AzTrials
AzTrials

BleedingPhase 3NAPLESIIINCT01465503

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

A Phase 3 study testing Bivalirudin and Unfractionated Heparin in people with Bleeding, run by Clinica Mediterranea at 2 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Bleeding
What is being tested?
Bivalirudin and Unfractionated Heparin
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
837 participants
Where
2 sitesItaly
Study dates
Jan 2008to Dec 2013
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • • 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
Show all 10Show fewer
  • Procedure planned via femoral approach
  • Double antiplatelet therapy.
  • 4.2.2 Angiographic inclusion criteria
  • Angiographic evidence of a de novo lesion > 50% requiring intervention

Who cannot join

  • • 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
Show all 13Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country.

Italy2 sites

  • IRCCS Policlinico Multimedica

    Milan, Milan, 20142

  • Clinica Mediterranea

    Naples, Naples, 80121

Other trials in Italy

About this study

Official title: 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.

Read the 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.

Conditions
Bleeding
Being tested
Bivalirudin, Unfractionated Heparin
Keywords
bleeding, percutaneous coronary intervention, heparin, bivalirudin
Medical subject headings
Hemorrhage

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BivalirudinDrug

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

    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 HeparinDrug

    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.

Study groups in NCT01465503
Study groupRoleWhat they receive
Unfractionated HeparinPlacebo comparatorPatients 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.
Receives: Drug: Unfractionated Heparin
BivalirudinActive comparatorPatients 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.
Receives: Drug: Bivalirudin

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Within 24 hours

Secondary outcomes (4)

  1. Cardiac death within 30, 180 and 360 days.

    Cardiac death: all deaths unless an unequivocal non-cardiac cause can be established.

    Measured: At 12 months from the PCI

  2. New myocardial infarction

    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 .

    Measured: at 12 months

  3. Major and minor bleeding rate

    1. Major bleeding = see above.
    2. Minor bleeding = clinically overt bleeding that did not meet criteria for major.

    Measured: at 30 days

  4. target vessel revascularization (TVR)

    TVR = revascularization procedure (repeat angioplasty or coronary bypass surgery) targeting the target vessel

    Measured: at 12 monhts

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Nov 2011 (estimated)
  2. Study startJan 2008
  3. Primary completionDec 2012
  4. Study completionDec 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
837 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01465503
Sponsor's protocol ID
NCTCM02
Acronym
NAPLESIII
Status last verified
Apr 2014
First submitted
1 Nov 2011
Last updated
8 Apr 2014
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 18191745

  • 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.

    PubMed 10636365

  • 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.

    PubMed 18228647

  • 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.

    PubMed 18279731

  • 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.

    PubMed 14563340

  • 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.

    PubMed 17950791

  • 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.

    PubMed 17659921

  • 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.

    PubMed 18499566

  • Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003 Feb 19;289(7):853-63. doi: 10.1001/jama.289.7.853.

    PubMed 12588269

  • 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.

    PubMed 18056903

  • Kinnaird TD, Stabile E, Mintz GS, Lee CW, Canos DA, Gevorkian N, Pinnow EE, Kent KM, Pichard AD, Satler LF, Weissman NJ, Lindsay J, Fuchs S. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol. 2003 Oct 15;92(8):930-5. doi: 10.1016/s0002-9149(03)00972-x.

    PubMed 14556868

  • Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006 Aug 22;114(8):774-82. doi: 10.1161/CIRCULATIONAHA.106.612812. Epub 2006 Aug 14.

    PubMed 16908769

  • 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.

    PubMed 17394970

  • 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.

    PubMed 1509402

  • Sobel M, Fish WR, Toma N, Luo S, Bird K, Mori K, Kusumoto S, Blystone SD, Suda Y. Heparin modulates integrin function in human platelets. J Vasc Surg. 2001 Mar;33(3):587-94. doi: 10.1067/mva.2001.112696.

    PubMed 11241131

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Bivalirudin and Unfractionated Heparin in people with Bleeding, run by Clinica Mediterranea at 2 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Apr 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01465503, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Apr 2014.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in