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Bivalirudin is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention.

ABSTRACT: BACKGROUND:Bivalirudin, a direct thrombin inhibitor, is a widely used adjunctive therapy in patients undergoing percutaneous intervention (PCI). Thrombin is a highly potent agonist of platelets and activates the protease-activated receptors, PAR1 and PAR4, but it is not known whether bivalirudin exerts antiplatelet effects in PCI patients. We tested the hypothesis that bivalirudin acts as an antiplatelet agent in PCI patients by preventing activation of PARs on the platelet surface. METHODS AND RESULTS:The effect of bivalirudin on platelet function and systemic thrombin levels was assessed in patients undergoing elective PCI. Mean plasma levels of bivalirudin were 2.7±0.5 ?mol/L during PCI, which correlated with marked inhibition of thrombin-induced platelet aggregation and significantly inhibited cleavage of PAR1. Unexpectedly, bivalirudin also significantly inhibited collagen-platelet aggregation during PCI. Collagen induced a conversion of the platelet surface to a procoagulant state in a thrombin-dependent manner that was blocked by bivalirudin. Consistent with this result, bivalirudin reduced systemic thrombin levels by >50% during PCI. Termination of the bivalirudin infusion resulted in rapid clearance of the drug with a half-life of 29.3 minutes. CONCLUSIONS:Bivalirudin effectively suppresses thrombin-dependent platelet activation via inhibition of PAR1 cleavage and inhibits collagen-induced platelet procoagulant activity as well as systemic thrombin levels in patients undergoing PCI.

SUBMITTER: Kimmelstiel C

PROVIDER: S-EPMC3086141 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Bivalirudin is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention.

Kimmelstiel Carey C Zhang Ping P Kapur Navin K NK Weintraub Andrew A Krishnamurthy Barath B Castaneda Vilma V Covic Lidija L Kuliopulos Athan A

Circulation. Cardiovascular interventions 20110301 2

<h4>Background</h4>Bivalirudin, a direct thrombin inhibitor, is a widely used adjunctive therapy in patients undergoing percutaneous intervention (PCI). Thrombin is a highly potent agonist of platelets and activates the protease-activated receptors, PAR1 and PAR4, but it is not known whether bivalirudin exerts antiplatelet effects in PCI patients. We tested the hypothesis that bivalirudin acts as an antiplatelet agent in PCI patients by preventing activation of PARs on the platelet surface.<h4>M ...[more]

PMID: 21364148

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Project description:BackgroundEast Asian patients receiving treatment with the potent P2Y12 inhibitors prasugrel or ticagrelor experience more potent platelet inhibition than with clopidogrel.MethodsThis study investigated differences in OPR rates with reduced doses of prasugrel (n = 38) or ticagrelor (n = 40) for maintenance therapy in 118 Korean ACS patients who had undergone PCI, in comparison to conventional-dose clopidogrel (n = 40). We assessed drug responses at one- and three-months post-PCI with VerifyNow and multiple electrode aggregometry assays.ResultsAt the one-month period, patients receiving standard-dose prasugrel or ticagrelor had lower platelet reactivity as determined by the three assays than those receiving the conventional dose of clopidogrel (VN: p = 0.000; MEA: p = 0.000; LTA: p = 0.000). At the 3-month point, platelet reactivity was lower in those receiving reduced-dose prasugrel or ticagrelor than the clopidogrel-treated patients (VN: p = 0.000; MEA: p = 0.012; LTA: p = 0.002). Prasugrel resulted in significantly lower platelet inhibition than ticagrelor as determined by VN and LTA (VN: p = 0.000; LTA: p = 0.003). At three months, there was a significant overall difference in OPR among the three groups when measured by VN (p < 0.001), but not when measured by MEA (p = 0.596). OPR in the reduced-dose prasugrel group was not significantly different to the clopidogrel group at three months (VN: p = 0.180; MEA: p = 0.711). OPR in the reduced-dose ticagrelor group was similar to clopidogrel as determined by MEA at three months, but was different when assessed by VN (VN: p = 0.000; MEA: p = 0.540). Compared to standard-dose, the reduced-dose prasugrel OPR rate was significantly increased (VN: p = 0.008; MEA: p = 0.020).ConclusionsOPR values for reduced-dose prasugrel and conventional-dose clopidogrel at three months were similar but higher than for reduced-dose ticagrelor as determined by VN, but no differences were noted by MEA. The MEA assay might have less sensitivity and consistency than the VN assay. Further studies are needed to explore this discrepancy.

Project description:Recent clinical trials have shown that while bivalirudin exhibits similar efficacy with heparin, it offers several advantages over heparin, such as a better safety profile. We aimed to evaluate the efficacy and safety of bivalirudin use during Percutaneous Coronary Intervention (PCI) in the treatment of angina and acute coronary syndrome (ACS). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, EMBASE, and Science Direct from January 1980 to January 2016. Randomized controlled trials (RCTs) comparing bivalirudin to heparin during the course of PCI in patients with angina or ACS were included. Outcome measures included all-cause mortality, myocardial infarction, revascularisation, stent thrombosis, stroke, and major bleeding. The selection, quality assessment, and data extraction of the included trials were done independently by four authors, and disagreements were resolved by consensus. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated. A total of 12 RCTs involving 44,088 subjects were included. Bivalirudin appeared to be non-superior compared to heparin in reducing all-cause mortality, myocardial infarction, revascularisation, and stroke. Bivalirudin appeared to be related to a higher risk of stent thrombosis when compared to heparin plus provisional use of a glycoprotein IIb/IIIa inhibitor (GPI) at day 30 (RR 1.94 [1.16, 3.24] p < 0.01). Overall, bivalirudin-based regimens present a lesser risk of major bleeding (RR 0.56 [0.44-0.71] p < 0.001), and Thrombolysis In Myocardial Infarction (TIMI) major bleeding (RR 0.56 [0.43-0.73]) compared with heparin-based regimens either with provisional or routine use of a GPI. However, the magnitude of TIMI major bleeding effect varied greatly (p < 0.001), depending on whether a GPI was provisionally used (RR 0.42 [0.34-0.52] p < 0.001) or routinely used (RR 0.60 [0.43 -0.83] p < 0.001), in the heparin arm. This meta-analysis demonstrated that bivalirudin is associated with a lower risk of major bleeding, but a higher risk of stent thrombosis compared to heparin.

Project description:BackgroundHigh platelet reactivity (HPR) and low platelet reactivity (LPR) are associated with an increased risk of ischemic/bleeding events in patients undergoing percutaneous coronary intervention (PCI). The role platelet miRNAs carry out in platelet reactivity regulation is largely unknown.MethodsIn this study, we profiled the expression pattern of platelet miRNA in patients undergoing PCI with HPR (n=4) and LPR (n=4) by miRNA microarray screening. The candidate miRNAs were further validated in a larger sample of 17 LPR and 22 HPR patients by quantitative reverse-transcription polymerase chain reaction (RT-qPCR), and miR-15b was found differentially expressed. MiR-15b mimic and inhibitor were transfected into MEG-01 cells, then Bcl-2 protein expression and cell apoptosis were assessed. The relationship between platelet reactivity and platelet apoptosis was further evaluated. ABT-737, a Bcl-2 inhibitor was used to induce platelet apoptosis in PCI patients in vitro, and the influence of enhanced platelet apoptosis on platelet reactivity was explored.ResultsTwo miRNAs were found to be differentially expressed in patients with LPR and HPR using microarray system. Furthermore, the expression of miR-15b, a miRNA known to induce cell apoptosis via targeting of Bcl-2, was confirmed by RT-qPCR (P=0.020) to be 1.4× higher in the platelets of LPR patients than in those of HPR patients. Overexpression of miR-15b was demonstrated to suppress Bcl-2 protein expression and enhance cell apoptosis in a megakaryocyte cell line (MEG-01). The platelets of LPR patients expressed lower levels of Bcl-2 protein than those of HPR patients, and an inverse relationship between platelet reactivity and platelet apoptosis was observed among 44 patients who underwent PCI. Inducing platelet apoptosis in PCI patients in vitro, we observed that their platelet reactivity was decreased in a dose-dependent manner.ConclusionsThrough the promotion of platelet apoptosis, platelet miR-15b negatively regulates platelet reactivity in patients undergoing PCI. Platelet apoptosis may represent a novel antiplatelet target for overcoming HPR in PCI treatment.

Dataset Information

Bivalirudin is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention.

Publications

Bivalirudin is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention.

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