BlueCross and BlueShield of Montana Medical Policy/Codes
Chelation Therapy
Chapter: Therapies
Current Effective Date: July 18, 2013
Original Effective Date: January 15, 1998
Publish Date: April 18, 2013
Revised Dates: June 13, 2012; April 17, 2013
Description

Chelation therapy is an established treatment for the removal of metal toxins by converting them to a chemically inert form that can be excreted in the urine.  Chelation therapy consists of the intravenous or oral administration of chelating agents that remove metal ions such as lead, aluminum, mercury, arsenic, zinc, iron, copper, and calcium from the body.

Specific chelating agents are used for particular heavy metal toxicities.  For example, desferrioxamine (desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB or desferal) is used for patients with iron toxicity, and calcium-ethylenediaminetetraacetic acid (-EDTA) is used for patients with lead poisoning.  Note that disodium-EDTA is not recommended for acute lead poisoning due to the increased risk of death from hypocalcemia.  Another class of chelating agents, called metal protein attenuating compounds (MPACs), is under investigation for the treatment of Alzheimer’s disease, which is associated with the disequilibrium of cerebral metals.  Unlike traditional systemic chelators that bind and remove metals from tissues systemically, MPACs have subtle effects on metal homeostasis and abnormal metal interactions.  In animal models of Alzheimer’s disease, MPACs promote the solubilization and clearance of Aβ-amyloid protein by binding its metal-ion complex and also inhibit redox reactions that generate neurotoxic free radicals.  MPACs therefore interrupt two putative pathogenic processes of Alzheimer’s disease.  However, no MPACs have received U.S. Food and Drug Administration (FDA) approval for the treatment of Alzheimer’s disease.  Chelation therapy has also been discussed as a treatment for other indications including atherosclerosis, Alzheimer’s disease and autism.  For example, EDTA chelation therapy has been proposed in patients with atherosclerosis as a method of decreasing obstruction in the arteries.

Calcium-EDTA was approved by the FDA for lowering blood lead levels among patients with lead poisoning.  Disodium-EDTA was approved by the FDA for use in selected patients with hypercalcemia and for use in patients with heart rhythm problems due to intoxication with the drug digitalis.  In 2008, the FDA withdrew approval of disodium-EDTA due to safety concerns and recommended that other forms of chelation therapy be used.

Several iron chelating agents have received FDA approval.  Desferroxamine for subcutaneous, intramuscular or intravenous injections was approved for treating acute iron intoxication and chronic iron overload due to transfusion-dependent anemia.  Deferasirox, approved in 2005, is available as a tablet for oral suspension and is indicated for the treatment of chronic iron overload due to blood transfusions in patients age two years and older.  In 2011, the FDA approved the iron chelator deferiprone for the treatment of patients with transfusional overload due to thalassemia syndromes when other chelation therapy is inadequate.  Deferiprone is available in tablet form for oral use.

Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan or contract, the benefit plan or contract will govern.

Medically Necessary

BCBSMT may consider chelation therapy medically necessary in the treatment of each of the following conditions:

  • Control of ventricular arrhythmias or heart block associated with digitalis toxicity;
  • Emergency treatment of hypercalcemia;
  • Extreme conditions of metal toxicity;
  • Chronic iron overload due to blood transfusions (transfusional hemosiderosis);
  • Wilson's disease (hepatolenticular degeneration); and
  • Lead poisoning.

NOTE:  Prior to the administration of any chelating agent, diagnosis of metal toxicity MUST be established through appropriate diagnostic testing, such as serum and/or 24-hr urinalysis.

The administration of any chelating agents prior to diagnosis of metal toxicity is considered not medically necessary, and therefore will not be covered.

Investigational

Other applications of chelation therapy are considered experimental, investigational and unproven including, but not limited to:

  • Atherosclerosis (i.e., coronary artery disease or peripheral vascular disease);
  • Multiple sclerosis;
  • Arthritis (includes rheumatoid arthritis);
  • Hypoglycemia;
  • Autism;
  • Alzheimer’s disease;
  • Diabetes.

Rationale

Chelation therapy is an established treatment for the medically necessary indications listed here, particularly for the treatment of metal toxicity and transfusional hemosiderosis.  Thus, literature searches have focused on the use of chelation therapy for other conditions including, but not limited to, atherosclerosis, autism, Alzheimer’s disease, multiple sclerosis and diabetes.

Atherosclerosis

In 2002, a Cochrane review was published evaluating studies on ethylenediaminetetraacetic acid (EDTA) chelation therapy for treating patients with atherosclerotic cardiovascular disease.  Five placebo-controlled randomized-controlled trials (RCTs) were identified, none of which reported mortality, non-fatal events and cerebrovascular vascular events.  Four of the five studies (total n=250) found no significant benefits of EDTA chelation therapy on outcomes reported including direct or indirect measurement of disease severity and subjective measures of improvement.  The fifth study, which included only 10 patients, was apparently stopped early due to benefit, but relevant outcome data were not available.  The Cochrane reviewers concluded that there was insufficient evidence to draw conclusions of the efficacy of chelation therapy for treating atherosclerosis.  Additional RCTs reported on health outcomes that included mortality and cerebrovascular events.

Among the published random controlled trials (RCTs), Knudtson and colleagues randomized 84 patients with coronary artery disease and a positive treadmill test to receive EDTA chelation therapy or placebo, three hours per treatment twice weekly for 15 weeks, and once per month for an additional three months.  The main outcome measures included change in time to ischemia, functional reserve for exercise, and quality of life.  There was no significant difference between the two groups.  Another double-blind, randomized controlled study of EDTA chelation or placebo showed no change in short- or long-term improvement in vasomotor response to EDTA when compared to placebo.  Two small randomized trials have also reported no benefit of chelation therapy as a treatment of peripheral arterial disease.

Several RCTs have been published on chelation therapy for treating atherosclerosis; these have generally reported intermediate outcomes and have not found EDTA chelation therapy to be more effective than to placebo.  Additional RCTs that report health outcomes are needed to establish the efficacy of this treatment.

Autism

Based on similarities between mercury poisoning and autism spectrum disorder symptoms, Bernard and colleagues hypothesized a link between environmental mercury and autism.  This theory was rejected by Nelson and Bauman, who found that many of the characteristics of mercury poisoning such as ataxia, constricted visual fields, peripheral neuropathy, hypertension, skin eruption, and thrombocytopenia, are never seen in autistic children.  In 2007, a systematic review by Ng and colleagues concluded that there was no association between mercury poisoning and autism.

In 2009, Rossignol published a systematic review of novel and emerging treatments for autism and did not identify any studies that included a control group.  The author stated the case series suggest that chelation might be a viable form of treatment in some autistic individuals with known elevated heavy metal levels and that this possibility needs to be further investigated in controlled studies.

There is a lack of controlled studies on the effect of chelation therapy on health outcomes in patients with autism.

Alzheimer’s Disease

A 2008 Cochrane Review evaluated metal protein attenuating compounds (MPAC) for treating Alzheimer’s disease.  The review identified one placebo-controlled RCT.  This study, by Richie and colleagues, was published in 2003.  Patients were treated with PBT1, a MPAC also known as clioquinol, an anti-fungal medication that crosses the blood-brain barrier.  Clioquinol was withdrawn for oral use in 1970 because of its association with subacute myelo-optic neuropathy.  In the study, oral clioquinol was administered in doses increasing to 375 mg twice daily to 16 Alzheimer’s disease patients and the effects were compared to 16 matched controls who received placebo.  At 36 weeks, there was no statistically significant between-group difference in cognition measured by the Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog scale).  One patient in the treatment group developed impaired visual acuity and color vision during weeks 31 to 36 while she was receiving clioquinol, 375 mg twice daily.  Her symptoms resolved on treatment cessation.

Further studies of PBT1 have been abandoned in favor of a successor compound, PBT2.  Lannfelt and colleagues completed a double-blind, placebo-controlled RCT in which 78 Alzheimer’s disease patients were treated for 12 weeks with 50 mg PBT2 (n=20), 250 mg PBT2 (n=29), or placebo (n=29).  There was no statistically significant difference in ADAS-Cog scale or Mini-Mental Status Exam scores among groups in this short-term study.  The most common adverse event was headache.  Two serious adverse events (urosepsis and transient ischemic event) were reported, both by patients receiving placebo.

Ongoing investigations in chelation therapy for the treatment of Alzheimer’s disease and other neurodegenerative diseases include linking a carbohydrate moiety to drug molecules to enhance drug delivery across the blood-brain barrier; this strategy may solve the potential problem of premature and indiscriminate metal binding.  In addition, multi-function drugs that not only bind metal but also have significant antioxidant capacity are in development.

There is insufficient evidence on the safety and efficacy of chelation therapy for treating patients with Alzheimer’s disease.  The few published RCTs did not find that the treatment was superior to placebo for improving health outcomes.

Left ventricular hypertrophy in patients with diabetes

One RCT was identified; it was published in 2009 by Cooper and colleagues in New Zealand and evaluated the effect of copper chelation using oral trientine hydrochloride on left-ventricular hypertrophy in 30 patients with type 2 diabetes.  A total of 21/30 (70%) of the participants completed the 12-month follow-up.  At 12 months, there was a significantly greater change in left ventricular mass (LVM) indexed to body surface area in the group receiving active treatment compared to placebo (-10.6 g/m2 vs. -0.1 g/m2, p=0.01).  The study was limited by the small sample size and high drop-out rate.

One small RCT with limitations represents insufficient evidence that chelation therapy is effective for treating cardiovascular disease in patients with diabetes.  Additional RCTs with larger numbers of patients and those that report health outcomes such as cardiovascular events and mortality are needed.

Other potential indications

No RCTs or other controlled studies were identified that evaluated the safety and efficacy of chelation therapy for other conditions such as multiple sclerosis or arthritis.

Practice Guidelines and Position Statements

A 2004 clinical practice guideline from the American College of Physicians stated that chelation therapy  “should not be used to prevent myocardial infarction or death or to reduce symptoms in patients with symptomatic chronic stable angina.”  (Level of evidence B: Based on evidence from a limited number of randomized trials with small numbers of patients, careful analyses of nonrandomized studies, or observational registries.)

In 2005, the American College of Cardiology stated that chelation “is not indicated for treatment of intermittent claudication and may have harmful adverse effects.”  (Level of Evidence A: Data derived from multiple randomized clinical trials or meta-analyses.)

Summary

Chelation therapy is an established treatment for the medically necessary indications listed in the policy statement, such as treatment of metal toxicity and transfusional hemosiderosis.  There is insufficient evidence that chelation therapy improves health outcomes for patients with other conditions including, but not limited to, atherosclerosis, autism, Alzheimer’s disease, diabetes and arthritis.  Thus, chelation therapy for these other applications is experimental, investigational and unproven.

Coding

Disclaimer for coding information on Medical Policies          

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

99.16, 99.22, 99.29, 250.0 - 250.9, 250.1, 250.10, 250.11, 250.12, 250.13, 250.2, 250.20, 250.21, 250.22, 250.23, 250.3, 250.30, 250.31, 250.32, 250.33, 250.4, 250.40, 250.41, 250.42, 250.43, 250.5, 250.50, 250.51, 250.52, 250.53, 250.6, 250.63, 250.7, 250.70-250.73, 250.8-250.83, 250.9-250.93, 251.0, 251.1, 251.2, 275.0, 275.1, 275.42, 282.4, 282.41, 282.42,  282.49, 282.64, 299.0, 299.00, 299.01, 331.0, 340, 414.0-414.7, 426.6, 427.1, 427.4, 427.41, 427.42,  440.0, 440.1, 440.2, 440.20 – 440.29, 440.3, 440.30, 440.31, 440.32, 440.4,  440.8, 440.9, 714.0, 714.2, 714.3, 714.30,  714.31, 714.32, 714.33, 714.4, 714.8, 714.81, 714.89, 714.9, 715, 715.0, 715.00, 715.04, 715.09, 715.1, 715.1, 715.10-715.18, 715.2-715.28, 715.3-715.38, 715.8, 715.80, 715.89, 715.9, 715.90-715.98, 716, 716.2, 716.20-716.39, 716.4, 716.40-716.49, 716.5, 716.50-716.59, 716.6, 716.60-716.68, 716.8, 716.80-716.89, 716.9, 716.90716.99,  961.1, 961.2, 964.0, 965.69, 972.1, 984.0, 984.1, 984.8, 984.9, 985,  985.0-985.9

ICD-10 Codes
E83.0, E83.52, M10.1-M19, T46.0x1A – T46.0x6S, T56.0x1A – T56.94xS, T80.89, 3E030GC, 3E033GC, 3E040GC, 3E043GC, 3E050GC, 3E053GC, 3E060GC, 3E063GC 
Procedural Codes: 96365, 96366, 96374, M0300, J0470, J0600, J0895, J3520, S9355
References
  1. Guldager, B., Jelnes, R., et al.  EDTA treatment of intermittent claudication--a double-blind placebo-controlled study.  Journal of  Internal Medicine (1992) 231(3):261-7.
  2. Van Rij, A.M., Solomon C., et al.  Chelation therapy for intermittent claudication.  A double-blind, randomized, controlled trial.  Circulation (1994) 90(3):1194-9.
  3. Ernst, E.  Chelation therapy for peripheral arterial occlusive disease: a systematic review.  Circulation (1997) 96(3):1031-3.
  4. Ernst, E.  Chelation therapy for coronary heart disease: an overview of all clinical investigations.  American Heart Journal (2000) 140 (1):139-41.
  5. Bernard, S., Enayati, A., et al.  Autism: a novel form of mercury poisoning.  Med Hypotheses (2001) 56(4):462-71.
  6. Villarruz, M.V., Dans, A., et al.  Chelation therapy for atherosclerotic cardiovascular disease.  Cochrane Database Systems Review (2002) 4:CD002785.
  7. Knudtson, M.L., Wyse, D.G., et al.  Chelation therapy for ischemic heart disease: a randomized controlled trial.  Journal of the American Medical Association (2002) 287(4):481-6.
  8. Anderson, T.J., Hubacek, J., et al.  Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH sub-study.  Journal of the American College of Cardiology (2003 February 5) 41 (3):420-5.
  9. Ritchie, C,W., Bush, A.I., et al.  Metal-protein attenuation with Iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial.  Arch Neurol (2003) 60(12):1685-91.
  10. Nelson, K.B., Bauman, M.L.  Thimerosal and autism?  Pediatrics (2003) 111(3):674-9.
  11. Snow, V. Fihn, B.D., et al.  Primary care management of chronic stable angina and asymptomatic suspected or known coronary artery disease: a clinical practice guideline from the American College of Physicians.  Annals of Internal Medicine (2004) 141(7):562-7.
  12. Vogel, J.H., Bolling, S.F., et al.  Integrating complementary medicine into cardiovascular medicine.  A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine).  Journal of the American College of Cardiology (2005) 46:184-221.
  13. Centers for Disease Control and Prevention (CDC).  Deaths associated with hypocalcaemia from chelation therapy--Texas, Pennsylvania, and Oregon, 2003-2005.  MMWR Morbidity and Mortality Weekly Report (2006) 55(8):204-7.
  14. Hirsch, A.T., Haskal, Z.J., et al.  ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.  Circulation (2006) 113(11):e463-654.
  15. Ng, D.K., Chan, C.H., et al.  Low-level chronic mercury exposure in children and adolescents: meta-analysis.  Pediatric International (2007) 49(1):80-7. 
  16. Sampson, E., Jenagaratnam, L., et al.  Metal protein attenuating compounds for the treatment of Alzheimer’s disease.  Cochrane Database Syst Rev (2008) (1):CD005380.
  17. Stokstad, E.  Medicine.  Stalled trial for autism highlights dilemma of alternative treatments.  Science (2008) 321(5887):326.
  18. Lannfelt, L., Blennow, K., et al.  Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial.  Lancet Neurol (2008)7(9):779-86.
  19. Cavalli, A., Bolognesi, M.L., et al.  Multi-target-directed ligands to combat neurodegenerative diseases.  J Med Chem (2008) 51(3):347-72.
  20. Mitka, M.  Chelation therapy trials halted.  JAMA (2008) 300(19):2236.
  21. Rossignol, D.A..  Novel and emerging treatments for autism spectrum disorders: A systematic review.  Ann Clin Psychiatry (2009) 21(4):213-36.
  22. American Heart Association. Chelation Therapy. Available at: http://www.americanheart.org.  (accessed – 2012 May).
  23. Cooper, G.J., Young, A.A., et al.  A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomized placebo-controlled study.  Diabetologia (2009) 52(4):715-22.
  24. U.S. National Institutes of Health.  ClinicalTrials.gov. www.clinicaltrials.gov.  (accessed – 2012 May).
  25. Trial to Assess Chelation Therapy (TACT) (NCT00044213).  Sponsored by the National Heart, Lung and Blood Institute.  Last updated (26 July 2010).  Available at: www.ClinicalTrials.gov.  (accessed 2012 May).
  26. U.S. Food and Drug Administration.  FDA approved drug products.  www.accessdata.fda.gov.
  27.  (accessed - 2012 May).
  28. Chelation Therapy.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 April) Therapy 8.01.02.
History
June 2012 Policy updated with literature review. Rationale re-written. References 16 and 17 added; other references renumbered or removed. No changes to policy statements.
April 2013 Added "Prior to the administration of any chelating agent, diagnosis of metal toxicity MUST be established through appropriate diagnostic testing" to the Medically Necessary statement.  Removed CPT codes 90765, 90766, 90774, 99199.  Added CPT codes 96365, 96366, 96374.
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Chelation Therapy