Difference between revisions of "Chelation therapy for cardiovascular disease"

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{{CMG}}, Gervasio Lamas, M.D.; {{AE}} {{Rim}}
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'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.
  
 
'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br>
 
'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br>
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==Overview==
 
==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 [[atherosclerosis|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.
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[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract). Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels (2012 CDC recommendations), patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia (American Association for the Study of Liver Diseases Guidelines), or [[sickle cell disease]] and transfusion acquired iron-overload (NHLBI Transfusion Guidelines), to name a few instances.
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[[Ethylene diamine tetraacetic acid]] (EDTA, edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as lead, cadmium, nickel, cobalt, iron, aluminum, and others. The initial medical use for EDTA began after World War II for the treatment of lead-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]].  The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the hypocalcemia it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.
  
 
==Chelation Therapy and CVD==
 
==Chelation Therapy and CVD==
The use of [[chelation therapy]] as a treatment for [[atherosclerosis|atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of [[EDTA]] for the treatment of [[angina pectoris]].<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Opinions regarding the use of chelation therapy for [[CVD]] have long been controversial as there was not enough evidence supporting its use.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref>  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]].<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref>  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.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[PAD|peripheral artery occlusive disease]] revealed no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref>  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.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref>  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]].<ref name="pmid23165665">{{cite journal| author=Qaseem A, Fihn SD, Dallas P, Williams S, Owens DK, Shekelle P et al.| title=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. | journal=Ann Intern Med | year= 2012 | volume= 157 | issue= 10 | pages= 735-43 | pmid=23165665 | doi=10.7326/0003-4819-157-10-201211200-00011 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23165665 }} </ref>
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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 and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell (Kitchell, Meltzer, & Seven, 1961; Kitchell, Palmon, Aytan, & Meltzer, 1963) were less positive, and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negativeTo be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref>
  
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy.  Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used.  A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> 
  
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.<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050  }} </ref>  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.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref>
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy.  Professional organizations recommended against chelation therapy (Lewin, 1997).  Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.
  
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In light of the persistent controversy 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 efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less).  The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050  }} </ref>
  
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 adjustmentBecause 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.<ref name="pmid24254885">{{cite journal| author=Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y et al.| title=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). | journal=Circ Cardiovasc Qual Outcomes | year= 2014 | volume= 7 | issue= 1 | pages= 15-24 | pmid=24254885 | doi=10.1161/CIRCOUTCOMES.113.000663 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24254885  }} </ref>
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A follow up period of 55 months revealed a 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 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050  }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref>
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015).  Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.
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These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy (ACC/AHA 2014 SIHD guidelines). The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].  
  
 
==Mechanism of Action==
 
==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]].<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy helps in the elimination of metals including [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]] and [[aluminum]] from the bloodXenobiotic 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.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632  }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939  }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277  }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838  }} </ref> 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]].<ref>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.</ref><ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref>  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.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> 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.<ref name="pmid13810514">{{cite journal| author=CLARKE NE| title=Atherosclerosis, occlusive vascular disease and EDTA. | journal=Am J Cardiol | year= 1960 | volume= 6 | issue= | pages= 233-6 | pmid=13810514 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13810514 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> 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.<ref>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</ref>
+
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals.  In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solutionPlacebo did not increase the excretion of toxic metals.  Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%.  Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium.  A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al).
 +
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632  }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939  }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277  }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838  }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza).  
 +
Heavy metals may play a role in the development of cardiovascular disease through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as cadmium, mercury, manganese, chromium, cobalt, nickel, iron, and copper, metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids (pubmed ID: PMC345326, PMC425370, 8847477). Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability (15894814), endothelial cell dysfunction (7710289), and hypertension (18567711). Heavy metal exposure is also associated with genetic and epigenetic manifestations. Cadmium promotes atherosclerosis and endothelial dysfunction through multiple genetic changes (19556524).  One of the mechanisms involves DNA strand breaks and damage with subsequent apoptosis in endothelial cells (Messner Knoflack ATVB). Also, maternal lead exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of DNA methylation early in life (Sen, Heredia, Senut et al, Nature Scientific Reports Jan 2015).
 +
 
 +
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of chelation therapy may result from enhanced excretion of heavy metals, and subsequent reduction in processes listed above.  Additionally, in patients with diabetes, a reduction in the metal-catalyzed formation of reactive oxygen species, formation of advanced glycation end-products, and lipid peroxidation has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases inflammation and oxidative stress that characterize atherosclerosis.<ref>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</ref> Recent research, including chelation-activity assays, indicates that many common diabetes drugs, such as metformin and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).
 +
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use.  This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as  ascorbic acid, B-vitamins and magnesium, thought to have a protective effect on endothelial cells,<ref>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.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.  
 +
 
 +
==Future Studies==
 +
TACT was a unique study with an unexpected result that could have vast public health implications.  In order to consider its broad applicability, the medical and scientific community require the results reproduced.  TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients.  If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.
  
 
==Side Effects==
 
==Side Effects==
Line 41: Line 57:
  
 
==Landmark Trials==
 
==Landmark Trials==
[[TACT]]
+
[[TACT]] <br>
 +
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])
  
 
==References==
 
==References==

Revision as of 15:22, 6 December 2016

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

To read more about chelation therapy click here.

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

Overview

Chelation is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. Chelation therapy, which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract). Common chelators include penicillamine, which binds copper and can be used to treat Wilson’s disease, deferoxamine, which binds iron and is used in the treatment of thalassemia and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels (2012 CDC recommendations), patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia (American Association for the Study of Liver Diseases Guidelines), or sickle cell disease and transfusion acquired iron-overload (NHLBI Transfusion Guidelines), to name a few instances.

Ethylene diamine tetraacetic acid (EDTA, edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as lead, cadmium, nickel, cobalt, iron, aluminum, and others. The initial medical use for EDTA began after World War II for the treatment of lead-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of atherosclerotic disease. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the hypocalcemia it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.

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 and reported improvement in 19 of 20 patients.[1] Later studies by Kitchell (Kitchell, Meltzer, & Seven, 1961; Kitchell, Palmon, Aytan, & Meltzer, 1963) were less positive, and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of chelation therapy for cardiovascular disease (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.[2]

For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.[3] Another study demonstrated that EDTA supplemented with several B vitamins (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 reported no benefit associated with chelation therapy.[5] The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.[6]

The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy (Lewin, 1997). Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for cardiovascular disease and other diagnoses.

In light of the persistent controversy 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 efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function (creatinine 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium EDTA combined with ascorbic acid, B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, stroke, MI, coronary revascularization, and hospitalization for angina.[7]

A follow up period of 55 months revealed a 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 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for statins in post-MI patients (NNT=16 for the secondary prevention of a major coronary event).[7] The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.[8]

TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and diabetes (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.

These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy (ACC/AHA 2014 SIHD guidelines). The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the NIH.

Mechanism of Action

Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.[9] Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al). While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.[10] This evidence is strongest for lead and cadmium.[11][12][13] Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). Heavy metals may play a role in the development of cardiovascular disease through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as cadmium, mercury, manganese, chromium, cobalt, nickel, iron, and copper, metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids (pubmed ID: PMC345326, PMC425370, 8847477). Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability (15894814), endothelial cell dysfunction (7710289), and hypertension (18567711). Heavy metal exposure is also associated with genetic and epigenetic manifestations. Cadmium promotes atherosclerosis and endothelial dysfunction through multiple genetic changes (19556524). One of the mechanisms involves DNA strand breaks and damage with subsequent apoptosis in endothelial cells (Messner Knoflack ATVB). Also, maternal lead exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of DNA methylation early in life (Sen, Heredia, Senut et al, Nature Scientific Reports Jan 2015).

Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of chelation therapy may result from enhanced excretion of heavy metals, and subsequent reduction in processes listed above. Additionally, in patients with diabetes, a reduction in the metal-catalyzed formation of reactive oxygen species, formation of advanced glycation end-products, and lipid peroxidation has been postulated.[14] Metal detoxification in the context of diabetes possibly decreases inflammation and oxidative stress that characterize atherosclerosis.[15] Recent research, including chelation-activity assays, indicates that many common diabetes drugs, such as metformin and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524). The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as ascorbic acid, B-vitamins and magnesium, thought to have a protective effect on endothelial cells,[16] making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.

Future Studies

TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.

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
TACT 2 [2] (link to press release [3])

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. 7.0 7.1 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.
  8. 8.0 8.1 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.
  9. 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.
  10. 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.
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