1. Aetna considers the use of chelation therapy medically necessary in the treatment of any of the following diseases/disorders:
   1. Biliary cirrhosis; or
   2. Cooley's anemia (thalassemia major); or
   3. Cystinuria; or
   4. Heavy metal poisoning (e.g., arsenic, cadmium, copper, gold, iron, lead, mercury)*; or
   5. Wilson's disease; or
   6. Sickle cell anemia; or
   7. Secondary hemochromatosis (i.e., due to iron overload from multiple transfusions); or
   8. Aluminum overload in persons with end-stage renal failure.

   * Testing of whole blood lead level is the most sensitive and specific means in assessing lead toxicity. Urinary lead level, which is an index of plasma lead concentration rather than whole blood lead concentration, is not an accurate measure of blood lead levels since plasma lead fluctuates more rapidly than blood lead levels.

2. Aetna considers the use of chelation therapy experimental and investigational in the prevention and treatment of cardiovascular disease, peripheral vascular disease, individuals at risk from drug-eluting stents, and other conditions (e.g., autism). The safety and effectiveness of this treatment for these indications has not been established.

3. Aetna considers laboratory testing medically necessary for heavy metal poisoning (e.g., mercury, arsenic, cadmium, copper, gold, iron) for members with specific signs and symptoms of heavy metal toxicity and/or a history of likely exposure to heavy metals.

   Aetna does not consider screening for heavy metal poisoning medically necessary for members with only vague, ill-defined symptoms (e.g., fatigue, dysphoria, malaise, and vague pain) and no history of likely heavy metal exposure.

See also CPB 553 - Lead Testing; CPB 300 - Hair Analysis.

Chelation therapy is an established treatment for heavy metal poisoning.  Heavy metals, which cannot be metabolized, persist in the body and exert their toxic effects by combining with one or more reactive groups (ligands) essential for normal physiological functions.  Chelating agents, also known as heavy metal antagonists, form complexes with toxic heavy metals rendering them physiologically inactive and enhancing their excretion in the urine.  Specific chelating agents include edetate calcium disodium (EDTA), deferoxamine (Desferal), dimercaprol (BAL in oil) and penicillamine (Cuprimine, Depen).

Dimercaprol was developed as an antidote to lewisite, an arsenic-based war gas and was designated British anti-Lewisite or BAL.  It is used principally to treat arsenic, gold and mercury poisoning and in combination with edetate calcium disodium, to treat lead poisoning.The main therapeutic use of edetate calcium disodium is in the treatment of metal intoxication, especially lead intoxication.  Mercury poisoning does not respond to this drug.Penicillamine is used for treating copper, mercury, lead and arsenic poisoning, and cystinuria.  It is the drug of choice for Wilson's disease (hepatolenticular degeneration due to an excess of copper).Deferoxamine has a highly affinity for iron and is the drug of choice for acute or chronic iron intoxication.

Chelation therapy with appropriate chelating agents is established treatment for biliary cirrhosis, Cooley's anemia (thalassemia major), cystinuria, heavy metal (arsenic, cadmium, copper, gold, iron, mercury) poisoning, Wilson's disease, and sickle cell anemia, i.e., secondary hemachromatosis (iron overload from multiple transfusions).

The administration of the chelating agent calcium EDTA as a mobilization test (provocative chelation) to determine if chelation therapy is indicated is controversial. The provocative chelation test was developed to assess the total body lead burden and efficacy of chelation treatment. The tests involve obtaining a timed urine collection after administering a dose of calcium EDTA. In view of a paucity of relevant clinical outcome studies of provocative chelation, and in view of and animal studies suggesting that single doses of chelation might cause harm from mobilizing lead and redistributing to the central nervous system, the use of provocative chelation is not indicated.

Intravenous or oral chelation therapy is indicated in all children with acute lead intoxication, and in children with moderate to severe chronic lead intoxication (blood lead level of 45 mcg/dl or greater). For children with mild intoxication (blood level less than 45 mcg/dl), oral chelation (DMSA or D-penacillamine) is indicated for those with blood levels are between 20 and 44 mcg/dl). Chelation therapy is not necessary for children with blood levels of lead less than 20 mcg/dl.

For adults, intravenous or oral chelation therapy is recommended for those with acute lead toxicity, and for adults with blood lead levels greater than 80 mcg/dL . Chelation therapy is also indicated for adults with blood lead levels between 60 and 80 mcg/dL if they have lead-related symptoms. In addition, chelation therapy may be considered in adults with blood lead levels between 40 and 60 mcg/dL, if they have continued symptoms and elevated blood lead levels after two weeks of removal from exposure.

Treatment with chelators should be considered in persons with acute symptoms arising from the central nervous system due to confirmed mercury poisoning (e.g., via measurement of mercury in air, blood, or urine). The normal range of mercury concentrations in whole blood is 0-10 mcg/L. Early signs and symptoms may occur with concentrations greater than 35 mcg/L.Clinically significant poisoning from mercury is unlikely if blood and urine concentrations are below 100 µg/L.

A concentration greater than or equal to 50 mcg/L or 100 mcg of arsenic per gram creatinine in the absence of recent fish or shellfish intake strongly suggests arsenic poisoning. Chelation indicated in symptomatic arsenic poisoning and in all patients whose speciated urine arsenic level exceeds 200 mcg/L. Patients who are minimally symptomatic and have chronic arsenic poisoning may be removed from the source of their exposure without chelation therapy. Chelation can be accomplished with oral penicillamine; IV dimercaprol can be used for person who cannot take oral medications.

Chelation therapy with calcium EDTA may be indicated in acute cadmium toxicity. Blood levels of cadmium above 5 mcg/dL suggest acute cadmium toxicity. There is a lack of evidence of beneficial effects of chelating agents on cadmium toxicity after prolonged exposure. The literature on the influence of chelating agents on cadmium distribution and excretion is limited to animal studies, and is confined to the early period after acute cadmium exposure, Developing an effective chelation therapy for cadmium is difficult because cadmium is tightly bound to metallothionein in liver and kidney.

Gold is used in the treatment of rheumatoid arthritis (RA) and other rheumatic diseases. Chelation therapy may be used in persons with gold toxicity with severe reactions who are unresponsive to steroids. Moderate to high dose steroid therapy may be beneficial in gold-induced thrombocytopenia, bone marrow toxicity, enterocolitis, and pulmonary infiltrates. Dimercaprol, penicillamine, N-acetylcysteine, and other chelating agents have been used to treat reactions unresponsive to glucocorticoids.

Chelation therapy may be indicated in copper toxicity. For copper toxicity due to ingesting grams of copper, prompt gastric lavage followed by daily intramuscular injections of dimercaprol may prevent death. The oral chelating drug penicillamine binds copper, facilitating its excretion, and may promote excretion of copper absorbed from burned skin. Chronic oral chelation therapy may be necessary in persons with inherited chronic copper toxicity (Wilson's disease).

There is insufficient evidence to support the use of chelation therapy for prevention or treatment of cardiovascular disease. Chelation therapy for atherosclerosis involves the intravenous infusion of ethylene diaminetetraacetic acid, also known as edetate disodium, endrate or EDTA.  It may involve as many as 20 to 40 infusions, each 3 to 4 hours long, administered 1 to 3 times weekly.

Used since the 1950s, the premise for EDTA chelation is the removal of calcium from the atherosclerotic lesion. Proponents claim that EDTA forms a chelated soluble complex with the calcium which is excreted in the urine.  Calcium, however, is not a major constituent in the pathogenesis of atherosclerosis.  The atherosclerotic lesion is highly cellular and contains smooth muscle, macrophages, lipid particles, and connective tissue. Within the lesion there are areas of necrotic debris, cholesterol crystal and calcification.  Lesions are primarily fibrous overgrowths and calcium deposition is an insignificant part of the total lesion.

Proponents also champion EDTA as the original calcium-channel antagonist.  However, there is no evidence that lowering serum, tissue and bone calcium with EDTA produces the same physiologic effects as the calcium-channel antagonists.  These work by binding to calcium-channel receptors to reduce calcium influx into the myofibril, therefore producing relaxation of smooth muscle without affecting the serum concentration of calcium.

Explanations for individual positive responses to chelation therapy include placebo effect (often seen in the controlled evaluation of therapies for angina pectoris), lifestyle changes and natural variations in the disease.  There are case reports of symptomatic improvement with angiographically documented persistence of the lesion.  Toxic effects may include death, renal failure, arrhythmias, tetany and hypocalcemia.

A systematic review of chelation therapy for cardiovascular disease (Villaruz, et al., 2003) reached the following conclusions: "At present, there is insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of patients with atherosclerotic cardiovascular disease. This decision must be preceded by conducting randomized controlled trials that would include endpoints that show the effects of chelation therapy on longevity and quality of life among patients with atherosclerotic cardiovascular disease."

The American Heart Association (2002) has concluded that there is "no scientific evidence to demonstrate any benefit from this form of therapy."

A assessment of chelation therapy by the West Midlands Health Technology Assessment Collaboration (Connock, et al., 2002) concluded that “[c]urrently there is little objective evidence that CT [chelation therapy] is effective for CHD [coronary heart disease] or IC [intermittent claudication].”

The New Zealand Guidelines Group (2003) found that insufficient evidence to recommend chelation for the treatment of prevention of cardiovascular disease, stroke, or type 2 diabetes.

A Canadian Cardiovascular Society consensus conference statement on heart failure (2006) concluded that "[c]helation therapy should not be used as heart failure therapy."

The American College of Cardiology (Hirsch, et al., 2005) stated that "[c]helation (e.g., ethylenediaminetetraacetic acid) is not indicated for treatment of intermittent claudication and may have harmful adverse effects." The Scottish Intercollegiate Guidelines Network (2006) explained: "Chelation has been studied in only one robust trial of patients with intermittent claudication [citing van Rig, et al., 1994], which showed no difference between experimental and placebo groups, leaving no evidence on which to base a recommendation. Adverse effects are potentially serious."

The American College of Physicians (Snow, et al., 2004) concluded that chelation should not be used to prevent MI or death or to reduce symptoms in patients with symptomatic chronic stable angina.

In August 2002, the National Center for Complementary and Alternative Medicine (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI) announced that they have launched the Trial to Assess Chelation Therapy (TACT), which is the first large-scale, multicenter study to find out if EDTA chelation therapy is safe and effective for people with coronary heart disease. This placebo-controlled, double-blind study will involve 2,372 participants age 50 years and older with a history of myocardial infarction.   Recruitment for this study began in March 2003, and the study will take five years to complete.

In a randomized double-blind, placebo-controlled study (n = 47), Anderson, et al. (2003) reported that EDTA chelation therapy in combination with vitamins and minerals did not provide additional benefits on abnormal vasomotor responses in patients with coronary artery disease optimally treated with proven therapies for atherosclerotic risk factors.

Recently, chelation therapy has also been advocated by some practitioners to treat patients with autism.  However, there is a lack of scientific evidence regarding its effectiveness for this indication.  Well-designed clinical trials are needed to ascertain the clinical value, if any, of chelation therapy for autistic individuals.

Chelation therapy has been shown to be useful in treatment of aluminum toxicity in renal failure. Hernandez and Johnson (1990) noted that aluminum (AL) toxicity, common among individuals with chronic renal failure, is associated with disabling osteomalacia, encephalopathy, and anemia.  The control of AL intake has included standards to limit the amount of AL in the dialysis fluid in addition to the use of non-AL containing phosphate binders.  Deferoxamine (DFO) mesylate, a heavy metal chelating agent, is used to remove AL from the tissues of dialysis patients.  Chelation therapy has resulted in improvements of clinical symptoms and bone histology.  Ocular, auditory, and infectious adverse effects have occurred with the use of DFO.  Day and Ackrill (1993) stated that DFO now finds extensive use in the treatment and diagnosis of AL-related diseases in renal patients.  Moreover, the American Academy of Pediatrics' statement on Al toxicity in infants and children (1996) stated that intravenous DFO has been used successfully in treating Al toxicity in children.

Barata and colleagues(1996) reported that according to the recommendations proposed at the 1992 consensus conference on diagnosis and treatment of AL overload in end-stage renal failure patients, low-dose DFO treatment was applied for the first time in 41 acutely Al-intoxicated patients.  DFO-related neurological/ophthalmological side-effects were observed in 9 of 11 patients with a post-DFO serum Al level greater than 300 ug/L and in 2 patients of 30 below this level after a single administration of a 5 mg/kg dose of the chelator in the conventional way (i.e., the last hour of a dialysis session).  They were no longer observed after introducing an alternative DFO administration schedule (i.e., administration of the chelator 5 hours prior to the start of a hemodialysis session; group I: n = 14).  A significant decrease in the serum Al levels as well as in the post-DFO serum Al increment (delta sAl) was observed during the first 6 months, course of low-dose DFO treatment in group I as well as group II (which consisted of patients receiving DFO in the conventional way; n = 27).  Low-dose DFO treatment was accompanied by a significant increase in the mean +/- SD serum iPTH levels (group I: 174 +/- 245 up to 286 +/- 285 ng/L; group II: 206 +/- 272 up to 409 +/- 424 ng/L; p < 0.005) and the mean corpuscular volume (group I: 80 +/- 6.4 up to 85 +/- 3.7 fL, p < 0.005; group II: 76 +/- 5.0 up to 87 +/- 4.3 fL, (p < 0.0001).  Serum ferritin levels significantly decreased in both groups.  No further side-effects were observed during the DFO course.  Patients in which DFO treatment could be stopped (i.e., subjects in which both serum Al and delta sAl were below 50 ug/L at two successive occasions) before the end of the 6 months' treatment course had a significantly greater residual diuresis (700 +/- 682 ml/min versus 84 +/- 109 ml/24 hours).  Also, residual diuresis was found to protect against Al intoxication as reflected by the values noted in group I versus those in group II.  The authors concluded that the 5 mg/kg DFO treatment provides a safe and adequate therapy for Al overload.  In severely Al-intoxicated patients presenting post-DFO serum Al levels above 300 ug/L, DFO should be given once weekly 5 hours prior to high-extraction dialysis ensuring (i) maximal chelation of Al, (ii) limited exposure to circulating Al noxamine levels, and (iii) adequate removal of the latter compound.