Successful use of eptifibatide as an adjunct to coronary stenting in a patient with abciximab-associated acute profound thrombocytopenia

A 72-year-old male who was given abciximab for unstable angina developed acute profound thrombocytopenia with a platelet count nadir of 6,000/mm3. He was treated with steroids and platelet transfusion. Four days later, he underwent coronary angioplasty after pretreatment with eptifibatide without development of thrombocytopenia. This suggests that the development of thrombocytopenia with abciximab is not necessarily a contraindication to subsequent use of glycoprotein (GP) IIb/IIIa receptor antagonists. Eptifibatide may be an appropriate consideration in high-risk patients who would benefit from a GP IIb/IIIa receptor antagonist, in spite of acute profound thrombocytopenia due to abciximab therapy.     

Platelet glycoprotein IIb/IIIa inhibitor therapy in non-ST segment elevation acute coronary syndromes

Platelet glycoprotein (GP) IIb/IIIa inhibitors prevent fibrinogen binding and platelet aggregation. They decrease ischemic complications associated with non-ST segment elevation acute coronary syndromes and percutaneous coronary intervention. Meta-analyses of 6 randomized trials of parenteral GP IIb/IIIa inhibitors in patients with acute coronary syndromes suggest a significant reduction in death and myocardial infarction in high risk patients. These include patients undergoing early percutaneous coronary intervention or those with high TIMI risk score, elevated troponin values, or diabetes mellitus. Despite guideline recommendations supporting therapy for these indications, only a minority of appropriate candidates are being treated. The risk of major bleeding is small; thrombocytopenia can result from abciximab therapy. Optimal dosing strategies continue to evolve.     

Profound thrombocytopenia associated with tirofiban: case report and review of literature

Platelet glycoprotein (GP)IIb/IIIa inhibitors prevent fibrinogen binding and platelet aggregation. Inhibition of platelet activity at the injured coronary plaque is a target for novel therapeutic strategies. They decrease ischemic complications associated with non-ST-segment elevation acute coronary syndromes and percutaneous coronary intervention. Thrombocytopenia is a serious complication well described with the use of the prototype GP IIb/IIIa inhibitor abciximab. Its association with other agents of this class has been underemphasized. It is important to monitor platelet counts closely after initiation of GP IIb/IIIa inhibitor therapy, not only for abciximab, but also for small molecule inhibitors such as eptifibatide and tirofiban. Monitoring of platelet counts at 2 to 6 hours and 24 hours will detect most cases of acute thrombocytopenia. Adverse events may be prevented by prompt discontinuation of GP IIb/IIIa inhibitor therapy. The authors present a case of profound thrombocytopenia after the administration of tirofiban in the treatment of a patient with an acute coronary syndrome.     

Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization

Objectives. This study sought to determine the frequency of thrombocytopenia and its relation with clinical outcomes in high risk patients undergoing percutaneous coronary revascularization who received either the platelet glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (ReoPro, c7E3 Fab) or conventional therapy.Background. The development of thrombocytopenia on exposure to GPIIb/IIIa antagonists threatens the utility and economic viability of this drug class for patients with vascular disease.Methods. We analyzed data from the Evaluation of c7E3 for the Prevention of Ischemic Complications trial (EPIC), a 2,099-patient, randomized trial of placebo, abciximab bolus or abciximab bolus plus a 12-h infusion during high-risk coronary revascularization.Results. Thrombocytopenia (nadir platelet count <100 × 10⁹/liter) developed in 81 patients (3.9%) during their hospital stay, with 19 (0.9%) developing severe (<50 × 10⁹/liter) thrombocytopenia. Both thrombocytopenia and severe thrombocytopenia were more frequent in the bolus-plus-infusion arm (5.2% and 1.6%, respectively) than in the bolus-only and placebo arms combined (p = 0.020 and p = 0.025, respectively). Acute profound thrombocytopenia developed in two patients in the bolus-plus-infusion arm. Patients with thrombocytopenia experienced more unfavorable clinical outcomes than those who did not develop thrombocytopenia, regardless of treatment assignment, but those with thrombocytopenia who received abciximab had fewer worse outcomes at 30 days. Multivariable logistic modeling revealed a lower baseline platelet count, older age and lighter weight to be important predictors of thrombocytopenia. In a logistic regression model, bolus-plus-infusion treatment was a significant predictor of thrombocytopenia (p = 0.016) and remained so after adjustment for procedures and baseline risk factors (p = 0.0077).Conclusions. Thrombocytopenia was associated with adverse clinical outcomes and excessive bleeding, but patients receiving abciximab fared better than those receiving placebo.     

Delayed thrombocytopenia following abciximab therapy

Inhibitors of glycoprotein (GP) IIb/IIIa are currently approved for the treatment of acute coronary syndromes and during performance of percutaneous coronary interventions (PCIs). More than 500 000 patients annually undergo PCIs in the USA alone. Of these, 35% are receiving GPIIb/IIIa inhibitors. Currently, three different intravenous GPIIb/IIIa inhibitors are commercially available. Profound thrombocytopenia occurs almost exclusively with abciximab. Usually thrombocytopenia develops within 24 hours following abciximab administration. This paper describes three patients who developed delayed profound thrombocytopenia, occurring five days following abciximab therapy. These cases of thrombocytopenia were self-limited and reversible. Absence of serious bleeding complications was noted. The pathophysiology, differential diagnosis, natural history and management of the coronary patients with abciximab-induced thrombocytopenia are discussed.     

A Review of Clinical Trials with Eptifibatide in Cardiology

Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit the binding of ligands to activated platelet GP IIb/IIIa receptors and, therefore, prevent the formation of platelet thrombi. Additional antithrombin therapy should be given in connection with GP IIb/IIIa administration. Eptifibatide is a small heptapeptide, which is highly selective and rapidly dissociates from its receptor after cessation of therapy. In clinical trials (IMPACT‐II and ESPRIT) concomitant administration of eptifibatide to patients undergoing percutaneous coronary intervention (PCI) reduced thrombotic complications. In the PURSUIT trial, in patients with non‐ST‐elevation acute coronary syndromes, eptifibatide, compared to placebo, significantly reduced the primary endpoint of death and nonfatal myocardial infarction at 30 days. In patients with STEMI eptifibatide has been studied as an adjunct to fibrinolysis and primary PCI; it improved epicardial flow and tissue reperfusion. Current studies are evaluating eptifibatide as upstream therapy in high‐risk patients with NSTE‐ACS, in the EARLY‐ACS and in comparison with abciximab in patients with primary PCI in the EVA‐AMI trial.     

GP IIb/IIIa inhibitors during primary percutaneous coronary intervention for STEMI: New trial and registry data

Primary percutaneous coronary intervention (PCI) with adjunctive glycoprotein (GP) IIb/IIIa receptor inhibitor therapy administered in the cardiac catheterization laboratory is the optimal reperfusion strategy for patients with ST-elevation myocardial infarction. Most available data regarding these agents are from trials comparing abciximab to placebo alone. Noninferiority trials comparing small-molecule GP IIb/IIIa receptor inhibitors, such as tirofiban and eptifibatide with abciximab, have used markers for myocardial reperfusion as primary end points but are underpowered to detect significant differences in hard clinical outcomes. Such a trial would need to enroll a very large number of patients and thus make it practically impossible to perform. Registry data reveal that most patients undergoing primary PCI are treated with small-molecule GP IIb/IIIa receptor inhibitors in clinical practice, and no observed difference is observed in safety and efficacy when compared with patients treated with abciximab therapy.     

An audit of the use and complications of glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention against national UK standards

Coronary thrombosis is a pivotal event in the pathogenesis of acute coronary syndromes and ischemic complications resulting from coronary intervention. Activation of the platelet glycoprotein (GP) IIb/IIIa receptor is the final common pathway leading to platelet aggregation, coronary thrombus formation, and myocardial ischemia. Inhibitors of platelet GP IIb/IIIa are potent agents to prevent progression to myocardial infarction and death.

We prospectively surveyed the indications, frequency, and complications associated with the use of GP IIb/IIIa inhibitors in percutaneous coronary intervention in a tertiary center setting.

A total of 170 patients underwent screening over a period of 6 weeks. One hundred four (61%) had coronary intervention, out of which eight (8%) had failed intervention. Glycoprotein IIb/IIIa inhibitors were used in 57 (55%) patients; 47 (45%) did not have any agent periprocedure. Eptifibatide was the most commonly used agent in 35 (33%), followed by abciximab in 19 (18%) and tirofiban in 3 (3%).

Out of 57 patients in whom GP IIb/IIIa agents were used, 22 (38%) had visible intracoronary thrombus, 22 (38%) had diffuse disease, 8 (14%) had complex intervention, and 5 (9%) had diabetes.

The overall incidence of complications was not increased by the use of GP IIb/IIIa inhibitors; serious complications were rare with the use of GP IIb/IIIa agents; no stroke, thrombocytopenia, gastrointestinal bleed, or death was recorded. The overall use in emergency settings was not associated with increased complications. Bradycardia and vomiting were more common with abciximab group, whereas puncture site pain was commoner in eptifibatide group.     

Bleeding complications of platelet glycoprotein IIb/IIIa inhibitor abciximab (ReoPro )

Studies of patients scheduled for percutaneous coronary intervention with acute coronary syndrome have shown that the addition of intravenous glycoprotein (GP) IIb/IIIa inhibitors to aspirin and heparin is associated with a reduction in death or myocardial infarction compared to therapy with aspirin and heparin alone. The principle safety issue with GP IIb/IIIa inhibitors is the risk of bleeding, as the potent antiplatelet effect of these drugs may adversely affect hemostasis. In addition, antagonists of GP IIb/IIIa may increase the risk of thrombocytopenia. We report a case of abciximab-induced severe thrombocytopenia which led to fatal intra-cranial hemorrhage.     

Efficacy of abciximab readministration in coronary intervention

Abciximab, an Fab monoclonal antibody fragment that blocks the platelet glycoprotein IIb/IIIa receptor, is increasingly used as an adjunct to coronary intervention. Little is known, however, about the efficacy and safety of readministration of abciximab. This study examined and characterized outcomes of patients receiving abciximab for a second time. From April 1995 to June 1997, 164 consecutive patients were readministered abciximab at our 3 institutions. We retrospectively examined and analyzed in-hospital outcomes in this cohort. The median time to readministration was 95 days. The angiographic success rate of percutaneous intervention was 99.5%. Rates and 95% confidence intervals of in-hospital events were death 2% (0.7% to 6.1%), myocardial infarction 3% (1% to 7%), coronary bypass surgery 0% (0% to 2.2%), and intracranial hemorrhage 2% (0.4% to 5.3%). Severe thrombocytopenia was observed in 4% of patients (1.4% to 7.8%) after readministration. Allergic or anaphylactic reactions were not observed. Major bleeding was associated with excessive concomitant antithrombotic therapy. Patients undergoing readministration of abciximab within 2 weeks of first administration experienced a higher incidence of severe thrombocytopenia (12% vs. 2%, p = 0.046). Thus, abciximab remains clinically efficacious when readministered as an adjunct to percutaneous coronary intervention. However, concomitant heparin administration must be carefully monitored and warfarin therapy should be avoided. Vigilant surveillance for thrombocytopenia should be employed. Reduced dosing may be necessary when abciximab is readministered within days of the initial administration.     

Glycoprotein IIb/IIIa inhibitor-associated thrombocytopenia: clinical predictors and effect on outcome

Glycoprotein IIb/IIIa inhibitors are used as an adjunct to antiplatelet therapy in percutaneous coronary intervention to reduce postprocedural enzyme elevations. Previous studies have shown a risk for thrombocytopenia that is associated with these agents. We sought to evaluate the incidence and outcomes of glycoprotein IIb/IIIa inhibitor-associated thrombocytopenia in an unselected series of patients undergoing percutaneous coronary intervention. We reviewed 984 interventions performed on 908 subjects over a specific time period. Glycoprotein IIb/IIIa inhibitors were used in 58.8% of cases. Their use increased from 38 to 82% during the study period (p < 0.0001). The incidence of glycoprotein IIb/IIIa inhibitor-associated thrombocytopenia was 5.4%. The occurrence of thrombocytopenia was not associated with higher age, gender or ethnicity. The preprocedural platelet count was not associated with induced thrombocytopenia (237 +/- 76 vs. 209 +/- 68 x 10(3), p > 0.05). The occurrence of thrombocytopenia was not associated with increased in-hospital mortality, 1-year mortality, myocardial infarction or revascularization, but was associated with a hospital stay twice as long as in those patients without thrombocytopenia (5.6 +/- 11.3 vs. 2.1 +/- 2.2 days, p < 0.001). Of the 5.4% of patients who developed thrombocytopenia, only 2 patients (7.1%) required platelet or blood cell transfusion.     

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.     

Design and methodology of the ESPRIT trial: evaluating a novel dosing regimen of eptifibatide in percutaneous coronary intervention

BACKGROUND: Clinical trials of the glycoprotein (GP) IIb/IIIa inhibitors have shown that these potent antiplatelet agents are effective in reducing the ischemic complications of percutaneous coronary interventions. However, even though stents are now implanted in >75% of percutaneous interventional procedures, only one study, a trial of the monoclonal antibody abciximab, has formally evaluated adjunctive GP IIb/IIIa inhibition in this setting. METHODS AND RESULTS: Eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has also undergone evaluation as an adjunct to coronary intervention. In clinical trials performed heretofore, however, it has appeared to have less relative clinical efficacy than the monoclonal antibody abciximab. Since the early seminal trials, it has been recognized that the doses of eptifibatide previously used achieved only 30% to 50% of maximal platelet GP IIb/IIIa integrin inhibition. This is considerably less than the 80% level of receptor inhibition that has been proposed to prevent coronary thrombus formation in animal models and that has been achieved in clinical trials with abciximab. CONCLUSIONS: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial was designed to test the safety and efficacy of a high-dose, "180/2.0/180" double-bolus regimen of eptifibatide (a 180-microg/kg bolus followed 10 minutes later by a second 180-microg/kg bolus of eptifibatide combined with a 2.0-microg/kg per minute infusion) as an adjunct to nonacute percutaneous coronary intervention with stent implantation. In this report, we review the rationale, design, and methods of this clinical investigation.     

Acute stent thrombosis associated with heparin-induced thrombocytopenia and abciximab-induced profound thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a wellknown complication after exposure to heparin products. Profound thrombocytopenia has also been reported with the use of abciximab, a glycoprotein IIb/IIIa receptor antagonist, which is used during percutaneous coronary intervention. Acute stent thrombosis is a rare but serious complication of HIT. We report an unusual case of acute stent thrombosis with concomitant heparin- and abciximab-induced profound thrombocytopenia and discuss the subsequent treatment strategies. Prompt identification and management of this disorder is critically important to avoid devastating complications.     

Glycoprotein IIb/IIIa Receptor Inhibitors During Primary Angioplasty for Acute Myocardial Infarction

Platelet glycoprotein IIb/IIIa receptors are the final common pathway leading to platelet aggregation and coronary thrombosis during acute myocardial infarction (AMI). Therefore, they are ideal candidates for pharmacologic intervention. The recent development of glycoprotein IIb/IIIa receptor antagonists has led to several studies that have shown the benefits and efficacy of these agents in the treatment of acute coronary syndromes and in the setting of percutaneous intervention. To date, six published trials have examined the safety and efficacy of intravenous abciximab, a mouse/human chimeric version of the 7E3 antibody, as an adjunct to primary mechanical reperfusion in patients with AMI. In this article, we review these trials, as well as new studies currently underway that will provide further information on the long-term benefits of combining these pharmacologic agents and stenting in the treatment of AMI.     

Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis

BACKGROUND: Despite the increasingly prevalent role of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors in acute coronary syndromes and percutaneous coronary interventions, the incidence and clinical relevance of thrombocytopenia occurring with their use remain unclear. METHODS: We identified 8 placebo-controlled, randomized, large trials of GP IIb/IIIa receptor inhibitors reporting the incidence of thrombocytopenia, grouped by severity. The clinical courses of 42 patients with GP IIb/IIIa-related thrombocytopenia in these studies and other case reports were reviewed for bleeding complications. RESULTS: Abciximab increased mild thrombocytopenia compared with placebo (4.2% vs 2.0%; P <.001; odds ratio 2.14) and increased severe thrombocytopenia compared with placebo (1.0% vs 0.4%; P =.01; odds ratio 2.48). Small-molecule IIb/IIIa inhibitors did not significantly increase mild or severe thrombocytopenia compared with placebo. Mild thrombocytopenia occurred more frequently in acute coronary syndrome trials than in coronary intervention trials, even in patients not receiving any IIb/IIIa inhibitors. No major bleeding sequelae were reported in 23 patients with severe thrombocytopenia or in 19 patients with profound thrombocytopenia. CONCLUSIONS: Abciximab, but not eptifibatide or tirofiban, increases the incidence of thrombocytopenia compared with placebo in patients also treated with heparin. Thrombocytopenia associated with GP IIb/IIIa inhibition does not routinely lead to severe bleeding complications.     

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.     

Antithrombotic therapy in the acute phase of unstable angina

Low molecular weight heparins appear to be a better choice in patients with unstable angina than unfractionated heparin. In addition, the excellent predictable dose-response makes them suitable to prevent ischemic complications of percutaneous coronary intervention. Although direct comparisons between LMWH and UH are limited, substantial evidence exists that patients receiving LMWH can be safely brought to cardiac catheterization. Therefore, previous concern regarding transitioning such therapy from the medical service to the cardiac catheterization laboratory should not impede the upstream use of thèse agents. Although UH remains an option in conjunction with GP IIB/IIIa inhibitors, there is substantial evidence that LMWH and GP IIb/IIIa inhibitor therapy can be used safely in combination. Although GP IIb/IIIa inhibitors are very potent to prevent ischemic events after percutaneous coronary interventions, their benefit in the medical management of unstable angina is much more modest. ADP receptor antagonists reduce major ischemic events in combination with aspirin in the medical management of unstable angina patients but also when PCI is planned. Their combination with GP IIB/IIIa receptor antagonist does not impair the benefit of GP IIb/IIIa antagonists. The development of biologic tools to monitor these antithrombotic regimen is highly warranted especially in high risk patients (chronic renal failure, elderly).     

Update on the treatment with platelet antiaggregation agents]

Antiplatelet agents are primarily used to prevent and treat arterial thrombosis. Their mechanism of action is related to the interaction with metabolism of arachidonic acid, the increase of intraplatelet cAMP or the antagonism of ADP or GP IIb/IIIa receptors. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and more recently clopidogrel have been introduced. In the CAPRIE study, clopidogrel was shown to be more effective than aspirin in the prevention of vascular events in patients with atherothrombotic disease. The newer antiplatelet agents are GP IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab, which act at the end of the common pathway of platelet aggregation. Their benefits after intravenous administration have been shown in the treatment of acute coronary syndrome and percutaneous coronary angioplasty. The potential application of GIIb/IIIa targeted therapy might theortically be expanded by the new class of oral GP IIb/IIIa antagonists. However, their performance in clinical trials has been disappointing.     

Glycoprotein IIb/IIIa and P2Y12 receptor antagonists yield additive inhibition of platelet aggregation, granule secretion, soluble CD40L release and procoagulant responses

Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists, including abciximab and tirofiban, are administered concurrently with clopidogrel, a P2Y12 antagonist, and aspirin in some patients undergoing percutaneous coronary intervention. We studied the effects of, and interactions between, abciximab, tirofiban, aspirin and the P2Y12 antagonist cangrelor on platelet aggregation, alpha and dense granule secretion and procoagulant responses in vitro. Blood was obtained from healthy volunteers. Platelet aggregation, dense granule secretion, alpha granule secretion (PAI-1 and soluble CD40 ligand levels) and procoagulant responses (annexin-V and microparticle formation) were assessed using collagen and thrombin receptor activating peptide (TRAP) as agonists. All the antagonists used singularly inhibited collagen-induced responses. Combinations of abciximab or tirofiban with aspirin and/or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor. Cangrelor inhibited TRAP-induced responses and, again, there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor. The GPIIb/IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between GPIIb/IIIa antagonists and inhibitors of both P2Y12 receptor activation and, to a lesser extent, thromboxane A2 generation. These interactions are likely to have important influences on the safety and efficacy of combination anti-platelet therapies.