Fondaparinux: A Different Weaponin the War on ClotUpdate for the Clinical Nurse Specialist

PATRICIA O’MALLEY, PhD, RN, CNS

Despite the chemical arsenal available for thrombosisprevention, unfractionated heparin (UFH), and low-

molecular-weight heparins (LMWHs), clot remains a majorthreat for medical and surgical patients.1 In the absence ofprophylaxis, venous thromboembolism (VTE) occurs in10% to 40% of medical and general surgery patients andin 40% to 60% of major orthopedic patients.2

Heparin was discovered by chance 60 years ago from theextracts of dog livers. For 40 years, heparin was the mainstayfor parenteral anticoagulation, although the mechanisms ofaction were not clearly understood. Low-molecular-weightheparins were also found by chance in the late 1970s andwere in clinical use nearly a decade before the benefits of usewas discovered. Now, a new class of parenteral anticoagu-lants, pentasaccharides, offers clinicians another pathway tomodulate the coagulation cascade to prevent clot.3

PATHOPHYSIOLOGY OF CLOT

Thrombosis in arterial circulation is usually related todisruption of the endothelial lining of vessel walls, particularlyin areas of atheroma. The resulting exposure of subendothelialtissue results in formation of platelet plugs or white thrombus.The atheroma and platelets express tissue factor, whichactivates the coagulation pathway. Because of the major roleplatelets play in the formation of white thrombi, antiplateletagents are the preferred choice to prevent arterial thrombi.4

In the venous tree and cardiac atria, red thrombus canresult from blood stasis and activation of the coagulationcascade with entrapment of erythrocytes. Anticoagulants arethe preferred choice to prevent venous thrombi. Unfraction-ated heparin and LMWHs must be administered parenterallyand share in the risky side effects of heparin-induced

thrombocytopenia (HIT) and osteoporosis with long-termuse. Unfractionated heparin requires regular laboratory testsfor monitoring.4

A COMPARISON OF PARENTERAL AGENTS

After entering the bloodstream via intravenous or subcuta-neous (SC) route, UFH binds to a variety of plasma proteinsincluding glycoprotein platelet factor 4, vitronectin, and vonWillebrand, which lowers bioavailability and produces avariable anticoagulant response. Unfractionated heparininhibits multiple factors in the coagulation cascade particu-larly factor IIa or thrombin.3 Receptor-mediated uptake byendothelial cells and macrophages with renal activity clearsheparin from the plasma. As a result, drug effects are notlinearly related to dose in a therapeutic range. For example,the half-life of 25 U/kg of heparin is 30 minutes, whereas adose of 400 U/kg is 150 minutes.1 In patients requiringreversal, protamine can rapidly and completely neutralizeUFH, which makes this agent perfect for coronary bypasssurgery. Unfractionated heparin is also safe for patients withrenal disease.3 Unfractionated heparin is associated with HITand osteoporosis with long-term use and requires regularblood tests for monitoring effects.4 Unfractionated heparinremains the most common parenteral agent in the treatmentof patients with acute coronary syndromes (ACSs).5 Unfrac-tionated heparin is the anticoagulant of choice in pregnancybecause it does not cross the placental barrier.1

Each of the LMWHs differs significantly in physiologicaleffects, biochemical signature, and pharmacological profilebecause they were developed individually for a specificindication. In general, LMWHs inhibit factor Xa or anti-thrombin activity.5 However, agents within this class are notinterchangeable, nor are they a substitute for UFH.3 Eachagent is considered unique by the Food and Drug Admin-istration and World Health Organization. Although LMWHshave gradually replaced heparin for the prevention of deepvein thrombosis, the evidence for these agents for interven-tional and surgical procedures is still being established.1

Although LMWHs have demonstrated a somewhat greatereffectiveness for ACS, like UFH, these agents also confer a

Patricia O’Malley, PhD, RN, CNS

Column Editor

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Author Affiliations: Miami Valley Hospital, Dayton, Ohio.

Corresponding author: Patricia O’Malley, PhD, RN, CNS, 1096 Meadow

Dr, Beavercreek, OH 45434 (pomalley@mvh.org; paomalley@riva.net).

9Copyright @ 200 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

risk of major bleeding.5 Low-molecular-weight heparins offeradvantages compared with UFH related to ease of dosing,and daily blood test monitoring is not required. The risk forHIT is reduced but not eliminated when using LMWHs.6

Whereas traditional agents such as UFH and LMWHs arepolytherapeutic, newer agents such as pentasaccharidesare monotherapeutic in that these agents do not provideadditional therapeutic effects like the heparins such asmodulating thrombin-mediated activation of tissue factorpathway inhibitor at vascular sites, antithrombin, and profi-brinolytic actions. The physiological basis of fondaparinuxlies where the intrinsic and extrinsic coagulation pathwaysmerge and factor X. Theoretically, control of factor X activityreduces but does not inhibit thrombin generation, which mayreduce the risk of bleeding during treatment because bloodcoagulation is still possible. Fondaparinux (Arixtra; Sanofi-Synthelabo/Organon, Bridgewater, NJ) became the first druglicensed for clinical use from the pentasaccharide factor Xinhibitor class of anticoagulants.1,4

Fondaparinux is heparinomimetic in that the drug bindsto antithrombin III, which then facilitates the binding ofantithrombin III to factor Xa, interrupting the blood co-agulation cascade. Binding changes the antithrombinmolecule enhancing the inhibitory effects.1 Fondaparinuxhas no significant effect on factor IIa (thrombin) or plateletaggregation, which makes this agent distinct from UFHand LMWHs. Activated factor VII can partially reverse theanticoagulant effects.5 Platelets exposed to fondaparinuxdo form antiheparin/platelet antibodies. However, becausefondaparinux does not bind to platelets and binds only toantithrombin, HIT and osteoporosis are not a risk.3

This synthetic anticoagulant has desirable pharmacoki-netics, which includes superior bioavailability, predictable doseeffects, no animal or viral contaminants, and no interactionwith platelet factor 4 or heparin antibody. Administration bySC route results in rapid onset with no evidence of metabolism.The lack of nonspecific protein binding or drug interactionsand a fixed dose across a range of patient weights make thisnew weapon against clot attractive.6 Activated clotting timemonitoring is not needed for once-a-day dosing, andfondaparinux does not affect the activated partial thrombo-plastin time or prothrombin time. There is no antidote, anddrug levels can be determined only by anti-Xa assays.1

Half-life ranges from 14 to 20 hours in healthy volunteers,and peak plasma levels are achieved 2 hours after dosing.Steady state is achieved in 3 to 4 days of repeated once-dailydosing. Distribution seems to be limited to the vascular space,and elimination takes place through renal pathways. Clear-ance is reduced in renal disease and in patients weighing lessthan 50 kg.1

Fondaparinux is contraindicated in patients with creatinineclearance less than 30 mL/min and should not be administeredto patients actively bleeding. In Europe, fondaparinux isindicated for thrombus prevention in patients with ACS,including patients with ST-segment elevation myocardial infarc-tion (STEMI), non-STEMI (NSTEMI), and unstable angina.5

SIGNIFICANT RESEARCH

In theOASIS-5 trial of 20,078 patients, 2.5mg/d fondaparinuxfor less than 8 days was noninferior to enoxaparin 1 mg/kgtwice daily in patients with normal renal function in reducing

death or ischemia at 9 days. This efficacy was maintained forup to 6 months for patients with unstable angina or NSTEMI.Major bleeding events, death, and reinfarction at 30 days weresignificantly lower for patients with STEMI who receivedfondaparinux compared with those who received standardcare including UFH.5

In the OASIS-6 trial, in patients with ACS presenting asSTEMI who received 2.5 mg fondaparinux via SC route forless than 8 days following an intravenous dose on day 1,death and reinfarction were significantly less comparedwith patients who received standard care. For patientsrequiring percutaneous coronary intervention, fondapari-nux provided outcomes similar to enoxaparin for NSTEMIor UFH in patients with STEMI.5

Additional evidence suggests that fondaparinux may bemore effective than enoxaparin in preventing VTE in patientsafter orthopedic surgery and as effective as UFH withenoxaparin in patients with pulmonary embolism or deep veinthrombosis.7,8 Reported side effects include nausea, vomiting,dizziness, and rash, and similar to enoxaparin, 5% of patientsmay develop significant thrombocytopenia. Bleeding risk maybe higher with fondaparinux; however, further research isneeded to determine if the risk is significantly different fromLMWHs. Current evidence suggests that there are nosignificant differences for fatal bleeding, critical organ bleed-ing, operations, infection, and increased length of stay orhospital readmission with fondaparinux.4,9

CURRENT PRACTICE

Despite the effective chemical arsenal available for clinicians,VTE prophylaxis is underused.10 Patients and clinicians needan oral anticoagulant to replace warfarin that targets factorsXa and IIa. However, bringing an oral agent to market willbe an expensive undertaking because of the large sample sizeand extended follow-up required.3

For now, keep watch over fluid evidence-based practiceguidelines to guide prescribing and monitoring interven-tions. For guidance regarding all available parenteralanticoagulants, the eighth edition of the American Collegeof Chest Physicians Clinical Practice Guidelines is veryhelpful for prescribing and practice decisions.10

With regard to fondaparinux use during pregnancy,reports are very limited and anecdotal. Further research isnecessary for this population. Current recommendations arelimited to heparins that do not cross the placenta. Low-molecular-weight heparins are preferred over UFH related to alonger half-life and presumed fewer side effects. However,UFH is preferred during the period close to delivery related todosing and opportunity for reversal. For women with highrisk ofHIT or allergy requiring anticoagulation, fondaparinuxis an option.11,12

References1. Bick RL, Frenkel EP, Walenga J, Fareed J, Hoppensteadt DA.

Unfractionated heparin, low molecular weight heparins, andpentasaccharide: basic mechanisms of actions, pharmacology andclinical use.Hematol Oncol Clin North Am. 2005;19(1):1Y51.

2. Caprini JA. The future of medical therapy for venousthromboemboli. Am J Med. 2008;121(11 suppl 1):S10YS19.

3. Hirsh J, O_Donnell MO, Eikelboom JW. Beyond unfraction-ated heparin and warfarin: current and future advances.Circulation. 2007;116(5):552Y560.

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4. Tan KT, Lip GY. Fondaparinux. Curr Pharm Des. 2005;11(4):415Y419.

5. Blick SK, Orman JS, Wagstaff AJ, Scott LJ. Fondaparinuxsodium. A review of its use in the management of acute coronarysyndromes. Am J Cardiovasc Drugs. 2008;8(2):113Y125.

6. Shorr AF. The pharmacoeconomics of deep vein thrombosistreatment. Am J Med. 2007;120(10 suppl 2):S35YS41.

7. Reynolds NA, Perry CM, Scott LJ. Fondaparinux sodium: areview of its use in the prevention of venous thromboembo-lism following major orthopaedic surgery.Drugs. 2004;64(14):1575Y1596.

8. Robinson DM, Wellington K. Fondaparinux sodium: a reviewof its use in the treatment of acute venous thromboembolism.Am J Cardiovasc Drugs. 2005;5(5):335Y346.

9. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vsenoxaparin for the prevention of venous thromboembolism inmajor orthopedic surgery: ameta-analysis of 4 randomizeddouble-blind studies. Arch Intern Med. 2002;162(16):1833Y1840.

10. Spyropoulos AC. Emerging strategies in the prevention ofvenous thromboembolism in hospitalized medical patients.Chest. 2005;128(2):958Y969.

11. Gerhardt A, Zotz RB, Stockschlaeder M, Scharf RE. Fonda-parinux is an effective alternative anticoagulant in pregnantwomen with high risk of venous thromboembolism andintolerance to low molecular-weight heparins and heparin-oids. Thromb Haemost. 2007;97(3):496Y497.

12. James AH. Prevention and management of venous thromboemb-olism in pregnancy. Am J Med. 2007;120(10 suppl 2):S26YS34.

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