Abciximab: a reappraisal of its use in coronary care

Platelet reactivity plays a pivotal role in the pathogenesis of ischemic adverse events during and after acute coronary syndromes (ACS), and percutaneous coronary intervention (PCI). Glycoprotein (GP) IIb/IIIa inhibitors are the strongest antiplatelet agents currently available on the market and three different compounds, namely abciximab, tirofiban, and eptifibatide, have been approved for clinical use. Abciximab has been investigated in the clinical field far more extensively than the other GPIIb/IIIa inhibitors. Abciximab is an anti-integrin Fab fragment of a human – mouse chimeric monoclonal antibody with high affinity and a slow dissociation rate from the GP IIb/IIIa platelet receptor. Abciximab, given shortly before the coronary intervention, is superior to placebo in reducing the acute risk of ischemic complications (EPIC, EPISTENT, EPILOG trials); moreover, in the ISAR-REACT 2 study abciximab has been shown to reduce the risk of adverse events in patients with non ST-segment elevation ACS who are undergoing PCI even after optimal pre-treatment with 600 mg of clopidogrel. Finally, abciximab has been also used in abciximab-coated stent, with only bolus administration regimen and for direct intracoronary use with promising results that may extend and/or modify its current use in clinical practice in future

Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction

Aims To compare the efficacy and safety of drug-eluting stents vs. bare-metal stents in patients with acute ST-segment elevation myocardial infarction. Methods and results We performed a meta-analysis of eight randomized trials comparing drug-eluting stents (sirolimus-eluting or paclitaxel-eluting stents) with bare-metal stents in 2786 patients with acute ST-segment elevation myocardial infarction. All patients were followed up for a mean of 12.0-24.2 months. Individual data were available for seven trials with 2476 patients. The primary efficacy endpoint was the need for reintervention (target lesion revascularization). The primary safety endpoint was stent thrombosis. Other outcomes of interest were death and recurrent myocardial infarction. Drug-eluting stents significantly reduced the risk of reintervention, hazard ratio of 0.38 (95% CI, 0.29-0.50), P < 0.001. The overall risk of stent thrombosis: hazard ratio of 0.80 (95% CI, 0.46-1.39), P = 0.43; death: hazard ratio of 0.76 (95% CI, 0.53-1.10), P = 0.14; and recurrent myocardial infarction: hazard ratio of 0.72 (95% CI, 0.48-1.08, P = 0.11) was not significantly different for patients receiving drug-eluting stents vs. bare-metal stents. Conclusion The use of drug-eluting stents in patients with acute ST-segment elevation myocardial infarction is safe and improves clinical outcomes by reducing the risk of reintervention compared with bare-metal stent

Tirofiban: A critical reappraisal of the clinical use, recent developments and future perspectives

Platelet activation and aggregation has been shown to be heightened in the setting of acute coronary syndromes and to be an independent predictor of adverse events. Blocking platelet aggregation with medical therapy (aspirin, clopidogrel, glycoprotein [GP]IIb/IIIa antagonists) has been demonstrated to be of unequivocal benefit. GPIIb/IIIa is a platelet-specific adhesion receptor that mediates the formation of platelet aggregates. Tirofiban is a small, synthetic, nonpeptide, competitive GPIIb/IIIa antagonist with high specificity and affinity for the GPIIb/IIIa receptor. The Platelet Receptor Inhibition for ischemic Syndrome Management (PRISM) and Platelet Receptor Inhibition for ischemic Syndrome Management in Patients Limited by Unstable signs and Symptoms (PRISM-PLUS) studies found that tirofiban, administered in the upstream setting - based on an infusion of a 30-min bolus - reduced the incidence of major adverse cardiovascular events in patients with non-ST segment elevation acute coronary syndromes, compared with heparin alone. Accordingly, the use of tirofiban in this setting has become a class I indication in the US and European guidelines. A 3-min bolus was also developed to allow the use of tirofiban directly in the catheterization laboratory. However, the do Tirofiban And ReoPro™ Give Similar Efficacy Trial (TARGET) study has demonstrated clinical inferiority of tirofiban versus abciximab due to suboptimal platelet inhibition soon after administration of 10 μg/kg bolus. To achieve an inhibition of platelet aggregation of more than 90% in the first hour after treatment, a new bolus of tirofiban was identified (10-25 μg/kg). The first case-control and randomized studies based on this new regimen have shown that this dosage was safe and effective in reducing the incidence of adverse events in patients treated with percutaneous coronary intervention. Several Phase II and III studies are ongoing to extend these preliminary

Stent and Dual Antiplatelet Therapy Duration Comparisons in the Setting of a Multicenter Randomized Controlled Trial: Can the Operator Experience Affect the Study Results?

Background-Operator experience influences outcomes after percutaneous coronary intervention, but this association in the controlled setting of a randomized, clinical trial is unclear.Methods and Results-We investigated operator-related outcomes (30-day and 2-year efficacy and safety end points) among patients undergoing percutaneous coronary intervention and randomized to different dual antiplatelet therapy durations and stent types. A total of 2003 patients were analyzed, and 7 operator groups were compared. The majority of preprocedural and postprocedural characteristics were imbalanced. The primary end point of the study, the composite of death, myocardial infarction, or cerebrovascular accidents, did not differ among operators at 30 days or 2 years. There were no significant differences also for all other individual and composite end points analyzed at 30 days and 2 years, except for 2-year stent thrombosis (P=0.048) and bleeding events (P=0.022 for Bleeding Academic Research Consortium type 2, 3, or 5). Adjusted comparisons for the main end points showed slight differences among operators at 30 days, but not at 2 years. There was no interaction of operator with dual antiplatelet therapy duration (P=0.112) or stent type (P=0.300). Results remained entirely consistent when operators were stratified by their experience.Conclusions-There was a weak signal of heterogeneity across study operators for the 30-day, but not the 2-year, main study outcomes. No clear effect of operator or operator experience was observed for the comparative efficacy and safety profile of the randomized stent types or dual antiplatelet therapy duration regimens

Tumor necrosis factor-alpha receptor 1 is a major predictor of mortality and new-onset heart failure in patients with acute myocardial infarction: the Cytokine-Activation and Long-Term Prognosis in Myocardial Infarction (C-ALPHA) study.

BACKGROUND: Tumor necrosis factor alpha-alpha (TNF-alpha) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. METHODS AND RESULTS: We performed a systematic evaluation of TNF-alpha and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64+/-12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-alpha and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65+/-6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95\% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak. CONCLUSIONS: sTNFR-1 is a major short- and long-term predictor of mortality and HF in patients with acute myocardial infarction

Long-term clinical outcomes after drug eluting stent implantation in women with de novo coronary lesions: Results from the REAL (REgistro Regionale AngiopLastiche Emilia-Romagna) multicenter registry

Background: The long-term effectiveness of drug eluting stents (DESs) in a real-world setting of female patients is currently unclear. Methods and results: We analyzed long-term follow-up (up to 3 years) data from all female patients with de novo lesions enrolled in a prospective web-based multicenter registry (REAL Registry; study period, July 2002-June 2006) including all 15 hospitals performing PCI in the Emilia-Romagna region of Italy. Among the 3549 women without ST elevation myocardial infarction, 2434 were treated with BMSs alone and 1115 with DESs alone. At 3 years, use of DESs was associated with a lower propensity score adjusted incidence of MACE [cardiac mortality, non-fatal myocardial infarction and target vessel revascularization (TVR); 19.5% vs. 24.4%; HR 0.75, p = 0.006)] and TVR (11.6% vs. 15.6%; HR 0.68, p = 0.004) compared with BMSs. No difference was apparent in terms of adjusted 3-year cardiac mortality or myocardial infarction. Nevertheless, after the first 6 months of follow-up, a non significantly increased risk of myocardial infarction and stent thrombosis was found in the DES group. Conclusions: In this real-world female registry, the use of DESs was associated with a 3-year reduction of TVR and MACE in comparison with the use of BMSs. However, the observed (non-significant) increment of late AMI makes performing larger studies to clarify the long-term safety of DESs mandatory. \ua9 2009 Elsevier Ireland Ltd

Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: the MULTISTRATEGY randomized trial.

CONTEXT: Abciximab infusion and uncoated-stent implantation is a complementary treatment strategy to reduce major adverse cardiac events in patients undergoing angioplasty for ST-segment elevation myocardial infarction (STEMI). It is uncertain whether there may be similar benefits in replacing abciximab with high-dose bolus tirofiban. Similarly, the use of drug-eluting stents in this patient population is currently discouraged because of conflicting results on efficacy reported in randomized trials and safety concerns reported by registries. OBJECTIVE: To evaluate the effect of high-dose bolus tirofiban and of sirolimus-eluting stents as compared with abciximab infusion and uncoated-stent implantation in patients with STEMI undergoing percutaneous coronary intervention. DESIGN, SETTING, AND PATIENTS: An open-label, 2 x 2 factorial trial of 745 patients presenting with STEMI or new left bundle-branch block at 16 referral centers in Italy, Spain, and Argentina between October 2004 and April 2007. INTERVENTIONS: High-dose bolus tirofiban vs abciximab infusion and sirolimus-eluting stent vs uncoated stent implantation. MAIN OUTCOME MEASURES: For drug comparison, at least 50% ST-segment elevation resolution at 90 minutes postintervention with a prespecified noninferiority margin of 9% difference (relative risk, 0.89); for stent comparison, the rate of major adverse cardiac events, defined as the composite of death from any cause, reinfarction, and clinically driven target-vessel revascularization within 8 months. RESULTS: ST-segment resolution occurred in 302 of 361 patients (83.6%) who had received abciximab infusion and 308 of 361 (85.3%) who had received tirofiban infusion (relative risk, 1.020; 97.5% confidence interval, 0.958-1.086; P < .001 for noninferiority). Ischemic and hemorrhagic outcomes were similar in the tirofiban and abciximab groups. At 8 months, major adverse cardiac events occurred in 54 patients (14.5%) with uncoated stents and 29 (7.8%) with sirolimus stents (P = .004), predominantly reflecting a reduction of revascularization rates (10.2% vs 3.2%). The incidence of stent thrombosis was similar in the 2 stent groups. CONCLUSIONS: In patients with STEMI undergoing percutaneous coronary intervention, compared with abciximab, tirofiban therapy was associated with noninferior resolution of ST-segment elevation at 90 minutes following coronary intervention, whereas sirolimus-eluting stent implantation was associated with a significantly lower risk of major adverse cardiac events than uncoated stents within 8 months after intervention. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00229515