The human body contains small quantities of certain heavy metals, such as iron and copper, that (in the proper concentration) are essential for normal bodily function and are considered to be micronutrients. The body also contains nonessential heavy metals, such as lead and aluminum, that are not used for biological processes. When any of these types of heavy metals build up in the body, whether through a metabolic dysfunction or from ingestion, they can reach toxic levels, which can lead to serious, and even fatal, health effects. Intravenous (IV) chelation therapy (also known as chemical endarterectomy) is a method of removing these toxic substances (e.g., lead, zinc, iron, copper, calcium) from the body.
IV chelation agents reduce the accumulation of heavy metals by binding with the metal ions. This binding effect enhances urinary and fecal excretion, through which the toxic metals are removed, which in turn reverses the toxic effects. Specific chelating agents are used for the treatment of certain heavy metal toxicities. For example, desferroxamine is used for patients with iron toxicity and calcium-ethylenediaminetetraacetic acid (calcium-EDTA) is used in the treatment of lead poisoning. IV chelation therapy is also used to reverse the effects of digoxin toxicity in individuals with ventricular irregularity and heart block, and it is used as a pharmacologic treatment in the long-term management of certain inherited diseases (e.g., Wilson's disease, which is a disorder of copper overload with a pathological impact on the liver).
Individuals experiencing toxicity may require IV chelation therapy two to six times a day, for two to five days, depending on the level of toxicity, the agent used, and the condition of the individual. The definitive methodology for the detection of heavy metal toxicity in blood and urine is atomic absorption spectrometry.
A class of chelating agents, metal protein-attenuating compounds (MPACs), has been investigated for the treatment of Alzheimer’s disease. MPACs have been evaluated as treatment options for Alzheimer’s disease due to the association of the disease with the disequilibrium of cerebral metals and the agent’s subtle effects on metal homeostasis and abnormal interactions (e.g., the promotion of solubilization and clearance of Aß-amyloid protein etc). No MPACs have received U.S. Food and Drug Administration (FDA) approval for the treatment of Alzheimer’s disease.
The Cochrane Collaboration published results from a systematic review intended to evaluate the efficacy of MPACs for the treatment of cognitive impairment due to Alzheimer’s disease (2008). The authors identified a single randomized trial of MPACs in Alzheimer's disease. The included trial compared the clioquinol (PBT1) with placebo in n=36 patients; however, the results showed no statistically significant difference in cognition between active treatment and placebo groups at 36 weeks. The authors of the systematic review therefore concluded that there is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with Alzheimer’s disease, or whether the drug is safe.
The Cochrane Collaboration published the results from a systematic review intended to assess the effects of ethylene diamine tetraacetic acid (EDTA) chelation therapy on clinical outcomes among individuals with atherosclerotic cardiovascular disease (2002). The authors identified five randomized placebo-controlled trials that fulfilled their inclusion/exclusion criteria. Four of the 5 identified trials, with a combined study population of n=250 individuals, found no significant difference in outcomes related to direct or indirect measurements of disease severity and subjective measures of disease improvement. The remaining study was reported as being stopped early due to an apparent positive treatment effect; however, relevant data were not presented. None of the identified trials reported data regarding mortality, non-fatal events, and cerebrovascular vascular events. Based on the results from the systematic review, the authors concluded that there was insufficient evidence to draw conclusions for the efficacy of chelation therapy for treating atherosclerosis.
An additional systematic review, similarly intended to evaluate the best available evidence for the use of EDTA chelation therapy in the treatment of cardiovascular disease, was conducted by Seely et al. in 2005. The Seely et al. workgroup identified two additional trials that were not included in the aforementioned Cochrane review, but concurrently concluded that the best available evidence does not support the therapeutic use of EDTA chelation therapy in the treatment of cardiovascular disease.
Similarities between mercury poisoning and autism spectrum disorders (ASD) have previously prompted the development of a hypothesized link between environmental mercury and autism. In a subsequent meta-analysis Ng et al. (2007) reviewed the available data on the nature, pathophysiology, pharmacokinetics, diagnostic methods, treatment, and the linkage to neurodevelopmental disabilities of mercury exposure in children. Based on the available data and a subsequent meta-analysis, the Ng et al. workgroup concluded that there was no evidence to support the association between mercury poisoning and autism.
An additional systematic review, published by Rossignol in 2009, reviewed the currently novel and emerging treatments for autism spectrum disorders (ASD), including chelation therapy. Literature searches, conducted by the reviewer, identified multiple publications, although the available data presented with methodological flaws, most notably the unanimous lack of control groups. The authors ultimately concluded that the available data suggest that chelation might be a viable form of treatment in some individuals with an ASD who have elevated heavy metal burden, while dually acknowledging the limitations of the available data (e.g., lack of comparisons or controls, heterogeneous study populations, etc) and the need for further evaluation in controlled studies.
Clinical practice guidelines published in 2012 and 2013 by the National Institute for Health and Clinical Excellence (NICE) addressing autism in adults and children do not recommend the use of chelation therapy for the management of core symptoms of autism in adults and children.
In 2009, Cooper and colleagues in New Zealand reported the results of a 12 month randomized, placebo-controlled study evaluating the effects of copper chelation using oral trientine on left ventricular hypertrophy (LVH) in 30 patients (n=15/group at baseline) with type 2 diabetes. Participants, caregivers, and those assessing outcomes were blinded to group assignment. Left ventricular variables were measured at baseline, at 6 months, and at 12 months. Twenty-one (70%) of 30 participants completed 12 months of follow-up. At 12 months, there was a significantly greater reduction in left ventricular mass indexed to body surface area (LVMbsa) in the active treatment group compared with the placebo group (-10.6 g/m2 vs -0.1 g/m2, p=0.0088). The authors concluded that copper chelation "merits further exploration as a potential pharmacotherapy for diabetic heart disease". The study was limited by the small sample size and high dropout rate.
In 2012, Chen and colleagues in China reported the results of a 24 month single-blind, randomized controlled trial, of chelation therapy effects on the progression of diabetic nephropathy in patients with high-normal lead levels. Fifty patients with diabetes and high-normal body lead levels were randomized to the treatment (weekly chelation therapy [EDTA] for 3 months to reduce their body lead levels to <60 micrograms and then as needed for 24 months to maintain this level) or control (placebo for 3 months and then weekly for 5 weeks at 6 month intervals for 24 months) groups. All patients completed the 27-month trial. The primary outcome measured was change in estimated glomerular filtration rate (eGFR). A secondary end point measured was the number of patients in whom the baseline serum creatinine doubled or who required renal replacement therapy. Mean yearly rate of decrease in eGFR was 5.6 mL/min/1.73 m2 in the chelation group and 9.2 mL/min/1.73 m2 in the control group (p=0.04). Nine patients (36%) in the treatment group and 17 patients (68%) in the control group attained the secondary end point (p=0.02). The study was limited by the small sample size and not being double-blinded.
In 2013, the National Center for Complementary and Alternative Medicine (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI) published results from the Trial to Assess Chelation Therapy (TACT). The double-blind, placebo-controlled, 2x2 factorial randomized trial was designed to evaluate if an EDTA-based chelation regimen will reduce cardiovascular events in patients with a history of myocardial infarction (MI) (Lamas et al. 2013). The TACT trial enrolled n=1708 individuals (originally designed to enroll n=2300 individuals) aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior to enrollment. Enrolled individuals were randomized to receive 40 infusions of either chelation solution (3 g of disodium EDTA, 7g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) or placebo (500 mL of normal saline and 1.2% dextrose) (n=869). Participants were evaluated at baseline and at each of the 40 infusion visits. Following the infusion phase of the trial, patients were contacted quarterly by telephone, had annual clinic visits, and were seen at the end of the trial or at 5-year follow-up, whichever occurred first. The primary endpoint of the study was a composite of all-cause mortality, myocardial infarction (MI), stroke, coronary revascularization, and hospitalization for angina. Additional secondary endpoints were a composite of cardiovascular death, non-fatal MI, or non-fatal stroke. Additional pre-specified subgroups, including underrepresented populations (women and minorities), elderly persons (aged 70 years or older), high-risk patients (MI location, diabetes, and metabolic syndrome) were assessed. The interaction of the chelation therapy with the oral high-dose vitamin and mineral component of the trial and with the type of enrolling site (chelation practice vs. not a chelation practice) was also evaluated. A total of 361 patients in the chelation group (43%) and 464 patients in the placebo group (57%) discontinued treatment after starting it, withdrew consent during follow-up, or were lost to follow-up.
The Lamas et al. workgroup observed primary endpoint events among 222 (26%) individuals in the chelation group and 261 (30%) in the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P=.035). No effect on total mortality was observed (chelation, 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P=.64); although the study was not statistically powered for this comparison. The effect of EDTA treatment on the individual elements of the primary endpoint was similar to the overall effect on the composite primary endpoint (MI/chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke/chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization/chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina/chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). The pre-specified subgroup analysis did not identify any significant interaction. Considering these results, the authors concluded that among patients with a history of MI, EDTA chelation regimens moderately reduced the risk of cardiovascular outcomes, but the results are not sufficient to support the routine use of chelation therapy in this particular patient population. The results of the trial are limited by low and disproportionate follow-up rates between study groups, including a greater number of patients who withdrew consent in the placebo group compared to the treatment group, as well primary endpoint-containing components of varying levels of clinical significance.
IV chelation has been accepted as a treatment option for a number of indications, particularly for the treatment of various metal toxicities, as well as transfusional hemosiderosis, among other indications. The safety and effectiveness of chelation therapy for the treatment of additional indications (e.g., Alzheimer's disease, arthritis, arthrosclerosis, autism, diabetes, hypoglycemia, multiple sclerosis, myocardial infarction, etc.) is being investigated within clinical research settings; however, the effectiveness of chelation therapy in the treatment of these indications has not been demonstrated within well-designed, controlled clinical trials.
PRACTICE GUIDELINES AND POSITION STATEMENTS
In 2012, the American College of Physicians, American College of Cardiology Foundation, American
Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and Society of Thoracic Surgeons published a clinical practice guideline on the management of stable ischemic heart disease (IHD). The guidelines recommended that “chelation therapy should not be used with the intent of improving symptoms or reducing cardiovascular risk in patients with stable IHD. (Grade: strong recommendation; low-quality evidence)”
In 2005, the American College of Cardiology and the American Heart Association 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.)”
A 2004 clinical practice guideline from the American College of Physicians stated that chelation “should not be used to prevent myocardial infarction or death or to reduce symptoms in patients with symptomatic chronic stable angina. (Level of evidence B: Based on evidence from a limited number of randomized trials with small numbers of patients, careful analyses of nonrandomized studies, or observational registries.)”