Safety and Efficacy of Delayed Continuous Use of Bivalirudin 4 Hours After ePCI (COBER Study)

Overview

Since the development of percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD), unfractionated heparin (UFH) and low molecular weight heparin (LWMH) have been the preferred anticoagulants in peri-operative period. However, UFH has some defects, such as incomplete and unstable inhibition of thrombin, large individual differences, multiple monitoring of activated coagulation time (ACT), ineffective thrombin binding to fibrin, non-specific protein binding and induced thrombocytopenia (HIT). Compared with UFH, LWMH has lower non-specific protein binding rate, but it is not superior to UFH in efficacy, hemorrhage and HIT.

Bivalirudin can bind specifically to thrombin catalytic site and anionic external binding site, directly inhibit thrombin activity, thereby inhibiting thrombin-catalyzed and induced reactions. At the same time, thrombin can also inactivate it by enzymatic hydrolysis of bivalirudin. Therefore, the inhibition of bivalirudin on thrombin is reversible and transient, and the risk of bleeding after drug withdrawal is relative small. It has been reported that bivalirudin can significantly reduce the risk of peri-operative bleeding during PCI period compared with UFH. Clopidogrel had not yet played a role in most patients after emergency PCI, and there was a "blank period" for 2-4 hours without effective antithrombotic concentration, which was also the peak period of acute stent thrombosis. Han and coworkers have shown that for acute myocardial infarction (AMI) patients undergoing emergency PCI, whether or not glycoprotein IIb/IIIa inhibitors were added, delayed peri-operative injection of bivalrudin was significantly better than UFH in terms of net clinical adverse event. However, for patients with elective PCI (ePCI), delayed bivalirudin injection was only used in some patients in REPLACE-2 and ISAR-REACT-3 studies, and the delayed time of bivalrudin use after ePCI was not definite.

Therefore, in the current study we aim to explore the efficacy and safety of delayed bivalirudin injection 4 hours after elective PCI in patients with CHD.

Full Title of Study: “Safety and Efficacy of Delayed Continuous Use of Bivalirudin 4 Hours After Elective PCI in Patients With CHD (COBER Study)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 1, 2022

Detailed Description

The current study is designed as a single-center, randomized and prospective study aiming to evaluate the safety and efficacy of delayed continuous use of bivalirudin 4 hours after ePCI for the treatment of peri-operative myocardial injury (PMI) compared with bivalirudin use during ePCI. Based on previous study reported and estimated 10% loss follow-up of these patients in each arm, a total of 330 patients with CHD were required in our study, and with 165 patients per group as a ratio of 1:1 randomization.

Interventions

  • Drug: delayed continuous use of bivalirudin
    • delayed continuous use of bivalirudin 4 hours after elective PCI (dose: 0.75 mg/kg bolus plus 1.75 mg/kg per hour)
  • Drug: bivalirudin use during ePCI
    • bivalirudin use during ePCI (0.75 mg/kg bolus plus 1.75 mg/kg per hour)

Arms, Groups and Cohorts

  • Experimental: delayed continuous use of bivalirudine
    • A total of 165 patients are assigned to group with delayed continuous use of bivalirudin after randomization schedule.
  • Other: bivalirudin use during ePCI
    • A total of 165 patients are assigned to group with bivalirudin use during ePCI after randomization schedule.

Clinical Trial Outcome Measures

Primary Measures

  • The incidence rate of PMI in CHD patients 3 days after ePCI
    • Time Frame: Clinical follow up at 3 days after ePCI
    • the incidence rate of PMI indicated by the changes of myocardial injury biomarkers (such as TNI and CK-MB) in CHD patients between delayed continuous use of bivalirudin and bivalirudin use during ePCI groups

Secondary Measures

  • The incidence rate of patient-related ischemic events and bleeding
    • Time Frame: Clinical follow up at 30 days, 6, 9 and 12 months after the operation
    • The incidence rate of patient-related ischemic events including all myocardial infarction , any revascularization and all-cause death, and bleeding between delayed continuous use of bivalirudin and bivalirudin use during ePCI groups

Participating in This Clinical Trial

Inclusion Criteria

  • elective PCI
  • Preoperative score of CRUSADE > 30 or suspected or confirmed HIT patients

Exclusion Criteria

  • PCI within 1 month
  • Complicated with blood or rheumatism and immune system diseases
  • Life expectancy no more than 1 year or factors causing difficulties in clinical follow up
  • A history of peptic ulcer or GI bleeding in the previously
  • Stroke within 6 months prior to the operation
  • A history of severe hepatic or renal failure

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 100 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Nanjing First Hospital, Nanjing Medical University
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Zhiming Wu, MD, Principal Investigator, Nanjing First Hospital, Nanjing Medical University
  • Overall Contact(s)
    • Zhiming Wu, MD, +86 18001599783, wuzhiming1997@126.com

References

Han Y, Guo J, Zheng Y, Zang H, Su X, Wang Y, Chen S, Jiang T, Yang P, Chen J, Jiang D, Jing Q, Liang Z, Liu H, Zhao X, Li J, Li Y, Xu B, Stone GW; BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015 Apr 7;313(13):1336-46. doi: 10.1001/jama.2015.2323.

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. Erratum in: JAMA. 2003 Apr 2;289(13):1638.

Schulz S, Mehilli J, Ndrepepa G, Neumann FJ, Birkmeier KA, Kufner S, Richardt G, Berger PB, Schömig A, Kastrati A; Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 Trial Investigators. Bivalirudin vs. unfractionated heparin during percutaneous coronary interventions in patients with stable and unstable angina pectoris: 1-year results of the ISAR-REACT 3 trial. Eur Heart J. 2010 Mar;31(5):582-7. doi: 10.1093/eurheartj/ehq008. Epub 2010 Feb 11.

Devereaux PJ, Xavier D, Pogue J, Guyatt G, Sigamani A, Garutti I, Leslie K, Rao-Melacini P, Chrolavicius S, Yang H, Macdonald C, Avezum A, Lanthier L, Hu W, Yusuf S; POISE (PeriOperative ISchemic Evaluation) Investigators. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med. 2011 Apr 19;154(8):523-8. doi: 10.7326/0003-4819-154-8-201104190-00003.

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