BACKGROUND Blockade of the platelet glycoprotein IIb/IIIa receptor with abciximab (a monoclonal-antibody Fab fragment directed against the receptor) has been shown to diminish ischemic complications among patients undergoing high-risk coronary angioplasty or directional atherectomy but increases bleeding complications. The widespread applicability of this treatment is unknown, particularly in view of the observed risk of hemorrhage. METHODS In a prospective, double-blind trial, we randomly assigned patients undergoing urgent or elective percutaneous coronary revascularization at 69 centers to receive abciximab with standard-dose, weight-adjusted heparin (initial bolus of 100 U per kilogram of body weight); abciximab with low-dose, weight-adjusted heparin (initial bolus of 70 U per kilogram); or placebo with standard-dose, weight-adjusted heparin. The primary efficacy end point was death from any cause, myocardial infarction, or urgent revascularization within 30 days of randomization. RESULTS The trial was terminated at the first interim analysis, with 2792 of the planned 4800 patients enrolled. At 30 days, the composite event rate was 11.7 percent in the group assigned to placebo with standard-dose heparin; 5.2 percent in the group assigned to abciximab with low-dose heparin (hazard ratio, 0.43; 95 percent confidence interval, 0.30 to 0.60; P<0.001); and 5.4 percent in the group assigned to abciximab with standard-dose heparin (hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.63; P<0.001). There were no significant differences among the groups in the risk of major bleeding, although minor bleeding was more frequent among patients receiving abciximab with standard-dose heparin. CONCLUSIONS Inhibition of the platelet glycoprotein IIb/IIIa receptor with abciximab, together with low-dose, weight-adjusted heparin, markedly reduces the risk of acute ischemic complications in patients undergoing percutaneous coronary revascularization, without increasing the risk of hemorrhage.

Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization

Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety.

Background—The benefit of catheter-based reperfusion for acute myocardial infarction (MI) is limited by a 5% to 15% incidence of in-hospital major ischemic events, usually caused by infarct artery reocclusion, and a 20% to 40% need for repeat percutaneous or surgical revascularization. Platelets play a key role in the process of early infarct artery reocclusion, but inhibition of aggregation via the glycoprotein IIb/IIIa receptor has not been prospectively evaluated in the setting of acute MI. Methods and Results—Patients with acute MI of <12 hours’ duration were randomized, on a double-blind basis, to placebo or abciximab if they were deemed candidates for primary PTCA. The primary efficacy end point was death, reinfarction, or any (urgent or elective) target vessel revascularization (TVR) at 6 months by intention-to-treat (ITT) analysis. Other key prespecified end points were early (7 and 30 days) death, reinfarction, or urgent TVR. The baseline clinical and angiographic variables of the 483 (242 placeb...

Randomized, Placebo-Controlled Trial of Platelet Glycoprotein IIb/IIIa Blockade With Primary Angioplasty for Acute Myocardial Infarction

The selectins are calcium-dependent C-type lectins that bind certain sialylated, fucosylated, sulfated glycoprotein ligands L-selectin also recognizes endothelial proteoglycans in a calcium-dependent manner, via heparan sulfate (HS) glycosaminoglycan chains enriched in unsubstituted glucosamine units We now show that these HS chains can also bind P-selectin, but not E-selectin However, while L-selectin binding requires micromolar levels of free calcium, P-selectin recognition is largely divalent cation-independent Despite this, HS chains bound to P-selectin are eluted by ethylenediamine tetraacetic acid (EDTA), but only at high concentrations Porcine intestinal mucosal (mast cell-derived) heparin (PIM-heparin) shows similar properties, with no binding to E-selectin, calcium-dependent binding of a subfraction to L-selectin and to P-selectin, and calcium-independent binding of a larger fraction to P-selectin, the latter being disrupted by high EDTA concentrations Analysis of defined heparin fragment pools shows a size dependence for interaction, with tetradecasaccharides showing easily detectable binding to L- and P-selectin affinity columns L-selectin binding fragments include more heavily sulfated and epimerized regions and, as with the endothelial HS chains, they are enriched in free amino groups The P-selectin binding component includes this fraction as well as some less highly modified regions Thus, endothelium-derived HS chains and mast cell-derived heparins could play a role in modulating the biology of selectins in vivo Notably, P- and L-selectin binding to sialyl-Lewisx and to HL-60 cells (which are known to carry the native ligand PSGL-1) is inhibited by unfractionated pharmaceutical heparin preparations at concentrations 12-50-fold lower than those recommended for effective anticoagulation in vivo In contrast, two low molecular weight heparins currently considered as clinical replacements for unfractionated heparin are much poorer inhibitors Thus, patients undergoing heparin therapy for other reasons may be experiencing clinically significant inhibition of L- and P-selectin function, and the current switchover to low-molecular weight heparins may come at some loss of this effect Low-dose unfractionated heparin should be investigated as a treatment option for acute and chronic diseases in which P- and L-selectin play pathological roles

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Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.

ContextAlthough factorial trials have become common, standards for the analysis
and reporting of such trials have not been established and, despite concerns
about the possibility of unrecognized interactions between therapies in factorial
trials, the magnitude of this potential problem is unknown.ObjectiveTo examine the rationale, methods, and analysis of randomized factorial
trials.Data Sources and Study SelectionWe searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Register
using the terms factorial, interaction, 2 × 2, 2 by 2,
and incremental to identify factorial randomized
trials published from January 2000 to July 2002. To identify trials missed
by the electronic search, we performed a hand search of English-language trials
in a defined topic area (using the term myocardial ischemia
[exp]) listed in MEDLINE (1966-2002), EMBASE (1980-2002), and the Cochrane
Controlled Trials Register, as well as all trials in any topic area published
in December 2000, excluding trials reporting only continuous surrogate end
points. The final set of 33 eligible publications described 29 unique trials.Data ExtractionTwo investigators independently identified factorial trials, generated
a list of items affecting validity of results, and abstracted these items
from each trial.Data SynthesisThe sensitivity of electronic searching for identifying factorial trials
was 76%. Our 3-pronged search strategy identified 44 factorial trials with
clinically important binary outcomes: 36 (82%) were done for reasons of efficiency
(testing 2 interventions in the same patient population), and 8 (18%) were
done to assess the incremental benefits of combining the 2 treatments. All
but 1 of the trials reported treatment effects by comparing all patients who
received treatment A (ie, those receiving either A alone or both A and B)
vs all those not receiving treatment A (ie, those receiving either B alone
or neither A nor B). Twenty-nine of the 44 trials (66%) reported the data
from each of the treatment groups separately; 26 trials (59%) reported testing
for interactions between the treatments. Only 2 of 31 (6%) comparisons demonstrated
a statistically significant interaction between the 2 treatments.ConclusionsAccurate interpretation of factorial trials depends on the transparent
reporting of data for each treatment cell. Despite concerns about unrecognized
interactions, our findings suggest that investigators are appropriately restricting
their use of the factorial design to those situations in which 2 (or more)
treatments do not have the potential for substantive interaction.

Analysis and reporting of factorial trials: a systematic review

Blockade of the platelet glycoprotein IIb/IIIa receptor by abciximab (c7E3 Fab) during coronary intervention reduces the incidence of ischemic complications, but has been associated with a doubling of the risk for bleeding complications. The present pilot study investigated whether modification of heparin dosing and/or early sheath removal would reduce the hemorrhagic complications associated with abciximab. One hundred three patients undergoing coronary intervention received abciximab (0.25 mg/kg bolus, 10 μ g/min infusion for 12 hours) and aspirin and were randomized by a 2 × 2 factorial design to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. In the "standard-dose heparin" group, an initial bolus of 100 U/kg was administered to achieve a procedural activated clotting time (ACT) ≥300 seconds; in the "low-dose heparin" group, an initial bolus of 70 U/kg was administered without adjustment for ACT. In the "late sheath removal" arm, heparin infusion was continued for the 12-hour duration of abciximab infusion, followed by sheath removal; in the "early sheath removal" group, heparin was stopped after the interventional procedure and sheaths were removed during the abciximab infusion. There were no apparent differences between patients randomized to the different treatment groups with regard to the occurrence of ischemic end points. Rates of bleeding and blood transfusion were reduced by low-dose heparin and early sheath removal and were lowest when both strategies were combined. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention may be useful in diminishing the incidence of hemorrhagic complications without loss of clinical efficacy. Patients undergoing coronary intervention received abciximab and were randomized to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention appeared to diminish the incidence of hemorrhagic complications without loss of clinical efficacy.

Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment Abciximab (c7E3 Fab) during percutaneous coronary revascularization

711-3-A Multicenter, Randomized, Double-Blind Pilot Trial of Standard Versus Low Dose Weight-Adjusted Heparin in Patients Treated with the Platelet GP IIb/IIIa Receptor Antibody c7E3 During Percutaneous Coronary Revascularization

Maura H. Musco

Papers

Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment Abciximab (c7E3 Fab) during percutaneous coronary revascularization

711-3-A Multicenter, Randomized, Double-Blind Pilot Trial of Standard Versus Low Dose Weight-Adjusted Heparin in Patients Treated with the Platelet GP IIb/IIIa Receptor Antibody c7E3 During Percutaneous Coronary Revascularization