Chelation therapy for cardiovascular disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Gervasio Lamas, M.D.; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

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Synonyms and keywords: Chelation therapy, EDTA, post-myocardial infarction, diabetes

Overview

Chelation is a process by which a charged molecule captures an ion with an opposite charge, inactivates it, and then permits its excretion, usually by a renal route. Thus, chelation therapy, which involves multiple administrations of the chelating agent, helps detoxify the blood. Ethylene diamine tetraacetic acid (EDTA), a commonly used chelating agent, binds to and permits excretion of metals such as lead, cadmium, nickel, cobalt, iron and aluminum. In addition to its use for the treatment of metal poisoning, chelation therapy has been considered an alternative medicine for the treatment of atherosclerotic disease. Many mechanisms have been postulated, including decalcification of atherosclerotic vessels. Other potential mechanisms, more accepted in the modern era, center around metal detoxification. Opinions regarding the use of chelation therapy for cardiovascular diseases (CVD) have long been controversial, as, until recently, there was not enough high-quality evidence for or against its use. Most recently, the Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled, 2x2 factorial trial, investigated the effect of EDTA-based infusions among stable post-myocardial infarction patients more than 50 years of age and with fairly normal kidney function. TACT revealed a modest decrease in major adverse cardiovascular events among enrolled patients randomized to EDTA-based infusions. When the pre-specified subgroup of patients with diabetes was analyzed, the decrease in adverse cardiovascular outcomes was even more robust.

Chelation Therapy and CVD

The use of chelation therapy as a treatment for atherosclerotic disease dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris.[1] Opinions regarding the use of chelation therapy for CVD have long been controversial as there was not enough evidence supporting its use.[2] Several studies investigated the use of chelation therapy as a treatment modality for atherosclerotic diseases, but studies were not prospective, nor randomized. For example, according to an extensive case series, there was an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral vascular disease.[3] Another study demonstrated that EDTA supplemented with several vitamin B (Vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving endothelium-dependent forearm blood flow.[4] A systematic review of four randomized clinical trials on chelation therapy and peripheral artery occlusive disease revealed no benefit associated with chelation therapy.[5] In addition, a systematic review on the role of chelation therapy in coronary heart disease (CHD) in 2002 concluded that the data on chelation therapy and CHD was insufficient to recommend for or against chelation therapy.[6] Finally, according to the 2012 summary of clinical practice guidelines from the 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, it was recommended that chelation therapy should not be used for symptomatic treatment or cardiovascular risk reduction among patients with stable ischemic heart disease.[7]


Yet in spite of the recommendations against chelation therapy by professional organizations, patients continued to seek, and practitioners to administer, chelation infusions. In the light of the controversies regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, The National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the effect of EDTA based infusions among 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function. The infusions consisted of disodium EDTA combined with ascorbic acid, vitamin B and other components. The median age of patients was 65 years, and they were well-treated with evidence-based medicines for post-MI patients. The primary outcome of this trial was a composite of all-cause mortality, coronary revascularization, recurrence of myocardial infarction, stroke or angina requiring hospitalization. A follow up period of 55 months revealed a modest but statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 20 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for statins in post-MI patients.[8] The point estimate for the risk of each of the components of the primary endpoint was <1, thus consistent with the aggregate result. In an abundance of caution, the investigators called for a cautious interpretation and more research before recommending chelation therapy for post-MI patients.[9]


TACT prespecified several subgroups for analysis, and found that there appeared to be an interaction between EDTA treatment and self-reported diabetes (interaction p=0.02). The diagnosis of diabetes was made more accurate and then the effect of chelation therapy was assessed in the 633-patient subgroup with diabetes (defined as self-reported diabetes, taking treatment for diabetes or having a fasting blood glucose of at least 126 mg/dL at enrollment). The use of chelation therapy infusions among post-MI diabetic patients was associated with a decrease in the primary end point of extraordinary magnitude. In fact, the primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who were not (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The effect of chelation therapy on the primary end point remained significant following a highly conservative Bonferroni adjustment for multiple subgroups (99.4% CI, 0.39–0.88; adjusted P=0.002). The 5-year NNT to prevent one event was 6.5, comparing favorably to an NNT of 12-15 for statin therapy in diabetics with established vascular disease. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction) and reinfarction (52% reduction); however, these associations were no longer significant following Bonferroni adjustment. Because diabetes was examined as a subgroup, the most conservative interpretation of these striking findings is that they are hypothesis-generating, and should lead to more research, rather than guidelines to treat all post-MI diabetics with an EDTA-based chelation regimen. Still, the individual clinician should retain the right to individualize his or her patient’s post-MI therapy.[10]

Mechanism of Action

Ethylenediamine tetraacetic acid (EDTA), a type of chelating agent, binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.[11] Hence, chelation therapy helps in the elimination of metals including lead, cadmium, nickel, cobalt, iron and aluminum from the blood. Xenobiotic metals, or those metals like lead, cadmium, cobalt, arsenic, mercury, and many others, have no role in the human body. As a group they all have unique toxicities, and toxicities that are common to all of them. Common toxicities, for example, include interaction and inactivation of our own enzymatic systems for quenching the oxidant stress of reactive oxygen species. Most importantly there is robust epidemiological evidence linking urine metals with cardiovascular disease.[12] This evidence is strongest for lead and cadmium.[13][14][15] EDTA chelates both. The standard chelation infusion has been modified by clinical practitioners to have additives such as vitamin B, ascorbic acid and magnesium which are thought to have a protective effect on the endothelial cells.[16][17] Cardiovascular benefits of chelation therapy may result from its antioxidant effect as it decreases the metal-dependent formation of reactive oxygen species, formation of glycation end-products and lipid peroxidation.[17] In addition, the removal of calcium from arterial wall by chelation therapy might possibly lead to a regression of the atherosclerotic plaques, although it is not clear that this calcium pool is accessible to EDTA.[18][19] In addition, metal detoxification in the context of diabetes possibly decreases inflammation and oxidative stress that characterize atherosclerosis by decreasing metal-dependent formation of glycation end products.[20]

Side Effects

Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.

Landmark Trials

TACT

References

  1. ↑ CLARKE CN, CLARKE NE, MOSHER RE (1956). "Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid". Am J Med Sci. 232 (6): 654–66. PMID 13372537.
  2. ↑ Villarruz MV, Dans A, Tan F (2002). "Chelation therapy for atherosclerotic cardiovascular disease". Cochrane Database Syst Rev (4): CD002785. doi:10.1002/14651858.CD002785. PMID 12519577.
  3. ↑ Olszewer E, Carter JP (1988). "EDTA chelation therapy in chronic degenerative disease". Med Hypotheses. 27 (1): 41–9. PMID 3144646.
  4. ↑ Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR (1999). "Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function". Clin Exp Pharmacol Physiol. 26 (11): 853–6. PMID 10561804.
  5. ↑ Ernst E (1997). "Chelation therapy for peripheral arterial occlusive disease: a systematic review". Circulation. 96 (3): 1031–3. PMID 9264515.
  6. ↑ 6.0 6.1 Ernst E (2000). "Chelation therapy for coronary heart disease: An overview of all clinical investigations". Am Heart J. 140 (1): 139–41. doi:10.1067/mhj.2000.107548. PMID 10874275.
  7. ↑ Qaseem A, Fihn SD, Dallas P, Williams S, Owens DK, Shekelle P; et al. (2012). "Management of stable ischemic heart disease: summary of a clinical practice guideline from the 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". Ann Intern Med. 157 (10): 735–43. doi:10.7326/0003-4819-157-10-201211200-00011. PMID 23165665.
  8. ↑ Costa J, Borges M, David C, Vaz Carneiro A (2006). "Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials". BMJ. 332 (7550): 1115–24. doi:10.1136/bmj.38793.468449.AE. PMC 1459619. PMID 16585050.
  9. ↑ 9.0 9.1 Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL; et al. (2013). "Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial". JAMA. 309 (12): 1241–50. doi:10.1001/jama.2013.2107. PMID 23532240.
  10. ↑ Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y; 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)". Circ Cardiovasc Qual Outcomes. 7 (1): 15–24. doi:10.1161/CIRCOUTCOMES.113.000663. PMID 24254885.
  11. ↑ WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM (1962). "Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle". Surgery. 52: 793–5. PMID 14000694.
  12. ↑ Agarwal S, Zaman T, Tuzcu EM, Kapadia SR (2011). "Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006". Angiology. 62 (5): 422–9. doi:10.1177/0003319710395562. PMID 21421632.
  13. ↑ Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E (2006). "Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults". Circulation. 114 (13): 1388–94. doi:10.1161/CIRCULATIONAHA.106.628321. PMID 16982939.
  14. ↑ Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E (2004). "Lead, cadmium, smoking, and increased risk of peripheral arterial disease". Circulation. 109 (25): 3196–201. doi:10.1161/01.CIR.0000130848.18636.B2. PMID 15184277.
  15. ↑ Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W; et al. (2013). "Cadmium exposure and incident cardiovascular disease". Epidemiology. 24 (3): 421–9. doi:10.1097/EDE.0b013e31828b0631. PMID 23514838.
  16. ↑ Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.
  17. ↑ 17.0 17.1 Lamas GA, Ackermann A (2000). "Clinical evaluation of chelation therapy: is there any wheat amidst the chaff?". Am Heart J. 140 (1): 4–5. doi:10.1067/mhj.2000.107549. PMID 10874253.
  18. ↑ CLARKE NE (1960). "Atherosclerosis, occlusive vascular disease and EDTA". Am J Cardiol. 6: 233–6. PMID 13810514.
  19. ↑ KITCHELL JR, PALMON F, AYTAN N, MELTZER LE (1963). "The treatment of coronary artery disease with disodium EDTA. A reappraisal". Am J Cardiol. 11: 501–6. PMID 14033183.
  20. ↑ Escolar E, Lamas G, Mark D et al(2013) "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. 2013


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