MEDICAL POLICY

POLICY
RELATED POLICIES
POLICY GUIDELINES
DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
CODING
APPENDIX
HISTORY

Chelation Therapy for Off-Label Uses

Number 8.01.02

Effective Date December 17, 2014

Revision Date(s) 12/08/14; 08/12/13; 06/12/12; 06/13/11; 03/09/10; 02/10/09; 07/10/07; 02/10/04; 11/12/02; 01/97

Replaces N/A

Policy

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

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

Related Policies

2.04.502

Heavy Metals Testing

Policy Guidelines

FDA Approved Uses of Chelation Therapy

Chelation therapy has received FDA approval and is considered the standard of care treatment for a number of indications. 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);
  • 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)

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)

Arsenic

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)

Description

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.

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 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 two 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.

Regulatory 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.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

N/A

Rationale

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 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, non-fatal 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 two 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

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 one 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 anti-fungal 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, multi-function 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 drop-out 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 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 (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 1,708 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 endpoint 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 endpoint 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 endpoint 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 endpoint included components of varying clinical significance, and the largest difference between groups was for revascularization events. The primary endpoint 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 1,170 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 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 drop-out 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)

Clinical Trials

A search of online site, ClinicalTrials.gov, 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.

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

Title

Ages

Enrollmenta

Completiona

Phase IV trial

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

Child

Adult

90

Aug 2015

Phase II trials

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

Adult

36

Dec 2013

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

Adult

140

Mar 2014

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

Adult

50

Mar 2015

NR, not reported.

a Estimated.

Summary

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

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 (ACP/ACCF/AHA/AATS/PCNA/STS)

In 2012, the ACP/ACCF/AHA/AATS/PCNA/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)”

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.)”

American College of Physicians (ACP)

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)

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.

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.
  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: http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-13273.htm. Last accessed November, 2014.
  3. Adal A, Tarabar A et al. Heavy metal toxicity. Medscape; updated January 23, 2014. Available online at: http://emedicine.medscape.com/article/814960-overview. Last accessed November, 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: http://www.cdc.gov/nceh/lead/ACCLPP/blood_lead_levels.htm. Last accessed November, 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: http://www.atsdr.cdc.gov/ToxProfiles/TP.asp?id=115&tid=24. Last accessed November, 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/agent/thallium/casedef.asp. Last accessed November, 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 Administration (OSHA). Safety and Health Regulations for Construction. Available online at: http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=10642. Last accessed November, 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: Autism | Guidance and guidelines | NICE. Last accessed November, 2014.
  35. National Institute for Health and Care Excellence. Autism in adults (clinical guidance 142), June 2012. Available online at: http://www.nice.org.uk/CG142. Last accessed November, 2014.

Coding

Codes

Number

Description

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

HCPCS

M0300

Chelation therapy (Chemical endarterectomy)

 

J0470

Dimercaprol injection, per 100 mg

 

J0600

Edetate calcium disodium, up to 1000mg

 

J0895

Injection, deferoxamine mesylate, 500 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

Type of Service

Injection

 

Place of Service

Inpatient

 

Appendix

N/A

History

Date

Reason

01/97

Add to Therapy Section - New Policy

11/12/02

Replace Policy - Policy reviewed; policy statement unchanged, rationale, references added.

02/10/04

Replace Policy - Policy reviewed without literature review; new review date only.

02/06/06

Codes Updated - No other changes.

06/02/06

Disclaimer and Scope Updates - No other changes.

07/10/07

Replace Policy - Policy updated with literature review; no change in policy statement. Status changed to BC; no longer utilizing AR status.

02/10/09

Replace Policy - Policy updated with literature search. Policy statement revised to indicate that chelation therapy may be considered medically necessary in the treatment of iron overload due to transfusional hemosiderosis. All other applications are summarized as being investigational. References and codes added.

03/09/10

Replace Policy - Policy updated with literature search. Includes investigational conditions, policy intent is unchanged. References added.

06/13/11

Replace Policy - Policy updated with literature review; reference numbers 2 and 21 added; other references renumbered. No change to policy statements. ICD-10 codes added to policy.

06/26/12

Replace policy. Policy updated with literature review. Rationale re-written. References 16 and 17 added; other references renumbered or removed. Policy statement unchanged.

08/15/12

Update Related Policies – Add 2.04.502.

09/28/12

Update Coding Section – ICD-10 codes are now effective 10/01/2014.

08/12/13

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.”

12/17/14

Annual Review. 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. Policy updated with literature review through May 21, 2014; references 3-8, 20, 28-30, 34-35 added; references 2, 25, 31 updated. Investigational policy statement unchanged. ICD-9 and ICD-10 diagnosis and procedure codes removed; these do not relate to policy adjudication.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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