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

NCT01465503 | Completed Phase 3 DMC

• 1 other identifier: NCTCM02
• Study Type: interventional
• Target: 837
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Bleeding

Keywords

bleeding; percutaneous coronary intervention; heparin; bivalirudin

Outcome Measures

Primary Outcomes (1)

• The primary end point will be the rate of in-hospital major bleeding, defined according to the REPLACE-2 criteria.

  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 Outcomes (4)

• Cardiac death within 30, 180 and 360 days.

  At 12 months from the PCI

• New myocardial infarction

  at 12 months

• Major and minor bleeding rate

  at 30 days

• target vessel revascularization (TVR)

  at 12 monhts

Study Arms (2)

Unfractionated Heparin

PLACEBO COMPARATOR

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

Bivalirudin

ACTIVE COMPARATOR

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

Interventions

Bivalirudin DRUG

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.

Also known as: Bivalirudin (Angiox; The Medicine Company - NJ 07054 U.S.A)

Bivalirudin

Unfractionated Heparin DRUG

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.

Unfractionated Heparin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Clinica Mediterranea: lead

Study Sites (2)

IRCCS Policlinico Multimedica

Milan, Milan, 20142, Italy

Location

Clinica Mediterranea

Naples, Naples, 80121, Italy

Location

Related Publications (18)

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  PMID: 18191745 BACKGROUND

• 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.

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• 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.

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• 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.

  PMID: 17950791 BACKGROUND

• 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.

  PMID: 17659921 BACKGROUND

• Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008 May 22;358(21):2218-30. doi: 10.1056/NEJMoa0708191.

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  PMID: 12588269 BACKGROUND

• 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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  PMID: 16908769 BACKGROUND

• Manoukian SV, Feit F, Mehran R, Voeltz MD, Ebrahimi R, Hamon M, Dangas GD, Lincoff AM, White HD, Moses JW, King SB 3rd, Ohman EM, Stone GW. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol. 2007 Mar 27;49(12):1362-8. doi: 10.1016/j.jacc.2007.02.027. Epub 2007 Mar 9.

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• Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemost. 1992 Jun 1;67(6):639-43.

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• Nikolsky E, Mehran R, Dangas G, Fahy M, Na Y, Pocock SJ, Lincoff AM, Stone GW. Development and validation of a prognostic risk score for major bleeding in patients undergoing percutaneous coronary intervention via the femoral approach. Eur Heart J. 2007 Aug;28(16):1936-45. doi: 10.1093/eurheartj/ehm194. Epub 2007 Jun 15.

  PMID: 17575270 BACKGROUND

• Briguori C, Visconti G, Focaccio A, Donahue M, Golia B, Selvetella L, Ricciardelli B. 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 Mar;8(3):414-423. doi: 10.1016/j.jcin.2014.10.015. Epub 2015 Feb 18.

  PMID: 25703878 DERIVED

• Briguori C, Visconti G, Focaccio A, Donahue M, Golia B, Selvetella L, Ricciarelli B. Novel Approaches for Preventing or Limiting Events (NAPLES III) Trial: randomised comparison of bivalirudin versus unfractionated heparin in patients at high risk of bleeding undergoing elective coronary stenting throught the femoral approach. rationale and design. Cardiovasc Drugs Ther. 2014 Jun;28(3):273-9. doi: 10.1007/s10557-014-6518-9.

  PMID: 24781074 DERIVED

MeSH Terms

Conditions

Hemorrhage

Interventions

bivalirudin; Heparin

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Chief of Interventional Cardiology

Study Record Dates

• First Submitted: November 1, 2011
• First Posted: November 4, 2011
• Study Start: January 1, 2008
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2013
• Last Updated: April 8, 2014

Record last verified: 2014-04

Locations

IT (2)