Pending Policies - Therapy


Chelation Therapy

Number:THE801.008

Effective Date:08-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Chelation therapy may be considered 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*(see NOTE 1);

Chronic iron overload due to blood transfusions (transfusional hemosiderosis) or non-transfusion-dependent thalassemia (NTDT);

Wilson's disease (hepatolenticular degeneration); AND

Lead poisoning.

*NOTE 1: 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.

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

Atherosclerosis (i.e., coronary artery disease, secondary prevention in patients with myocardial infarction, or peripheral vascular disease);

Multiple sclerosis;

Arthritis (includes rheumatoid arthritis);

Hypoglycemia;

Autism;

Alzheimer’s disease;

Diabetes.

Description:

Background

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 comprises 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 (not U.S. Food and Drug Administration [FDA] approved) 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). (1)

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, they promote the solubilization and clearance of beta amyloid by binding its metal-ion complex, and inhibit redox reactions that generate neurotoxic free radicals. MPACs therefore interrupt 2 putative pathogenic processes of Alzheimer disease. However, no MPACs have received FDA approval for the treatment of Alzheimer disease.

Chelation therapy also has been discussed 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.

Suggested toxic or normal levels of select heavy metals are listed in Table 1. Reference standards for bismuth, chromium, and manganese were not identified and are not included in Table 1.

Table 1 Toxic or Normal Concentrations of Heavy Metals (3)

Metal

Toxic Levels (Normal Levels Where Indicated)

Arsenic

24-h urine: ≥50 µg/L urine or 100 µg/g creatinine.

Cadmium

Proteinuria and/or ≥15 µg/g creatinine.

Cobalt

Normative excretion: 0.1-1.2 µg/L (serum), 0.1-2.2 µg/L (urine) .

Copper

Normative excretion: 25 µg/24 h (urine).

Iron

Nontoxic: <300 µg/dL Severe: >500 µg/dL.

Lead

Pediatric

Symptoms or blood lead level ≥45 µg/dL (blood)

CDC level of concern: 5 µg/dL (4).

Adult

Symptoms or blood lead level ≥40 µg/dL

CDC level of concern: 10 µg/dL (5).

Mercury

Background exposure normative limits: 1-8 µg/L (whole blood); 4-5 µg/L (urine) (6)a .

Nickel

Excessive exposure: ≥8 µg/L (blood)

Severe poisoning: ≥500 µg/L (8-h urine).

Selenium

Mild toxicity: >1 mg/L (serum).

Serious toxicity: >2 mg/L.

Silver

Asymptomatic workers have mean levels of 11 µg/L (serum) and 2.6 µg/L (spot urine).

Thallium

24-hour urine thallium >5 µg/L (7).

Zinc

Normative range: 0.6-1.1 mg/L (plasma), 10-14 mg/L (red cells).

Table key: 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. (8)

Regulatory Status

The U.S. FDA approved calcium-EDTA (Versenate) for lowering blood lead levels among both pediatric and adult patients with lead poisoning. Succimer is approved 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 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. (2)

Digitalis toxicity is currently treated in most patients with Fab monoclonal antibodies. The FDA removed the approval for NaEDTA as chelation therapy due to safety concerns and they recommended that other chelators be used. This was the most common chelation agent used to treat digitalis toxicity and hypercalcemia. They determined that most patients should be treated with other modalities for the control of ventricular arrhythmias or heart block associated with digitalis toxicity and for emergency treatment of hypercalcemia.

Several iron chelating agents are FDA approved:

Deferoxamine for subcutaneous, intramuscular, or intravenous injections was approved to treat 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 patient’s 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 (NTDT) syndromes and specific liver iron concentration and serum ferritin levels. An oral tablet formulation for deferasirox (Jadenu™) was approved by the FDA in 2015. All formulations of deferasirox carry a black box 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. (36)

Deferiprone (Ferriprox®) was FDA approved in 2011, for 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. Ferriprox® carries a black box 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. (36)

In a June 2014 warning to consumers, the FDA advised that FDA-approved chelating agents would be available by prescription only. (37) There are no FDA-approved over-the-counter chelation products.

Rationale:

This policy was created in 1990 and updated regularly with literature searches using MEDLINE. The most recent literature review covered the period through June 21, 2018. Chelation therapy is an established treatment of metal toxicity, transfusional hemosiderosis and non-transfusion dependent thalassemia (NTDT). Literature searches have focused on the use of chelation therapy for off-label conditions including, but not limited to, atherosclerosis, autism, Alzheimer disease, diabetes, and other conditions, such as multiple sclerosis.

Atherosclerosis

In 2002, Villarruz et al. published a Cochrane review that evaluated ethylenediaminetetraacetic acid (EDTA) chelation therapy for treating patients with atherosclerotic cardiovascular disease. (9) Five randomized placebo-controlled trials were identified, none of which reported mortality, nonfatal events, or cerebrovascular vascular events. Four of the 5 studies (total N=250) found no significant benefit of EDTA chelation therapy on reported outcomes, 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 unavailable. The Cochrane reviewers concluded that evidence was insufficient to draw conclusions about the efficacy of chelation therapy for treating atherosclerosis; additional randomized controlled trials (RCTs) that report health outcomes including mortality and cerebrovascular events were needed.

Among published RCTs, Knudtson et al. (2002) randomized 84 patients with coronary artery disease and a positive treadmill test to receive EDTA chelation therapy or placebo. (10) Treatment was administered for 3 hours twice weekly for 15 weeks and then monthly for 3 months. Outcome measures included change in time to ischemia, functional reserve for exercise, and quality of life. There was no significant difference between the 2 groups. Another double-blind, placebo-controlled RCT of EDTA chelation showed no difference between groups in short- or long-term improvement in vasomotor response. (11) Two small RCTs from the 1990s also reported no benefit of chelation therapy as a treatment for peripheral arterial disease. (12, 13)

Section Summary

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

Autism Spectrum Disorders

Based on similarities between mercury poisoning and autism spectrum disorder symptoms, Bernard et al. (2001) hypothesized a link between environmental mercury and autism. (14) This theory was rejected by Nelson and Bauman (2003), who found that many characteristics of mercury poisoning such as ataxia, constricted visual fields, peripheral neuropathy, hypertension, skin eruption, and thrombocytopenia, are never seen in autistic children. (15) A 2007 systematic review by Ng et al. concluded that there was no association between mercury poisoning and autism. (16)

In 2009, Rossignol published a systematic review of novel and emerging treatments for autism and identified no controlled studies. (17) The author stated that case series suggested a potential role for chelation in treating some autistic people with known elevated heavy metal levels, but this possibility needed further investigation in controlled studies.

Section Summary

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

Alzheimer Disease

A 2008 Cochrane review evaluated metal protein attenuating compounds (MPAC) for treating Alzheimer disease. (18) The review identified 1 placebo-controlled RCT. This study, by Richie et al., was published in 2003. Patients were treated with PBT1, an MPAC also known as clioquinol, an antifungal medication that crosses the blood-brain barrier. (19) The FDA withdrew clioquinol for oral use in 1970 because of its association with subacute myelo-optic neuropathy. Richie et al. administered oral clioquinol to 16 Alzheimer disease patients in doses increasing to 375 mg twice daily and compared this group with 16 matched controls who received placebo. At 36 weeks, there was no statistically significant between-group difference in cognition measured by the Alzheimer Disease Assessment Scale–Cognitive (ADAS-Cog). One patient in the treatment group developed impairments in visual acuity and color vision during weeks 31 to 36 during treatment with clioquinol 375 mg twice daily. Her symptoms resolved on treatment cessation. A 2012 update of this review included trials through December 2011. Only the Lannfelt et al. trial discussed next was identified. (20)

Further studies of PBT1 have been abandoned in favor of a successor compound, PBT2. Lannfelt et al. (2008) completed a double-blind, placebo-controlled RCT of 78 Alzheimer disease patients who were treated for 12 weeks with 50 mg PBT2 (N=20), 250 mg PBT2 (N=29), or placebo (N=29). (21) There was no statistically significant difference in ADAS-Cog or Mini-Mental Status Examination 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 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, multifunction drugs that not only bind metal but also have significant antioxidant capacity are in development. (22)

Section Summary

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

Diabetes

Cardiovascular Disease in Patients with Diabetes

A 2009 trial by Cooper et al. in New Zealand evaluated the effect of copper chelation using oral trientine on left ventricular hypertrophy in 30 patients with type 2 diabetes. (23) Twenty-one (70%) of 30 participants completed 12 months of follow-up. At 12 months, there was a significantly greater reduction in left ventricular mass indexed to body surface area in the active treatment group compared with the placebo group (-10.6 g/m² vs -0.1 g/m², p=0.01). The study was limited by the small sample size and high dropout rate.

Diabetic Nephropathy

Chen et al. (2012) in China conducted a single-blind RCT of chelation therapy effects on the progression of diabetic nephropathy in patients with high-normal lead levels. (24) Fifty patients with diabetes, high-normal body lead burden (80-6000 µg), and serum creatinine 3.8 mg/dL or lower were included. Baseline mean blood lead levels were 6.3 µg/dL in the treatment group and 7.1 µg/dL in the control group, and baseline mean body lead burden was 151 mcg in the treatment group and 142 µg in the control group. According to the United States Occupational and Health Safety Administration, maximum acceptable blood lead level in adults is 40 µg/dL. (25) Patients were randomized to 3 months of calcium disodium EDTA or placebo. During 24 months of treatment, patients in the chelation group received additional chelation treatments as needed (i.e., for serum creatinine level above pretreatment levels or body lead burden >60 mcg), and patients in the placebo group continued to receive placebo medication. All patients completed the 27-month trial. The primary outcome was change in estimated glomerular filtration rate (eGFR). Mean (SD) yearly rate of decrease in eGFR was 5.6 mL/min/173 m² (5.0) in the chelation group and 9.2 mL/min/173 m² (3.6) in the control group, a statistically significant difference (p=0.04). Secondary end-point was the number of patients in whom the baseline serum creatinine doubled or who required renal replacement therapy. Nine patients (36%) in the treatment group and 17 (68%) in the control group attained the secondary end-point, a statistically significant difference (p=0.02). There were no reported adverse effects of chelation therapy during the 27-month trial period.

Section Summary

Two small RCTs with limitations represent insufficient evidence that chelation therapy is effective for treating cardiovascular disease in patients with diabetes. One small, single-blind RCT is insufficient evidence that chelation therapy is effective for treating diabetic nephropathy in patients with high-normal lead levels. Additional RCTs with larger numbers of patients that report health outcomes such as cardiovascular events, end-stage renal disease, and mortality are needed.

Myocardial Infarction

In 2013, results of the multicenter, randomized, double-blind Trial to Assess Chelation Therapy (TACT) were published. (26) The trial included 1708 patients, age 50 years or older, who had a history of myocardial infarction (MI) at least 6 weeks before enrollment and a serum creatinine level of 2.0 mg/dL or less. Patients were randomized to receive 40 infusions of disodium EDTA (N=839) or placebo (N=869). The first 30 infusions were given weekly, and the remaining 10 infusions were given 2 to 8 weeks apart. Primary end-point was a composite outcome that included death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina at 5 years. The threshold for statistical significance was adjusted for multiple interim analyses to a p value of 0.036. A total of 361 patients in the chelation group (43%) and 464 patients in the placebo group (57%) discontinued treatment, withdrew consent, or were lost to follow-up. Kaplan-Meier 5-year estimates for the primary end-point were 33% (95% confidence interval [CI], 29 to 37) in the chelation group and 39% (95% CI, 35 to 42) in the control group, a statistically significant difference (log-rank test, p=0.035). The most common individual clinical end-point was coronary revascularization, which occurred in 130 (15%) of 839 patients in the chelation group and 157 (18%) of 869 patients in the control group (p=0.08). The next most frequent end-point was death, which occurred in 87 patients (10%) in the chelation group and 93 patients (11%) in the placebo group (p=0.64). No individual component of the primary outcome differed statistically between groups; however, the study was not powered to detect differences in individual components. Four severe adverse events that were definitely or possibly related to study therapy occurred. There were 2 events each in the treatment and control groups, including 1 death in each group. The study is limited by the high number of withdrawals, with differential withdrawals between groups. The primary end-point included components of varying clinical significance, and the largest difference between groups was for revascularization events. The primary end-point barely met the significance threshold; if more patients had remained in the study and experienced events, results could have differed. Moreover, as noted in an editorial accompanying the publication, 60% of patients were enrolled at centers described as complementary and alternative medicine sites, and this may have resulted in a population that is not generalizable to that seen in general clinical care. (27)

Escolar et al. (2014) published results of a prespecified subgroup analysis of diabetic patients in TACT. (28) In TACT, there was a statistically significant interaction between treatment (EDTA or placebo) and presence of diabetes: Among 538 self-reported diabetic patients (31% of the trial sample), those randomized to EDTA had a 39% reduced risk of the primary composite outcome compared with placebo (hazard ratio [HR], 0.61; 95% CI, 0.45 to 0.83; log rank test, p=0.02); among 1170 nondiabetic patients, risk of the primary outcome did not differ statistically between treatment groups (HR=0.96; 95% CI, 0.77 to 1.20; log rank test, p=0.73). (26) For the subsequent subgroup analysis, the definition of diabetes mellitus was broadened to include self-reported diabetes, use of oral or insulin treatment for diabetes, or fasting blood glucose 126 mg/dL or more at trial entry. Of 1708 patients in TACT, 633 (37%) had diabetes mellitus by this definition; 322 were randomized to EDTA, and 311 to placebo. Compared with all other trial participants, this subgroup of diabetic patients had higher body mass index, fasting blood glucose, and prevalence of heart failure, stroke, hypertension, peripheral artery disease, and hypercholesterolemia. Within this subgroup, baseline characteristics were similar between treatment groups. With approximately 5 years of follow-up, the primary composite end-point occurred in 25% of the EDTA group and 38% of the placebo group (HR=0.59; 99.4% CI [adjusted for multiple subgroups], 0.39 to 0.88; log rank test, p=0.002). In adjusted analysis of the individual components of the primary end-point, there were no statistically significant differences between treatment groups. There were 36 adverse events attributable to study drug that led to trial withdrawal, 16 in the EDTA group and 20 in the placebo group.

This sub-study has the same limitations as the parent study previously described, namely, high and differential withdrawal and heterogeneous composite end-point. Additionally, because diabetes was not a stratification factor in TACT, results of this subgroup analysis are preliminary and require replication.

Section Summary

One RCT with limitations, including high dropout with differential dropout between groups, reported that cardiovascular events were reduced in patients treated with chelation therapy. This effect was greater among patients with diabetes mellitus. However, this was not a high-quality trial and therefore results may be biased. Further trials of high quality are needed to corroborate whether chelation therapy improves outcomes in patients with prior MI.

Other Potential Indications

No RCTs or other controlled trials that evaluated safety and efficacy of chelation therapy for other conditions, such as multiple sclerosis or arthritis, were identified. Iron chelation therapy is being investigated for Parkinson disease (29) and endotoxemia. (30)

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT02728843a

Study of Parkinson's Early Stage With Deferiprone (SKY).

140

July 2018

NCT02175225

Study of Deferoxamine Mesylate in Intracerebral Hemorrhage.

294

August 2018

NCT02655315

Conservative Iron Chelation as a Disease-modifying Strategy in Parkinson's Disease (FAIRPARKII).

338

Dec 2018

NCT02733185

Trial to Assess Chelation Therapy 2 (TACT2).

1200

August 2021

Unpublished

NCT02367248

Safety and Effectiveness Study of Deferoxamine and Xingnaojing Injection in Intracerebral Hemorrhage.

180

Dec 2016 (unknown)

NCT01741532a

A Randomized, Double-blind, Placebo-controlled Trial of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN).

89

Jan 2017 (completed)

Table key: NCT: national clinical trial; a Denotes industry-sponsored or cosponsored trial

Practice Guidelines and Position Statements

American College of Physicians et al.

In 2012, the American College of Physicians (ACP), American College of Cardiology Foundation (ACCF), American Heart Association (AHA), American Association for Thoracic Surgery (AATS), Preventive Cardiovascular Nurses Association (PCNA), and Society of Thoracic Surgeons (STS) published a clinical practice guideline on management of stable ischemic heart disease (IHD). (31) The guidelines recommended that “chelation therapy should not be used with the intent of improving symptoms or reducing cardiovascular risk in patients with stable IHD. (Grade: strong recommendation; low-quality evidence)” However, citing the Trial to Assess Chelation Therapy, (26) a 2014 focused update of these guidelines 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.” (38) The recommendation was upgraded from 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 2004 clinical practice guideline from ACP (33) stated that chelation “should not be used to prevent MI 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.)”

American College of Cardiology (ACC)

In 2005, ACC (32) 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.)” In 2013, the American College of Cardiology Foundation and AHA compiled previous American College of Cardiology/AHA and American College of Cardiology Foundation/AHA recommendations issued in 2005 and 2011 on the management of peripheral artery disease. (39) The recommendation against chelation therapy remained unchanged.

National Institute for Health and Care Excellence (NICE)

NICE issued clinical guidance on autism in children and young people in 2013 (34) and autism in adults in 2012. (35) Both documents specifically recommend against the use of chelation therapy for the management of autism.

Canadian Cardiovascular Society

The evidence-based, consensus guidelines (2014) from the Canadian Cardiovascular Society included a conditional recommendation (based on moderate-quality evidence) that chelation therapy should not be used to attempt to improve angina or exercise tolerance in patients with stable IHD. (40)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description 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, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

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.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

96365, 96366, 96374

HCPCS Codes

M0300, J0470, J0600, J0895, J3520, S9355

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Centers for Disease Control and Prevention. Deaths associated with hypocalcemia from chelation therapy--Texas, Pennsylvania, and Oregon, 2003-2005. MMWR Morb Mortal Wkly Rep. 2006; 55(8):204-7. PMID 16511441

2. Food and Drug Administration. Hospira, Inc., et al. Withdrawal of Approval of One New Drug Application and Two Abbreviated New Drug Application. Available online at: <https://www.fda.gov> (Last accessed October 2014).

3. Adal A, Tarabar A. et al. Heavy metal toxicity. Medscape; updated January 6, 2018. Available online at: <http:emedicine.medscape.com> Last accessed June 21, 2018.

4. Centers for Disease Control and Prevention (CDC). Lead: what do parents need to know to protect their children? (Last updated 10/30/2012). Available online at: <https://www.cdc.gov> (Last accessed June 2014).

5. Very high blood lead levels among adults - United States. 2002-2011. Morbidity and Mortality Weekly Report. 2013; 62(47):967-71. PMID 24280917

6. Centers for Disease Control and Prevention (CDC). Toxicological profile for mercury, chapter 2- health effects, March 1999. Available online at: <http://www.atsdr.cdc.gov> (Last accessed June 2014).

7. Centers for Disease Control and Prevention (CDC). Emergency preparedness and response: case definition - thallium (last updated 04/25/2013). Available online at: <http://emergency.cdc.gov> (Last accessed June 2014).

8. Kempson IM, Lombi E. Hair analysis as a biomonitor for toxicology, disease and health status. Chemical Society Reviews. 2011; 40(7):3915-40. PMID 21468435

9. Villarruz MV, Dans A, Tan F, Chelation therapy for atherosclerotic cardiovascular disease. Cochrane Database Syst Rev. 2002; (4):CD002785. PMID 12519577

10. Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. Jama. 2002; 287(4):481-6. PMID 11798370

11. Anderson TJ, Hubacek J, Wyse DG, et al. Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH substudy. Journal of the American College of Cardiology. 2003; 41(3):420-5. PMID 12575969

12. 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. PMID 1556523

13. Van Rij AM, Solomon C, Packer SG, et al. Chelation therapy for intermittent claudication: A double-blind, randomized, controlled trial. Circulation. 1994; 90(3):1194-9. PMID 8087928

14. Bernard S, Enayati A, Redwood L, et al. Autism: a novel form of mercury poisoning. Med Hypotheses. 2001; 56(4):462-71. PMID 11339848

15. Nelson KB, Bauman ML. Thimerosal and autism? Pediatrics. 2003; 111(3):674-9. PMID 12612255

16. 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. PMID 17250511

17. Rossignol DA. Novel and emerging treatments for autism spectrum disorders: A systematic review. Ann Clin Psychiatry. 2009; 21(4-Jan):213-36. PMID 19917212

18. Sampson E, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev. 2008; (1):CD005380. PMID 18254079

19. Ritchie CW, Bush AI, Mackinnon A, et al. Metal-protein attenuation with Iodochlorhydroxyquin (clioquinol) targeting Aß amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003; 60(12):1685-91. PMID 14676042

20. Sampson EL, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer's dementia. Cochrane Database Syst Rev. 2012; 5:CD005380. PMID 22592705

21. Lannfelt L, Blennow K, Zetterberg 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 neurology. 2008; 7(9):779-86. PMID 18672400

22. Cavalli A, Bolognesi ML, Minarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008; 51(3):347-72. PMID 18181565

23. 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. PMID 19172243

24. 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. American journal of kidney diseases: the official journal of the National Kidney Foundation 2012; 60(4):530-8. Available online at: < https://pdfs.semanticscholar.org> (Last accessed June 21 2018). PMID 24254885

25. U.S. Department of Labor Occupational Health and Safety Adminstration (OSHA). Safety and Health Regulations for Construction. Available online at: <https://www.osha.gov>. Last accessed May 2014.

26. 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. PMID 23532240

27. Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). Jama. 2013; 309(12):1293-4. PMID 23532246

28. 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). Circulation. Cardiovascular quality and outcomes. 2014; 7(1):15-24. PMID 24254885

29. Weinreb O, Mandel S, Youdim MB, et al. Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators. Free radical biology & medicine. 2013; 62:52-64. PMID 23376471

30. van Eijk LT, Heemskerk S, van der Pluijm RW, et al. The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial. Haematologica. 2014; 99(3):579-87. PMID 24241495

31. Qaseem A, Fihn SD, Dallas P, et al. Management of Stable Ischemic Heart Disease: Summary of a Clinical Practice Guideline From the American College of Physicians/American College of Cardiology Foundation/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society of Thoracic Surgeons. Annals of Internal Medicine. 2012; 157(10):735-43. PMID 23165665

32. Hirsch AT, Haskal ZJ, Hertzer NR, 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. PMID 16549646

33. Snow V, Barry P, Fihn SD, 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. PMID 15466774

34. National Institute for Health and Care Excellence. Autism - management of autism in children and young people (clinical guidance 170), August 2013. Available online at: <https://www.nice.org.uk> (Last accessed May 2014).

35. National Institute for Health and Care Excellence. Autism in adults (clinical guidance 142), June 2012. Available online at: <https://www.nice.org.> (Last accessed January 23, 2018).

36. Chelation Therapy for Off-Label Uses. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 February) Therapy 8.01.02.

37. U.S Food and Drug Administration. FDA warns consumers about potential health risks from using Thorne Research’s Captomer products. 2014 June 12; Available online at: <http://www.fda.gov> (Last accessed June 21, 2018).

38. 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 Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. Nov 4 2014; 64(18):1929-1949. PMID 25077860.

39. 2011 ACCF/AHA Focused Update of the Guideline for the Management of patients with peripheral artery disease (Updating the 2005 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. Nov 1 2011; 124(18):2020-2045. PMID 21959305.

40. Mancini GB, Gosselin G, Chow B, et al. Canadian Cardiovascular Society guidelines for the diagnosis and management of stable ischemic heart disease. Can J Cardiol. Aug 2014; 30(8):837-849. PMID 25064578.

Policy History:

Date Reason
8/15/2018 Document updated with literature review. No coverage changes. References 36-40 added.
12/1/2016 Reviewed. No changes.
2/1/2015 Document updated with literature review. The following was added to the coverage section: 1) Chelation therapy may be considered medically necessary in the treatment of non-transfusion-dependent thalassemia (NTDT); 2) Other applications of chelation therapy are considered experimental, investigational and/or unproven including, but not limited to, secondary prevention in patients with myocardial infarction.
7/15/2012 Document updated with literature review. No coverage change.
10/15/2010 Document updated with literature review. The following was added to Coverage: Prior to the administration of any chelating agent, diagnosis of metal toxicity MUST be established through appropriate diagnostic testing; the administration of any chelating agents prior to diagnosis of metal toxicity is considered not medically necessary, and therefore will not be covered. Description updated and Rationale revised. CPT/HCPCS codes were updated.
10/15/2007 Routine update, policy no longer scheduled for routine literature review and update.
8/15/2003 Revised/updated entire document
6/1/1998 Revised/updated entire document
5/1/1996 Revised/updated entire document
7/1/1995 Revised/updated entire document
4/1/1994 Revised/updated entire document
5/1/1990 New Medical Document

Archived Document(s):

Title:Effective Date:End Date:
Chelation Therapy12-01-201608-14-2018
Chelation Therapy02-01-201511-30-2016
Chelation Therapy07-15-201201-31-2015
Chelation Therapy10-15-201007-14-2012
Chelation Therapy10-15-200710-14-2010
Chelation Therapy08-15-200310-14-2007
Back to Top