Clinical Policy Title: Chelation therapy

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1 Clinical Policy Title: Chelation therapy Clinical Policy Number: Effective Date: June 1, 2017 Initial Review Date: April 19, 2017 Most Recent Review Date: April 10, 2018 Next Review Date: April 2019 Policy contains: Heavy metal poisoning. Heavy metal overload. Chelation therapy. Related policies: CP# CP# Blood lead screening and exposure Hematopoietic stem cell transplant for thalassemia major and sickle cell disease ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers the use of chelation therapy to be clinically proven and, therefore, medically necessary when the member has specific signs and symptoms of heavy metal toxicity or a history of likely exposure to heavy metals with standard-of-care laboratory confirmation, and when U.S. Food and Drug Administration (FDA)-approved chelating agents are used for the following clinical indications (FDA, 2018): Chronic iron overload caused by transfusion-dependent anemias (secondary hemochromatosis) such as thalassemia, sickle cell anemia, Cooley s anemia, Diamond-Blackfan anemia, sideroblastic anemia, and myelodysplastic syndrome). Chronic iron overload caused by primary hemochromatosis in whom therapeutic phlebotomy is not tolerated. Chronic iron overload due to non-transfusion-dependent thalassemia. Acute heavy metal overload or toxicity (e.g., lead, arsenic, mercury, iron, copper, or gold) confirmed by appropriate laboratory results (e.g., blood, plasma, or urine) and clinical findings consistent with metal toxicity or a history of likely exposure to heavy metals. Copper overload or toxicity due to Wilson s disease (hepatolenticular degeneration). 1

2 Known or suspected internal contamination with cesium, radioactive or non-radioactive thallium, plutonium, americium, or curium. Cystinuria. Aluminum overload in persons with end-stage renal failure (National Kidney Foundation Kidney Disease Outcomes Quality Initiative, 2003). Limitations: All other uses of chelation therapy are not medically necessary. Provoked testing for lead and mercury levels is not medically necessary. Intravenous (IV) chelation therapy is medically necessary only when administered in facilities with sufficient resources to provide close monitoring of member s physical signs and symptoms, heavy metal levels, and resultant sequelae (e.g., inpatient hospital, outpatient hospital, emergency room, renal dialysis facilities, and skilled nursing facilities). Screening for heavy metal poisoning is not 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. Alternative covered services: Physical examination, diagnosis, and treatment in accordance with standards of care. Background Clinically, the term "heavy metal" generally refers to those metals and semi-metals with potential human or environmental toxicity. From a chemical standpoint, heavy metals have a high specific gravity, typically larger than 5. Many heavy metals, such as zinc, copper, chromium, iron, and manganese are ubiquitous, present in trace amounts in the body, and essential to body function. Others such as arsenic, cadmium, lead, and mercury have no beneficial role in humans and contribute to non-communicable chronic diseases (Sears, 2013; Wax, 2013). Exogenous sources and certain diseases can expose humans to abnormal levels of heavy metals that, in toxic amounts, can accumulate in the soft tissues of the body and result in serious organ damage. The heavy metals most commonly associated with poisoning of humans are lead, mercury, arsenic, and cadmium (Wax, 2013). Symptoms and physical findings associated with heavy metal poisoning vary according to the metal accumulated. Chelation therapy: A chelating (or sequestering) agent is a ligand that binds to a central metal atom at two or more points. Chelators are natural or synthetic compounds that have a high affinity for heavy metal ions, forming a 2

3 water-soluble complex that can be eliminated in the urine or feces. Chelating agents may be taken orally, intravenously, or intramuscularly, based on the agent and type of toxicity. A chelating agent will mobilize the most readily available metals first, typically in the plasma, kidney, liver, and, to a lesser extent, bone, and central nervous system (Sears, 2013). Chelation therapy can affect the accumulations of both non-essential metals and essential trace heavy metals (Wax, 2013). As a consequence, chelation therapy has the potential to cause harm because of its action on these essential metals. Chelators are available by prescription, through compounding pharmacies, and by direct over-the-counter purchase. Any licensed medical provider can prescribe a chelator, including naturopaths and other types of alternative medicine physicians (Wax, 2013). However, the FDA issued a consumer advisory to avoid all over-the-counter products for chelation or detoxification, due to their significant risks, and perform chelation only under medical supervision (FDA, 2018). The FDA has not approved any over-the-counter chelators. The FDA has approved 12 chelators for prescription use. Their approved indications are as follows (FDA, 2018; Wax, 2013): Deferasirox Chronic iron overload due to blood transfusions in patients two years of age and older; chronic iron overload due to nontransfusion-dependent thalassemia in patients age 10 years and older. Deferiprone Transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Deferoxamine mesylate Acute iron intoxication and chronic iron overload due to transfusiondependent anemias. Dimercaprol Arsenic, gold, and mercury poisoning; lead poisoning when used concomitantly with calcium disodium EDTA. D-penicillamine Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Calcium disodium EDTA Lead poisoning (acute and chronic) and lead encephalopathy, in both pediatric and adult populations. Ferric hexacyanoferrate (Prussian blue) Known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium. Pentetate calcium trisodium Known or suspected internal contamination with plutonium, americium, or curium. Pentetate zinc trisodium Known or suspected internal contamination with plutonium, americium, or curium. Succimer Lead poisoning in pediatric patients with blood lead levels above 45 μg/dl. Trientine hydrochloride Wilson s disease who are intolerant of penicillamine. The FDA approved disodium EDTA many years ago as an emergency treatment for acute hypercalcemia or ventricular arrhythmias as a result of digitalis toxicity. Since then, newer drugs have been approved to treat 3

4 these conditions, and, in 2008, the FDA withdrew approval for disodium EDTA as chelation therapy for these conditions due to safety concerns (FDA, 2018). Disodium EDTA remains available through compounding pharmacies. The FDA recommends that most patients be treated with other first-line modalities, for example, fragment antigen-binding monoclonal antibodies for digitalis toxicity, and calcitonin, bisphosphonates, zoledronic acid, and denosumab for emergency treatment of hypercalcemia. Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on February 28, Search terms were: Chelation Therapy (MeSH), Heavy Metal Poisoning, Nervous System/therapy (MeSH), Heavy Metal Toxicity (Supplementary Concept), Metals, Heavy/therapy (MeSH), Metals, Heavy/toxicity (MeSH), Hepatolenticular Degeneration/therapy (MeSH). We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings For chelation to be effective, the presumed metal toxicity must correlate with a clinical disease burden, and chelation must be able to reduce the toxicity and affect a clinical difference (Smith, 2013). This requires an established dose-response relationship, a valid assessment of toxicity (e.g., clinical, biochemical, or radiographical), and an appropriate assessment of clinical disease burden. These requirements eliminate many over-the-counter chelators and many proposed off-label uses of prescribed chelators from consideration. The FDA-approved chelators are established treatment for acute heavy metal toxicity and several clinically relevant conditions that cause heavy metal overload. They demonstrate biological plausibility and provide direct or indirect evidence of effectiveness through long-standing clinical experience, observational research, or animal research. Still, in the setting of limited treatment options, some remain available 4

5 despite weak supportive evidence, while others have been surpassed by newer agents. For acute hypercalcemia or ventricular arrhythmia caused by digitalis toxicity, disodium EDTA no longer represents the standard of care (Walsh, 2016; FDA, 2013, updated 2018). Disodium EDTA has been proposed as treatment of atherosclerosis in stable patients with history of myocardial infarction. Results of the Trial to Assess Chelation Therapy; clinicaltrials.gov identifier NCT ) compared chelation with placebo in patients with stable ischemic heart disease who had experienced myocardial infarction. Disodium EDTA reduced the risk of adverse cardiovascular outcomes by 18 percent overall, and by 41 percent among those with diabetes (Lamas, 2013; Escolar, 2014). Despite these positive outcomes, a high dropout rate, treatment noncompliance, questionable biological basis, and the risks of chelation limit the findings. The American College of Cardiology/American Heart Association found insufficient evidence to recommend disodium EDTA chelation in this population (Fihn, 2014). Deferoxamine mesylate s labeled indication is iron acute toxicity and chronic overload. The accumulation of aluminum on bone surfaces can impair bone formation, leading to either osteomalacia or adynamic bone disease. Deferoxamine mesylate has demonstrated technical efficacy and clinical efficacy for documented aluminum toxicity in persons with end stage renal failure secondary to hemodialysis, as measured by bone biopsy. Despite being an off-label use, deferoxamine mesylate is considered the standard of care for this indication (National Kidney Foundation Kidney Disease Outcomes Quality Initiative, 2003). Chelation therapy has also been proposed for many other non-overload conditions. These include: atherosclerotic vascular diseases; coronary artery disease; progressive renal insufficiency in Type II diabetic nephropathy; Alzheimer s disease; primary biliary cirrhosis; and autism. However, additional research is needed to determine the safety and efficacy of chelation therapy for these conditions. Policy updates: In 2018, we added one new Cochrane review of deferasirox for managing iron overload in people with thalassemia (Bollig, 2017). Their findings suggest that the newer oral chelator deferasirox is safe and effective in the short- and intermediate-term and may be a viable treatment option for persons with a preference for it or intolerance to other established treatments (e.g., deferoxamine and deferiprone), but long-term outcomes are needed. These findings are consistent with the current policy, and no policy changes are warranted. Summary of clinical evidence: Citation Bollig (2017) Cochrane review Deferasirox for managing iron overload in people with Content, Methods, Recommendations Systematic review and meta-analysis of 16 randomized controlled trials with 1,807 total participants. Overall quality: variable very low to moderate depending on outcome measure. Data suggest that deferasirox achieves similar efficacy to deferoxamine depending on 5

6 Citation thalassaemia Walsh (2016) for the Society for Endocrinology (UK) Guideline: emergency management for acute hypercalcemia in adults National Institute for Health and Clinical Excellence (2012, updated 2016) Guideline: autism spectrum disorder in adults: diagnosis and management James (2015) Cochrane review Chelation for autism spectrum disorder Fihn (2014) for the American College of Cardiology/ American Heart Association Stable ischemic heart disease National Heart, Lung and Blood Institute (2014) Sickle cell disease Yang (2014) Content, Methods, Recommendations the ratio of doses being compared, but long-term outcomes for deferasirox need confirmation. Deferasirox may be a first-line option to individuals who show a strong preference for it and may be a reasonable treatment option for people showing an intolerance or poor adherence to deferoxamine. Intravenous hydration with 0.9% saline 4 6 L in 24 hours. Intravenous bisphosphonates. Second-line treatments: glucocorticoids, calcimimetics, denosumab, calcitonin, or parathyroidectomy. No mention of disodium EDTA as treatment. Do not use chelation to manage core symptoms of autism in adults. Systematic review included one low-quality randomized controlled trial with 77 total patients comparing oral succimer versus placebo. Insufficient evidence of effectiveness of chelation with succimer for autism spectrum disorder. High risk of potentially serious adverse events, such as hypocalcemia, renal impairment, and death. A causal link between heavy metals and autism needs further study. Despite some positive outcomes of the Trial to Assess Chelation Therapy trial, high rate of patient withdrawals, absence of adequate scientific basis for the therapy, possibility of a false positive outcome, and risks of chelation therapy limit conclusions of effectiveness. The usefulness of chelation therapy is uncertain for reducing cardiovascular events in these patients (Level of Evidence: B). Administer iron chelation therapy for documented transfusion-acquired iron overload (moderate recommendation, moderate-quality evidence). Reno protective effects of Ca-EDTA lead chelation in chronic kidney disease Meta-analysis of randomized controlled trials suggests Ca-EDTA lead chelation can delay the progression of chronic kidney disease in patients with measurable body lead burdens by increasing the estimated glomerular filtration rate and creatinine clearance rate. Potential for adverse effects such as acute tubular necrosis. Insufficient evidence that Ca-EDTA decreases proteinuria. 6

7 Citation Lamas (2013), Lamas (2014), Mark (2014), Escolar (2014) for the Trial to Assess Chelation Therapy trial) Disodium EDTA for atherosclerosis in stable patients with history of myocardial infarction National Collaborating Centre for Mental Health (2013) Children and young people on the autism spectrum Smith (2013) Overview: chelates for aluminum, cadmium, chromium, cobalt, and uranium Sumorok (2013) Overview: cystinuria Ma (2012) Content, Methods, Recommendations Randomized controlled trial compared IV disodium EDTA versus placebo, and highdose oral multivitamins and multi-minerals versus oral placebo. Study enrolled 1,708 patients (37% diabetes) age 50 years, and creatinine 2.0. Median follow-up = 55 months. Composite primary endpoint was death, reinfarction, stroke, coronary revascularization, or hospitalization for angina. Disodium EDTA modestly reduced the risk of adverse cardiovascular outcomes by18% (5-year number needed to treat = 18), many of which were revascularization procedures and by 41% in persons with diabetes (P=0.02). No detectable effect on quality of life during two years of follow-up. High dropout rate, treatment noncompliance. Fifty percent more persons withdrew from chelation therapy than placebo. Findings should be replicated before routine use. Do not use chelation therapy to manage autism in any context in children and young people Deferoxamine mesylate is accepted for appropriately documented aluminum toxicity. Acute cadmium toxicity: no definitive chelation benefit described, but succimer, pentetate calcium or zinc trisodium, and EDTA have been considered; not for chronic toxicity. Chromium chelators: insufficient evidence of efficacy. Cobalt: insufficient evidence; pentetate calcium or zinc trisodium has been recommended, and succimer, EDTA, and N-acetylcysteine have been suggested. Uranium: insufficient evidence for pentetate calcium or zinc trisodium; sodium bicarbonate is currently recommended, although animal evidence is conflicting. Treatment is focused on the prevention of stone formation. Classification now based on genotype, rather than phenotype. Cystine-binding thiol drugs (D-penicillamine or tiopronin) are current standard of care. Cochrane review No randomized controlled trials identified. Iron chelators for acute stroke Lindor (2009) for the American Association for the Study of Liver Diseases Primary biliary cirrhosis D-penicillamine not beneficial as a single agent. Ursodeoxycholic acid is the recommended treatment. 7

8 Citation National Kidney Foundation Kidney Disease Outcomes Quality Initiative (2003) Guideline: bone metabolism and disease in chronic kidney disease. Content, Methods, Recommendations Bone biopsy is the gold standard for the diagnosis of aluminum bone disease. Aluminum overload leading to aluminum bone disease should be treated with deferoxamine mesylate. A deferoxamine mesylate test should be performed if there are elevated serum aluminum levels (60 to 200 µg/l), clinical signs and symptoms of aluminum toxicity, or prior to parathyroid surgery if the patient has had aluminum exposure. References Professional society guidelines/other: Autism: recognition, referral, diagnosis and management of adults on the autism spectrum. Clinical guideline; no Published June Last updated August National Institute for Health and Care Excellence website. Accessed February 28, Chapter 6. Blood transfusion in the management of sickle cell disease. In: Evidence-based management of sickle cell disease. Expert Panel Report National Heart, Lung, and Blood Institute (NHLBI) website. Accessed February 28, Fihn SD, Blankenship JC, Alexander KP, et al 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. Circulation. 2014; 130(19): DOI: /cir Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009; 50(1): DOI: /hep NKF KDOQI Guidelines. KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease National Kidney Foundation website. Accessed February 28, Peer-reviewed references: Bollig C, Schell LK, Rucker G, et al. Deferasirox for managing iron overload in people with thalassaemia. Cochrane Database Syst Rev. 2017; 8: Cd DOI: / CD pub3. 8

9 Escolar E, Lamas GA, Mark DB, et al. 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). Circ Cardiovasc Qual Outcomes. 2014; 7(1): DOI: /circoutcomes FDA Approved Drug Products. FDA website Accessed February 28, FDA Public Health Advisory: Edetate Disodium (marketed as Endrate and generic products). Last updated July 10, FDA website htm. Accessed February 28, James S, Stevenson SW, Silove N, Williams K. Chelation for autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2015; (5): Cd DOI: / CD pub2. Lamas GA, Boineau R, Goertz C, et al. 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. 2014; 168(1): e35. DOI: / Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. Jama. 2013; 309(12): DOI: /j.ahj Ma J, You C, Hao L. Iron chelators for acute stroke. Cochrane Database Syst Rev. 2012; (9): Cd DOI: / CD pub2. Mark DB, Anstrom KJ, Clapp-Channing NE, et al. 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. 2014; 7(4): DOI: /circoutcomes Sears ME. Chelation: harnessing and enhancing heavy metal detoxification--a review. ScientificWorldJournal. 2013; 2013: DOI: /2013/ Smith SW. The role of chelation in the treatment of other metal poisonings. J Med Toxicol. 2013; 9(4): DOI: /s Sumorok N, Goldfarb DS. Update on cystinuria. Curr Opin Nephrol Hypertens. 2013; 22(4): DOI: /MNH.0b013e c5d. Walsh J, Gittoes N, Selby P. Society for Endocrinology Endocrine Emergency Guidance: Emergency management of acute hypercalcaemia in adult patients. Endocr Connect. 2016; 5(5): G9 g11. DOI: /ec

10 Toxic Substances Portal. Agency for Toxic Substances and Disease Registry website. Accessed February 28, Wax PM. Current use of chelation in American health care. J Med Toxicol. 2013; 9(4): DOI: /s Yang SK, Xiao L, Song PA, et al. Is lead chelation therapy effective for chronic kidney disease? A metaanalysis. Nephrology (Carlton). 2014; 19(1): DOI: /nep CMS National Coverage Determinations (NCDs): Chelation Therapy for Treatment of Atherosclerosis Ethylenediamine-Tetra-Acetic (EDTA) Chelation Therapy for Treatment of Atherosclerosis. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hr Each additional hours Additional sequential infusions of a new drug, up to 1 hour Concurrent infusion ICD-10 Code Description Comments E Hereditary hemochromatosis E Hemochromatosis due to repeated red blood cell transfusion T45.1X1-1X4 Gold overload or toxicity T45.4X1-4X4 Iron overload or toxicity T47.7X1-7X4 Copper overload or toxicity T56.0X1-0X4 Lead overload or toxicity T56.1X1-1X4 Mercury overload or toxicity T57.0X1-0X4 Arsenic overload or toxicty HCPCS Level II Code J0470 Description Injection, dimercaprol, per 100 mg Comments 10

11 HCPCS Level II Code J0600 J0895 J3520 S9355 Description Injection, edetate calcium disodium, up to 1000 mg Injection, deferoxamine mesylate, 500 mg Edetate,disodium, per 150 mg Home infusion therapy, chelation therapy, administrative services, per dium Comments 11