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.     

Glycoprotein IIb/IIIa inhibitors in unstable angina

During the last ten years we have considerably update our knowledge about the pathogenesis of unstable angina or acute coronary syndromes. The platelet activity have in this settings the central role in development of the thrombotic process. Platelet glycoprotein IIb/IIIa inhibitors block fibrinogen binding to platelets, and the effect of this on the final common pathway of platelet aggregation makes these compounds extremely potent antiplatelet drugs. Three intravenous IIb/IIIa receptor antagonists are approved for clinical use, and this class of therapy has update our pharmacologic armatarium to avoid ischemic complication in the settings of percutaneous coronary revascularization at first and now in medical treatment of acute coronary syndromes. Results of large trials using this drugs suggest that this agents are effective in patient with unstable angina particularly in those presenting a high score of risk for acute ischemic events and those requiring coronary intervention.     

Effects of glycoprotein IIb/IIIa inhibition on clinical stabilization parameters in patients with unstable angina and non-Q-wave myocardial infarction

Glycoprotein IIb/IIIa receptor inhibition prevents the major cardiac events and improves the prognosis of patients with acute coronary syndromes. The purpose of the study was to evaluate the effects of tirofiban on clinical stabilization parameters in patients with unstable angina (UA) and non-Q-wave myocardial infarction (MI). Eighty-three patients presenting with prolonged ongoing chest pain and ST segment depression were included in the study. Forty-two patients were randomized to aspirin and heparin therapy, and 41 patients to tirofiban therapy in addition to the aspirin and heparin therapy. The interval between the initiation of the treatment and the disappearance of angina, recovery time of ST segment depression, creatine kinase-MB (CK-MB) levels, onset of decrease and normalization of CK-MB, and frequency of in-hospital major cardiac events were compared. The interval between initiation of the treatment and the disappearance of angina was significantly shorter in the tirofiban group (3.5 ± 4.2 vs 9.1 ± 8.6h, P 0.001). Recovery time of ST depression was also significantly shorter in the tirofiban group (5.1 ± 7.3 vs 12.3 ± 11.5h, P 0.05). The peak CK-MB values were significantly lower in the non-Q-wave MI and UA subgroups of tirofiban than in the heparin group (P = 0.04 for both). The onset of the CK-MB decrease was significantly earlier in the tirofiban group (15 ± 14 vs 24 ± 15h, P = 0.02). The normalization time of the CK-MB was relatively shorter in the tirofiban group but without statistical significance (50 ± 22 vs 60 ± 25h). The tirofiban group had a lower frequency of total major cardiac events (26% vs 54%, P = 0.01), acute MI (2.4% vs 19%, P = 0.03), and recurrent angina (26% vs 50%, P = 0.04). The frequency of death and urgent revascularization did not differ between the groups. Tirofiban, in addition to heparin, provides earlier clinical stability and prevents major in-hospital cardiac events in patients with UA and non-Q-wave MI as compared to heparin therapy alone.     

Effect of platelet glycoprotein IIb/IIIa receptor blockade with tirofiban on adverse cardiac events in women with unstable angina/non-ST-elevation myocardial infarction (PRISM-PLUS Study)

Background

Previous trials demonstrated the efficacy of platelet glycoprotein IIb/IIIa receptors blockade with tirofiban in reducing acute ischemic events in patients with unstable angina/non-ST-elevation myocardial infarction. Little is known about the effect of tirofiban among women with acute coronary syndromes.

Objective

We aimed to determine the benefit and safety of tirofiban plus heparin versus heparin alone on cardiac ischemic events among women with unstable angina/non-ST-elevation myocardial infarction.

Method and results

We performed a post hoc analysis of all women enrolled in the PRISM-PLUS trial. At early time points, there appeared to be a reduction of the primary composite end point of death, myocardial infarction, or refractory ischemia among women treated with tirofiban plus heparin (RR, 0.78 and 0.67) compared with women treated with heparin alone. However, at 30 and 180 days, there was no significant reduction of events with the combination therapy of tirofiban plus heparin (treatment-by-sex interaction, P = .05). Death or myocardial infarction was not significantly reduced by the combination therapy among women at all time points.

Conclusions

Although the effects of tirofiban in reducing the primary composite outcome were similar among men and women early in the study, there appeared to be a difference at the later time points. In particular, tirofiban was effective among men, but there was no clear effect among women at 30 and 180 days.     

Results of IIb/IIIa receptor blockade in patients with unstable angina.

The efficacy of GPIIb/IIIa inhibitors has now been evaluated in over 20 000 patients with unstable angina and non-Q MI. These agents have shown great efficacy in patients undergoing percutaneous coronary intervention. They are also effective, even if to a lesser degree, as an addition to medical treatment. The safety profile is satisfactory. Several issues have to be investigated in the future: comparison of agents, use of oral inhibitors, associations with Heparin, consequences on management, and cost efficacy. As of now, it is clear that GPIIb/IIIa inhibitors represent a significant progress in the treatment of patients with acute coronary syndromes.     

A risk score system for predicting adverse outcomes and magnitude of benefit with glycoprotein IIb/IIIa inhibitor therapy in patients with unstable angina pectoris

Clinical outcomes of patients with unstable angina are variable. We sought to identify predictors of adverse clinical outcomes in patients with unstable angina and to investigate whether these factors would predict the magnitude of benefit achieved with platelet glycoprotein IIb/IIIa inhibition. We analyzed 20 variables in the 1,915 patients enrolled in the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. Five independent predictors were identified: age >65 years, prior coronary artery bypass grafting, antecedent aspirin use, antecedent beta-blocker use, and ST depressions on the presenting electrocardiogram. A risk score system was created using these predictors in which patients were assigned 1 point for the presence of each risk factor. There was a progressive increase in the rate of the composite end point of death, myocardial infarction, or refractory ischemia at 7 days with an increasing number of risk factors. For patients treated with heparin alone, the composite end point event rate was 6.5% in the group with 0 or 1 predictor, 14.6% in the group with 2 predictors, 22.7% in the group with 3 predictors, and 37.1% in the group with 4 or 5 predictors (p <0.00001). When dividing patients into low- (0 or 1 point), medium- (2 or 3 points), and high-risk (4 or 5 points) groups, the addition of tirofiban to heparin therapy was associated with no significant benefit in the low-risk group, a 5.2% absolute reduction in the medium-risk group (p = 0.05), and a 16% absolute reduction in the high-risk group (p = 0.0055). Thus, we have developed a risk score system using 5 variables that can be used to identify patients at high risk for death and cardiac ischemic events and who experience the greatest benefit from the addition of a glycoprotein IIb/IIIa inhibitor to their treatment regimen.     

The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events

PURPOSE: Despite the success of intravenous glycoprotein IIb/IIIa antagonists, oral formulations have failed to show benefit and have been associated with increased mortality. To understand these findings, we performed a meta-analysis of results from four phase 3 trials. SUBJECTS AND METHODS: Trials were identified by MEDLINE search; review of abstracts from American College of Cardiology, European Society of Cardiology, and American Heart Association scientific sessions; or querying investigators in the field. Published, phase 3, randomized, placebo-controlled trials involving more than 1000 patients with coronary artery disease that compared an oral glycoprotein IIb/IIIa antagonist with or without background aspirin versus aspirin, and that had a planned follow-up of > or =30 days, were included. Four trials met these criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were generated from results, and combined using an empirical Bayes random-effects model. RESULTS: Among 33,326 patients, oral glycoprotein IIb/IIIa agents were associated with 31% increased mortality (OR = 1.31; 95% CI: 1.12 to 1.53; P= 0.0001). Results were similar whether the agent was added to (OR = 1.38; 95% CI: 1.15 to 1.67) or substituted for (OR = 1.37; 95% CI: 1.00 to 1.86) aspirin. Ischemic events or sudden death (OR = 1.22; 95% CI: 0.91 to 1.63) were also more common. Among patients with acute coronary syndromes, the incidence of myocardial infarction was increased (OR = 1.16; 95% CI: 1.03 to 1.29). CONCLUSION: Oral glycoprotein IIb/IIIa inhibitor therapy is associated with increased mortality and myocardial infarction. No single explanation for these findings is satisfactory; the problem is likely to be multifactorial.     

Platelet glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction

There are many limitations to reperfusion therapy for acute myocardial infarction. Preliminary studies have explored the potential of using more potent antiplatelet therapy. Abciximab, eptifibatide, and lamifiban are new agents that inhibit platelet glycoprotein IIb/IIIa, which serves as the final common pathway for platelet aggregation. Infarct artery patency occurs more rapidly, normal coronary blood flow is more often restored, and reperfusion is more stable when these agents are used with standard- or reduced-dose fibrinolytic therapy. Moreover, abciximab monotherapy has thrombolytic activity and facilitates primary angioplasty or stenting. Further studies are needed to define safety, efficacy, and cost effectiveness.     

Intravascular ultrasound predictors of major adverse cardiac events in patients with unstable angina

BACKGROUND: Intravascular ultrasound (IVUS) predictors of native culprit lesion morphology for occurrence of major adverse cardiac events (MACE) have not been reported. Moreover, the published data on IVUS predictors of restenosis include patients with stable and unstable angina, although the development and progression of atherosclerosis related to unstable coronary syndrome is different from that of stable angina. HYPOTHESIS: This study investigated whether IVUS-derived qualitative and quantitative parameters of native (preangioplastic) plaque morphologic features can predict major adverse cardiac events in patients with unstable angina. METHODS: Clinical (age, gender, coronary risk factors), qualitative and quantitative angiographic (lesion localization, morphology, pre- and postangioplastic minimal lumen diameter, reference diameter, and percent diameter stenosis), and IVUS variables (soft/fibrocalcific plaque, calcification, presence of thrombus or plaque disruption, different types of arterial remodeling, pre- or postangioplastic minimal lumen, external elastic membrane and plaque cross-sectional area, and plaque burden of the target lesion and reference segments) were analyzed by regression analyses using the Cox model, assuming proportional hazards. RESULTS: Of 60 consecutively enrolled patients, 21 suffered from MACE, while 39 remained event-free during the followup period. Multivariate regression analyses revealed that the presence of adaptive remodeling [p = 0.0177, risk ratio (RR) = 3.108, with 95% confidence interval (CI) = 1.371-8.289] and the preangioplastic lumen cross-sectional area (p = 0.0130, RR = 0.869, with 95% CI = 0.667-0.913) are independent predictors of MACE during follow-up, as is postangioplastic angiographic minimal lumen diameter (p = 0.0330, RR = 0.715 with 95% CI = 0.678-0.812). CONCLUSIONS: Adaptive remodeling and preangioplastic lumen cross-sectional area determined by IVUS and postangioplastic minimal lumen diameter calculated by quantitative angiography are significant independent predictors of time-dependent MACE in patients with unstable angina.     

阿魏酸钠联合低分子肝素对不稳定型心绞痛的疗效观察

目的观察阿魏酸钠(SF)联合低分子肝素(LMWH)对不稳定型心绞痛的疗效。方法将80例不稳定型心绞痛患者随机分为治疗组和对照组,每组40例,两组均给予常规治疗。对照组给予低分子肝素(LMWH)5000U,皮下注射,1次/12h,共用10d。治疗组在对照组的基础上加用阿魏酸钠(SF)300mg,静脉滴注,共用14d,LMWH疗程同对照组。14d后分别观察两组治疗前、后心绞痛的发作频率、血清总胆固醇(TC)、低密度脂蛋白(LDL)和心电图疗效等。结果阿魏酸钠(SF)注射液与低分子肝素钠联合治疗不稳定型心绞痛能有效缓解症状,改善心电图疗效,降低TC、LDL,心肌耗氧量明显下降(P<0.05)。结论SF注射液与低分子肝素钠联合治疗不稳定型心绞痛安全、有效。     

Safety and efficacy of low-dose intravenous enoxaparin and GP IIb/IIIa inhibitor therapy during PCI

The use of intravenous enoxaparin, a glyco-protein (GP) IIb/IIIa inhibitor, during percutaneous coronary intervention (PCI) has been shown to be safe and to possibly reduce in-hospital and 30-day major adverse cardiac events(MACE). NICE-4, a recent PCI observational study, evaluated a reduced dose of intravenous (IV) enoxaparin (0.75 mg/kg) with abciximab. However, prior PCI studies evaluating IV enoxaparin have not used percutaneous closure devices. The purpose of this study was to observe the safety and efficacy of a lower dose of IV enoxaparin (0.5 mg/kg) in conjunction with any GP IIb/IIIa inhibitor. The Angio-Seal femoral closure device was also employed as part of the treatment strategy. We administered 0.5 mg/kg IV enoxaparin and a GP IIIb/IIIa inhibitor to 75 eligible PCI patients. None received anticoagulation 24 hours prior to PCI; all received pre-procedural aspirin, post-procedural deployment of the Angio-Seal and clopidogrel therapy, and were discharged home within 36 hours. TIMI minor bleeding was 1.3%; there were no TIMI major bleeding events or major adverse cardiac events during in-hospital stay or at 30-day follow-up. Our small observational study shows that IV enoxaparin is safe and efficacious during PCI when given at a dose 33% lower than previously reported in conjunction with any GP IIb/IIIa inhibitor and Angio-Seal. However, large, randomized PCI trials are needed to confirm the clinical efficacy, safety and cost-effectiveness of lower doses of enoxaparin with GPIIb/IIIa inhibitors and vascular closure devices.