Novel Approaches in Preventing and Limiting Events III Trial (NAPLES III): Bivalirudin in High-risk Bleeding Patients
NCT ID: NCT01465503
Last Updated: 2014-04-08
Study Results
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Basic Information
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COMPLETED
PHASE3
837 participants
INTERVENTIONAL
2008-01-31
2013-12-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
DOUBLE
Study Groups
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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.
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.
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.
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.
Interventions
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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.
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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.
• Angiographic evidence of a de novo lesion \> 50% requiring intervention
Exclusion Criteria
* 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
18 Years
ALL
No
Sponsors
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Clinica Mediterranea
OTHER
Responsible Party
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Carlo Briguori
MD, PhD, Chief of Interventional Cardiology
Locations
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IRCCS Policlinico Multimedica
Milan, Milan, Italy
Clinica Mediterranea
Naples, Naples, Italy
Countries
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References
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King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, Jacobs AK, Morrison DA, Williams DO, Feldman TE, Kern MJ, O'Neill WW, Schaff HV, Whitlow PL; ACC/AHA/SCAI; Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol. 2008 Jan 15;51(2):172-209. doi: 10.1016/j.jacc.2007.10.002. No abstract available.
Topol EJ, Mark DB, Lincoff AM, Cohen E, Burton J, Kleiman N, Talley D, Sapp S, Booth J, Cabot CF, Anderson KM, Califf RM. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet. 1999 Dec 11;354(9195):2019-24. doi: 10.1016/s0140-6736(99)10018-7.
Medina HM, Bhatt DL. Evolution of anticoagulant and antiplatelet therapy: benefits and risks of contemporary pharmacologic agents and their implications for myonecrosis and bleeding in percutaneous coronary intervention. Clin Cardiol. 2007 Oct;30(10 Suppl 2):II4-15. doi: 10.1002/clc.20237.
Ndrepepa G, Berger PB, Mehilli J, Seyfarth M, Neumann FJ, Schomig A, Kastrati A. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol. 2008 Feb 19;51(7):690-7. doi: 10.1016/j.jacc.2007.10.040.
Moscucci M, Fox KA, Cannon CP, Klein W, Lopez-Sendon J, Montalescot G, White K, Goldberg RJ. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J. 2003 Oct;24(20):1815-23. doi: 10.1016/s0195-668x(03)00485-8.
Feit F, Voeltz MD, Attubato MJ, Lincoff AM, Chew DP, Bittl JA, Topol EJ, Manoukian SV. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol. 2007 Nov 1;100(9):1364-9. doi: 10.1016/j.amjcard.2007.06.026. Epub 2007 Aug 16.
Anand SX, Kim MC, Kamran M, Sharma SK, Kini AS, Fareed J, Hoppensteadt DA, Carbon F, Cavusoglu E, Varon D, Viles-Gonzalez JF, Badimon JJ, Marmur JD. Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin. Am J Cardiol. 2007 Aug 1;100(3):417-24. doi: 10.1016/j.amjcard.2007.02.106. Epub 2007 Jun 13.
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Stone GW, Ware JH, Bertrand ME, Lincoff AM, Moses JW, Ohman EM, White HD, Feit F, Colombo A, McLaurin BT, Cox DA, Manoukian SV, Fahy M, Clayton TC, Mehran R, Pocock SJ; ACUITY Investigators. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA. 2007 Dec 5;298(21):2497-506. doi: 10.1001/jama.298.21.2497.
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Other Identifiers
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NCTCM02
Identifier Type: -
Identifier Source: org_study_id
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