Currentblue cross blue shield - kansasPolicy N/A

Chelation Therapy for Off-Label Uses

Policy governs coverage of chelation therapy for off-label indications (Alzheimer disease, atherosclerosis/cardiovascular disease, autism spectrum disorder, diabetes, multiple sclerosis, arthritis) and notes FDA-approved indications and guidance; defines these off-label uses as experimental/investigational and not covered. Applies to professional and institutional settings for BCBSKS members.

Policy Summary

Payerblue cross blue shield - kansas

PolicyChelation Therapy for Off-Label Uses

Policy CodePolicy N/A

Change TypeTitle and policy language revised; coding and guideline clarifications

Effective DateAug 19, 2016

Next Review Date

Key ActionProviders must verify a member's benefits and consider state/federal mandates and contract language which take precedence over this medical policy.

POLICY UPDATE CHANGES

Policy states off-label applications (Alzheimer disease, atherosclerosis, autism, diabetes, multiple sclerosis, arthritis) are experimental/investigational.

Policy title changed to 'Chelation Therapy for Off-Label Uses' and policy language updated to restate FDA-approved indications in Policy Guidelines and identify off-label uses as experimental/investigational.

Policy guideline updated to change phrasing for iron overload indication to 'or' (transfusional hemosiderosis or NTDT).

Coding section updated over time (CPT correction: replaced 96375 with 96374) and removal of ICD diagnosis box; appendix changes and removal.

6Off-label Indications Listed as Experimental/Investigational

6FDA-approved Indications Listed

2025-01-29Literature search date (most recent update)

MultipleOff-label Indications Considered Experimental

NumerousReferenced Trials/Studies in Evidence Review

Coverage Summary

Overview: This policy governs coverage of chelation therapy for off-label indications (including Alzheimer disease, atherosclerosis/cardiovascular disease, autism spectrum disorder, diabetes, multiple sclerosis, and arthritis) and designates these off-label uses as experimental/investigational and not covered. FDA-approved indications for chelation therapy (listed in Policy Guidelines) are acknowledged as standard of care but coverage for those FDA-approved uses is subject to the member's contract benefits and applicable state/federal mandates. Effective date: 2016-08-19. Last review: 2025-03-27.

Policy statistics and dates

Off-label Indications Listed as Experimental/Investigational6

FDA-approved Indications Listed6

Literature search date2025-01-29

Referenced Trials/StudiesNumerous

Policy effective date2016-08-19

Last review date2025-03-27

Medical-Necessity Criteria

Coverage Determination

Off-label applications of chelation therapy are considered experimental / investigational (not covered) when used for the following indications:

ALL of the following

Any of the following off-label indications
- Alzheimer's disease
- Atherosclerosis (e.g., coronary artery disease, secondary prevention in individuals with myocardial infarction, or peripheral vascular disease)
- Autism
- Diabetes

Coding (informational)

No procedure or diagnosis codes specified in this partmixed

No codes listed

Infusion / Injection / Procedure Codes (informational)CPT|HCPCS|mixed

96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis; initial, up to 1 hour
96366	Intravenous infusion; each additional hour
96374	Therapeutic, prophylactic, or diagnostic injection; intravenous push, single or initial substance/drug
M0300	IV chelation therapy (chemical endarterectomy)
S9355	Home infusion therapy, chelation therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment, per diem

Drug/J-Code Codes (informational)HCPCS|mixed

J0470	Injection, dimercaprol, per 100 mg
J0600	Injection, edetate calcium disodium, up to 1,000 mg
J0895	Injection, deferoxamine mesylate, 500 mg
J3520	Edetate disodium, per 150 mg

Provider Actions & Billing Impact

Documentation Required

Verify member benefits

Providers must verify a member's benefits and consider state/federal mandates and contract language which take precedence over this medical policy.

Prior Authorization

Prior authorization and coverage determination

Coverage of chelation for FDA-approved indications should be determined per member contract benefits; off-label uses are considered experimental/investigational and will not be covered.

Background

Background: Chelation therapy involves intravenous or oral administration of chelating agents that bind metal ions to facilitate excretion and is an established treatment for certain heavy metal toxicities and transfusional hemosiderosis. A subclass of agents, metal protein attenuating compounds (MPACs), has been investigated for Alzheimer disease because they modulate cerebral metal interactions rather than producing systemic metal removal; however, no MPACs have received FDA approval for Alzheimer disease. Several iron chelators are FDA-approved for iron overload: deferoxamine (approved for acute iron intoxication and chronic iron overload due to transfusion-dependent anemia), deferasirox (approved for chronic iron overload due to transfusions and, under expanded/accelerated indications, some non–transfusion-dependent thalassemia patients; carries boxed warnings for serious renal, hepatic, and gastrointestinal toxicity and requires monitoring), and deferiprone (approved for transfusional overload due to thalassemia when other chelation is inadequate; carries a boxed warning for agranulocytosis requiring absolute neutrophil count monitoring). The FDA has also withdrawn or modified approvals for some chelators (for example, disodium-EDTA approval was withdrawn for certain uses because of safety concerns).

Definitions

Chelation therapyAdministration (intravenous or oral) of chelating agents that bind metal ions to facilitate excretion.

MPACMetal protein attenuating compounds — agents under investigation that modulate metal homeostasis rather than systemic metal removal.

Evidence Summary

Evidence overview: The policy summarizes randomized controlled trials and systematic reviews assessing chelation therapy for off-label indications. Systematic reviews and meta-analyses of EDTA chelation for cardiovascular disease found insufficient evidence to support efficacy, and the largest RCT (TACT, n=1708) reported a small composite endpoint benefit but had important limitations; a subsequent replication trial (TACT2) failed to confirm the original TACT findings. For Alzheimer disease, small RCTs of MPACs (PBT1/clioquinol and PBT2) did not show cognitive benefit, and a 2025 phase 2 RCT of the iron chelator deferiprone showed accelerated cognitive decline versus placebo. For diabetic nephropathy, a single small single-blind RCT reported slower eGFR decline but is insufficient to establish efficacy. Overall, available RCTs and systematic reviews do not provide adequate, consistent evidence of net benefit for the off-label uses summarized below.

Evidence summary

RCT - Alzheimer disease (PBT1/clioquinol)Small RCT (Ritchie) no significant cognitive benefit; safety concerns (visual impairment) noted

RCT - PBT2Lannfelt 2008: 12-week RCT (n=78) no significant difference in cognitive scores

RCT - deferiprone (2025)Phase 2 RCT showed accelerated cognitive decline vs placebo in early Alzheimer disease

Medicare Determinations

Number	Name	Type	Effective Date
20.21	CHELATION THERAPY for Treatment of Atherosclerosis	NCD
20.22	Ethylenediamine-Tetra-Acetic (EDTA) CHELATION THERAPY for Treatment of Atherosclerosis	NCD

Revision History

03-31-2014clarified

Policy Guidelines list FDA-approved indications separately; no explicit material change indicated in this part. Policy states off-label applications (Alzheimer disease, atherosclerosis, autism, diabetes, multiple sclerosis, arthritis) are experimental/investigational.

08-19-2016revised

04-11-2018revised

Multiple historical coding and appendix revisions listed; coding section updated over time (CPT correction: replaced 96375 with 96374) and removal/addition of appendix items.

Policy Summary

Payerblue cross blue shield - kansas

PolicyChelation Therapy for Off-Label Uses

Policy CodePolicy N/A

Change TypeTitle and policy language revised; coding and guideline clarifications

Effective DateAug 19, 2016

Next Review Date

Key ActionProviders must verify a member's benefits and consider state/federal mandates and contract language which take precedence over this medical policy.

On This Page

Arthritis (includes rheumatoid arthritis)

Coverage Determination

FDA-approved / Standard Indications (policy guidelines)

Chelation therapy is considered standard of care (coverage subject to member contract benefits) for specific FDA-approved indications:

ALL of the following

FDA-approved indications
- 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 disease (hepatolenticular degeneration)
- Lead poisoning
- Control of ventricular arrhythmias or heart block associated with digitalis toxicity
- Emergency treatment of hypercalcemia
Coverage condition: Coverage for FDA-approved indications is subject to the member's contract benefits in effect at time of service

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Policy Guidelines / Indications Considered Standard of Care

Chelation therapy is considered standard of care for specific FDA-approved indications (Policy Guidelines). Notes describe alternative therapies and EDTA approval removal.

Policy Guidelines - Standard of Care Indications

Extreme conditions of metal toxicity (FDA-approved)
Treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) or due to non-transfusion-dependent thalassemia (NTDT)
Wilson disease (hepatolenticular degeneration)
Lead poisoning
Control of ventricular arrhythmias or heart block associated with digitalis toxicity (note: most patients treated with other modalities such as Fab monoclonal antibodies)
Emergency treatment of hypercalcemia (note: FDA removed approval for NaEDTA; other chelators recommended)

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Off-Label Applications / Experimental / Investigational

Off-label applications of chelation therapy are considered experimental/investigational and not supported by randomized controlled trial evidence or have trial-level limitations:

Evidence summary

Off-label uses (including but not limited to treatment of atherosclerotic cardiovascular disease, peripheral artery disease, multiple sclerosis, arthritis, Parkinson disease, Alzheimer disease, autism spectrum disorder) are experimental/investigational
Randomized trials for Alzheimer disease (PBT1/clioquinol, PBT2) found no significant cognitive benefit; recent 2025 deferiprone RCT showed accelerated cognitive decline with deferiprone versus placebo
RCT evidence for cardiovascular disease (eg, TACT) had important limitations (high dropout, composite endpoint, subgroup findings) and TACT2 (2024) failed to replicate TACT findings
No randomized controlled trials or controlled trials identified to support safety and efficacy for multiple sclerosis or arthritis
Small single-blind RCT for diabetic nephropathy (Chen 2012) showed slower eGFR decline but is insufficient; larger RCTs reporting clinical outcomes are needed

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Documentation Required

Adhere to Policy Indications

Providers must ensure chelation therapy is performed only for medically necessary, FDA-approved indications listed in policy guidelines to be considered standard of care; off-label uses are considered experimental/investigational and are not supported by the policy.

Billing Rule

Use Listed Procedure/Drug Codes for Chelation Services

When chelation therapy is performed per the policy, report the applicable infusion, injection, or drug J/HCPCS codes provided in the coding section; inclusion of codes is informational and does not guarantee coverage — verify member contract benefits.

96365
96366
96374
M0300
S9355
J0470
J0600
J0895
J3520

Non-transfusion-dependent thalassemia.

NCTNational Clinical Trial identifier.

Systematic reviews - cardiovascular

Cochrane (2020) and Ravalli (2022) found insufficient evidence; mixed/limited results

TACT (2013) RCT1708 patients; small statistically significant primary composite outcome benefit but important limitations and subgroup findings

TACT2 (2024) RCTFailed to replicate TACT findings among patients with diabetes

Diabetic nephropathy RCT (Chen 2012)Small single-blind RCT showed slower eGFR decline in chelation group; limited evidence

RCT evidence for Parkinson disease (deferiprone)Phase 2 RCT (Devos 2022) showed worse outcomes with deferiprone vs placebo

04-16-2021clarified

Updated policy guideline 1b wording to change 'and' to 'or' for the iron overload indication (transfusional hemosiderosis or NTDT).

03-27-2025revisedLatest

Multiple historical coding and appendix revisions recorded through 2025-03-27, including removal of ICD diagnosis box and ongoing updates to description, rationale, and references.