Rheolytic thrombectomy and platelet glycoprotein IIb/IIIa blockade for stent thrombosis.

Conventional transcatheter-based strategies result in good procedural success but poor clinical outcome in the treatment of intracoronary stent thrombosis. A combined approach of mechanical thrombus burden reduction using AngioJet rheolytic thrombectomy with adjunctive glycoprotein (GP) IIb/IIIa antagonists has not been studied. Between July 1998 and August 2000, 15 patients (17 procedures) underwent AngioJet thrombectomy for stent thrombosis at the Beth Israel Deaconess Medical Center. Patients were followed clinically through 6 months following the AngioJet procedure. All patients presented with signs of acute myocardial infarction at a median of 6 days following the original stenting procedure. Most vessels (88%) were occluded at presentation. A GP IIb/IIIa inhibitor was administered during 16 of the 17 procedures. Rheolytic thrombectomy resulted in complete removal of filling defects in all reviewed cases and led to significant improvement in lumen diameter and TIMI flow with reduction in the thrombotic lesion length (all P values < 0.05). Angiographic success (< 30% residual stenosis, TIMI 3 flow) was attained in all but one procedure. No patient required emergent coronary bypass grafting, repeat coronary angioplasty, or died in-hospital. At 6 months, there were no deaths and repeat revascularization was performed in four patients (29%). A combined approach of rheolytic thrombectomy with adjunctive GP IIb/IIIa blockade was highly effective in resolving stent thrombosis and was associated with favorable acute and long-term outcomes.     

Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease

New strategies for profound inhibition of platelet activity at the injured coronary plaque focus on blockade of the platelet surface membrane glycoprotein IIb/IIIa receptor, which binds circulating fibrinogen or von Willebrand factor and crosslinks platelets as the final common pathway to platelet aggregation. Intravenous agents directed against this receptor include the chimeric monoclonal antibody fragment abciximab, the peptide inhibitor eptifibatide and nonpeptide mimetics tirofiban and lamifiban. Over 33,000 patients have been evaluated in 11 large-scale, placebo-controlled trials of these agents. During percutaneous coronary intervention, an absolute reduction of 1.5% to 6.5% in the 30-day risk of death, myocardial infarction or repeat urgent revascularization has been observed, with some variability in treatment effect among the agents tested (abciximab, eptifibatide and tirofiban). Treatment effect is achieved early with every modality of revascularization and is maintained over the long-term (up to three years). Increased bleeding risk may be minimized by reduction and weight-adjustment of concomitant heparin dosing. In the acute coronary syndromes without ST segment elevation, absolute 1.5% to 3.2% reductions in 30-day rates of death or myocardial (re-) infarction have been achieved with two to four day courses of eptifibatide or tirofiban. Clinical benefit accrues during the period of drug infusion and is durable. Treatment effect may be enhanced among patients undergoing early coronary revascularization, with evidence of stabilization before intervention and suppression of postprocedural ischemic events. Thus, blockade of the platelet glycoprotein IIb/IIIa receptor reduces ischemic complications when used as an adjunct to percutaneous coronary intervention or the management of acute ischemic syndromes.     

Safety of femoral closure devices after percutaneous coronary interventions in the era of glycoprotein IIb/IIIa platelet blockade

We compared in-hospital femoral complications of Angio-Seal, Perclose, and manual compression in consecutive patients who underwent percutaneous coronary interventions in the era of glycoprotein IIb/IIIa platelet inhibition. Femoral closure devices have a similar overall risk profile as manual compression, even in patients treated with glycoprotein IIb/IIIa platelet inhibition, although certain rare complications such as retroperitoneal hemorrhage and severe access-site infection may be more common with the use of these devices.     

Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina

OBJECTIVES: We designed a study to explore the effect of glycoprotein (GP) IIb/IIIa blockade on the atherosclerotic plaque and distal coronary vasculature. BACKGROUND: Platelet GP IIb/IIIa blockers have been proven to be beneficial in acute ischemic syndromes. This effect has also been attributed to the prevention of microvascular obstruction, although the underlying mechanisms have not been fully defined. METHODS: Eighteen patients with unstable refractory angina pectoris underwent cardiac catheterization and angioplasty. Trans-stenotic and microvascular resistances to flow were measured at baseline, during hyperventilation, and after intracoronary adenosine. Measurements were repeated early after abciximab administration and after successful percutaneous transluminal coronary angioplasty. RESULTS: Hyperventilation induced an ischemic attack in 12 of 18 patients and increased epicardial (12.8 +/- 16.9 vs. 6.1 +/- 6.1 mm Hg/ml per min, p < 0.05) and microvascular (9.9 +/- 7.5 vs. 6.8 +/- 5.8 mm Hg/ml per min, p < 0.05) coronary resistance. Abciximab had no significant effect on epicardial resistance, although it significantly reduced distal coronary resistance under all study conditions, including baseline (4.8 +/- 4.8 mm Hg/ml per min, p < 0.01), hyperventilation (5.1 +/- 5.4 mm Hg/ml per min, p < 0.01), and intracoronary adenosine (2.7 +/- 3.0 vs. 4.3 +/- 4.3 mm Hg/ml per min, p < 0.05). The hyperventilation test became negative in all patients after abciximab administration. CONCLUSIONS: These observations confirm the immediate beneficial effects of platelet GP IIb/IIIa blockade with abciximab in acute ischemic syndromes and suggest that improvement of microvascular function may play a central role in the mechanism of action of this drug.     

Role of oral blockade of platelet glycoprotein IIb/IIIa on neutrophil activation in patients with acute coronary syndromes

Orbofiban is a unique antiplatelet agent that inhibits the binding of fibrinogen to gycoprotein (GP) IIb/IIIa integrin receptors and thus prevents platelet aggregation induced by various agents. However, recent studies indicate that treatment with orbofiban does not reduce the incidence of recurrent ischemic events. The mechanisms underlying the lack of benefit of orbofiban in patients with acute coronary syndromes are not completely clear. The purpose of this study was to characterize the effects of orbofiban on cellular activation (neutrophil superoxide generation) and surface expression of adhesion molecules of circulating neutrophils (CD18, CD11b, and L-selectin) and platelets (P-selectin and GP IIb/IIIa) in patients with acute coronary syndromes. After 5–7 days, orbifiban (50 mg BID) did not reduce PMN adhesion molecule expression and ex vivo-stimulated PMN superoxide generation—as was observed in the placebo group, without orbofiban. In contrast, orbofiban induced marked reductions in GP IIb/IIIa and P-selectin expressions after 5–7 days of treatment. The sustained neutrophil activation observed with orbofiban may have a role on the recurrent thrombotic events observed with orbofiban treatment in the OPUS-TIMI 16 trial.     

Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy

OBJECTIVES: The purpose of this study was to assess if clopidogrel pretreatment affects the relative efficacy of bivalirudin versus heparin with glycoprotein (GP) IIb/IIIa blockade for percutaneous coronary interventions (PCI). BACKGROUND: Although thienopyridine pretreatment may improve clinical outcomes with PCI, it is unknown if bivalirudin's efficacy compared with heparin is dependent upon such pretreatment. METHODS: The Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE-2) trial was a double-blind, triple-dummy, randomized-controlled trial comparing heparin plus routine GP IIb/IIIa blockade (heparin group) with bivalirudin plus provisional GP IIb/IIIa blockade (bivalirudin group) during PCI. The primary end point was a composite of death, myocardial infarction (MI), urgent revascularization at 30 days, and major in-hospital bleeding. The secondary end point was a 30-day composite of death, MI, and urgent revascularization. Clopidogrel pretreatment was encouraged (300 mg loading, 75 mg/day). RESULTS: Of 6,010 patients enrolled, 5,893 received clopidogrel, with 85.8% in the bivalirudin and 84.6% in the heparin group receiving clopidogrel pretreatment. Bivalirudin (provisional GP IIb/IIIa blockade 7.2%) was noninferior to the heparin group for both primary and secondary end points. Clopidogrel pretreatment did not affect the relative efficacy of bivalirudin versus heparin with GP IIb/IIIa blockade, irrespective of pretreatment duration. Pretreatment was associated with significantly lower primary end point with bivalirudin (8.7% pretreatment vs. 12.9% no pretreatment, p = 0.007), and nonsignificantly with heparin (9.7% vs. 11.7%, respectively, p = 0.20). Multivariable models showed a trend toward lower primary and secondary end points with clopidogrel pretreatment. CONCLUSIONS: Clopidogrel pretreatment at the doses and time administered in this trial did not influence the relative efficacy of bivalirudin versus heparin plus GP IIb/IIIa blockade for PCI. However, pretreatment was associated with a trend towards lower clinical events after PCI.     

Controversies surrounding platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention and acute coronary syndromes

Platelet-dependent thrombosis is an important part of the pathophysiology of both percutaneous coronary interventions (PCI) and acute coronary syndrome (ACS). Data support the use of acute therapies that interfere with platelets to provide clinical benefit to patients presenting with acute cardiovascular disease. The discovery of platelet glycoprotein (GP) IIb/IIIa receptor antagonists has been a major advance in the pharmacotherapy for patients undergoing PCI and those presenting with ACS without ST-segment elevation. This article will cover the role of platelets in acute cardiovascular disease, as well as the discovery and development of the platelet GPIIb/IIIa inhibitors. The major focus of this article will be on examining key lessons from the trials in each of these areas as well as presenting a series of questions that still require answers from either ongoing or future research.     

替罗非班对急性冠脉综合征患者血小板活化度的影响

目的:评价GPⅡb/Ⅲa受体拮抗剂(盐酸替罗非班)对急性冠脉综合征(ACS)患者血小板活化度的影响及临床安全性。方法:受试组患者为来自2005年1月～2008年1月我院就诊的急性非ST段抬高型心肌梗塞和不稳定型心绞痛ACS患者,共126例,接受盐酸替罗非班持续泵入24～48h,根据年龄、性别选取同期就诊的稳定型心绞痛冠心病患者112例作为对照组。应用流式细胞仪分别对受试组和对照组患者CD61、CD62p、活化的GPⅡb/Ⅲa(PAC-1)的表达情况进行分析。结果:受试组CD61、PAC-1指标应用替罗非班1.5～2h,10h,48h比用药前明显降低(P均0.01),而对照组在治疗前后无明显变化;CD61仅用药1.5h时两组间比较有显著差异(P0.001);受试组PAC-1水平在治疗1.5～2h,10h时明显下降(P0.05),在48h又出现明显升高(P0.05)。结论:急性冠脉综合征患者应用GPⅡb/Ⅲa受体拮抗剂可改善长期的临床预后,同时我们的研究也显示替罗非班治疗急性冠脉综合症是有效的和安全的。     

Clinical correlates and course of thrombocytopenia during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade

BACKGROUND: Thrombocytopenia is infrequently associated with abciximab therapy but may contribute to hemorrhagic risk. Factors associated with development of thrombocytopenia, the role of weight-adjustment in concomitant heparin administration, and clinical outcomes in patients with thrombocytopenia are not well defined. METHODS AND RESULTS: Pooled data from 3 placebo-controlled, randomized trials (EPIC, EPILOG, and EPISTENT) of abciximab therapy during percutaneous coronary intervention identified 178 patients (2. 4% of 7290 patients) in whom thrombocytopenia (platelet count <100 x 10(9)/L) developed after enrollment. Multivariate regression analysis identified age (>65 years; P <.001), weight (<90 kg; P =. 023), baseline platelet count (<200 x 10(9)/L; P <.001), abciximab therapy (P =.002), and enrollment into the EPIC trial (P <.001) to be associated with development of thrombocytopenia. Major and minor nonsurgical hemorrhage and transfusion were more frequent (all P <. 001) in thrombocytopenic patients. Although the primary composite clinical end point of these trials (death, myocardial infarction, or urgent revascularization to 30 days) was observed with similar frequency in patients with (11.2%) and those without (7.9%; P =.114) thrombocytopenia, 30-day mortality rate was higher in thrombocytopenic patients (8.4% vs 0.6%, respectively; P <.001). This excess mortality rate persisted after excluding patients in whom thrombocytopenia was first noted after the performance of coronary bypass surgery (4.8% vs 0.6%; P <.001). Among patients in whom thrombocytopenia developed during these trials, those who received prophylactic abciximab had fewer primary end point events (7.1% vs 23.1%; P =.056) and had a lower 30-day mortality rate (3.5% vs 15.4%; P =.048) than patients with thrombocytopenia who had received prophylactic placebo. CONCLUSIONS: Thrombocytopenia associated with abciximab therapy for percutaneous coronary intervention was more frequent in older, lighter-weight patients, those with lower baseline platelet counts, and in those patients who were enrolled into the EPIC trial. Both bleeding and transfusion events occur more frequently in patients with thrombocytopenia. Patients in whom thrombocytopenia developed during these trials had increased mortality rates to 30 days not attributable to the performance of coronary bypass surgery. Among patients with thrombocytopenia, those who received prophylactic abciximab had better clinical outcomes including survival than those who did not.     

Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction.

OBJECTIVES: This prospective randomized study investigated platelet-induced upregulation of Mac-1 on monocytes and its inhibition by glycoprotein (GP) IIb/IIIa blockage in patients with acute myocardial infarction (AMI). BACKGROUND: In experimental AMI, Mac-1 on leukocytes is the pivotal adhesion molecule for detrimental inflammatory responses. In vitro, platelet adhesion to monocytes upregulates Mac-1. METHODS: Patients undergoing stenting in AMI within 48 h after onset of symptoms were randomly assigned to receive either standard-dose heparin (n = 50) or abciximab plus low-dose heparin (n = 50). In serial blood samples, we assessed platelet-monocyte interaction and Mac-1 surface expression by triple color immunofluorescence flow cytometry. RESULTS: Compared with platelet-negative monocytes, Mac-1 surface expression on monocytes with attached platelets was upregulated (median fluorescence intensity [interquartile range]: 259 [179 to 367] vs. 135 [78 to 195] arbitrary units, p < 0.001). As an indicator of platelet-monocyte interaction, mean fluorescence of the platelet marker GP Ib alpha in the monocytes population decreased after abciximab, although it remained unaffected by heparin alone. Abciximab achieved this effect by a reduction in platelet mass attached to monocytes (GP Ib alpha fluorescence intensity of heterotypic aggregates at 24 h [arbitrary units]: 187 [143 to 236] after abciximab vs. 228 [156 to 332] after heparin, p = 0.02), whereas it did not affect the percentage of monocytes with adherent platelets. Reduction of platelet-monocyte interaction resulted in decreased Mac-1 surface expression (fluorescence intensity at 24 h [arbitrary units]: 116 [68 to 153] after abciximab vs. 162 [117 to 239] after heparin, p = 0.001). CONCLUSIONS: In patients with AMI, platelet-leukocyte interactions modulate Mac-1 expression on monocytes. Glycoprotein IIb/IIIa blockade is a therapeutic option to interfere with this mechanism.     

Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions

We performed a cumulative meta-analysis of available studies to evaluate the effect of intravenous platelet glycoprotein (GP) IIb/IIIa antagonists on survival at 30 days and 6 months after percutaneous coronary intervention (PCI). Compounds that block the GP IIb/IIIa receptor substantially reduce myocardial infarctions (MIs) and repeat revascularization. We included 12 trials, which enrolled 20,186 patients in all, in the analysis. Overall, 30-day mortality was significantly reduced with GP IIb/IIIa inhibition (odds ratio 0.73, 95% confidence interval 0.55 to 0.96, p = 0.024). Although 10 of the 12 trials showed a beneficial effect of GP IIb/IIIa inhibitor treatment on mortality, no individual trial detected a statistically significant mortality benefit. The 30-day mortality benefit became significant at the p <0.05 level with addition of the ADMIRAL trial and was further enhanced by the CADILLAC trial. No significant heterogeneity was detected in the collection of trials. At 6 months, the odds ratio was 0.84 (95% confidence interval 0.69 to 1.03, p = 0.087). This survival benefit amounts to preventing approximately 1 of every 3 deaths that occur within 30 days after PCI, saving 2.8 lives/1,000 patients treated (number needed to treat, 357). Thus, patients who undergo PCI can expect significantly lower 30-day mortality, in addition to known reductions in nonfatal MI and repeat procedures, with GP IIb/IIa inhibition. There also is increasing evidence that mortality reductions are preserved at 6 months.     

The effect of β-adrenergic blockade on infarct size following experimental coronary occlusion

Summary The effect of Pindolol on myocardial infarct size was studied in 10 open chest dogs. In each animal a sequential occlusion and reperfusion of 2 medium-sized branches of the left coronary artery was performed in the same heart. After occlusion and reperfusion of the control artery the initial dose of Pindolol (0.25 mg/kg body weight) was administered. Thereafter the test artery was occluded, followed by a maintenance dose of Pindolol (0.3 mg/kg body weight).The drug caused a significant decrease in LVP and LV-dp/dt but no change in heart rate. MVO₂ also decreased significantly. Regional myocardial blood flow was measured with the tracer microsphere method. Collateral flow in the perfusion area of the control artery was 11.2±5.9% and in the area of the test artery 10.0±4.4% of normal. No change in the endo/epi ratio as a result of treatment was observed.The area of infarction (p-nitroblue tetrazolium-reaction) was divided by the area of perfusion (angiography). Infarct size, expressed as the percentage of the perfusion area. was 48.2±22.2% in the region of the control artery and 43.0±23.9% in the region of the test artery. The difference was statistically not significant.With 1 table     

Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion. A quantitative myocardial contrast echocardiography study

OBJECTIVES: We assessed the effect of glycoprotein IIb/IIIa inhibition (GPI) on microvascular flow after coronary occlusion/reperfusion using quantitative myocardial contrast echocardiography (QMCE). BACKGROUND: Platelets may play a major role in the dissociation of epicardial artery recanalization and tissue-level reperfusion, referred to as the "no-reflow phenomenon." Therefore, GPI might improve myocardial reperfusion, distinct from its effects on epicardial patency.T METHOD: hree-hour occlusion of the left anterior descending coronary artery (LAD) was followed by 3-h reperfusion in 16 open-chest dogs: 8 controls and 8 given a continuous infusion of the GPI tirofiban, starting 45 min before LAD reopening. Perfusion of the LAD bed was quantified by the rate of intensity rise (b) by QMCE; myocardial blood flow (MBF) was assessed by fluorescent microspheres. RESULTS: No differences in b or MBF were observed within the risk area between the control and GPI groups at baseline or occlusion. However, b and MBF were higher in GPI dogs than in controls during reperfusion, despite similar epicardial flow (p < 0.05 at 30, 60, and 90 min; p = NS at 180 min). Infarct area size was significantly reduced in GPI dogs compared with non-treated dogs (26.9 +/- 10.5% vs. 49.0 +/- 11.1% of at-risk area, respectively). CONCLUSIONS: As demonstrated by QMCE, GPI improves microvascular flow and reduces the infarct area after coronary occlusion/reperfusion, independent of epicardial flow. These data demonstrate the usefulness of QMCE in assessing microvascular flow, provide novel evidence for the role of platelets in the early phase of reperfusion injury, and show that GPI is of value in preserving microvascular perfusion after coronary reperfusion.     

Synthetic inhibitors of platelet glycoprotein IIb/IIIa in clinical development

Activation of the platelet glycoprotein (GP IIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GP IIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic and nonpeptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as 2 weeks, whereas synthetic GP IIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion, but some have the advantage of also being orally active. In the secondary prevention of atherothrombosis, large-scale trials were successfully conducted with aspirin, dipyridamole, ticlopidine, and clopidogrel. In the first large-scale trials with GP IIb/IIIa inhibitors, abciximab was investigated. In aggregate, synthetic GP IIb/IIIa inhibitors, combined with aspirin and heparin, were shown to reduce ischemic events in patients with high- and low-risk coronary intervention, stents, unstable angina, and non-Q-wave infarction. With short-term use of synthetic GP IIb/IIIa inhibitors, there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses currently used, bleeding occurs more often with the synthetic GP IIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours), but there are no direct comparisons between these drugs.     

Rapid assessment of glycoprotein IIb/IIIa blockade with the platelet function analyzer (PFA-100) during percutaneous coronary intervention

BACKGROUND: The platelet function analyzer PFA-100 (Dade Behring, Miami, Fla) evaluates platelet function by determining the time to occlusion of an aperture in a membrane coated with collagen and adenosine diphosphate or epinephrine as whole blood flows under shear stress conditions. Platelet aggregation causes aperture occlusion, and results are reported as closure time (CT). Interindividual variability is observed in the level of platelet inhibition achieved with use of the current abciximab dosing regimen (0.25-mg/kg bolus + 10-microg/min infusion for 12 hours). The relationships between specific levels of platelet inhibition and clinical efficacy and safety have not been fully established. METHODS AND RESULTS: We prospectively studied platelet function in 27 patients receiving abciximab during percutaneous coronary intervention. This evaluation included determinations of platelet-rich plasma aggregometry, receptor occupancy studies (D3 assay), and CT measurements at baseline and 10 minutes, 4 hours, 12 hours, and 24 hours after the bolus. All patients received abciximab, aspirin, and heparin; patients undergoing coronary stent implantation received aspirin and ticlopidine after the procedure. CT results were reported within 10 minutes after initiation of testing. For 96% of patients, CT was 300 seconds (maximum CT) immediately after abciximab bolus and remained so throughout the infusion. At 24 hours we observed variable recovery from platelet inhibition and in 72% of patients CT returned to normal (< or =130 seconds). CONCLUSIONS: Findings with the PFA-100 were similar to results observed with platelet aggregometry and receptor occupancy measurements. Most patients treated with abciximab exhibit normalized platelet function at 24 hours despite moderate levels of receptor occupancy, suggesting dissociation between occupancy and function.