Chelation Therapy

POLICY NUMBER

A.8.01.02

DESCRIPTION

Chelation therapy, an established treatment for heavy metal toxicitiesand transfusional hemosiderosis, has been investigated for a variety of off-label applications, such as treatment of atherosclerosis, Alzheimer disease, and autism.

Chelation Therapy

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 comprisesintravenous 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 is used for patients with iron toxicity, and calcium-ethylenediaminetetraacetic acid (EDTA) is used for patients with lead poisoning. 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 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 disease, MPACs promote the solubilization and clearance of beta amyloid by binding its metal-ion complex, and also inhibit redox reactions that generate neurotoxic free radicals. Therefore, MPACs interrupt two putative pathogenic processes of Alzheimer disease. However, no MPACs have received FDA approval for treating Alzheimer disease.

Chelation therapy also has been considered as a treatment for other indications, including atherosclerosis and autism spectrum disorder. For example, EDTA chelation therapy has been proposed in patients with atherosclerosis as a method of decreasing obstruction in the arteries.

In 1953, EDTA (Versenate) was approved by the FDA for lowering blood lead levels among both pediatric and adult patients with lead poisoning. In 1991, succimer (Chemet) was approved by the FDA for the treatment of lead poisoning in pediatric patients only. The FDA approved disodium-EDTA for use in selected patients with hypercalcemia and for use in patients with heart rhythm problems due to intoxication with 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 are FDA-approved:

• In 1968, deferoxamine (Desferal®; Novartis) was approved by the FDA for subcutaneous, intramuscular, or intravenous injections to treat acute iron intoxication and chronic iron overload due to transfusion-dependent anemia. Several generic forms of deferoxamine have been approved by the FDA.

• In 2005, deferasirox (Exjade®; Novartis) was approved by the FDA, 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 2 years and older. Under the accelerated approval program, the FDA expanded the indications for deferasirox in 2013 to include treatment of patients age 10 years and older with chronic iron overload due to non-transfusion-dependent thalassemia syndromes and specific liver iron concentration and serum ferritin levels. A generic version of deferasirox tablet for oral suspension has also been approved by the FDA. In 2015, an oral tablet formulation for deferasirox (Jadenu®) was approved by the FDA. All formulations of deferasirox carry a boxed warning because it may cause serious and fatal renal toxicity and failure, hepatic toxicity and failure, and gastrointestinal hemorrhage. As a result, treatment with deferasirox requires close patient monitoring, including laboratory tests of renal and hepatic function.

• In 2011, the iron chelator, deferiprone (Ferriprox®) was approved by the FDA for treatment of patients with transfusional overload due to thalassemia syndromes when another chelation therapy is inadequate. Deferiprone is available in tablet and oral solution. Ferriprox® carries a boxed warning because it can cause agranulocytosis, which can lead to serious infections and death. As a result, absolute neutrophil count should be monitored before and during treatment.

In a June 2014 warning to consumers, the FDA advised that FDA-approved chelating agents would be available by prescription only. There are no FDA-approved over-the-counter chelation products.

Related medical policy -

• Chronic Iron Overload

POLICY

Chelation therapy is considered medically necessary when based on blood levels and used to treat the following:

• Treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) and due to nontransfusion-dependent thalassemia (NTDT) [See Chronic Iron Overload Medical Policy]

• Extreme conditions of metal toxicity

• Lead poisoning

• Wilson's disease (hepatolenticular degeneration)

• Emergency treatment of hypercalcemia

• Control of ventricular arrhythmias or heart block associated with digitalis toxicity.

Off-label applications of chelation therapy (see Policy Guidelines section for FDA-approved uses) are considered investigational, including, but not limited to:

• Atherosclerosis (e.g., coronary artery disease, secondary prevention in individuals with myocardial infarction, or peripheral vascular disease)

• Alzheimer disease

• Arthritis (includes rheumatoid arthritis)

• Multiple sclerosis

• Diabetes

• Autism.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

There are a number of indications for chelation therapy that have received FDA approval and for which chelation therapy is considered standard of care. These indications include:

• extreme conditions of metal toxicity;

• treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) or due to non-transfusion-dependent thalassemia (NTDT);

• Wilson's disease (hepatolenticular degeneration);

• lead poisoning

• control of ventricular arrhythmias or heart block associated with digitalis toxicity; and

• emergency treatment of hypercalcemia.

For the last two bullet points, most individuals should be treated with other modalities. Digitalis toxicity is currently treated in most individuals with Fab monoclonal antibodies. The FDA removed the approval for NaEDTA as chelation therapy due to safety concerns and recommended that other chelators be used. NaEDTA was the most common chelation agent used to treat digitalis toxicity and hypercalcemia.

Suggested toxic or normal levels of select heavy metals are listed in the table below. Reference standards for bismuth, chromium, and manganese were not identified and are not included in the table.

Toxic or Normal Concentrations of Heavy Metals

CDC: Centers for Disease Control and Prevention

ª Hair analysis is useful to assess mercury exposure in epidemiologic studies. However, hair analysis in individual patients must be interpreted with consideration of the patient’s history, signs, and symptoms, and possible alternative explanations. Measurement of blood and urine mercury levels can exclude exogenous contamination; therefore, blood or urine mercury levels may be more robust measures of exposure in individual patients.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D: 

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

5/2000: Approved by Medical Policy Advisory Committee (MPAC).

5/23/2001: Code reference section revised, ICD-9 diagnosis code 174.0-174.9, 175.0-175.9, 198.1, 233.0, 909.5, 973.0 added covered codes, non-covered table added, ICD-9 diagnosis code 250.0X-250.9X, 251.0-251.3, 331.0, 340, 390-459.9, 714.0-714.9, 716.9X, 998.89 added non-covered codes.

2/14/2002: Investigational definition added.

4/18/2002: Type of Service and Place of Service deleted.

11/4/2004: Code Reference section updated, ICD-9 diagnosis code 174.0-174.9, 175.0-175.9, 198.1, 233.0 deleted covered codes, ICD-9 diagnosis 790.6, 796.0, 961.2, 985.8 added covered codes, ICD-9 diagnosis 973.0 description revised covered codes, non-covered table deleted, ICD-9 diagnosis code 250.0X-250.9X, 251.0-251.3, 331.0, 340, 390-459.9, 714.0-714.9, 716.9X, 998.

1/6/2009: Policy reviewed, policy section re-written for clarity.

06/22/2010: Policy description updated regarding available chelating agents. Reworded the policy statement regarding Wilson’s disease. Added “includes rheumatoid arthritis” to the investigational policy statement for arthritis, and added autism as an investigational application. Deleted outdated references from the Sources section. Added ICD-9 code 275.42.

10/14/2010: Annual ICD-9 code update: 275.0 deleted/expanded to the fifth digit. Added 275.02 and 275.09 to the Covered Codes table.

06/22/2011: Policy reviewed; no changes.

05/09/2012: Policy reviewed; no changes.

05/07/2013: Removed deleted ICD-9 diagnosis code 275.0 from the Code Reference section. Also deleted 275.09 from the Code Reference section. Added 985.0 and 985.1 to the Code Reference section.

11/15/2013: Added treatment of chronic iron overload due to nontransfusion-dependent thalassemia (NDTD) as a medically necessary condition. Investigational statement on atherosclerosis updated to include coronary artery disease, secondary prevention in patients with myocardial infarction, or peripheral vascular disease.

08/08/2014: Policy title changed from "Chelation Therapy" to "Chelation Therapy for Off-Label Uses." Policy description updated regarding chelating agents. Investigational policy statement revised to change "Other" to "Off-label" and remove "Hypertension" from the list. Policy guidelines updated to add chelation therapy indications and information regarding suggested toxic or normal levels of select heavy metals.

08/28/2015: Medical policy revised to add ICD-10 codes.

11/12/2015: Policy description updated regarding chelating agents. Removed hypoglycemiafrom investigational policy statement. Investigative definition updated in policy guidelines section.

04/18/2016: Policy reviewed. Policy statements unchanged. Policy guidelines updated to add medically necessary definition.

05/27/2016: Policy number A.8.01.02 added.

02/28/2017: Policy description updated regarding iron chelating agents. Policy statements unchanged.

03/08/2018: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding adult lead levels.

03/26/2019: Policy title changed from "Chelation Therapy for Off-Label Uses" to "Chelation Therapy." Policy statements unchanged.

03/12/2020: Policy reviewed; no changes.

05/21/2021: Policy description updated. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

09/17/2021: Added link to Chronic Iron Overload medical policy.

04/22/2022: Policy reviewed; no changes.

03/22/2023: Policy description updated. Policy statement and Policy Guidelines updated to change "patients" to "individuals." Table regarding toxic or normal concentrations of heavy metals updated for pediatric patients.

09/29/2023: Code Reference section updated to add new ICD-10 diagnosis codes T56.821A, T56.821D, T56.821S, T56.822A, T56.822D, T56.822S, T56.823A, T56.823D, T56.823S, T56.824A, T56.824D, and T56.824S, effective 10/01/2023.

03/21/2024: Policy reviewed. Policy statements unchanged. Policy Guidelines updated.

04/14/2025: Policy reviewed; no changes.

09/09/2025: Policy reviewed and approved by the Pharmacy & Therapeutics (P&T) Committee. Medically necessary criteria updated to add link to Chronic Iron Overload medical policy.

SOURCE(S)

Blue Cross Blue Shield association policy # 8.01.02

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document. 

Covered Codes

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