You will be provided with a reference and some statements. Please determine whether each statement is 'supported', 'unsupported', or 'unknown' with respect to the reference. Please note:
First, assess whether the reference contains any valid content. If the reference contains no valid information, such as a 'page not found' message, then all statements should be considered 'unknown'.
If the reference is valid, for a given statement: if the facts or data it contains can be found entirely or partially within the reference, it is considered 'supported' (data accepts rounding); if all facts and data in the statement cannot be found in the reference, it is considered 'unsupported'.

You should return the result in a JSON list format, where each item in the list contains the statement's index and the judgment result, for example:
[
    {
        "idx": 1,
        "result": "supported"
    },
    {
        "idx": 2,
        "result": "unsupported"
    }
]

Below are the reference and statements:
<reference>
Name of Blue Advantage Policy:

Chelation Therapy

Policy #: 085
Latest Review Date: February 2025
Category: Pharmacology

BACKGROUND:

Blue Advantage medical policy does not conflict with Local Coverage Determinations (LCDs),
Local Medical Review Policies (LMRPs) or National Coverage Determinations (NCDs) or with
coverage provisions in Medicare manuals, instructions or operational policy letters. In order to
be covered by Blue Advantage, the service shall be reasonable and necessary under Title XVIII
of the Social Security Act, Section 1862(a)(1)(A). The service is considered reasonable and
necessary if it is determined that the service is:
1. Safe and effective;
2. Not experimental or investigational*;
3. Appropriate, including duration and frequency that is considered appropriate for the
service, in terms of whether it is:
• Furnished in accordance with accepted standards of medical practice for the
diagnosis or treatment of the patient’s condition or to improve the function of a
malformed body member;
• Furnished in a setting appropriate to the patient’s medical needs and condition;
• Ordered and furnished by qualified personnel;
• One that meets, but does not exceed, the patient’s medical need; and
• At least as beneficial as an existing and available medically appropriate alternative.
*Routine costs of qualifying clinical trial services with dates of service on or after September 19,
2000, which meet the requirements of the Clinical Trials NCD, are considered reasonable and
necessary by Medicare. Providers should bill Original Medicare for covered services related to
clinical trials that meet Medicare requirements (Refer to Medicare National Coverage
Determinations Manual, Chapter 1, Section 310 and Medicare Claims Processing Manual,
Chapter 32, Sections 69.0-69.11).

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Blue Advantage Medical Policy #085

Page 1 of 11

POLICY:

Blue Advantage will treat chelation therapy as a covered benefit in the treatment of each of
the following conditions when performed in the in-patient setting:
• Control of ventricular arrhythmias or heart block associated with digitalis toxicity;
• Emergency treatment of hypercalcemia;
• *Extreme conditions of metal toxicity (i.e. arsenic, cadmium, copper, mercury);
• Treatment of chronic iron overload due to blood transfusions (transfusional
hemosiderosis) and due to non-transfusion-dependent thalassemia (NDTD);
• Wilson's disease (hepatolenticular degeneration);
• Lead poisoning.
Blue Advantage will treat chelation therapy for the treatment of sickle cell anemia
thalassemias and iron overload in patients requiring frequent transfusion as a covered
benefit when taken orally or performed as an outpatient procedure or given in the home
health setting.
Blue Advantage will treat chelation therapy in any form (IV, PO, transdermal, topical or
rectal) as a non-covered benefit when performed in an inpatient or outpatient setting to treat
any other condition, including but not limited to Alzheimer’s disease, atherosclerosis,
myocardial infarction, autism, and diabetes, and as non-covered benefit and as investigational.
Blue Advantage will treat any treatment associated with non-covered chelation therapy
(e.g., glutathione and vitamin C) as a non-covered benefit and as investigational.
*Blue Advantage will treat chelation therapy performed to treat heavy metal and/or lead
poisoning detected by a provocative urine test as a non-covered benefit.
Blue Advantage does not approve or deny procedures, services, testing, or equipment for our
members. Our decisions concern coverage only. The decision of whether or not to have a certain
test, treatment or procedure is one made between the physician and their patient. Blue
Advantage administers benefits based on the members' contracts and medical policies.
Physicians should always exercise their best medical judgment in providing the care they feel is
most appropriate for their patients. Needed care should not be delayed or refused because of a
coverage determination.

DESCRIPTION OF PROCEDURE OR SERVICE:

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.

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Blue Advantage Medical Policy #085

Page 2 of 11

There are a number of indications for chelation therapy that have received FDA approval and for
which chelation therapy is considered standard of care treatment. These include:
• Extreme conditions of metal toxicity
• Treatment of chronic iron overload due to blood transfusions and due to non-transfusiondependent thalassemia
• Wilson disease
• Lead poisoning
• Control of ventricular arrhythmias or heart block associated with digitalis toxicity; and
• Emergency treatment of hypercalcemia
Chelation therapy has been investigated for a variety of other applications, including the
treatment of atherosclerosis, arthritis, diabetes, multiple sclerosis, and autism. However, there is
insufficient evidence that chelation therapy improves health outcomes for any condition other
than those that have received FDA approval.
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, they promote the solubilization and
clearance of β-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’s disease. However, no MPACs have received U.S. Food and Drug Administration
(FDA) approval for the treatment of Alzheimer’s disease.

KEY POINTS:
This policy was updated with a literature search through January 29, 2025.
Summary
For individuals who have Alzheimer disease, cardiovascular disease, arthritis, autism, arthritis,
diabetes, or multiple sclerosis who receive chelation therapy, the evidence includes a small
number of RCTs and case series. Relevant outcomes include symptoms, change in disease status,
morbid events, functional outcomes, health status measures, quality of life, and treatment-related
morbidity. One RCT, the Trial to Assess Chelation Therapy (TACT), reported that chelation
therapy reduced cardiovascular events in patients with a previous myocardial infarction and that
the benefit was greater in diabetic patients compared with nondiabetic patients. However, this
trial had significant limitations, including high dropout rates, and therefore conclusions are not
definitive. Outcomes from the TACT2 RCT, which restricted enrollment to individuals with
diabetes, were published in 2024 and failed to replicate the findings from the original TACT
trial. For other conditions, the available RCTs did not report improvements in health outcomes
with chelation therapy and, as evidence, the case series are inadequate to determine efficacy.
The evidence is insufficient to determine the technology results in an improvement in net health
outcomes.
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Blue Advantage Medical Policy #085

Page 3 of 11

Practice Guidelines and Position Statements
American Heart Association and American College of Cardiology
In 2016, the American College of Cardiology (ACC) and the American Heart Association
(AHA) published a joint guideline on the management of patients with lower extremity
peripheral artery disease, which stated that chelation therapy (e.g., ethylenediaminetetraacetic
acid) is not beneficial for the treatment of claudication.
In 2014, the ACC and AHA published a focused update of the guideline for the management of
stable ischemic heart disease, in conjunction with the American Association for Thoracic
Surgery, Preventative Cardiovascular Nurses Association, Society for Cardiovascular
Angiography and Interventions, and the Society of Thoracic Surgeons. This update included a
revised recommendation on chelation therapy stating that the “usefulness of chelation therapy is
uncertain for reducing cardiovascular events in patients with stable IHD.” Compared to the
original publication of this guideline in 2012, the recommendation was upgraded from a class III
(no benefit) to class IIb (benefit ≥ risk), and the level of evidence from C (only consensus expert
opinion, case studies, or standard of care) to B (data from a single randomized trial or
nonrandomized studies). A 2023 guideline from these organizations on managing chronic
coronary disease provided comments about chelation therapy but no formal recommendations.
American Heart Association
In 2023, the AHA published a scientific statement about the cardiovascular risk of contaminant
metals. The authors cited the TACT trial findings of a reduced relative risk of cardiovascular
events among patients who received chelation therapy, but also noted that TACT did not
evaluate metal levels.
American Academy of Pediatrics
In 2019, the American Academy of Pediatrics published guidance for the management of
children with autism spectrum disorder. The guidance cautioned against the use of chelation
therapy due to safety concerns and lack of supporting efficacy data.
U.S. Preventive Services Task Force Recommendations
Not applicable

KEY WORDS:

Chelation therapy, toxic metal ions, dimercaprol, edetate calcium disodium, deferoxamine,
penicillamine, Succimer, Desferal

APPROVED BY GOVERNING BODIES:

In 1953, calcium-ethylenediaminetetraacetic acid (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. FDA-approved disodium-EDTA for use in selected patients with
hypercalcemia and for use in patients with heart rhythm problems due to intoxication with
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Page 4 of 11

digitalis. In 2008, 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.
• In 1968, deferoxamine (Desferal®; Novartis) was approved by the FDA for
subcutaneous, intramuscular or intravenous injections was approved for treating 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 (ExjadeÒ; Novartis) was approved by the FDA and 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. Under the accelerated approval
program, the FDA expanded the indications for deferasirox in 2013 to include treatment
of patients ages ten years and older with chronic iron overload due to non-transfusiondependent thalassemia syndromes and specific liver iron concentration and serum ferritin
levels. A generic version of the 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 FDA approved the iron chelator deferiprone (Ferriporx®) for the treatment
of patients with transfusional overload due to thalassemia syndromes when other
chelation therapy is inadequate. Deferiprone is available in tablet and oral solution.
Ferriprox® carries a boxed warning because it can cause agranulocytosis that 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, FDA advised that FDA-approved chelating agents are
available by prescription only. There are no FDA-approved over-the-counter chelation products.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this
policy when applicable.

CURRENT CODING:
HCPCS codes:
M0300

IV chelation therapy (chemical endarterectomy)

J0470

Injection, dimercaprol

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Page 5 of 11

J0600

Injection, edetate calcium disodium, up to 1,000 mg

J0895

Injection, deferoxamine mesylate, 500 mg

J3520

Edetate disodium (EDTA, Diostate) per 150 mg

S9355

Home infusion therapy, chelation therapy; administrative services, professional pharmacy
services, care coordination, and all necessary supplies and equipment, per diem.

REFERENCES:

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http://emedicine.medscape.com/article/814960-overview. Accessed January 24, 2018.
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3. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral
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a report of the American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. Circulation. Apr 2 2013; 127(13):1425-1443.
4. Anderson TJ, Hubacek J, Wyse DG et al. Effect of chelation therapy on endothelial
function in patients with coronary artery disease: PATCH substudy. J Am Coll Cardiol
2003; 41(3):420-5.
5. Ayton S, Barton D, Brew B, et al. Deferiprone in Alzheimer Disease: A Randomized
Clinical Trial. JAMA Neurol. Jan 012025; 82(1): 11-18.
6. Ballas and Samir K. Iron overload is a determinant of morbidity and mortality in adult
patients with sickle cell disease. Seminars in Hematology, January 2001, Vol. 38, No. 1,
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7. Bartholomew John R and Gray Bruce H. General medical care of the patient with
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4, 2023.
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Mortal Wkly Rep 2006; 55(8):204-7.
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13. Centers for Disease Control and Prevention (CDC). Emergency preparedness and
response. Case definition: thallium. 2015November 18;
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15. Chen KH, Lin JL, Lin-Tan DT et al. Effect of chelation therapy on progressive diabetic
nephropathy in patients with type 2 diabetes and high-normal body lead burdens. Am J
Kidney Dis 2012;60(4):530-8.
16. Cohen Alan R and Martin Marie B. Iron chelation therapy in sickle cell disease. Seminars
in Hematology, January 2001, Vol. 38, No. 1, Suppl 1, pp. 69-72.
17. Cooper GJ, Young AA, Gamble GD 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.
18. Cuajungco Math P, et al. Metal chelation as a potential therapy for Alzheimer’s disease.
Annals of the New York Academy of Sciences, 2000, 920:292-304.
19. Dellanna F, Winkler RE, Bozkurt F, et al. Dosing strategies for conversion of
haemodialysis patients from short acting erythropoiesis stimulating agents to oncemonthly C.E.R.A.: experience from the MIRACEL study. Int J Clin Pract. Jan
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20. Devos D, Labreuche J, Rascol O, et al. Trial of Deferiprone in Parkinson's Disease. N
Engl J Med. Dec 01 2022; 387(22):2045-2055.
21. Ernst E. Chelation therapy for coronary heart disease: An overview of all clinical
investigations. Acute Ischemic Heart Disease, American Heart Journal, July 2000, Vol.
140, No. 1.
22. Ernst E. Chelation therapy for peripheral arterial disease: A systematic review.
Circulation 1997, 96:1031.
23. Escolar E, Lamas GA, Mark DB et al. The effect of an EDTA-based chelation regimen
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24. Escolar E, Ujueta F, Kim H, et al. Possible differential benefits of edetate disodium in
post-myocardial infarction patients with diabetes treated with different hypoglycemic
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Aug 2020; 34(8): 107616.
25. Fihn SD, Blankenship JC, Alexander KP, et al. 2014
ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis
and management of patients with stable ischemic heart disease: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines,
and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
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Thoracic Surgeons. J Am Coll Cardiol. Nov 4 2014; 64(18):1929-1949.
26. Food and Drug Administration. Hospira, Inc., et al. Withdrawal of approval of one new
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www.fda.gov/OHRMS/DOCKETS/98fr/E8-13273.htm; June 12, 2008.
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27. Food and Drug Administration. FDA warns consumers about potential health risks from
using Thorne Research’s Captomer products. 2014 June 12;
www.fda.gov/Drugs/DrugSafety/ucm400977.htm?source=govdelivery&utm_medium=e
mail&utm_source=govdelivery.
28. George GN, et al. Mercury binding to the chelation therapy agents DMSA and DMPS
and the rational design of custom chelators for mercury. Chemical Res Toxicology,
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29. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the
Management of Patients With LowerExtremity Peripheral Artery Disease: A Report of
the American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines. Circulation. Mar 21 2017; 135(12): e726-e779.
30. Grolez G, Moreau C, Sablonniere B, et al. Ceruloplasmin activity and iron chelation
treatment of patients with Parkinson's disease. BMC Neurol. 2015; 15:74.
31. Guldager B, Jelnes R, Jorgensen SJ et al. EDTA treatment of intermittent claudication--a
double-blind placebo-controlled study. J Intern Med 1992; 231(3):261-7.
32. Hyman SL, Levy SE, Myers SM, et al. Identification, Evaluation, and Management of
Children With Autism Spectrum Disorder. Pediatrics. Jan 2020; 145(1).
33. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust.
Washington, DC: The National Academies Press.
34. Kempson IM, Lombi E. Hair analysis as a biomonitor for toxicology, disease and health
status. Chem Soc Rev. Jul 2011;40(7):3915-3940.
35. Knudtson ML, Wyse DG, Galbraith PD et al. Chelation therapy for ischemic heart
disease: a randomized controlled trial. JAMA 2002; 287(4):481-6.
36. Lamas GA, Anstrom KJ, Navas-Acien A, et al. The trial to assess chelation therapy 2
(TACT2): Rationale and design. AmHeart J. Oct 2022; 252: 1-11.
37. Lamas GA, Bhatnagar A, Jones MR, et al. Contaminant Metals as Cardiovascular Risk
Factors: A Scientific Statement From the American Heart Association. J Am Heart
Assoc. Jul 04 2023; 12(13): e029852.
38. Lamas GA, Anstrom KJ, Navas-Acien A, et al. Edetate Disodium-Based Chelation for
Patients With a Previous Myocardial Infarction and Diabetes: TACT2 Randomized
Clinical Trial. JAMA. Sep 10 2024; 332(10): 794-803.
39. 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. Jul 2014;
168(1):37-44 e35.
40. Lamas GA, Goertz C, Boineau R et al. Effect of disodium EDTA chelation regimen on
cardiovascular events in patients with previous myocardial infarction: the TACT
randomized trial. JAMA 2013; 309(12):1241-50.
41. Lannfelt L, Blennow K, Zetterbert H 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.
42. Lewis EF, Ujueta F, Lamas GA, et al. Differential Outcomes With Edetate DisodiumBased Treatment Among Stable PostAnterior vs. Non-Anterior Myocardial Infarction
Patients. Cardiovasc Revasc Med. Nov 2020; 21(11): 1389-1395.
43. Mark DB, Anstrom KJ, Clapp-Channing NE, et al. Quality-of-life outcomes with a
disodium EDTA chelation regimen for coronary disease: results from the trial to assess
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chelation therapy randomized trial. Circ Cardiovasc Qual Outcomes. Jul 2014; 7(4):508516.
44. Maron DJ, Hlatky MA. Trial to Assess Chelation Therapy (TACT) and equipoise: When
evidence conflicts with beliefs. Am Heart J. Jul 2014; 168(1):4-5.
45. Nelson KB, Bauman ML. Thimerosal and autism? Pediatrics 2003; 111(3):674-9.
46. Ng DK, Chan CH, Soo MT et al. Low-level chronic mercury exposure in children and
adolescents: meta-analysis. Pediatr Int 2007; 49(1):80-7.
47. Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT).
JAMA 2013; 309(12):1293-4.
48. Qaseem A, Fihn SD, Dallas P, et al. Management of Stable Ischemic Heart Disease:
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Association/American Association for Thoracic Surgery/Preventive Cardiovascular
Nurses Association/Society of Thoracic Surgeons. Annals of Internal Medicine. 2012;
157(10):735-743.
49. Ravalli F, Vela Parada X, Ujueta F, et al. Chelation Therapy in Patients With
Cardiovascular Disease: A Systematic Review. J Am Heart Assoc. Mar 15 2022; 11(6):
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chelating agents in the diagnosis and treatment of putative mercury poisoning.
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POLICY HISTORY:

Adopted for Blue Advantage, March 2005
Available for comment May 1-June 14, 2005
Medical Policy Group, February 2006
Available for comment March 1-April 14, 2006
Medical Policy Group, April 2006
Available for comment April 22-June 5, 2006
Medical Policy Group, June 2006
Available for comment July 13-August 28, 2006
Medical Policy Group, June 2009
Available for comment July 1-August 14, 2009
Medical Policy Group, April 2012
Medical Policy Group, September 2013
Available for comment September 19 through November 2, 2013
Medical Policy Group, June 2014
Medical Policy Group, June 2015
Medical Policy Group, February 2016
Medical Policy Group, February 2017
Medical Policy Group, October 2017
Medical Policy Group, February 2018
Medical Policy Group, May 2018
Medical Policy Group, March 2019
Medical Policy Group, February 2020
Medical Policy Group, February 2021
Medical Policy Group, February 2022
Medical Policy Group, February 2023
UM Committee, December 2023: Policy approved by UM Committee for use for Blue
Advantage business.
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Medical Policy Group, February 2024
UM Committee, February 2024: Annual review of policy approved by UM Committee for use for
Blue Advantage business.
Medical Policy Group, February 2025
UM Committee, February 2025: Annual review of policy approved by UM Committee for use
for Blue Advantage business.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and
benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date
services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of
common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other
providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels
of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, predeterminations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plans contracts.

Proprietary Information of Blue Cross and Blue Shield of Alabama
An Independent Licensee of the Blue Cross and Blue Shield Association
Blue Advantage Medical Policy #085

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</reference>

<statements>
1. Health insurance programs and commercial payers classify off-label chelation for coronary atherosclerosis as not medically necessary, noting the absence of reliable evidence demonstrating clinical benefit
</statements>

Begin the assessment now. Output only the JSON list, without any conversational text or explanations.