Impacts of glycoprotein IIb/IIIa inhibition on QT dispersion after successful percutaneous coronary intervention

Coronary ischemia augments inhomogeneity in ventricular repolarization. Decrease in the QT dispersion (QTd) following restoration of coronary blood flow to the ischemic myocardium by successful percutaneous coronary intervention (PCI) is an expected outcome. The purpose of the study was to seek whether glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition has additional beneficial effects on QT dispersion after angiographically successful PCI. The study involved 111 consecutive patients scheduled for elective coronary balloon angioplasty with or without stent implantation. Sixty patients (mean age 58 +/-9) were randomized to receive standard therapy including preprocedural aspirin, ticlopidine, and IV heparin, and 51 patients (mean age 54 +/-10) were randomized to receive additional IV tirofiban infusion before the lesion was crossed with the guidewire. Standard 12-lead simultaneous ECG recordings for the measurement of QTd and corrected QTd (QTcd) (calculated by using Bazett's formula) were obtained before and immediately after the procedure, and at the 6th, and 24th hours. Blood samples for detection of postprocedural myocardial damage (CK-MB and cTn-I) were taken before and immediately after the procedure, at the 6th, 12th, and 24th hours. In total, 128 stenoses were treated with PCI. Seventy of these lesions were in the standard therapy group and 58 in the tirofiban group. QTd and QTcd were not statistically different between the 2 groups before and immediately after the procedure and at the 6th hours, but at the 24th hour QTd and QTcd were significantly longer in the standard therapy group (p=0.047 and p=0.001, respectively). Postprocedural troponin-I elevation (B=0.692, p=0.037), maximum inflation pressure (B=0.182, p=0.001), and previous myocardial infarction (MI) (B=0.885, p=0.004) were defined as the predictors of the final QT dispersion at the 24th hour. QT dispersion significantly decreased after successful percutaneous coronary intervention. GP IIb/IIIa inhibition therapy was not superior by means of recovery of increased QT dispersion during the early hours of the intervention, but it prevented minor myocardial necrosis and provided more long-lasting recovery in QT dispersion as compared with heparin therapy. This impact of GP IIb/IIIa receptor inhibition on QTd may be a possible mechanism by which these drugs reduce cardiovascular events after PCI.     

Incidence and predictors of major vascular complications after percutaneous coronary intervention in the glycoprotein IIb/IIIa platelet inhibitor era

Since the introduction of platelet glycoprotein (GP) IIb/IIIa inhibitors, reports of vascular complications after percutaneous coronary intervention (PCI) have focused on bleeding and the need for surgical repair, whereas specific major vascular complications have been less consistently identified. Moreover, data from clinical trials may lack applicability to the general population. The purpose of this study was to determine the incidence of major vascular complications after PCI and to identify associated risk factors in patients routinely receiving GP IIb/IIIa inhibitors. During a 12-month period, 1,634 consecutive patients underwent PCI at a single institution. Clinical characteristics and procedural data were collected prospectively; data regarding vascular sheath removal were obtained retrospectively. Univariate and multivariable regression methods were used to identify independent predictors of major vascular complications. Major vascular complications occurred in 2.9% of patients. Multivariable analysis revealed advanced age (odds ratio [OR] 1.05, P = 0.0025) and female sex (OR 2.9, P = 0.0002) as clinical characteristics associated with major vascular complications, whereas hypertension had an inverse relationship (OR 0.46, P = 0.013). Procedural factors included use of the following: stents (OR 5.59, P < 0.0001), vascular sheaths >6F (OR 3.25, P = 0.016), and mechanical clamp (OR 2.71, P = 0.0012). The presence of a hematoma >4 cm(2) had a positive predictive value of 12% for major vascular complications. The incidence of major vascular complications in this large, single-center study from the GP IIb/IIIa inhibitor era is consistent with data from the pre-GP IIb/IIIa inhibitor era and recent randomized trials.     

Combination platelet glycoprotein IIb/IIIa receptor and lepirudin administration during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia.

We evaluated a combination therapy using glycoprotein IIb/IIIa receptor antagonism and direct thrombin inhibition in nine patients with heparin-induced thrombocytopenia (HIT) undergoing 10 percutaneous coronary interventions (PCIs). In selected patients with HIT, the combination of a direct thrombin inhibitor, lepirudin, and abciximab, tirofiban, or eptifibatide appears to be a safe and effective anticoagulation strategy for 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.     

Oral platelet glycoprotein IIb/IIIa inhibition

Platelet aggregation plays a central role in the pathogenesis of thrombosis and the acute coronary syndromes. When given intravenously, potent selective antagonists of fibrinogen binding to the glycoprotein (GP) IIb/IIIa receptor, the final common pathway for platelet aggregation, have been effective in the treatment of acute coronary syndromes. Their benefit ceases, however, with the end of the infusion. Aspirin reduces the incidence of secondary vascular events by 25% to 30% after an acute coronary syndrome, and clopidogrel provides modest improvement over aspirin. However, both are relatively weak antiplatelet agents that each block only one of many pathways to platelet activation and surface membrane expression of the competent GP IIb/IIIa receptor. With the success of the intravenous GP IIb/IIIa antagonists in the acute setting, recent interest has focused on the potential benefit of oral GP IIb/IIIa antagonists used long-term for secondary prevention. The oral agents tested in phase III studies thus far have not performed up to expectations, however. The following paper reviews these studies and the implications of their results.     

A propensity analysis of the impact of platelet glycoprotein IIb/IIIa inhibitor therapy on in-hospital outcomes after percutaneous coronary intervention

It is unknown whether the benefits of parenteral platelet glycoprotein (GP) IIb/IIIa inhibitors as an adjunct to percutaneous coronary intervention (PCI) demonstrated in randomized clinical trials extend to patients treated outside the setting of clinical trials. A contemporary registry of 10,847 consecutive PCI procedures was analyzed to determine the effect of GP IIb/IIIa inhibitor treatment on in-hospital major adverse coronary events ([MACEs] composite of death, urgent coronary artery bypass surgery, periprocedural myocardial infarction, abrupt closure, and stent thrombosis). In this registry, GP IIb/IIIa inhibitors were administered to 20.1% of patients. These patients were younger, more often men, and less often hypertensive than untreated patients. GP IIb/IIIa inhibitor-treated patients were more likely to present with acute myocardial infarction or unstable angina. Stents were placed in 79% of patients treated with GP IIb/IIIa inhibitors. MACEs occurred in 7.8% of GP IIb/IIIa inhibitor-treated patients compared with 3.8% of untreated patients (p <0.001). After multivariable adjustment for the propensity of GP IIb/IIIa inhibitor treatment as well as other possible confounders and interactions known to influence MACEs, GP IIb/IIIa inhibitor treatment was associated with a 57% increase in the risk of a MACE (odds ratio 1.57, 95% confidence interval 1.22 to 2.03; p = 0.0004). In a data set consisting of patients with a high degree of acuity predominantly treated with stent placement, GP IIb/IIIa inhibitor treatment is associated with an increase in thrombotic complications of PCI.     

The use of the glycoprotein IIb/IIIa receptor antagonists during percutaneous coronary intervention

Coronary thrombosis is the major cause of ischemic complications during percutaneous coronary interventions (PCI). The glycoprotein (GP) IIb/IIIa receptor plays a critical role in the process of platelet thrombus formation since it serves as the final common pathway for platelet aggregation. Presently, there are three commercially available intravenous GPIIb/IIIa inhibitors that block fibrinogen binding to its receptor. These agents significantly reduce the incidence of death and nonfatal myocardial infarction at 30 days in patients undergoing percutaneous coronary revascularization. In addition, the early benefits appear to be sustained at 6 months to 1 year. Increasing evidence shows that the predominant mechanism of benefit is due to a reduction in embolization to the microcirculation that occurs during PCI. While data regarding the comparative efficacy and cost-effectiveness of these agents are scarce, the magnitude of benefit appears to be greatest for abciximab. Furthermore, a mortality benefit has been demonstrated only for abciximab. Although high risk patients reap the greatest benefit from the use of these agents, it is clear that even patients who are classified as low-to-moderate risk still derive substantial benefit from their use. Finally, evidence indicates that the majority of patients with acute coronary syndromes without ST segment elevation who are scheduled to undergo PCI should be pretreated with a GPIIb/IIIa receptor antagonist.     

Variability in extent of platelet function inhibition after administration of optimal dose of glycoprotein IIb/IIIa receptor blockers in patients undergoing a high-risk percutaneous coronary intervention

The Ultegra Rapid Platelet Function Assay was used to measure the inhibition of platelet aggregation at baseline and 10 minutes and 8 hours after starting therapy in 114 patients undergoing high-risk percutaneous coronary intervention with the planned use of a glycoprotein IIb/IIIa inhibitor. The abciximab-treated patients received a 0.25 mg/kg bolus, followed by a 0.125 microg/kg/min infusion for 12 hours; the eptifibatide-treated patients received 2 boluses of 180 microg/kg administered 10 minutes apart, followed by a 2 microg/kg/min infusion for 24 hours; the tirofiban-treated patients received a 25 microg/kg bolus, followed by a 0.15 microg/kg/min infusion for 18 hours. Ten minutes after starting therapy, the mean level of platelet inhibition was 86 +/- 9% for abciximab, 92 +/- 6% for eptifibatide, and 95 +/- 5% for tirofiban (p <0.001); > or =95% platelet inhibition was achieved in 29% of the patients treated with abciximab, 44% of those receiving eptifibatide, and 68% of the those receiving tirofiban (p = 0.02). In conclusion, at the evaluated doses, tirofiban seemed to be the most effective drug in achieving "optimal" platelet inhibition very early after percutaneous coronary intervention.     

Meta-analysis of randomized controlled trials of intracoronary versus intravenous administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention for acute coronary syndrome

It is unclear whether intracoronary (IC) bolus administration of glycoprotein IIb/IIIa inhibitors (GPIs) during percutaneous coronary intervention (PCI) in patients with acute coronary syndromes is superior to intravenous (IV) administration. We conducted a meta-analysis of randomized controlled trials (RCTs) to compare the effects of IC and IV administrations of GPIs in patients with acute coronary syndromes. We systematically searched the Cochrane Library, EMBASE, and MEDLINE databases for RCTs comparing IC to IV administration of GPIs (abciximab, eptifibatide, tirofiban) during PCI. Data were pooled and stratified into short (1 month to 3 months) and mid-/long-term (≥6 months) follow-up durations. Ten RCTs involving 1,590 patients met our inclusion criteria. Compared to the IV group the IC group was more likely to have complete perfusion (Thrombolysis In Myocardial Infarction grade 3 flow) after PCI (risk ratio [RR] 1.08, 95% confidence interval [CI] 1.02 to 1.15). IC administration was associated with similar bleeding rates as IV (RR 0.92, 95% CI 0.68 to 1.24) but with a significant decrease in short-term target vessel revascularization (RR 0.54, 95% CI 0.30 to 0.96). IC administration was also associated with a significant decrease in short-term mortality (RR 0.45, 95% CI 0.23 to 0.90) but this decrease was no longer significant in mid-/long-term RCTs. In conclusion, compared to IV administration IC administration of GPIs has favorable effects on Thrombolysis In Myocardial Infarction flow, target vessel revascularization, and short-term mortality after PCI, with no difference in rates of bleeding. Data regarding mid-/long-term outcomes were limited and inconclusive. Large RCTs with longer follow-up are required to determine long-term safety and efficacy.     

Effect of glycoprotein IIb/IIIa receptor inhibition on angiographic complications during percutaneous coronary intervention in the ESPRIT trial

OBJECTIVES: We sought to determine whether eptifibatide decreases the incidence of in-laboratory angiographic complications and to determine the relationship of angiographically evident complications to elevations of creatine kinase-MB (CK-MB) enzyme levels during percutaneous coronary intervention. BACKGROUND: In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, eptifibatide during coronary intervention was associated with decreased ischemic complications at 48 h and 30 days. METHODS: Patients (n = 2,064) were randomized to placebo versus eptifibatide (two 180 microg/kg boluses 10 min apart and as a continuous infusion of 2 microg/kg per min) during percutaneous coronary stenting. Angiographic complications including major dissection, distal embolization, residual thrombus, abrupt closure, residual stenosis >50% and side-branch occlusion were prospectively recorded by the operator. Creatine kinase-MB levels were measured after the procedure and every 6 h thereafter. The incidence of angiographic complications and CK-MB elevation was determined for eptifibatide versus placebo groups. RESULTS: Eptifibatide-treated patients demonstrated nonsignificant trends toward fewer angiographic complications (10 vs. 12% for placebo patients, p = 0.13) and, for patients with angiographic complications, fewer subsequent CK-MB elevations (43 vs. 50% for placebo patients, p = 0.31). In patients without any angiographic complications, the incidence of CK-MB elevation >3 times the normal was 7% with placebo and 4% with eptifibatide (p = 0.003). CONCLUSIONS: Eptifibatide during nonurgent coronary stent intervention only minimally (and insignificantly) reduces the incidence of angiographic complications and subsequent CK-MB elevations in patients developing an angiographic complication. The greater effect is to reduce myocardial infarction in patients undergoing otherwise uneventful coronary stent implantation as well as in the overall study population.     

Association of glycoprotein IIb/IIIa inhibitors and long-term survival following administration during percutaneous coronary intervention for acute myocardial infarction

Objectives: We sought to evaluate the impact of GP IIb/IIIa receptor blockers on long-term mortality in patients undergoing PCI for AMI. Background: Glycoprotein (GP) IIb/IIIa inhibitors are potent suppressors of platelet aggregation and when used during percutaneous coronary intervention (PCI) for the treatment of acute myocardial infarction (AMI) may improve short-term clinical outcomes, including survival. However, the impact of GP IIb/IIIa treatment during PCI for AMI on long-term survival is unknown. Methods: Patients undergoing primary or rescue PCI for AMI within 24 hours of symptom onset with or without GP IIb/IIIa inhibitor treatment were identified from a multicenter PCI database. All cause mortality at a mean follow-up of 3 years was the primary end point. Results: Of the 269 patients treated with primary or rescue PCI for AMI, 107 (40%) received a GP IIb/IIIa antagonist. Patients treated with GP inhibitors were more likely to present with or develop heart failure (13% vs. 6.2%, P = 0.052). Left ventricular ejection fraction was reduced in those treated with GP IIb/IIIa antagonists (44% vs. 48%, P = 0.051). The extent of coronary artery disease did not differ between groups. Stent use was 80% in both groups. Procedural success was high and did not differ between groups. In-hospital mortality was low and did not differ between groups. The mortality at a mean follow-up of 3 years was 1.9% among patients treated with a GP IIb/IIIa antagonist and 15% for those who were not treated (log-rank P = 0.0005). Treatment with a GP IIb/IIIa antagonist was independently associated with a significant reduction in the hazard of long-term mortality (Hazard Ratio, 0.159; 95% Confidence Interval, 0.034–0.729; P = 0.018). Conclusions: Treatment of patients undergoing PCI for AMI with GP IIb/IIIa antagonists appears to be associated with a profound reduction in late mortality.     

Use of platelet glycoprotein IIb/IIIa inhibitors in saphenous vein graft percutaneous coronary intervention and clinical outcomes

Platelet glycoprotein (GP) IIb/IIIa inhibitors are widely used in percutaneous coronary intervention (PCI). Previous studies have suggested that they do not offer benefit in saphenous vein graft PCI. Nonetheless, their use remains widespread during vein graft angioplasty. We retrospectively analyzed 1,537 patients who underwent saphenous vein graft PCI. Patients who received a GP IIb/IIIa inhibitor (n = 941) were compared with those who did not receive any GP IIb/IIIa inhibitor (n = 596). The primary end point was myonecrosis after PCI (creatine kinase-MB level >3 times the upper reference limit). The incidence of myonecrosis after PCI was similar between the group that received GP IIb/IIIa and the group that did not (odds ratio for GP IIb/IIIa use 1.39, 95% confidence interval 0.97 to 2.00, p = 0.07). Propensity-adjusted analysis demonstrated no significant difference in myonecrosis after PCI, in-hospital mortality, Q-wave myocardial infarction, or bleeding (blood transfusion, retroperitoneal bleed, or hematoma) between the 2 groups. In an analysis restricted to patients who were treated with an emboli protection device, GP IIb/IIIa use was not associated with decreased myonecrosis after PCI (this was also the case for patients who were not treated with an emboli protection device). Unadjusted survival (mean follow-up 5.5 +/- 0.1 years) was similar between the group that received GP IIb/IIIa and the group that did not (log-rank test, p = 0.89). There was no difference in survival after adjusting for the propensity to receive a GP IIb/IIIa inhibitor (adjusted odds ratio for GP IIb/IIIa use 0.92, 95% confidence interval 0.69 to 1.23, p = 0.59). In conclusion, adjunctive use of platelet GP IIb/IIIa inhibitors in saphenous vein graft PCI does not appear to be associated with less myonecrosis or improved survival.