Clinical UM Guideline


Subject:Use of Low Molecular Weight Heparin Therapy, Fondaparinux (Arixtra®), and Direct Thrombin Inhibitors in the Outpatient Setting
Guideline #:  CG-DRUG-04Current Effective Date:  07/09/2013
Status:ReviewedLast Review Date:  05/09/2013

Description

This document addresses the following injectable drugs used for the prevention and treatment of blood clots: low molecular weight heparin (LMWH), fondaparinux (Arixtra®), argatroban (Argatroban) and desirudin (Iprivask™).

LMWH is an anticoagulant drug used in both the prevention of clot formation in the blood vessels (thrombosis) and in the treatment of conditions caused by clot formation or embolization.  It is an injectable drug that may be administered by the individual or by a health care practitioner.  LMWH may be used in some circumstances as an alternative to oral warfarin or injectable unfractionated heparin therapy (UFH).

Fondaparinux (Arixtra) is a synthetic pentasaccharide selective inhibitor of factor Xa used in a similar fashion and for some similar indications as LMWHs.

Desirudin (Iprivask) is a recombinant anticoagulant that functions as a direct thrombin inhibitor.  It is similar in structure to hirudin, a naturally occurring anticoagulant found in the body of medicinal leeches.

Argatroban (Argatroban) is a synthetic direct thrombin inhibitor drug. 

Please note: This document addresses only the outpatient uses of LMWH, fondaparinux, and direct thrombin inhibitors and is not intended to apply to the inpatient use of these drugs.

Clinical Indications

Medically Necessary: 

  1. The use of low molecular weight heparin (LMWH) in the outpatient setting is considered medically necessary for any of the following conditions:
    1. Deep Vein Thrombosis (DVT)
      1. Treatment
        • Acute:  May be initiated on an outpatient basis in conjunction with warfarin, continued for at least 5 days, and discontinued when the international normalized ratio (INR) is in the therapeutic range (greater than or equal to 2.0) for at least 24 hours.
        • Long Term: 
          • Treatment for 3 to 6 months following acute DVT in individuals in whom warfarin is contraindicated or not tolerated.
          • Treatment of individuals with cancer, who have venous thromboembolism (VTE) for at least 3 months, followed by either LMWH or vitamin K antagonists (VKA) for as long as the cancer is active.
          • Treatment of individuals with upper extremity DVT (UEDVT) associated with a central venous catheter while the catheter remains in place.
          • Treatment for 3 months with UEDVT NOT associated with an indwelling central venous catheter.
      2. Prevention
        For prevention of DVT post-operatively in the case of the following procedures:
        • Hip fracture or total hip replacement surgery given for up to 5 weeks post-procedure.
        • Knee replacement surgery given for up to 10 days post-procedure.
        • Major general, or vascular surgery for individuals at high risk for venous thromboembolism due to malignancy, history of DVT or pulmonary embolism (PE), or other comorbidity given for up to 4 weeks post-discharge.
        • Gynecological surgery for individuals at high risk for VTE, including surgery for malignancy, age greater than 60 years, or previous VTE, given for up to 4 weeks post-discharge.
    2. Pulmonary Embolism (PE)
      • Long Term: Following pulmonary embolism, given for up to 3-6 months in individuals who have cancer, or in whom warfarin is contraindicated or not tolerated.
    3. Pregnancy
      • Treatment or prevention of thrombophilic disease or venous thromboembolism in pregnancy.  (For women on long-term warfarin treatment, LMWH should be substituted when pregnancy is achieved.)
      • For pregnant women with acute VTE, treatment should be continued until at least 6 weeks post partum.
    4. Thrombophlebitis
      • Treatment of spontaneous superficial thrombophlebitis, given for up to 4 weeks.
    5. Children with Cerebral Sinovenous Thrombosis (CSVT)
      • For children with CSVT without significant intracranial hemorrhage, initial anticoagulation with LMWH may be followed subsequently by either LMWH or VKAs, for a minimum of 3 months.
    6. Miscellaneous
      • Individuals for whom long term warfarin treatment is generally indicated and appropriate (for example, following a DVT in an individual who does not have cancer) but who are intolerant or have contraindications to warfarin, or develop recurrent VTE while on therapeutic doses of warfarin (i.e., INR in appropriate therapeutic range).
      • Individuals with mechanical heart valves where bridging with LMWH is needed until stable on VKA therapy.
      • Individuals with atrial fibrillation (AF) prior to undergoing cardioversion (electrical or pharmacologic) (expect at least 3 weeks when AF present more than 48 hours).
      • Individuals with atrial fibrillation (AF) for up to 4 weeks after undergoing successful cardioversion.
  2. The use of fondaparinux (Arixtra®) in the outpatient setting is considered medically necessary for any of the following conditions:
    1. Deep Vein Thrombosis (DVT)
      1. Treatment
        • Acute:  May be initiated on an outpatient basis in eligible individuals in conjunction with warfarin, continued for at least 5 days, and discontinued when the INR is in the therapeutic range (greater than or equal to 2.0) for at least 24 hours.
        • Long Term:  Treatment for 3 to 6 months following acute DVT in individuals who have cancer, or in whom warfarin is contraindicated or not tolerated.
      2. Prevention
        For prevention of DVT post-operatively for the following procedures:
        • Hip fracture or total hip replacement surgery - given for up to 5 weeks post-procedure.
        • Knee replacement surgery - given for up to 10 days post-procedure.
        • Major abdominal surgery for individuals at high risk for VTE - given for up to 4 weeks post discharge.
    2. Pulmonary Embolism (Treatment)
      • Long Term: When initially administered as an inpatient, outpatient administration may be continued concomitantly with warfarin for between 5 and 26 days after initial dose.
  3. The use of desirudin (Iprivask™) in the outpatient setting is considered medically necessary for the following conditions:
    1. Deep Vein Thrombosis (DVT)
      1. Prevention
        For prevention of deep vein thrombosis in individuals undergoing elective hip replacement surgery.
  4. The use of argatroban (Argatroban) in the outpatient setting is considered medically necessary for the following conditions:
    1. Thrombosis
      1. Treatment
        • Treatment of thrombosis in individuals with heparin-induced thrombocytopenia.
        • Treatment of cerebral thrombosis.
    2. Thrombosis
      1. Prevention
        • Prophylaxis of thrombosis in individuals with heparin-induced thrombocytopenia.
        • Prophylaxis of cerebral thrombosis.

Not Medically Necessary:

The use of low molecular weight heparin (LMWH), fondaparinux (Arixtra®), or desirudin (Iprivask™) is considered not medically necessary for the following:

  1. Switching from UFH to treat individuals with heparin-induced thrombocytopenia.
  2. Individuals with severe renal failure.
  3. Individuals in whom long term warfarin treatment is generally indicated and appropriate and where either LMWH has not been shown to improve health outcomes compared to warfarin, or who do not exhibit intolerance or have contraindications to warfarin and have not developed recurrent VTE while on therapeutic doses of warfarin.
  4. To prevent thrombosis related to long term indwelling central venous lines in individuals with cancer.
  5. Women with two or more miscarriages but without antiphospolipid antibodies (APLA) or thrombophilia.

The use of argatroban (Argatroban) is considered not medically necessary for the following:

  1. Individuals in whom long term warfarin treatment is generally indicated and appropriate and where either LMWH has not been shown to improve health outcomes compared to warfarin, or who do not exhibit intolerance or have contraindications to warfarin and have not developed recurrent VTE while on therapeutic doses of warfarin.
  2. To prevent thrombosis related to long term indwelling central venous lines in individuals with cancer.
Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS 
C9121Injection, argatroban, per 5 mg
J1645Injection, dalteparin sodium, per 2500 IU (Fragmin)
J1650Injection, enoxaparin sodium, 10 mg (Lovenox)
J1652Injection, fondaparinux sodium, 0.5 mg (Arixtra)
J1655Injection, tinzaparin sodium, 1000 IU (Innohep)
J3490Unclassified drugs [when specified as desirudin (Iprivask) or argatroban]
  
ICD-9 Diagnosis 
 All diagnoses
  
ICD-10 DiagnosisICD-10-CM draft codes; effective 10/01/2014:
 All diagnoses
  
Discussion/General Information

The formation of blood clots in veins and arteries, also known as thrombosis, may be caused by injury to a blood vessel, abnormal blood flow and blood that clots too easily due to a medical or genetic condition.  The most common site of formation for a blood clot (thrombus, plural thrombi) is the legs, but they may also form in the veins of the arms, the right side of the heart, at the tip of a catheter placed in a vein, or other locations.  Blood clots (also referred to as thrombi) pose a significant threat to an individual's health because they may detach from their place of origin, forming an embolus (a free-floating mass in the blood stream) that can migrate through the blood vessels and block the flow of blood to vital organs such as the lung, brain, and heart.

A major area of thrombus formation is in the large veins of the calf and thigh.  Such clot formation is referred to as deep venous thrombosis (DVT).  DVTs most frequently form in individuals with limited mobility, those with abnormal blood flow in their legs, or those with abnormal blood clotting physiology.  Other risk factors include childbirth within the last 6 months, the use of medications such as estrogen and birth control pills, a history of certain blood diseases, or the presence of a malignant tumor.

Emboli from the other areas of the body, including those from DVT, commonly travel to the lungs (pulmonary emboli or PE) where they result in a blockage of blood flow.  PE with small emboli may only partially block blood flow to the lungs, resulting in some tissue damage but allowing some level of function to continue.  Larger emboli can completely block blood flow to the lungs, which can be fatal. 

Prevention and treatment of DVT and PE is achieved mainly through the use of drugs that affect the components of the blood involved in clot formation or clot dissolution.  One class of drugs used is anticoagulants, which decrease the clotting ability of the blood and help to prevent harmful clots from forming.  These drugs will not dissolve clots already formed but may prevent such clots from becoming larger and causing more serious problems.  The most common anticoagulant agent used in the U.S. is warfarin (Coumadin®), a vitamin K antagonist (VKA).  Another class of drugs used is antiplatelet agents, which work by preventing platelets in the blood from clumping and forming thrombi.  Examples of antiplatelet drugs include aspirin, clopidogrel, ticlopidine, prasugrel, ticagrelor, and dipyridamole. 

The next group of drugs used to prevent DVT and PE are the antithrombotics, which include unfractionated heparin (UFH), low molecular-weight heparins (LMWHs), and fondaparinux.  Like anticoagulant and antiplatelet drugs, these drugs will not dissolve clots already formed but may prevent such clots from becoming larger.  UFH, when administered via intravenous infusion or in adjusted subcutaneous doses requires frequent monitoring of an individual's blood because of wide variations in drug bioavailability in the body which may result in too much or too little activity leading to complications such as excessive bleeding.  The need for frequent monitoring and the potential for significant complications make the use of intravenous or adjusted dose subcutaneous UFH difficult outside the hospital setting without proper supervision.  As an alternative, LMWH is injected under the skin once or twice a day by either the individual or a healthcare professional, generally does not require laboratory monitoring because of a longer half-life, and has better bioavailability and more predictable dose response than UFH.  Finally, thrombolytic drugs are used to actively break down thrombi and emboli.  The drugs in this class activate the natural processes in the blood that dissolve clots and include streptokinase (SK), reteplase, tenecteplase, urokinase, lanoteplase, and staphylokinase, among others.

An extensive literature review and evaluation of the evidence regarding the use of LMWH, fondaparinux and other forms of antithrombotic therapy and prophylaxis was conducted by the Ninth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy and published in "Chest" in February 2012.  Many recommendations for the appropriate use of intravenous antithrombotics are contained in these Evidence Based Guidelines.

There are currently three LMWHs available in the United States, including dalteparin (Fragmin), enoxaparin (Lovenox), and tinzaparin (Innohep).  A fourth drug, fondaparinux (Arixtra), is a factor Xa inhibitor with some similar indications and activity as the LMWHs.  It may, in some cases, be used as an alternative to LMWHs for certain indications.  Despite the fact each LMWH has different indications and dosing regimens, and has been studied for different uses, there is considerable overlap for use in similar clinical circumstances as an alternative to UFH.  Several recent studies have found other indications for the utilization of these drugs within the hospital inpatient setting.  However, these trials are not applicable to this document which focuses on outpatient intravenous and infusion usage only.

The  treatment of acute deep vein thrombosis was addressed in a meta-analysis of 13 randomized studies comparing weight adjusted LMWH or fondaparinux with intravenous infusion of UFH. The results essentially show equivalence in efficacy and safety (Bijsterveld, 1999).  In addition, several studies support the efficacy and safety of outpatient treatment with weight-adjusted LMWH for uncomplicated acute DVT in eligible individuals with results comparable to intravenous UFH administered in the hospital setting.  In most cases, warfarin is started concomitantly with LMWH or fondaparinux and the latter discontinued after 5 days and when the INR is within the appropriate therapeutic range (Breddin, 2001; Buller, 2004).  Subsequent long-term treatment would generally continue with warfarin.  However, studies have shown that, for individuals suffering from DVT in the presence of a malignancy LMWH is more effective in reducing recurrent DVT than warfarin, and in this situation therefore, LMWH would be recommended for 3-6 months following the acute episode.  LMWH is also recommended if warfarin is not tolerated or is contraindicated or if the individual develops recurrent venous thromboembolism (VTE) while on therapeutic doses of warfarin (INR in appropriate therapeutic range).  Similar criteria are applied to the long-term treatment of acute pulmonary embolism in terms of choice of anticoagulant and duration of therapy.

With regard to post-operative prophylaxis for VTE, LMWH and fondaparinux have been shown to be more effective than UFH or warfarin following total hip replacement and hip fracture surgery, and more effective than warfarin following total knee replacement.  Similarly, in the case of major general surgical procedures, for individuals at high risk for VTE, including those who have undergone major cancer surgery, post-hospital discharge prophylaxis with LMWH or fondaparinux is recommended for up to 4 weeks.  Similar recommendations are made for high-risk individuals who have undergone gynecological procedures.

Other situations in which LMWH is recommended include treatment or prevention of thrombophilic disease or VTE in pregnancy.  Warfarin is thought to be fetopathic with potential for causing central nervous system abnormalities.   The true risk remains unknown, and it is questionable whether it is in fact fetopathic in the first 6 weeks of pregnancy.  Nevertheless, the use of warfarin is not recommended in the pregnant woman, and therefore, a form of heparin is more appropriate.  Since the duration of treatment is likely to exceed 1 month, the ACCP recommends that LMWH be used in preference to UFH.  There is evidence LMWH does not cross the placenta, and several case series studies concluded that LMWH was safe for the fetus (Carp, 2003; Leduc 2007).  In addition, there is a more predictable dose response with LMWH and evidence that LMWH is less likely to be associated with osteoporosis and thrombocytopenia than UFH in the long term.  For women who require postpartum antithrombotic therapy, warfarin is stated to be safe, including in circumstances where the woman is breast feeding.  However, for women unable to tolerate warfarin, treatment with other agents is needed. Due to the risk of fetal loss and possible teratogenicity, the ACCP provides several recommendations against the use of direct thrombin and factor Xa inhibitors for women who are pregnant or breastfeeding. They suggest that for women unable to be treated with warfarin, the use of LMWH is the most appropriate option.  Finally, the data addressing antithrombotic therapy for women with inherited thrombophilias is conflicting.  The ACCP recommends against antithrombotic therapy for this populations at this time (Boyd, 2012, Coppens, 2007).

To summarize, the use of outpatient LMWH and fondaparinux may be recommended in preference to other anticoagulants or antithrombotics in the clinical situations listed in the "Medically Necessary" section of this document.  When there is a choice between long term UFH and LMWH/fondaparinux, LMWH/fondaparinux has advantages in terms of frequency of administration, predictability of response, and decreased incidence of complications such as osteoporosis or heparin-induced thrombocytopenia.  Given these options, it is reasonable that LMWH/fondaparinux would be the drug(s) of choice.  However, when the options for long-term anticoagulation lie between LMWH administered subcutaneously and warfarin taken orally, the less invasive option generally remains the anticoagulant of choice.  This may not be the case when a significant clinical health outcome advantage exists related to the use of LMWH in place of warfarin, there are contraindications to warfarin, the individual is intolerant, or there is recurrent VTE while on therapeutic doses of warfarin (INR in appropriate range).  In these circumstances, or in the presence of a clinical condition listed in the "Medically Necessary" section of this document, LMWH/fondaparinux would then be medically necessary as a warfarin alternative.

Hirudin is a direct thrombin inhibitor anticoagulant that is a naturally occurring compound found in the body of medicinal leeches.  Several drugs have been developed which mimic the chemical structure of hirudin.  One drug, desirudin (Iprivask)  has been investigated in the treatment of clotting-related medical conditions.  Desirudin has outpatient indications recognized in authoritative drug compendia, including DVT prophylaxis following hip replacement surgery (Salazar, 2010)

Argatroban (brand name Argatroban) is a synthetic direct thrombin inhibitor anticoagulant derived from L- arginine.  It has been investigated in the treatment of clotting-related medical conditions and is recommended for both the treatment and prevention of clotting in specific populations (LaMonte, 2004; Lewis, 2001, 2003).

Definitions

Argatroban (Argatroban): A synthetic peptide anticoagulant and antithrombotic drug. 

Desirudin (Iprivask: A naturally occurring anticoagulant and antithrombotic similar to hirudin, a compound found in the body medicinal leeches. 

Embolus: Any free mass; either solid, liquid, or gas; carried in the blood circulation, which is capable of clogging arterial capillary beds at a site distant from its point of origin.

Fondaparinux (Arixtra): A drug used to prevent blood clotting (an anticoagulant); fondaparinux is not a low molecular weigh heparin.

Low molecular weight heparin (LMWH): A class of drugs used to prevent blood clotting (anticoagulants). 

Deep vein thrombosis (DVT): A condition where blood clots in the veins located deep in the extremities. The term "DVT" is usually understood to refer to blood clots in the legs unless otherwise specified. 

Pulmonary embolism (PE): A condition where a blood clot lodges in the lungs, preventing blood flow to the pulmonary circulation.

Thrombus: Another name for a blood clot. 

Thrombophilia: A disorder of that predisposes an individual to abnormal blood clotting function that may lead to an increased risk of thrombus formation.  Also known as hypercoagulability or a prothrombotic state.

Thrombophlebitis: A condition characterized by inflammation of a vein associated with formation of a blood clot.

Upper extremity DVT (UEDVT): A condition where blood clots in the veins located deep in the arms.

References

Peer Reviewed Publications:

  1. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126(3 Suppl):627S-644S.
  2. Bijsterveld NR, Hettiarachchi R, Peters R, et al. Low-molecular weight heparins in venous and arterial thrombotic disease. Thromb Haemost. 1999; 82(Suppl 1):139-147.
  3. Breddin HK, Hach-Wunderle V, Nakov R, et al.; CORTES Investigators. Clivarin: assessment of regression of thrombosis, efficacy, and safety. Effects of a low-molecular-weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med. 2001; 344(9):626-631.
  4. Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. J Thromb Haemost. 2003; 1(3):433-48.
  5. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997; 337(7):447-452.
  6. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996; 335(10):701-707.
  7. Harenberg J, Riess H, Buller HR, et al. Comparison of six-month outcome of patients initially treated for acute deep vein thrombosis with a low molecular weight heparin Certoparin at a fixed, body-weight-independent dosage or unfractionated heparin. Haematologica. 2003; 88(10):1157-1162.
  8. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001; 119(1 Suppl):64S-94S.
  9. Kakkar VV, Gebska M, Kadziola Z, et al.; Bemiparin Investigators. Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis. Thromb Haemost. 2003; 89(4):674-680.
  10. Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med. 1996; 334(11):682-687.
  11. LaMonte MP, Nash ML, Wang DZ, et al. Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study. Stroke. 2004; 35(7):1677-82.
  12. Leduc L, Dubois E, Takser L, Rey E, David M. Dalteparin and low-dose aspirin in the prevention of adverse obstetric outcomes in women with inherited thrombophilia. J Obstet Gynaecol Can. 2007; 29(10):787-793.
  13. Lee AY, Levine MN, Baker RI, et al. Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003; 349(2):146-153.
  14. Leizorovicz A, Cohen AT, Turpie AG, et al.; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004; 110(7):874-889.
  15. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996; 334(11):677-681.
  16. Lewis BE,  Wallis DE, Leya F, et al;  The Argatroban-915 Investigators Argatroban Anticoagulation in Patients With Heparin-Induced Thrombocytopenia Arch Intern Med. 2003; 163:1849-1856.
  17. Lewis BE, Wallis DE, Berkowitz SD, et al; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001; 103(14):1838-1843.
  18. Pettila V, Kaaja R, Leinonen P, et al. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res. 1999; 96(4):275-282.
  19. Ramacciotti E, Araujo GR, Lastoria S, et al.; CLETRAT Investigators. An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis. Thromb Res. 2004; 114(3):149-153.
  20. Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med. 1997; 337(10):663-669.
  21. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997; 337(10):657-662.
  22. Thorevska N, Amoateng-Adjepong Y, Sabahi R, et al. Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs. enoxaparin. Chest. 2004; 125(3):856-863.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Ageno W, Gallus AS, Wittkowsky A, et al. Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e44S-e88S.
  2. Akl EA, Labedi N, Barba M, et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD006650.
  3. Akl EA, Rohilla S, Barba M, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006649.
  4. Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic Therapy in Peripheral Artery Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e669S-e690S.
  5. American College of Obstetricians and Gynecologists. Prevention of deep vein thrombosis and pulmonary embolism. ACOG Practice Bulletin No. 84. Obstet Gynecol. 2007; 110(2 Pt 1):429-440.
  6. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2010®. Bethesda, MD: American Society of Health-System Pharmacists®, 2012.
  7. Argatroban. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 1, 2012. Available at: http://www.micromedexsolutions.com.  Accessed on February 15, 2013.
  8. Bates SM, Greer IA, Middeldorp S, et al. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e691S-e736S.
  9. Chande N, McDonald JWD, MacDonald JK, Wang JJ. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD006774.
  10. Che Yaakob CA, Dzarr AA, Ismail AA, et al. Anticoagulant therapy for deep vein thrombosis (DVT) in pregnancy. Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD007801.
  11. Coutinho J, de Bruijn SFTM, deVeber G, Stam J. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No.: CD002005.
  12. Dalteparin Sodium. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 1, 2012. Available at: http://www.micromedexsolutions.com Accessed on February 15, 2013..
  13. Desirudin. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 1, 2012. Available at: http://www.micromedexsolutions.com.
  14. Di Nisio M, Porreca E, Ferrante N, et al.  Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD008500.
  15. Dörffler-Melly J, Büller HR, Koopman MM, Prins MH. Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD000536.
  16. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e326S-e350S.
  17. Eikelboom JW, Hirsh J, Spencer FA, et al. Antiplatelet Drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest; 2012; 141(2 suppl):e89S-e119S.
  18. Empson MB, Lassere M, Craig JC, Scott JR. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002859.
  19. Enoxaparin Sodium. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 1, 2012. Available at: http://www.micromedexsolutions.com. Accessed on February 15, 2013.
  20. Erkens PMG, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No.: CD001100.
  21. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in Orthopedic Surgery Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e278S-e325S.
  22. Fondaparinux Sodium In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 1, 2012. Available at: http://www.micromedexsolutions.com. Accessed on February 15, 2013.
  23. Garcia GA, Baglin TP, Weitz JI, Samama MM. Parenteral Anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e24S-e43S;
  24. Geraghty AJ, Welch K. Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery. Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD000536.
  25. Gould MK, Garcia DA, Wren SM, et al Prevention of VTE in Nonorthopedic Surgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e227S-e277S.
  26. Guyatt GH, Akl EA, Crowther M, et al.; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed. Chest. 2012; 141;7S-47S.
  27. Handoll HHG, Farrar MJ, McBirnie J, et al. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD000305.
  28. Heparin Sodium In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 1, 2012. Available at: http://www.micromedexsolutions.com.  Accessed on February 15, 2013.
  29. Hirsh J, Anand SS, Halperin JL, Fuster V; American Heart Association. Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation. 2001; 103(24):2994-3018. Available at: http://circ.ahajournals.org/content/103/24/2994.full.pdf+html. Accessed on March 28, 2012. 
  30. Holbrook A, Schulman A, Witt DM, et al. Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e152S-e184S.
  31. Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No: CD004734.
  32. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e195S-e226S;
  33. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e419S-e494S.
  34. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e601S-e636S.
  35. Linkins,LA, Dans AL, Moores COL Lisa K, et al. Treatment and Prevention of Heparin-Induced Thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e495S-e530S.
  36. Magee K, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003462.
  37. Magee KD, Sevcik W, Moher D, Rowe BH. Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002132.
  38. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic Therapy in Neonates and Children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e737S-e801S.
  39. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium(electronic version). Available at: http://www.nccn.org. Accessed on March 28, 2012.
  40. National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. January 2010. Available at: http://www.nice.org.uk/nicemedia/live/12695/47920/47920.pdf. Accessed on March 28, 2012.
  41. National Institute for Health and Clinical Excellence. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults (TA245). January 2012.  Available at: http://www.nice.org.uk/nicemedia/live/13648/57895/57895.pdf.  Accessed on February 15, 2013.
  42. National Institute for Health and Clinical Excellence. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults (TA170).  April 2009.  Review Date: February 2012.  Available at: http://www.nice.org.uk/nicemedia/live/12133/43811/43811.pdf. Accessed on February 15, 2013.
  43. National Institute for Health and Clinical Excellence. Clinical guidelines: Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital (CG92). January 2010. Available at: http://www.nice.org.uk/nicemedia/live/12695/47195/47195.pdf. Accessed on February 15, 2013.
  44. Othieno R, Abu Affan M, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD003076.
  45. Salazar CA, Malaga G, Malasquez G. Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD005981.
  46. Sandercock PAG, Counsell C, Kamal AK. Anticoagulants for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD000024.
  47. Sandercock PAG, Counsell C, Tseng MC. Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD000119.
  48. Snow V, Qaseem A, Barry P, et al. The Joint American College Of Physicians/American Academy Of Family Physicians Panel On Deep Venous Thrombosis/pulmonary Embolism. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Fam Med. 2007; 5(1):74-80.
  49. Tinzaparin Sodium. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 1, 2012. Available at: http://www.micromedexsolutions.com.  Accessed on February 15, 2013..
  50. Tooher R, Gates S, Dowswell T, Davis LJ. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database of Systematic Reviews 2010, Issue 5. Art. No.: CD001689.
  51. van der Heijden JF, Hutten BA, Büller HR, Prins MH. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Cochrane Database of Systematic Reviews 2001, Issue 3. Art. No.: CD002001.
  52. Vardi M, Zittan E, Bitterman H. Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD006771.
  53. Weitz JI, Eikelboom JW, Samama MM. New Antithrombotic Drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e120S-e151S
  54. Whitlock RP, Sun JC, Fremes SE, Antithrombotic and Thrombolytic Therapy for Valvular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e576S-e600S.
  55. You JJ, Singer DE, Howard PA, et al. Antithrombotic Therapy for Atrial Fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e531S-e575S.
Web Sites for Additional Information
  1. National Library of medicine. Medical Encyclopedia: Blood clots. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001124.htm. Accessed on February 15, 2013.
Index

Antiphospholipid Antibodies
Antithrombin
Argatroban (Argatroban)
Dalteparin (Fragmin®)
Deep Vein Thrombosis (DVT)
Desirudin (Iprivask™)
Enoxaparin (Lovenox®)
Factor V Leiden
Fondaparinux (Arixtra®)
Hip Fracture
Hip Replacement
Homocysteinemia
Knee Replacement
Low Molecular Weight Heparin
LMWH
Pregnancy
Protein C
Protein S
Prothombin20210 Mutation
Pulmonary Embolism (PE)
Thromboembolism
Thrombophlebitis
Tinzaparin (Innohep®)
Unstable Angina

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
StatusDateAction
Reviewed05/09/2013Medical Policy & Technology Assessment Committee (MPTAC) review. No change to position statement. Updated Reference section.
Revised05/10/2012MPTAC review. Updated Description section clarifying that document addresses only injectable drugs.  Added medically necessary indications for individuals with UEDVT, mechanical heart valves, and atrial fibrillation.  Added not medically necessary indications for women with APLA or thrombophilia.  Deleted position statements related to lepirudin (Refludan®).  Updated Description, Rationale, Definitions, Background, Reference, and Index sections.  Updated Coding section; removed HCPCS J1945.
Revised05/19/2011MPTAC review. Clarified position statement regarding lepirudin. Updated reference section.
Revised11/18/2010Medical Policy & Technology Assessment Committee (MPTAC) review. Updated title. Added desirudin (Iprivask™), lepirudin (Refludan®) and argatroban (Argatroban) to medically necessary and not medically necessary sections.  Updated Scope, Coding, Background, Reference, and Index sections.
Reviewed05/13/2010MPTAC review.  No change to clinical indications.  Updated Reference section.
 10/01/2009Updated Coding section with 10/01/2009 ICD-9 changes.
Revised05/21/2009MPTAC review.  Added "for at least 24 hours" to medically necessary statement regarding acute treatment of DVT with LMWH and fondaparinux.  Added treatment of cancer individuals with VTE to LMWH medically necessary statement. For LMWH and pregnancy section, added that treatment should be continued for at least 6 weeks post-partum.  Added treatment of children with cerebral sinovenous thrombosis (CSVT) as medically necessary with LMWH. Added long term treatment of pulmonary embolism with fondaparinux as medically necessary. Updated Coding, Background and Reference sections.
 10/01/2008Updated Coding section with 10/01/2008 ICD-9 changes.
Reviewed05/15/2008MPTAC review.  No change to position. Updated Background and Reference sections.
Reviewed05/17/2007MPTAC review.  Coding updated.
Revised06/08/2006MPTAC revision. Removal of Unstable angina or Non Q wave MI indication as this is an inpatient indication. Updated review date, coding and references. 
New07/14/2005MPTAC initial guideline development.