Low molecular weight heparin (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™) and lepirudin (Refludan^®) are recombinant anticoagulants that function as direct thrombin inhibitors.  They are 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.

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.
      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 vitamin K antagonists, 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).
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 lepirudin (Refludan^®) in the outpatient setting is considered medically for the treatment of individuals with HIT or a history of HIT, for the prevention of further thrombosis
   
4. 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.
5. 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.

The use of lepirudin (Refludan^®) is considered not medically necessary for the following:

1. Individuals with severe renal failure.
2. 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.
3. To prevent thrombosis related to long term indwelling central venous lines in individuals with cancer.

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.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  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.

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.  Thrombi pose a significant threat to an individual's health because they may detach from their place of origin, forming an embolus 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, such as those bedridden after surgery, 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 and can be fatal. 

Prevention and treatment of DVT and PE is achieved mainly through the use of drugs that affect the function of parts of the blood resulting 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.  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, and dipyridamole. 

The next level 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, and generally does not require laboratory monitoring because of a longer half-life, 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 process 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 Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy and published in "Chest" in June 2008.  Many recommendations for the appropriate use of LMWH 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 usage only.

With the case of treatment of acute deep vein thrombosis, meta-analysis of 13 randomized studies comparing weight adjusted LMWH or fondaparinux with intravenous infusion of UFH has essentially shown equivalence in efficacy and safety.  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 would also be recommended if warfarin was not tolerated or was contraindicated or if the individual developed recurrent venous thromboembolism (VTE) while on therapeutic doses of warfarin (INR in appropriate therapeutic range).  Similar criteria would be 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 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 central nervous system abnormalities, although the true risks remain 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, it is recommended LMWH be used in preference to UFH.  There is evidence LMWH does not cross the placenta and an overview of a large series of cases concluded LMWH was safe for the fetus.  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.

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 two 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.  These drugs, desirudin (Iprivask™) and lepirudin (Refludan^®), have been investigated in the treatment of clotting-related medical conditions.  Desirudin and lepirudin both have outpatient indications recognized in authoritative drug compendia, including DVT prophylaxis following hip replacement surgery (desirudin) and as an adjunct to thrombolytic therapy in individuals with a history of heparin-induced thrombocytopenia (HIT) who have acute MI as well as for the prevention of further thrombosis in individuals with HIT accompanied by thromboembolic complications (lepirudin).

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.

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. 

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

Lepirudin (Refludan^®): A naturally occurring anticoagulant and antithrombotic similar to hirudin, a compound found in the body medicinal leeches. 

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 legs. 

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. 

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

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. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Pettila V, Kaaja R, Leinonen P, et al. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res. 1999; 96(4):275-282.
13. 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.
14. 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.
15. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997; 337(10):657-662.
16. 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.

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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. Akl EA, van Doormaal FF, Barba M, et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database of SystematicReviews 2007, Issue 3, Art. No.: CD006652.
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®, 2010.
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9. Berge E, Sandercock P. Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD003242.
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12. 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.
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17. 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.
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20. Gates S, Brocklehurst P, Davis LJ. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD001689.
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37. Sandercock PAG, Counsell C, Kamal AK. Anticoagulants for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD000024.
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44. Wille-Jørgensen P, Rasmussen MS, Andersen BR, Borly L. Heparins and mechanical methods for thromboprophylaxis in colorectal surgery. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD001217.

1. National Library of medicine. Medical Encyclopedia: Blood clots. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001124.htm. Accessed on May 12, 2011.

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
Lepirudin (Refludan^®)
lecular 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.