Safety and Efficacy of Low-Dose Intravenous Enoxaparin and Glycoprotein IIb/IIIa Inhibitor Therapy During Percutaneous Coronary

Louis Carnendran, MD, Robert Borkowski, MD, Bashar Markabawi, MD, Mark F. Warner, MD
Louis Carnendran, MD, Robert Borkowski, MD, Bashar Markabawi, MD, Mark F. Warner, MD
Enoxaparin, a low molecular weight heparin, has demonstrated superior efficacy over unfractionated heparin (UFH) in the medical management of acute coronary syndromes (ACS), e.g., unstable angina and non-ST elevation myocardial infarction.1 Prior studies have shown that enoxaparin administered during percutaneous coronary interventions (PCI) is as safe and efficacious as UFH.2–4 Enoxaparin used with the glycoprotein (GP) IIb/IIIa inhibitor tirofiban has also been found to be safe and to demonstrate enhanced consistency of platelet inhibition in a small pilot trial.5 In addition, two large observational registries have confirmed the safety of enoxaparin and GP IIb/IIIa inhibitors during PCI and have reported a low rate of in-hospital and 30-day major adverse cardiac events (MACE).3,6,7 Recently, a very low dose of UFH (1,000 units) with abciximab was found to be safer and more efficacious than standard dose UFH during PCI;8 however, the minimum effective dose of intravenous (IV) enoxaparin during PCI with GP IIb/IIIa inhibitors is unknown. In addition, femoral vascular closure devices have not been routinely employed in prior PCI studies evaluating enoxaparin GP IIb/IIIa inhibitor therapy. Our study evaluated the in-hospital and 30-day safety and efficacy of half-dose enoxaparin (0.5 mg/kg) and GP IIb/IIIa inhibitors during PCI. All patients received a bio-absorbable hemostatic vascular anchor (Angio-Seal™) at the conclusion of the procedure in order to improve patient comfort and to observe its contribution to early discharge planning. Methods Between October 2000 and April 2002, we administered IV enoxaparin and GP IIb/IIIa inhibitors to 75 patients presenting to our cardiac catheterization laboratory for PCI at the discretion of their interventional cardiologist and after obtaining informed written consent from the patients. Patients were excluded if they had thrombocytopenia (platelet count = 25 kg/m2), mean age was 64.8 ± 11.6 years, eighteen percent were female, eleven percent were diabetic, eight-seven percent were hypertensive and 33% had prior coronary artery disease (Table 1). Eighty-seven percent of lesions were high-risk (B2 and C), five percent were graft interventions and 5% were brachytherapy for in-stent restenosis; twenty-eight percent of the patients had >= 2 vessel interventions, eighty-seven percent had stent deployment with balloon-expandable Medtronic AVE stents, and post-procedural ACT ranged from 134–236 seconds (Tables 1 and 2). No TIMI major bleeding was observed during in-hospital stay. However, one patient developed a self-limited retroperitoneal hematoma with a fall in hemoglobin level of 3 g% (TIMI minor bleeding incidence, 1.3%). Another patient had mild, asymptomatic thrombocytopenia (platelet count dropped from 120,000 to 60,000/mm3), which spontaneously resolved within 12 hours after discontinuation of abciximab. No patient had angina, ischemic ECG changes, elevation of CK-MB (> 3 times upper limit of normal or > 10% rise from initial value), or required repeat coronary angiography [urgent target vessel revascularization (TVR)]. Furthermore, there were no other groin complications, including groin hematoma, arteriovenous fistulae, infection or need for femoral vascular surgery. There were also no post-discharge bleeding complications or MACE (death, ACS, TVR) at 30-day follow-up. Discussion Enoxaparin is theoretically more advantageous than UFH due to its ease of administration, enhanced anti-Xa/IIa activity, greater predictability of antithrombin activity, reduced risk of thrombocytopenia and more predictable dose response facilitating weight-adjusted dosing without the need for monitoring.2,10,11 Since enoxaparin does not increase platelet surface proteins (P-selectin, GP IIb/IIIa) or adenosine diphosphate-induced platelet aggregation, it may also provide a greater antiplatelet effect and more potent inhibition of thrombin generation when combined with GP IIb/IIIa inhibitors.5,12,13 Currently, the minimum effective dose of IV enoxaparin in combination with GP IIb/IIIa during PCI is not known. Our study shows that IV enoxaparin can be safely used in a dosage lower than previously reported during PCI in combination with GP IIb/IIIa inhibitors. We observed no TIMI major bleeding or MACE up to 30 days, and a TIMI minor bleeding rate of 80% inhibition of platelet aggregation) than UFH and a similar small molecule GP IIb/IIIa inhibitor combination.18 We did not evaluate the anti-Xa activity of this new dose (0.5 mg/kg); however, the negative in-hospital and 30-day MACE attest to its efficacy when combined with GP IIb/IIIa inhibitors. ACT measured at the end of procedures did not reflect the clinical antithrombotic activity as noted in prior reports.2 The patient who had mild thrombocytopenia was on chronic methotrexate therapy for rheumatoid arthritis, which together with abciximab could have lowered his platelet count. Almost all of our patients were overweight (body mass index >= 25 kg/m2)19 and all received Angio-Seal™ deployment at the conclusion of the procedure with early ambulation at 4 hours. A recent PCI study using Angio-Seal™ reported rates of 1.4% non-CABG major bleeding and 9.5% non-CABG minor bleeding despite UFH and abciximab therapy.20 It also showed that Angio-Seal™ performed better than manual compression or another percutaneous suture device with respect to successful deployment, shorter time to hemostasis, decreased time to ambulation, and reduced bleeding complications during 30-day follow-up. The superior hemostasis provided by Angio-Seal™, together with the lower bleeding potential of reduced dose enoxaparin, could have contributed to the low bleeding rate in our study despite the fact that the majority of our patients had some high-risk features for femoral vascular complications, such as obesity and hypertension. The patient who had TIMI minor bleeding was older (> 80 years) and had uncontrolled hypertension and a small antecedent hematoma at the femoral access site from prior coronary angiography; all of these factors together with deployment technique might have contributed to the retroperitoneal leak. The use of Angio-Seal™ together with a lower dose of enoxaparin could have contributed to the early ambulation and early discharge of our patients. In prior enoxaparin PCI studies,3,6 the removal of femoral sheaths was delayed up to 4 hours post-procedure, requiring patients to experience the discomfort of manual sheath removal followed by 4–6 hours of absolute bed rest. Our study also suggests that the addition of vascular closure devices to this IV low-dose antithrombin and full-dose antiplatelet therapy combination during elective PCI may offer additional cost-effectiveness by facilitating patient discharge in 24 hours; however, larger randomized trials are needed to confirm this benefit. Study limitations. This study is limited by its size and the fact that patients were not randomized or compared with patients receiving UFH or other doses of enoxaparin in conjunction with GP IIb/IIIa inhibitors. However, the safety and efficacy of UFH or other doses of enoxaparin (1 mg/kg or 0.75 mg/kg) used with GP IIb/IIIa inhibitors during PCI have already been reported.21,22 We did not demonstrate in vitro anti-Xa activity, but have shown in vivo efficacy as judged by successful PCI without abrupt vessel closure or stent thrombosis. The Coronary Revascularization Utilizing Integrilin and Single-bolus Enoxaparin (CRUISE) randomized trial is evaluating the safety and efficacy of IV enoxaparin (0.75 mg/kg) and eptifibatide compared to UFH and eptifibatide.23 Conclusion. Our small observational study shows that anticoagulation with lower dose IV enoxaparin (33% lower than previously reported dose) is feasible and appears to be safe and effective during PCI when used in conjunction with GP IIb/IIIa inhibitors and a bio-absorbable hemostatic vascular anchor (Angio-Seal™). Patients also seem to enjoy the additional benefits of immediate sheath removal, with early ambulation resulting in early hospital discharge. Large, randomized trials are needed to confirm the clinical efficacy, safety and possible superiority of lower doses of enoxaparin with GP IIb/IIIa inhibitors and vascular closure devices during PCI.
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