criteria:
    - intracranial,
    - intraocular,
    - retroperitoneal,
    - access-site hemorrhage requiring intervention,
    - clinically overt blood loss resulting in a decrease in hemoglobin by ≥3 g/dl,
    - any decrease in hemoglobin ≥4 g/dl,
    - transfusion of ≥2 U packed cells or whole blood

Secondary Endpoints:

  • Rate of in-hospital major and minor bleeding, defined according the REPLACE 2 criteria
  • Rate of in-hospital, 30-day, and 1-year MACE, defined as death, nonfatal MI, repeat revascularization
  • Rate of stent thrombosis, according to the Academic Research Consortium criteria
  • Rate of major bleeding according to other criteria

Drug/Procedures Used:

Patients with a bleeding risk score ≥10 (>5% absolute risk of bleeding) were randomized to receive either UFH or bivalirudin as the anticoagulant of choice during elective PCI. UFH was administered as a bolus dose of 70 U/kg prior to the start of the procedure, with additional boluses of 20 U/kg in case the activated clotting time (ACT) was <250.

Bivalirudin was administered as a bolus of 0.75 mg/kg i.v. prior to the start of the procedure, followed by infusion of 1.75 mg/kg/hr for the duration of the procedure. An additional bolus 0.3 mg/kg was administered in case the ACT was <250 seconds.

Concomitant Medications:

Glycoprotein (GP) IIb/IIIa inhibitors (1%). Clopidogrel was the thienopyridine of choice in all patients.

Principal Findings:

A total of 837 patients were randomized, 418 to bivalirudin and 419 to UFH. Baseline characteristics were similar between the two arms. There was minimal cross-over to the radial approach (0.5%) and use of glycoprotein (GP) IIb/IIIa inhibitors (1%). The baseline body mass index was 28 kg/m2, with prior myocardial infarction (MI) in 40%, prior PCI in 35%, and prior coronary artery bypass grafting (CABG) in 13%. The mean glomerular filtration rate (GFR) was 65, with 45% having a GFR value <60. Approximately 45% had diabetes mellitus, and approximately 69% were undergoing PCI for stable angina and 23% for unstable angina. The majority of patients had two-vessel disease (34%) or three-vessel disease (45%).

A drug-eluting stent was implanted in nearly 83% of patients, with mitral valve stenting in 24%; rotational atherectomy was necessary in 7% of patients. The mean right ventricular diameter was 3.06 mm and had a lesion length of 17.5 mm. A mean number of 1.3 stents was implanted per patient, with a mean stent length of 29.5 mm.

The primary endpoint of in-hospital bleeding was similar between the bivalirudin and UFH arms (3.3% vs. 2.6%, p = 0.54). Access-site bleeding requiring intervention was numerically higher in the bivalirudin arm (1.7% vs. 0.5%, p = 0.1), whereas clinically overt bleeding with a hemoglobin drop >3 g/dl was lower (0.2% vs. 1.4%). Major bleeding was reclassified with different definitions, with similar results: BARC (4.1% vs. 2.6%, p = 0.24), TIMI (0.5% vs. 0.7%, p = 0.65), GUSTO (0.7% vs. 1.2%, p = 0.72). Periprocedural MI was also similar (21.8% vs. 21.5%, p = 0.93).

Clinical endpoints at 30 days were similar: death (2.4% vs. 1.4%), MI (0.2% vs. 0%), stent thrombosis (0.5% vs. 0.5%, p = 0.99), major bleeding (3.3% vs. 2.6%, p = 0.58). Similarly, outcomes at 1 year were similar: death (4.8% vs. 5.0%, p = 1.0), stent thrombosis (1% vs. 0.7%, p = 0.71).

Interpretation:

The results of the NAPLES III trial indicate that in patients at an elevated risk of bleeding (>5% absolute risk) who undergo transfemoral PCI for mostly elective reasons, periprocedural bleeding rates were similar after anticoagulation with UFH (without concomitant GP IIb/IIIa inhibitor use) and bivalirudin. Ischemic complications including periprocedural MI and stent thrombosis rates are also similar.

Bivalirudin has been shown to be superior to UFH + GP IIb/IIIa inhibitor use in reducing bleeding complications in the REPLACE 2, ACUITY, and HORIZONS-AMI trials. A few mostly older trials have compared bivalirudin directly to UFH. These include BAS/BAT, REPLACE 1, ISAR-REACT 3, and ARNO. The majority of these have demonstrated a persistent bleeding reduction with bivalirudin, although the dose of UFH used in these trials was very high; for example, 140 U/kg in the ISAR-REACT 3 trial. In the NAPLES III trial, the dose was reduced to 70 U/kg (which is the commonly used dose currently).

These findings are interesting, and could impact clinical practice. It is also unclear if these findings will persist in patients undergoing transradial PCI. Additional cost-benefit analyses are awaited.

References:

Briguori C, Visconti G, Focaccio A, et al. Novel Approaches for Preventing or Limiting Events (Naples) III Trial: Randomized Comparison of Bivalirudin Versus Unfractionated Heparin in Patients at Increased Risk of Bleeding Undergoing Transfemoral Elective Coronary Stenting. JACC Cardiovasc Interv 2015;8:414-23.

Presented by Dr. Carlo Briguori at the American College of Cardiology Scientific Session, Washington, DC, March 29, 2014.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Heart Failure and Cardiac Biomarkers, Interventions and ACS, Chronic Angina

Keywords: Follow-Up Studies, Atherectomy, Coronary, Angina, Stable, Thienopyridines, Hemoglobins, Thrombosis, Stroke Volume, Confidence Intervals, Mitral Valve, Platelet Glycoprotein GPIIb-IIIa Complex, Odds Ratio, Myocardial Infarction, Cost-Benefit Analysis, Acute Coronary Syndrome, Drug-Eluting Stents, Human Rights, Heparin, Hirudins, Platelet Membrane Glycoprotein IIb, Body Mass Index, Recombinant Proteins, Peptide Fragments, Glomerular Filtration Rate, Coronary Artery Bypass, Diabetes Mellitus, ACC Annual Scientific Session


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