hirudin and Carotid-Stenosis

Bivalirudin, has been shown to have comparable efficacy and better safety profile when compared to unfractionated heparin (UFH) in percutaneous coronary interventions. Bivalirudin's safety in carotid artery stenting (CAS) was associated with better outcomes than heparin in some studies. In this Meta analysis we examine the hemorrhagic and ischemic outcomes associated with Bivalirudin compared to UFH during CAS.. A comprehensive literature search was conducted with the electronic databases MEDLINE, EMBASE, and CENTRAL. Random-effects meta-analysis method was used to pool risk ratio (RR) for both Heparin and Bivalirudin with 95% confidence interval (CI). Study outcomes included hemorrhagic complications; major/minor bleeding and intracranial hemorrhage (ICH) as well as ischemic complications including ischemic stroke, myocardial infarction, and 30 day mortality.. A total of four studies were included enrolling 7,784 patients. Compared to UFH, Bivalirudin was associated with significantly lower major bleeding events with a relative risk (RR) of 0.53 (95% CI: 0.35-0.80; I. Compared to UFH, Bivalirudin is associated with lower bleeding risk when used during CAS. © 2016 Wiley Periodicals, Inc.

Topics: Antithrombins; Brain Ischemia; Carotid Stenosis; Fibrinolytic Agents; Global Health; Heparin; Hirudins; Humans; Incidence; Peptide Fragments; Postoperative Hemorrhage; Recombinant Proteins; Stents

General recommendations indicate that, during a carotid artery stenting (CAS), sufficient unfractionated heparin (UFH) has to be given to maintain the activated clotting time between 250 to 300 seconds. Bivalirudin use is able to reduce postprocedural bleedings in percutaneous interventions when compared with UFH. The study purpose was to evaluate, in a randomized study, the safety and efficacy of bivalirudin versus heparin during CAS, using proximal endovascular occlusion (PEO) as a distal protection device.. From January 2006 to December 2009, 220 patients undergoing CAS using PEO have been randomly assigned to one of the study arms (control arm: 100 UI/kg UFH or bivalirudin arm: 0.75 mg/kg intravenous bolus and intraprocedural infusion at 1.75 mg/kg/h).. Procedural success was achieved in all the patients. No episodes of intraprocedural thrombosis occurred. One major stroke occurred in the bivalirudin arm, and two minor strokes occurred, one in each group. A significant difference in the incidence of postprocedural bleedings was observed between the study groups; bivalirudin use was associated with reduced number of bleedings according to Thrombolysis In Myocardial Infarction criteria.. The use of bivalirudin should be considered a safe and effective anticoagulation regimen during CAS, using PEO as a distal protection device. Bivalirudin use is associated with a reduced incidence of bleedings.

Topics: Aged; Anticoagulants; Balloon Occlusion; Blood Loss, Surgical; Carotid Artery, Internal; Carotid Stenosis; Endovascular Procedures; Female; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Stents; Stroke; Thrombosis; Whole Blood Coagulation Time

The direct thrombin inhibitor, bivalirudin, is associated with similar efficacy and superior safety in patients undergoing percutaneous coronary intervention. However, the role of direct thrombin inhibitors in carotid artery stenting is not well defined. The objective of this study was to compare the safety and effectiveness of bivalirudin and unfractionated heparin (UFH) for carotid artery stenting. We hypothesized that bivalirudin would be associated with less in-hospital postprocedure bleeding than UFH but similar rates of in-hospital and 30-day ischemic outcomes.. We compared the incidence of in-hospital hemorrhagic and in-hospital/30-day ischemic outcomes among patients in the CARE Registry who underwent carotid artery stenting between May 2005 and March 2012 using bivalirudin or UFH. Propensity score matching was used to obtain a balanced cohort of 3555 patients in each treatment group. Patients treated with bivalirudin had a significantly lower incidence of bleeding or hematoma requiring red blood cell transfusions (0.9% versus 1.5%; odds ratio, 0.57 [0.36-0.89]; P=0.01) when compared with UFH-treated patients. The incidence of in-hospital and 30-day ischemic outcomes, including death, myocardial infarction, stroke, transient ischemic attack, and the composite outcome, death/myocardial infarction/stroke, did not differ significantly between groups.. Bivalirudin was associated with lower rates of hemorrhagic outcomes compared with UFH during the index hospitalization for carotid artery stenting. In-hospital and 30-day ischemic events were similar between the 2 groups. Randomized comparisons of these agents are needed to confirm these findings.

Topics: Aged; Aged, 80 and over; Angioplasty; Anticoagulants; Antithrombins; Brain Ischemia; Carotid Stenosis; Female; Hemorrhage; Heparin; Hirudins; Humans; Incidence; Male; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Registries; Risk Factors; Stents; Stroke

To analyze and report the safety and effectiveness of bivalirudin in a large patient population undergoing carotid artery stenting (CAS).. Between January 2001 and November 2010 extracranial CAS was performed in 272 patients in our institution. These patients were stratified according to the anticoagulant used during the CAS procedure into 2 groups (bivalirudin n = 217 vs. unfractionated heparin [UFH] n = 55) and analyzed regarding bleeding complications and periprocedural (within 30 days) stroke and myocardial infarction (MI) rates.. The combined end-point of death, stroke, and MI occurred in 12 patients (4.4%) with no significant difference between the groups (bivalirudin 4.6% vs. UFH 3.6% P value 0.96). Stroke rates were 1.8% in the bivalirudin and 1.8% in the UFH group (P value 1.00), with 4/5 strokes being nondisabling. Periprocedural MI was observed in 7 patients (2.1%) with no significant differences between the groups (bivalirudin 2.7% vs. UFH 1.8%, P value 0.94). Bleeding complications occurred in 13/272 patients (4.7%) with no significant difference between the groups (bivalirudin 3.6% vs. UFH 9.0%, P value 0.15). The first activated clotting time after administration of the anticoagulants was therapeutic in 209/217 (96%) in the bivalirudin group and in 30/55 (55%) in the UFH group (P < 0.001).. In this single-center study, bivalirudin was a safe and efficient anticoagulation strategy for CAS and could be considered a therapeutic alternative to UFH.

Topics: Adult; Aged; Aged, 80 and over; Antithrombins; Carotid Stenosis; Clopidogrel; Female; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Platelet Aggregation Inhibitors; Recombinant Proteins; Ticlopidine

Prior to June 2011, carotid artery stenting (CAS) had been limited to patients deemed high risk for surgical revascularization due to medical or anatomic reasons. Intraprocedural anticoagulation for CAS has traditionally been carried out with unfractionated heparin (UFH). The direct thrombin inhibitor bivalirudin has emerged as a possible alternative choice for anticoagulation in this patient population. In patients undergoing coronary interventions, bivalirudin has been shown in large prospective analysis to reduce major adverse events and hemorrhagic complications (TIMI major bleeding rates, 0.6%-3.1%; TIMI minor bleeding rates, 1.3%-3.7%). As of now, the safety and efficacy of bivalirudin for use during carotid stenting has not been rigorously evaluated. To date, the published evidence in favor of bivalirudin for CAS exists in small retrospective analyses and two prospective studies.. We present a retrospective analysis of 331 patients with a total of 365 carotid artery lesions undergoing CAS between February 2007 and September 2010. The procedures were performed by five experienced operators from four separate sites within the same metropolitan area. Patients were included who received bivalirudin as the anticoagulation strategy and underwent CAS. The primary endpoints of the study were 30-day incidence of death, stroke, TIMI major bleeding (defined as ≥5 g/dL Hgb drop or intracranial hemorrhage), TIMI minor bleeding (defined as ≥3 g/dL Hgb drop), and blood transfusion. All data were collected by retrospective chart review.. A total of 365 CAS procedures were performed. There were no deaths, strokes, or TIMI major bleeds. There was a 2.19% incidence of TIMI minor bleeding (8/365) and a 1.64% rate of blood transfusion (6/365).. In our patient population, the major endpoints of stroke, death, MI, major and minor bleeding rates were well within those previously reported overall for carotid artery revascularization. Hence, we conclude that bivalirudin may be safe for use in CAS procedures with a safety profile similar to that validated in percutaneous coronary interventions.

Topics: Aged; Angioplasty, Balloon; Antithrombins; Carotid Arteries; Carotid Stenosis; Combined Modality Therapy; Female; Hirudins; Humans; Male; Peptide Fragments; Radiography; Recombinant Proteins; Recurrence; Retrospective Studies; Stents

The purpose of this study was to examine the outcome of carotid stenting using bivalirudin and the influence of vascular closure devices (VCD) on the incidence and severity of peri-procedural hypotension.. Bivalirudin, a short-acting direct thrombin inhibitor, has been shown to be an effective anticoagulant in coronary interventions, with less risk of bleeding compared with heparin. Routine use of VCD has become the standard of care, facilitating patient ambulation after percutaneous carotid and coronary interventions. The combined use of these two therapies (bivalirudin and VCD) may improve outcomes in carotid interventions where prolonged patient immobilization may exacerbate hypotension following stenting.. A total of 514 patients underwent 536 carotid stenting procedures in the 3-year period from September 2004 to September 2007. All patients received adjunctive bivalirudin, with and without VCD. This cohort was analyzed for peri-procedural and 30-day clinical outcomes and length of hospitalization.. Thirty-day stroke and death rate was 1.7%. A total of 83 patients (15.4%) experienced intra- or post-procedural hypotension (systolic BP < 80 mm Hg). There were four (0.7%) major bleeding complications requiring transfusion, and length of stay was delayed more than 24 hr in five patients (0.93%), all of whom were in the manual compression group.. This was a negative study, with no significant difference on prolonged hypotensive events in patients with vascular closure device and bivalirudin, compared with those with manual compression and bivalirudin. Vascular closure devices were safe and effective with a low incidence of complications. In carotid artery stenting, bivalirudin is safe with low incidence of major bleeding and acceptable 30-day adverse event rates (stroke and death).

Topics: Aged; Aged, 80 and over; Anticoagulants; Carotid Stenosis; Combined Modality Therapy; Female; Hemostatic Techniques; Hirudins; Humans; Hypotension; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Stents; Treatment Outcome

We report a combined carotid endarterectomy and coronary revascularization surgery with cardiopulmonary bypass using bivalirudin for systemic anticoagulation in a patient with a positive titer for the heparin-platelet factor 4 antibody. The patient experienced procedural success for both the carotid and coronary surgeries. Increased blood and blood product transfusion was required postoperatively.

Topics: Anticoagulants; Autoantibodies; Blood Coagulation; Cardiopulmonary Bypass; Carotid Stenosis; Coronary Artery Bypass; Coronary Artery Disease; Endarterectomy, Carotid; Heparin; Hirudins; Humans; Intraoperative Care; Male; Middle Aged; Peptide Fragments; Platelet Factor 4; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

To understand the role of epidermal growth factor receptor (EGFR) transactivation in G protein-coupled receptor (GPCR) agonist-induced signaling events, we have studied the capacity of thrombin in the activation of Gab1-SHP2 in vascular smooth muscle cells (VSMCs). Thrombin activated both Gab1 and SHP2 in EGFR-dependent manner. Similarly, thrombin induced Rac1 and Cdc42 activation, and these responses were suppressed when either Gab1 or SHP2 stimulation is blocked. Thrombin also induced PAK1 activation in a time- and EGFR-Gab1-SHP2-Rac1/Cdc42-dependent manner. Inhibition of activation of EGFR, Gab1, SHP2, Rac1, Cdc42, or PAK1 by pharmacological or genetic approaches attenuated thrombin-induced VSMC stress fiber formation and motility. Thrombin activated RhoA in a time-dependent manner in VSMCs. LARG, a RhoA-specific GEF (guanine nucleotide exchange factor), was found to be associated with Gab1 and siRNA-mediated depletion of its levels suppressed RhoA, Rac1 and PAK1 activation. Dominant negative mutant-mediated interference of RhoA activation inhibited thrombin-induced Rac1 and PAK1 stimulation in VSMCs and their stress fiber formation and migration. Balloon injury induced PAK1 activity and interference with its activation led to attenuation of SMC migration from media to intima, resulting in reduced neointima formation and increased lumen size. Inhibition of thrombin signaling by recombinant hirudin also blocked balloon injury-induced EGFR tyrosine phosphorylation and PAK1 activity. These results show that thrombin-mediated PAK1 activation plays a crucial role in vascular wall remodeling and it could be a potential target for drug development against these vascular lesions.

Topics: Angioplasty, Balloon; Animals; Carotid Artery Diseases; Carotid Stenosis; cdc42 GTP-Binding Protein; Cell Movement; Cells, Cultured; Disease Models, Animal; ErbB Receptors; Fibrinolytic Agents; Gene Transfer Techniques; Genetic Therapy; Guanine Nucleotide Exchange Factors; Hirudins; Humans; Muscle, Smooth, Vascular; Mutation; p21-Activated Kinases; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Quinazolines; rac1 GTP-Binding Protein; Rats; Rho Guanine Nucleotide Exchange Factors; rhoA GTP-Binding Protein; RNA Interference; RNA, Small Interfering; Stress Fibers; Thrombin; Time Factors; Transfection; Tyrphostins

Carotid artery stenting (CAS) has become accepted as an alternative to carotid endarterectomy for revascularization of the internal carotid artery (ICA) among high risk patients. CAS from the femoral approach can be problematic due to access site complications as well as technical difficulties related to peripheral vascular disease (PVD) and/or anatomical variations of the aortic arch. The purpose of the present study is to evaluate the feasibility of the radial artery as an alternative approach for CAS.. Forty-two patients (mean age 71 +/- 1, 26 male) underwent CAS. All had a CA stenosis greater than 80% and comorbid conditions increasing the risk of carotid endarterectomy. The target common carotid artery (CCA) was initially cannulated via the radial artery using a 5F Simmons 1 diagnostic catheter which was then advanced to the external CA (ECA) over an extra support 0.014" coronary guidewire. After removing the coronary guidewire, a 0.035" guidewire was advanced into the ECA, and the Simmons 1 was exchanged for a 5F or 6F shuttle sheath and positioned in the distal CCA. In four patients with a bovine aortic arch, the left CCA was accessed with a 5F Amplatz R2 catheter which was then exchanged for a shuttle sheath over a 0.035" guidewire. CAS was performed using standard techniques with weight-based bivalirudin for anticoagulation.. CAS was successful in 35/42 (83%) patients, including 28/29 (97%) right CA, 4/5 (80%) bovine left CA, 7/13 (54%) left CA. Mean interventional time was 30 +/- 3 minutes. The sheath was removed immediately after the procedure. There were no radial access site complications. One patient sustained a stroke 24 hrs after the procedure with complete resolution of symptoms (Mean NIH stroke scale 2.0 +/- 0.3 before, 1.9 +/- 0.3 after). Median hospital stay was 2 +/- 0.6 days. Inadequate catheter support at the origin of the CCA was the technical cause of failure in the seven unsuccessful cases.. CAS using the transradial approach appears to be safe and technically feasible. The technique may be particularly useful in patients with right ICA lesions and severe PVD or unfavorable arch anatomy, and among patients with a bovine aortic arch.

Topics: Aged; Angiography; Anticoagulants; Blood Vessel Prosthesis Implantation; Carotid Arteries; Carotid Artery, Common; Carotid Artery, External; Carotid Artery, Internal; Carotid Stenosis; Feasibility Studies; Female; Hirudins; Humans; Length of Stay; Male; Peptide Fragments; Prosthesis Design; Radial Artery; Recombinant Proteins; Research Design; Stents; Treatment Outcome

To study the effects of fusion gene encoding the hVEGF(165) and fused hirudin on restenosis of injured carotid artery.. A fusion gene encoding hVEGF(165) and fused hirudin (hVEGF(165)-FH) was constructed and clone into the eukaryotic expression vector pcDNA3.0, thus constructing the plasmid VEGF(165)-FH/pcDNA3.0. Its activities to stimulate endothelial cell proliferation and to inhibit thrombosis were identified. Sixteen New Zealand rabbits underwent ligation of external carotid artery and a balloon was inserted into the common carotid artery for 30 minutes so as to construct model of restenosis of injured carotid artery. Then the rabbits were randomly divided into 4 equal groups. In the one-week and 3-week control groups, 400 microg of DNA of the plasmid pcDNA3.0 were transfused into the arterial lumen at the injured part immediately after the angioplasty, and 400 microg of DNA of the plasmid VEGF(165)-FH/pcDNA3.0 were transfused in the 1-week and 3-week experimental groups. One week and 3 weeks after the treatment peripheral blood samples were collected to detect the activated partial thromboplastin time (APTT), thrombin time (TT), and platelet aggregation rate, and then the rabbits underwent angiography to observe the situation of restenosis. Then the rabbits were killed to take out the injured part of artery to undergo pathological examination and Western blotting.. The values of APTT, TT, and platelet aggregation rate were not significantly different among the 4 groups. Angiography conducted 1 and 3 weeks later showed that restenosis was significantly mild in the 2 experimental groups in comparison with the 2 control groups, and severe restenosis was seen in the 3-week control group. Western blotting showed that expression of specific fused protein could be found in the 1-week and 3-week experimental group, the amount of the latter group being less than that of the former group; however, no expression of specific fused protein was found in the 2 control groups. Pathological examination showed that the narrowing of lumen 1-week and 3-week experimental groups were 11.50% and 19.75%, both significantly milder than those of the 1-week and 3-week control groups (33.25% and 52.25% respectively, both f P < 0.05). VB staining showed that the (intima/media (I/M) ratio of the 1-week and 3-week experimental groups were 0.12 and 0.35 respectively, both significantly lower than those of the 2 control groups (0.50 and 1.07 respectively, both P < 0.05).. Accelerating re-endothelialization and inhibiting thrombosis, the fused gene hVEGF(165)-FH effectively prevents restenosis after angioplasty, On the basis of endothelial repair, construction of fused genes with double even multiple targets may be a novel and potential therapeutic approach for restenosis after percutaneous coronary intervention.

Topics: Animals; Blotting, Western; Carotid Artery Injuries; Carotid Stenosis; Genetic Therapy; Hirudins; Partial Thromboplastin Time; Rabbits; Recombinant Fusion Proteins; Thrombin Time; Time Factors; Vascular Endothelial Growth Factor A

Topics: Anticoagulants; Carotid Stenosis; Catheterization; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hirudins; Humans; Male; Peptide Fragments; Radiography; Randomized Controlled Trials as Topic; Recombinant Proteins; Sensitivity and Specificity; Stents; Thromboembolism

Restenosis is responsible to approximately 30% of long-term failure following therapeutic vascular procedures. Thrombosis plays a key role in the development of restenosis. Thrombin-specific inhibitors have been considered as one type of candidates for the prevention of restenosis. Previous studies by our group demonstrated that a novel thrombin-specific inhibitor, hirulog-like peptide (HLP), reduced balloon catheter-induced neointima formation in rat carotid arteries. The present study examined the effect of HLP on angioplasty-induced restenosis in carotid arteries of atherosclerotic rabbits. New Zealand white rabbits were subject to air desiccation of the lumen of the right carotid arteries, then received high cholesterol/fat diet for 3 weeks. The rabbits were intravenously infused with HLP (1.6 mg/(kg/h)) or saline (n=7 per group) for 4 h started before angioplasty which dilated atherosclerotic lesions in right common carotid artery. Four weeks after the angioplasty, neointimal area, stenosis and neointima/media ratio in injured carotid arteries were reduced in atherosclerotic rabbits treated with HLP compared to saline controls by 62, 39 and 59% (P<0.05). The expression of tissue factor (TF) and transforming growth factor (TGF)-beta in the neointima of carotid arteries of rabbits treated with HLP was significantly weaker than saline controls (P<0.05 or <0.01). Activated partial thromboplastin time and bleeding time in HLP-treated rabbits were not significantly prolonged compared to controls. The results of the present study suggest that HLP may substantially reduce angioplasty-induced restenosis in atherosclerotic rabbits without increasing bleeding tendency. The inhibition on the expression of TF and TGF-beta in the neointima of the arterial wall may contribute to the preventive effect of HLP on restenosis in atherosclerotic rabbits.

Topics: Animals; Arteriosclerosis; Bleeding Time; Carotid Artery, Common; Carotid Stenosis; Collagen; Hirudins; Humans; Immunohistochemistry; Male; Partial Thromboplastin Time; Peptide Fragments; Rabbits; Rats; Recombinant Proteins; Recurrence; Thromboplastin; Transforming Growth Factor beta; Tunica Intima

We previously reported that plasminogen activator inhibitor 1 (PAI-1), in the presence of vitronectin (VN), inhibits thrombin activity in vitro. Furthermore, we demonstrated in human atherosclerotic plaques the colocalization of thrombin, PAI-1, and VN, as well as activity of thrombin and PAI-1. Here, we show that PAI-1 is a local thrombin inhibitor in vivo.. We used the murine carotid artery ligation model to assess the role of PAI-1 and VN in stenosis by using PAI-1-deficient (PAI-1(-/-)) and VN(-/-) mice. Ligation resulted in a smooth muscle cell (SMC)-rich intima without infiltrating cells. We show that PAI-1(-/-) and VN(-/-) mice generate a larger intima than wild-type mice as the result of more extensive SMC proliferation, as evidenced by cell counting and staining for proliferating cell-nuclear antigen.. In PAI-1(-/-) mice, excessive intima formation is prevented by the thrombin-specific inhibitor hirudin. Finally, immunohistochemical analysis revealed PAI-1, VN, and (pro)thrombin antigen in intimal lesions. Our observations are compatible with inhibition of thrombin-mediated SMC proliferation by PAI-1/VN complexes.

Topics: Animals; Carotid Arteries; Carotid Stenosis; Cell Division; Connective Tissue; Disease Models, Animal; Hirudins; Immunohistochemistry; Ligation; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Plasminogen Activator Inhibitor 1; Prothrombin; Tunica Intima; Tunica Media; Vitronectin

We sought to determine whether brief, profound inhibition of thrombin or prothrombin activation by factor Xa limits neointimal formation and stenosis after arterial injury.. Thrombin has been implicated as a mediator of neointimal formation, but adjunctive administration of anticoagulant agents has not proven effective to decrease restenosis in patients undergoing coronary angioplasty.. We infused recombinant desulfatohirudin (r-hirudin, bolus of 2 mg/kg body weight followed by 2 mg/kg per h, n = 9), heparin (100 U/kg per h, n = 6) or recombinant tick anticoagulant peptide (rTAP, 1-mg/kg bolus followed by 3 mg/kg per h, n = 5), a specific inhibitor of factor Xa, intravenously, beginning 15 min before and for up to 3 h after repetitive balloon hyperinflations sufficient to disrupt the internal elastic lamina in a carotid artery of minipigs with hypercholesterolemia induced by feeding them an atherogenic diet.. Partial thromboplastin time was increased six- to sevenfold over baseline levels at the end of the infusions of the anticoagulant agents. Lumen stenosis measured histologically 4 weeks after balloon-induced carotid injury was 29 +/- 16% (mean +/- SEM) in r-hirudin-treated, 52 +/- 19% in rTAP-treated and 76 +/- 18% in heparin-treated pigs (p < 0.02 for r-hirudin vs. heparin treatment).. The marked reduction of stenosis in r-hirudin-treated animals indicates that thrombin plays a major role in neointimal formation after balloon-induced arterial injury. A relatively brief interval of profound, direct inhibition of thrombin may be particularly effective to attenuate restenosis after balloon angioplasty.

Topics: Angioplasty, Balloon; Animals; Anticoagulants; Arthropod Proteins; Carotid Arteries; Carotid Artery Injuries; Carotid Stenosis; Factor Xa; Factor Xa Inhibitors; Heparin; Hirudins; Hypercholesterolemia; Intercellular Signaling Peptides and Proteins; Male; Partial Thromboplastin Time; Peptides; Prothrombin; Recombinant Proteins; Swine; Swine, Miniature; Thrombin; Tunica Intima

Topics: Angioplasty, Balloon; Animals; Arterial Occlusive Diseases; Blood Vessels; Carotid Stenosis; Hirudin Therapy; Hirudins; Humans; Recurrence; Thrombin; Tunica Intima