Effects of glycoprotein IIb/IIIa receptor inhibition with tirofiban on minor myocardial damage in angiographically successful percutaneous coronary angioplasty

AIM: The aim of the study was to evaluate the effects of glycoprotein (GP) IIb/IIIa inhibition on minor myocardial injury characterized by cardiac troponin I (cTn-I) and cardiac troponin T (cTn-T) elevation after elective successful percutaneous coronary intervention (PCI). METHODS: The study consisted of 119 consecutive patients scheduled for elective coronary balloon angioplasty with or without stent implantation. Sixty-three patients (mean age 58 +/- 9.4 years) were randomized to receive standard therapy, including preprocedural aspirin, ticlopidine and intravenous heparin, and 56 patients (mean age 55 +/- 9.6 years) were randomized to additionally receive intravenous tirofiban infusion. cTn-I, cTn-T and CK-MB were measured before and immediately after the procedure, and every 6 h for the first 24 h. A total of 128 stenoses were treated with PCI. Seventy of these lesions were in the standard therapy group and 58 in the tirofiban group. RESULTS: The frequency of postprocedural abnormal cTn-I levels was significantly higher in the standard therapy group than that in the tirofiban group (37 vs. 16%; p = 0.017). Postprocedural cTn-T elevation occurred in 23% of patients in the standard therapy group and in 8% of patients in the tirofiban group (p = 0.037). The frequencies of CK-MB elevation higher than the upper limit of normal (ULN), and higher than 2 times the ULN were not significantly different between the standard therapy and tirofiban groups (12 vs. 4%, and 7 vs. 2%, respectively). CONCLUSIONS: GP IIb/IIIa inhibition may reduce the incidence of minor myocardial injury, which may also be a possible mechanism in reducing long-term cardiac events after PCI.     

Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival: results from the Do Tirofiban and ReoProGive Similar Efficacy Outcome Trial (TARGET)

OBJECTIVE: We sought to examine if clopidogrel treatment initiated before coronary stenting improved clinical outcomes among patients receiving aspirin and a glycoprotein (GP) IIb/IIIa inhibitor. BACKGROUND: Antiplatelet therapy plays a pivotal role in contemporary percutaneous coronary interventions (PCI). METHODS: Outcomes among 4,809 patients randomized to tirofiban or abciximab during PCI with stent placement were compared according to whether they received 300 mg of clopidogrel before PCI (93.1%) versus immediately after the procedure. RESULTS: The 30-day primary composite end point (death, myocardial infarction [MI], or urgent target vessel revascularization [TVR]) was lower among clopidogrel-pretreated patients (6.6% vs. 10.4%, p = 0.009), mainly because of reduction of MI (6.0% vs. 9.5%, p = 0.012). The benefit of clopidogrel pretreatment was sustained at six months (death, MI, any TVR: 14.6% vs. 19.8%, HR = 0.71, p = 0.010), and this was due mainly to lowering of death and MI (7.8% vs. 13.0%, p = 0.001). At one year, clopidogrel pretreatment was associated with a lower mortality rate (1.7% vs. 3.6%, p = 0.011). Because clopidogrel pretreatment was not randomized, multivariable and propensity analyses were performed. After adjusting for baseline heterogeneity, clopidogrel pretreatment was an independent predictor for death or MI at 30 days (HR = 0.63, p = 0.012) and at six months (HR = 0.61, p = 0.003), and survival at one year (HR = 0.53, p = 0.044). No excess in 30-day bleeding events was noted with clopidogrel pretreatment. CONCLUSIONS: Among patients undergoing coronary stent placement with aspirin and a GP IIb/IIIa inhibitor, clopidogrel pretreatment is associated with a reduction of death and MI irrespective of the type of GP IIb/IIIa inhibitor used.     

Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R). Rationale for the Study and Protocol Design

PURPOSE: To assess whether glycoprotein IIb/IIIa inhibition using tirofiban in low risk patients undergoing percutaneous coronary intervention (PCI) may reduce the risk of periprocedural myocardial infarction compared to standard care in poor responders to aspirin and/or clopidogrel. METHODS: We will enroll patients at ten European sites or more to participate in the Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel (3T/2R) study with a pre-specified sample size of 240 patients out of 1,100 or more who will undergo screening. The primary outcome measure is troponin I or T elevation ratio at least three times the upper limit of normal within 48 h after completion of the PCI. CONCLUSION: The results of 3T/2R study will evaluate whether tailored intensification of anti-platelet treatment based on poor individual response to oral anti-platelet agents may modulate the risk of periprocedural myocardial infarction during PCI. Our findings attempt at unraveling a new era of individualized anti-platelet treatment through the use of point-of-care assessment.     

Achieved platelet aggregation inhibition after different antiplatelet regimens during percutaneous coronary intervention for ST-segment elevation myocardial infarction

OBJECTIVES: To evaluate the extent of platelet aggregation inhibition in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), treated with different antiplatelet agents and dosages. BACKGROUND: The extent of platelet aggregation inhibition is an independent predictor of major cardiac events after elective PCI. In STEMI patients undergoing PCI, routine dose of antiplatelet agents may be associated with less effective platelet aggregation inhibition. METHODS: Patients were treated with clopidogrel before angiography and randomized to abciximab, tirofiban, high-dose tirofiban, or no glycoprotein (GP) IIb/IIIa inhibitor; GP IIb/IIIa inhibitor bolus, followed by maintenance infusion, was administered after angiography, but before PCI. Platelet aggregation inhibition was assessed before angiography, immediately after PCI, and 1 and 6 h afterwards. RESULTS: The total study population consisted of 112 patients. Platelet aggregation inhibition was variable for individuals and suboptimal for all agents, particularly in the periprocedural period. Only with high-dose tirofiban, mean periprocedural platelet aggregation inhibition exceeded 80%. Angiographic parameters after PCI were not different between the groups. No relationship was found between the level of platelet aggregation and parameters of PCI success (Thrombolysis In Myocardial Infarction frame count and myocardial blush grade), after combining the data from all four groups studied. CONCLUSIONS: Platelet aggregation inhibition in STEMI patients undergoing PCI, treated with antiplatelet agents, is variable and suboptimal for all agents and dosages studied. Only with high-dose tirofiban, mean periprocedural platelet aggregation inhibition exceeded 80%. However, no relationship of platelet aggregation inhibition and angiographic outcome was found in this patient cohort.     

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。     

Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. Results of the platelet activity extinction in non-Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study

OBJECTIVES: The present study hypothesis was that eptifibatide offered further antiplatelet efficacy above clopidogrel in non-ST-elevation myocardial infarction (NSTEMI) patients before an expeditive coronary intervention. BACKGROUND: Although thienopyridines and glycoprotein (GP) IIb/IIIa antagonists are often co-prescribed in the context of NSTEMI, the antiplatelet interaction of these agents is poorly described and the superiority of GP IIb/IIIa antagonists above thienopyridine treatment alone is not clear. METHOD: Thirty-two NSTEMI patients treated with aspirin and enoxaparin were studied using flow cytometry to define parameters of platelet activation with a panel of agonists before clopidogrel, after clopidogrel, and during an eptifibatide infusion following the clopidogrel load. RESULTS: After platelet activation with adenosine diphosphate, thrombin receptor-activating peptide, or U46-619, relative reductions in conformationally activated GP IIb/IIIa receptor expression (evaluated with PAC-1) of 48%, 43%, and 33%, respectively (all p < 0.0001), were seen with clopidogrel, but further 80%, 78%, and 72% (all p < 0.0001) reductions were seen with eptifibatide. With the same agonists, fibrinogen binding was significantly reduced after clopidogrel by 70%, 64%, and 81% (all p < 0.0001) and again further reduced with eptifibatide by 90%, 95%, and 69% (all p < 0.0001). The total number of GP IIb/IIIa receptors (measured as P2 expression) and P-selectin expression fell after clopidogrel, after ex vivo stimulation with the same agonists; however, both parameters increased slightly during the eptifibatide infusion. CONCLUSIONS: The activated GP IIb/IIIa expression and fibrinogen binding findings indicate that eptifibatide provides significant potent antiplatelet activity above aspirin and clopidogrel, suggesting additive immediate protection in the treatment of NSTEMI. The P2 and P-selectin findings suggest the possibility of a partial agonist and/or pro-inflammatory effect.     

Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention

Aspirin and clopidogrel are proven to prevent thromboembolic events during percutaneous coronary intervention (PCI). Enzyme release of creatine kinase-MB (CK-MB) enzyme during PCI has been associated with an increased risk of future adverse cardiac events. This study examined the correlation between measurements of aspirin resistance and the level of inhibition of the thienopyridine-specific P2Y12 platelet receptor and CK-MB release after PCI. We prospectively studied 330 patients with elective PCI treated with drug-eluting stents. Patients were pretreated with aspirin and clopidogrel. Patients with positive CK-MB or acute coronary syndrome and those on glycoprotein IIb/IIIa inhibitors were excluded. Serum assays of aspirin resistance (Ultegra Rapid Platelet Function Assay-ASA, Accumetrics) and clopidogrel resistance (Rapid Platelet Function Assay P2Y12, Accumetrics) were performed before PCI. Serum troponinI and CK-MB levels were measured at 8, 16, and 24 hours after PCI. Aspirin resistance unit (ARU) measurement > or =550 was detected in 12 patients (3.7%). Mean platelet reactivity unit (PRU; measurement of inhibition of P2Y12 activity) was 192.2 +/- 95.4 (lower PRU, more inhibition of P2Y12 receptor). There was no correlation between level of ARU or PRU and troponin I or CK-MB release after PCI at any time point. Only multivessel coronary disease was found to be a predictor of any increase in CK-MB in a multivariate analysis (odds ratio 2.2, 95% confidence interval 1.4 to 3.3, p = 0.0003). A positive correlation was found between levels of ARU and PRU. Target vessel revascularization/major adverse cardiac event rate at 6 months was 8.2% with no correlation between ARU or PRU and release of cardiac enzymes or occurrence of adverse cardiac events. In conclusion, this study does not support routine measurements of aspirin and clopidogrel resistance in stable patients undergoing PCI.     

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.     

Closure devices and vascular complications among percutaneous coronary intervention patients receiving enoxaparin, glycoprotein IIb/IIIa inhibitors, and clopidogrel.

The objectives of this study were to explore the rate of vascular complications using closure devices (CDs) vs. manual compression (MC) among percutaneous coronary intervention (PCI) patients receiving enoxaparin, clopidogrel, aspirin, and GP IIb/IIIa inhibitors. The Evaluating Enoxaparin Clotting Times (ELECT) study enrolled patients receiving enoxaparin, clopidogrel, and GP IIb/IIIa inhibitors when necessary. Any approved CD or MC was allowed post-PCI, and clinical outcome data were prospectively collected. Four hundred forty-five patients had anti-Xa levels measured by a core laboratory and by a novel point-of-care device that reports ENOX times. All received enoxaparin, aspirin, and clopidogrel, and 75% received a concomitant GP IIb/IIIa inhibitor. Major and minor bleeding were defined according to TIMI criteria. "Any bleeding" included the occurrence of access site complications including hematoma, significant rebleeding, or bleeding delaying hospital discharge. TIMI major plus minor bleeding occurred in 1.5% of the patients who received CD vs. 1.8% of patients with MC (P = 0.83). Any bleeding occurred in 12.2% of CD vs. 5.7% MC (P = 0.02), and in 9.5% of patients receiving GP IIb/IIIa inhibitor vs. 2.8% (P = 0.01) among those who did not. For patients receiving both a GP IIb/IIIa inhibitor and CD, any bleeding was observed in 13.7% vs. 3.4% (P = 0.006) among patients who received neither. While minor and major TIMI bleeding remained very low in both groups, CD was associated with a twofold increase in risk of any-bleeding event when compared to MC, especially when using GP IIb/IIIa inhibitors.     

Effect of clopidogrel with and without eptifibatide on tumor necrosis factor-alpha and C-reactive protein release after elective stenting: results from the CLEAR PLATELETS 1b study.

OBJECTIVES: This study was performed to compare the effects of antiplatelet regimens on early inflammation and cardiac marker release after elective stenting. BACKGROUND: Few data exist regarding the comparative effects of specific antiplatelet regimens on early inflammation marker release after stenting. METHODS: In a 2 x 2 factorial randomized investigation, patients undergoing stenting were treated with either clopidogrel alone (300 mg or 600 mg; n = 60) or clopidogrel with eptifibatide (n = 60). Platelet aggregation (5 and 20 muM adenosine diphosphate [ADP]), ADP-stimulated expression of active glycoprotein (GP) IIb/IIIa, and platelet-bound P-selectin, tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP), and cardiac markers were measured. RESULTS: Compared with a strategy of clopidogrel alone, clopidogrel + eptifibatide reduced the release of cardiac markers. A marked reduction in platelet aggregation and active GP IIb/IIIa expression (p < or = 0.001) with clopidogrel + eptifibatide was associated with a decrease in CRP and TNF-alpha release (p < or = 0.001). CONCLUSIONS: A strategy of clopidogrel with GP IIb/IIIa blockade resulted in superior inhibition of inflammation and cardiac marker release, which was accompanied by superior platelet inhibition immediately after percutaneous coronary intervention compared with a strategy of clopidogrel alone. The mechanistic and clinical implications of attenuated periprocedural inflammation and myocardial necrosis with a strategy of GP IIb/IIIa inhibition warrant further investigation.     

Platelet glycoprotein IIb/IIIa inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors including abciximab, eptifibatide and tirofiban have been studied extensively as short-term adjuncts to short-term heparin and indefinite aspirin in patients with acute coronary syndrome or undergoing percutaneous coronary interventions on native vessels. The drugs provide a small advantage in the composite endpoint of death, myocardial infarction, and need for revascularization at 30 days (1-2% of treated patients) at the expense of an increase in major and potentially fatal bleeding complications (1% of treated patients over heparin plus aspirin alone). Highest-risk patients appear to benefit the most; clopidogrel should also be considered in these patients. Patients undergoing percutaneous interventions on bypass grafts do not benefit. Whether one GP IIb/IIIa inhibitor is superior to another is incompletely clarified. Abciximab causes severe immune-mediated thrombocytopenia (<20,000/microl) in 0.7% of cases; this is more often than eptifibatide or tirofiban (0.2%). Pseudothrombocytopenia should be differentiated. Effective use of GP IIb/IIIa inhibitors for acute coronary syndrome and percutaneous coronary interventions requires discerning clinical judgment. The value of GP IIb/IIIa inhibitors is not established in other forms of vascular disease.     

Debate of adjunctive pharmacology for percutaneous coronary intervention: anticoagulation and clopidogrel are not (always) enough

Substantial controversy exists regarding the optimal pharmacologic cocktail for percutaneous coronary intervention (PCI). The most common approach typically includes aspirin, clopidogrel, unfractionated heparin (or enoxaparin), and (variably) a glycoprotein (GP) IIb/IIIa inhibitor. Some substitute bivalirudin with "bail-out" GP IIb/IIIa blockade for heparin and planned GP IIb/IIIa integrin blockade, an approach that necessarily includes aspirin and clopidogrel (for their antiplatelet effects). These shifts in adjunctive treatment paradigms should be examined in the context of available data from clinical studies. Several studies have demonstrated the phenomenon of clopidogrel resistance to be fairly prevalent; even in clopidogrel-responsive patients, steady state is achieved only 4-6 hours after a 600-mg loading dose. It would thus be anticipated that clopidogrel-resistant patients would benefit from GP IIb/IIIa blockade, particularly during the period immediately after intervention. Neither REPLACE-2 nor the recent ACUITY trial demonstrated an efficacy advantage for bivalirudin as a substitute for heparin plus GP IIb/IIIa blockade; instead, any advantage appears to be limited to reducing the propensity for bleeding. As bleeding is directly correlated with the degree of anticoagulation and is further augmented by GP IIb/IIIa blockade, an alternative to the bivalirudin strategy is to simply reduce the amount of heparin anticoagulation during PCI. Finally, the benefit-to-risk ratio of aggressive adjunctive antiplatelet/antithrombotic therapy might be further improved via risk stratification, with patients at higher risk for periprocedural events receiving intensive therapy and lower-risk patients being managed with less intensive regimens focused on minimizing the risk of bleeding.     

Safety of glycoprotein IIb/IIIa inhibitors in urgent or emergency coronary artery bypass graft surgery

Approximately 2% to 4% of patients undergo urgent or emergency coronary artery bypass grafting (CABG) for complications of percutaneous coronary intervention (PCI) after treatment with glycoprotein (GP) IIb/IIIa inhibitors. The pharmacokinetic and pharmacodynamic properties of GP IIb/IIIa inhibitors play a large role in determining the safety of their use in the setting of urgent or emergency CABG procedures. Emergency or urgent CABG after treatment with the GP IIb/IIIa inhibitor, abciximab, may be associated with increased risk of hemorrhage and the requirement of platelet transfusions if surgery is performed within 12 h of abciximab discontinuation. Eptifibatide is associated with a similar risk compared with placebo, even when surgery is performed within 2 h of eptifibatide cessation. Limited data for tirofiban show that bleeding is not increased when compared with acetylsalicylic acid or heparin. Eptifibatide and tirofiban appear to have favourable safety profiles compared with abciximab in the setting of emergency or urgent CABG after failed PCI.     

Efficacy and safety of triple antiplatelet therapy with and without concomitant anticoagulation during elective percutaneous coronary intervention (the REMOVE trial)

Adjunctive glycoprotein IIb/IIIa inhibition decreases ischemic events after percutaneous coronary intervention (PCI) but is associated with increased bleeding. We hypothesized that maximal antiplatelet therapy with aspirin, a thienopyridine, and a glycoprotein IIb/IIIa inhibitor without unfractionated heparin (UFH) would result in fewer bleeding complications and maintain efficacy in elective PCI. A total of 159 patients undergoing elective PCI were randomized to intraprocedural eptifibatide alone or eptifibatide plus UFH. Patients received aspirin 325 mg and clopidogrel 300 mg before the procedure. The primary end point was the Landefeld bleeding index. Secondary end points included the composite clinical outcome of in-hospital death, myocardial infarction, urgent target vessel revascularization, and Thrombolysis In Myocardial Infarction major bleeding, and a composite bleeding outcome of major, minor, and nuisance bleeding. The Landefeld bleeding index was significantly lower in the eptifibatide-only group compared with the eptifibatide-plus-UFH group (3.0 vs 3.9, p = 0.03). There was no significant difference in the composite clinical end point between groups (eptifibatide only 17% vs eptifibatide plus UFH 15%, p = 0.7). There was a trend toward a decrease in the composite bleeding end point in the eptifibatide-only compared with the eptifibatide-plus-UFH group (43% vs 56%, p = 0.10). In conclusion, during elective PCI, a strategy of aggressive antiplatelet therapy using aspirin, clopidogrel, and eptifibatide without anticoagulant therapy appears to decrease bleeding complications.     

Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris

Impaired responses to antiplatelet therapy assessed by laboratory tests are associated with an increased risk of recurrent ischemic events after percutaneous coronary intervention (PCI). This study was designed to determine the relation between responses to aspirin and clopidogrel as assessed by a point-of-care assay (Verify Now, Accumetrics, San Diego, California) and periprocedural myocardial infarction (PMI) in patients undergoing elective PCI for stable angina. One hundred twenty-two consecutive patients undergoing elective coronary stenting prospectively received aspirin 500 mg and clopidogrel 600 mg >or=12 hours before PCI. Clopidogrel response was measured with P2Y12 reaction units (PRUs) and percent inhibition P2Y12 from baseline (percent inhibition P2Y12) and aspirin response with aspirin reaction units (ARUs). Troponin T level was considered positive if it was >0.03 ng/ml. Responses to aspirin and clopidogrel were correlated (r=0.42, p <0.0001). PMI occurred in 27 patients (22%) who showed significantly lower percent inhibition P2Y12 (25.3+/-26 vs 38.3+/-25, p=0.01) and a trend toward higher PRU values (221+/-87 vs 193+/-94, p=0.21). We did not find any difference for aspirin response as assessed by ARUs in patients with or without PMI (460+/-82 vs 454+/-73, p = 0.82). Stratification of percent inhibition P2Y12 isolated a quartile of clopidogrel nonresponders (inhibition P2Y12 <15%) with significantly higher incidence of PMI (44% vs 15%, odds ratio 4.6, 95% confidence interval 1.9 to 11.5, p=0.001). In conclusion, point-of-care assessment of clopidogrel response reliably predicted PMI after low- to medium-risk elective PCI for stable angina.     

Routine upstream versus selective down stream use of tirofiban in non-ST elevation myocardial infarction patients scheduled for early invasive therapy; a randomized comparison

Background Despite their proven beneficial effects and inclusion in the guidelines, glycoprotein (GP) IIb/IIIA blockers are underused in daily practice in patients with non ST-segment elevation acute coronary syndrome (NSTE ACS). This study combines the data from two randomized controlled trials, comparing routine upstream versus selective down stream use of tirofiban in patients with NSTE ACS. Methods Inclusion criteria for both studies (ELISA-1 and 2) were angina pectoris, with ST depression >1 mm and or a positive cardiac biomarkers. All patients were scheduled for coronary angiography. The primary and secondary end points for both studies were enzymatic infarct size (LDHQ48) and initial TIMI flow of the culprit lesion respectively. Results From August 2000 to January 2005, 273 patients were randomized to routine upstream tirofiban and 275 patients to selective down stream use of tirofiban. Selective down stream tirofiban was used in 55 patients (20%). Patients in the upstream group more often had a patent culprit lesion (65% vs. 50%, P=0.003) and a significantly smaller enzymatic infarct size, LDHQ48 median (25–75%): 125 (55–309) vs. 189 (68–504) IU/l, P=0.006 as compared to the selective down stream group. Subgroup analysis showed that routine upstream tirofiban was particularly effective in males, patients with a positive troponin on admission and in those not pretreated with clopidogrel. Conclusion Routine upstream GP IIb/IIIa is mainly effective in patients with elevated troponin on admission and those not pretreated with clopidogrel. Large scale randomized trials are needed to evaluate the effect of GP IIb/IIIa blockers on top of clopidogrel pretreatment on major adverse cardiac events.     

Antiplatelet Strategies: Evaluating Their Current Role in the Setting of Acute Coronary Syndromes

Numerous clinical trials have established the value of antiplatelet therapies for acute coronary syndromes (ACS). Aspirin (ASA), thienopyridines (i.e., clopidogrel and ticlopidine) and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS and for the prevention of thrombotic complications of percutaneous coronary intervention (PCI). Clopidogrel is beneficial when administered before and after PCI, and is more effective when combined with either ASA or GP IIb/IIIa inhibitors in preventing post‐PCI complications, coronary subacute stent thrombosis, and thrombotic events in general. It is currently unclear whether a higher loading dose of clopidogrel (600 mg) is better than the standard loading dose (300 mg), how long therapy should continue, and which maintenance dose is optimal. The role of the GP IIb/IIIa antagonists in ACS is less clear due to conflicting data from several studies with different patient populations. Currently, it appears that the use of GP IIb/IIIa antagonists might be most beneficial in high‐risk ACS patients scheduled to undergo PCI, who demonstrate non‐ST‐segment elevation myocardial infarction and elevated troponin levels. Copyright © 2008 Wiley Periodicals, Inc.     

Randomized comparison of upstream tirofiban versus downstream high bolus dose tirofiban or abciximab on tissue-level perfusion and troponin release in high-risk acute coronary syndromes treated with percutaneous coronary interventions: the EVEREST trial.

OBJECTIVES: We aimed to compare the effects of upstream tirofiban versus downstream high-dose bolus (HDB) tirofiban and abciximab on tissue level perfusion and troponin I release in high-risk non-ST-segment elevation acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). BACKGROUND: Optimal timing and dosage of glycoprotein IIb/IIIa inhibitors for ACS remain to be explored. METHODS: We randomized 93 high-risk ACS patients undergoing PCI to receive upstream (in the coronary care unit) tirofiban, downstream (just prior to PCI) HDB tirofiban, and downstream abciximab. We evaluated the effects of the three drug regimens on tissue-level perfusion using the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count, the TIMI myocardial perfusion grade (TMPG), and intracoronary myocardial contrast echocardiography (MCE) before and immediately after PCI and after cardiac troponin I (cTnI). RESULTS: The TMPG 0/1 perfusion was significantly less frequent with upstream tirofiban compared with HDB tirofiban and abciximab both before (28.1% vs. 66.7% vs. 71%, respectively; p = 0.0009) and after PCI (6.2% vs. 20% vs. 35.5%, respectively; p = 0.015). Upstream tirofiban was also associated with a significantly higher MCE score index (0.88 +/- 0.18 vs. 0.77 +/- 0.32 vs. 0.71 +/- 0.30, respectively; p < 0.05). Post-procedural cTnI elevation was significantly less frequent among patients in the upstream tirofiban group compared with the HDB tirofiban and abciximab groups (9.4% vs. 30% vs. 38.7%, respectively; p = 0.018). The cTnI levels after PCI were significantly lower with upstream tirofiban compared with HDB tirofiban (3.8 +/- 4.1 vs. 7.2 +/- 12; p = 0.015) and abciximab (3.8 +/- 4.1 vs. 9 +/- 13.8; p = 0.0002) CONCLUSIONS: Among high-risk non-ST-segment-elevation ACS patients treated with an early invasive strategy, upstream tirofiban is associated with improved tissue-level perfusion and attenuated myocardial damage.     

Cytokine response after percutaneous coronary intervention in stable angina: effect of selective glycoprotein IIb/IIIa receptor antagonism

Background It is unclear whether modulation of inflammatory markers by glycoprotein IIb/IIIa receptor inhibition after percutaneous coronary intervention (PCI) is caused by an interaction with the α_vβ₃ and α_Mβ₂ receptor or it correlates with ischemic events during PCI. This study investigates the inflammatory profile after elective, nonacute PCI and whether and how administration of the glycoprotein IIb/IIIa receptor antagonist tirofiban modulates the postinterventional inflammatory myocardial response. Methods The time course of inflammatory parameters (C-reactive protein [CRP], interleukin-1 [IL-1], interleukin-6 [IL-6], and tumor necrosis factor α [TNF-α]) of patients receiving peri- and postinterventional placebo (n = 46) or tirofiban infusion (n = 50) was analyzed by use of enzyme-linked immuno assays. Samples were collected before and 30 minutes, 2.5 hours, 6.5 hours, 12 hours, 24 hours, and 48 hours after elective PCI. Results Among the inflammatory markers analyzed, TNF-α, IL-6, and CRP levels increased significantly. However, the latter markers followed individual time courses in patients given placebo and patients treated with tirofiban after PCI, compared with pre-PCI levels (P < .01), with no significant differences between the placebo and tirofiban-treated groups. However, by subgroup analysis, significant differences were revealed in TNF-α, IL-6, and CRP levels of patients who were troponin T-positive versus patients who were troponin T-negative after PCI. Conclusions The administration of the selective glycoprotein IIb/IIIa receptor antagonist tirofiban has no direct impact on the inflammatory profile after elective PCI. Change of the inflammatory profile was only related to the presence or absence of postinterventional troponin. (Am Heart J 2003;145:693-9.)     

Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis

There is no information on long-term platelet reactivity and activation following elective stenting in patients treated with clopidogrel and aspirin. We measured platelet reactivity and activation at baseline and at 2 h, 24 h, 5 days and 30 days following coronary stenting (n = 94). Patients were treated with the standard aspirin (325 mg) and clopidogrel regimen (300 mg load/75 mg qd). Reactivity was measured by aggregation (5 and 20 μM ADP) and activation was determined by the expression of total and active GP IIb/IIIa. Reactivity and activation were defined as heightened when post-stent aggregation and receptor expression exceeded baseline levels, respectively. Prolonged heightened platelet reactivity was detected by both 5 and 20 μM ADP aggregation. Using 20 μM ADP aggregation, heightened reactivity occurred in 55% of patients at 2 h, 26% at 24 h, 21% at 5 days, and 15% at 30 days post-stenting. A high frequency of heightened platelet activation was detected by both total and active GP IIb/IIIa expression. Using expression of the active GP IIb/IIIa receptor as the marker, activation was greater than baseline in 27% of patients at 2 h, 20% at 24 h, 30% at 5 days, and 22% at 30 days post-stenting. This is the first report demonstrating that a significant percentage of patients receiving standard clopidogrel and aspirin therapy for coronary stenting will have post-drug platelet reactivity and activation above baseline that persists for 30 days after the procedure. These finding suggest insufficient platelet inhibition. The clinical importance of these findings should be further investigated to establish the potential link between insufficient platelet inhibition, stent thrombosis, and restenosis.