Medical Policy



Subject: Chelation Therapy
Document #: DRUG.00003 Current Effective Date:    06/28/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses the uses of chelation therapy. Chelation therapy uses naturally occurring or chemically designed molecules to reduce potentially dangerous levels of heavy metals within the body. Chelation therapy is routinely performed for cases of iron overload, lead poisoning, copper toxicity, and other heavy metal conditions.  This document is not applicable to agents used for the treatment of drug overdose or toxicities.

Position Statement

Medically Necessary:

The administration of U.S. Food and Drug Administration (FDA) approved chelating agents is considered medically necessary treatment in any of the following conditions:

  1. Individuals with disorders of iron metabolism (for example, primary or secondary hemochromatosis); or
  2. Lead overload in cases of acute or long-term lead exposure; or
  3. Individuals with disorders of copper metabolism (for example, Wilson's disease); or
  4. Arsenic, mercury, iron, copper or gold poisoning when long-term exposure and toxicity has been confirmed through lab results (that is, blood, plasma, or non-challenged urinalysis) or clinical findings (that is, symptoms consistent with metal toxicity); or
  5. Aluminum overload in individuals on chronic hemodialysis.

Investigational and Not Medically Necessary:

Chelation therapy is considered investigational and not medically necessary for the treatment of all other conditions, including but not limited to:

  1. Alzheimer's disease;
  2. Autism Spectrum Disorders (ASD);
  3. Cadmium exposure;
  4. Cardiovascular disease (prevention and treatment);
  5. Chronic fatigue syndrome secondary to dental amalgam therapy;
  6. Parkinson's disease;
  7. Peripheral vascular disease;
  8. Rheumatoid arthritis.
Rationale

Chelation therapy can be a safe and effective therapy for conditions where heavy metal overload has been accurately diagnosed. The diagnostic workup must consider the individual's history, an appropriate choice of testing methods, and the use of accurate and specific reference values. With specific regard to urine testing, the diagnosis and use of chelation therapy should not be performed based on post-challenge urine testing. In post-challenge or post-provoked urine testing, the individual is first given a chelating agent followed by urine testing for heavy metals. The American College of Medical Toxicology (ACMT), in their 2009 position statement on the use of "Post-Chelator Challenge Metal Urine Testing," states that "Scientific investigation to date has failed to establish a valid correlation between prior metal exposure and post-challenge test values" and that post-challenge urine testing is being conducted without needed reference values. The ACMT further states the following:

It is therefore, the position of the American College of Medical Toxicology that post-challenge urinary metal testing has not been scientifically validated, has no demonstrated benefit, and may be harmful when applied in the assessment and treatment of patients in whom there is concern for metal poisoning.

With appropriate heavy metal toxicity diagnosis, several studies published in the peer-reviewed medical literature have established that chelation therapy can be useful in binding toxic metal ions and facilitating their excretion through the liver or kidneys, and mitigating the morbidity associated with heavy metal toxicity such as end organ damage and impaired neurologic functioning.

Although chelation therapy has been investigated as a treatment of a wide variety of diseases and conditions, including Alzheimer's disease, Parkinson's, autism spectrum disorders, and rheumatoid arthritis, there has not been adequate scientific evidence to prove the effectiveness and safety of such methods. A meta-analysis by Ng and colleagues (2007) evaluated chronic mercury exposure in children and adolescents. The authors concluded that there was "no evidence to support the association between mercury poisoning and autism" and "there is a lack of data in the literature about the effect of chelation therapy in children with neuro-developmental disabilities." Further study is needed to ascertain the causal role of heavy metal overload in these conditions, followed by studies demonstrating the efficacy and safety of chelation therapy.

Dental amalgams have been investigated as a cause of increased blood levels of mercury, potentially associated with a number of diseases and disorders such as chronic fatigue syndrome and Alzheimer's disease. In 2009, the American Dental Association's (ADA) Council on Scientific Affairs reviewed the scientific literature on amalgam and stated: "The scientific evidence supports the position that amalgam is a valuable, viable and safe choice for dental patients." The Journal of the American Dental Association (JADA) reported that researchers found "no significant association of Alzheimer's Disease with the number, surface area or history of having dental amalgam restorations" and "no statistically significant differences in brain mercury levels between subjects with Alzheimer's disease and control subjects." The ADA's position has been reaffirmed by the U.S. FDA Center for Devices and Radiological Health in 2002, 2006 and 2009. The ADA's 2010 amalgam safety update cites that "studies continue to support the position that dental amalgam is a safe restorative option for both children and adults."

Chelation therapy has been proposed as a treatment of coronary artery disease (CAD), based in part on the hypothesis that chelation could remove atherosclerotic calcium deposits or provide an antioxidant benefit. One small placebo-controlled randomized study of 84 individuals with atherosclerotic heart disease did not report any advantage of chelation therapy, as measured by time to ischemia, at 27 weeks of follow-up (Anderson, 2003; Knudtson, 2002). The use of chelation therapy in lieu of established therapies, the lack of adequate prior research to verify its safety and effectiveness, and the overall impact of CAD prompted the National Center for Complementary and Alternative Medicine (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI) to sponsor a large-scale clinical study. The 5 year Trial to Assess Chelation Therapy (TACT) in CAD began recruiting individuals in March of 2003. This multicenter, randomized, double-blind study enrolled more than 1600 participants aged 50 or older who had a history of heart attack. The study tested whether chelation therapy or high-dose vitamin therapy are effective for the treatment of CAD. The primary study endpoint of this trial was a composite of heart attack, stroke, hospitalization for angina, coronary revascularization, and death. The study also evaluated cardiac deaths, nonfatal heart attacks, health-related quality of life (HR-QOL), and cost effectiveness, among other factors. Final results indicated that among stable individuals with a history of heart attack, an intravenous chelation regimen with disodium ethylenediaminetetraacetic acid (EDTA), when compared with placebo, modestly reduced the risk of negative cardiovascular outcomes, particularly revascularization procedures. Study authors emphasized that these results are insufficient to support the routine use of chelation therapy for treatment of individuals who have previously suffered from a heart attack (Lamas, 2013; Lamas, 2014; Escolar, 2014).

Background/Overview

Chelation therapy involves the administration of drugs that bind heavy metal ions such as lead, arsenic, iron, and mercury in the blood stream preventing their interaction with vital organs, such as the brain and kidneys. Drugs used in the administration of chelation therapy are known as chelating agents. The presence of heavy metals in the blood stream can be the result of several environmental exposures, including intake in water and food or in some instances such as lead, inhaling the metal from the air in a location where it is in excess. One common cause of lead exposure is through older buildings (built before 1978) in which lead based paints were used. There are occupational settings where high levels of metals can occur as well. Additionally, certain medical conditions lead to excess iron in the blood that may cause health problems. Chelation therapy reduces the accumulation of essential heavy metals, such as iron and copper or nonessential metals, such as lead and aluminum. Chelators bind with heavy metal ions and enhance the urinary and fecal excretion of these toxic metals. Specific chelating agents are used to bind specific heavy metals.

Chelation therapy has been proposed as a treatment for the removal of heavy metal ions to reduce cellular oxidative damage caused by the production of hydroxyl radicals. This therapy is under investigation for the treatment of numerous non-overload conditions including, but not limited to, cardiovascular disease, reperfusion injury during coronary angioplasty or cardiopulmonary bypass surgery, anthracycline-associated cardiac damage, Alzheimer's disease, Parkinson's disease, autism spectrum disorders (ASD), and rheumatoid arthritis.

Chelation agents, however, also have potential toxicity. Chelation agents have been known to bind elements in the body which are necessary for regular functioning, including zinc and calcium. Large doses of vitamins usually accompany the use of chelation agents to lessen these types of side effects. When there is life threatening heavy metal toxicity necessitating treatment with high doses of chelating agents, treatment in the hospital may be needed to monitor for possible side effects. Under less urgent circumstances, chelating agents may be administered on an outpatient basis.

Definitions

Autism Spectrum Disorder (ASD): A collection of associated developmental disorders that affect the parts of the brain associated with social interaction and verbal and non-verbal communication.

Primary hemochromatosis: A rare genetic disease that results in the overabundance of iron in the liver, brain, heart and kidneys, causing liver dysfunction, diabetes, changes in skin pigmentation, heart problems, arthritis and testicular atrophy.

Secondary hemochromatosis: A type of hemochromatosis which is usually the result of another condition or disease that causes the overabundance of iron. This disease and condition may include anemias, chronic liver diseases, and the requirement of blood transfusions.

Sickle cell disease: An inherited genetic disorder that causes red blood cells to take on a characteristic crescent or sickle-like shape with decreased ability to carry oxygen.

Sideroblastic anemia: A condition in which there is excess iron in the bone cells.

Thalassemia intermedia: A genetic form of anemia in which there is an abnormality in the oxygen carrying portion of red blood cells.

Wilson's disease: An inherited (autosomal recessive) disorder where excessive quantities of copper build up in the body, particularly in the liver and central nervous system.

Coding

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.

When services are Medically Necessary:

HCPCS  
J0470 Injection, dimercaprol, per 100 mg [BAL in oil]
J0600 Injection, edetate calcium disodium up to 1,000 mg
J0895 Injection, deferoxamine mesylate, 500 mg [Desferal]
J3520 Edetate disodium, per 150 mg
M0300 IV chelation therapy
S9355 Home infusion therapy, chelation therapy; administrative services, care coordination, and all necessary supplies and equipment, per diem
   
ICD-10 Diagnosis  
E83.00-E83.09 Disorders of copper metabolism [includes Wilson's disease]
E83.10-E83.19 Disorders of iron metabolism [includes hemochromatosis]

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above for the following diagnosis codes:

ICD-10 Diagnosis  
D56.0-D56.9 Thalassemia
D57.00-D57.819 Sickle-cell disorders
D61.01-D61.9 Other aplastic anemias and other bone marrow failure syndromes
D64.0-D64.3 Sideroblastic anemias (hereditary, secondary, other)
N18.6 End stage renal disease
T45.4X1S Poisoning by iron and its compounds, accidental (unintentional); sequela
T45.4X2S Poisoning by iron and its compounds, intentional self-harm; sequela
T45.4X3S Poisoning by iron and its compounds, assault; sequela
T45.4X4S Poisoning by iron and its compounds, undetermined; sequela
T45.4X5S Adverse effect of iron and its compounds, sequela
T56.0X1A-T56.0X4S Toxic effect of lead and its compounds
T56.1X1S Toxic effect of mercury and its compounds, accidental (unintentional); sequela
T56.1X2S Toxic effect of mercury and its compounds, intentional self-harm; sequela
T56.1X3S Toxic effect of mercury and its compounds, assault; sequela
T56.1X4S Toxic effect of mercury and its compounds, undetermined; sequela
T56.4X1S Toxic effect of copper and its compounds, accidental (unintentional); sequela
T56.4X2S Toxic effect of copper and its compounds, intentional self-harm; sequela
T56.4X3S Toxic effect of copper and its compounds, assault; sequela
T56.4X4S Toxic effect of copper and its compounds, undetermined; sequela
T56.891S Toxic effect of other metals, accidental (unintentional); sequela [gold]
T56.892S Toxic effect of other metals, intentional self-harm; sequela  [gold]
T56.893S Toxic effect of other metals, assault; sequela [gold]
T56.894S Toxic effect of other metals, undetermined; sequela [gold]
T57.0X1S Toxic effect of arsenic and its compounds, accidental (unintentional); sequela
T57.0X2S Toxic effect of arsenic and its compounds, intentional self-harm; sequela
T57.0X3S Toxic effect of arsenic and its compounds, assault; sequela
T57.0X4S Toxic effect of arsenic and its compounds, undetermined; sequela
Z77.010 Contact with and (suspected) exposure to arsenic
Z77.011 Contact with and (suspected) exposure to lead
Z99.2 Dependence on renal dialysis

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Anderson TJ, Hubacek J, Wyse DG, Knudtson ML. Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH study. J Am Coll Cardiol. 2003; 41(3):420-425.
  2. Bellinger DC, Trachtenberg F, Barregard L, et al. Neuropsychological and renal effects of dental amalgam in children: a randomized clinical trial. JAMA. 2006: 295(25):1775-1783.
  3. Botzenhardt S, Li N, Chan EW, et al. Safety profiles of iron chelators in young patients with haemoglobinopathies. Eur J Haematol. 2017; 98(3):198-217.
  4. Casale M, Citarella S, Filosa A, et al. Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with β-thalassemia major. Am J Hematol. 2014; 89(12):1102-1106.
  5. Cid J, Palomera L, Díaz M, et al. Clinical characteristics and management of iron overload in 631 patients with chronic transfusion dependency: results from a multicentre, observational study. Blood Transfus. 2014; 12 Suppl 1:s119-123.
  6. Cohen AR, Martin MB. Iron chelation therapy in sickle cell disease. Semin Hematol. 2001; 38(1 Suppl1):69-72.
  7. Delforge M, Selleslag D, Beguin Y, et al. Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes. Leuk Res. 2014; 38(5):557-563.
  8. Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid Redox Signal. 2014; 21(2):195-210.
  9. Escolar E, Lamas GA, Mark DB, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014; 7(1):15-24.
  10. Franchini M, Gandini G, de Gironcoli M, et al. Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood. 2000; 95(9):2776-2779.
  11. Guha Mazumder DN, De BK, Santra A, et al. Randomized placebo-controlled trial of 2,3-dimercapto-1-propanesulfonate (DMPS) in therapy of chronic arsenicosis due to drinking arsenic-contaminated water. J Toxicol Clin Toxicol. 2001; 39(7):665-674.
  12. Ho PJ, Tay L, Teo J, et al. Cardiac iron load and function in transfused patients treated with deferasirox (the MILE study). Eur J Haematol. 2017; 98(2):97-105.
  13. Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA. 2002; 287(4):481-486.
  14. Lamas GA, Boineau R, Goertz C, et al. EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: the factorial group results of the Trial to Assess Chelation Therapy. Am Heart J. 2014; 168(1):37-44.
  15. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with pervious myocardial infarction: the TACT randomized trial. JAMA. 2013; 309(12):1241-1250.
  16. Ng DK, Chan CH, Soo MT, Lee RS. Low-level chronic mercury exposure in children and adolescents: meta-analysis. Pediatr Int. 2007; 49(1):80-87.
  17. Taher AT, Cappellini MD, Aydinok Y, et al. Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study. Blood Cells Mol Dis. 2016; 57:23-29.
  18. Rogan WJ. Safety and efficacy of succimer in toddlers with blood lead levels of 20-44 microg/dL. Treatment of lead-exposed children (TLC) trial group. Pediatr Res. 2000; 48(5):593-599.
  19. Rogan WJ, Dietrich KN, Ware JH, et al. The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med. 2001; 344(19):1421-1426.
  20. Rombos Y, Tzanetea R, Konstantopoulos K, et al. Chelation therapy in patients with thalassemia using the orally active iron chelator deferiprone (L1). Haematologica. 2000; 85(2):115-117.
  21. Shimizu N, Yamaguchi Y, Aoki T. Treatment and management of Wilson's disease. Pediatr Int. 1999; 41(4):419-422.
  22. Waters RS, Bryden NA, Patterson KY, et al. EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. Biol Trace Elem Res. 2001; 83(3):207-221.
  23. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014; 312(10):1033-1048.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Academy of Pediatrics. Policy Statement. Lead exposure in children: prevention, detection, and management. Pediatrics. 2005; 116(4):1036-1046.
  2. American College of Medical Toxicology. Position Statement. Post-chelator challenge urinary metal testing. 2009. Available at: http://www.acmt.net/cgi/page.cgi/zine_service.html?aid=2999&zine=show. Accessed on March 16, 2017.
  3. American Dental Association. Amalgam safety update. September 2010. Available at: http://www.ada.org/~/media/ADA/Member%20Center/FIles/amalgam_literature_review_1009.ashx. Accessed on March 16, 2017.
  4. American Dental Association. Statement on Dental Amalgam. ADA council on scientific affairs. Revised August 2009. Available at: http://www.ada.org/1741.aspx. Accessed on March 16, 2017.
  5. Centers for Medicare and Medicaid Services. Available at: http://www.cms.hhs.gov/mcd/index_list.asp?list_type=ncd. Accessed on March 16, 2017.
    • National Coverage Determination: Chelation Therapy for Treatment of Atherosclerosis. NCD #20.21. Effective date not posted
    • National Coverage Determination: Ethylenediamine-Tetra-Acetic (EDTA) Chelation Therapy for Treatment of Atherosclerosis. NCD #20.22. Effective date not posted
  6. Dans AL, Tan FN, Villarruz-Sulit EC. Chelation therapy for atherosclerotic cardiovascular disease. Cochrane Database Syst Rev. 2002;(4):CD002785.
  7. Fisher S, Brunskil S, Doree C, et al. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. Cochrane Database Sys Rev. 2013a; (3):CD004450.
  8. Fisher S, Brunskil S, Doree C, et al. Oral deferiprone for iron chelation in people with thalassaemia. Cochrane Database Sys Rev. 2013b; (3):CD004839.
  9. James S, Stevenson SW, Silove N, Williams K. Chelation for autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2015;(5):CD010766.
  10. Meerphol J, Antes G, Rucker G, et al. Deferasirox for managing iron overload in people with thalassaemia. Cochrane Database Syst Rev. 2012;(2):CD007476.
  11. Meerphol J, Schell L, Rucker G, et al. Deferasirox for managing iron overload in people with myelodysplastic syndrome. Cochrane Database Syst Rev. 2014a;(10):CD007461.
  12. Meerphol J, Schell L, Rucker G, et al. Deferasirox for managing transfusional iron overload in people with sickle cell disease. Cochrane Database Syst Rev. 2014b;(3):CD007477.
  13. Sampson EL, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer's disease. Cochrane Database Syst Rev. 2014;(5):CD005380.
Websites for Additional Information
  1. National Institutes of Health:
  2. U.S. Food and Drug Administration Center for Devices and Radiological Health (CDRH). CDRH consumer information. Dental amalgams. Updated January 27, 2015. Rockville, MD: FDA. Available at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DentalProducts/DentalAmalgam/default.htm. Accessed on March 16, 2017.
Index

Autism
BAL
Calcium disodium Versenate®
Calcium EDTA
CaNa2-EDTA
Cooley's anemia
Deferoxamine mesylate
Desferal®
Desferrioxamine
Dimercaprol
DMSA
Edathamil calcium disodium
Edathamil disodium
Edetate calcium disodium
Hemochromatosis
Pervasive Development Disorders
Sodium calcium EDTA
Wilson's Disease

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

Status

Date

Action

Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Revised INV/NMN to DSM-5 language for ASD. Updated Rationale, Background/Overview, Definitions and References sections.
Revised 05/05/2016 MPTAC review. Fixed typo in position statement. Updated Reference section. Removed ICD-9 codes from Coding section.
Reviewed 05/07/2015 MPTAC review. Updated Description/Scope, Rationale, Background/Overview and Reference sections.
  01/01/2015 Updated Coding section with additional anemia diagnosis codes.
Reviewed 05/15/2014 MPTAC review. Updated Rationale, Coding and Reference sections.
Revised 05/09/2013 MPTAC review. Removed emergency treatment of hypercalcemia from Position Statement. Updated Coding section and Index.
Revised 02/14/2013 MPTAC review. Clarification to Position Statement about urine tests. Addition of autism and PDD to Investigational and Not Medically Necessary Position Statement. Updated Rationale, Background/Overview, References and Index.
Reviewed 02/16/2012 MPTAC review. Rationale, References, and Index updated.
  10/01/2011 Updated Coding section with 10/01/2011 ICD-9 changes.
Reviewed 02/17/2011 MPTAC review. Updated Rationale and References.
  10/01/2010 Updated Coding section with 10/01/2010 ICD-9 changes.
Revised 02/25/2010 MPTAC review. Clarification of medical necessity statement from "Patients with hemochromatosis who are not able to tolerate frequent phlebotomy" and "Secondary hemochromatosis due to chronic iron overload due to transfusion-dependent anemias (e.g., thalassemias, Cooley's anemia, sickle cell anemia, sideroblastic anemia)" to read "Individuals with disorders of iron metabolism (e.g., primary or secondary hemochromatosis)". "Copper overload in patients with Wilson's disease, a rare, hereditary condition" clarified to read "Individuals with disorders of copper metabolism (e.g., Wilson's disease)". Updated Background/Overview, Coding, References, Web Sites, Index.
Reviewed 05/21/2009 MPTAC review. Updated Rationale, References and Web Sites.
Reviewed 05/15/2008 MPTAC review. Updated Rationale, References, and Web Sites.
  02/21/2008 The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 05/17/2007 MPTAC review. Clarified Description. Updated Rationale, References, Web Sites and Coding.
Reviewed 06/08/2006 MPTAC review. References updated. No change in position.
  11/18/2005 Added reference for Centers for Medicare and Medicaid Services (CMS) – National Coverage Determination (NCD).
Revised 07/14/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations

Last Review Date

Document Number

Title

Anthem, Inc.

07/27/2004

DRUG.00003 Chelation Therapy
WellPoint Health Networks, Inc.

06/24/2004

8.01.05 Chelation Therapy