Overcoming thrombolytic resistance: rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction.

OBJECTIVES: We sought to review the emerging data and the clinical rationale for combining glycoprotein (GP) IIb/IIIa inhibitors with thrombolytic therapy for acute myocardial infarction (AMI). BACKGROUND: Although thrombolytic therapy has been a major advance in the treatment of acute ST segment elevation MI, new single-bolus thrombolytic agents have been unable to break the "thrombolytic ceiling" in infarct-related artery (IRA) patency. METHODS: Recent literature on GPIIb/IIIa inhibitors in acute coronary syndromes was reviewed. RESULTS: A new approach toward improving current thrombolytic-antithrombotic regimens focuses on "targeted therapy" for each component of the occlusive coronary thrombus: fibrin, thrombin and platelets. For the fibrin component, front-loading and/or bolus dosing of plasminogen activators (PAs) has identified the currently available doses of tissue-type plasminogen activator (t-PA) and recombinant tissue-type plasminogen activator (r-PA). For the thrombin component, several recent trials have shown that lower doses of heparin improve the safety profile of the thrombolytic-antithrombotic regimen. For the platelet component, aspirin has been shown to be effective, but the GPIIb/IIIa inhibitors offer the potential for more effective platelet inhibition and improved clinical efficacy. The benefits of GPIIb/IIIa inhibition in reducing death, MI or urgent revascularization in the setting of percutaneous coronary intervention are well established. Emerging experimental and clinical data now suggest that combining GPIIb/IIIa inhibition with reduced-dose thrombolytic therapy may improve early IRA patency without increasing bleeding risk. CONCLUSIONS: Given the strong clinical and physiologic rationale, clinical investigation in acute ST segment elevation MI is currently focused on combining the potent GPIIb/IIIa receptor inhibitors with reduced-dose fibrinolytic agents in acute MI, with the goal of overcoming "thrombolytic resistance."     

ST-segment elevation myocardial infarction

Opinion statement ST-segment elevation myocardial infarction (MI) is an emergency medical condition. Expediting the steps leading to coronary reperfusion is of critical importance in improving survival after acute MI. After the diagnosis of acute MI is made, patients should be treated with oxygen, aspirin, nitroglycerin, beta-blockers, heparin, and analgesics, barring any contraindications. If an experienced cardiac catheterization laboratory is available within 60 to 90 minutes, then catheter-based reperfusion therapy is recommended; otherwise, thrombolysis should be considered as an alternate therapy. Therapy with a reduced-dose thrombolytic agent and a glycoprotein IIb/IIIa receptor inhibitor appears to be of an added benefit in establishing TIMI (Thrombolysis in Myocardial Infarction) 3 flow, but this approach awaits final approval prior to widespread use. The adjunctive use of glycoprotein IIb/IIIa receptor inhibitors with percutaneous transluminal coronary angioplasty, with or without stenting, appears to be beneficial and is being used more frequently in the acute setting. Coronary angiography should be performed in patients who fail to respond to thrombolytic therapy or who have evidence of recurrent ischemia. This procedure should not be routinely performed in patients who have responded to thrombolytic therapy. Four to 6 days after an acute MI event, assessment of left ventricular function is recommended. Submaximal exercise test (with or without nuclear or echocardiographic imaging) should be considered in patients prior to discharge from the hospital—an exception can be made in patients with one-vessel disease treated successfully with percutaneous transluminal coronary angioplasty. After discharge, a regular exercise test should be obtained 4 to 6 weeks after an uncomplicated acute MI event. Secondary prevention measures such as weight loss, cessation of smoking, aspirin, beta-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors should be considered in all patients, barring contraindications.     

A subacute left ventricular free wall rupture after thrombolytic and glycoprotein IIb/IIIa inhibitor treatment: an overlooked finding of left ventriculography

Subacute left ventricular free wall rupture is a rare complication in acute myocardial infarction. With the increasing use of thrombolytic agents and glycoprotein IIb/IIIa inhibitors, this complication has been increasing recently. We report a case of subacute cardiac rupture with frank pericardial effusion receiving thrombolytic and glycoprotein IIb/IIIa inhibitor therapies.     

Use of Glycoprotein IIb/IIIa Inhibition Plus Fibrinolysis in Acute Myocardial Infarction

Pharmacological reperfusion therapy for acute myocardial infarction with intravenous fibrinolytic agents improves survival yet fails to achieve early and complete coronary blood flow in nearly half of treated patients. In principle, glycoprotein (GP) IIb/IIIa inhibitors, potent antiplatelet agents, might improve the efficacy and clinical outcomes associated with fibrinolysis. Preclinical research suggests more rapid and effective reperfusion with combined platelet GP IIb/IIIa inhibition and fibrinolysis. Early clinical studies confirm improved early patency and more rapid electrocardiographic resolution, but increased bleeding complications, with the addition of GP IIb/IIIa antagonists to conventional fibrinolysis. Future studies may combine reduced-dose fibrinolytic therapy with GP IIb/IIIa inhibition to optimize efficacy and safety.     

Glycoprotein IIb/IIIa receptor inhibitor-thrombolytic combination therapy for acute myocardial infarction

Over the past two decades, we have witnessed a large decrease in the death and complication rate of patients experiencing acute myocardial infarction (MI), due to our ability to restore blood flow to infarct-related arteries. Therapies include strategies to inhibit platelet function and induce fibrinolysis, and mechanical reperfusion with percutaneous intervention. Despite decreases in morbidity and mortality with thrombolytic therapy, reperfusion rates remain less than optimal. With standard fibrinolytic therapy in combination with aspirin, it is thought that thrombolyticinduced platelet activation may be an important reason for failure to induce perfusion, or maintain reperfusion in the infarct-related artery. In the past 10 years we have moved from platelet inhibition with aspirin to newer, more potent platelet inhibitors such as glycoprotein (GP) IIb/IIIa antagonists. Recent trials have evaluated the efficacy and safety of combining thrombolytic drugs with GP IIb/IIIa receptor antagonists. Future trends may use combination therapy as a part of a mechanical strategy, using these medications to induce early reperfusion as the patient is prepared for percutaneous intervention. This review summarizes recently published trials using combination thrombolytic and GP IIb/ IIIa receptor inhibitor therapy in the treatment of acute MI.     

Adjunctive therapies in the cath lab. Combination of tirofiban and alteplase in acute myocardial infarction

Primary angioplasty results in higher reperfusion rates than fibrinolysis in patients with acute myocardial infarction (MI). Two recent trials have shown improved rates of reperfusion when a reduced-dose thrombolytic is combined with the platelet glycoprotein IIb/IIIa receptor inhibitor abciximab. We present a case report of acute MI successfully treated with a combination of tirofiban and half-dose alteplase and eventual percutaneous coronary intervention.     

Facilitated percutaneous coronary intervention in acute myocardial infarction: attractive concept but difficult to prove!

Facilitated percutaneous coronary intervention (PCI) refers to a strategy of immediate PCI following the administration of pharmacological therapies in acute myocardial infarction. It has evolved primarily from the time delays (due to geography or logistics) in getting acute myocardial infarction patients to the catheterization laboratory and the associated irreversible loss of myocardial muscle that occurs as door-to-balloon time increases. Facilitated PCI provides an opportunity to start treating many of these patients before they reach the catheterization laboratory and provides an ability to open the infarct-related artery before PCI, which is associated with better outcomes for AMI patients. Pharmacological strategies before PCI include: thrombolytic therapy, glycoprotein IIb/IIIa inhibitor alone, or a combination of thrombolytic therapy plus glycoprotein IIb/IIIa inhibitor. Initial results of angiographic studies show better patency with the latter strategy but at the expense of higher bleeding event rates. Ongoing trials are evaluating different combinations of thrombolytic and glycoprotein IIb/IIIa inhibitor therapy.     

Vertebrobasilar Thrombolysis with Intravenous Tirofiban: Case Report

The use of thrombolytic agents in the setting of established cerebral infarction is limited by concerns for hemorrhagic transformation. Novel thrombolytic approaches, which have received minimal consideration, may be associated with lower risks of hemorrhage. We illustrate vertebrobasilar thrombolysis with intravenous tirofiban, a selective platelet glycoprotein IIb/IIIa receptor antagonist, and discuss the potential thrombolytic properties of this class of antithrombotics.     

Primary angioplasty compared with thrombolysis: new issues in the era of glycoprotein IIb/IIIa inhibition and intracoronary stenting.

The past decade has witnessed a dramatic expansion in the scope of both mechanical and pharmacologic methods for opening occluded arteries in patients with acute myocardial infarction. Although the relative merits of conventional balloon angioplasty and thrombolysis have been evaluated, this old debate is being eclipsed by new comparisons. New device technologies, such as intracoronary stenting; more potent and more fibrin-specific thrombolytic agents; and new antithrombotic and antiplatelet agents all offer the potential for improved outcomes. But despite these recent developments, the time-dependent open artery hypothesis--which states that the achievement of early, full, and sustained reperfusion is associated with better outcomes--remains essentially unchanged. This article reviews data on the ability of six revascularization strategies--stand-alone thrombolysis, conventional percutaneous transluminal coronary angioplasty, stenting, glycoprotein IIb/IIIa inhibitors plus thrombolytic agents, glycoprotein IIb/IIIa inhibitors plus interventions, and the combination of pharmacologic and mechanical interventions--to produce early, full, and sustained reperfusion.     

Anti-thrombotic, anti-platelet and fibrinolytic therapy: current management of acute myocardial infarction

Significant advances in the treatment of patients with acute myocardial infarction (MI) have been obtained in recent times. In particular, thrombolytic therapy has been shown to preserve ventricular function and improve survival in patients with acute MI. Therapies now include third-generation thrombolytic agents, percutaneous transluminal coronary angioplasty (PTCA) and intracoronary stenting, and new anti-thrombotic therapies including anti-platelet treatment with glycoprotein (GP) IIb/IIIa inhibition and direct anti-thrombin agents. This review will focus on the use of GP IIb/IIIa antagonists and thrombin inhibitors as adjunctive therapies to thrombolytic treatment of patients with acute MI.     

Glycoprotein IIb/IIIa inhibitors during rescue percutaneous coronary intervention in acute myocardial infarction

Although percutaneous coronary intervention (PCI) following full-dose thrombolytic therapy (rescue angioplasty) is a common procedure, there is ample controversy regarding the usefulness of the procedure. Moreover, few data are available concerning the safety and efficacy of concomitant treatment with glycoprotein (GP) IIb/IIIa inhibitors in these patients. The aim of the present study was to compare the clinical outcomes of patients who underwent rescue PCI with stents and were treated with GP IIb/IIIa inhibitors. A total of 59 consecutive patients underwent rescue PCI at our institution during the study period, 29 patients (49.2%) were treated concomitantly with a GP IIb/IIIa inhibitor and 30 patients (50.8%) were not. Baseline clinical characteristics were similar between the two groups. In-hospital outcomes regarding death, reinfarction and the need for urgent target vessel revascularization was significantly lower in patients treated with GP IIb/IIIa inhibitors compared to those who were not treated (3.4% vs. 26.7%; p = 0.01, respectively). However, GP IIb/IIIa inhibitor administration was not an independent predictor of better outcomes by multivariate analysis. There was a higher rate of major bleeding complications in patients who received GP IIb/IIIa inhibitors, though it did not achieve statistical significance (6.9% vs. 0%; p = 0.14, respectively). The composite endpoint of major, minor bleeding and vascular complications was similar in both groups (24.1% vs. 16.7%; p = 0.48). In conclusion, the administration of GP IIb/IIIa inhibitors in patients undergoing rescue PCI after failed thrombolysis with stents was safe and may have a beneficial effect on 30-day event-free survival rates, without a significant increase in bleeding or vascular complications. These results warrant further investigation.     

Platelet activation in acute myocardial infarction and the rationale for combination therapy

Current fibrinolytic regimens fail to fully restore coronary blood flow in slightly less than 50% of patients with acute myocardial infarction. Platelet activation and aggregation may be responsible for a large proportion of these therapeutic failures. Therefore, platelet inhibition may enhance thrombolysis. Experimental and early clinical evidence suggest that glycoprotein IIb/IIIa antagonists may enhance reperfusion when combined with reduced doses of thrombolytic agents. However, the clinical benefit of combination therapy will depend on the outcomes of a number large clinical trials that are currently being performed.     

Patterns of upstream antiplatelet therapy use before primary percutaneous coronary intervention for acute ST-elevation myocardial infarction (from the CRUSADE National Quality Improvement Initiative)

We sought to determine the usage patterns and impact of upstream glycoprotein IIb/IIIa inhibitor and clopidogrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). We studied trends in the use of upstream glycoprotein IIb/IIIa inhibitors and clopidogrel in 3,895 patients with STEMI undergoing primary PCI at 124 hospitals in the United States participating in the CRUSADE initiative from March 2005 to December 2006. Administration of these agents >15 minutes before PCI was considered pre-PCI use, and administration < or =15 minutes before, during, and after PCI was considered peri-PCI use. A total of 3,566 patients (91.6%) received glycoprotein IIb/IIIa inhibitors within 24 hours of presentation, of whom 1,225 (34.4%) received this medication before PCI. Similarly, 3,785 patients (97.2%) received clopidogrel within 24 hours of presentation, of whom 1,029 (27.2%) received this medication before PCI. From 2005 to 2006, pre-PCI glycoprotein IIb/IIIa inhibitor use decreased from 43.4% to 33.5%, whereas pre-PCI clopidogrel use increased from 21.2% to 31.5%. Clinical characteristics, risk of adverse outcomes, and bleeding events were similar in the pre- versus peri-PCI glycoprotein IIb/IIIa inhibitor and clopidogrel cohorts, respectively. In conclusion, most patients with STEMI undergoing primary PCI receive glycoprotein IIb/IIIa inhibitors and clopidogrel, but only (1/3) are treated upstream with these agents and this upstream use does not have a significant impact on outcomes. These results indicate that further studies are needed to determine the optimal dosing and timing of antiplatelet therapies for patients undergoing primary PCI.     

Intravenous glycoprotein IIb/IIIa inhibition in non-ST segment elevation acute coronary syndromes

Over recent years, substantial clinical trial evidence regarding glycoprotein IIb/IIIa inhibition for the medical management of non-ST segment elevation acute coronary syndromes has been compiled. Despite being recently advocated for the management of coronary instability within widely accepted guidelines, its use among patients presenting with acute coronary syndromes remains somewhat contentious. Within randomized placebo-controlled trials, uniform efficacy with the glycoprotein IIb/IIIa inhibitors has not been shown, whereas a disturbing excess in adverse events is evident within some trials. Currently, the basis for this heterogeneity of clinical evidence has not been adequately explained. However, evolving insights from clinical trials and basic research have further refined our understanding of glycoprotein IIb/IIIa antagonist therapy and the potential effects beyond the inhibition of the fibrinogen receptor. Likewise, appreciation of the pharmacokinetic characteristics of these agents provides putative explanations for the diverse findings of the randomized trials. Reexamination of the clinical trial data in light of this recent evidence provides a basis for interpreting the marginal results of glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Consideration of these factors may facilitate the optimal clinical application of this class of agents to the management of coronary instability.     

Glycoprotein IIb/IIIa inhibition in the setting of acute ST-segment elevation myocardial infarction

Glycoprotein (GP) IIb/IIIa inhibitors have been extensively studied in the setting of percutaneous coronary intervention (PCI) and in the management of non-ST-segment elevation acute coronary syndromes. However, the use of GP IIb/IIIa inhibitors is less well established in the setting of acute ST-segment elevation myocardial infarction (MI). Multiple nonrandomized studies suggest that combination therapy with GP IIb/IIIa inhibitors and thrombolytic agents leads to increased rates of TIMI 3 flow. However, two clinical trials involving over 22,000 patients demonstrated that combination therapy is associated with only modest reductions in major adverse cardiac events, does not reduce mortality, and is associated with an increase in bleeding. In the setting of primary PCI, four clinical trials involving over 3,000 patients demonstrated that GP IIb/IIIa inhibition results in a significant decrease in the need for urgent target vessel revascularization but not in reductions of death or recurrent MI. Thus, GP IIb/IIIa inhibition may provide only limited benefits in the setting of acute ST-segment elevation MI.     

Impact of platelet glycoprotein IIb/IIIa Inhibition on the paclitaxel-eluting stent in patients with stable or unstable angina pectoris or provocable myocardial ischemia (a TAXUS IV substudy)

Whether the benefits that glycoprotein IIb/IIIa inhibitors confer in patients who undergo bare metal stent implantation extend to drug-eluting stents is unknown. We performed a prespecified subgroup analysis of the TAXUS IV study population to examine the effect of procedural glycoprotein IIb/IIIa inhibition during paclitaxel-eluting stent implantation on periprocedural creatine kinase-MB (CK-MB) levels. Glycoprotein (GP) IIb/IIIa inhibitors were administered to 57.7% of patients who had been randomized to receive the TAXUS stent and to 56.7% of those who had been randomized to receive the control stent. Among patients who received the TAXUS stent, the rate of CK-MB increases of >3 times the normal level was 2.6-fold higher in those who received a GP IIb/IIIa inhibitor than in those who did not (11.4% vs 4.4%, p = 0.0015). Composite rates of major adverse cardiac events and target vessel failure were also higher at 1 month in the GP IIb/IIIa group. By multivariate analysis, use of GP IIb/IIIa inhibitors during stenting with the TAXUS stent was an independent predictor of CK-MB increases >3 times the normal level. Further studies are warranted.     

The role of risk stratification in the decision to provide upstream versus selective glycoprotein IIb/IIIa inhibitors for acute coronary syndromes: a cost-effectiveness analysis.

OBJECTIVES: We endeavored to determine under what conditions a strategy of upstream use of small molecule platelet glycoprotein (GP) IIb/IIIa inhibitors for all acute coronary syndromes (ACS) patients is cost effective compared to that of selective use of abciximab in only those patients requiring percutaneous coronary intervention (PCI). BACKGROUND: Small molecule GP IIb/IIIa inhibitors have shown benefit in ACS, but abciximab, the more expensive GP IIb/IIIa inhibitor, may be more effective during PCI. However, abciximab does not have proven efficacy in medical management. No prior study has attempted to balance these competing benefits. METHODS: A decision analysis was performed to examine two strategies: 1) treat all ACS patients upstream with a small molecule GP IIb/IIIa inhibitor and continue through medical management and PCI, if performed; or 2) wait, and selectively use abciximab only in patients who ultimately undergo PCI. Applicable randomized controlled trial data were used for the principal analysis. RESULTS: The strategy of upstream use of a small molecule GP IIb/IIIa inhibitor was superior to selective use, and economically acceptable, with a cost-effectiveness ratio of 18,000 dollars per year of life gained. The superiority of the upstream use strategy persisted over the majority of sensitivity analyses. When stratified by risk according to Thrombolysis in Myocardial Infarction risk score, a strategy of upstream use was only cost effective in those patients with moderate or high risk. CONCLUSIONS: Upstream use of small molecule GP IIb/IIIa inhibition in ACS patients with moderate or high risk for cardiovascular events is a cost-effective approach that should be considered in this subset of patients.     

Randomized,placebo-controlled study of Lamifiban with thrombolytic therapy for the treatment of acute myocardial infarction: Rationale and design for the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) study

The benefits of thrombolytic therapy in the treatment of acute myocardial infarction are incontrovertible. Large-scale studies combining angiographic and clinical endpoints have demonstrated a perfusion-mortality relationship, with the highest survival rate among patients with early restoration of TIMI grade 3 coronary arterial flow. Despite advances in thrombolytic strategies, a substantial number of patients fail to rapidly achieve and maintain adequate coronary perfusion with thrombolysis. Conjunctive therapy with aspirin has proven useful in thrombolytic regimens, likely countering the heightened platelet activity central to acute coronary syndromes. The antiplatelet effect of aspirin is relatively weak compared with that of glycoprotein IIb/IIIa platelet receptor antagonists, which block the final common pathway of platelet aggregation. Lamifiban is a nonpeptide glycoprotein IIb/IIIa receptor antagonist. In early experimental studies, Lamifiban in combination with thrombolytic therapy has been shown to effectively restore coronary arterial patency, and phase I and phase II data have shown its use to be safe. To determine the optimal dose with regard to safety and efficacy of Lamifiban to be used with thrombolytic therapy in a large-scale trial, a phase II study is underway. The Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) study is a randomized, placebo-controlled study of Lamifiban in 400 patients receiving thrombolysis as treatment for acute myocardial infarction. By studying 90-minute angiography, platelet aggregation, continuous electrocardiography, and clinical outcome in PARADIGM, important insights will be obtained to determine the optimal dose of Lamifiban for phase III study. We provide the background and rationale for the study of Lamifiban in PARADIGM and other ongoing studies in acute coronary syndromes.     

The role of glycoprotein IIb/IIIa inhibition in the management of acute coronary syndromes

Recent advances in the understanding of the pathophysiology of thrombus formation and the role of platelet adhesion have led to a new pharmacologic era in cardiology. The advent of the glycoprotein IIb/IIIa inhibitor, primarily used in conjunction with percutaneous coronary intervention, has proved to be beneficial beyond the confines of the cardiac catheterization laboratory. The glycoprotein IIb/IIIa inhibitor has inspired much research in the past few years of its use in the management of acute coronary syndromes. The CAPTURE, PURSUIT, PRISM, and PRISM-PLUS trials have all documented the beneficial effects of glycoprotein IIb/IIIa inhibition that have reduced 2 of the major sequelae of acute coronary syndromes: myocardial infarction and death. Through the implementation of primary research-based data, it is the job of practitioners to appropriately stratify and implement judicious use of glycoprotein IIb/IIIa inhibition with the population affected by acute coronary syndromes.     

Role of new antiplatelet agents as adjunctive therapies in thrombolysis

Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion.