Abciximab

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Abstract
Abciximab (Reopro®) is an antibody fragment that dose-dependently inhibits platelet aggregation and leucocyte adhesion by binding to the glycoprotein (GP) IIb/IIIa, vitronectin and Mac-1 receptors. Abciximab (0.25 mg/kg bolus plus infusion of 0.125 μg/kg/min for 12 hours) showed greater efficacy than tirofiban in reducing the 30-day composite endpoint of death, nonfatal myocardial infarction (MI) or urgent target-vessel revascularisation in the randomised, double-blind TARGET study in patients scheduled for stent placement. In addition, the beneficial effects of treatment with abciximab previously observed in the randomised, multicentre, placebo-controlled EPILOG and EPISTENT studies have been maintained to 1 year, with a significantly reduced incidence of ischaemic complications relative to placebo consistently observed across a range of subgroups including age, sex, bodyweight and indication for revascularisation. The incidence of the composite endpoint was reduced in patients presenting with acute MI of 80% of GP IIb/IIIa receptors and produces the maximum antiplatelet effect (>80% inhibition of ADP-induced platelet aggregation) at 10 minutes after treatment initiation. Continuous infusion (0.125 μg/kg/min or 10 μg/ min) after the bolus maintains near maximal platelet inhibition. However, marked interindividual variability has been observed in the degree of platelet inhibition in patients undergoing revascularisation. Ex vivo, administration of abciximab (0.25 mg/kg bolus then 10 μg/min for 12 hours) to patients undergoing percutaneous coronary revascularisation has shown generally equivalent inhibition of platelet aggregation in response to ADP or thrombin receptor-activating peptide (TRAP) as tirofiban or eptifibatide, although dosage regimens of tirofiban and eptifibatide varied between some studies. Platelet aggregation was significantly increased relative to baseline following fibrinolytic therapy with either alteplase or reteplase in patients with acute myocardial infarction (MI; n = 51) enrolled in the dose-finding TIMI-14 trial, but no significant differences in platelet aggregation at 90 minutes or 24 hours were evident between patients who received abciximab (0.25 mg/kg bolus) with either reduced doses of reteplase (a 5U bolus and either 5 or 10U bolus) or alteplase (dose range 35 to 65mg); all patients receiving combination abciximab/fibrinolytic therapy achieved >80% inhibition of platelet aggregation at 90 minutes which was sustained for ≥24 hours after initiation of abciximab treatment. The addition of ticlopidine to treatment maintained the platelet inhibition achieved with abciximab therapy during the first 24 hours. In addition to inhibition of platelet aggregation, abciximab has shown potentially antithrombotic effects which are independent of heparin administration. Abciximab inhibits platelet-dependent thrombin generation, most likely through blockade of both GP IIb/IIIa and vitronectin receptors. Blockade of vitronectin receptors prevents smooth muscle cell adhesion and migration, thus reducing intimal proliferation. Moreover, abciximab may inhibit activated Mac-1 receptors, thus reducing monocyte and polymorphonuclear leucocyte recruitment at the site vascular injury. Abciximab binds rapidly to platelets after administration and has an initial half-life of > 10 minutes and a second phase half-life of about 30 minutes. Platelet function generally recovers within 48 hours, although platelet-bound abciximab is still detectable 15 days or more after administration in a platelet-bound state. in General Patient Populations: Abciximab (0.25 mg/kg bolus plus infusion of 0.125 μg/kg/min for 12 hours) has been investigated as an adjunct to aspirin and heparin in patients undergoing percutaneous coronary intervention. Large well designed studies have shown abciximab prevents acute ischaemic complications (death, MI or urgent revascularisation). Abciximab demonstrated greater efficacy at 30 days than tirofiban treatment (10 μg/kg bolus then 0.15 μg/kg/min IV infusion for 18 to 24 hours) in the randomised, double-blind, multicentre TARGET study in patients scheduled for stent placement. At 30 days, the composite endpoint of death, nonfatal MI or urgent target-vessel revascularisation occurred in significantly fewer patients who received abciximab than received tirofiban (6.0 and 7.6%, respectively), mainly because of a greater number of MI events in patients treated with tirofiban (5.4 vs 6.9%). p ]The beneficial effects of treatment with abciximab previously observed in the randomised, multicentre, placebo-controlled EPILOG and EPISTENT studies have been maintained to 1 year, with a significantly reduced incidence of ischaemic complications relative to placebo which was consistently observed across a range of subgroups (including age, sex, bodyweight and indication for evascularisation). Factors which were significantly and independently associated with improved survival at 1 year in multivariate analysis in EPISTENT were use of abciximab in combination with stenting (versus placebo and stenting alone), and preprocedural percentage diameter stenosis, whereas worse survival was associated with previous congestive heart failure, type 1 diabetes mellitus, age >70 years and postprocedural TIMI grade 0 flow. Nonetheless, abciximab has demonstrated efficacy, reducing the composite endpoint of death, MI or target-vessel revascularisation, in a prospectively defined subset of patients with diabetes mellitus undergoing percutaneous coronary intervention in the EPISTENT study. In Acute Myocardial Infarction: Five randomised comparative studies (ADMIRAL, CADILLAC, STOPAMI, STOPAMI-2, and ISAR-2) have investigated the use of abciximab in combination with stent placement in patients with acute MI. Both STOPAMI and ADMIRAL studies reported that patients receiving abciximab plus stent showed a significantly reduced composite endpoint compared to either fibrinolytic therapy or stent alone at 30 days. In STOPAMI-2 atients receiving abciximab plus stent showed a greater myocardial salvage index than those receiving abciximab plus alteplase. Results of the CADILLAC study suggest that stent plus abciximab, angioplasty plus abciximab and stent alone each leads to significantly better outcomes at 30 days compared to angioplasty alone. Patients receiving stent plus abciximab showed a significantly lower rate of revascularisation than those receiving angioplasty either alone or in combination with abciximab. In the ADMIRAL study, blood flow was greater in patients who received abciximab than in placebo recipients immediately following revascularisation (TIMI grade 3 flow achieved in 95.1% vs 86.7% of patients; p = 0.04) and at 6 months with (94.3% vs 82.8%). Recent large randomised, nonblind, multicentre studies (ASSENT-3 and GUSTO-V) have shown higher efficacy with abciximab in combination with either a reduced dose of tenecteplase or reteplase than the full-dose fibrinolytic drug alone. The effect of abciximab in combination with fibrinolytic therapy (either alteplase, streptokinase or reteplase) on reperfusion after acute MI was investigated in the TIMI-14 and SPEED trials. More patients who received abciximab in combination with fibrinolytic therapy in TIMI-14 and SPEED achieved TIMI grade 3 flow rates at 60 and 90 minutes than those who received abciximab alone. In TIMI-14, at both 60 and 90 minutes TIMI grade 3 flow rates were significantly greater in patients receiving abciximab plus fibrinolytic therapy than than in those receiving full-dose fibrinolytic alone (p = 0.0009 and 0.02, respectively). In the multicentre SPEED study, the percentage of patients achieving TIMI grade 3 flow rates 60 to 90 minutes after reperfusion treatment was greatest in patients who received two 5U boluses reteplase plus abciximab (62%). Pooled Analyses: Pooled analysis of large, randomised, placebo-controlled trials involving abciximab (>9000 patients) showed a decrease in mortality of approximately 30% compared with placebo at 1 year; mortality was also reduced to a similar extent with either angioplasty or stenting (both approximately 30%). Analyses from the EPIC, EPILOG and EPISTENT trials showed that the overall treatment benefit (as indicated by 30-day and 6-month ischaemic outcomes) with abciximab was observed irrespective of sex or smoking status. In meta-analyses of prospective, randomised placebo-controlled trials GP IIb/ IIIa antagonists reduced the need for urgent revascularisation but had no effect on mortality compared to placebo. Abciximab but not eptifibatide or tirofiban significantly reduced the incidence of acute MI compared to placebo. In Patients Without Early Revascularisation: In the randomised, multicentre GUSTO IV-ACS study, no differences were apparent between groups of patients with ACS who were not scheduled to undergo early revascularisation (within 12 hours of end of infusion) who had received abciximab (bolus and either 24- or 48-hour infusion) in addition to aspirin and heparin in any of the ischaemic endpoints at either 7 or 30 days (primary endpoint) compared with placebo. The most common adverse events associated with the use of abciximab are bleeding complications and thrombocytopenia, although the risk of major bleeding can be limited through careful selection of patients, use of a low-dose, bodyweight-adjusted regimen of heparin, discontinuation of heparin immediately following revascularisation, early removal of the vascular sheath and femoral artery access site care. In recent large, randomised clinical trials (ADMIRAL, GUSTO IV-ACS and TARGET), the incidence of major bleeding with a standard dose of abciximab (0.6–0.7% of patients) was similar to that seen with placebo (0% and 0.3%) and tirofiban (0.9%), although extension of the abciximab infusion to 48 hours significantly increased the incidence of major bleeding complications relative to placebo in one arm of the GUSTO IV-ACS trial (1% vs 0.3%). Rates of minor bleeding were significantly greater (3–12.1%) than with either placebo (2% and 3.3%) or tirofiban (2.8%). Thrombocytopenia (platelet count 9/L) developed in 2.4–7% of abciximab-treated patients (the higher value was recorded in patients receiving a 48 hour infusion of abciximab in GUSTO IV-ACS) compared with ≈1% of placebo and 0.5% of tirofiban recipients in the ADMIRAL, GUSTO IV-ACS and TARGET clinical trials. Severe thrombocytopenia (platelet count 9/L) was observed in 0.9–2% of patients who received abciximab, 0.04% and 1.3% of placebo recipients and 0.1% of tirofiban recipients. 2.1% of patients treated with abciximab were identified as having pseudothrombocytopenia in pooled data from the CAPTURE, EPIC, EPILOG and EPISTENT trials compared with 0.6% of patients who received placebo. In the ASSENT-3 trial, rates of major and minor bleeding were significantly higher in patients receiving abciximab plus tenecteplase than in those receiving tenecteplase alone or plus enoxaparin. Similarly, in GUSTO-V rates of major and minor bleeding were significantly higher in patients receiving abciximab plus reteplase than in those receiving reteplase alone. In both studies, the rates of intracranial haemorrhage were similar for each treatment group. No cases of anaphylactic, allergic or other hypersensitivity reactions have been reported in 500 patients enrolled in the ReoPro Readministration Registry. Cumulative treatment costs from a prospectively defined subset of patients in the US who participated in the EPISTENT study at 1 year were significantly higher in both the stent plus abciximab (by $US932) and angioplasty plus abciximab ($US581) groups than in the stent plus placebo group, primarily because of the acquisition cost of abciximab. The addition of abciximab to stenting also significantly increased the estimated mean costs per patient after 6 months’ treatment when results of the EPISTENT trial were extrapolated to a European setting based on an economic evaluation from the BElgian NEtherlands Stent (BENESTENT)-II study. Cost savings associated with abciximab in a prospectively defined economic substudy of EPILOG were for the most part attributed to a reduced requirement for repeat revascularisation, bailout stenting and shorter hospital stays. Over a 6-month follow-up period, hospitalisation costs remained increased in the abciximab groups because of an increase in the number of patients undergoing nonurgent revascularisation. Increased costs in the abciximab group were primarily because of drug acquisition costs. Two nonrandomised studies (based in the US and Netherlands) showed a reduced incidence of ischaemic complications with abciximab and stenting; however, overall treatment costs were similar or increased in these patients compared with those who underwent only percutaneous coronary intervention. Among lower risk patients undergoing elective percutaneous coronary revascularisation, abciximab has been associated with higher total in-hospital and 6-month medical costs than eptifibatide in the prospective PRICE cost analysis study. Abciximab appeared most cost beneficial in high-risk patients in a retrospective cost analysis; the estimated cost to prevent one event was $US39 201 compared with $US74 047 for tirofiban. Patients treated with abciximab spent fewer days in hospital than patients who received either tirofiban or eptifibatide according to a retrospective analysis. An incremental cost of $US932, or cost-effectiveness ratio of $US6213 per added life-year, was seen in the stent plus abciximab group compared with stent and placebo in EPISTENT. Patients who received abciximab plus stent had an incremental cost of $US581 and a cost-effectiveness ratio of $US5291 per added life-year in comparison with the abciximab and angioplasty group. One Italian-based analysis has evaluated the cost effectiveness of abciximab based on 6-month results from the EPILOG, EPIC (not including patients who received only abciximab bolus) and CAPTURE studies. Cost-effectiveness ratios for patients in the abciximab and placebo groups were L16.6 and L15.4 million Lire per event-free patient (approximately $US7543 and $US6998; 2002 values), resulting in an incremental cost-effectiveness ratio of L34.3 ($US15 587) per event avoided at 6 months after intervention. The recommended dosage of abciximab is a 0.25 mg/kg IV bolus administered 10 to 60 minutes before the start of percutaneous coronary intervention, followed by a continuous IV infusion of 0.125 μg/kg/min (up to a maximum of 10 μg/min) for 12 hours. For patients with refractory unstable angina pectoris in whom percutaneous coronary revascularisation is planned within 24 hours, the recommended dosage is an IV bolus of 0.25 mg/kg followed by an infusion of 10 μg/min for 18 to 24 hours before the procedure and finishing 1 hour (US recommendation) or 12 hours (UK recommendation) after the procedure. Abciximab should be used in combination with aspirin and heparin. Abciximab is contraindicated in patients at high risk for bleeding complications or in whom bleeding complications would have serious consequences, those requiring IV dextran and those with known hypersensitivity to the drug. Haemostatic parameters should be measured before administration. Caution is required in patients receiving other drugs that affect haemostasis. Infusion of abciximab and heparin should be stopped if uncontrollable serious bleeding occurs or if emergency surgery is required. To reduce the risk of bleeding, careful femoral artery access site care, use of a low-dose, bodyweight-adjusted regimen of heparin, discontinuation of heparin immediately after the procedure, early removal of the arterial sheath and careful patient management are recommended. Platelet counts should be monitored before and during treatment. If the platelet count decreases by ≥25% and to 9/L, abciximab should be discontinued and appropriate treatment initiated.