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

April 6, 2014 updated by: Carlo Briguori, Clinica Mediterranea

Bivalirudin in Patient at High Risk of Bleeding Undergoing Percutaneous Coronary Interventions.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

837

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Milan, Italy, 20142
        • IRCCS Policlinico Multimedica
      • Naples, Italy, 80121
        • Clinica Mediterranea

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
PLACEBO_COMPARATOR: Unfractionated Heparin
Patients randomized to the Control group will receive unfractionated heparin (UFH) before and during the procedure. UFH bolus will be of 70 UI/kg. If the activated clotting time measured 5 minutes after the study drug administration is lower than 270 seconds, an additional bolus of the randomised drug (UFH 20 U/kg) will be given.
Drug: Unfractionated Heparin
Patients randomized to the Control group will receive unfractionated heparn (UFH) before and during the procedure. UFH bolus will be of 70 UI/kg. If the activated clotting time measured 5 minutes after the study drug administration is lower than 270 seconds, an additional bolus of the randomised drug (UFH 20 U/kg) will be given.
ACTIVE_COMPARATOR: Bivalirudin
Patients randomized to Bivalirudin group will be treated by bivalirudin before and during the procedure. Bivalirudin will be given as bolus of 0.75 mg/kg prior to the start of the intervention, followed by infusion of 1.75 mg/kg per hour for the duration of the procedure.The infusion will be lowered to 1.0 mg/kg per hour in patients with eGFR <30 ml/min/1.73 m2.
Drug: Bivalirudin
Patients randomized to Bivalirudin group will be treated by bivalirudin before and during the procedure. Bivalirudin will be given as bolus of 0.75 mg/kg prior to the start of the intervention, followed by infusion of 1.75 mg/kg per hour for the duration of the procedure.The infusion will be lowered to 1.0 mg/kg per hour in patients with eGFR <30 ml/min/1.73 m2.
Other Names:
  • Bivalirudin (Angiox; The Medicine Company - NJ 07054 U.S.A)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The primary end point will be the rate of in-hospital major bleeding, defined according to the REPLACE-2 criteria.
Time Frame: Within 24 hours
Major bleeding are defined as intracranial, intraocular, or retroperitoneal haemorrhage, clinically overt blood loss resulting in a decrease in haemoglobin of more than 3 g/dL, any decrease in haemoglobin of more than 4 g/dL, or transfusion of 2 or more units of packed red blood cells or whole blood.
Within 24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cardiac death within 30, 180 and 360 days.
Time Frame: At 12 months from the PCI
Cardiac death: all deaths unless an unequivocal non-cardiac cause can be established.
At 12 months from the PCI
New myocardial infarction
Time Frame: at 12 months
  1. Q wave MI will = development of a new abnormal or worsened Q-waves not present on the patient's baseline ECG.
  2. Non-Q-wave MI = as MB iso-enzyme of creatinine kinase (CK-MB)>3X ULN .
at 12 months
Major and minor bleeding rate
Time Frame: at 30 days
  1. Major bleeding = see above.
  2. Minor bleeding = clinically overt bleeding that did not meet criteria for major.
at 30 days
target vessel revascularization (TVR)
Time Frame: at 12 monhts
TVR = revascularization procedure (repeat angioplasty or coronary bypass surgery) targeting the target vessel
at 12 monhts

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Clinica Mediterranea

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2008

Primary Completion (ACTUAL)

December 1, 2012

Study Completion (ACTUAL)

December 1, 2013

Study Registration Dates

First Submitted

November 1, 2011

First Submitted That Met QC Criteria

November 3, 2011

First Posted (ESTIMATE)

November 4, 2011

Study Record Updates

Last Update Posted (ESTIMATE)

April 8, 2014

Last Update Submitted That Met QC Criteria

April 6, 2014

Last Verified

April 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCTCM02

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Bleeding

Clinical Trials on Unfractionated Heparin

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Brazil

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe