Anticoagulation in Peripheral Interventions

A review of the current use of heparin and alternative anticoagulants in percutaneous interventions.

By GERALD GRUBBS, MD
 

To view the Table 1 for this article, please refer to the print version of our March 2003 issue, page 31.

Unfractionated heparin (UFH) has been the predominate anticoagulant used in both percutaneous coronary interventions (PCIs) and percutaneous peripheral interventions (PPIs) since Andreas Gruentzig, MD, developed the first balloon catheter. Heparin has several limitations, but until recently, there have been no suitable alternatives. The advent of newer anticoagulants, particularly the direct thrombin inhibitors (DTIs), holds promise to replace heparin in all percutaneous interventions.

HEPARIN USE IN PCI AND PPI
Heparin is commercially prepared from animal lungs or intestines1 and was first identified by a medical student almost 100 years ago. It is a heterogeneous mixture of polysaccharide chains that vary in molecular size and anticoagulant activity. UFH has traditionally been the anticoagulant used in the majority of endovascular procedures. Its widespread use is predominantly a result of its familiarity, low cost, and, until recently, the lack of suitable alternatives. Heparin has a number of increasingly visible disadvantages, however, that make it a suboptimal choice for anticoagulation in interventional procedures (Table 1).2 These limitations include unpredictable pharmacokinetics, an indirect mechanism of action that requires antithrombin III as an intermediary, the inability to neutralize clot-bound thrombin, platelet activation, and antibody production. In addition, the potentially catastrophic complication of type II heparin-induced thrombocytopenia (HIT) has been reported to occur in 1% to 5% of patients treated with heparin.3

Endovascular procedures are a primary method of improving flow and decreasing ischemic symptoms in patients with both coronary and peripheral arterial disease. Since the introduction of balloon catheters for treating stenotic lesions, significant progress has been made in the diagnosis and treatment of atherosclerotic disease. These advances include imaging modalities such as MRI, improved balloon catheters, intravascular lasers, atherectomy devices, stents, endoluminal radiation, fibrinolytic agents, and lipid-lowering drugs. Until recently, however, advances in antithrombotic therapy have languished, with clinicians continuing to employ UFH or one of its low-molecular-weight variants (low-molecular-weight heparin [LMWH]) for therapeutic and prophylactic anticoagulation. Indeed, anticoagulation regimens for PCI and PPI have stagnated as the rest of the armamentarium used in these procedures has moved forward several generations.

DTIs FOR THROMBOPROPHYLAXIS
DTIs represent a class of antithrombotic medications with the same potential for improving outcomes in endovascular interventions as newer intravascular devices, stents, and imaging procedures. Agents in this class include bivalirudin (Angiomax, The Medicines Company, Parsippany, NJ), lepirudin (Refludan, Aventis Pharmaceuticals, Bridgewater, NJ), and argatroban (Argatroban, GlaxoSmithKline Pharmaceuticals, Philadelphia, PA). Although the agents share some pharmacodynamic properties, each possesses distinctly different, clinically significant pharmacokinetic properties. DTIs provide predictable anticoagulant activity and directly inhibit free and clot-bound thrombin, independent of cofactors such as antithrombin.4 Bivalirudin is a DTI with pharmacokinetic properties and clinical evidence that support its use during PCI and peripheral endovascular procedures (Table 2).

Bivalirudin Overview
Bivalirudin is in the same class of thrombin inhibitors as hirudin; however, it was engineered to be structurally and pharmacologically distinct. It is a synthetic, 20-amino-acid peptide. A bivalent, specific, direct, and reversible inhibitor of thrombin, bivalirudin is capable of binding and inhibiting both free and clot-bound thrombin.5 It consists of a dodecapeptide analogue of the C-terminus of hirudin linked via a tetraglycine spacer to the peptide D-Phe-Pro-Arg-Pro. The C-terminal region binds to exosite I, while the N-terminal peptide binds to the active site of thrombin. Thrombin slowly cleaves the Arg3-Pro4 bond in the N-terminal peptide, however, thereby recovering the function of its active site. In this manner, bivalirudin produces transient inhibition of the active site of thrombin and allows thrombin to return to hemostatic functions. This transient inhibition represents a significant theoretical advantage over lepirudin, and with bivalirudin’s short (25-minute) half-life, may account for the relatively low bleeding rates reported in clinical trials.5

Bivalirudin also has been shown to completely inhibit thrombin-mediated platelet aggregation and to have an immediate and predictable anticoagulant effect. These characteristics contribute to this agent’s predictable anticoagulation properties and reduced ischemic complications. The drug is metabolized predominately by plasma proteases; only approximately 20% of the drug is metabolized via the kidney, making bivalirudin a more attractive anticoagulant than indirect thrombin inhibitors such as UFH and LMWH, which have a much higher proportion of renal clearance. In addition, bivalirudin is not associated with the development of the HIT-2 syndrome and the corresponding potentially lethal complications seen in patients treated with either UFH or LMWH.

BIVALIRUDIN’S EFFICACY AND SAFETY IN PCI
Bivalirudin has demonstrated significant reductions in both ischemic and bleeding complications in patients undergoing PCI, and these benefits may also prove to be applicable to PPI. In the Bivalirudin Angioplasty Trial (BAT), investigators compared bivalirudin with heparin during coronary angioplasty for unstable or postinfarction angina.6 In this study, differences in rates of a composite endpoint including death, MI, or repeat revascularization were compared at 7, 90, and 180 days in 4,312 patients undergoing coronary angioplasty for unstable angina pectoris. The anticoagulant used was either UFH or bivalirudin. Bivalirudin significantly reduced both the combined ischemic endpoints (reduction of 22%, P=.039) and the risk of bleeding (reduction of 62%, P<.001) compared with heparin. Patients with more severe disease (post-MI or with unstable angina previously treated with heparin) received even greater benefit from bivalirudin compared with heparin. There was a reduction in the triple ischemic endpoint of 51% and an 80% reduction in major hemorrhage. Bivalirudin is the first anticoagulant used in interventional procedures to concurrently reduce both ischemic and bleeding complications.

The advantages of bivalirudin compared with heparin for PCI were further strengthened by the recent release of the results of the REPLACE-2 trial at the American Heart Association Annual Meeting in November 2002, and the subsequent publication of the trial in the Journal of the American Medical Association.7 This study was an international, multicenter, randomized, double-blind, triple-dummy, active-controlled trial of 6,010 patients undergoing elective or urgent PCI. Patients were randomized to receive bivalirudin with provisional GP IIb/IIIa inhibitor versus the current standard of heparin and planned GP IIb/IIIa inhibitor. Stents were used in approximately 85% of patients, and approximately 86% of patients were pretreated with thienopyridines (mostly clopidogrel). The quadruple composite 30-day endpoint (death, MI, urgent revascularization, or major in-hospital bleeding) occurred among 9.2% of patients in the bivalirudin arm versus 10% of patients in the heparin plus GP IIb/IIIa arm. Furthermore, major bleeding rates were 2.4% in the bivalirudin arm versus 4.1% in the heparin plus GP IIb/IIIa arm (P<.001) (Table 3).

The REPLACE-2 investigators concluded that bivalirudin plus provisional GP IIb/IIIa blockade (administered in only 7.2% of patients) is superior to heparin alone and as effective as heparin plus planned GP IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic endpoints. Bivalirudin plus provisional GP IIb/IIIa blockade is also associated with significantly less bleeding. All major and minor bleeding complications were reduced with bivalirudin treatment versus heparin plus GP IIb/IIIa inhibition, with a striking 68% reduction in sheath access site bleeding complications. The reductions in ischemic and bleeding complications exhibited by bivalirudin in the BAT and REPLACE-2 trials are potentially clinically relevant to physicians performing peripheral endovascular procedures (Table 4).

BIVALIRUDIN USE IN
PERIPHERAL INTERVENTIONS
Preliminary evidence supports the use of bivalirudin in patients undergoing peripheral endovascular procedures. Potential benefits of this drug over UFH include improved procedural efficiency, superior clinical outcomes, less bleeding, earlier sheath withdrawal due to the agent’s short half-life, and no risk for the development of heparin antibodies and the HIT syndrome. Single-center experiences of bivalirudin in peripheral interventions have been reported at various scientific meetings. I presented data at a poster session at the 2003 meeting of the Cardiovascular Revascularization Therapies in Washington, DC.8 Bivalirudin was the sole anticoagulant used in a diverse group of representative peripheral vascular interventions in 69 patients (Table 5). In this registry, bivalirudin dosages varied with the anticipated duration of the procedure, the usual target ACT for the procedure, and procedural complexity. Due to the relative difficulty in predicting procedure length for many peripheral interventions, the short (25-minute) half-life of bivalirudin, and the pharmacokinetic profile of this agent, it may be prudent to utilize a dosing regimen consisting of a bolus plus infusion, such as that employed in large prospective clinical trials such as REPLACE-2; (0.75 mg/kg bolus in concert with a 1.75 mg/kg per hour infusion for the duration of the procedure). Of note is that anticoagulation with bivalirudin in this registry was achieved immediately, with an average ACT reading at 1 minute utilizing the 0.75 mg/kg bolus of 321 seconds.

Our registry showed that bivalirudin provided optimal anticoagulation for all peripheral interventions and did not show adverse events such as bleeding, procedural failure, acute thrombosis, death, or development of HIT. A historical review of the usual complication rates for this group of procedures among 1,200 patients at this institution (in which UHF was the anticoagulation agent) was 6%. This information indicates the potential clinical benefits of direct thrombin inhibition with bivalirudin in peripheral endovascular procedures. These results are particularly striking for the arterial lysis cases. In the 12 reported cases, bivalirudin bolus plus intravenous infusion was associated with a success rate of 100%, compared with a historical success rate of 78% when using UFH as the anticoagulant. These data represent an enviable new standard for procedures of this type.

Knopf et al9 administered bivalirudin to 72 patients with 88 peripheral lesions at a dose of 0.75 mg/kg bolus (100% of patients) followed by a 1.75 mg/kg per hour infusion (in 50% of patients) for the duration of the procedure. The procedural success was 100%, no major bleeding was observed, and there were no deaths, strokes, evidence of distal emboli, or significant changes in serum creatinine concentrations. The mean ACT was 286 seconds, the mean time to sheath removal was 108 minutes, and the mean time to discharge was 0.6 days.

Allie et al10 studied 180 renal and 75 iliac peripheral interventions using bivalirudin at a dose of 0.75 mg/kg bolus followed by a 1.75 mg/kg per hour infusion (for the duration of the procedure). The procedural success rate was 100%. Restenosis greater than 50% (resulting in repeat intervention) was observed in 3.8% of the renal and 4% of the iliac cases. There were no major complications reported.

In a pilot study11 utilizing bivalirudin in carotid artery stenting, Adamyan et al evaluated this agent in 33 consecutive patients who were administered the drug as a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for the duration of the procedure. The average patient age was 70 years, 52% of the patients were male, 31% were diabetic, and 78% had hypertension. No GP IIb/IIIa inhibitors were used; closure devices were used in 52% of patients. There were no major adverse events and no vascular complications in the study cohort. One patient suffered a major stroke after the procedure.

CONCLUSION
Choosing the optimal antithrombotic therapy is a clinical necessity for both coronary and peripheral endovascular procedures. Clinical trial data in PCI indicate that bivalirudin is equivalent to the current “gold standard” of heparin plus GP IIb/IIIa inhibitors to prevent ischemic complications of coronary interventions, while significantly reducing bleeding. Registry data indicate that this agent holds promise for its use in peripheral vascular procedures as well. Advantages of this drug compared with heparin include immediate anticoagulation, predictable pharmacokinetic and pharmacodynamic features, the ability to inhibit both circulating and clot-bound thrombin, and an absence of heparin antibodies and their complications. Additionally, bivalirudin is easy to use and may improve procedural efficiency due to its proven reductions in access site complications. This is particularly advantageous for endovascular procedures, due to the size of the requisite catheters and the length and complexity of some procedures. Additional ongoing clinical trials are expected to provide supplemental evidence of the drug’s benefits in patients treated for a variety of coronary and peripheral vascular diseases. These trials should provide the necessary data regarding the various available anticoagulation options, thus helping to optimize the care of patients undergoing endovascular therapies.

Gerald Grubbs, MD, is an cardiovascular and interventional radiologist at Naples Endovascular Specialists, Naples Radiologists, P.A., in Naples, Florida. Naples Endovascular Specialists has received financial support from The Medicines Company for clinical trial participation and data collection. Dr. Grubbs may be reached at (239) 262-2708; drgrubbs@earthlink.net.

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3. Warkentin TE, Sheppard J-A I, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96:1703-1708.
4. Bauer KA. Selective inhibition of coagulation factors: advances in antithrombotic therapy. Semin Thromb Hemost. 2002;28(Suppl):15-24.
5. Bates SM, Weitz JI. The mechanism of action of thrombin inhibitors. J Invasive Cardiol. 2000;12(Suppl F):27F-32F.
6. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J. 2001;142:952-959.
7. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention; the REPLACE-2 randomized trial. JAMA. 2003;289:853-863.
8. Grubbs G. Single center experience with bivalirudin anticoagulation in peripheral vascular interventions: possible benefits over unfractionated heparin. Poster presented at: Cardiovascular Revascularization Therapy conference; January 26-29, 2003; Washington, DC.
9. Knopf W. St. Joseph’s Hospital experience; Direct thrombin inhibitors in ACS and PCI: the case for bivalirudin replacing unfractionated heparin in PCI. Paper presented at: Transcatheter Cardiovascular Therapeutics 14th Annual Scientific Symposium; September 24-28, 2002; Washington, DC.
10. Allie D. Bivalirudin as sole anticoagulant in peripheral vascular disease: a safe and feasible alternative in renal and iliac interventions. To be presented at American College of Cardiology 52nd Annual Scientific Session; March 30-April 2, 2003; Chicago, IL.
11. Adamyan Y, News G, Vitek J, et al. Feasibility and safety of bivalirudin during carotid stenting: results of the pilot study. Am J Cardiol. 2002; 90 (suppl 6A): 55H.

 

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