Chelation Therapy

Number: 0234

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses chelation therapy for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

1. Medical Necessity

   Aetna considers the following medically necessary (unless otherwise specified):

   1. Deferoxamine (Desferal)

      1. Criteria for Initial Approval

         Aetna considers deferoxamine (Desferal) injection, an iron-chelating agent, medically necessary for the treatment of the following indications when criteria is met:

         1. Transfusional iron overload in members with chronic anemia when the pretreatment serum ferritin level is consistently greater than 1000 mcg/L; or
         2. Aluminum toxicity in members undergoing dialysis; or
         3. Hereditary hemochromatosis when phlebotomy is not an option (e.g., poor venous access, poor candidate due to underlying medical disorders) or the member had an unsatisfactory response to phlebotomy.

         Aetna considers deferoxamine (Desferal) experimental and investigational for all other indications.

      2. Continuation of Therapy

         Aetna considers continuation of deferoxamine (Desferal) therapy medically necessary for an indication listed in Section I.A.1 when the following criteria is met:

         1. Transfusional iron overload in members with chronic anemia when member is experiencing benefit from therapy as evidenced by a decrease in serum ferritin levels as compared to pretreatment baseline; or
         2. Aluminum toxicity in members undergoing dialysis when member is experiencing benefit from therapy as evidenced by any of the following:
            
            
            1. Decreased serum aluminum concentrations; or
            2. Symptomatic improvement (e.g., neurological symptom improvement, decreased bone pain); or

         3. Hereditary hemochromatosis when member is experiencing benefit from therapy as evidenced by a decrease in serum ferritin levels as compared to pretreatment baseline.

   2. Other Chelation Therapy

      Aetna considers the use of other chelation therapy medically necessary in the treatment of any of the following diseases/disorders:
      

      1. Aceruloplasminemia (hereditary ceruloplasmin deficiency); or
      2. Aluminum overload in persons with end-stage renal failure; or
      3. Biliary cirrhosis; or
      4. Cooley's anemia (thalassemia major); or
      5. Cystinuria; or
      6. Diamond-Blackfan anemia; or
      7. Heavy metal toxicity (e.g., arsenic, cadmium, copper, gold, iron, lead, mercuryFootnote1*) when both of the following criteria are met:
         
         
         1. Member's symptoms are suggestive of heavy metal toxicity; and
         2. Heavy metal toxicity has been confirmed by laboratory testing; or
      8. Secondary hemochromatosis (i.e., due to iron overload from multiple transfusions including persons with IPSS Low- or Intermediate-1-risk myelodysplastic syndrome); or
      9. Sickle cell anemia; or
      10. Wilson's disease.

      Footnote1*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.

   3. Testing

      1. Laboratory testing for heavy metal poisoning (e.g., arsenic, cadmium, copper, gold, iron, mercury) 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., dysphoria, fatigue, malaise, and vague pain) and no history of likely heavy metal exposure;
         
      2. Laboratory testing for manganese for persons with specific signs and symptoms of manganese toxicity (dyscoordination, loss of balance, confusion) who have a history of likely exposure to high levels of manganese (e.g., occupational exposures to manganese aerosols or dust in the welding or steel industries, exposure to high levels of manganese in contaminated drinking water, suspected manganese toxicity in persons on chronic total parenteral nutrition). Aetna considers testing for serum or urinary manganese medically necessary to direct manganese supplementation in persons on long-term parenteral nutrition. Aetna considers laboratory testing for manganese experimental and investigational persons with vague, ill-defined symptoms (e.g., dysphoria, fatigue, malaise, and vague pain) without a history of manganese exposure, and for all other indications.

2. Experimental and Investigational

   The following are considered experimental and investigational:

   1. Chelation Therapy

      For the prevention and treatment of any of the following indications because the safety and effectiveness of this treatment for these indications has not been established:

      1. Cancer
      2. Cardiovascular disease (e.g., atherosclerotic cardiovascular disease, coronary artery disease, individuals who had a myocardial infarction)
      3. Individuals at risk from drug-eluting stents
      4. Neurodegenerative diseases (e.g., Alzheimer's disease, Friedreich's ataxia, Huntington disease, multiple sclerosis, pantothenate kinase-associated neurodegeneration, and Parkinson disease)
      5. Optic nerve injury
      6. Peripheral vascular disease
      7. Uveitis
      8. Zygomycosis
      9. Other conditions (e.g., autism, attention deficit hyperactivity disorder, diabetic cataract, Lyme disease, Sickle cell ulcers, prevention of diabetes-associated cardiovascular events, and treatment of "mercury toxicity" from dental amalgam fillings);

   2. Testing

      Dimercaptosuccinic acid (DMSA) or ethylenediaminetetraacetic (EDTA) provocative chelation/mobilization test as a means of diagnosing lead toxicity because of insufficient evidence of its effectiveness.

3. Related Policies

   For deferiprone (Ferriprox), deferasirox (Exjade and Jadenu), see Pharmacy Clinical Policy Bulletins.

   See also:

   1. CPB 0300 - Hair Analysis
   2. CPB 0553 - Lead Testing.

Dosage and Administration

Deferoxamine mesylate for injection, USP, is an iron-chelating agent, available in vials for intramuscular, subcutaneous, and intravenous administration. Deferoxamine mesylate (Hospira, Inc.) is supplied as vials containing 500 mg and 2 g of deferoxamine mesylate USP in sterile, lyophilized form. Deferoxamine mesylate is also available as Desferal (Novartis Pharmaceuticals Corp.) and is supplied as vials containing 500 mg of deferoxamine mesylate USP in sterile, lyophilized form. 

Acute Iron Intoxication

Intramuscular (IM) Administration

The IM route is preferred and should be used for persons not in shock. 

The initial recommended dose is 1,000 mg intramuscularly once. If needed based on the clinical response, administer subsequent doses of 500 mg every 4 hours to 12 hours. The maximum recommended daily dose is 6,000 mg in 24 hours.

Intravenous (IV) Administration

The IV route should be used only for persons in a state of cardiovascular collapse and then by slow infusion. As soon as the clinical condition permits, intravenous administration should be discontinued, and the drug should be administered intramuscularly.

The initial recommended IV dose is 1,000 mg administered at an infusion rate of up to 15 mg/kg/hr. If needed based on the clinical response administer additional doses of 500 mg over 4 hours to 12 hours at a slower infusion rate of up to 125 mg/hr. The maximum recommended daily dose is 6,000 mg in 24 hours.

Chronic Iron Overload

Subcutaneous Administration

The average daily dose is usually between 20 and 60 mg/kg. In general, persons with serum ferritin level below 2,000 ng/mL require about 25 mg/kg/day. Persons with serum ferritin level between 2,000 and 3,000 ng/mL require about 35 mg/kg/day. Persons with higher serum ferritin may require up to 55 mg/kg/day. It is not advisable to regularly exceed an average daily dose of 50 mg/kg/day except when very intensive chelation is needed in patients who have completed growth. If ferritin levels fall below 1,000 ng/mL, the risk of toxicity increases; it is important to monitor carefully and perhaps to consider lowering the total weekly dose. The doses specified here are the average daily doses. Since most persons use deferoxamine mesylate less than 7 days a week, the actual dose per infusion usually differs from the average daily dose; e.g., if an average daily dose of 40 mg/kg/day is required and the person wears the pump 5 nights a week, each infusion should contain 56 mg/kg. Slow subcutaneous infusion using a portable, light-weight infusion pump over a period of 8 to 12 hours is regarded as effective and especially convenient for ambulatory persons but may also be given over a 24-hour period. Deferoxamine mesylate should normally be used with the pump 5 to 7 times a week. Deferoxamine mesylate is not formulated to support subcutaneous bolus injection.

Intravenous Administration

Deferoxamine mesylate can be administered intravenously if needed in persons with intravenous access.

The recommended dose of deferoxamine mesylate in adults is 40 mg/kg/day to 50 mg/kg/day over 8 hours to 12 hours at a rate of up to 15 mg/kg/hour for 5 days to 7 days per week. Maximum dose is 60 mg/kg/day.

The recommended dose of deferoxamine mesylate in pediatrics is 20 mg/kg/day to 40 mg/kg/day over 8 hours to 12 hours for 5 days to 7 days per week. The maximum recommended daily dose is 40 mg/kg/day until growth (body weight and linear growth) has ceased.

In case of missed doses, deferoxamine mesylate may be administered prior to or following same day blood transfusion (for example, 1 gram over 4 hours on the day of transfusion); however, the contribution of this mode of administration to iron balance is limited. Deferoxamine mesylate should not be administered concurrently with the blood transfusion as this can lead to errors in interpreting side effects such as rash, anaphylaxis and hypotension.

Intramuscular Administration

A daily dose of 500 to 1,000 mg may be administered intramuscularly. The maximum recommended daily dose is 1,000 mg per day.

Source: Hospira, 2023; Novartis, 2022

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Chelation therapy:
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
HCPCS codes covered if selection criteria are met:
G0068	Professional services for the administration of anti-infective, pain management, chelation, pulmonary hypertension, and/or inotropic infusion drug(s) for each infusion drug administration calendar day in the individual's home, each 15 minutes
J0470	Injection, dimercaprol, per 100 mg
J0600	Injection, edetate calcium disodium, up to 1000 mg
J3520	Edetate disodium, per 150 mg
M0300	IV chelation therapy (chemical endarterectomy)
S9355	Home infusion therapy, chelation therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-10 codes covered if selection criteria are met:
D46.22	Refractory anemia with excess of blasts 2
D46.9	Myelodysplastic syndrome, unspecified
D46.C	Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality
D46.Z	Other myelodysplastic syndromes
D56.0 - D56.9	Thalassemia
D57.00 - D57.819	Sickle-cell disorders [not covered for sickle-cell ulcers]
D61.01	Constitutional (pure) red blood cell aplasia [Blackfan-Diamond syndrome]
E72.01	Cystinuria
E83.01	Wilson's disease
E83.10, E83.19	Other and unspecified disorders of iron metabolism
E83.111	Hemochromatosis due to repeated red blood cell transfusions
G23.0	Hallervorden-Spatz disease [Aceruloplasminemia (hereditary ceruloplasmin deficiency)] [not covered for pantothenate kinase-associated neurodegeneration]
K74.3 - K74.5	Biliary cirrhosis
N18.6	End stage renal disease [due to iron overload from multiple transfusions]
T37.8X1+ - T37.8X4+	Poisoning by, adverse effect of and underdosing of other specified systemic anti-infectives and antiparasitics [not covered for treatment of (mercury toxicity) from dental amalgam fillings]
T39.4X1+ - T39.4X6+	Poisoning by, adverse effect of and underdosing of antirheumatics, not elsewhere classified [gold salts]
T45.4X1+ - T45.4X4+	Poisoning by, adverse effect of and underdosing of iron and its compounds
T56.0X1+ - T56.0X4+	Toxic effect of lead and its compounds [not covered for treatment of (mercury toxicity) from dental amalgam fillings]
T56.1X1+ - T56.1X4+	Toxic effect of mercury and its compounds
T56.3X1+ - T56.3X4+	Toxic effect of cadmium and its compounds
T56.4X1+ - T56.6X4+	Toxic effects of copper, zinc, tin and its compounds
T56.811+ - T56.894+	Toxic effects of thallium and other metals
T57.0X1+ - T57.0X4+	Toxic effect of arsenic and its compounds
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A69.20 - A69.29	Lyme disease
B46.0 - B46.9	Zygomycosis
C00.0 - C96.9	Malignant neoplasm
D00.00 - D09.9	Carcinoma in situ
E08.00 – E13.9	Diabetes mellitus [prevention of diabetes-associated cardiovascular events]
F84.0	Autistic disorder
F90.0 - F90.9	Attention-deficit hyperactivity disorder
G10 - G12.9, G13.8, G20 - G23.9 G24.02 - G26, G30 - G31.09, G31.2, G31.83 - G31.9, G80.3, G90.09, G91.0 - G91.9, G93.7, G94, G95.81 - G95.9	Hereditary and degenerative diseases of the central nervous system
G35	Multiple sclerosis
G93.31, G39.32, G39.39	Postviral fatigue syndrome
H20.0 - H20.9	Iridocyclitis [uveitis]
I00 - I52	Diseases of the circulatory system
I70.201 - I70.299	Atherosclerosis of native arteries of the extremities
I70.301 - I70.799	Atherosclerosis of bypass graft of the extremities
I70.8	Atherosclerosis of other arteries
I70.90 - I70.91	Unspecified and generalized atherosclerosis
I73.00 - I73.9	Other peripheral vascular diseases
R53.0 - R53.83	Malaise and fatigue
S04.011A - S04.019S	Injury of optic nerve
Z41.8 - Z41.9	Encounter for other and unspecified procedures for purposes other than remedying health state [prevention of cardiovascular disease]
Z98.61	Coronary angioplasty status
Deferoxamine mesylate:
HCPCS codes covered if selection criteria are met:
J0895	Injection, deferoxamine mesylate, 500 mg
ICD-10 codes covered if selection criteria are met:
E83.110	Hereditary hemochromatosis
E83.111	Hemochromatosis due to repeated red blood cell transfusions
E87.71	Transfusion associated circulatory overload
T56.811A - T56.894S	Toxic effects of other metals
Z49.01 - Z49.32	Encounter for care involving renal dialysis
Z99.2	Dependence on renal dialysis
Laboratory tests for heavy metal poisoning:
CPT codes covered if selection criteria are met:
83015	Heavy metal (e.g., arsenic, barium, beryllium, bismuth, antimony, mercury); screen
83018	quantitative, each
ICD-10 codes covered if selection criteria are met (not all-inclusive):
D50.0 - D50.9	Iron deficiency anemia
D80.0 - D80.9	Immunodeficiency with predominantly antibody defects
F50.8	Other eating disorders [pica in adults]
F80.0 - F82	Specific developmental disorders of speech and language
F91.9	Conduct disorder, unspecified
F98.3	Pica of infancy and childhood
G44.1	Vascular headache, not elsewhere classified
H90.0 - H90.8	Conductive and sensorineural hearing loss
H91.01 - H91.93	Other and unspecified hearing loss
K05.00 - K05.6	Gingivitis and periodontal diseases
K11.7	Disturbances of salivary secretion
K52.0 - K52.9	Other and unspecified noninfective gastroenteritis and colitis
K59.00 - K59.09	Constipation
L29.8 - L29.9	Other and unspecified pruritis
M62.81	Muscle weakness (generalized)
N05.0 - N05.9	Unspecified nephritic syndrome
N28.9	Disorder of kidney and ureter, unspecified
R10.0 - R10.33	Abdominal and pelvic pain
R11.0 - R11.2	Nausea and vomiting
R19.7	Diarrhea, unspecified
R20.0 - R20.9	Disturbances of skin sensation
R21	Rash and other nonspecific skin eruption
R22.0 - R22.9	Localized superficial swelling, mass and lump of skin and subcutaneous tissue
R23.4	Changes in skin texture
R25.0 - R25.9	Abnormal involuntary movements
R27.0	Ataxia, unspecified
R34	Anuria and oliguria
R40.20 - R40.4	Coma
R41.1 - R41.3	Amnesia
R45.0	Nervousness
R51	Headache
R56.9	Unspecified convulsions
R60.0 - R60.9	Edema, not elsewhere classified
R62.0 - R62.59	Lack of expected normal physiological development in childhood and adults
R63.0	Anorexia
R63.4	Abnormal weight loss
R94.4	Abnormal results of kidney function studies
T37.8X1+ - T37.8X4+	Poisoning by, adverse effect of and underdosing of other specified systemic anti-infectives and antiparasitics
T39.4x1+ - T39.4x4+	Poisoning by, adverse effect of and underdosing of antirheumatics, not elsewhere classified [gold salts]
T45.4X1+ - T45.4X4+	Poisoning by, adverse effect of and underdosing of iron and its compounds
T49.4X1+ - T49.4X4+	Poisoning by, adverse effect of and underdosing of keratolytics, keratoplastics, and other hair treatment drugs and preparations
T56.0x1+ - T56.94x+	Toxic effect of metals
T56.0X1+ - T56.0X4+	Toxic effect of lead and its compounds
T56.1X1+ - T56.1X4+	Toxic effect of mercury and its compounds
T56.3X1+ - T56.3X4+	Toxic effect of cadmium and its compounds
T56.4X1+ - T56.6X4+	Toxic effects of copper, zinc, tin and its compounds
T56.811+ - T56.894+	Toxic effects of thallium and other metals
T57.0x1+ - T57.0x4+	Toxic effect of arsenic and its compounds
T74.01X+	Adult neglect or abandonment, confirmed
T74.02X+	Child neglect or abandonment, confirmed
T76.01X+	Adult neglect or abandonment, suspected
T76.02X+	Child neglect or abandonment, suspected
T74.92X+	Unspecified child maltreatment, confirmed
T76.92X+	Unspecified child maltreatment, suspected
Z77.011	Contact with and (suspected) exposure to lead
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
R53.83	Other fatigue [lethargy]
Laboratory testing for manganese:
CPT codes covered if selection criteria are met:
83785	Manganese
ICD-10 codes covered if selection criteria are met:
R26.0	Ataxic gait
R26.2	Difficulty in walking, not elsewhere classified
R26.81 – R26.89	Other abnormalities of gait and mobility
R27.0 - R27.9	Other lack of coordination
R41.0	Disorientation, unspecified
T57.2X1A - T57.2X4S	Toxic effect of manganese and its compounds
Z57.5	Occupational exposure to toxic agents in other industries [manganese aerosols]
E61.3	Manganese deficiency
Z76.0	Encounter for issue of repeat prescription [long-term parenteral nutrition]
ICD-10 codes not covered for indications listed in the CPB:
M79.601 – M79.609	Pain in limb, unspecified
M79.621 – M79.629	Pain in upper arm
M79.631 – M79.639	Pain in forearm
M79.641 – M79.646	Pain in hand and fingers
M79.651 – M79.659	Pain in thigh
M79.661 – M79.669	Pain in lower leg
M79.671 – M79.676	Pain in foot and toes
R07.0 – R07.9	Pain in throat and chest
R10.0 – R10.9	Abdominal and pelvic pain
R53.0 – R53.83	Malaise and fatigue
Dimercaptosuccinic acid (DMSA) or ethylenediaminetetraacetic (EDTA) provocative chelation/mobilization test:
NO specific code
ICD-10 codes not covered for indications listed in the CPB:
T56.0x1+ - T56.0x4+	Toxic effects of lead and its compounds

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications for Deferoxamine Mesylate

• As an adjunct to standard measures for the treatment of acute iron intoxication
• For the treatment of transfusional iron overload in patients with chronic anemia

Compendial Uses for Deferoxamine Mesylate

• Aluminum toxicity in patients undergoing dialysis
• Hereditary hemochromatosis

Chelation therapy is an established treatment for heavy metal toxicity. Heavy metals, which can not 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 mesylate (Desferal), dimercaprol (BAL in oil) and penicillamine (Cuprimine, Depen).

Deferoxamine mesylate, available as Desferal (Novartis Pharmaceuticals Corp.) and generic formulation (Hospira, Inc.), is FDA approved as an adjunct to standard measures for the treatment of acute iron intoxication and for the treatment of transfusional iron overload in patients with chronic anemia. Desferal is not indicated for the treatment of primary hemochromatosis (since phlebotomy is the method of choice for removing excess iron in this disorder).

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 toxicity and in combination with edetate calcium disodium, to treat lead toxicity (also referred as lead poisoning).  The main therapeutic use of edetate calcium disodium is in the treatment of metal intoxication, especially lead intoxication.  Mercury toxicity does not respond to this drug.  Penicillamine is used for treating copper, mercury, lead and arsenic toxicity, and cystinuria.  It is the drug of choice for Wilson's disease (hepato-lenticular 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) toxicity, 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 2 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 toxicity (e.g., via measurement of mercury in air, blood, or urine).  The normal range of mercury concentrations in whole blood is 0 to 10 mcg/L.  Early signs and symptoms may occur with concentrations greater than 35 mcg/L.  Clinically significant toxicity 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/g creatinine in the absence of recent fish or shellfish intake strongly suggests arsenic toxicity.  Chelation indicated in symptomatic arsenic toxicity and in all patients whose speciated urine arsenic level exceeds 200 mcg/L.  Patients who are minimally symptomatic and have chronic arsenic toxicity 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 can not 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 intra-muscular 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).

Bolognin et al (2009) stated that available evidence suggests a central role for transition biometals in the pathogenesis of neurodegenerative diseases (ND).  It has become increasingly evident that biometals and non-physiological aluminum are often involved in pathological onset and progression, either by affecting the conformation of specific proteins or by exacerbating local oxidative stress.  The apparently critical role played by metal dishomeostasis in ND makes chelation therapy an attractive pharmacological option.  However, classical metal chelation approaches, relying on potent metal ligands, turned out to be successful only in those rare cases where exceptional brain metal accumulation occurs due to specific defects in metal metabolism.  In contrast, metal-targeted approaches using ligand of intermediate strength seem to be more appropriate in fighting the major ND, although their benefits are still questioned.

Glotzer (1993) stated that 2,3-dimercaptosuccinic acid (DMSA) is an orally active chelating agent used in the treatment of lead and other heavy metal poisonings.  In animals, DMSA chelates lead from soft tissues, including the brain, without clinically evident adverse effects or histopathological changes.  In lead-poisoned children and adults, DMSA significantly increases urinary lead excretion, and, at least transiently, reduces the blood lead concentration.  The safety profile of DMSA in both children and adults is encouraging, with few clinically apparent or biochemical adverse effects reported.  However, clinical experience with DMSA is limited, and is not sufficient to exclude the possibility that other more serious drug-related adverse events including hypersensitivity or idiosyncratic reactions may occur.  No data currently exist to determine whether drug-enhanced lead excretion with DMSA (or any other chelating agent) is beneficial in reducing lead-related neurotoxicity.  The efficacy of DMSA in reducing neuropsychological morbidity, and additional safety data, are key areas requiring additional study before DMSA can be clearly recommended as the chelating agent of choice for the treatment of lead-poisoned children.

An UpToDate review on "Adult lead poisoning" (Goldman and Hu, 2012) states that "Provocative chelation is a mobilization test that has been proposed to give an indirect measure of lead body burden and thereby determine if chelation therapy is indicated.  Some medical practices assess lead poisoning by provocative chelation with DMSA or CaEDTA, comparing urinary excretion to reference ranges for non-challenged urine specimens.  Studies have failed to establish a valid correlation between prior metal exposure and post-challenge test values.  The American College of Medical Toxicology (ACMT) does not support provocative chelation".  Furthermore, an UpToDate review on "Childhood lead poisoning: Management" (Hurwitz and Lee, 2012) states that "CaNa2EDTA mobilization tests, once used as indicators of potential response to chelation therapy in children with moderate lead intoxication, are no longer used by most centers that treat childhood lead poisoning.  They are thought to be unnecessary because most patients with BLL [blood lead levels] greater than 40 microgram/dL (1.93 micromol/L) have an adequate response.  In addition, they are expensive and difficult to administer".

A report of the Advisory Committee on Childhood Lead Poisoning Prevention of the Centers for Disease Control and Prevention (2012) states that "There is no medical foundation for relying on the following methods to diagnose over-exposure to lead: gingival lead lines, testing of neurophysiologic function; evaluation of renal function (except during chelation with EDTA); testing of hair, teeth, packed red cells, saliva or fingernails for lead; radiographic imaging of long bones, nor is provocative chelation prior to measurement of lead in urine testing recommended.  The widely accepted sequelae of BLLs less than 45 μg/dL are cognitive and behavioral impairment.  Chelation of children with BLLs greater than or equal to 20 and less than or equal to 45 μg/dL has not been shown to offer therapeutic benefit for these outcomes".

Rajkumar and colleagues (2023) state that acute heavy metal exposure usually has dramatic presentation. Inhalation causes respiratory symptoms. Topical contamination, skin lesions, and ingestion mimics acute gastroenteritis or dysentery. The authors acknowledge that chronic exposure is more difficult to detect and needs a high index of suspicion. "Depending on the organ system involved, the symptoms will vary. Typical findings may be present only in selected cases, while the majority may be non-specific". In addition to obtaining a history and physical, which includes history of heavy metal exposure, patient examination of blood, urine, hair, nail, and tissues may be used to confirm toxicity. "Management includes preventing any further exposure, removal of the offending agent using chelating agents, supportive therapy, and patient education."

Aceruloplasminemia (Hereditary Ceruloplasmin Deficiency)

Aceruloplasminemia is a rare autosomal recessive disorder in which iron gradually accumulates in the retina, basal ganglia, and other organs. Treatment includes the use of iron chelating agents (such as desferrioxamine) to lower serum ferritin concentration, brain and liver iron stores, and to prevent progression of neurologic symptoms. This, combined with fresh-frozen human plasma (FFP) effectively in decreasing liver iron content.

Poli and associates (2017) reported the case of a patient with hereditary ceruloplasmin deficiency due to a novel gene mutation in ceruloplasmin gene (CP), treated with fresh frozen plasma (FFP) and iron chelation therapy.  A 59-year old man with a past history of diabetes was admitted to the authors’ department due to progressive gait difficulties and cognitive impairment.  Neurological examination revealed a moderate cognitive decline, with mild extrapyramidal symptoms, ataxia, and myoclonus.  Brain T2-weighted MR imaging showed bilateral basal ganglia hypo-intensity with diffuse iron deposition.  Increased serum ferritin, low serum copper concentration, undetectable ceruloplasmin, and normal urinary copper excretion were found.  The genetic analysis of the CP (OMIM #604290) reported compound heterozygosity for 2 mutations, namely, c.848G > A and c.2689_2690delCT.  Treatment with FFP and administration of iron chelator (deferoxamine followed by deferiprone) were undertaken.  At the 6-month follow-up, clinical improvement of gait instability, trunk ataxia, and myoclonus was observed; brain MRI scan showed no further progression of basal ganglia T2 hypo-intensity.  The authors concluded that the findings of this case report suggested that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and to improve the neurological symptoms.

Alzheimer's Disease

Hedge et al (2009) noted that a close association between brain metal dishomeostasis and the onset and/or progression of Alzheimer's disease (AD) has been established in a number of studies, although the underlying biochemical mechanisms remain obscure.  This observation renders chelation therapy an attractive pharmacological option for the treatment of this disease.  However, a number of requirements must be fulfilled in order to adapt chelation therapy to AD.

A Cochrane systematic evidence review found insufficient evidence for the use of chelation (metal protein attenuating compounds) in AD (Sampson et al, 2008).  Metal protein attenuating compounds have great affinity for copper and zinc ions, preventing them from binding to beta amyloid, a protein strongly implicated in the development of AD.  Chelation of these metal ions promotes dissolution of beta amyloid, thus presenting a potential therapeutic target for AD.  The Cochrane systematic evidence review found 1 RCT (n = 36) of metal protein attenuating compounds in AD.  That trial, of clioquinol (also known as PBT1) showed no statistically significant difference in cognition between active treatment and placebo groups at 36 weeks.  The authors concluded that there is no current evidence that treatment with clioquinol (PBT1) has any significant effect on cognition (as measured by the ADAS-Cog scale) in patients with AD.

Autism and Attention Deficit Hyperactivity Disorder

Although chelation therapy has been cited as a potential treatment for autism and attention deficit hyperactivity disorder (ADHD) (e.g., Curtis and Patel, 2008), there is insufficient evidence to support its use for these indications.  Well-designed clinical trials are needed to ascertain the clinical value, if any, of chelation therapy for autism and ADHD.

In a systematic review on novel and emerging treatments for autism spectrum disorders (ASD), Rossignol (2009) stated that currently only 1 medication (risperidone) is Food and Drug Administration (FDA)-approved for the treatment of ASD; and the use of novel, unconventional, and off-label treatments is common, with up to 74 % of children with ASD using these treatments.  The author performed a systematic literature search of electronic scientific databases to identify studies of novel and emerging treatments for ASD, including nutritional supplements, diets, medications, and non-biological treatments.  A grade of recommendation ("Grade") was then assigned to each treatment using a validated evidence-based guideline as outlined in this review: "Grade A": Supported by at least 2 prospective randomized controlled trials (RCTs) or 1 systematic review; "Grade B": Supported by at least 1 prospective RCT or 2 non-randomized controlled trials; "Grade C": Supported by at least 1 non-randomized controlled trial or 2 case series; and "Grade D": Troublingly inconsistent or inconclusive studies or studies reporting no improvements.  Potential adverse effects for each treatment were also reviewed.  Grade A treatments for ASD included melatonin, acetylcholinesterase inhibitors, naltrexone, and music therapy.  Grade B treatments include carnitine, tetrahydrobiopterin, vitamin C, alpha-2 adrenergic agonists, hyperbaric oxygen treatment (HBOT), immunomodulation and anti-inflammatory treatments, oxytocin, and vision therapy.  Grade C treatments for ASD include carnosine, multi-vitamin/mineral complex, piracetam, polyunsaturated fatty acids, vitamin B6/magnesium, elimination diets, chelation, cyproheptadine, famotidine, glutamate antagonists, acupuncture, auditory integration training, massage, and neurofeedback.  The author concluded that the reviewed treatments for ASD are commonly used, and some are supported by prospective RCTs.  Promising treatments include melatonin, antioxidants, acetylcholinesterase inhibitors, naltrexone, and music therapy.  All of the reviewed treatments are currently considered off-label for ASD (i.e., not FDA-approved) and some have adverse effects.  Further studies exploring these treatments are needed.

Furthermore, in a review on autism, Levy et al (2009) stated that popular biologically based treatments include anti-infectives, chelation medications, gastrointestinal medications, HBOT, and immunoglobulins.  Non-biologically based treatments include auditory integration therapy, chiropractic therapy, cranio-sacral manipulation, interactive metronome, and transcranial stimulation.  However, few studies have addressed the safety and effectiveness of most of these treatments.

In a Cochrane review, James et al (2015) evaluated the potential benefits and adverse effects of chelation therapy for ASD symptoms.  These investigators searched the following databases on November 6, 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and 15 other databases, including 3 trials registers.  In addition they checked references lists and contacted experts.  All RCTs of pharmaceutical chelating agents compared with placebo in individuals with ASD were selected for analysis.  Two review authors independently selected studies, assessed them for risk of bias and extracted relevant data.  They did not conduct a meta-analysis, as only 1 study was included.  These researchers excluded 9 studies because they were non-randomized trials or were withdrawn before enrolment.  They included 1 study, which was conducted in 2 phases.  During the 1st phase of the study, 77 children with ASD were randomly assigned to receive 7 days of glutathione lotion or placebo lotion, followed by 3 days of oral dimercaptosuccinic acid (DMSA); 49 children who were found to be high excreters of heavy metals during phase I continued on to phase II to receive 3 days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to 6 times.  The 2nd phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a 3-day course of oral DMSA.  Overall, no evidence suggested that multiple rounds of oral DMSA had an effect on ASD symptoms.  This review included data from only 1 study, which had methodological limitations.  As such, no clinical trial evidence was found to suggest that chelation therapy is an effective intervention for ASD.  The authors concluded that given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits.  Moreover, they stated that before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed.

Cardiovascular Diseases

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: "[a]t 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: "[c]helation 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 myocardial infarction (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, multi-center 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 aged 50 years and older with a history of MI.  Recruitment for this study began in March 2003, and the study will take 5 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.

Chappell (2007) stated that the recently reported increased risk of blood clots, resulting in MI and sudden death beginning 6 months after medicated stents were implanted in patients following percutaneous transluminal coronary angioplasty (PTCA), has left physicians pondering what course of action to take.  The purpose of adding implanted medication to a stent is to prevent thrombin accumulation and re-stenosis.  However, these stents may increase, rather than decrease, the risk.  Although long-term treatment with clopidogrel plus aspirin for at least 12 months has been suggested as a preventive treatment, there is no evidence from randomized, controlled trials that this approach is effective for more than 6 months.  Clopidogrel also increases the risk of major bleeding episodes.  The author served as the primary investigator for a study that showed cardiovascular patients treated with EDTA chelation therapy had a lower rate of subsequent cardiac events, including MI and death, than those treated with cardiac medications, PTCA, or coronary artery bypass graft.  The data also indicated chelation therapy might be effective in preventing thrombosis and cardiac events from stent implantation.  There is evidence that EDTA chelation therapy might prevent hyper-coagulability resulting from the placement of stents, although not specifically medicated stents.  Based on the limited data currently available, intravenous EDTA may be safe and effective for treating patients who have implanted medicated stents.  The author noted that prospective clinical trials are needed, and EDTA should be included in those trials.

Whayne (2010) noted that a wide range of alternative medications with relevance or connection to cardiovascular (CV) disease have been considered.  While many are worthless, others have definite benefit, and at least one, chelation therapy, is associated with definite harm, significant risk, no benefit, and enrichment of the practitioners who prescribe it.  The issues concerning alternative therapies will likely never be studied with randomized clinical trials due to the lack of a profit motive on the part of pharmaceutical companies – only rarely do other institutions, such as the National Institutes of Health, support medicinal studies.  Basic knowledge of alternative therapies is essential for the CV specialist and other practicing physicians and other practitioners, since at least a few of their patients will take these medications regardless of medical advice.  The result is that a number of these alternative medications will then interact with conventional CV medications, many times unfavorably.

In a double-blind, placebo-controlled, 2 × 2 factorial randomized trial, Lamas and colleagues (2013) examined if an EDTA-based chelation regimen reduces cardiovascular events.  A total of 1,708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less were included in this study.  Participants were recruited at 134 U.S. and Canadian sites.  Enrollment began in September 2003 and follow-up took place until October 2011 (median of 55 months).  A total of 289 patients (17 % of total; n = 115 in the EDTA group and n = 174 in the placebo group) withdrew consent during the trial.  Patients were randomized to receive 40 infusions of a 500-ml chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n = 839) versus placebo (n = 869) and an oral vitamin-mineral regimen versus an oral placebo.  Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart.  Fifteen percent discontinued infusions (n = 38 [16 %] in the chelation group and n = 41 [15 %] in the placebo group) because of adverse events.  The pre-specified primary end-point was a composite of total mortality, recurrent MI, stroke, coronary re-vascularization, or hospitalization for angina.  This report described the intention-to-treat comparison of EDTA chelation versus placebo.  To account for multiple interim analyses, the significance threshold required at the final analysis was p = 0.036.  Qualifying previous MIs occurred at a median of 4.6 years before enrollment.  Median age was 65 years, 18 % were female, 9 % were non-white, and 31 % were diabetic.  The primary end-point occurred in 222 (26 %) of the chelation group and 261 (30 %) of the placebo group (hazard ratio [HR], 0.82 [95 % confidence interval [CI]: 0.69 to 0.99]; p = 0.035).  There was no effect on total mortality (chelation: 87 deaths [10 %]; placebo, 93 deaths [11 %]; HR, 0.93 [95 % CI: 0.70 to 1.25]; p = 0.64), but the study was not powered for this comparison.  The effect of EDTA chelation on the components of the primary end-point other than death was of similar magnitude as its overall effect (MI: chelation, 6 %; placebo, 8 %; HR, 0.77 [95 % CI: 0.54 to 1.11]; stroke: chelation, 1.2 %; placebo, 1.5 %; HR, 0.77 [95 % CI: 0.34 to 1.76]; coronary revascularization: chelation, 15 %; placebo, 18 %; HR, 0.81 [95 % CI: 0.64 to 1.02]; hospitalization for angina: chelation, 1.6 %; placebo, 2.1 %; HR, 0.72 [95 % CI: 0.35 to 1.47]).  Sensitivity analyses examining the effect of patient drop-out and treatment adherence did not alter the results.  The authors concluded that among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were re-vascularization procedures.  Moreover, they stated that these results provided evidence to guide further research; but were insufficient to support the routine use of chelation therapy for treatment of patients who had an MI.

Escolar et al (2014) examined the effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior MI.  Patients received 40 infusions of EDTA chelation (n = 322) or placebo (n = 311); EDTA reduced the primary end-point (death, re-infarction, stroke, coronary re-vascularization, or hospitalization for angina; 25 % versus 38 %; hazard ratio, 0.59; 95 % CI: 0.44 to 0.79; p < 0.001) over 5 years.  The result remained significant after Bonferroni adjustment for multiple subgroups (99.4 % CI: 0.39 to 0.88; adjusted p=0.002).  All-cause mortality was reduced by EDTA chelation (10 % versus 16 %; HR, 0.57; 95 % CI: 0.36 to 0.88; p = 0.011), as was the secondary end-point (cardiovascular death, re-infarction, or stroke; 11 % versus 17 %; HR, 0.60; 95 % CI: 0.39 to 0.91; p = 0.017).  However, after adjusting for multiple subgroups, those results were no longer significant.  The number needed to treat to reduce 1 primary end-point over 5 years was 6.5 (95 % CI: 4.4 to 12.7).  There was no reduction in events in non-diabetes mellitus (n = 1,075; p = 0.877), resulting in a treatment by diabetes mellitus interaction (p = 0.004).  The authors concluded that post-MI patients with diabetes mellitus aged greater than or equal to 50 demonstrated a marked reduction in cardiovascular events with EDTA chelation.  They stated that these findings supported efforts to replicate these findings and define the mechanisms of benefit.  However, they do not constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI patients with diabetes mellitus.

An UpToDate review on "Prevention of cardiovascular disease events in those with established disease or at high risk" (Hennekens and Lopez-Sendon, 2016) stated that "The totality of evidence does not support a recommendation for chelation therapy in patients with coronary artery disease.  There is only one randomized trial of this issue, the TACT trial. TACT assigned 1,708 patients with prior MI at random to 40 infusions of a chelation solution or placebo over one to two years.  The primary composite end-point (total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) occurred less frequently in the chelation group (26 versus 30 percent; HR, 0.82, 95 % CI: 0.69 to 0.99) during a median follow-up of 4.6 years.  This observed possible benefit needs to be interpreted in the context of the potential for unmasking and the use of multiple interim analyses, as well as the high rate of drop-outs. Further randomized evidence is necessary in order to make any evidence-based recommendations".

Ibad and colleagues (2016) examined the effect of chelation therapy on cardiovascular diseases (CVDs).  These investigators searched PubMed for English language articles addressing the effect of chelation therapy on CVD events.  Articles pertinent to the topic were reviewed in detail.  They identified 128 articles addressing the therapeutic value of chelation therapy on CVD; 38 were reviewed in detail including 20 case series and 7 RCTs; 16 case series and 3 RCTs showed benefit with chelation.  The Trial to Assess Chelation Therapy included 1,708 post-myocardial infarction patients and demonstrated benefit with chelation therapy, but the Trial to Assess Chelation Therapy investigators concluded that their results did not support the routine use of chelation therapy for post-myocardial infarction patients.  The authors concluded that the effectiveness of chelation therapy in reducing recurrent CVD events is unclear, but possible, and warrants additional, carefully designed clinical trials.

Sultan and colleagues (2017) noted that the off-label use of chelation therapy (disodium edetate or EDTA) for prevention of CVD is widespread, despite the lack of convincing evidence for efficacy or approval from the FDA.  After the publication of results from the National Institute of Health (NIH)-sponsored Trial to Assess Chelation Therapy (TACT), a RCT in patients after MI, there is a renewed interest in clarifying the role of this treatment modality for patients with coronary artery disease (CAD).  These investigators highlighted the evidence from observational studies and RCT in assessing the effect of chelation therapy on cardiovascular outcomes and potential for AEs or harm.  Although encouraging results were reported in TACT, the evidence was insufficient to recommend the routine use of chelation therapy even in the post-MI diabetic subgroup, which appeared to benefit.  The ongoing TACT2 trial may clarify its use in post-MI diabetic patients.  The authors concluded that un-substantiated claims of chelation therapy as an effective treatment of atherosclerosis should be avoided and patients made aware of the inadequate evidence for efficacy and potential adverse effects, especially the harm that can occur if used as a substitute for proven therapies.

In a Cochrane review, Villarruz-Sulit and colleagues (2020) examined the effects of EDTA chelation therapy versus placebo or no treatment on clinical outcomes among individuals with atherosclerotic cardiovascular disease.  For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to August 6, 2019.  These investigator also searched the bibliographies of the studies retrieved by the literature searches for further trials.  They included studies if they were RCTs of EDTA chelation therapy versus placebo or no treatment in patients with atherosclerotic cardiovascular disease.  The main outcome measures included all-cause or cause-specific mortality, non-fatal cardiovascular events, direct or indirect measurement of disease severity, and subjective measures of improvement or AEs.  Two review authors independently extracted data and assessed trial quality using standard Cochrane procedures.  A 3rd author considered any unresolved issues, and these researchers discussed any discrepancies until a consensus was reached; they contacted study authors for additional information.  These investigators included 5 studies with a total of 1993 randomized subjects; 3 studies enrolled subjects with peripheral vascular disease and 2 studies included subjects with CAD, 1 of which specifically recruited individuals who had had a MI.  The number of subjects in each study varied widely (from 10 to 1,708), but all studies compared EDTA chelation to a placebo.  Risk of bias for the included studies was generally moderate-to-low, but 1 study had high risk of bias because the study investigators broke their randomization code halfway through the study and rolled the placebo subjects over to active treatment.  Certainty of the evidence, as assessed by GRADE, was generally low-to-very low, which was mostly due to a paucity of data in each outcome's meta-analysis.  This limited the ability to draw any strong conclusions.  These investigators also had concerns regarding 1 study's risk of bias pertaining to blinding and outcome assessment that may have biased the results; 2 studies with CAD patients reported no evidence of a difference in all-cause mortality between chelation therapy and placebo (risk ratio (RR) 0.97, 95 % CI: 0.73 to 1.28; 1,792 subjects; low-certainty).  One study with CAD patients reported no evidence of a difference in coronary heart disease deaths between chelation therapy and placebo (RR 1.02, 95 % CI: 0.70 to 1.48; 1,708 subjects; very low-certainty).  Two studies with CAD patients reported no evidence of a difference in MI (RR 0.81, 95 % CI: 0.57 to 1.14; 1,792 subjects; moderate-certainty), angina (RR 0.95, 95 % CI: 0.55 to 1.67; 1,792 subjects; very low-certainty), and coronary re-vascularization (RR 0.46, 95 % CI: 0.07 to 3.25; 1,792 subjects).  Two studies (1 with CAD patients and 1 with peripheral vascular disease [PVD] patients) reported no evidence of a difference in stroke (RR 0.88, 95 % CI: 0.40 to 1.92; 1,867 subjects; low-certainty).  Ankle-brachial pressure index (ABPI; also known as ankle brachial index) was measured in 3 studies, all including patients with PVD; 2 studies found no evidence of a difference in the treatment groups after 3 months treatment (mean difference (MD) 0.02, 95 % CI: -0.03 to 0.06; 181 subjects; low-certainty).  A 3rd study reported an improvement in ABPI in the EDTA chelation group, but this study was at high risk of bias.  Meta-analysis of maximum and pain-free walking distances 3 months after treatment included patients with PVD and showed no evidence of a difference between the treatment groups (MD -31.46, 95 % CI: -87.63 to 24.71; 165 subjects; 2 studies; low-certainty).  Quality of life (QOL) outcomes were reported by 2 studies that included patients with CAD, but these investigators were unable to pool the data due to different methods of reporting and varied criteria.  However, there did not appear to be any major differences between the treatment groups.  None of the included studies reported on vascular deaths.  Overall, there was no evidence of major or minor AEs associated with EDTA chelation treatment.  The authors concluded that there is currently insufficient evidence to determine the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of individuals with atherosclerotic cardiovascular disease.  These researchers stated that more high-quality RCTs are needed that examine the effects of chelation therapy on longevity and QOL among individuals with atherosclerotic cardiovascular disease.

Ravalli et al (2022) noted that EDTA is an IV chelating agent with high affinity to di-valent cations (cadmium, calcium, and lead) that may be beneficial in the treatment of cardio-vascular disease (CVD).  Although a large, randomized, clinical trial showed benefit, smaller studies were inconsistent.  In a systematic review, these investigators examined published studies on the effect of repeated EDTA on clinical outcomes in adults with CVD.  They searched 3 databases (Medline, Embase, and Cochrane) from database inception to October 2021 to identify all studies involving EDTA treatment in patients with CVD.  Pre-determined outcomes included mortality, disease severity, plasma biomarkers of disease chronicity, and QOL.  A total of 24 studies (4 randomized clinical trials, 15 prospective before/after studies, and 5 retrospective case-series studies) evaluated the use of repeated EDTA chelation treatment in patients with pre-existent CVD.  Of these, 17 studies (1 randomized clinical trial) found improvement in their respective outcomes following EDTA treatment.  The largest improvements were observed in studies with high prevalence of subjects with diabetes and/or severe occlusive arterial disease.  A meta-analysis conducted with 4 studies reporting ankle-brachial index (ABI) indicated an improvement of 0.08 (95 % CI: 0.06 to 0.09) from baseline.  The authors concluded that 17 studies suggested improved outcomes, 5 reported no statistically significant effect of treatment, and 2 reported no qualitative benefit.  These researchers stated that repeated EDTA for CVD treatment may provide more benefit to patients with diabetes and severe peripheral arterial disease (PAD); and differences across infusion regimens, including dosage, solution components, and number of infusions, limited comparisons across studies.  They stated that additional research is needed to confirm these findings and to examine the potential mediating role of metals.  Moreover, these researchers stated that in-vitro and epidemiologic evidence suggested that reduction of toxic metal burden may be causal for clinical benefit, a hypothesis that fits well with the emerging field of environmental cardiology.  Future clinical research on EDTA chelation on patients with diabetes and PAD must include a mechanistic component, as is being carried out with the ongoing 1,000‐patient NIH-sponsored Assess Chelation Therapy 2 (TACT2) Trial, which may help clarify if chelation therapy truly represents a significant benefit for this population subgroup, contributing to precision environmental medicine.

Cataracts

Zhang et al (2011) noted that oxidative stress plays a critical role in cataractogenesis, the leading cause of blindness worldwide.  Since transition metals generate reactive oxygen species (ROS) formation, metal chelation therapy has been proposed for treatment of cataracts.  However, the effectiveness of most chelators is limited by low tissue penetrability.  This study was the first to demonstrate that the topically applied di-valent metal chelator EDTA combined with the carrier and permeability enhancer methyl sulfonyl methane (MSM) ameliorates both oxidation-induced lens opacification and the associated toxic accumulation of protein-4-hydroxynonenal (HNE) adducts.  Both in vitro (rat lens culture) and in vivo (diabetic rats), EDTA-MSM

1. significantly reduced lens opacification by about 40 to 50 %,
2. significantly diminished lens epithelial cell proliferation and fiber cell swelling in early stages of cataract formation in vivo, and
3. notably decreased the levels of protein-HNE adducts.

The authors stated that these findings have important implications specifically for the treatment of cataract and generally for other diseases in which oxidative stress plays a key pathogenic role.

Dental Amalgam

Dental amalgam is a widely used restorative material containing 50 % elemental mercury that emits mercury vapor.  Available evidence indicates that this low-level mercury exposure in children with dental amalgam is not associated with adverse health outcomes (Bellinger et al, 2006; DeRouen et al, 2006; and Shenker et al, 2008).  Moreover, when chelation therapy is used to treat individuals who attribute their health problems to mercury from dental amalgam, there appears to be a strong placebo effect (Grandjean et al, 1997).

In a randomized study, Bellinger et al (2006) compared the neuropsychological and renal function of children whose dental caries were restored using amalgam or mercury-free materials.  A total of 534 children aged 6 to 10 years at baseline with no prior amalgam restorations and 2 or more posterior teeth with caries were randomly assigned to receive dental restoration of baseline and incident caries during a 5-year follow-up period using either amalgam (n = 267) or resin composite (n = 267) materials.  The primary neuropsychological outcome was 5-year change in full-scale IQ scores.  Secondary outcomes included tests of memory and visuomotor ability.  Renal glomerular function was measured by creatinine-adjusted albumin in urine.  Children had a mean of 15 tooth surfaces (median, 14) restored during the 5-year period (range of 0 to 55).  Assignment to the amalgam group was associated with a significantly higher mean urinary mercury level (0.9 versus 0.6 microg/g of creatinine at year 5, p < 0.001).  After adjusting for randomization stratum and other covariates, no statistically significant differences were found between children in the amalgam and composite groups in 5-year change in full-scale IQ score (3.1 versus 2.1, p = 0.21).  The difference in treatment group change scores was 1.0 (95 % confidence interval: -0.6 to 2.5) full-scale IQ score point.  No statistically significant differences were found for 4-year change in the general memory index (8.1 versus 7.2, p = 0.34), 4-year change in visuomotor composite (3.8 versus 3.7, p = 0.93), or year 5 urinary albumin (median, 7.5 versus 7.4 mg/g of creatinine, p = 0.61).  The authors concluded that there were no statistically significant differences in adverse neuropsychological or renal effects observed over the 5-year period in children whose caries were restored using dental amalgam or composite materials.  Although it is possible that very small IQ effects cannot be ruled out, these findings suggested that the health effects of amalgam restorations in children need not be the basis of treatment decisions when choosing restorative dental materials.

In a randomized clinical trial, DeRouen et al (2006) evaluated the safety of dental amalgam restorations in children.  A total of 507 children in Lisbon, Portugal, aged 8 to 10 years with at least 1 carious lesion on a permanent tooth, no previous exposure to amalgam, urinary mercury level less than 10 microg/L, blood lead level less than 15 microg/dL, Comprehensive Test of Nonverbal Intelligence IQ greater than or equal to 67, and with no interfering health conditions were included in this study.  Routine, standard-of-care dental treatment was provided, with one group receiving amalgam restorations for posterior lesions (n = 253) and the other group receiving resin composite restorations instead of amalgam (n = 254).  Main outcome measures were neurobehavioral assessments of memory, attention/concentration, and motor/visuomotor domains, as well as nerve conduction velocities.  During the 7-year trial period, children had a mean of 18.7 tooth surfaces (median, 16) restored in the amalgam group and 21.3 (median, 18) restored in the composite group.  Baseline mean creatinine-adjusted urinary mercury levels were 1.8 microg/g in the amalgam group and 1.9 microg/g in the composite group, but during follow-up were 1.0 to 1.5 microg/g higher in the amalgam group than in the composite group (p < 0.001).  There were no statistically significant differences in measures of memory, attention, visuomotor function, or nerve conduction velocities (average z scores were very similar, near zero) for the amalgam and composite groups over all 7 years of follow-up, with no statistically significant differences observed at any time point (P values from 0.29 to 0.91).  Starting at 5 years after initial treatment, the need for additional restorative treatment was approximately 50 % higher in the composite group.  The authors concluded that children who received dental restorative treatment with amalgam did not, on average, have statistically significant differences in neurobehavioral assessments or in nerve conduction velocity when compared with children who received resin composite materials without amalgam.  These findings, combined with the trend of higher treatment need later among those receiving composite, suggested that amalgam should remain a viable dental restorative option for children.

Shenker et al (2008) evaluated a subpopulation of the participants in the New England Children's Amalgam Trial for in-vitro manifestations of immunotoxic effects of dental amalgam.  These investigators conducted a randomized clinical trial in which children requiring dental restorative treatment were randomly assigned to receive either amalgam for posterior restorations or resin-based composite restorations.  They assessed 66 children, aged 6 to 10 years, for total white blood cell counts, specific lymphocyte (T-cell and B-cell) counts and lymphocyte, neutrophil and monocyte responsiveness across a 5-year period.  Because of the small number of participants, the authors acknowledged that the study is exploratory in nature and has limited statistical power.  The mean number of tooth surfaces restored during the 5-year period was 7.8 for the amalgam group and 10.1 for the composite group.  In the amalgam group, there was a slight, but statistically insignificant, decline in responsiveness of T cells and monocytes at 5 to 7 days after treatment; these researchers consistently observed no differences at 6, 12 or 60 months.  The authors concluded that these findings confirmed that treatment of children with amalgam restorations leads to increased, albeit low-level, exposure to mercury.  In this exploratory analysis of immune function, amalgam exposure did not cause overt immune deficits, although small transient effects were observed 5 to 7 days after restoration placement.  They stated that these findings suggested that immunotoxic effects of amalgam restorations are minimal and transient in children and most likely do not need to be of concern to practitioners considering the use of this restorative dental material.

Furthermore, an UpToDate review on "Epidemiology and toxicity of mercury" (Elinder, 2012) states that "The release of mercury from amalgam fillings is proportional to the number of fillings and the total amalgam surface area.  It has been difficult to accurately estimate the release from amalgam fillings; however, an expert committee from the World Health Organization believes that the average exposure from dental amalgam is approximately 10 mcg/day.  Measurements of urinary excretion of mercury have revealed that persons with a habit of tooth grinding release considerably more mercury from their dental fillings than those without this habit.  Health studies have focused on identifying the early effects of mercury on the central nervous system.  Overall, there is no evidence suggesting a link between exposure to mercury from amalgam fillings and degenerative changes of the nervous system.  There is also little evidence to support the removal of existing fillings …. Treatment with chelators may be considered in patients 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)".

Grandjean et al (1997) stated that treatment of patients who attribute their environmental illness to mercury from amalgam fillings is largely experimental.  On the Symptom Check List, overall distress, and somatization, obsessive-compulsive, depression, and anxiety symptom dimensions, were increased in 50 consecutive patients examined, and Eysenck Personality Questionnaire scores suggested less extroversion and increased degree of emotional liability.  Succimer (meso-2, 3-dimercaptosuccinic acid) was given at a daily dose of 30 mg/kg for 5 days in a double-blind, randomized placebo-controlled trial.  Urinary excretion of mercury and lead was considerably increased in the patients who received the chelator.  Immediately after the treatment and 5 to 6 weeks later, most distress dimensions had improved considerably, but there was no difference between the succimer and placebo groups.  The authors concluded that these findings suggested that some patients with environmental illness may substantially benefit from placebo.

Diamond-Blackfan Anemia

Vlachos and Muir (2010) stated that Diamond-Blackfan anemia (DBA) is characterized by red cell failure, the presence of congenital anomalies, and cancer predisposition.  In addition to being an inherited bone marrow failure syndrome, DBA is also categorized as a ribosomopathy as, in more than 50 % of cases, the syndrome appears to result from haplo-insufficiency of either a small or large subunit-associated ribosomal protein.  Nonetheless, the exact mechanism by which haplo-insufficiency results in erythroid failure, as well as the other clinical manifestations, remains uncertain.  New knowledge regarding genetic and molecular mechanisms combined with robust clinical data from several international patient registries has provided important insights into the diagnosis of DBA and may, in the future, provide new treatments as well.  Diagnostic criteria have been expanded to include patients with little or no clinical findings.  Patient management is therefore centered on accurate diagnosis, appropriate use of transfusions and iron chelation, corticosteroids, hematopoietic stem cell transplantation, and a coordinated multi-disciplinary approach to these complex patients.

An UpToDate review on "Anemia in children due to decreased red blood cell production" (Sandoval, 2013) states that "The mainstays of therapy of DBA are corticosteroids and blood transfusion.  However, spontaneous remissions have been reported in as many as 25 percent of patients.  Overall, approximately 40 percent of individuals with DBA are steroid-dependent, 40 percent are transfusion-dependent, and 20 percent go into remission by age 25 years.  In most cases the remission is stable …. Transfusion therapy is the mainstay of treatment for patients in whom steroid therapy is ineffective or in whom corticosteroid toxicity is prohibitive.  To avoid red cell sensitization and transfusion reactions, complete red cell typing should be performed, and blood should be leuko-depleted.  Patients are transfused to maintain Hgb levels compatible with normal activity (Hgb ≥ 8 g/dL), usually every four to six weeks.  Immediate family members should not be used as blood donors, to avoid allosensitization which might jeopardize future hematopoietic cell transplantation.  The major complication of transfusion therapy is hemosiderosis, which may result in significant morbidity and mortality.  Iron chelation therapy should, therefore, be instituted in patients with evidence of significantly increased iron stores".

Also, the CDC’s DBA Fact Sheet states that "In Diamond Blackfan anemia (DBA) the bone marrow (the center of the bones where blood cells are made) does not make enough red blood cells.  One of the treatments for DBA is blood transfusion therapy.  Blood transfusions temporarily increase the number of red blood cells.  Some people need blood transfusions only now and then, such as when they are sick.  Other people need regular blood transfusions over a long period of time.  This is called chronic transfusion therapy.  One of the risks of chronic transfusion therapy is getting too much iron in the body.  Blood contains a lot of iron.  Because the body has no natural way to get rid of iron, the iron in transfused blood builds up in the body, a condition called iron overload.  Eventually, after dozens of transfusions, the iron will build up to toxic levels and can damage different organs in the body.  The iron cannot be removed from the blood before transfusion, as it is a critical component of hemoglobin, a protein in red blood cells that carries oxygen.  Fortunately, iron overload and organ damage can be prevented with chelation therapy …. There are currently 2 chelation drugs available in the United States:

1. deferoxamine (Desferal), and
2. deferasirox (Exjade)".

Iron Chelation Cancer Therapy

Komot and colleagues (2020) noted that cancer cells have high iron requirements due to their rapid growth and proliferation.  Iron depletion using iron chelators has a potential in cancer treatment.  Previous studies have demonstrated that DFO specifically chelates Fe(III) and exhibited anti-tumor activity in clinical studies.  However, its poor pharmacokinetics has limited the therapeutic potential and practical application.  Although polymeric iron chelators have been developed to increase the blood retention, none of previous studies has demonstrated their potential in iron chelation cancer therapy.  These researchers developed polymeric DFO by the covalent conjugation of DFO to poly(ethylene glycol)-poly(aspartic acid) (PEG-PAsp) block copolymers.  The polymeric DFO exhibited iron-chelating ability comparable to free DFO, thereby arresting cell cycle and inducing apoptosis and antiproliferative activity.  After intravenous (IV) administration, the polymeric DFO showed marked increase in blood retention and tumor accumulation in subcutaneous tumor models.  Consequently, polymeric DFO showed significant suppression of the tumor growth compared with free DFO.  The authors concluded that the findings of this study revealed the first success of the design of polymeric DFO for enhancing iron chelation cancer therapy. 

Iron Chelation for the Prevention of Diabetes-Associated Cardiovascular Events

Diaz and colleagues (2018) noted that for over 60 years, chelation therapy with EDTA had been used for the treatment of CVD despite lack of scientific evidence for its safety and efficacy.  The TACT was developed and received funding from the NIH to ascertain the safety and efficacy of chelation therapy in patients with CVD.  This pivotal trial demonstrated an improvement in outcomes in post-MI patients; it also showed a particularly large reduction in CVD events and all-cause mortality in the pre-specified subgroup of patients with diabetes.  The TACT results may support the concept of metal chelation to reduce metal-catalyzed oxidation reactions that promote the formation of advanced glycation end products, a precursor of diabetic atherosclerosis.  The authors summarized the epidemiological and basic evidence linking toxic metal accumulation and diabetes-related CVD, supported by the salutary effects of chelation in TACT.  These researchers stated that if the ongoing NIH-funded TACT2, in diabetic post-MI patients, proves positive, this unique therapy will enter the armamentarium of endocrinologists and cardiologists seeking to reduce the atherosclerotic risk of their diabetic patients.

Iron Chelation for the Treatment of Neurodegenerative Diseases

Wang and colleagues (2017) stated that iron accumulation in substantia nigra pars compacta (SNpc) has been proved to be a prominent pathophysiological feature of Parkinson's diseases (PD), which can induce the death of dopaminergic (DA) neurons, up-regulation of reactive oxygen species (ROS), and further loss of motor control.  In recent years, iron chelation therapy has been demonstrated to be an effective treatment for PD, which has shown significant improvements in clinical trials. However, the current iron chelators are suboptimal due to their short circulation time, side effects, and lack of proper protection from chelation with ions in blood circulation. These researchers designed and constructed iron chelation therapeutic nanoparticles protected by a zwitterionic poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC) to delay the saturation of iron chelators in blood circulation and prolong the in-vivo lifetime, with HIV-1 trans-activating transcriptor (TAT) served as a shuttle to enhance the blood-brain barrier (BBB) permeability. These investigators examined if Parkinsonian neurodegeneration and the corresponding symptoms in behaviors and physiologies could be prevented or reversed both in-vitro and in-vivo. The results demonstrated that iron chelator loaded therapeutic nanoparticles could reverse functional deficits in Parkinsonian mice not only physiologically but also behaviorally. On the contrary, both untreated PD mice and non-TAT anchored nanoparticle treated PD mice showed similar loss in DA neurons and difficulties in behaviors.  The authors concluded that with protection of zwitterionic polymer and prolonged in-vivo lifetime, iron chelator loaded nanoparticles with delayed saturation provided a PD phenotype reversion therapy and significantly improved the living quality of the Parkinsonian mice.

Dusek and co-workers (2016) noted that disturbance of cerebral iron regulation is almost universal in neurodegenerative disorders.  There is a growing body of evidence that increased iron deposits may contribute to degenerative changes.  Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as PD, Alzheimer's disease, and multiple sclerosis.  These investigators  summarized recent advances in understanding the role of iron in the etiology of neurodegeneration.  Iron chelators, particularly the BBB-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI.  Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or PD.

Nunez and Chana-Cuevas (2018) stated that iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload.  At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the BBB.  Given the promising but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results.  Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction.  In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micro-molar range, but not high enough to disrupt physiological iron homeostasis.  Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment.  O the basis of a number of clinical trials, these researchers discussed the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component.  The list includes AD, PD, Friedreich's ataxia, Huntington disease, and pantothenate kinase-associated neurodegeneration.  Furthermore, these investigators reviewed the up-surge of new multi-functional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.  The authors concluded that given the neurodegenerative process is multi-factorial, the use of multi-functional iron chelators is a promising developmental avenue.  They stated that additional properties of future iron chelator drugs should comprise high selectivity for iron, free radical quenching capacity, mitochondrial distribution and the capacity to block protein aggregation.  Several of the compounds now in experimental stages have one or more of these additional characteristics.

Iron Chelation for the Treatment of Sickle Cell Ulcers

Rodrigues and colleagues (2018)noted that Sickle cell ulcers (SCUs) are a devastating co-morbidity affecting patients with sickle cell disease (SCD); SCUs form over the medial or lateral malleoli of the lower extremity, are slow to heal, and prone to recidivism.  Some SCUs may never heal, leading to chronic pain and foot deformities.  There is no specific and effective therapy for SCUs.  Systemic deferoxamine (DFO) has been demonstrated to prevent some of the sequelae of SCD by chelating iron.  These researchers tested the ability of DFO delivered via a transdermal delivery system (DFO-TDDS) to accelerate healing in a murine model of SCU.  Excisional wounds were created in a transgenic murine model of SCD expressing greater than 99 % human sickle hemoglobin, and healing rates were compared with wounds in wild-type mice.  Next, excisional wounds in SCD mice were treated with DFO-TDDS, DFO injection, or left untreated.  Wound closure rates, histology, and iron in the healed wounds were analyzed.  Wounds in SCD mice healed significantly slower than wild-type mice (***p < 0.001).  DFO-TDDS-treated wounds demonstrated significantly accelerated time to closure, reduced size, and improved wound remodeling compared with untreated wounds (***p < 0.001) and DFO injection treatment (*p < 0.05).  DFO released from the TDDS into wounds resulted in chelation of excessive dermal-free iron.  DFO-TDDS was a novel therapeutic that was effective in healing wounds in sickle cell mice.  The authors concluded that DFO-TDDS significantly accelerated healing of murine SCUs by chelation of excessive free iron and is currently manufactured in an FDA-compliant facility to be translated for treating human SCUs.

Myelodysplastic Syndromes

A consensus statement on iron overload in myelodysplastic syndromes (MDS) from the MDS Foundation's Working Group on Transfusional Iron Overload (Bennett, 2008) stated that MDS patients most likely to benefit from managing iron overload include:

• Transfusion-dependent patients; requiring 2 units/month greater than 1 year
• Patients with ferritin levels greater than 1,000 ng/ml
• Patients with low-risk MDS
• PSS low or intermediate-I
  
  
  • WHO RA, RARS, and 5q-
  • Patients with life expectancy of at least one year
    
    
• Patient without co-morbidities that would limit prognosis
• Candidate for allograft
• Patient in whom there is a need to preserve organ function.

Rose and colleagues (2010) stated that iron chelation therapy improves survival in thalassemia major but its beneficial effects on survival in patients with myelodysplastic syndrome (MDS) remain uncertain.  These researchers analyzed, by multi-variate analysis, survival and causes of deaths in 97 low or intermediate 1 International Prognostic Scoring System (IPSS) patients regularly transfused as outpatients, chelated or not, who were included during a month period and followed for 2.5 years.  A total of 44 (45 %) of patients were not chelated and 53 (55 %) received chelation therapy, mainly with deferoxamine, for at least 6 months (median duration of chelation of 36 months, range of 6 to 131+ months).  During the follow-up period, 66 of the 97 patients died, including 51 % and 73 % of chelated and non-chelated patients, respectively.  Median overall survival was 53 months and 124 months in non-chelated and in chelated patients, respectively (p < 0.0003).  Causes of death did not significantly differ between the 2 groups (p = 0.51).  In multi-variate Cox analysis, adequate chelation was the strongest independent factor associated with better overall survival.  The authors concluded that iron chelation therapy appears to improve survival in heavily transfused lower risk MDS.  Moreover, they stated that prospective randomized studies are needed to confirm these findings, and to determine more precisely the mechanisms of this potential survival benefit.

Garcia-Manero et al (2011) noted that myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML).  Myelodysplastic syndromes occurs more frequently in older male and in individuals with prior exposure to cytotoxic therapy.  Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy.  Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic.  Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and more recently cytogenetic profile.  Goals of therapy are different in lower risk patients than in higher risk.  In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML.  In higher risk, the goal is to prolong survival.  Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation.  The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration.  5-azacitidine and decitabine have activity in higher risk MDS.  5-azacitidine has been shown to improve survival in higher risk MDS.  Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation.  At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy.  Options include cytarabine-based therapy, transplantation, and participation on a clinical trial.

In the National Comprehensive Cancer Network's clinical practice guidelines on MDS, Greenberg et al (2011) stated that 4 drugs have recently been approved by the FDA for treating specific subtypes of myelodysplastic syndromes (MDS):

1. lenalidomide for MDS patients with del(5q) cytogenetic abnormalities;
2. azacytidine and
3. decitabine for treating patients with higher-risk or non-responsive MDS; and
4. deferasirox for iron chelation of iron overloaded patients with MDS.

Delforge and colleagues (2014) noted that most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicated that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as IPSS Low or Intermediate-1 (Low/Int-1).  In a follow-up of a retrospective study, outcomes of 127 Low/Int-1 MDS patients from 28 centers in Belgium were analyzed.  Statistical analysis stratified by duration (greater than or equal to 6 months versus less than 6 months) and quality of chelation (adequate versus weak).  Crude chelation rate was 63 %, but 88 % among patients with serum ferritin greater than or equal to 1,000 μg/L.  Of the 80 chelated patients, 70 % were chelated adequately mainly with deferasirox (26 %) or deferasirox following deferoxamine (39 %).  Mortality was 70 % among non-chelated, 40 % among chelated, 32 % among patients chelated greater than or equal to 6 months, and 30 % among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients.  Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p < 0.001).  For patients chelated greater than or equal to 6 months or patients classified as adequately chelated, median OS was 10.5 years.  Mortality increased as a function of average monthly transfusion intensity (HR = 1.08, p = 0.04), but was lower in patients receiving adequate chelation or chelation greater than or equal to 6 months (HR = 0.24, p < 0.001).  The authors concluded that 6 or more months of adequate ICT is associated with markedly better overall survival.

Angelucci and associates (2014) stated that in the absence of RCT data to support ICT in transfusion-dependent patients with MDS, continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted.  The safety and efficacy of deferasirox was examined in a prospective, open-label, single-arm, multi-center trial of transfusion-dependent patients with IPSS Low- or Intermediate-1-risk MDS and evidence of transfusion-related iron overload.  The effects of deferasirox therapy on hematological response and disease progression were also examined.  Of 159 participants enrolled from 37 Italian centers, 152 received greater than or equal to 1 dose of deferasirox (initiated at 10 to 20 mg/kg/day and titrated as appropriate), and 68 completed the study.  Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event (AE).  Fourteen treatment-related grade 3 AEs occurred in 11 patients, whereas no grade 4 or 5 drug-related AEs were reported.  Significant risks for drop-out were a higher serum ferritin level at baseline, a higher MDS-Specific Comorbidity Index, and a shorter diagnosis-enrollment interval.  Median serum ferritin level fell from 1,966 ng/ml to 1,475 ng/mL (p < 0.0001).  The cumulative incidence of transfusion independence, adjusted for death and disease progression, was 2.6 %, 12.3 %, and 15.5 % after 6, 9, and 12 months, respectively.  The authors concluded that deferasirox therapy in transfusion-dependent patients with MDS was moderately well-tolerated and effectively lowered serum ferritin levels.  Positive hematological responses were observed, and a subset of patients achieved transfusion independence.

Remacha et al (2015) evaluated the evolution of iron overload, assessed by serum ferritin (SF), in transfusion-dependent lower risk patients with MDS, as well as described the occurrence of organ complications, and analyzed its relationship with ICT.  This observational retrospective study was conducted from March 2010 to March 2011 in 47 Spanish hospitals.  A total of 263 patients with lower risk MDS (IPSS Low/Intermediate-1 risk or Spanish Prognostic Index [SPI] 0-1 risk), transfusion-dependent, and who had received greater than or equal to 10 packed red blood cells (PRBC) were included.  At MDS diagnosis, patients received a mean of 2.8 ± 3.9 PRBC/month, and 8.7 % of patients showed SF greater than or equal to 1,000 μg/L.  Over the course of the disease, patients received a mean of 83.4 ± 83.3 PRBC, and 36.1 % of patients presented SF greater than or equal to 2,500 μg/L.  Cardiac, hepatic, endocrine, or arthropathy complications appeared/worsened in 20.2, 11.4, 9.9, and 3.8 % of patients, respectively.  According to investigator, iron overload was a main cause of hepatic (70.0 %) and endocrine (26.9 %) complications.  A total of 96 (36.5 %) patients received iron chelation therapy for greater than or equal to 6 months; deferasirox being the most frequent first chelation treatment (71.9 %).  Chelation-treated patients showed longer overall survival (p < 0.001), leukemia-free survival (p = 0.007), and cardiac event-free survival (p = 0.017) than non-chelated patients.  In multi-variable analyses, age (p = 0.011), IPSS (p < 0.001), and chelation treatment (p = 0.015) were predictors for overall survival; IPSS (p = 0.014) and transfusion frequency (p = 0.001) for leukemia-free survival; and chelation treatment (p = 0.040) and Sorror comorbidity index (p = 0.039) for cardiac event-free survival.  The authors concluded that these results confirmed the potential survival benefit of ICT and provided additional evidence on the deleterious effect of iron overload in lower risk MDS patients.

The National Comprehensive Cancer Network’s clinical practice guideline on "Myelodysplastic syndromes." (Version 1.2015) recommends "consideration of once-daily deferoxamine SC or deferasirox/ICL670 orally to decrease iron overload (aiming for a target ferritin level less than 1,000 ng/ml) in the following IPSS Low- or Intermediate-1-risk patients:

1. patients who have received  or are anticipated to receive greater than 20 RBC transfusions;
2. patients for whom ongoing RBC transfusions are anticipated; and
3. patients with serum ferritin greater than 2,500 ng/ml".

Liu and colleagues (2020) noted that iron overload remains a concern in MDS patients especially those requiring recurrent blood transfusions.  Whether iron chelating therapy (ICT) is beneficial to the long-term survival of MDS is still a controversial issue; thus, these researchers carried out a systematic review and meta-analysis to clarify the relationship between ICT and long-term survival in patients with MDS.  A total of 14 studies involving 7,242 participants were identified; the outcomes revealed that for patients with MDS, ICT resulted in a lower risk of mortality compared to those with no ICT (HR 0.57; 95 % CI: 0.44 to 0.70; p < 0.001); what was more, ICT led to a lower risk of leukemia transformation (HR 0.70; 95 % CI: 0.52 to 0.93; p = 0.016).  Results of subgroup analyses based on adequate ICT or any ICT, low/int-1 IPSS or unclassified IPSS and study types indicated that the ICT had a beneficial role in all these groups of patients.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Myelodysplastic syndromes” (Version 3.2021) states that “The NCCN Guidelines panel recommends consideration of once-daily deferoxamine SC or deferasirox/ICL670 orally to decrease iron overload (aiming for a target ferritin level less than 1,000 ng/ml) in the following IPSS low or int-1-risk patients: 1) patients who have received or are anticipated to receive greater than 20 RBC transfusions; 2) patients for whom ongoing RBC transfusions are anticipated; and 3) patients with serum ferritin levels greater than 2,500 ng/ml”.

Optic Nerve Injury

Trakhtenberg and associates (2018) stated that the inability of axons to regenerate over long-distances in the central nervous system (CNS) limits the recovery of sensory, motor, and cognitive functions after various CNS injuries and diseases.  Although pre-clinical studies have identified a number of manipulations that stimulate some degree of axon growth after CNS damage, the extent of recovery remains quite limited, emphasizing the need for improved therapies.  These researchers used traumatic injury to the mouse optic nerve as a model system to examine the effects of combining several treatments that have recently been found to promote axon regeneration without the risks associated with manipulating known tumor suppressors or oncogenes.  The treatments tested included TPEN, a chelator of mobile (free) zinc (Zn2+); shRNA against the axon growth-suppressing transcription factor Klf9; and the atypical growth factor oncomodulin combined with a cAMP analog.  Whereas some combinatorial treatments produced only marginally stronger effects than the individual treatments alone, co-treatment with TPEN and Klf9 knockdown had a substantially stronger effect on axon regeneration than either one alone.  This combination also promoted a high level of cell survival at longer time-points. The authors concluded that Zn2+ chelation in combination with Klf9 suppression holds therapeutic potential for promoting axon regeneration after optic nerve injury, and may also be effective for treating other CNS injuries and diseases.

Renal Failure

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

1. maximal chelation of Al,
2. limited exposure to circulating Al noxamine levels, and
3. adequate removal of the latter compound.

Uveitis

Chen and co-workers (2017) noted that inflammatory eye diseases such as uveitis are common and may eventually result in vision loss.  Iron can play a critical role in ocular inflammation via promoting the generation of oxygen free radicals and it is also nutritionally essential for microbial growth.  Considering this involvement of iron in inflammation and microbial infection, these researchers hypothesized that administration of iron chelators has potential to function as a novel therapy in uveitis and help improve clinical outcomes.

Zygomycosis

In a review on current and future treatments of zygomycosis, Rogers (2008) noted that zygomycosis is a frequently lethal invasive infection in high-risk patients such as the immunocompromised (especially hematopoietic stem cell transplant (HSCT) recipients) and patients with type 2 diabetes mellitus.  However, zygomycosis has also been reported in individuals without known risk factors.  Zygomycosis can present clinically as rhinocerebral, pulmonary or disseminated disease which progresses rapidly.  The management of cases is based on early diagnosis, surgical debridement when possible and aggressive anti-fungal therapy.  Based on clinical experience, but without the benefit of comparative studies, liposomal amphotericin B has become the therapeutic agent of choice.  Posaconazole is a new orally administered triazole anti-fungal and the first member of this class to have comparable in vitro activity to amphotericin B against most zygomycetes.  Studies of salvage therapy of zygomycosis with posaconazole have yielded promising results and there are additional case reports of successful outcomes using these and other anti-fungal drugs as combination therapy.  Moreover, adjunctive approaches that are showing promise but with limited clinical experience are iron chelation and immunotherapy.

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References