Evaluation of bleeding complications associated with glycoprotein IIb/IIIa inhibitors

BACKGROUND: Platelet glycoprotein IIb/IIIa inhibitors are used with aspirin and heparin to decrease rates of death, myocardial infarction, and urgent revascularization in patients with acute coronary syndromes. OBJECTIVE: To determine whether bleeding event rates differed among 3 glycoprotein IIb/IIIa inhibitors prescribed in a high-risk, elderly veteran population and identify risk factors for bleeding. METHODS: A retrospective chart analysis of patients who received abciximab, eptifibatide, or tirofiban was conducted. chi(2) Analysis evaluated the incidence of bleeding complications, and stepwise regression analysis was utilized to identify bleeding risk factors. Parameters evaluated as possible risk factors for bleeding included age, renal function, weight, heparin and glycoprotein IIb/IIIa inhibitor dosing and infusion duration, concomitant antiplatelet and/or anticoagulant medications or disease states, and baseline hemoglobin, hematocrit, or platelet counts. RESULTS: Of 348 patients whose charts were reviewed, 79 patients were included. There were 37.9% who received abciximab (n = 30), 30.3% who received eptifibatide (n = 24), and 31.6% who received tirofiban (n = 25). Twenty-one bleeding events not related to coronary artery bypass grafting occurred: only 1 major bleed (tirofiban) and 20 minor bleeds. Bleeding rates were not significantly different between groups: abciximab 30% (n = 9), eptifibatide 21% (n = 5), and tirofiban 28% (n = 7). Significant risk factors for bleeding included patient weight, infusion duration, and baseline platelet count (p = 0.024). Patients who bled received significantly more transfusions of packed red blood cells and platelets than patients with no bleeding (p = 0.047). CONCLUSIONS: Although bleeding complications did not differ significantly between the 3 drugs, several risk factors for bleeding events were identified. A considerable rate of bleeding events occurred in this high-risk patient population.     

Occupancy of the internal and external pools of glycoprotein IIb/IIIa following abciximab bolus and infusion

The internal pool of GPIIb/IIIa, which is expressed upon platelet activation, may be inaccessible to inhibition by GPIIb/IIIa antagonists. To determine the occupancy of the internal and external pools of GPIIb/IIIa and platelet function following an abciximab bolus and infusion, 15 patients undergoing elective percutaneous transluminal coronary angioplasty were administered abciximab as a bolus and 36-h infusion. GPIIb/IIIa receptor number and occupancy in resting and TRAP-6 (20 microM)-activated samples (to expose the internal pool of GPIIb/IIIa) was quantified using a monoclonal antibody-based assay. Antibody binding was quantified by flow cytometry and platelet inhibition by light transmittance aggregation and by the rapid platelet function analyser (Accumetrics, San Diego, CA). The target of >80% receptor occupancy (range 82--99% occupancy) of the external pool of GPIIb/IIIa was achieved in all patients at 3 min. Receptor occupancy of the combined internal and external pools of GPIIb/IIIa was less, ranging from 75 to 93% and again was maximal at 3 min. Platelet aggregation was markedly inhibited to 20 microM ADP (maximal, 11 +/- 2% of baseline), but less so to 5 microM TRAP-6 (maximal, 36 +/- 25% of baseline). Following discontinuation of the drug, there was a gradual fall in receptor occupancy over 15 days coinciding with the disappearance of abciximab from the platelet surface. Maximum inhibition of platelet function and receptor occupancy of the external pool of GPIIb/IIIa occurs within 3 min of an abciximab bolus and infusion. However, some internal receptors that are expressed by potent agonists are not occupied, which may explain the incomplete inhibition of platelet aggregation.     

Effect of glycoprotein IIb/IIIa inhibitors on CD62p expression, platelet aggregates, and microparticles in vitro

Flow cytometry can detect platelet activation (CD62p), aggregate formation, microparticle formation, and glycoprotein IIb/IIIa (GP IIb/IIIa) receptor occupancy in one sample at the level of single particles. We studied the effect of GP IIb/IIIa inhibitors on platelet activation with flow cytometry in vitro. Citrated whole blood was incubated with increasing concentrations of three different GP IIb/IIIa inhibitors (c7E3, DMP728, XJ757), then thrombin or adenosine diphosphate (ADP) was added, and after 1 minute the sample was fixed. Samples with thrombin but without c7E3 had a decrease in platelet count, from a mean of 260,000 platelets/microl to 56,000 platelets/microL, and aggregates increased. Samples with concentrations of c7E3 that resulted in 80% or more receptor blockade had no decrease in platelet count, and no aggregates were formed, but the number of CD62p-positive single platelets increased from 1200 to 7400 platelets/microL. The two other inhibitors (DMP 725, XJ757) or ADP instead of thrombin gave similar results. Microparticle formation did not change with platelet activation in the presence of a GP IIb/IIIa inhibitor. With small inhibitor doses resulting in <80% receptor blockade, the number of aggregates did not change or was even higher than that in samples without inhibitor. GP IIb/IIIa inhibitors do prevent aggregate formation but they do not prevent activation of platelets. With GP IIb/IIIa inhibition, more activated single platelets remain in the blood. One may expect an increasing number of circulating, activated platelets with the use of GP IIb/IIIa inhibitors.     

Glycoprotein IIb/IIIa inhibitors increase COAT-platelet production in vitro

Platelets activated simultaneously with thrombin and collagen reveal a subpopulation of cells that express on their surfaces high levels of several alpha-granule proteins, including factor V and fibrinogen; these COAT platelets (collagen and thrombin-activated platelets) represent roughly 30% of the total population. Evidence of enhanced stability of proteins on the COAT-platelet surface was provided by the observation that PAC-1, a mAB recognizing the activated form of glycoprotein (GP) IIb/IIIa, did not inhibit fibrinogen binding to COAT-platelets. We therefore undertook a systematic evaluation of the effects of other GP IIb/IIIa inhibitors on the production of COAT platelets. Not only did GP IIb/IIIa antagonists fail to inhibit the retention of fibrinogen on COAT-platelets, but several actually increased the absolute percentage of COAT platelets produced. The increases over control values in the presence of eptifibatide, tirofiban, and DMP-802 were 1.36-, 1.20-, and 1.05-fold, respectively (P <.01 for each comparison). COAT-platelet production in the presence of abciximab was not significantly affected. However, platelet activation with thrombin plus ALB6, an Fc-receptor agonist, produces a product, referred to as FcRT platelets, that is indistinguishable from COAT platelets; all 4 GP IIb/IIIa antagonists tested potentiated formation of FcRT platelets. These findings indicate that fibrinogen binding to COAT platelets and FcRT platelets is not affected by available GP IIb/IIIa inhibitors. More importantly, our study demonstrates a potentiation of COAT-platelet production by some GP IIb/IIIa antagonists that may be relevant to the observation that long-term administration of orally available GP IIb/IIIa inhibitors not only failed to protect patients but actually increased the frequency of acute coronary events.     

Outcomes with changes in prescribing of glycoprotein IIb/IIIa inhibitors in PCI

BACKGROUND: Glycoprotein IIb/IIIa receptor antagonists have been shown to have an impact on the outcomes of death/myocardial infarction (MI) in patients undergoing percutaneous coronary intervention. At our institution, tirofiban has largely replaced abciximab in an attempt to decrease costs. OBJECTIVE: To assess the impact of this change on patient outcomes in the absence of head-to-head trials. METHODS: Medical records were reviewed and telephone follow-ups were conducted on patients receiving tirofiban (n = 83) at our facility between February and November 1999. Death/MI at 30 days and 6 months after infusion were recorded. Safety and length of stay (LOS) were also assessed. These data were compared using chi2 analysis with results obtained from a previous review of abciximab use (n = 83) collected between May 1997 and November 1998. RESULTS: There was no difference in the baseline incidence of (1) cardiovascular risk factors, (2) prior revascularization, (3) prior MI, (4) the number of vessels with atherosclerotic disease assessed by angiography, and (5) the number of vessels receiving procedures. Death/MI trended to be worse with tirofiban versus abciximab at our institution at 30 days (4.8% abciximab vs. 12% tirofiban; p = 0.163) and 6 months (6% abciximab vs. 18.1% tirofiban; p = 0.032). Bleeding and median LOS (3 d abciximab vs. 3 d tirofiban) were not different. Despite an increase in pharmacy cost, the use of abciximab provided these outcomes without an increase in total hospital cost. CONCLUSIONS: The perceived economically driven change in medication selection from abciximab to tirofiban may not have been appropriate based on the negative trends seen in this review. To maintain optimal patient outcomes, this change should be reevaluated.     

Use of glycoprotein IIb/IIIa inhibitors in unstable angina and non-ST-elevation myocardial infarction

Acute coronary syndromes (ACS) are a major cause of morbidity and mortality in Western society. The commonest underlying pathology is the coronary atherosclerotic plaque complicated by thrombosis. Platelets play a central role. As the glycoprotein IIb/IIIa receptor is involved in the final step of platelet thrombus formation development and investigation of its blockage in ACS is at the fore. Initial hospital management of ACS occur in the ED setting. The present article outlines the above topics and clarifies the place of glycoprotein IIb/IIIa receptor inhibition in ED.     

The evolving role of platelet glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndromes.

OBJECTIVE: To briefly discuss the pathophysiology of acute coronary syndromes (ACS) and to present the clinical data currently available regarding the use of platelet glycoprotein (GP) IIb/IIIa inhibitors in the management of ACS. DATA SOURCES: Literature on antithrombotic therapy in ACS was identified using a MEDLINE search (January 1988-September 1998), along with the Agency on Health Care Policy and Research guidelines for the management of unstable angina. Abstracts from recent scientific meetings were also reviewed. STUDY SELECTION: Review articles from the cardiology literature (pathophysiology) and randomized, controlled clinical trials of currently approved platelet GP IIb/IIIa inhibitors in ACS were evaluated. Ex vivo platelet aggregation studies and pharmacology literature were also included. Abstract data were included to illustrate specific points when published literature was not available. DATA EXTRACTION: Study data were evaluated based on study design, outcome parameters, and adverse drug reactions. Clinical information from review articles was evaluated based on applicability to the treatment of ACS. DATA SYNTHESIS: Platelet adhesion and aggregation are pivotal events in the pathophysiology of ACS. The GP IIb/IIIa inhibitors represent a new and unique class of drugs that block fibrinogen and von Willebrand factor-mediated platelet aggregation, the common end point of all biologic pathways of platelet aggregation. Three agents are currently approved by the Food and Drug Administration: abciximab, a monoclonal antibody; eptifibatide, a synthetic peptide; and tirofiban, a synthetic nonpeptide. CONCLUSIONS: Clinical trial data demonstrate efficacy of all three GP IIb/IIIa inhibitors in reducing the combined end point of morbidity and mortality in patients undergoing angioplasty. Eptifibatide and tirofiban also reduce the combined end point of morbidity and mortality in patients with unstable angina. These data expand the present role of platelet GP IIb/IIIa inhibitors by providing evidence for their effectiveness in the medical treatment of ACS. However, the specific role that these agents will have in the management of ACS is yet to be fully defined.     

Additive effects between platelet concentrates and desmopressin in antagonizing the platelet glycoprotein IIb/IIIa inhibitor eptifibatide

BACKGROUND: Platelet (PLT) glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated efficacy in decreasing ischemic complications of percutaneous coronary intervention and/or unstable angina. In case of bleeding, the drug can be stopped and PLT transfusions can be given. STUDY DESIGN AND METHODS: This crossover study tested the additive effects of PLT concentrates (PCs) after desmopressin (DDAVP) infusion in antagonizing the anti-PLT effects of GPIIb/IIIa inhibitors and aspirin. After eptifibatide and aspirin infusion (at standard dosages), 10 healthy volunteers received DDAVP or placebo. Thereafter, increasing amounts of PLTs from fresh single-donor apheresis concentrates were added in vitro to blood samples of all volunteers to increase PLT counts by 30 x 10(9), 60 x 10(9), or 120 x 10(9) per L. RESULTS: Adding platelets in vitro further improved PLT function after DDAVP: it shortened collagen-adenosine diphosphate closure times (p < 0.01), to normal ranges as measured by the PLT function analyzer (PFA-100). In contrast, normal PLT function could not be restored even when PLT counts were increased by 50 percent (120 x 10(9)/L) in the placebo group. CONCLUSION: Combined use of PLTs from fresh apheresis PC and DDAVP additively enhances recovery of normal PLT function after eptifibatide infusion. Such a strategy may help to avoid excessive transfusion of PC.     

Risks and benefits of glycoprotein IIb/IIIa antagonists in acute coronary syndrome

BAcKGROUND: Recommendations for the use of glycoprotein (GP) IIb/IIIa antagonists should consider not only their effectiveness but also their links with other clinical findings (both favorable and adverse), the risk/benefit ratio in different subgroups of patients, and the existence of other therapeutic alternatives; additionally, the estimates underlying the recommendation should be explicit. OBJECTIVE: To establish explicit evidence-based recommendations regarding the use of GP IIb/IIIa antagonists in medically treated patients with acute coronary syndrome without ST-segmentelevation. DATA SOURCES: MEDLINE-based search (1980 to November 1999) of randomized controlled trials for effectiveness data and nonsystematic review of published data regarding utilities of relevant status and clinical events. STUDY SELECTION: We included clinical trials in which the patients were randomly assigned either to an experimental group treated with intravenous GP IIb/IIIa antagonists or to a control group. We excluded studies in which the intention to perform a percutaneous procedure was a criterion for inclusion. DATA EXTRACTION: The effectiveness of the treatment was defined as the incidence of death or a nonfatal infarct at 30 days. The risks of the treatment were estimated using the incidence of moderate to severe hemorrhage. DATA SYNTHESIS: Meta-analysis of randomized controlled trials in patients with acute coronary syndrome and calculation of the threshold number needed to treat (t-NNT). RESULTS: Compared with conventional treatment, GP IIb/IIIa antagonists reduce the risk of death or nonfatal infarct at 30 days by approximately 11.7% (number needed to treat [NNT] = 65 for the basal risk of patients included in the studies; 95% CI 40 to 203). However, the use of GP IIb/IIIa antagonists increases the risk of moderate to severe hemorrhage by 32%. In an analysis biased in favor of the use of GP IIb/IIIa antagonists, these risks imply a t-NNT of approximately 150, which overlaps with the confidence interval of the basal NNT. The limits of a 95% confidence interval of the NNT are only lower than the t-NNT in patients with a high risk of death/infarct (at least 5%) and low risk of hemorrhage (less than the weighted basal risk in the trials analyzed). CONCLUSIONS: At present, there is no conclusive evidence that the expected benefits outweigh the nsks in the average patient included in the available trials. The benefit is probably greater than the risks in patients with a high risk of death/infarct and low risk of hemorrhage. In patients with a low risk of death/infarct and/or high risk of hemorrhage, the risks seem to outweigh the benefits and so, in the latter case, such therapy should not be used.     

Activation in stored platelet concentrates: correlation between membrane expression of P-selectin, glycoprotein IIb/IIIa, and beta- thromboglobulin release

By using two distinct measurements of alpha-degranulation (surface P- selectin [alpha-granule membrane protein-140] expression and beta- thromboglobulin [beta-TG] release) and quantitation of glycoprotein (GP) IIb/IIIa surface density, stored platelet concentrates were evaluated to determine a) which method of measuring platelet alpha- granule release was more sensitive in detecting early platelet activation; b) whether Day 1 levels of activation predicted the extent of activation or cell lysis on Day 5 of storage; and c) whether changes in surface GPIIb/IIIa density were primarily dependent on platelet activation. By using samples from paired and unpaired units stored for 1, 3, and 5 days, four observations could be made. 1) A flow cytometric assay for the percentage of P-selectin-positive platelets was more sensitive for early detection of platelet activation than was measurement of beta-TG release. This finding was most likely due to enhanced sensitivity in detecting platelets that had undergone partial alpha-granule release. 2) Total P-selectin expression correlated with beta-TG release, which indicated that the extent of alpha-granule membrane fusion with the external platelet membrane was proportional to the amount of alpha-granule contents released into the supernatant. 3) All of the activation measurements on Day 1 predicted the activation values, but did not predict the degree of cell lysis (measured by lactate dehydrogenase discharge), on Day 5 of storage. 4) Surface GPIIb/IIIa density was increased on the subset of P-selectin-positive platelets as compared with the P-selectin-negative subset at all times during storage, but, within each subset, GPIIb/IIIa surface density did not significantly increase over the time of storage.     

New antithrombotics for the intensive care unit setting: GP IIb/IIIa inhibitors, low-molecular-weight heparins, and direct thrombin inhibitors

Thromboembolic disease (TED) is a frequent problem encountered by clinicians in the intensive care unit (ICU). Traditionally, unfractionated heparin (UFH) has been used in the treatment and prophylaxis of TED. However, newer antithrombotic agents have evolved as effective alternatives to UFH. Low-molecular-weight heparins are effective for both the treatment and prophylaxis of TED. Lepirudin is useful for patients with TED and a history of heparin-induced thrombocytopenia. The platelet glycoprotein IIb/IIIa inhibitors are synergistic with UFH for the treatment of acute coronary syndromes and percutaneous coronary interventions (PCI). Several drugs are now available to clinicians for the treatment and prophylaxis of TED.     

Glycoprotein IIb/IIIa receptor inhibitors in percutaneous coronary intervention and acute coronary syndrome

OBJECTIVE: To review the contemporary role of the glycoprotein (GYP) IIb/IIIa receptor inhibitors abciximab, eptifibatide, and tirofiban in patients undergoing percutaneous coronary intervention (PCI) and those with an acute coronary syndrome (ACS), and to provide an algorithm based on currently available evidence for specific agents. DATA SOURCES: Primary articles were identified by a MEDLINE search (1966-January 2003); references cited in these articles provided additional resources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from data sources were considered for relevant information; this article primarily addresses large, controlled or comparative studies, and meta-analyses. DATA SYNTHESIS: The role of GYP IIb/IIIa inhibitors in patients undergoing PCI and those with ACS has progressed markedly. To date, abciximab has the most robust data in patients undergoing PCI, particularly high-risk individuals. In PCI patients with lower risk (e.g., elective stenting), eptifibatide is a reasonable first-line option. Data do not support tirofiban for routine use in patients undergoing PCI. For individuals with signs and symptoms of ACS, specifically unstable angina or non-ST-segment elevation myocardial infarction (MI), eptifibatide or tirofiban is recommended in high-risk patients when a conservative approach is used (PCI is not planned). Abciximab is not recommended in this situation. In patients with ST-segment elevation MI (STEMI), abciximab is the only GYP IIb/IIIa inhibitor evaluated in large, well-designed investigations. For medical management in combination with a fibrinolytic agent, the role of abciximab remains unclear. For patients undergoing primary PCI for the management of STEMI, the available evidence supports the use of abciximab, albeit further investigation is warranted. CONCLUSIONS: The role of GYP IIb/IIIa inhibitors in clinical cardiology continues to evolve. Choice of the agent depends on situation of use, patient-specific characteristics and risk stratification, and, in the case of ACS, chosen management strategy (medical management or intervention).