Novel Approaches in Preventing and Limiting Events III Trial (NAPLES III): Bivalirudin in High-risk Bleeding Patients

Bleeding occurring during percutaneous coronary interventions (PCI has now emerged as one of the most common complication of PCI and adversely affect in-hospital, short- and long-term outcome.As bivalirudin proved its effectiveness in decreasing haemorrhagic events during PCI, its administration may be advocated in subjects deemed at high risk of bleeding.Objective of the present trial is to compare the safety and effectiveness of procedural use of bivalirudin in comparison to unfractionated heparin (UFH) in patients undergoing PCI deemed at high risk of procedural bleeding.

Antithrombotic and antiplatelet therapies have been the focus of extensive clinical investigations over the past 2 decades. In PCI settings all therapies inhibiting coagulation and primary hemostasis may limit ischaemic event rates, but are associated with an increased risk of bleeding. Retrospective and registry data indicates that haemorrhage is associated with mortality in patients undergoing PCI, emphasizing the potential importance of minimizing bleeding, as well as ischemic events, bleeding has now emerged as one of the most common complication of PCI. Major bleeding and blood transfusion have been strongly associated with increased rates of in-hospital and late mortality, MI and repeat revascularization after PCI. Also minor bleeding, although represent a complication significantly less dangerous than major haemorrhages, are associated with prolonged hospitalization, increased cost and adversely affect short- and long-term outcome.

UFH is the most commonly used anticoagulant drug during PCI. Bleeding events during PCI may be in part due to the use of this drug. Bivalirudin (The Medicine's Co., Parsippany, NJ) is a synthetic direct thrombin inhibitor approved for patients with stable and unstable coronary syndromes undergoing PCI. Favourable properties of bivalirudin may minimize bleeding.

Several clinical and procedural factors have been evaluated to identify patients exposed to a higher risk of hemorrhages. Nikolsky et al. have developed a risk score (validated on REPLACE-1 and REPLACE-2 data) based on clinical variable useful to predict the incidence of major peri-procedural bleeding after contemporary PCI using the femoral approach. The clinical variables considered into this algorithm are age \>55 years (integer score 4 for every 10 years over 55), female gender (integer score 3), eGFR \<60 ml/min/1.73 m2 (integer score 2), pre-existing anaemia (integer score 2), and administration of low-molecular weight heparin within 48 hours (integer score 2). Global risk score 0-1 anticipated a major bleeding rate of 1.3%; a risk score 2-6 was associated with a 1.8% risk of major bleeding; a risk score 7-9 associated with a 2.7% risk if major bleeding, whereas a risk score \>=10 was associated with a 5% rate of major bleeding.

Our hypothesis is that bivalirudin, compared with UFH, may provide significant benefits in term of bleeding in the selected population of patients deemed at high risk of bleeding. Our aim is thus to prove, in a double-centres, randomized, blind controlled trial enrolling patients undergoing PCI via the femoral approach, the efficacy in term of haemorrhagic events and, secondarily, the effectiveness and safety of bivalirudin by means of the study drug vs UFH.

Sample size estimation: in this high risk population we expect a rate of major and minor bleeding of \>5% for the UFH group vs a 3% event rate in the bivalirudin group. Aiming for a 0.05 alpha and 0.80 power, a total of 662 patients will need to be enrolled (331 patients per group). This will be increased by about 25% (leading to a total of 830 patients) because of considerable uncertainty about expected end-point rates.

Eligibility Criteria:
Inclusion Criteria:

* • Male or female able to understand and sign a witnessed informed consent

  * Age ≥ 18 ys
  * Patients with stable (CCS 1-4) or unstable angina pectoris (but with the most recent anginal episode occurring \>48 hours before the procedure) or documented silent ischemia
  * Stable Hemodynamic conditions (systolic BP \> 100 HR \> 40 \< 100).
  * No clinical and ECG changes suggestive of ongoing acute or recent (\<48 hours) myocardial infarction.
  * Bleeding risk score ≥ 10
  * Procedure planned via femoral approach
  * Double antiplatelet therapy.

4.2.2 Angiographic inclusion criteria

• Angiographic evidence of a de novo lesion \> 50% requiring intervention

Exclusion Criteria:

* • Female sex with childbearing potential

  * Age \<18 years
  * Ongoing or recent episode (\<48 hours) of unstable coronary artery disease (including both ST-elevation and non-ST-elevation acute coronary syndromes)
  * Chronic kidney disease (estimated glomerular filtration rate \<30mL/min/1.73 m2).
  * Ongoing serious bleeding or bleeding diathesis
  * Previous stroke in the last 6 months
  * Platelet count ≤100,00 per mm3
  * History of heparin- induced-thrombocytopenia
  * Known hypersensitivity or contraindication to aspirin, heparin, clopidogrel, or sensitivity to contrast which cannot be adequately pre-medicated.
  * Hemodynamic instability (systolic blood pressure \< 100 mm Hg; heart rate \< 40 bpm or \>100 bpm; complex ventricular arrhythmias; AV block) requiring balloon counterpulsation or inotropic support.
  * The patient is simultaneously participating in another device or drug study. Patient must have completed the follow-up phase of any previous study at least 30 days prior to enrolment in this study.
  * Positive clinical history for intracranial neoplasia, AV malformation, aneurysm.
  * INR ≥ 2.0 or prothrombin time 1.2 times upper limit of normality