Coverage Policy Manual
Policy #: 1997007
Category: Pharmacy
Initiated: October 1993
Last Review: August 2023
  Antithrombin III Replacement
Description:
Antithrombin III (Human) (e.g., Thrombate III®) is a sterile, stable, lyophilized preparation of purified human Antithrombin III.  Antithrombin III (Human) (e.g., Thrombate III®) is supplied in 500 IU or 1000IU single use vials.  It is to be administered by IV infusion over 10-20 minutes.  Dosage is determined on an individual basis based on plasma antithrombin III levels prior to treatment.
 
Coding
 
See CPT/HCPCS Code section below.
 
Policy/
Coverage:
Effective August 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Antithrombin III Replacement meets member benefit certificate coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when administered for one of the following indications (FDA Thrombate III, 1991; FDA Atryn, 2009):
 
    1. Prophylaxis against development of thrombotic complications in individuals with hereditary Antithrombin III deficiency in situations in which the risk of thromboembolism is  increased such as surgery, delivery and prolonged immobilization, OR
2. Adjunct to heparin therapy for the treatment of thromboembolism in individuals with hereditary antithrombin III deficiency, OR
3. Adjunct to heparin therapy for the treatment of thromboembolism associated with acquired antithrombin III deficiency when heparin alone is ineffective AND
4. Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
Antithrombin III dosing is in accordance with the U.S. Food and Drug Administration (FDA) approved labeling: administer a loading dose as a 15-minute intravenous infusion immediately followed by continuous infusion as a maintenance dose
 
ATryn loading dose = [(100 – baseline AT activity)/2.3] x Body Wt(kg)
 
Thrombate III loading dose = [120% - baseline AT% x Body Wt(kg)] / 1.4%
 
Authorization is for no longer than 1 month.
 
Antithrombin III (Human) (e.g., Thrombate III®) is available in 500 IU or 1000 IU single use vials.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Antithrombin III replacement, for any indication or circumstance not described above, including but not limited to use as an adjunct to heparin therapy for the treatment of thromboembolism associated with acquired antithrombin III deficiency when heparin therapy alone is effective, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Antithrombin III replacement, for any indication or circumstance not described above, including but not limited to use as an adjunct to heparin therapy for the treatment of thromboembolism associated with acquired antithrombin III deficiency when heparin therapy alone is effective, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
  
Effective December 1, 2021 to July 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Antithrombin III Replacement meets member benefit certificate coverage criteria that there be scientific evidence of effectiveness when administered for one of the following indications (FDA Thrombate III, 1991; FDA Atryn, 2009):
 
    1. Prophylaxis against development of thrombotic complications in patients with hereditary Antithrombin III deficiency in situations in which the risk of thromboembolism is  increased such as surgery, delivery and prolonged immobilization, OR
 
2. Adjunct to heparin therapy for the treatment of thromboembolism in patients with hereditary antithrombin III deficiency, OR
 
3. Adjunct to heparin therapy for the treatment of thromboembolism associated with acquired antithrombin III defiency when heparin alone is ineffective.
 
Dosing
 
Antithrombin III dosing is in accordance with the U.S. Food and Drug Administration (FDA) approved labeling: administer a loading dose as a 15-minute intravenous infusion immediately followed by continuous infusion as a maintenance dose
 
    • Atryn loading dose = [(100 – baseline AT activity)/2.3] x Body Wt(kg)
    • Thrombate III loading dose = [120% - baseline AT% x Body Wt(kg)] / 1.4%
 
    • Authorization is for no longer than 1 month
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
For Member Benefit Contracts or Plans with Primary Coverage Criteria, Antithrombin III replacement in patients with recquired deficiency in any circumstance not noted above, is not covered because it fails to meet the Primary Coverage Criteria (“The Criteria”) of the applicable benefit certificate or health plan. (The Criteria require, among other things, that there be scientific evidence of effectiveness, as defined in The Criteria.  The Criteria exclude coverage of treatments, such as Antithrombin III replacement in patients with acquired deficiency in any circumstance not noted above for which there is lack of scientific evidence).
  
For Member Benefit Contracts or Plans with explicit exclusion language for experimental or investigational services, replacement therapy in acquired Antithrombin III deficiency in any circumstance not noted above, is not covered because it is considered experimental or investigational treatment, as defined in the applicable benefit contract or health plan, which
excludes coverage of experimental or investigational treatment or services.
 
Effective date prior to December 1, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Intravenous replacement of Antithrombin III meets primary coverage criteria for effectiveness and is covered for prophylaxis against development of thrombotic complications in patients with hereditary Antithrombin III deficiency in situations in which the risk of thromboembolism is increased such as surgery, delivery and prolonged immobilization.   
 
Antithrombin III meets primary coverage criteria for effectiveness and is covered as an adjunct to heparin therapy for the treatment of thromboembolism in patients with hereditary antithrombin III deficiency.
 
Antithrombin III meets primary coverage criteria for effectiveness and is covered as an adjunct to heparin therapy for the treatment of thromboembolism associated with acquired antithrombin III deficiency when heparin alone is ineffective.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
For Member Benefit Contracts or Plans with Primary Coverage Criteria, Antithrombin III replacement in patients with acquired deficiency in any circumstance not noted above, is not covered because it fails to meet the Primary Coverage Criteria (“The Criteria”) of the applicable benefit certificate or health plan. (The Criteria require, among other things, that there be scientific evidence of effectiveness, as defined in The Criteria.  The Criteria exclude coverage of treatments, such as Antithrombin III replacement in patients with acquired deficiency in any circumstance not noted above for which there is lack of scientific evidence).
 
For Member Benefit Contracts or Plans with explicit exclusion language for experimental or investigational services, replacement therapy in acquired Antithrombin III deficiency in any circumstance not noted above, is not covered because it is considered experimental or investigational treatment, as defined in the applicable benefit contract or health plan, which excludes coverage of experimental or investigational treatment or services.
Rationale:
Antithrombin III deficiency is a rare inherited or acquired disorder. It affects approximately one in every 2000-5000 males and females worldwide.  Individuals with this deficiency have a high risk of developing deep vein thrombosis and pulmonary embolus. Pregnancy, childbirth, oral contraceptives use, operations and trauma are the most common cause of thrombosis . Thrombate III received Orphan drug designation for the treatment of hereditary antithrombin III deficiency in connection with surgical or obstetrical procedures or thrombo-embolism.
 
The efficacy of ATryn to prevent the occurrence of venous thromboembolic events was assessed by comparing the incidence of the occurrence of such events in 31 ATryn treated hereditary AT deficient patients with the incidence in 35 human plasma-derived AT treated hereditary AT deficient patients. Data on ATryn-treated patients were derived from two prospective, single-arm, open-label studies. Data on plasma AT treated patients were collected from a prospectively designed concurrently conducted retrospective chart review. Patients in both studies had confirmed hereditary AT deficiency (AT activity ≤ 60% of normal) and a personal history of thromboembolic events. Patients had to be treated in the peri-operative and peri-partum period. ATryn was administered as a continuous infusion for at least 3 days, starting one day prior to the surgery or delivery. Plasma AT was administered for at least two days as single bolus infusions. Due to the retrospective nature of the study, dosing was done with the locally available AT concentrate according to the local practice.
 
In the ATryn-treated group there was one confirmed diagnosis of an acute deep vein thrombosis (DVT). The incidence of any thromboembolic event from the start of treatment to 7 days after last dosing is summarized by treatment group in Table 6 as are the Clopper-Pearson exact 95% CI for the proportion of patients with a thromboembolic event and the exact 95% lower confidence bound for the difference between treatments.
 
Table 6: Overall Incidence of Any Confirmed Thromboembolic Event
 
Plasma AT
No. Of Ptx Assessed     No. Of Pts. With Events     % of Pts. With Events     95% CI*
             35                                0                                      0.0                    0.00, 10.00   
 
ATryn  
No. Of  Pts. Assessed     No. Of Pts. With Events     % of Pts. With Events     95% CI
              31                                      1                                   3.2                  0.08, 16.70
 
Lower 95% Confidence Bound of Difference
                          -0.167
 
*The 95% confidence intervals were calculated using Clopper-Pearson methodology. AT=Antithrombin, No.=Number, Pts=Patients, CI=Confidence Interval
 
2012 Update
A literature search was conducted through June 2012.  There was no new information identified that would prompt a change in the coverage statement.
 
2015 Update
This policy was reviewed and a literature search was conducted using the MEDLINE database. There was no new information identified that would prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Niebler and colleagues published a randomized, double-blinded, placebo-controlled pilot study of antithrombin replacement to neonates prior to CPB was conducted (Niebler, 2016). Preoperative antithrombin levels determined the dose of recombinant antithrombin or placebo to be given. Antithrombin levels were measured following the dosing of the antithrombin/placebo, after initiation of bypass, near the completion of bypass, and upon intensive care unit admission. Eight subjects were enrolled. No subject had safety concerns. Mediastinal exploration occurred in two antithrombin subjects and one placebo subject. Antithrombin activity levels were significantly higher in the treated group following drug administration; levels continued to be higher than preoperatively but not different from the placebo group at all other time points. Total heparin administration was less in the antithrombin group; measurements of blood loss were similar in both groups. A single dose of recombinant antithrombin did not maintain 100% activity levels throughout the entire operation. Although no safety concerns were identified in this pilot study, a larger trial is necessary to determine clinical efficacy.
  
2018 Update
A literature search conducted using the MEDLINE database through January 2018 did not reveal any new literature that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search conducted through January 2020 did not reveal any new information that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
J7196Injection, antithrombin recombinant, 50 i.u.
J7197Antithrombin iii (human), per i.u.
References: Patnaik MM, Moll S.(2008) Inherited antithrombin deficiency: a review. Haemophilia 2008;14:1229-39.

Afshari A, Wetterslev J, Brok J, et al.(2008) Antithrombin III for critically ill patients. The Cochrane Library, Issue 3, 2008. http://www.thecochranelibrary.com. Accessed 1/21/2009.

AHFS Drug Information. Antithrombin III. http:// www.ashp.org/mngrphs/essentials/a308006e.htm. Accessed 1/21/2009.

Antithrombin III(Human) Thrombate III. Package Insert. Talecris Biotherapeutics. Rev. August 2008.

Du Cheyron D, Bouchet B, Bruel C, et al.(2006) Antithrombin supplementation for anticoagulation during continuous hemofiltration in critically ill patients with septic shock: a case-control study. Critical Care. 2006 10:R45. Online at http://ccforum.com/content/10/2/R45. Accessed 1/21/09.

Garlund B.(2002) Antithrombin therapy of no value in sepsis according to a large clinical trial. Lakartidningen. 2002 Mar 27;99(13):1456-1460.

Harper PL, Williamson L, Park G.(1991) A pilot study of antithrombin replacement in intensive care management: the effects on mortality, coagulation and renal function. Transfus Med. 1991 Jun;1(2):121-128.

Haussmann U, Fischer J, Eber S, et al.(2006) Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy. Haematologica. 2006 Jun;91(6):795-800.

Millar BD, Millar D, Schmidt B.(2006) Antithrombin for respiratory distress syndrome in preterm infants. The Cochrane Library, Issue 4, 2006. http://www.thecochranelibrary.com. Accessed 1/21/2009.

Niebler RA, Woods KJ, Murkowski K(2016) A Pilot Study of Antithrombin Replacement Prior to Cardiopulmonary Bypass in Neonates. Artif Organs. 2016 Jan;40(1):80-5

Peres E, Kintzel P, Dansey R, et al.(2008) Early intervention with antithrombin III therapy to prevent progression of hepatic veno-occlusive disease. Blood Coagul Fibrinolysis. 2008 Apr;18(3): 203-207.

Schwartz RS, Bauer KA, Rosenberg RD, et al.(1989) Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin. Am J Med. 1989; 87(suppl 3B) 3B-53S.

USPDI, 2007

Wiedermann CJ, Hoffman JN, Juers M, et al.(2006) High-Dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med. 2006 Feb;34(2):285-292.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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