- Control of ventricular arrhythmias or heart block associated with digitalis toxicity;
- Emergency treatment of hypercalcemia;
- Extreme conditions of metal toxicity;
- Chronic iron overload due to blood transfusions (transfusional hemosiderosis);
- Wilson's disease (hepatolenticular degeneration); and
- Lead poisoning.
NOTE: Prior to the administration of any chelating agent, diagnosis of metal toxicity MUST be established through appropriate diagnostic testing, such as serum and/or 24-hr urinalysis.
The administration of any chelating agents prior to diagnosis of metal toxicity is considered not medically necessary, and therefore will not be covered.
Other applications of chelation therapy are considered experimental, investigational and unproven including, but not limited to:
- Atherosclerosis (i.e., coronary artery disease or peripheral vascular disease);
- Multiple sclerosis;
- Arthritis (includes rheumatoid arthritis);
- Alzheimer’s disease;
Chelation therapy is an established treatment for the medically necessary indications listed here, particularly for the treatment of metal toxicity and transfusional hemosiderosis. Thus, literature searches have focused on the use of chelation therapy for other conditions including, but not limited to, atherosclerosis, autism, Alzheimer’s disease, multiple sclerosis and diabetes.
In 2002, a Cochrane review was published evaluating studies on ethylenediaminetetraacetic acid (EDTA) chelation therapy for treating patients with atherosclerotic cardiovascular disease. Five placebo-controlled randomized-controlled trials (RCTs) were identified, none of which reported mortality, non-fatal events and cerebrovascular vascular events. Four of the five studies (total n=250) found no significant benefits of EDTA chelation therapy on outcomes reported including direct or indirect measurement of disease severity and subjective measures of improvement. The fifth study, which included only 10 patients, was apparently stopped early due to benefit, but relevant outcome data were not available. The Cochrane reviewers concluded that there was insufficient evidence to draw conclusions of the efficacy of chelation therapy for treating atherosclerosis. Additional RCTs reported on health outcomes that included mortality and cerebrovascular events.
Among the published random controlled trials (RCTs), Knudtson and colleagues randomized 84 patients with coronary artery disease and a positive treadmill test to receive EDTA chelation therapy or placebo, three hours per treatment twice weekly for 15 weeks, and once per month for an additional three months. The main outcome measures included change in time to ischemia, functional reserve for exercise, and quality of life. There was no significant difference between the two groups. Another double-blind, randomized controlled study of EDTA chelation or placebo showed no change in short- or long-term improvement in vasomotor response to EDTA when compared to placebo. Two small randomized trials have also reported no benefit of chelation therapy as a treatment of peripheral arterial disease.
Several RCTs have been published on chelation therapy for treating atherosclerosis; these have generally reported intermediate outcomes and have not found EDTA chelation therapy to be more effective than to placebo. Additional RCTs that report health outcomes are needed to establish the efficacy of this treatment.
Based on similarities between mercury poisoning and autism spectrum disorder symptoms, Bernard and colleagues hypothesized a link between environmental mercury and autism. This theory was rejected by Nelson and Bauman, who found that many of the characteristics of mercury poisoning such as ataxia, constricted visual fields, peripheral neuropathy, hypertension, skin eruption, and thrombocytopenia, are never seen in autistic children. In 2007, a systematic review by Ng and colleagues concluded that there was no association between mercury poisoning and autism.
In 2009, Rossignol published a systematic review of novel and emerging treatments for autism and did not identify any studies that included a control group. The author stated the case series suggest that chelation might be a viable form of treatment in some autistic individuals with known elevated heavy metal levels and that this possibility needs to be further investigated in controlled studies.
There is a lack of controlled studies on the effect of chelation therapy on health outcomes in patients with autism.
A 2008 Cochrane Review evaluated metal protein attenuating compounds (MPAC) for treating Alzheimer’s disease. The review identified one placebo-controlled RCT. This study, by Richie and colleagues, was published in 2003. Patients were treated with PBT1, a MPAC also known as clioquinol, an anti-fungal medication that crosses the blood-brain barrier. Clioquinol was withdrawn for oral use in 1970 because of its association with subacute myelo-optic neuropathy. In the study, oral clioquinol was administered in doses increasing to 375 mg twice daily to 16 Alzheimer’s disease patients and the effects were compared to 16 matched controls who received placebo. At 36 weeks, there was no statistically significant between-group difference in cognition measured by the Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog scale). One patient in the treatment group developed impaired visual acuity and color vision during weeks 31 to 36 while she was receiving clioquinol, 375 mg twice daily. Her symptoms resolved on treatment cessation.
Further studies of PBT1 have been abandoned in favor of a successor compound, PBT2. Lannfelt and colleagues completed a double-blind, placebo-controlled RCT in which 78 Alzheimer’s disease patients were treated for 12 weeks with 50 mg PBT2 (n=20), 250 mg PBT2 (n=29), or placebo (n=29). There was no statistically significant difference in ADAS-Cog scale or Mini-Mental Status Exam scores among groups in this short-term study. The most common adverse event was headache. Two serious adverse events (urosepsis and transient ischemic event) were reported, both by patients receiving placebo.
Ongoing investigations in chelation therapy for the treatment of Alzheimer’s disease and other neurodegenerative diseases include linking a carbohydrate moiety to drug molecules to enhance drug delivery across the blood-brain barrier; this strategy may solve the potential problem of premature and indiscriminate metal binding. In addition, multi-function drugs that not only bind metal but also have significant antioxidant capacity are in development.
There is insufficient evidence on the safety and efficacy of chelation therapy for treating patients with Alzheimer’s disease. The few published RCTs did not find that the treatment was superior to placebo for improving health outcomes.
Left ventricular hypertrophy in patients with diabetes
One RCT was identified; it was published in 2009 by Cooper and colleagues in New Zealand and evaluated the effect of copper chelation using oral trientine hydrochloride on left-ventricular hypertrophy in 30 patients with type 2 diabetes. A total of 21/30 (70%) of the participants completed the 12-month follow-up. At 12 months, there was a significantly greater change in left ventricular mass (LVM) indexed to body surface area in the group receiving active treatment compared to placebo (-10.6 g/m2 vs. -0.1 g/m2, p=0.01). The study was limited by the small sample size and high drop-out rate.
One small RCT with limitations represents insufficient evidence that chelation therapy is effective for treating cardiovascular disease in patients with diabetes. Additional RCTs with larger numbers of patients and those that report health outcomes such as cardiovascular events and mortality are needed.
Other potential indications
No RCTs or other controlled studies were identified that evaluated the safety and efficacy of chelation therapy for other conditions such as multiple sclerosis or arthritis.
Practice Guidelines and Position Statements
A 2004 clinical practice guideline from the American College of Physicians stated that chelation therapy “should not be used to prevent myocardial infarction or death or to reduce symptoms in patients with symptomatic chronic stable angina.” (Level of evidence B: Based on evidence from a limited number of randomized trials with small numbers of patients, careful analyses of nonrandomized studies, or observational registries.)
In 2005, the American College of Cardiology stated that chelation “is not indicated for treatment of intermittent claudication and may have harmful adverse effects.” (Level of Evidence A: Data derived from multiple randomized clinical trials or meta-analyses.)
Chelation therapy is an established treatment for the medically necessary indications listed in the policy statement, such as treatment of metal toxicity and transfusional hemosiderosis. There is insufficient evidence that chelation therapy improves health outcomes for patients with other conditions including, but not limited to, atherosclerosis, autism, Alzheimer’s disease, diabetes and arthritis. Thus, chelation therapy for these other applications is experimental, investigational and unproven.