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Carlo Briguori, MD, FACC, FSCAI Clinica Mediterranea, Naples, Italy

NAPLES III N ovel A pproaches in P reventing or L imiting E vent III Tria L Randomised Comparison of Bivalirudin versus Unfractionated Heparin in Patients at High Risk of Bleeding Undergoing Elective Coronary Stenting thought the Femoral Approach.

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Carlo Briguori, MD, FACC, FSCAI Clinica Mediterranea, Naples, Italy

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  1. NAPLES IIINovel Approaches in Preventing or Limiting Event III TriaLRandomisedComparisonofBivalirudin versus UnfractionatedHeparin in Patients at High RiskofBleedingUndergoingElectiveCoronaryStentingthought the FemoralApproach Carlo Briguori, MD, FACC, FSCAIClinica Mediterranea, Naples, Italy

  2. I, Carlo Briguori DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. Disclosure Statement of Financial Interest

  3. Background • Major bleeding and blood transfusion after PCI have been strongly associated with increased rates of in-hospital and late mortality, myocardial infarction (MI) and repeat revascularization1-2 • Unfractionated heparin (UFH) is the most commonly used anticoagulant drug during PCI in order to prevent thrombotic complications • Limitations of UFH include4-5 • inability to inactivate clot-bound thrombin, • the indirect mechanism of thrombin inhibition via anti-thrombin-III activation, • the nonspecific protein binding • Non-linear pharmacokinetic, requiring a continuous monitoring of the effect in order to confirm the optimal anticoagulation regimen and, on the contrary, avoid a high bleeding risk 1 Doyle BJ et al. J Am CollCardiol 2009;53:2019-27 2 Rao SV. et al. Am Heart J 2008;155:369-74 3.Young E, et al. Thrombosis and Haemostasis1992; 67:639-43. 4. Sobel M et al. J VascSurg2001;33:587-94

  4. Background • Bivalirudin (The Medicine’s Co., Parsippany, NJ) is a synthetic direct thrombin inhibitor approved for patients with stable and unstable coronary syndromes undergoing PCI1. • Favorable properties of bivalirudin include: • its ability to inhibit both circulating and clot-bound thrombin, • an inherent anti-platelet effect by inhibition of thrombin-induced platelet activation, • ashort half-life, which may minimize bleeding. • direct binding to thrombin without co-factors and no binding to plasma proteins. • linear kinetics, resulting in predictable serum concentrations2-4 1. Levine GN et al. J Am CollCardiol2011;58:e44 2. Stone GW et al. JAMA 2007;298:2497 3. Stone GW, et al. N Engl J Med 2008;358:2218 4. Lincoff AM et al. JAMA 2003;298;853

  5. Background • The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial1showed that bivalirudin led to a net clinical outcome comparable with that achieved with UFH. However: • an high (140 U/Kg) single bolus dose of UFH was used • Not specifically designed for high-risk bleeding patients • The ISAR-REACT 3A2showed that, in biomarker negative patients, a low dosing regimen (100 U/Kg) of UFH represents a simple and safe method of lowering the bleeding peri-procedural risk without compromise the risk of ischemic complications. However: • Single-arm prospective study • Not specifically designed for high-risk bleeding patients 1. Kastrati et al. N Engl J Med 2008;359:688-96 2. Schultz S et al. Eur Heart J 2010;31:582-7

  6. High risk bleeding patients Nikolski E et al EurHeart J2007; 28:1936-45

  7. Background • At present there is a lack of prospective clinical trial assessing the safety and the efficacy of bivalirudin compared with UFH in the subset of patients exposed to high risk of bleeding.

  8. Purpose • We performed a prospective, randomized, double-blind, single center, investigator-initiated study comparing the 2 different strategies in high-risk bleeding patients: • Unfractionated heparin (UFH Group) • Bivalirudin (Bivalirudin Group)

  9. NAPLES III trial • DESIGN: Prospective, randomized, double-blind single center, investigator-initiated clinical study Elective PCI in biomarker negative patients at high risk of bleeding (risk score ≥10) Bivalirudin group UFH group In-hospital major bleeding

  10. Hypothesis: Reduction in the primary endpoint from >5%1-3in the UFH group to <3%2-3in the Bivalirudin group Sample size: A total of 830 patients (415 each group) will be necessary to gave the study 80% power and a significance level <0.05 Sample size 1. Nikolski E et al. Eur Heart J 2007; 28:1936-45 2. Kastrati A et al. N Engl J Med 2008;359:688-96 3. Schultz S et al. Eur Heart J 2010;31:582-7

  11. Inclusioncriteria • Age 18 y • Bleeding risk score ≥10 • Procedure planned through the femoral approach • Angiographic evidence of de novo or restenotic lesions requiring revascularization • Stable or unstable angina or documented silent ischemia • Negative biomarkers of myocardial injury • Double antiplatelet therapy • Stable hemodynamic conditions

  12. Exclusion criteria • Bleeding risk score <10 • Pregnancy • Ongoing or recent (<48 h) episode of STEMI or NSTEMI • Negative biomarkers of myocardial injury • Chronic dialysis and/or history or previous dialysis • Hemodynamic instability requiring inotropic support or IABP • Ongoing or recent (<7 days) treatment with glycoprotein IIb/IIIa inhibitors • Ongoing or recent (6 months) bleeding or bleeding diathesis. • Recent (within 6 months) stroke • History of heparin-induced thrombocitopenia • Platelet count <100.000/mm3

  13. NAPLES III trial UFH group Bivalirudin group 70 U/Kg i.v.priorto start the procedure Additionalbolus 20 U/Kg in case ACT <250 sec Bolus of 0.75 mg/kg i.v. prior to the start of the procedure, followed by infusion of 1.75 mg/kg per hour for the duration of the procedure Additionalbolus 0.3mg/Kg in case ACT <250 sec

  14. Primary endpoint: Rate of in-hospital major bleeding, defined according the REPLACE 2 criteria: intracranial, intraocular, retroperitoneal, access-site haemorrhage requiring intervention, clinically overt blood loss resulting in a decrease in haemoglobin by ≥3 g/dl, any decrease in haemoglobin ≥4 g/dl, transfusion of ≥2 units of packed cells or whole blood Endpoints

  15. Secondary endpoints: Rate of in-hospital major and minor bleeding, defined according the REPLACE 2 criteria Rate of in-hospital, 30-day and 1-year major adverse cardiac events, defined as death, non-fatal myocardial infarction, repeat revascularization Rate of stent thrombosis, according to the ARC criteria Rate of major bleeding according to other criteria Endpoints

  16. Assessed for eligibility ( n= 1859) • Exclusion (n = 1021) • Not meeting inclusion/exclusion criteria (n = 998) • Radial access (n = 275) • Acute myocardial infarction (n = 219) • End-stage renal disease = 238) • IIbIIIa inhibitors (n = 211) • Recent bleeding (n = 55) • Refused to partecipate (n = 23) Enrollement Randomized (n = 837) • Patients allocated in the Bivalirudin Group (n = 418) • Received allocated treatment (n = 418) • Did not receive the allocated treatment (n =0) • Patients allocated in the UFH group (n = 419) • Received allocated treatment (n = 419) • Did not receive the allocated treatment (n= 0) Allocation Patients lost at follow-up (n = 0) Discontinued treatement (n = 0) Patients lost at follow-up (n = 0) Discontinued treatment (n = 0) Follow-up Analysis Patients analized ( n = 418) Patients excluded from analysis (n = 0) Patients analized ( n 419) Patients excluded from analysis (n = 0)

  17. Clinical Characteristics

  18. Procedural Characteristics

  19. Procedural Characteristics

  20. Procedural Characteristics

  21. Procedural Characteristics

  22. 16/146 Primaryendpoint Odds ratio = 1.28; 95% CI= 0.58-2.86 p = 0.54 14/418 3.3% 3,5 3,0 14/418 2.6% 2,5 11/419 2,0 % 1,5 1,0 0,5 0,0 UFH group Bivalirudin group

  23. Primary endpoint

  24. Primaryendpoint p = 0.80 2,5 2.1% UFH group 7/418 9/419 2,0 p = 0.10 1.7% 1.7% 7/418 7/418 1,5 % 1,0 0.5% 0,5 2/419 0,0 Entry-site Non entry-site Bivalirudin group

  25. Secondary endpoint

  26. Allbleeding(major and minor) 10.0 Odds ratio = 0.88; 95% CI= 0.55-1.44; p = 0.63 9.1% 9.0 8.1% 38/419 8.0 34/418 % 7.0 UFH group 6.0 5.0 4.0 p = 1.00 6.0 5.2% 5.2% p = 0.56 5.0 22/419 22/418 3.8% 4.0 16/419 % 2.9% 3.0 12/418 2.0 1.0 Bivalirudin group 0 Entry-site Non entry-site

  27. Peak ACT & Bleeding p = 0.36 p = 0.77 380 365±151 364±150 355±141 360 Event yes 340 316±86 320 Event no 300 peak ACT (seconds) 280 260 240 220 200 Major bleeding Major&Minor bleeding

  28. PeriproceduralMyocardialInfarction(TnI >5x ULN) p = 0.93 25 21.8 21.5 90/419 91/418 20 % 15 10 5 0 UFH group Bivalirudin group

  29. Secondary endpoint30-day MACE

  30. Secondary endpoint1-year MACE

  31. Conclusions • In patients at high risk of bleeding undergoing to elective PCI through the femoral approach, the use of bivalirudin does not reduce the rate of in-hospital major bleeding compared to UFH. • Entry-site bleeding still represent an important issue • Radial approach should be routinely used in this subgroup of patients

  32. NAPLES III Investigators

  33. NAPLES III Investigators

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