CAM 80102

Chelation Therapy for Off-Label Uses

Category:Therapy   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:December 1995    

Description:
Chelation therapy, an established treatment for heavy metal toxicities and transfusional hemosiderosis, has been investigated for a variety of off-label applications, such as treatment of atherosclerosis, Alzheimer disease, and autism. This evidence review does not address indications for chelation therapy approved by the U.S. Food and Drug Administration. Instead, we will address off-label indications, including: Alzheimer disease, cardiovascular disease, autism spectrum disorder, diabetes, multiple sclerosis, and arthritis.

For individuals who have Alzheimer's disease, cardiovascular disease, autism spectrum disorder, diabetes, multiple sclerosis, or arthritis who receive chelation therapy, the evidence includes a small number of randomized controlled trials (RCTs) and case series. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. One RCT (the Trial to Assess Chelation Therapy) reported that chelation therapy reduced cardiovascular events in patients with a previous myocardial infarction and that the benefit was greater in diabetic patients compared with nondiabetic patients. However, this trial had significant limitations (eg, high dropout rates) and, therefore conclusions are not definitive. For other conditions, the available RCTs did not report improvements in health outcomes with chelation therapy and, as evidence, the case series are inadequate to determine efficacy. The evidence is insufficient to determine the effect of the technology on health outcomes.

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 (see Appendix Table 1). Specific chelating agents are used for particular heavy metal toxicities. For example, desferrioxamine (not approved by the Food and Drug Administration [FDA]) 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 β-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 considered 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.

Regulatory Status
In 1953, EDTA (Versenate) was approved by the FDA for lowering blood lead levels among both pediatric and adult patients with lead poisoning. In 1991, succimer (Chemet) was approved by FDA for the treatment of lead poisoning in pediatric patients only. The FDA approved disodium-EDTA for use in selected patients with hypercalcemia and use in patients with heart rhythm problems due to intoxication with 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:

  • In 1968, deferoxamine (Desferal®; Novartis) was approved by FDA for subcutaneous, intramuscular, or intravenous injections to treat acute iron intoxication and chronic iron overload due to transfusion-dependent anemia. Several generic forms of deferoxamine have been approved by FDA.
  • In 2005, deferasirox (Exjade®; Novartis) was approved by FDA, is available as a tablet for oral suspension, and is indicated for the treatment of chronic iron overload due to blood transfusions in patients ages 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 non-transfusion-dependent thalassemia syndromes and specific liver iron concentration and serum ferritin levels. A generic version of deferasirox tablet for oral suspension has also been approved by FDA. In 2015, an oral tablet formulation for deferasirox (Jadenu™) was approved by FDA. 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.
  • In 2011, the iron chelator deferiprone (Ferriprox®) was approved by FDA for treatment of patients with transfusional overload due to thalassemia syndromes when another chelation therapy is inadequate. Deferiprone is available in tablet and oral solution. 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.

In a June 2014 warning to consumers, FDA advised that FDA-approved chelating agents would be available by prescription only.3 There are no FDA-approved over-the-counter chelation products. 

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)
  • Autism
  • Alzheimer's disease
  • Diabetes

Policy Guidelines
A number of indications for chelation therapy have received Food and Drug Administration (FDA) approval and for which chelation therapy is considered standard of care. They include:

  • extreme conditions of metal toxicity
  • treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) or due to non-transfusion-dependent thalassemia
  • 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. NaEDTA 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 Appendix Table 1.  

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. The following is a summary of the key literature to date.

Chelation therapy is an established treatment for metal toxicity and transfusional hemosiderosis. These uses are not discussed herein. Literature searches have focused on the use of chelation therapy for off-label conditions including, but not limited to, Alzheimer disease, atherosclerosis, autism spectrum disorder, diabetes, multiple sclerosis, and arthritis.

Alzheimer's Disease
A Cochrane review (2008) evaluated metal protein attenuating compounds for treating Alzheimer's disease.4, Reviewers identified a placebo-controlled randomized trial. This study by Ritchie et al (2003) assessed patients treated with PBT1, a metal protein attenuating compound also known as clioquinol, which is an antifungal medication that crosses the blood-brain barrier.5, The Food and Drug Administration withdrew clioquinol for oral use from the market in 1970 because of its association with subacute myelo-optic neuropathy. Ritchie administered oral clioquinol to 16 Alzheimer's 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's Disease Assessment Scale–Cognitive. One patient in the treatment group developed impaired visual acuity and color vision during weeks 31 to 36 of treatment with clioquinol 375 mg twice daily. Her symptoms resolved on treatment cessation. The update of this Cochrane review (2012) included trials through December 2011.6, Only the Lannfelt trial (discussed next) was identified.

Further study of PBT1 was abandoned in favor of a successor compound, PBT2. Lannfelt et al (2008) completed a double-blind, placebo-controlled randomized trial of 78 Alzheimer's disease patients who were treated for 12 weeks with PBT2 50 mg (n=20), PBT2 250 mg (n=29), or placebo (n=29).7, There was no statistically significant difference in Alzheimer's Disease Assessment Scale–Cognitive 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, transient ischemic event) were reported in the placebo arm.

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

Cardiovascular Disease
Atherosclerosis
Villarruzet al (2002) published a Cochrane review that evaluated ethylenediaminetetraacetic acid (EDTA) chelation therapy for treating patients with atherosclerotic cardiovascular disease.8, Five placebo-controlled randomized trials were identified, none of which reported mortality, nonfatal events, or cerebrovascular events. Four (n=250 patients) of the 5 studies found no significant benefit of EDTA chelation therapy on reported outcomes, including direct or indirect measures of disease severity and subjective measures of improvement. The fifth study (N=10 patients) was stopped early due to benefit, but relevant outcome data were unavailable. Cochrane reviewers found that the evidence was insufficient to support conclusions about the efficacy of chelation therapy for treating atherosclerosis. Additional RCTs reporting health outcomes like mortality and cerebrovascular events were suggested.

Among published RCTs, Knudtson et al (2002) randomized 84 patients with coronary artery disease and a positive treadmill test to EDTA chelation therapy or placebo.9, Treatment was administered for 3 hours twice weekly for 15 weeks and then monthly for 3 months. Outcome measures included a 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 randomized trial (2003) of EDTA chelation showed no difference between groups in short- or long-term improvement in vasomotor response.10, Two small RCTs from the 1990s also reported no benefit of chelation therapy as a treatment for peripheral arterial disease.11,12.

Section Summary: Atherosclerosis
Several RCTs of chelation therapy for treating atherosclerosis generally have reported on intermediate outcomes and have not found EDTA chelation therapy to be more effective than placebo. Additional RCTs reporting health outcomes would be needed to establish treatment efficacy.

Myocardial Infarction
Lamas et al (2013) published results of the multicenter, 2´2 factorial, double-blind, randomized Trial to Assess Chelation Therapy (TACT).13, TACT included 1708 patients, ages 50 years or older, who had a history of myocardial infarction at least 6 weeks before enrollment and a serum creatinine level of 2.0 mg/dL or less. Patients were randomized to 40 intravenous infusions of disodium EDTA (n=839) or placebo (n=869). Patients also received oral high-dose vitamin plus mineral therapy or placebo. The first 30 infusions were given weekly, and the remaining 10 infusions were given 2 to 8 weeks apart. The 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 (43%) patients in the chelation group and 464 (57%) patients in the placebo group discontinued treatment, withdrew consent, or were lost to follow-up. Kaplan-Meier 5-year estimates for the primary end point was 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 (p=0.035). The most common individual clinical end point was coronary revascularization, which occurred in 130 (16%) 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 (10%) patients in the chelation group and 93 (11%) patients in the placebo group (p=0.64). No individual component of the primary outcome differed statistically between groups; however, the trial was not powered to detect differences in individual components. Four severe adverse events definitely or possibly related to study therapy occurred, two each in the treatment and control groups, including 1 death in each. Quality of life outcomes (reported in 2014) did not differ between groups at 2-year follow-up.14,

Another 2014 follow-up publication reported results for the 4 treatment groups in the 2´2 factorial design (double-active group [disodium-EDTA infusions with oral high-dose vitamins; n=421 patients], active infusions with placebo vitamins [n=418 patients], placebo infusions with active vitamins [n=432 patients], double placebo [n=437 patients]).15, The proportions of patients who discontinued treatment withdrew consent, or were lost to follow-up per treatment group were not reported. Five-year Kaplan-Meier estimates for the primary composite end point were 32%, 34%, 37%, and 40%, respectively. The reduction in primary end point by double-active treatment compared with double placebo was statistically significant (hazard ratio [HR], 0.74; 95% CI, 0.57 to 0.95). In 633 patients with diabetes (»36% of each treatment group), the primary end point reduction in the double-active group compared with the double placebo group was more pronounced (HR=0.49; 95% CI, 0.33 to 0.75).

The trial was 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 original (2013) publication, 60% of patients were enrolled at centers described as complementary and alternative medicine sites, and this may have resulted in the selection of a population not generalizable to that seen in general clinical care.16, Editorialists commenting on the subsequent (2014) publication suggested that further research would be warranted to replicate the findings.17, This secondary analysis had the same limitations as the parent study previously described (ie, high and differential withdrawal, 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: Myocardial Infarction
One RCT with limitations, including high dropout rate 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. However, this trial was not of high-quality and, therefore, results might have been biased. More high-quality trials are needed to corroborate whether chelation therapy improves outcomes in patients with prior myocardial infarction.

Autism spectrum disorder
Based on symptoms similarities between mercury poisoning and autism spectrum disorder, Bernard et al (2001) hypothesized a link between environmental mercury and autism.18, 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.19, A meta-analysis by Ng et al (2007) concluded that there was no association between mercury poisoning and autism.20,

Rossignol (2009) published a systematic review of novel and emerging treatments for autism and identified no controlled studies.21, Rossignol stated that case series had 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: Autism Spectrum Disorder
There is a lack of controlled studies on how chelation therapy effects health outcomes in patients with autism.

Diabetes
Cardiovascular Disease in Patients With Diabetes
A trial by Cooper et al (2009) in New Zealand evaluated the effect of copper chelation using oral trientine on left ventricular hypertrophy in 30 patients with type 2 diabetes.22, 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 (-10.6 g/m2) than in the placebo group -0.1 g/m2; p=0.01). The trial was limited by small sample size and high dropout rate.

Escolar et al (2014) published results of a prespecified subgroup analysis of diabetic patients in TACT.23,In this trial (also discussed above), there was a statistically significant interaction between treatment (EDTA or placebo) and presence of diabetes: Among 538 (31% of the trial sample) self-reported diabetic patients, those randomized to EDTA had a 39% reduced risk of the primary composite outcome (ie, death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina at 5 years) compared with placebo (HR=0.61; 95% CI, 0.45 to 0.83; 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; p=0.73).13, For the subsequent subgroup analysis, the definition of diabetes was broadened to include self-reported diabetes, use of oral or insulin treatment for diabetes, or fasting blood glucose of 126 mg/dL or more at trial entry. Of 1708 patients in TACT, 633 (37%) had diabetes 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 (adjusted HR=0.59; 99.4% CI, 0.39 to 0.88; p=0.002). In adjusted analysis of the individual components of the primary end point, there were no statistically significant differences between treatment groups. Thirty-six adverse events attributable to the study drug led to trial withdrawal (16 in the EDTA group vs 20 in the placebo group).

Diabetic Nephropathy
Chen et al (2012) conducted a single-blind RCT assessing the effects of chelation therapy on the progression of diabetic nephropathy in Chinese patients with high-normal lead levels.24, Fifty patients with diabetes, high-normal body lead burden (80-6000 μg), and serum creatinine of 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; baseline mean body lead burden was 151 μg in the treatment group and 142 μg in the control group. According to the U.S. Occupational and Health Safety Administration, the maximum acceptable blood lead level in adults is 40 μg/dL.25, Patients were randomized to 3 months of calcium disodium EDTA or to placebo. During 24 months of treatment follow-up, patients in the chelation group received additional chelation treatments as needed (ie, for serum creatinine level above pretreatment levels or body lead burden >60 μg), 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. Mean yearly rate of decrease in estimated glomerular filtration rate was 5.6 mL/min/173 m2 in the chelation group and 9.2 mL/min/173 m2 in the control group, a statistically significant difference (p=0.04). The secondary end point was the number of patients in whom the baseline serum creatinine doubled or who required renal replacement therapy. Nine (36%) patients 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 events of chelation therapy during the trial.

Section Summary: Diabetes
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 (eg, cardiovascular events, end-stage renal disease, mortality) are needed.

Other Potential Indications: Multiple Sclerosis and arthritis
No RCTs or other controlled trials evaluating the safety and efficacy of chelation therapy for other conditions (eg, multiple sclerosis, arthritis) were identified. Iron chelation therapy is being investigated for Parkinson disease26,27, and endotoxemia.28,

Summary of Evidence
For individuals who have Alzheimer's disease, or cardiovascular disease, or autism spectrum disorder, or diabetes, or multiple sclerosis, or arthritis who receive chelation therapy, the evidence includes a small number of RCTs and case series. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. One RCT (the Trial to Assess Chelation Therapy) reported that chelation therapy reduced cardiovascular events in patients with previous myocardial infarction and that the benefit was greater in diabetic patients compared with nondiabetic patients. However, this trial had significant limitations (eg, high dropout rates) and, therefore, conclusions are not definitive. For other conditions, the available RCTs did not report improvements in health outcomes with chelation therapy and, as evidence, the case series are inadequate to determine efficacy. The evidence is insufficient to determine the effect of the technology on health outcomes.

Practice Guidelines and Position Statements
American College of Physicians et al
The American College of Physicians, American College of Cardiology Foundation, American Heart Association (AHA), and 3 other medical associations published joint clinical practice guidelines (2012) on the management of stable ischemic heart disease (IHD).29, 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,13, 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.”30, 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).

The American College of Physician’s clinical practice guidelines (2004) 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.)”31,

American College of Cardiology et al
In 2005, the American College of Cardiology, AHA, and other medical societies 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).”32,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 200532, and 201133, on the management of peripheral artery disease.34, The recommendation against chelation therapy remained unchanged.

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.35,

National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence issued guidance reports (2013) on autism in children and young people,36, and autism in adults which was updated in 2016.37, Both documents specifically recommended against the use of chelation therapy for the management of autism.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing

NCT02728843a 

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

140 

August 2019 

NCT02175225

Study of Deferoxamine Mesylate in Intracerebral Hemorrhage

294

Jun 2019

NCT02655315 

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

338 

Feb 2021 

NCT02733185

Trial to Assess Chelation Therapy 2 (TACT2) 1,200

Aug 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 (cpmpleted)

NCT: national clinical trial.
Denotes industry-sponsored or cosponsored trial.  

References: 

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  30. 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
  31. 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. Oct 5 2004;141(7):562-567. PMID 15466774
  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. Mar 21 2006;113(11):e463-654. PMID 16549646
  33. 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
  34. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. Apr 2 2013;127(13):1425-1443. PMID 23457117
  35. 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
  36. National Institute for Health and Care Excellence. Autism spectrum disorder in under 19s: support and management [CG170]. 2013; https://www.nice.org.uk/guidance/cg170. Accessed January 23, 2018.
  37. National Institute for Health and Care Excellence. Autism spectrum disorder in adults: diagnosis and management [CG142]. 2016; https://www.nice.org.uk/guidance/CG142. Accessed January 23, 2018.
  38. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for CHELATION THERAPY for Treatment of Atherosclerosis (20.21). n.d.; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=86&ncdver=1&CoverageSelection=National&KeyWord=Chelation+Therapy&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAACAAAAAAAA%3d%3d&. Accessed January 23, 2018.
  39. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Ethylenediamine-Tetra-Acetic (EDTA) CHELATION THERAPY for Treatment of Atherosclerosis (20.22). n.d.; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=146&ncdver=1&CoverageSelection=National&KeyWord=Chelation+Therapy&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAACAAAAAAAA%3d%3d&. Accessed January 23, 2018.
  40. Centers for Disease Control and Prevention (CDC). What Do Parents Need to Know to Protect Their Children? 2017, May 17; http://www.cdc.gov/nceh/lead/ACCLPP/blood_lead_levels.htm. Accessed January 23, 2018.
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Coding Section 

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

ICD-9 Procedure 99.16

Injection of antidote (heavy metal antagonist)

ICD-9 Diagnosis  

Investigational for all off-label indications

HCPCS M300

IV chelation therapy (chemical endarterectomy)

  J0470

Injection, dimercaprol, per 100 mg

  J0600

Injection, edetate calcium disodium, up to 1000 mg

  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), perdiem

ICD-10-CM (effective 10/01/15)  

Investigational for all off-label uses

 

E08.00-E13.9

Diabetes mellitus code range

 

F84.0

Autism disorder

 

G30.0-G30.9

Alzheimer's disease code range

 

G35

Multiple sclerosis

 

I25.10-I25,9

Atherosclerosis code range

 

M05.00-M06.09

Rheumatoid arthritis code range

 

M15.0-M19.93

Osteoarthritis code range

ICD-10-PCS (effective 10/01/15)  

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

 

Place of Service

 

 

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. 

APPENDIX  
Suggested toxic or normal levels of select heavy metals are listed in Appendix Table 1.

Appendix Table 1. Toxic or Normal Concentrations of Heavy Metals  

Metal   Toxic Levels (Normal Levels Where Indicated)  
Arsenic   24-h urine: ≥ 50 μg/L urine or 100 μg/g creatinine  
Bismuth  No clear reference standard 
Cadmium   Proteinuria and/or ≥ 15 μg/g creatinine  
Chromium  No clear reference standard 
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/dL40
  • Adult
  • Symptoms or blood lead level ≥ 40 μg/dL
  • CDC level of concern: 10 μg/dL41
Mercury   Background exposure normative limits: 1-8 μg/L (whole blood); 4-5 μg/L (urine)(6)43,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/L43 
Zinc   Normative range: 0.6-1.1 μg/L (plasma), 10-14 μg/L (red cells)  

Adaped from Adal (2018)44
CDC: Centers for Disease Control and Prevention.
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. Measurementof 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.45    

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

07/01/2019 

Annual review, no change to policy intent. Updating rationale and references. 

07/09/2018 

Annual review, no change to policy intent. Changing the conjunction "and" to "or" in the guidelines section related to chronic iron overload due to blood transfusions. Also updating regulatory status, rationale and references. 

07/18/2017 

Annual review, no change to policy intent. Updating background, description, guidelines, rationale, references and table 1. 

07/19/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

07/30/2015 

Annual review, no change to policy intent. Updated background, description, regulatory status, guidelines, rationale and references. Added coding.

07/22/2014 

Updated title and changed policy verbiage to only include the off-label issues for chelation. Medically necessary chelation is now discussed in the policy guidelines. Updated rationale, references and guidelines.

12/5/2013

Annual review.   Updated rationale and references. Updated verbiage to include: "chronic iron overload due to non transfusion dependent thalassemia (NDTD) as medically necessary based on new FDA approval." Secondary prevention in patient with myocardial infarction added to investigational statement on atherosclerosis.


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