| Coverage Policy Manual | |
| Policy #: | 1998110 |
| Category: | Medicine |
| Initiated: | February 1998 |
| Last Review: | March 2024 |
|
|
|
|||||||||||
| Chelation Therapy | |
|
|
|
| Description: |
Chelation therapy, an established treatment for treating heavy metal toxicities, has been investigated for a variety of off-label applications including treatment of atherosclerosis, Alzheimer’s disease, and autism.
Background
Chelation therapy is an established treatment for the removal of metal toxins by converting them to a chemically inert form that can be excreted in the urine. Chelation therapy consists of the intravenous or oral administration of chelating agents that remove metal ions such as lead, aluminum, mercury, arsenic, zinc, iron, copper, and calcium from the body.
Specific chelating agents are used for particular heavy metal toxicities. For example, deferoxamine is used for patients with iron toxicity, and calcium-ethylenediaminetetraacetic acid (EDTA) is used for patients with lead poisoning. Note that disodium-EDTA is not recommended for acute lead poisoning due to the increased risk of death from hypocalcemia (Centers for Disease Control and Prevention, 2006). Another class of chelating agents, called metal protein attenuating compounds (MPACs), is under investigation for the treatment of Alzheimer’s disease, which is associated with the disequilibrium of cerebral metals. Unlike traditional systemic chelators that bind and remove metals from tissues systemically, MPACs have subtle effects on metal homeostasis and abnormal metal interactions. In animal models of Alzheimer’s disease, they promote the solubilization and clearance of β-amyloid protein by binding its metal-ion complex and also inhibit redox reactions that generate neurotoxic free radicals. MPACs therefore interrupt two putative pathogenic processes of Alzheimer’s disease. However, no MPACs have received U.S. Food and Drug Administration (FDA) approval for the treatment of Alzheimer’s disease. Chelation therapy has also been discussed as a treatment for other indications including atherosclerosis, Alzheimer’s disease, and autism. For example, EDTA chelation therapy has been proposed in patients with atherosclerosis as a method of decreasing obstruction in the arteries.
Regulatory Status
In 1953, EDTA (Versenate) was approved by the FDA for lowering blood lead levels among both pediatric and adult patients with lead poisoning. In 1991, succimer (Chemet) was approved by the FDA for the treatment of lead poisoning in pediatric patients only. The FDA approved disodium-EDTA for use in selected patients with hypercalcemia and use in patients with heart rhythm problems due to intoxication with digitalis. In 2008, the FDA withdrew approval of disodium-EDTA due to safety concerns and recommended that other forms of chelation therapy be used (FDA, 2008).
Several iron-chelating agents are FDA approved:
In a June 2014 warning to consumers, the FDA advised that FDA-approved chelating agents would be available by prescription only. There are no FDA approved over-the-counter chelation products.
|
|
|
|
|
Policy/ Coverage: |
Effective July 2013
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Chelation therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following applications:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The following applications of Chelation therapy do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes or are considered investigational for members with contracts without primary coverage criteria:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to July 2013
Chelation therapy is considered medically necessary in the treatment of:
Chelation therapy in the treatment of:
is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, chelation therapy in the treatment of:
is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
|
|
|
|
| Rationale: |
Chelation therapy is an established treatment for the medically necessary indications listed above, particularly for the treatment of metal toxicity (i.e., lead, iron, copper). However, its use in other indications has been controversial, particularly its use in the treatment of atherosclerosis, i.e., both coronary artery disease and peripheral vascular disease. The American College of Cardiology’s current position on chelation therapy states that:
“There is insufficient scientific evidence to justify the application of chelation therapy for atherosclerosis on a clinical basis. At the present time, therefore, chelation therapy for atherosclerosis should be applied only under an investigational protocol”
This position statement was originally adopted in 1985 and reapproved in 1990. A search of the MEDLINE database for the period of 1995 to May 2002 did not identify any studies that would change the policy determination for atherosclerosis or any other indication listed as investigational. Specifically, in 2002, Knudtson and colleagues published the results of a placebo controlled, double-blind clinical trial that randomized 84 patients with coronary artery disease and a positive treadmill test to receive EDTA chelation therapy or placebo, 3 hours per treatment twice weekly for 15 weeks and once per month for an additional 3 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 2 groups. Two small randomized trials have also reported no benefit of chelation therapy as a treatment of peripheral arterial disease. Other published studies consist primarily case reports and case series. The literature search did not identify any articles that focused on the use of chelation therapy for multiple sclerosis, arthritis, hypoglycemia, or diabetes.
2007 Update
A MEDLINE database search was performed for October 2002 through December 2007. No articles were identified that would change the above policy. A systematic review of EDTA chelation therapy for cardiovascular disease by the Canadian College of Naturopathic Medicine determined that the best available evidence does not support the therapeutic use of EDTA chelation in the treatment of cardiovascular disease. A 2005 Cochrane Systematic Review of desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassemia concluded that considerable uncertainty continues to exist about the optimal schedule for desferrioxamine in paeople with transfusion-dependent thalassemia, but that there was no reason to change the current treatment recommendations.
2011 Update
The policy was updated with a search of the MEDLINE database through February 2011.
Atherosclerosis
In 2003, the National Heart, Lung, and Blood Institute, in collaboration with the National Center for Complementary and Alternative Medicine, sponsored the Trial to Assess Chelation Therapy (TACT; ClinicalTrials.gov Identifier NCT00044213) to study the use of chelation in atherosclerosis. TACT began recruiting 2,400 patients randomized to either placebo or chelation therapy. The primary outcomes include a composite of cardiovascular morbidity and all-cause mortality. Enrollment to TACT was suspended as allegations of improper consent forms were evaluated, (Mitka, 2008) delaying by 2 years the study completion date. Further, the chelating agent investigated in the protocol, disodium-EDTA, has been discontinued by the FDA. However, the trial will continue with the approximately 1,700 subjects already enrolled.
Autism
Rossignol published a systematic review of novel and emerging treatments for autism and did not identify any studies that included a control group (Rossignol, 2009). 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.
Alzheimer’s Disease
A 2008 Cochrane Review (Sampson, 2008) identified one randomized, placebo-controlled, Phase II clinical trial by Ritchie et al. who studied PBT1, a metal protein attenuating compound (MPAC) from Prana Biotechnology. PBT1, 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, possibly caused by vitamin B12 deficiency. Ritchie et al. administered oral clioquinol in doses increasing to 375 mg twice daily to 16 Alzheimer’s disease patients and compared the effects to 16 matched controls who received placebo (Ritchie, 2003). 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 (Lannfelt, 2008) completed a randomized, double-blind, placebo-controlled Phase IIa study 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 (Cavalli, 2008).
2012 Update
A search of the MEDLINE database was conducted through September 2012. There was no new information identified that would prompt a change in the coverage statement.
One RCT was identified studying chelation therapy in diabetic patients with left ventricular hypertrophy. The study was published in 2009 by Cooper and colleagues in New Zealand and evaluated the effect of copper chelation using oral trientine on left-ventricular hypertrophy in 30 patients with type 2 diabetes (Cooper, 2009). 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 indexed to body surface area (LVM) 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.
Ongoing clinical trials
Trial to Assess Chelation Therapy (TACT) (NCT00044213) : This placebo-controlled RCT is sponsored by the National Heart, Lung, and Blood Institute, in collaboration with the National Center for Complementary and Alternative Medicine. The trial is evaluating the impact of EDTA chelation therapy on mortality in patients with coronary artery disease; estimated enrollment is n=1,700. The estimated study completion date is February 2013.
Addendum to 2012 Update
The results of the TACT trial were presented at the 2012 American Heart Association Meeting by Gervasio Lamas of Mount Sinai Medical Center (my.americanheart.org). The poster session concludes that those patients receiving chelation therapy experienced a smaller number of clinical events than those receiving placebo. Additionally, the conclusion indicates this therapy is “not ready for implantation into clinical practice”. According to an article in The New York Times, one critic, Dr. Steven Norris, said the study was “fatally flawed” (Pollack, 2012). The article also quotes a representative of the AHA, Dr. Elliot Antman, who states, “Intriguing as these results are, they are unexpected and should not be interpreted as an indication to adopt chelation therapy into clinical practice” (Pollack, 2012). The results of this study have not yet been published. The coverage statement is not changed based on the results presented at the AHA meeting.
2013 Update
The results of NCT 00044213 (Trial to Assess Chelation Therapy [TACT]), a placebo-controlled RCT sponsored by the National Heart, Lung, and Blood Institute, in collaboration with the National Center for Complementary and Alternative Medicine, were published in the March 2013 JAMA (Lamas, 2013). The objective of the study was to determine if an EDTA-based chelation regimen reduces cardiovascular events. The study enrolled 1708 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.
The primary end point occurred in 222 (26%) of the chelation group and in 261 (30%) of the placebo group. There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P=.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, 0.54-1.11]; 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]). Sensitivity analyses examining the effect of patient dropout 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 revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.” Two accompanying editorials discuss the limitations and reliability of the trial (Nissen, 2013; Bauchner, 2013). Neither editorialist recommend using the results of the TACT trial as evidence to increase the use of chelation therapy for the treatment with a previous MI. According to one author, the TACT trial findings, “do not support the routine use of chelation therapy as secondary prevention for patients with previous myocardial infarction and established coronary disease”.
Chen and colleagues in China investigated the effect of chelation therapy on the progression of diabetic nephropathy in patients with high-normal lead levels. Their 2012 single-blind study included 50 patients with diabetes, high-normal body lead burden (80-6,000 ug) and serum creatinine 3.8 mg/dL or lower (Chen, 2012). At baseline, the mean blood lead level was 6.3 ug/dL in the treatment group and 7.1 ug/dL in the control group and the mean body lead burden was 151 ug for patients in the treatment group and 142 ug for patients in the control group. According to the U.S. Occupational and Health Safety Administration (OSHA), the maximum acceptable blood lead level in adults is 40 ug/dL (OSHA, 2013). Patients were randomized to 3 months of calcium disodium EDTA or placebo. During the following 24 months, patients in the chelation group received additional chelation treatments as needed (i.e., if serum creatinine level exceeded pre-treatment levels or body lead burden was >60 ug) and patients in the placebo group continued to receive placebo medication. All patients completed the 27-month study. The primary outcome was change in estimated glomerular filtration rate (eGFR). The yearly rate of decrease in eGFR was 5.6 mL/min/173 m2 (standard deviation [SD]: 5.0) in the chelation group and 9.2 mL/min/173 m2 (SD: 3.6) in the control group. The difference between groups was statistically significant, p=0.04. The secondary endpoint was the number of patients in whom the baseline serum creatinine doubled or who required renal replacement therapy. A total of 9 patients (36%) in the treatment group and 17 (68%) in the control group attainted the secondary endpoint; the difference between groups was statistically significant (p=0.02). There were no reported side effects of chelation therapy during the 27-month study period.
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 management of stable ischemic heart disease (IHD) (ACP/ACCF/AHA/AATS/PCNA/STS, 2012). The organizations 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)”
2014 Update
A literature search conducted through June 2014 did not identify any new information that would prompt a change in the coverage statement.
Escolar et al (2014) published results of a prespecified subgroup analysis of diabetic patients in TACT (TACT is discussed in an earlier update) (Escolar, 2014). In TACT, there was a statistically significant interaction between treatment (EDTA or placebo) and presence of diabetes: Among 538 self-reported diabetic patients (31% of the trial sample), those randomized to EDTA had a 39% reduced risk of the primary composite outcome compared with placebo (hazard ratio [HR], 0.61; 95% CI, 0.45 to 0.83; log rank test, p=0.02); among 1170 nondiabetic patients, risk of the primary outcome did not differ statistically between treatment groups (HR=0.96; 95% CI, 0.77 to 1.20; log rank test, p=0.73) (Lamas, 2013). For the subsequent subgroup analysis, the definition of diabetes mellitus was broadened to include self-reported diabetes, use of oral or insulin treatment for diabetes, or fasting blood glucose 126 μg/dL or more at trial entry. Of 1708 patients in TACT, 633 (37%) had diabetes mellitus by this definition; 322 were randomized to EDTA, and 311 to placebo. Compared with all other trial participants, this subgroup of diabetic patients had higher body mass index, fasting blood glucose, and prevalence of heart failure, stroke, hypertension, peripheral artery disease, and hypercholesterolemia. Within this subgroup, baseline characteristics were similar between treatment groups. With approximately 5 years of follow-up, the primary composite end point occurred in 25% of the EDTA group and 38% of the placebo group (HR=0.59; 99.4% CI [adjusted for multiple subgroups], 0.39 to 0.88; log rank test, p=0.002). In adjusted analysis of the individual components of the primary end point, there were no statistically significant differences between treatment groups. There were 36 adverse events attributable to study drug that led to trial withdrawal, 16 in the EDTA group and 20 in the placebo group.
This substudy has the same limitations as the parent study previously described, namely, high and differential withdrawal and heterogeneous composite end point. Additionally, because diabetes was not a stratification factor in TACT, results of this subgroup analysis are preliminary and require replication.
NICE issued clinical guidance on autism in children and young people in 2013 (NICE, 2013) and autism in adults in 2012 (NICE, 2012). Both documents specifically recommend against the use of chelation therapy for the management of autism. The policy statement has been changed to specifically address autism as an indication.
Other Potential Indications
No RCTs or other controlled trials that evaluated safety and efficacy of chelation therapy for other conditions, such as multiple sclerosis or arthritis, were identified. Iron chelation therapy is being investigated for Parkinson disease(Weinreb, 2013) and endotoxemia (van Eijk, 2014).
2015 Update
A literature search conducted using the MEDLINE database through June 2015 did not reveal any new information that would prompt a change in the coverage statement. No new randomized controlled trials were identified.
In 2014, a subsequent publication (Lamas, 2014) reported results of the 4 treatment groups in the TACT trial which is discussed above (Lamas, 2014). The treatment groups included: 1) double active group (disodium EDTA infusions with oral high-dose vitamins; n=421 patients randomized), 2) active infusions with placebo vitamins (n=418), 3) placebo infusions with active vitamins (n=432), and 4) double placebo (n=437). The proportion of patients who discontinued treatment, withdrew consent, or were lost to follow-up per treatment group was not reported. Five-year Kaplan-Meier estimates for the primary composite end point were 32%, 34%, 37%, and 40%, respectively. The reduction in primary end point by double active treatment compared with double placebo was statistically significant (hazard ratio [HR]: 0.74 [95% CI: 0.57 to 0.95]). In 633 patients with diabetes (approximately 36% of each treatment group),the primary end point reduction of double active compared with double placebo was more pronounced (HR: 0.49 [95% CI: 0.33 to 0.75]). A subsequent publication in 2014 reported results of the 4 treatment groups in the 2x2 factorial design (double active group [disodium EDTA infusions with oral high-dose vitamins; n=421 patients randomized], active infusions with placebo vitamins [n=418], placebo infusions with active vitamins [n=432], and double placebo [n=437]) (Lamas, 2014). The proportion of patients who discontinued treatment, withdrew consent, or were lost to follow-up per treatment group was not reported. Five-year Kaplan-Meier estimates for the primary composite end point were 32%, 34%, 37%, and 40%, respectively. The reduction in primary end point by double active treatment compared with double placebo was statistically significant (hazard ratio [HR]: 0.74 [95% CI: 0.57 to 0.95]). In 633 patients with diabetes (approximately 36% of each treatment group), the primary end point reduction of double active compared with double placebo was more pronounced (HR: 0.49 [95% CI: 0.33 to 0.75]).
Ongoing Clinical Trials
NCT02175225- Study of Deferoxamine Mesylate in Intracerebral Hemorrhage. This study has a planned enrollment of 294 subjects. The completion date is estimated as Aug 2018.
NCT02367248- Safety and Effectiveness Study of Deferoxamine and Xingnaojing Injection in intracerebral Hemorrhage. The study has a planned enrollment of 180 subjects and is scheduled for completion in Dec 2016.
NCT00870883- Prospective, Randomized, Double-blinded, Placebo-controlled Study of N-acetylcysteine Plus Deferoxamine for Patients With Hypotension as Prophylaxis for Acute Renal Failure. The study has a planned enrollment of 140 subjects and is scheduled for completion in Mar 2015. The study is currently recruiting subjects.
NCT01741532- A Randomized, Double-blind, Placebo-controlled Trial of Deferiprone in Patients With Pantothenate Kinase-associated Neurodegeneration (PKAN). The study has a planned enrollemtn of subjects. The estimated completion date is Dec 2016.
NCT01627938 A Phase II Proof of Concept Study Evaluating the Reduction of Mitoxantrone-induced Cardiotoxicity and Neurological Outcome in the Combined Use of Mitoxantrone and Dexrazoxane (Cardioxane®) in Multiple Sclerosis (MSCardioPro). The study has a planned enrollment of 50 subjects with an estimated completion date of April 2016.
Practice Guidelines and Position Statements
American College of Physicians/American College of Cardiology Foundation/American Heart
Association/ American Association for Thoracic Surgery/Preventive Cardiovascular Nurses
Association/Society of Thoracic Surgeons
In 2012, the American College of Physicians (ACP), American College of Cardiology Foundation, American Heart Association (AHA), American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and Society of Thoracic Surgeons published a clinical practice guideline on management of stable ischemic heart disease (IHD) (Qaseem, 2012). The guidelines recommended that “chelation therapy should not be used with the intent of improving symptoms or reducing cardiovascular risk in patients with stable IHD. (Grade: strong recommendation; low-quality evidence)” However, citing TACT (Lamas, 2014), a 2014 focused update of this guideline included a revised recommendation on chelation therapy, stating that the “usefulness of chelation therapy is uncertain for reducing cardiovascular events in patients with stable IHD” (Fihn, 2014). The recommendation was upgraded from Class III (No Benefit) to Class IIb and the level of evidence from C (only consensus expert opinion, case studies, or standard of care) to B (data from a single randomized trial or nonrandomized studies).
American College of Cardiology
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)” (Hirsch, 2006). In 2013, the American College of Cardiology Foundation (ACCF) and AHA compiled previous ACC/AHA and ACCF/AHA recommendations issued in 2005 (Hirsch, 2006) and 2011 (ACCF/AHA, 2011) on the management of peripheral artery disease (Anderson, 2013). The recommendation against chelation therapy remained unchanged.
Canadian Cardiovascular Society
Evidence-based, consensus guidelines from the Canadian Cardiovascular Society in 2014 included a conditional recommendation (based on moderate quality evidence) that chelation therapy should not be used to attempt to improve angina or exercise tolerance in patients with stable ischemic heart disease (Mancini, 2014).
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
2018 Update
A literature search was conducted through June 2018. There was no new information identified that would prompt a change in the coverage statement.
2019 Update
A literature search was conducted through June 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Villarruz-Sulit et al published a Cochrane review that evaluated ethylenediaminetetraacetic acid (EDTA) chelation therapy for treating patients with atherosclerotic cardiovascular disease (Villarruz-Sulit, 2020). Five placebo-controlled trials were included (N=1,993, range 10 to 1,708); 3 studies included patients with peripheral vascular disease and 2 studies included patients with coronary artery disease, with 1 specifically recruiting patients with a previous myocardial infarction. One study had a high risk of bias, since investigators broke randomization part way through the trial, but all other trials were rated as moderate to low. A meta-analysis of included studies found no difference between chelation therapy and placebo with regard to all-cause mortality (n=1792, 2 studies; risk ratio [RR], 0.97; 95% confidence interval [CI], 0.73 to 1.28), cardiovascular death (n=1708, 1 study; RR, 1.02; 95% CI, 0.70 to 1.48), myocardial infarction (n=1792, 2 studies; RR, 0.81; 95% CI, 0.57 to 1.14), angina (n=1792, 2 studies; RR, 0.95; 95% CI, 0.55 to 1.67), or coronary revascularization (n=1792, 2 studies; RR, 0.46; 95% CI, 0.07 to 3.25). Cochrane reviewers found that the evidence was insufficient to support conclusions about the efficacy of chelation therapy for treating atherosclerosis. Additional RCTs reporting health outcomes like mortality and cerebrovascular events were suggested
A post-hoc analysis showed that chelation was associated with a lower risk of the primary endpoint compared with placebo in patients with post anterior myocardial infarction (n=674; hazard ratio [HR], 0.63, 95% CI, 0.47 to 0.86; p=0.003); however, this effect was not seen in post non-anterior myocardial infarction (Lewis, 2020).
In 2019, the American Academy of Pediatrics published guidance for the management of children with autism spectrum disorder. The guidance cautioned against the use of chelation therapy due to safety concerns and lack of supporting efficacy data (Hyman, 2020).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Ravalli et al published a systematic review and meta-analysis of 24 trials, including 4 RCTs, that evaluated the use of ethylenediaminetetraacetic acid (EDTA) in patients with cardiovascular disease (Ravalli, 2022). Ankle-brachial index was the only outcome reported in at least 3 studies and included in meta-analysis. Overall, 17 studies reported improved outcomes with EDTA, 5 reported no significant effect, and 2 reported no qualitative benefit. The studies included in this meta-analysis are limited by the lack of clinical outcomes, the variety of infusion methods, limited sample sizes, and minimal follow-up time.
The TACT2 study replicated the design of the original TACT study evaluating 40 weekly infusions of EDTA-based chelation in patients with prior myocardial infarction and diabetes (Lamas, 2022). Enrollment was complete in December 2020 and treatment was complete in December 2021. Subjects are now being followed for up to 5 years for a composite primary endpoint of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. Results are anticipated in 2024.
Devos et al conducted a phase 2, randomized, double-blind, 36-week trial in 372 patients with newly diagnosed Parkinson's disease (Devos, 2022). Patients randomized to iron chelation with deferiprone had worse outcomes than those treated with placebo, with 22% of deferiprone-treated patients requiring initiation of dopaminergic therapy versus 2.7% of those treated with placebo. In addition, scores on the Unified Parkinson's Disease Rating Scale were worse with deferiprone, worsening by 15.6 points from baseline compared with 6.3 points in the placebo group (difference, 9.3 points; 95% CI, 6.3 to 12.2; p<.001).
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2023 guideline from the ACC and AHA in conjunction with the American Association for Thoracic Surgery, Preventative Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons on managing chronic coronary disease provided comments about chelation therapy but no formal recommendations (Virani, 2023).
In 2023, the AHA published a scientific statement about the cardiovascular risk of contaminant metals (Lamas, 2023). The authors cited the TACT trial findings of a reduced relative risk of cardiovascular events among patients who received chelation therapy, but also noted that TACT did not evaluate metal levels. Results of the TACT2 trial (which finished in 2023), are awaited to provide objective data on the metal level lowering effects of chelation therapy.
|
|
|
|
| CPT/HCPCS: | |
|
|
|
| References: |
AHCPR 1986; 8:1-20. American College Cardiology Position Statement. Chelation Therapy. www.acc.org/clinical/ position/72540.htm. American College of Physicians/American College of Cardiology Foundation/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society of Thoracic Surgeons.(2013) Management of stable ischemic heart disease. Available online at: www.guideline.gov. Last accessed May, 2013. Anderson JL, Halperin JL, Albert NM, et al.(2013) Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. Apr 2 2013;127(13):1425-1443. PMID 23457117 Anderson JL, Halperin JL, Albert NM, et al.(2013) Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. Apr 2 2013;127(13):1425-1443. PMID 23457117 Ann Int Med 1994; 120:490-9. Ann Pharmacother 1993; 27:1504-9. Bauchner H, Fontanarosa PB, Golub RM.(2013) Evaluation of the Trial to Assess Chelation Therapy (TACT) The Scientific Process, Peer Review, and Editorial Scrutiny. JAMA. 2013:309(12):1291-1292. Blood Rev 1995; 9:33-45. Cavalli A, Bolognesi ML, Minarini A, et al.(2008) Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008; 51(3):347-72. Chelation therapy, non-overload condition. Hayes Technology Assessment. October 2004. Chen KH, Lin JL, Lin-Tan DT et al.(2012) Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens. Am J Kidney Dis 2012; 60(4):530-8. Clin Chem 1996; 42:1938-42. Cooper GJ, Young AA, Gamble GD et al.(2009) A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomized placebo-controlled study. Diabetologia 2009; 52(4):715-22. Devos D, Labreuche J, Rascol O, et al.(2022) Trial of Deferiprone in Parkinson's Disease. . N Engl J Med. Dec 01 2022; 387(22): 2045-2055. PMID 36449420 Diav-Citrin O, Loren G.(1997) Oral iron chelation with deferiprone. Ped Clin N Am 1997; 44:236-47. DM Seely, P Wu, EJ Mills.(2005) EDTA chelation therapy for cardiovascular disease; a systematic review. BMC Cardiovascular Disord, 2005; 5:32. Elihu N, Frishman WH.(1998) Chelation therapy in cardiovascular disease: ethylenediaminetetraacetic acid, deferoxamine, and dexrazoxane. J Clin Pharmacol 1998; 38:101-5. Ernst E.(1997) Chelation therapy for peripheral arterial occlusive disease: a systematic review. Circ 1997; 96(3):1031-3. Ernst E.(2000) Chelation therapy for coronary heart disease: an overview of all clinical investigations. Am Hrt J 2000;140(1):139-41. Escolar E, Lamas GA, Mark DB et al.(2014) The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circulation. Cardiovascular quality and outcomes 2014; 7(1):15-24. Fihn SD, Blankenship JC, Alexander KP, et al.(2014) 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. Nov 4 2014;64(18):1929-1949. PMID 25077860 Food and Drug Administration (FDA).(2008) Hospira, Inc., et al.; Withdrawal of Approval of One New Drug Application and Two Abbreviated New Drug Application. Federal Register. 2008;73(113):33440-33441. Food and Drug Administration. Hospira, Inc., et al.;(2011) Withdrawal of Approval of One New Drug Application and Two Abbreviated New Drug Application. Available online at: http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-13273.htm June 12, 2008. Last accessed March 2011. Grolez G, Moreau C, Sablonniere B, et al.(2015) Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease. BMC Neurol. 2015;15:74. PMID 25943368 Guldager B, Jelnes R, Jorgensen SJ, et al.(1992) EDTA treatment of intermittent claudication--a double-blind placebo-controlled study. J Intern Med 1992; 231(3):261-7. Hyman SL, Levy SE, Myers SM, et al.(2020) Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. Jan 2020; 145(1). PMID 31843864 Knudtson MI, et al.(2002) Chelation therapy for ischemic heart disease: A randomized controlled trial. JAMA 2002; 287:481-6. Lamas GA, Anstrom KJ, Navas-Acien A, et al.(2022) The trial to assess chelation therapy 2 (TACT2): Rationale and design. Am Heart J. Oct 2022; 252: 1-11. PMID 35598636 Lamas GA, Bhatnagar A, Jones MR, et al.(2023) Contaminant Metals as Cardiovascular Risk Factors: A Scientific Statement From the American Heart Association. J Am Heart Assoc. Jul 04 2023; 12(13): e029852. PMID 37306302 Lamas GA, Boineau R, Goertz C, et al.(2014) EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: The factorial group results of the Trial to Assess Chelation Therapy. Am Heart J. Jul 2014;168(1):37-44 e35. PMID 24952858 Lamas GA, Goertz C, Boineau R et al.(2013) Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. Jama 2013; 309(12):1241-50. Lamas GA, Goertz C, Boineau R, et al.(2013) Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction. The TACT Randomized Trial. JAMA. 2013;309(12):1241-1250. Lamas GA.(2012) Results of the trial to assess chelation therapy (TACT). AHA Scientific Session. Retrieved from http://my.americanheart.org. . Last accessed December 04, 2012. Lancet 1993; 341:1088-89. Lannfelt L, Blennow K, Zetterbert H et al.(2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2008:7(9):779-86. Lewis EF, Ujueta F, Lamas GA, et al.(2020) Differential Outcomes With Edetate Disodium-Based Treatment Among Stable Post Anterior vs. Non-Anterior Myocardial Infarction Patients. Cardiovasc Revasc Med. Nov 2020; 21(11): 1389-1395. PMID 32303436 Lin JL, Ho HH, Yu CC.(1999) Chelation therapy for patients with elevated body lead burden and progressive renal insufficiency. Ann Int Med 1999; 130:7-13. Mark DB, Anstrom KJ, Clapp-Channing NE, et al.(2014) Quality-of-life outcomes with a disodium EDTA chelation regimen for coronary disease: results from the trial to assess chelation therapy randomized trial. Circ Cardiovasc Qual Outcomes. Jul 2014;7(4):508-516. PMID 24987051 Maron DJ, Hlatky MA.(2014) Trial to Assess Chelation Therapy (TACT) and equipoise: When evidence conflicts with beliefs. Am Heart J. Jul 2014;168(1):4-5. PMID 24952853 Mitka M.(2008) Chelation therapy trials halted. JAMA 2008; 300(19):2236. National Institute for Health and Care Excellence. Autism - management of autism in children and young people (clinical guidance 170), August 2013. Available online at: http://www.nice.org.uk/guidance/index.jsp?action=byID&o=14257. Last accessed May 2014. National Institute for Health and Care Excellence. Autism in adults (clinical guidance 142), June 2012. Available online at: http://www.nice.org.uk/CG142. Last accessed May 2014. Nissen SE.(2013) Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA. Mar 27 2013;309(12):1293-1294. PMID 23532246 Nissen SE.(2013) Concerns About Reliability in the Trial to Assess Chelation Therapy (TACT). JAMA. 2013:309(12):1293-1294. O'Connor ME, Rich D.(1999) Children with moderately elevated lead levels: is chelation with DMSA helpful. Clin Pediatr 1999; 38:325-31. Pollack A.(2012) Much-debated treatment for heart disease shows slight benefit in clinical trial. The New York Times. The New York Times. November 4, 2012. Retrieved from http://www.nytimes.com. Last accessed December 04, 2012. Ravalli F, Vela Parada X, Ujueta F, et al.(2022) Chelation Therapy in Patients With Cardiovascular Disease: A Systematic Review. J Am Heart Assoc. Mar 15 2022; 11(6): e024648. PMID 35229619 Ritchie CW, Bush AI, Mackinnon A et al.(2003) Metal-protein attenuation with Iodochlorhydroxyquin (clioquinol) targeting Aß amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 2003; 60(12):1685-91. Roberts DJ, Rees D, Howard J, et al.(2005) Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalasemia. Cochrane Database Systematic Rev, 2005 Oct 19; CD004450. Rossignol DA.(2009) Novel and emerging treatments for autism spectrum disorders: A systematic review. Clin Psychiatry 2009; 21(4):213-36. Sampson E, Jenagaratnam L, McShane R.(2008) Metal protein attenuating compounds for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 2008; (1):CD005380. U.S Food and Drug Administration.(2014) U.S Food and Drug Administration. FDA warns consumers about potential health risks from using Thorne Research’s Captomer products, 06/12/2014. http://www.fda.gov/Drugs/DrugSafety/ucm400977.htm?source=govdelivery&utm_m edium=email&utm_source=govdelivery. Accessed May 22, 2015. U.S. Department of Labor Occupational Health and Safety Adminstration (OSHA). Safety and Health Regulations for Construction. Available online at: http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=10642. Last accessed May, 2013. U.S. National Institutes of Health. ClinicalTrials.gov. Available online at: clinicaltrials.gov. van Eijk LT, Heemskerk S, van der Pluijm RW et al.(2014) The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial. Haematologica 2014; 99(3):579-87. van Rij AM, Solomon C, Packer SG, et al.(1994) Chelation therapy for intermittent claudication. A double-blind, random, controlled trial. Circ 1994; 90:1194-99. Villarruz-Sulit MV, Forster R, Dans AL, et al.(2020) Chelation therapy for atherosclerotic cardiovascular disease. Cochrane Database Syst Rev. May 05 2020; 5: CD002785. PMID 32367513 Virani SS, Newby LK, Arnold SV, et al.(2023) 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. Aug 29 2023; 148(9): e9-e119. PMID 37471501 Weinreb O, Mandel S, Youdim MB et al.(2013) Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators. Free radical biology & medicine 2013; 62:52-64. |
|
|
|
|
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
|