Antithrombotic Regimens and Outcome
Information source: Careggi Hospital
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Coronary Artery Disease
Intervention: heparin (Drug); bivalirudin (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: Careggi Hospital Official(s) and/or principal investigator(s): David Antoniucci, MD, Study Director, Affiliation: Division of Cardiology, Careggi Hospital, Florence, Italy
Summary
PROTOCOL SYNOPSIS Title: Comparison of bivalirudin and unfractioned heparin (UFH)+ protamine
in elective percutaneous coronary interventions (PCI)
Design: Prospective, randomized, controlled trial
Hypothesis: Bivalirudin is superior to UFH + protamine for the improvement of outcomes in
patients undergoing elective PCI
Key Inclusion Criteria:
Patients older than 18 years of age to undergo PCI Clopidogrel loading > 6 hrs prior to PCI
according to the PCI guidelines Informed, written consent
Key Exclusion Criteria:
ST-elevation myocardial infarction within the prior 48 hours Active bleeding, bleeding
diathesis, recent surgery Severe renal failure Chronic coronary artery occlusion to be
treated
Primary endpoint:
Inhospital major bleeding
Secondary endpoints:
1. Composite rate of death, myocardial infarction (MI) or target vessel revascularization
(TVR) inhospital, and at 6 months
2. Composite rate of inhospital death, MI or TVR and major bleeding
3. Major and minor bleedings
4. Total vascular complications
5. Post-procedure renal failure
Randomization:
Bivalirudin versus unfractioned heparin followed by protamine at the end of the PCI
procedure
Sample size:
Assumed incidence of inhospital major bleeding of 6% in UFH + protamine and of 2% in
bivalirudin group; for a power of 80% and a level of 0. 05 for each group 425 patients are
needed. An interim analysis will be performed after the enrolment of 425 (50%) patients.
Follow-up:
Inhospital, and 6-month clinical follow-up (out-patient clinic or by phone)
Clinical Details
Official title: Comparison of Bivalirudin and Unfractioned Heparin in Elective Percutaneous Coronary Interventions
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: The primary outcome measure will be in-hospital major bleeding.
Secondary outcome: Composite rate of death, myocardial infarction (MI) or urgenttarget vessel revascularization (TVR) inhospital, and at 6 months Composite rate of inhospital death, MI or TVR and major bleeding Major and minor bleedings Total vascular complications Post-procedure renal failure
Detailed description:
Bivalirudin, a direct thrombin inhibitor, has been recently introduced as an alternative to
UFH given several important biologic and pharmacokinetic advantages. 1,2 In contrast to UFH,
it acts independently of antithrombin and inhibits both free and clotbound thrombin; it is
not neutralized by circulating inhibitors; does not bind to plasma protein and cause
thrombocytopenia. 1,2 In the Bivalirudin Angioplasty Study, bivalirudin was associated with a
45% reduction in the relative risk for the composite of death, myocardial infarction,
revascularization or hemorrhage as compared to UFH among patients with unstable angina
undergoing percutaneous coronary angioplasty. 3 Recently, in another randomized trial of
patients with intermediate risk undergoing coronary stenting after varying pre-treatment
intervals with different doses of thienopyridines, use of bivalirudin was estimated to
result in 38% reduction in the relative risk of death, myocardial infarction, urgent repeat
revascularization or in-hospital major bleeding at 30 days compared to UFH. 4 In addition,
bivalirudin was associated with a similar rate of ischemic events and less major bleeding
and estimated to be more cost-effective than abciximab administered in adjunct to UFH. 4,5
However, previous studies have included patients treated with plain balloon angioplasty or
stenting after inadequate pretreatment with thienopyridines (ticlopidine or clopidogrel).
Recent guidelines recommend that all patients undergoing PCI must receive a loading dose of
300 - 600 mg of clopidogrel. 6 Clopidogrel is a thienopyridine that acts by irreversibly
inhibiting the platelet adenosine 5'- diphosphate (ADP) receptor. Compared to ticlopidine,
it has the advantage of a more favourable side effect profile 7, 8 and more rapid onset of
action. 9 Pre-treatment with clopidogrel has been associated with better outcomes among
patients undergoing PCI. 10-12 After a loading dose of 600 mg, maximum inhibition of
aggregation with clopidogrel is achieved within two hours. 13 The Intracoronary Stenting and
Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial showed
that after pre-treatment with 600 mg clopidogrel for at least 2 hours before intervention,
additional use of abicximab to UFH was not associated with any clinically measurable benefit
among low-to-intermediate risk patients who underwent PCI. 14 On the other hand, patients who
received abciximab had a higher rate of thrombocytopenia and more frequently required blood
transfusions. Thus, an antithrombotic strategy consisting of a loading dose of 600 mg
clopidogrel in addition to UFH and aspirin is a safe and effective way to improve patients'
outcomes and reduce costs after PCI. There are few data about the use of protamine
neutralization of circulating heparin after successful stent implantation. 15-18 However, all
the previous studies showed no excess in ischemic complications after stent implantation and
subsequent protamine administration, with a strong potential for bleeding complication
limitation.
Based on the above-mentioned data it can be said that antithrombotic regimens based on
either bivalirudin or UFH intraprocedurally followed by protamine neutralization, are
effective strategies to reduce ischemic and hemorrhagic complications in patients with
coronary artery disease undergoing PCI. At present, it is not known whether bivalirudin is
superior to UFH in patients who have been optimally pre-treated with a loading dose of
clopidogrel.
We designed this study to assess whether bivalirudin is superior to unfractioned heparin +
protamine in patients undergoing PCI. All patients older than 18 years of age, who require
coronary angiography for suspected or established coronary artery disease, but without
ST-segment changes, will receive a loading dose of 600 mg clopidogrel at least 2 hours prior
to the procedure. Eligible patients who do not meet the exclusion criteria and in whom
angiography reveals that revascularization is required and the target lesion(s) is (are)
amenable to PCI, will be randomized to receive a bolus of 140 U/kg of heparin or bivalirudin
to be administered as an intravenous 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.
All patients will receive aspirin indefinitely and clopidogrel for at least 1 month after
PTCA or implantation of bare metal stents and for at least 6 months after implantation of
drug-eluting stents; clopidogrel treatment for more than 6 months will be encouraged. 19 The
primary end point of the study is in-hospital major bleeding. The study is designed to show
whether bivalirudin is superior to UFH + protamine with respect to the primary end point.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Patients older than age 18 to undergo PCI
2. Pretreatment at least 6 hours before PCI with clopidogrel according to the PCI
guidelines.
3. Informed, written consent by the patient or her/his legally-authorized representative
for participation in the study.
Exclusion Criteria:
1. Recent ST-elevation myocardial infarction within the last 48 hours.
2. Chronic coronary artery occlusion to be treated
3. Malignancies or other comorbid conditions (for example severe liver, renal and
pancreatic disease) with life expectancy less than one year or that may result in
protocol non-compliance.
4. Active bleeding, bleeding diathesis, recent surgery (< 15 days)
5. History of gastrointestinal or genitourinary bleeding within the last 6 weeks
6. Treatment with UFH within 6 hours or low-molecular weight heparin within 8 hours
before randomization.
7. Treatment with bivalirudin within 24 hours beforerandomization.
8. Severe uncontrolled hypertension >180/110 mmHg unresponsive to therapy
9. Relevant hematologic deviations: hemoglobin < 100 g/L OR platelet count < 100 x 109
/L.
10. Glomerular filtration rate (GFR) < 30 ml/min or serum creatinine > 30 mg/L or
dependence on renal dialysis.
11. Known allergy to the study medications: aspirin, clopidogrel, UFH, bivalirudin;
stainless steel; true anaphylaxis after prior exposure to contrast media.
12. Known heparin-induced thrombocytopenia
Locations and Contacts
Division of Cardiology, Careggi Hospital, Florence 50141, Italy
Additional Information
Starting date: March 2007
Last updated: February 9, 2009
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