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

ABSTRACT: The use of intravenous enoxaparin, a glycoprotein (GP) IIb/IIIa inhibitor, during percutaneous coronary intervention (PCI) has been shown to be safe and to possibly reduce in-hospital and 30-day major adverse cardiac events (MACE). NICE-4, a recent PCI observational study, evaluated a reduced dose of intravenous (IV) enoxaparin (0.75 mg/kg) with abciximab. However, prior PCI studies evaluating IV enoxaparin have not used percutaneous closure devices. The purpose of this study was to observe the safety and efficacy of a lower dose of IV enoxaparin (0.5 mg/kg) in conjunction with any GP IIb/IIIa inhibitor. The Angio-Seal femoral closure device was also employed as part of the treatment strategy. We administered 0.5 mg/kg IV enoxaparin and a GP IIb/IIIa inhibitor to 75 eligible PCI patients. None received anticoagulation 24 hours prior to PCI; all received pre-procedural aspirin, post-procedural deployment of the Angio-Seal and clopidogrel therapy, and were discharged home within 36 hours. TIMI minor bleeding was 1.3%; there were no TIMI major bleeding events or major adverse cardiac events during in-hospital stay or at 30-day follow-up. Our small observational study shows that IV enoxaparin is safe and efficacious during PCI when given at a dose 33% lower than previously reported in conjunction with any GP IIb/IIIa inhibitor and Angio-Seal. However, large, randomized PCI trials are needed to confirm the clinical efficacy, safety and cost-effectiveness of lower doses of enoxaparin with GP IIb/IIIa inhibitors and vascular closure devices. Key words: anticoagulation, coronary stents, percutaneous closure device, platelet inhibitors 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 3), renal insufficiency (calculated creatinine clearance 9 Thirty-day follow-up was done by telephone interview with the patient and their cardiologist. RESULTS In all, seventy-five patients received 0.5 mg/kg IV enoxaparin (mean dose, 46.5 ± 9 mg) and GP IIb/IIIa blockade, with a majority receiving eptifibatide. Sixty-seven were outpatients referred for coronary angiography due to a positive stress test, and 8 were inpatients medically stabilized following a recent (4–7 day) ACS. Among the inpatients, four had ruled in for non-ST elevation MI and 4 had recent ST elevation MI. Ninety-four percent were overweight (body mass index >= 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 6,7 Large, randomized PCI trials like EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting), ESPIRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) and TARGET (Do Tirofiban and Reopro give Similar Efficacy Outcomes Trial) used UFH and GP IIb/IIIa inhibitors and reported major bleeding to be 1–1.5%, minor bleeding to be 2.8–5.6% and 30-day MACE to be 5.3–7.6%.^14–16 Unlike prior studies, our patients received 0.5mg/kg IV enoxaparin with any one of the GP IIb/IIIa inhibitors in the absence of anticoagulation during the preceding 24 hours. The NICE (National Investigators Collaborating on Enoxaparin)-3 study pretreated ACS patients with 1 mg/kg subcutaneous enoxaparin every 12 hours plus a GP IIb/IIIa inhibitor. Patients proceeding to PCI (47% of total) received an additional 0.3 mg/kg IV enoxaparin if their procedure was 8–12 hours after the last subcutaneous dose.^6,17 The NICE-4 study used a dose of 0.75 mg/kg IV enoxaparin with abciximab in PCI patients.^3,7 Both studies found that the safety and clinical efficacy of this combination therapy was comparable to prior studies using UFH and GP IIb/IIIa inhibitors. A recent randomized PCI study showed that enoxaparin used in conjunction with either eptifibatide or tirofiban provided better anticoagulation (higher 4 hour anti-Xa activity) and more potent platelet inhibition (> 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.

1. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment of enoxaparin for unstable angina/non-Q wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation 1999;100:1602–1608. 2. Rabah MM, Premereur J, Graham M, et al. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. Am J Cardiol 1999;84:1391–1395. 3. Kereiakes DJ, Grines CL, Frye E, et al., NICE I and NICE 4 Investigators. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invas Cardiol 2001;13:272–278. 4. Dudek D, Dabrowski M, Ochala A, et al. Multicenter, prospective, double-blind randomized comparison of enoxaparin versus unfractionated heparin for percutaneous coronary interventions (Abstr). Am J Cardiol 2000;86(Suppl 18A):15-I. 5. Cohen M, Theroux P, Weber S, et al. Combination therapy with tirofiban and enoxaparin in acute coronary syndromes. Int J Cardiol 1999;71:273–281. 6. Ferguson J, Antman E, Bates E, et al., for the NICE 3 Investigators. The use of enoxaparin and IIb/IIIa antagonists in acute coronary syndromes, including PCI: The NICE 3 Study (Abstr). Am J Cardiol 2000;86(Suppl 18A):16I. 7. Kereiakes J, Fry E, Barr L, et al. Enoxaparin-abciximab combination for percutaneous coronary intervention: Final results of the NICE 4 Trial (Abstr). Am J Cardiol 2000;86(Suppl 18A):14I. 8. Denardo SJ, Davis KE, Tcheng JE, Reid PR. Extremely low dose heparin with abciximab in coronary intervention: Improved efficacy and decreased bleeding complications using a novel heparin dosing strategy. Circulation 2000;102(Suppl II):II-785. 9. Bovill EG, Terrin ML, Stump DC, et al., for the TIMI Investigators. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II trial. Ann Int Med 1991;115:256–265. 10. Fry E. Glycoprotein IIb/IIIa inhibitors and low-molecular weight heparins: A combined role in coronary interventions? Clin Cardiol 2001;24(Suppl I):I-8–I-11. 11. Kereiakes DJ, Fry E, Mathai W, et al. Combination enoxaparin and abciximab therapy during percutaneous coronary intervention: “Nice guys finish first.” J Invas Cardiol 2000;12(Suppl A):1A–5A. 12. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular weight heparin and with a direct thrombin inhibitor. Circulation 1998;97:251–256. 13. Li Y, Spencer FA, Ball SP, Becker RC. Inhibition of platelet-dependent prothrombinase activity and thrombin generation by glycoprotein IIb/IIIa receptor-directed antagonist: Potential contributing mechanisms of benefit in acute coronary syndromes. J Thromb Thrombolysis 2000;10:69–76. 14. The EPISTENT Investigators. Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:87–92. 15. The ESPIRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): A randomised, placebo-controlled trial. Lancet 2000;356:2037–2044. 16. Topol EJ, Moliterno DJ, Herrmann HC, et al., for the TARGET Investigators. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888–1894. 17. Ferguson JJ. Combining low molecular weight heparin and glycoprotein IIb/IIIa antagonists for the treatment of acute coronary syndromes: The NICE 3 story. J Invas Cardiol 2000;12(Suppl E):E10–E13. 18. Madan M, Radhakrishnan S, Pang JT, et al. Optimal anticoagulation and platelet inhibition are achieved when enoxaparin is combined with small molecule GP IIb/IIIa inhibitors during elective percutaneous coronary intervention (Abstr). Circulation 2001;104(Suppl II):II-385. 19. Willett WC, Dietz WH, Colditz GA. Primary care: Guidelines for a healthy weight. N Engl J Med 1999;341:427–434. 20. Duffin DC, Muhlestein JB, Allison SB, et al. Femoral arterial puncture management after percutaneous coronary procedures: A comparison of clinical outcomes and patient satisfaction between manual compression and two different vascular closure devices. J Invas Cardiol 2001;13:354–362. 21. Kong DF, Califf RM, Miller DP, et al. Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation 1998;98:2829–2835. 22. Brown DL, Fann CSJ, Chang CJ. Meta-analysis of effectiveness and safety of abciximab versus eptifibatide or tirofiban in percutaneous coronary intervention. Am J Cardiol 2001;87:537–541. 23. Bhatt DL, Lincoff AM. Combined use of eptifibatide and enoxaparin in patients undergoing percutaneous coronary interventions: The results of the CRUISE trial. Circulation 2001;104(Suppl II):II-384.