Community Blue • Traditional Blue
PO Box 15013 • Albany, New York 12212
Drug Therapy Guidelines:
Injectable Anticoagulants
®
Arixtra (fondaparinux), Lovenox® (enoxaparin),
Fragmin®NF (dalteparin), Innohep®NF (tinzaparin)
Effective Date: 1/20/06
Committee Review Dates: 4/1/99, 1/25/00, 1/16/01, 1/15/02, 1/7/03, 1/20/04, 1/11/05, 12/7/05
Original Policy Date: 4/1/99
Policy Statements:
•
Non-Formulary/ 3rd tier or Prior Authorization drugs may require an appropriate trial of a Formulary agent(s) based on
benefit coverage or criteria. A therapeutic trial of samples of a Non-Formulary or Prior Authorization agent will not be accepted as
rationale for medical necessity to continue that agent. Please be sure to list all therapies that have been previously tried on the
request form so that your request can be processed in a timely manner.
•
A drug will be approved based on coverage criteria for FDA approved indications. Requests for newly approved indications
will be reviewed by the Medical Director as per FDA labeling and an internal policy will be developed to assure consistency of review
until an updated guideline is approved and published.
•
Off-label/investigational uses will be reviewed for medical appropriateness on a case by case basis. Literary evidence will be
sought for well designed and well conducted investigations published in peer-reviewed articles that demonstrate safety, efficacy,
improvement in health outcomes and comparison data supporting effectiveness equal to or superior to established conventional
therapies.
For medical injectables administered by the healthcare provider, guidelines are designed to give providers a concise overview of medical
criteria utilized in determining coverage of services rendered. Guidelines provide clinically significant information about medical treatment
that if not adhered to, may affect the payment you receive. Please remember that when a service is denied because it does not meet the
medical necessity criteria contained within the guideline, the member is held harmless and cannot be billed.
For both self-medication obtained at the retail pharmacy and medical injectables administered by the provider, please note that
payment for covered services is subject to the limitations noted in the member’s contract and the member's eligibility at the time the
services are rendered.
Background / Overview:
Injectable anticoagulants (i.e. Unfractionated Heparin (UFH), Low Molecular Weight Heparins
(LMWH), and the synthetic pentasaccaride fondaparinux) prevent the formation and growth of
thrombi.
Fondaparinux (Arixtra®) is a synthetic pentasaccharide anticoagulant used for the treatment of
deep vein thrombosis (DVT) or pulmonary embolism (PE) and for the prevention of DVT and
PE in patients undergoing abdominal surgery, hip fracture surgery, hip replacement, or knee
replacement surgery. Fondaparinux is the first in a new class of agents, an indirect factor Xa
inhibitor, which selectively inhibits factor Xa via antithrombin-dependent actions. Unlike
unfractionated heparin or low molecular weight heparins (LMWHs), fondaparinux does not
inhibit thrombin (factor IIa). Therefore, fondaparinux inhibits a single, targeted step in the
coagulation cascade (factor Xa), resulting in antithrombotic action. In contrast to heparin
anticoagulants, fondaparinux lacks a specific antidote in the event of excessive anticoagulation
1
Arixtra® (fondaparinux), Lovenox® (enoxaparin),
Fragmin® (dalteparin), Innohep® (tinzaparin)
and does not require laboratory monitoring. There have been bleeding crisis reported following
surgery and should be used cautiously by experienced practitioners. The FDA approved
fondaparinux (Arixtra®) in December of 2001. The FDA approved fondaparinux for extended
prophylaxis of deep venous thrombosis in patients undergoing hip surgery in June 2003; this
approval is based on PENTHIFRA PLUS study results demonstrating 96% risk reduction for
post-operative venous embolism relative to placebo following hip fracture surgery.[4216]
Fondaparinux was approved by the FDA for the treatment of DVT or PE when administered in
conjunction with warfarin in May 2004. Fondaparinux was approved by the FDA for DVT and
PE prophylaxis in at-risk patients undergoing abdominal surgery in May 2005. Several uses of
fondaparinux are discussed below.
The use of LMWH has become more widespread due to its superior pharmacokinetic properties
over UFH. Consequently, the anticoagulant response is more predictable, making routine
monitoring unnecessary. Additionally, once daily, subcutaneous dosing is effective. There is
also a lower incidence of heparin-induced thrombocytopenia and osteopenia. Evidence from
clinical trails has shown that LMWHs are at least as effective as and are safer than UFH.
However, therapy may need to be monitored in patients with severe obesity or renal
insufficiency.
The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy is an evidence
based guideline. A number of large, well-designed trials were considered when forming the
recommendations. Careful attention was paid to the methodological quality of the studies.
LMWHs have replaced UFH (unfractionated heparin) for most indications, including prevention
and treatment of venous thrombosis, acute pulmonary embolis, and unstable angina. They are
considered at least as effective, and safer, than UFH. 1
Recommended Guidelines for LMWHs (Lovenox®, Fragmin®, Innohep®):
The use of low molecular weight heparin (LMWH-) in the outpatient is considered medically
appropriate when any of the following conditions are met:
1. Deep Vein Thrombosis (DVT)
a. Treatment
i. Acute: May be initiated on an outpatient basis in eligible patients in
conjunction with warfarin, continued for at least 5 days, and discontinued
when the international normalized ratio (INR) is in the therapeutic range
(2 - 3).
ii. Long Term: Treatment for 3 to 6 months following acute DVT in patients
who have cancer, or in whom warfarin is contraindicated or not tolerated.
b. Prevention
For prevention of DVT post-operatively in the case of the following procedures:
i. Hip fracture or total hip replacement surgery given for up to 5 weeks postprocedure.
ii. Knee replacement surgery given for up to 10 days post-procedure.
iii. Major general, or vascular surgery for patients 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 postdischarge.
iv. Gynecological surgery for patients at high risk for venous
thromboembolism (VTE) including surgery for malignancy, or age > 60
years, or previous VTE given for up to 4 weeks post-discharge.
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Arixtra® (fondaparinux), Lovenox® (enoxaparin),
Fragmin® (dalteparin), Innohep® (tinzaparin)
2. Pulmonary Embolism (PE)
a. Long Term: Following pulmonary embolism given for up to 3-6 months in
patients who have cancer, or in whom warfarin is contraindicated or not tolerated.
3. Pregnancy
a. 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.)
4. Unstable Angina Or Non-Q-Wave Myocardial Infarction
a. Treatment of unstable angina or non-Q-wave myocardial infarction when
administered concurrently with aspirin and for patients treated with glycoprotein
IIb/IIIa inhibitors.
5. Thrombophlebitis
a. Treatment of spontaneous superficial thrombophlebitis given for up to 4 weeks.
6. Miscellaneous
a. Patients for whom long term warfarin treatment is generally indicated and
appropriate (for example, following a DVT in a patient 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).
Recommended Guidelines for pentasaccaharide anticoagulant Arixtra®:
The use of fondaparinux (Arixtra®) in the outpatient setting is considered medically appropriate
for any of the following conditions:
1. Deep Vein Thrombosis (DVT)
a. Treatment
i. Acute: May be initiated on an outpatient basis in eligible patients in
conjunction with warfarin, continued for at least 5 days, and discontinued
when the international normalized ratio (INR) is in the therapeutic range
(2 - 3).
ii. Long Term: Treatment for 3 to 6 months following acute DVT in patients
who have cancer, or in whom warfarin is contraindicated or not tolerated.
b. Prevention
In patients weighing 50kg or more, prevention of DVT post-operatively in the
case of the following procedures.
i. Hip fracture or total hip replacement surgery given for up to 5 weeks postprocedure.
ii. Knee replacement surgery given for up to 10 days post-procedure.
iii. Major abdominal surgery for patients at high risk for VTE given for up to
4 weeks post discharge.
Medical Inappropriate or Investigational Use:
1. Switching from UFH to LMWH to treat patients with heparin-induced thrombocytopenia.
2. Patients with severe renal failure. (Arixtra® is contraindicated in patients with CrCL<30)
3. Patients 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 cancer
patients.
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Arixtra® (fondaparinux), Lovenox® (enoxaparin),
Fragmin® (dalteparin), Innohep® (tinzaparin)
*Indications and Dosing:
Lovenox®
DVT prophylaxis after hip or knee replacement surgery:
- 30 mg SQ every 12 hours, with the initial dose given within 12 to 24 hours postoperatively.
Usual duration is 7 to 10 days. Alternatively, a dose of 40mg SQ once daily, given 9 to 15
hours prior to surgery can be given for hip replacement surgery. Continue prophylaxis for 3
weeks.
DVT prophylaxis after abdominal surgery:
- 40 mg SQ once daily with initial dose given 2 hours prior to surgery. Usual duration is 7 to
10 days.
DVT prophylaxis for medical patients during acute illness:
- 40 mg SQ once daily. Usual duration is 6 to 11 days.
Acute DVT outpatient treatment:
- 1 mg/kg SQ every 12 hours. Initiate warfarin therapy when appropriate and continue
Lovenox for a minimum of 5 days and until a therapeutic anticoagulant effect has been
achieved (INR 2-3).
Acute DVT with or without PE inpatient treatment:
- 1 mg/kg SQ every 12 hours. Initiate warfarin therapy when appropriate and continue
Lovenox for a minimum of 5 days and until a therapeutic anticoagulant effect has been
achieved (INR 2-3). 1.5mg/kg SQ once daily may be used in some patients if injection
volume is appropriate for SQ use.
Unstable angina/Non-Q-wave MI:
1 mg/kg SQ every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once
daily). Usual duration is 2 to 8 days.
Arixtra®
DVT prophylaxis following hip fracture, or knee or hip replacement surgeries:
- 2.5mg SQ once daily.
- After hemostasis has been established, the initial dose should be given 6 to 8 hours after
surgery.
- Usual duration of administration is 5 to 9 days; up to 11 days administration has been
tolerated.
- In patients undergoing hip fracture surgery, an extended prophylaxis course of up to 24
additional days is recommended.
- Use for this indication is contraindicated in patients weighing <50 kg.
Treatment of DVT with or without PE:
- 5mg SQ once daily (body weight <50 kg), 7.5mg (body weight 50-100 kg), or 10 mg (body
weight >100kg).
- Continue for 5 days and until an oral therapeutic anticoagulant effect is established (INR 23).
- Concomitant warfarin should be initiated as soon as possible, usually within 72 hours.
- Usual duration is 5-9 days; up to 26 days.
Fragmin®
Unstable angina/Non-Q-wave MI:
- 120 IU/kg of body weight (but not > 10,000 IU) SQ every 12 hours with concurrent oral
aspirin (75 – 165 mg/day) therapy unless contraindicated.
- Continue treatment until the patient is clinically stabilized, usually 5-8 days.
DVT prophylaxis in abdominal surgery:
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Arixtra® (fondaparinux), Lovenox® (enoxaparin),
Fragmin® (dalteparin), Innohep® (tinzaparin)
-
2500 IU SQ once daily, starting 1 to 2 hours prior to surgery and repeat once daily for 5-10
days postoperatively. In high risk patients: 5000 IU SC the evening before surgery and
repeat once daily for 5-10 days postoperatively. Alternatively, administer 2500 IU SQ,
starting 1 to 2 hours prior to surgery with an additional 2500 IU SQ dose 12 hours later and
then 5000 IU SQ once daily for 5-10 days postoperatively.
Hip replacement surgery:
2500 IU SQ 4 to 8 hours after surgery followed by 5000 IU SQ daily; OR 2500 IU SQ within
2 hours before surgery, 2500 IU SQ 4 to 8 hours after surgery, followed by 5000 IU SQ
daily; OR 5000 IU SQ 10 to 14 hours before surgery, 5000 IU SQ 4 to 8 hours after surgery,
followed by 5000 IU SQ daily. Duration of treatment is 5 to 10 days after surgery, up to 14
days of treatment.
Innohep®
Treatment of DVT with or without PE:
- 175 anti-Xa IU/kg of body weight SQ once daily for > 6 days and until the patient is
adequately anticoagulated with warfarin to an INR of > 2 for 2 consecutive days.
* There is well documented safety and efficacy for extended dosing, please refer to the
recommended guidelines for guidance in length of therapy approvals, as outlined in the CHEST
guidelines1
References:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
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):626-31.
Clinical Pharmacology
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):447-52.
Geerts WH, Jay RM, Code KI, Chen 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):701-7.
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-weightindependent dosage or unfractionated heparin. Haematologica. 2003; 88(10):1157-62.
Hayes Medical Technology Directory. Outpatient low-molecular weight heparin therapy for deep-vein
thrombosis. Winifred S. Hayes, Inc. Lansdale, PA February 2000.
Hirsh J, Guyatt G, Albers G, et al. The Seventh (2004) ACCP Guidelines for Antithrombotic Therapy for
Prevention and Treatment of Thrombosis. Chest 2004;126:supplement.
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.
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):674-80.
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):682-7.
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):146-53.
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):874-9.
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Arixtra® (fondaparinux), Lovenox® (enoxaparin),
Fragmin® (dalteparin), Innohep® (tinzaparin)
13. 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):677-81.
14. Pettila V, Kaaja R, Leinonen P, et al. Thromboprophylaxis with low molecular weight heparin (dalteparin)
in pregnancy. Thromb Res. 1999; 96(4):275-82.
15. 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):149-53.
16. 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):663-9.
17. Snow V, Weiss KB, LeFevre M, et al; ACP Panel on Atrial Fibrillation. Management of newly detected
atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the
American College of Physicians. Ann Intern Med. 2003; 139(12):1009-17.
18. The Columbus Investigators Low-molecular-weight heparin in the treatment of patients with venous
thromboembolism. The Columbus Investigators. N Engl J Med. 1997; 337(10):657-62.
19. 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):856-63.
6
Arixtra® (fondaparinux), Lovenox® (enoxaparin),
Fragmin® (dalteparin), Innohep® (tinzaparin)