Lincoff MA for the Prolog Precursor to Epilog [Evaluation in PTCA to Improve Longterm Outcome with abciximab glycoprotein IIbIIIa blockade Investigators

Reference

Am J Cardiol 1997; 79: 286-291 Abstract

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 mg/min infusion for 12 hours) and aspirin and were randomized in a 2 x 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 100U/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 the 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.

Summary

This study was a follow-on to the EPIC (Evaluation of 7E3 for the Prevention of Ischaemic Complications) trial, where a doubling in the rates of major bleeding and blood transfusions were observed with abciximab (ReoPro) treatment during high-risk percutaneous coronary intervention (PCI). In EPIC, bleeding correlated inversely with the activated clotting time and with body weight, which led to the hypothesis that less anticoagulation and/or early sheath removal would reduce bleeding without attenuating the benefits of glycoprotein IIb/IIIa (GP IIb/IIIa) blockade.

In a randomized, parallel group, factorial design, 103 patients were randomized to late sheath removal after the completion of a 12 h abciximab and heparin infusion with either low- or highdose procedural heparin, or early sheath removal during the abciximab infusion (without further heparin by infusion) with either low- or high-dose procedural heparin. Bleeding complications and a composite endpoint of death, myocardial infarction, or urgent revascularization were tabulated at 7 days.

The combined strategy of early sheath removal and low-dose heparin resulted in the lowest rate of bleeding without affecting the composite efficacy endpoint rate.

Citation Count 79

Related References

1. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein Ilb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330: 956-961.

2. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689-1696.

Key message

When using abciximab as an adjunct to coronary intervention, rates of bleeding and transfusion can be reduced by a strategy of lower-dose peri-procedural heparin without subsequent heparin by intravenous infusion, along with sheath removal shortly after completion of the procedure.

Why it's important

PROLOG, the pilot study to the larger EPILOG (Evaluation in PTCA to Improve Long-term Outcome with abciximab Glycoprotein IIb/IIIa blockade) study, demonstrated that sheath haemostasis could be achieved while the patient was receiving a continuous infusion of the GP IIb/IIIa blocker abciximab. It provided sufficient evidence that substantially lower doses of heparin could also be safely evaluated in the subsequent EPILOG study.

Strengths

This was a small, elegantly designed, prospective randomized pilot study which concisely demonstrated the safety of a strategy of reduced procedural and post-procedural use of heparin coupled with vascular sheath removal shortly after PCI.

Weaknesses

This trial was (by design) underpowered to show definitive differences in either efficacy or in haem-orrhagic complications, and thus could not be considered definitive despite the compelling trends. The observations required a larger follow-up trial (EPILOG) to confirm the findings.

Relevance

Until the PROLOG study was conducted, the interventional community felt it to be heresy to substantially reduce heparin dosing during and after PCI. It was also unclear whether vascular haemostasis could be achieved with full GP IIb/IIIa blockade on board. PROLOG provided sufficient evidence to challenge conventional wisdom. This permitted the clinical trials community to move forward and conduct the definitive EPILOG trial.

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