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MP 8.01.02 Chelation Therapy for Off-Label Uses

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/6:2014
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


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


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 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 also 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. For example, EDTA chelation therapy has been proposed in patients with atherosclerosis as a method of decreasing obstruction in the arteries.

FDA Status

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. 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, FDA withdrew approval of disodium-EDTA due to safety concerns and recommended that other forms of chelation therapy be used.(2)

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 patients age 2 years and older. Under the accelerated approval program, FDA expanded the indications for deferasirox in 2013 to include treatment of patients age 10 years and older with chronic iron overload due to nontransfusion-dependent thalassemia (NTDT).
  • In 2011, FDA approved the iron chelator, deferiprone (Ferriprox®), 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.


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

  • atherosclerosis (eg, coronary artery disease, secondary prevention in patients with myocardial infarction, or peripheral vascular disease);
  • multiple sclerosis;
  • arthritis (includes rheumatoid arthritis);
  • hypoglycemia;
  • autism;
  • Alzheimer disease; and
  • diabetes.

Policy Guidelines

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 (transfusional hemosiderosis) and due to nontransfusion-dependent thalassemia (NTDT);
  • Wilson disease (hepatolenticular degeneration); and
  • lead poisoning
  • control of ventricular arrhythmias or heart block associated with digitalis toxicity;
  • emergency treatment of hypercalcemia;

For the last 2 bullet points, most patients should be treated with other modalities. Digitalis toxicity is currently treated in most patients with Fab monoclonal antibodies. FDA removed the approval for NaEDTA as chelation therapy due to safety concerns and recommended that other chelators be used. This 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 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)



Toxic Levels (Normal Levels Where Indicated)


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


Proteinuria and/or ≥15 μg/g creatinine


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


Normative excretion: 25 μg/24 h (urine)


Nontoxic: <300 μg/dL

Severe: >500 μg/dL



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

CDC level of concern: 5 μg/dL(4)


Symptoms or blood lead level ≥40 μg/dL

CDC level of concern: 10 μg/dL(5)


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


Excessive exposure: ≥8 μg/L (blood)

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


Mild toxicity: >1 μg/L (serum) Serious toxicity: >2 μg/L


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


24-hour urine thallium >5 μg/L(7)


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


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

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)

Benefit Application
BlueCard/National Account Issues

No applicable information 


This policy was created in 1995 and updated regularly with literature searches using MEDLINE. The most recent literature review covered the period through May 21, 2014. Chelation therapy is an established treatment metal toxicity and transfusional hemosiderosis. These uses are not covered in this policy. 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.


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.


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) 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.


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 μg/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 U.S. 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 (ie, 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 1708patients, 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 μg/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 μg/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 substudy 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 Clinical Trials

A search of online site,, for randomized trials of chelation therapy in heavy metal intoxication returned 14 actively-recruiting trials. All identified trials examined iron toxicity. Investigational indications are listed in Table 2 and include pantothenate kinase-associated neurodegeneration (PKAN) (NCT01741532), Parkinson disease (NCT01539837), hypotension (NCT00870883), and multiple sclerosis (NCT01627938).

Table 2. Ongoing Randomized Trials of Chelation Therapy for Investigational Uses (Current May 2014)





Phase 4 trial


A Two-arm Efficacy and Safety Study of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN) (NCT01741532)

Child Adult


Aug 2015

Phase 2 trials


A Pilot Clinical Trial With the Iron Chelator Deferiprone in Parkinson's Disease (DeferipronPD) (NCT01539837)



Dec 2013

N-acetylcysteine Plus Deferoxamine for Patients With Hypotension (NCT00870883)



Mar 2014

Study to Evaluate the Reduction of Cardiac Problems in Multiple Sclerosis Patients With Mitoxantrone and Dexrazoxane in Combination (MSCardioPro) (NCT01627938)



Mar 2015

NR, not reported.

a Estimated.


Chelation therapy is an established treatment for metal toxicities and transfusional hemosiderosis. There is insufficient evidence that chelation therapy improves health outcomes for patients with conditions that are off-label for Food and Drug Administration‒approved chelating agents, including, but not limited to, atherosclerosis, autism, Alzheimer disease, and diabetes. One randomized controlled trial, the TACT study, 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 study had significant limitations, including high dropout rates, and therefore the conclusions are not definitive. Thus, chelation therapy for these off-label applications is considered investigational.

Practice Guidelines and Position Statements


In 2012, the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and Society of Thoracic Surgeons 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)”

American College of Cardiology

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.)”

American College of Physicians

A 2004 clinical practice guideline from ACP(33) stated that chelation “should not be used to prevent myocardial infarction or death or to reduce symptoms in patients with symptomatic chronic stable angina. (Level of evidence B: Based on evidence from a limited number of randomized trials with small numbers of patients, careful analyses of nonrandomized studies, or observational registries.)”

National Institute for Health and Care Excellence

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.


  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.
  2. Food and Drug Adminstration. Hospira, Inc., et al.; Withdrawal of Approval of One New Drug Application and Two Abbreviated New Drug Application. Available online at: Last accessed May 2014.
  3. Adal A, Tarabar A et al. Heavy metal toxicity. Medscape; updated January 23, 2014. Available online at: Last accessed June 2014.
  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: Last accessed June 2014.
  5. Very high blood lead levels among adults - United States, 2002-2011. MMWR Morb Mortal Wkly Rep 2013; 62(47):967-71.
  6. Centers for Disease Control and Prevention (CDC). Toxicological profile for mercury, chapter 2- health effects, March 1999. Available online at: 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: 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.
  9. Villarruz MV, Dans A, Tan F. Chelation therapy for atherosclerotic cardiovascular disease. Cochrane Database Syst Rev 2002; (4):CD002785.
  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.
  11. 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.
  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.
  13. Van Rij A. M., Solomon C, Packer SG et al. Chelation therapy for intermittent claudication: A double-blind, randomized, controlled trial. Circulation 1994; 90(3):1194-9.
  14. Bernard S, Enayati A, Redwood L et al. Autism: a novel form of mercury poisoning. Med Hypotheses 2001; 56(4):462-71.
  15. Nelson KB, Bauman ML. Thimerosal and autism? Pediatrics 2003; 111(3):674-9.
  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.
  17. Rossignol DA. Novel and emerging treatments for autism spectrum disorders: A systematic review. Ann Clin Psychiatry 2009; 21(4-Jan):213-36.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  25. U.S. Department of Labor Occupational Health and Safety Adminstration (OSHA). Safety and Health Regulations for Construction. Available online at: 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.
  27. Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). Jama 2013; 309(12):1293-4.
  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.
  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.
  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.
  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.
  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.
  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. Ann Intern Med 2004; 141(7):562-7.
  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: Last accessed May 2014.
  35. National Institute for Health and Care Excellence. Autism in adults (clinical guidance 142), June 2012. Available online at: Last accessed May 2014.   




CPT  96365  Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour  
  96366 each additional hour (list separately in addition to code for primary procedure) 
  96374 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug 
ICD-9 Procedure  99.16  Injection of antidote (heavy metal antagonist) 
ICD-9 Diagnosis  275.1   
  275.4  Hypercalcemia 
  282.40-282.49 Thalassemia code range
  427.9  Arrhythmia 
  984–984.9  Lead poisoning code range 
  440  Atherosclerosis (code range) 
  999.8, 999.89 Other infusion and trasnfusion reaction not elsewhere classified
HCPCS  M0300  IV chelation therapy (chemical endarterectomy) 
  J0470  Injection, dimercaprol, per 100 mg 
  J0600  Injection, edetate calcium disodium, up to 1000 mg 
  J3520  Edetate disodium, per 150 mg 
  S9355 Home infusion therapy, chelation therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-10-CM (effective 10/1/15) D56.0-D56.9 Thalassemia code range
  E83.01 Wilson's disease
   E83.52 Hypercalcemia
   M10.1-M19 Lead induced gout code range
   T46.0x1A – T46.0x6S Poisoning by, adverse effect of and underdosing of cardiac-stimulant glycosides and drugs of similar action code range (7th character indicates initial encounter [A], subsequent encounter [D] or sequel [S])
   T56.0x1A – T56.94xS Toxic effects of metal code range (7th character indicates initial encounter [A], subsequent encounter [D] or sequel [S])
   T80.89 Other complications following infusion, transfusion and therapeutic injection (includes transfusionalhemosiderosis)
ICD-10-PCS (effective 10/1/15)    ICD-10-PCS codes are only used for inpatient services.
   3E030GC, 3E033GC Introduction, therapeutic substance, peripheral vein, code by approach (open or percutaneous)
   3E040GC, 3E043GC Introduction, therapeutic substance, central vein, code by approach (open or percutaneous)
   3E050GC, 3E053GC Introduction, therapeutic substance, peripheral artery, code by approach (open or percutaneous)
   3E060GC, 3E063GC Introduction, therapeutic substance, central artery, code by approach (open or percutaneous)
Type of Service  Injection 



Chelation therapy
Chemical endarterectomy

Policy History
Date Action Reason
12/1/95 Add to Surgery section New policy
07/12/02 Replace policy Policy reviewed; policy statement unchanged, rationale, references added
10/09/03 Replace policy Policy reviewed by consensus without literature review; no changes in policy; no further review scheduled
12/14/05 Replace policy – coding update only CPT coding updated
12/11/08 Replace policy  Policy returned to “active review” status. Policy updated with literature review; policy statements revised to indicate that chelation therapy may be considered medically necessary in the treatment of iron overload due to transfusional hemosiderosis and considered investigational in the treatment of autism and Alzheimer’s disease. Other policy statements are unchanged. Reference numbers 1-3,5, 10-13 added 
01/14/10 Replace policy Policy updated with literature review; references 14-23 added; policy statements unchanged. “Includes rheumatoid arthritis” was added to the investigational policy statement for arthritis.
4/14/11 Replace policy Policy updated with literature review; reference numbers 2 and 21 added; other references renumbered. No change to policy statements.
04/12/12 Replace policy Policy updated with literature review. Rationale re-written. References 16 and 17 added; other references renumbered or removed.
6/13/13 Replace policy Policy updated with literature review through April 24, 2013. References 17-21; other references renumbered or removed. Chronic iron overload due to nontransfusion-dependent thalassemia (NDTD) added to medically necessary statement based on new FDA approval. Secondary prevention in patients with myocardial infarction added to bullet point in investigational statement on atherosclerosis; in that bullet point, “i.e.” changed to “e.g.”
6/12/14 Replace policy Policy updated with literature review through May 21, 2014; references 3-8, 20, 28-30, and 34-35 added; references 2, 25, and 31 updated. Title changed to “Chelation Therapy for Off-Label Uses.” Medically necessary policy statement for on-label uses deleted from policy statement and moved to policy guidelines. Information about toxic and normal heavy metal levels added to policy guidelines. Investigational policy statement unchanged.

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