Effects of Unfractionated Heparin and Glycoprotein IIb/IIIa Antagonists Versus Bivalirdin on Myeloperoxidase Release From Neutrophils

Abstract

Objectives-The objective of this study was to determine whether adjunctive therapy during percutaneous coronary intervention (PCI) affects markers of systemic inflammation or platelet activation. Despite different mechanisms of action, direct-thrombin inhibition with bivalirudin during PCI provided similar protection from periprocedural and chronic ischemic complications as compared with unfractionated heparin (UFH) plus planned use of GPIIb/IIIa antagonists in the REPLACE-2 and ACUITY trials. Methods and Results-Patients undergoing nonurgent PCI of a native coronary artery were randomized to receive adjunctive therapy with bivalirudin or UFHϩeptifibatide. Interleukin (IL)-6 and C-reactive protein (CRP) transiently increased in both groups after PCI. In the UFHϩeptifibatide, but not the bivalirudin group, myeloperoxidase (MPO) levels were elevated 2.3-fold above baseline (Pϭ0.004) immediately after PCI. In an in vitro assay, heparin and to a lesser extent enoxaparin, but not bivalirudin or eptifibatide, stimulated MPO release from and binding to neutrophils and neutrophil activation. A mouse model of endoluminal femoral artery denudation was used to investigate further the importance of MPO in the context of arterial injury. Key Words: platelets Ⅲ neutrophils Ⅲ myeloperoxidase Ⅲ percutaneous coronary intervention Ⅲ adjunctive therapy A ggressive antithrombotic therapy, in particular antiplatelet therapy with glycoprotein (platelet glycoprotein [GP]) IIb/IIIa antagonists, thienopyridines, and aspirin used in conjunction with unfractionated heparin, have consistently been shown to decrease the risk of periprocedural thrombotic complications associated with percutaneous coronary interventions (PCI). 1,2 Bivalirudin, a direct thrombin inhibitor, was approved for use in PCI as an alternative to heparin before to widespread use of GPIIb/IIIa antagonists. Recently, the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 and the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trials demonstrated that bivalirudin used with GPIIb/IIIa antagonists on a provisional basis provided similar protection from periprocedural ischemic and hemorrhagic complications compared with heparin plus planned use of GPIIb/IIIa antagonists. 3,4 In the REPLACE-2 trial of low-to moderate-risk patients undergoing PCI, the primary composite end point at 30 days (incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding) occurred in 9.2% of patients in the bivalirudin group versus 10.0% of patients in the unfractionated heparin (UFH) plus GPIIb/IIIa antagonist group. 3 At 1 year, a nonsignificant trend toward lower mortality with bivalirudin was observed (1.9% in bivalirudin group and 2.5% in heparin plus GPIIb/ IIIa antagonist group). 3 The results from the ACUITY trial also suggest that in patients with acute coronary syndromes undergoing PCI, routine use of bivalirudin is associated with similar ischemic outcomes as UFH or low-molecular weight...

Leukocyte Count Is a Modulating Factor for the Mortality Benefit of Bivalirudin in ST-Segment–Elevation Acute Myocardial Infarction

“…Some studies have in fact reported that UFH plus eptifibatide, but not bivalirudin, may cause neutrophil activation and mieloperoxidase release in patients undergoing percutaneous coronary intervention. 8 Further studies have shown that UFH promotes proinflammatory interactions between platelets and WBC, increasing platelet reactivity and favoring formation of platelet-leukocyte aggregates 9 and monocyte tissue factor expression. 10 In contrast, treatment with bivalirudin compared with UFH has been associated with attenuation of inflammation after elective percutaneous coronary intervention 11 or in animal models of cardiopulmonary bypass.…”

Safety of Tirofiban in Acute Ischemic Stroke

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“…Следует отметить, что риск развития кровоизлияния на фоне применения ингибиторов ГП IIb/IIIa повы-шается при их использовании в сочетании с анти-коагулянтами, например с гепарином [20]. В данное исследование включили только тех пациентов, кото-рым назначали гепарин в профилактической дозе в качестве препарата для предотвращения тромбоза глубоких вен.…”

CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury

“…37 Briefly, neutrophils were isolated from blood of adult human healthy donors and suspended in Hanks' balanced salt solution containing 0.25% BSA. Aliquots of neutrophils (2 ϫ 10 5 cells in 200 l) were loaded with 1 mol/L DHR123 (Molecular Probes) for 5 minutes at 37°C and then stimulated with rh-CD40L under defined conditions.…”