Trial To Assess Chelation Therapy Research Articles

Edetate Disodium–Based Chelation for Patients With a Previous Myocardial Infarction and Diabetes

In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)-based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI). To replicate the finding of TACT in individuals with diabetes and previous MI. A 2 × 2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons. Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study. The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion. Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P = .53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 μg/L at baseline to 3.46 μg/L at infusion 40 (P < .001). Corresponding levels in the placebo group were 9.3 μg/L and 8.7 μg/L, respectively. Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI. ClinicalTrials.gov Identifier: NCT02733185.

Baseline characteristics including blood and urine metal levels in the Trial to Assess Chelation Therapy 2 (TACT2)

BackgroundThe reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. MethodsTACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2’s participants. ResultsAt baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. ConclusionsTACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. Clinical Trials RegistrationClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185

Low-Level Cadmium Exposure and Atherosclerosis.

Cadmium has been recognized as a potential risk factor for cardiovascular disease (CVD). We present a review of cadmium toxicity, its effect on cellular activities, and a summary of reported association between environmental cadmium exposure and CVD. We also discuss the possible therapeutic benefit of cadmium chelation. Experimental data suggest that cadmium affects several signaling pathways which may lead to endothelial dysfunction and vascular tissue damage, promoting atherosclerosis. This is further supported by epidemiological studies that have shown an association of even low-level cadmium exposure with an increased risk of clinical cardiovascular events. The Trial to Assess Chelation Therapy (TACT) provided inferential evidence for the cardiovascular benefit of treating toxic metal burden. However, at the present time, there is no direct evidence, but suggestive findings from clinical trials indicating that removal of cadmium from body stores may be associated with improved cardiovascular outcomes. An evolving body of evidence supports environmental cadmium exposure as a pro-atherosclerosis risk factor in CVD; however, the mechanisms for the proatherogenic effect of cadmium are still not completely understood. Further studies in translational toxicology are needed to fill the knowledge gaps regarding the molecular mechanisms of cadmium toxicity and the promotion of atherosclerosis.

Possible differential benefits of edetate disodium in post-myocardial infarction patients with diabetes treated with different hypoglycemic strategies in the Trial to Assess Chelation Therapy (TACT)

BackgroundThe NIH-funded Trial to Assess Chelation Therapy (TACT) randomized 1708 stable patients age ≥50 who were ≥6 months post myocardial infarction to 40 infusions of an edetate disodium-based regimen or placebo. In 633 patients with diabetes, edetate disodium significantly reduced the primary composite endpoint of mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44–0.79, p < 0.001). The principal secondary endpoint of a composite of cardiovascular death, myocardial infarction, or stroke was also reduced (HR 0.60, 95% CI 0.39–0.91, p = 0.017). It is unknown if the treatment effect differs by diabetes therapy. MethodsWe grouped the subset of 633 patients with diabetes according to glucose-lowering therapy at time of randomization. The log-rank test was used to compare active therapy versus placebo. All treatment comparisons were performed using 2-sided significance tests at the significance level of 0.05 and were as randomized. Relative risks were expressed as HR with associated 95% CI, calculated using the Cox proportional hazards model. ResultsThere were 162 (25.7%) patients treated with insulin; 301 (47.5%) with oral hypoglycemics only; and 170 (26.8%) receiving no pharmacologic treatment for diabetes. Patients on insulin reached the primary endpoint more frequently than patients on no pharmacologic treatment [61 (38%) vs 49 (29%) (HR 1.56, 95% CI 1.07–2.27, p = 0.022)] or oral hypoglycemics [61 (38%) vs 87 (29%) (HR 1.46, 1.05–2.03, p = 0.024)]. The primary endpoint occurred less frequently with edetate disodium based therapy versus placebo in patients on insulin [19 (26%) vs 42 (48%) (HR 0.42, 95% CI 0.25–0.74, log-rank p = 0.002)], marginally in patients on oral hypoglycemics [38 (25%) vs 49 (34%) (HR 0.66, 95% CI 0.43–1.01, log-rank p = 0.041)], and no significant difference in patients not treated with a pharmacologic therapy [23 (25%) vs 26 (34%) (HR 0.69, 95% CI 0.39–1.20, log-rank p = 0.225)]. The interaction between randomized intravenous treatment and type of diabetes therapy was not statistically significant (p = 0.203). ConclusionsEdetate disodium treatment in stable, post-myocardial infarction patients with diabetes suggests that patients on insulin therapy at baseline may accrue the greatest benefit.Clinical Trial Registration: clinicaltrials.gov identifier: http://clinicaltrials.gov/ct2/show/NCT00044213?term=TACT&rank=7 identifierTrial to Assess Chelation Therapy (TACT), NCT00044213.

Differential Outcomes With Edetate Disodium-Based Treatment Among Stable Post Anterior vs. Non-Anterior Myocardial Infarction Patients

BackgroundThe Trial to Assess Chelation Therapy (TACT) found that chelation therapy significantly reduced clinical events in patients with a history of myocardial infarction (MI). The initial report of TACT included the observation of an interaction between edetate disodium infusions and MI location, as well as diabetes. Thus, we examined in greater detail the effect of edetate disodium chelation therapy as a function of MI location and diabetes. MethodsPatients (n = 1708) at least 6 weeks post-MI and age ≥ 50 were randomized to receive 40 infusions of a 500 mL chelation solution or placebo (median follow-up 55 months). The effect of edetate disodium on the primary outcome (all-cause mortality, MI, stroke, hospitalization for angina, or coronary revascularization) was assessed as a function of MI location using log-rank test and Cox regression model, adjusting for other prognostic variables. ResultsAmong patients with post anterior MI (n = 674), chelation was associated with a lower risk of the primary endpoint (HR 0.63, 95% CI 0.47–0.86, p = 0.003) among anterior MI patients, but not in post non-anterior MI (n = 1034) patients (HR 0.96, 95% CI 0.77–1.20, p = 0.702) (p-for-interaction = 0.032). The point estimates for each component of the primary endpoint favored chelation therapy. The differing treatment effect in patients with post anterior vs. non-anterior MI was consistent among patients with or without diabetes and remained significant after adjusting for other prognostic variables (p < 0.01). ConclusionsEdetate disodium infusions reduced the risk of cardiovascular events among patients with a prior anterior MI. Future studies should focus on replicating these results and understanding the mechanisms of benefit.

Abstract P452: Urinary Metal Levels After Repeated Chelation With Edetate Disodium: Additional Evidence in Support of Metals as Cardiovascular Risk Factors

Background: Epidemiologic evidence supports lead and cadmium as CVD risk factors. In the Trial to Assess Chelation Therapy (TACT), edetate disodium infusions lowered CVD risk in patients with a prior myocardial infarction. The impact of repeated chelation on established biomarkers of metal body burden, post-chelation lead and pre-chelation urine cadmium, is unknown. Objective: To assess metals in urine samples collected at the first and at 10 or more infusions with edetate disodium. We hypothesized that post-chelation urine lead and pre-chelation urine cadmium would be lower after 10 infusions compared to the first infusion. Other metals were exploratory. Methods: 13 patients with coronary artery disease (CAD) received a median of 3 g of edetate disodium over 3h per infusion and a median of 51 infusions (range 22-61). We collected pre and post-chelation urine samples at infusions 1 and ≥10. Metals were analyzed with ICPMS and controlled for urine dilution. Pre and post-chelation geometric means (GM) of urine metals at the ≥10 vs. first infusion were compared using paired T-tests. Results: Mean (SD) age was 75 (11) years, 77% participants were men, 46% were past smokers, 92% had diabetes, and 92% had peripheral artery disease. Comparing infusions ≥10 to 1 (Table), the GM (μg/g creatinine) dropped from 0.45 to 0.03 (94% reduction; p=0.005) for pre-chelation lead and from 14.80 to 2.91 (80% reduction; p=0.04) for post-chelation lead. For pre and post-chelation cadmium, the corresponding figures were 0.34 to 0.12 (64% reduction; p=0.17) and 2.81 to 2.35 (16% reduction; p=0.48), respectively. Conclusions: TACT treatment may decrease total body burden of lead, further supporting lead is a modifiable CVD risk factor. Data are insufficient to inform on changes in the burden of cadmium or other metals. Ongoing, larger studies will assess the effect of repeated chelation on toxic metal burden and incident cardiovascular disease.

The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT)

ObjectiveApproximately 1 in 7 US adults have diabetes; and over 60% of deaths in patients with diabetes have cardiac disease as a principal or contributing cause. Both coronary and peripheral artery disease (PAD) identify high-risk cohorts among patients with diabetes. We have previously demonstrated improved cardiovascular outcomes with edetate disodium-based chelation in post-MI patients with diabetes, enrolled in the Trial to Assess Chelation Therapy (TACT). In these analyses we further studied the effect size of patients with diabetes and severe disease in 2 vascular beds; coronaries, and lower extremity arteries. We questioned whether greater atherosclerotic burden would attenuate the observed beneficial effect of edetate disodium infusions. Research design and methodsThe multicenter TACT used a double blind, placebo controlled, 2 × 2 factorial design with 1708 participants, randomly assigned to receive edetate disodium-based chelation, or placebo and high dose oral vitamins or placebo. There were 162 (9.5% of 1708) post-MI patients with a diagnosis of diabetes mellitus and PAD for this post hoc analysis. Patients received up to 40 double-blind intravenous infusions of edetate disodium-based chelation, or placebo. The composite primary endpoint of TACT consisted of death from any cause, myocardial infarction, stroke, coronary revascularization and hospitalization for angina. ResultsThe median age was 66 years, 15% female, 5% non-Caucasian, and BMI was 31. Insulin was used by 32% of patients. Active infusions significantly reduced the primary endpoint compared with placebo infusions (HR, 0.52; 95% CI, 0.30–0.92; P = 0.0069), with a 30% absolute risk reduction in the primary endpoint. There was a marked reduction in total mortality from 24% to 11%, although of borderline significance (P = 0.052). ConclusionAtherosclerotic disease in multiple vascular beds did not attenuate the beneficial effect of edetate disodium infusions in post MI patients with diabetes. Studies now in progress will prospectively test this post hoc finding.

Potential Role of Metal Chelation to Prevent the Cardiovascular Complications of Diabetes.

For decades, there has been epidemiologic evidence linking chronic toxic metal exposure with cardiovascular disease, suggesting a therapeutic role for metal chelation. Given the lack of compelling scientific evidence, however, the indications for metal chelation were never clearly defined. To determine the safety and efficacy of chelation therapy, the National Institutes of Health funded the Trial to Assess Chelation Therapy (TACT). TACT was the first double-blind, randomized, controlled trial to demonstrate an improvement in cardiovascular outcomes with edetate disodium therapy in patients with prior myocardial infarction. The therapeutic benefit was striking among the prespecified subgroup of patients with diabetes. We review the published literature focusing on the atherogenic nature of diabetes, as well as available evidence from clinical trials, complete and in progress, of metal chelation with edetate disodium therapy in patients with diabetes. The TACT results support the concept that ubiquitous toxic metals such as lead and cadmium may be modifiable risk factors for cardiovascular disease, particularly in patients with diabetes. The purpose of this review is to discuss the potential mechanisms unifying the pathogenesis of atherogenic factors in diabetes with toxic metal exposure, and the potential role of metal chelation.

Edetate Disodium-Based Treatment in a Patient With Diabetes and Critical Limb Ischemia After Unsuccessful Peripheral Arterial Revascularizations: A Case Report.

Peripheral artery disease (PAD) is a progressive form of atherosclerosis that affects the lower extremities, particularly in patients with diabetes. Critical limb ischemia (CLI), the end-stage manifestation of this disease, is associated with an increased risk of chronic leg ulcerations, infections, amputations, and mortality. At presentation, 30% of CLI patients require amputation, and 25% will die within 1 year (1). Toxic metal exposure, particularly to cadmium, has been associated with an increased risk of vascular disease in epidemiological studies and PAD severity in patients with coronary artery disease (CAD) (2–4). Toxic metals are ubiquitous and can induce increased oxidative stress, endothelial dysfunction, and inflammation (4). Similarly, chronic cadmium exposure has been found to play a role in the acceleration of vascular disease in animal models (5,6). Edetate disodium is a chelating agent with high affinity for lead and cadmium (7). The Trial to Assess Chelation Therapy (TACT) demonstrated that edetate disodium–based chelation reduced cardiovascular events, especially in patients with diabetes after myocardial infarction (8,9). An 81-year-old man with a 35-year history of insulin-dependent diabetes, a 20 pack-year smoking history (quit date October 2001), atrial fibrillation, and CAD requiring coronary artery bypass in 2001 presented to the vascular service. His medications at baseline included sotalol, rivaroxaban, pentoxifylline, clopidogrel, aspirin, insulin, pregabalin, and atorvastatin. His baseline serum creatinine was 0.77 mg/dL, and his BMI was 22 kg/m2. He had progressive CLI with nonhealing ulcers and pain unimproved by medical therapy. Noninvasive tests demonstrated abnormal ankle-brachial indices bilaterally. Lower-extremity angiography revealed total occlusions of the left external iliac artery, left superficial femoral artery, distal right …

Chelation therapy to prevent diabetes-associated cardiovascular events.

For over 60 years, chelation therapy with disodium ethylene diamine tetraacetic acid (EDTA, edetate) had been used for the treatment of cardiovascular disease (CVD) despite lack of scientific evidence for efficacy and safety. The Trial to Assess Chelation Therapy (TACT) was developed and received funding from the National Institutes of Health (NIH) to ascertain the safety and efficacy of chelation therapy in patients with CVD. This pivotal trial demonstrated an improvement in outcomes in postmyocardial infarction (MI) patients. Interestingly, it also showed a particularly large reduction in CVD events and all-cause mortality in the prespecified subgroup of patients with diabetes. The TACT results may support the concept of metal chelation to reduce metal-catalyzed oxidation reactions that promote the formation of advanced glycation end products, a precursor of diabetic atherosclerosis. In this review, we summarize the epidemiological and basic evidence linking toxic metal accumulation and diabetes-related CVD, supported by the salutary effects of chelation in TACT. If the ongoing NIH-funded TACT2, in diabetic post-MI patients, proves positive, this unique therapy will enter the armamentarium of endocrinologists and cardiologists seeking to reduce the atherosclerotic risk of their diabetic patients.

Chelation Therapy as a Cardiovascular Therapeutic Strategy: the Rationale and the Data in Review.

Chelation therapy, typically used to remove heavy metal toxins, has also been controversially used as a treatment for coronary artery disease. The first Trial to Assess Chelation Therapy (TACT) aimed to provide evidence on chelation therapy's potential for benefit or harm. Although TACT had some significant results, the trial does not provide enough evidence to recommend routine chelation therapy and has limitations. The second TACT was recently funded reigniting a discussion about the value of chelation therapy, its efficacy, and allocation of research resources. Despite limited evidence, patients continue to pursue chelation therapy as a treatment for coronary artery disease. As the medical community has a responsibility to understand all treatments patients pursue, it is important to comprehensively appraise chelation therapy for cardiovascular disease. Understanding the background of heavy metal toxicity, the putative target of chelation therapy, on the cardiovascular system is important to contextualize the role of chelation therapy in cardiovascular disease prevention. We review the clinical evidence of heavy metal toxicity and cardiovascular disease, and available clinical trial data on use of chelation therapy to minimize the cardiovascular burden of heavy metal toxicity.

Effect of high-dose oral multivitamins and minerals in participants not treated with statins in the randomized Trial to Assess Chelation Therapy (TACT)

In a prespecified subgroup analysis of participants not on statin therapy at baseline in the TACT, a high-dose complex oral multivitamins and multimineral regimen was found to have a large unexpected benefit compared with placebo. The regimen tested was substantially different from any vitamin regimen tested in prior clinical trials. To explore these results, we performed detailed additional analyses of participants not on statins at enrollment in TACT. TACT was a factorial trial testing chelation treatments and a 28-component high-dose oral multivitamins and multiminerals regimen versus placebo in post-myocardial infarction (MI) patients 50 years or older. There were 460 (27%) of 1,708 TACT participants not taking statins at baseline, 224 (49%) were in the active vitamin group and 236 (51%) were in the placebo group. Patients were enrolled at 134 sites around the United States and Canada. Daily high-dose oral multivitamins and multiminerals (6 tablets, active or placebo). The primary end point of TACT was time to the first occurrence of any component of the composite end point: all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for angina. The primary end point occurred in 137 nonstatin participants (30%), of which 51 (23%) of 224 were in the active group and 86 (36%) of 236 were taking placebo (hazard ratio, 0.62; 95% confidence interval, 0.44-0.87; P=.006). Results in the key TACT secondary end point, a combination of cardiovascular mortality, stroke, or recurrent MI, was consistent in favoring the active vitamin group (hazard ratio, 0.46; 95% confidence interval, 0.28-0.75; P=.002). Multiple end point analyses were consistent with these results. High-dose oral multivitamin and multimineral supplementation seem to decrease combined cardiac events in a stable, post-MI population not taking statin therapy at baseline. These unexpected findings are being retested in the ongoing TACT2.

Enhanced vasculotoxic metal excretion in post-myocardial infarction patients following a single edetate disodium-based infusion

Toxic metals have been associated with cardiovascular mortality and morbidity. We have hypothesized that enhanced excretion of vasculotoxic metals might explain the positive results of the Trial to Assess Chelation Therapy (TACT). The purpose of this study was to determine whether a single infusion of the edetate disodium- based infusion used in TACT led to enhanced excretion of toxic metals known to be associated with cardiovascular events. MethodsTwenty six patients (post-MI, age > 50 years, serum creatinine ≤ 2.0 mg/dL) were enrolled in this open-label study. Urinary levels of 20 toxic metals normalized to urinary creatinine concentrations were measured at baseline in overnight urine collections, for 6 h following a placebo infusion of 500 mL normal saline and 1.2% dextrose, and for 6 h following a 3 g edetate disodium-based infusion. Self-reported metal exposure, smoking status, food frequency, occupational history, drinking water source, housing and hobbies were collected at baseline by a metal exposure questionnaire. ResultsThe mean age was 65 years (range 51–81 years). All patients were male. 50% had diabetes mellitus and 58% were former smokers. Mean (SD) serum creatinine was 0.95 (0.31) mg/dL. Toxic metals were detected in the baseline urine of >80% of patients. After placebo infusion there were no significant changes in total urinary metal levels. After edetate infusion, total urinary metal level increased by 71% compared to baseline (1500 vs. 2580 µg/g creatinine; P<0.0001). The effect of edetate was particularly large for lead (3835% increase) and cadmium (633% increase). ConclusionsEdetate disodium-based infusions markedly enhanced the urinary excretion of lead and cadmium, toxic metals with established epidemiologic evidence and mechanisms linking them to coronary and vascular events.

Abstract 494: Safety of Chelation Therapy With Edta in Patients With Critical Limb Ischemia: A Pilot Trial of Limb Preservation in Diabetic Patients

Critical limb ischemia (CLI) carries a one year 30% risk of amputation and 25% risk of mortality. Toxic metals are associated with peripheral artery disease and overall cardiac mortality. In The Trial to Assess Chelation Therapy (TACT), EDTA-based chelation improved outcomes in patients with coronary artery disease, with a particular benefit observed in diabetic patients. Here we present the preliminary findings of an open label study aimed at evaluating the safety of EDTA-based chelation, as used in TACT, in diabetic patients with CLI. Methods: Diabetic patients with CLI Rutherford stage 4 to 5, ≥ 75% stenosis in two or more infra-popliteal arteries and skin perfusion pressure of &lt;40 mmHg in the affected limb were enrolled. Participants received 40 infusions of disodium EDTA over the course of a year, with the first 20 infusions administered bi-weekly and subsequent infusions administered weekly. Laboratory safety assessments were conducted at nine of the infusion visits. Lower extremity pressures and skin perfusion pressures were obtained at baseline and after 20 and 40 infusions using the SensiLase PAD-IQ. HIPAA compliant photographs along with clinical and quality of life questionnaires were also collected. Results: Three patients (2 women and 1 man) out of 10 planned patients have completed forty EDTA-based infusions. The mean (SD) age and creatinine clearance were 80(7) years and 55(3) mL/min, respectively. All patients had detectable levels of toxic metals in urine; lead was the most abundant toxic metal in the chelated urine. The lowest baseline tissue perfusion pressure in the affected limb was 22, 17 and 19 mmHg for each of the three patients, respectively. Patients have been followed up for an average of 61 (14) weeks. There have been no side effects related to therapy. No patient has been amputated or developed an acute cardiac event. One patient had a PTCA of her affected leg and underwent a debridement of a non-healing ulcer. No significant changes have been detected in skin perfusion pressures during follow up. Conclusions: Preliminary findings of this open label trial suggest that EDTA treatment in CLI patients is safe. Moreover, after more than a year of follow up, no patient has required any amputation or had any cardiovascular event.

Chronic Toxic Metal Exposure and Cardiovascular Disease: Mechanisms of Risk and Emerging Role of Chelation Therapy.

Over the last few decades, there has been a growing body of epidemiologic evidence linking chronic toxic metal exposure to cardiovascular disease-related morbidity and mortality. The recent and unexpectedly positive findings from a randomized, double-blind, multicenter trial of metal chelation for the secondary prevention of atherosclerotic cardiovascular disease (Trial to Assess Chelation Therapy (TACT)) have focused the discussion on the role of chronic exposure to toxic metals in the development and propagation of cardiovascular disease and the role of toxic metal chelation therapy in the secondary prevention of cardiovascular disease. This review summarizes the most recent evidence linking chronic toxic metal exposure to cardiovascular disease and examines the findings of TACT.

Abstract 10466: Post-myocardial Infarction Treatment With Edetate Disodium was Safe in the Trial to Assess Chelation Therapy

Introduction: Treatment with edetate disodium has been in use for nearly 60 years for cardiovascular disease despite safety concerns, including deaths from hypocalcemia. No careful prospective evaluation of safety had been reported prior to the NIH-sponsored Trial to Assess Chelation Therapy (TACT). Methods: In TACT, 1,708 post-MI patients age ≥ 50 and creatinine ≤ 2.0 mg/dL were randomized doule blind to edetate-based chelation (n=839) or placebo (n=869). TACT implemented extensive site education prior to site activation. During the infusion period, there was close monitoring of vitals and labs, particularly creatinine and calcium, special lab-based (creatinine, calcium, and platelets) algorithms to delay infusions or reduce infusion rate when abnormal criteria were met, and early intervention to respond to safety concerns. Electronic and in-person monitoring took place to ensure adherence to TACT infusion protocols. Results: There were 100 (12%) serious adverse events (SAEs) in the edetate group and 127 (15%) in the placebo group (p=0.1009). Two deaths were possibly or definitely attributed, by the blinded safety monitor, to study therapy, 1 in the chelation group and 1 in the placebo group. Heart failure was reported in 57 edetate patients (7%) and 71 placebo patients (8%) (p=.28). Physical exams were identical over the course of the study, except for more tachycardia (heart rate &gt;100) in the placebo arm (0.1% vs 1.3% p=0.006). There was more infusion site discomfort (1.5% vs. 0.6%, p=0.049) with chelation and more abdominal cramping with placebo (1.7% v. 3.3%, p= 0.029) Reductions in calcium (&lt;8.5mg/dL) occurred in 52 chelation patients (6.2%) and 30 placebo patients (3.5%) during the infusion phase (p=.008). Calcium at last blood draw was not different between groups (mean calcium 9.3 vs 9.3, p=0.15). There was no adverse effect on renal function from edetate disodium (mean creatinine 1.04 (edetate) vs 1.07 (placebo), p=0.03) Conclusions: The experience with 55,222 infusions of edetate disodium or placebo in TACT shows that this therapy is extremely safe when used according to the TACT safe infusion protocol. This finding will be pivotal in informing the design of the TACT2 confirmatory study.

Abstract 16911: Behind the Looking Glass: Comparing Time to First Event versus Multiple Events Analyses in a Post-myocardial Infarction Clinical Trial

Introduction: Standard analysis of clinical trials with composite endpoints compare time-to-first event. Subsequent events are not counted and therefore not taken into account in treatment comparisons. We compared standard analyses to analyses that take into account all the events a patient may have experienced. Methods: The Trial to Assess Chelation Therapy (TACT) enrolled 1708 post-MI pts in a factorial trial comparing edetate disodium infusions versus placebo infusions and oral vitamins and minerals versus oral placebo. TACT had a composite primary endpoint: death, MI, stroke, coronary revascularization, and hospitalization for angina. Pre-specified primary analysis for TACT was based on the standard approach of considering time until the occurrence of the first event. Two different approaches for multiple events analyses were compared to the standard approach: 1] a generalization of the Cox model to handle recurrent events, developed by Andersen &amp; Gill (AG), and 2] a marginal modeling approach developed by Wie, Lin, and Weissfeld (WLW). Each considers the correlation among multiple events occurring within a pt. Results: There were 743 events in TACT. 483/1708 (28%) of the patients had at least 1 event. Time-to-first-event analysis did not use information on 260 (35%) events. The standard analysis for edetate disodium vs placebo produced a hazard ratio (HR) 0.82, 95% confidence intervals 0.69,0.99, p=0.035. Both multiple events analyses demonstrated narrower confidence intervals and lower P values. AG: HR 0.80 (0.66,0.96), p=0.017; and WLW: HR 0.79 (0.66, 0.95), p=0.010. In the comparison of the active edetate + active MVM vs placebo edetate + placebo MVM, there were 247/858 (29%) pts with at least 1 event, but there were 371 events. Therefore, 124 (33%) were not used. Results of the standard analysis for edetate + MVM showed HR 0.74 (0.57,0.95), p=0.016; for AG HR 0.66 (0.51,0.85),p=0.002, and for WLW HR 0.38 (0.30,0.49), p&lt;0.001. Conclusion: In this post-MI trial, a standard time to first event analysis did not make use of over 1/3 of events. Multiple events analysis can improve the precision of the estimate of benefit by producing narrower confidence intervals. These methods could be considered to reduce sample size and budgets in future clinical trials.

EDTA Chelation Therapy to Reduce Cardiovascular Events in Persons with Diabetes.

The Trial to Assess Chelation Therapy (TACT) was a randomized double-blind placebo-controlled trial enrolling patients age ≥50 years with prior myocardial infarction. TACT used a 2 × 2 factorial design to study ethylene diamine tetraacetic acid (EDTA) chelation and high-dose vitamin supplementation. Chelation provided a modest but significant reduction in cardiovascular endpoints. The benefit was stronger and significant among participants with diabetes but absent in those without diabetes. Mechanisms by which chelation might reduce cardiovascular risk in persons with diabetes include the effects of EDTA chelation on transition and toxic metals. Transition metals, particularly copper and iron, play important roles in oxidative stress pathways. Toxic metals, in particular cadmium and lead, are toxic for the cardiovascular system. This review discusses the epidemiologic evidence and animal and human studies supporting the role of these metals in the development of diabetes and ischemic heart disease and potential ways by which EDTA chelation could confer cardiovascular benefit.

The protection conferred by chelation therapy in post-MI diabetics might be replicated by high-dose zinc supplementation

The recent Trial to Assess Chelation Therapy (TACT) study, enrolling subjects who had previously experienced a myocardial infarction, has provided strong evidence that intravenous chelation therapy can markedly reduce risk for mortality and vascular events in diabetics, whereas no discernible benefit was observed in non-diabetics. It has plausibly been suggested that this reflects a role for transition metal ions – iron or copper – in the genesis of advanced glycation end products, key mediators of diabetic complications that can destabilize plaque. Since phlebotomy therapy fails to prevent vascular events in diabetics, we hypothesize that labile copper may be the chief culprit whose removal by chelation mediated the benefit observed in TACT. If so, strategies less time and labor intensive than chelation therapy might provide comparable benefit. A number of recent studies report that the copper-specific orally-active chelator trientine can reduce risk for range of diabetic complications in rodents; a clinical trial with this agent demonstrated some decrease in left ventricular mass in diabetics with ventricular hypertrophy. However, until this agent becomes less expensive, supplementation with high-dose zinc may represent a more feasible alternative. Zinc opposes the absorption and redox activity of copper via induction of the antioxidant protein metallothionein, which binds copper tightly. A great many studies demonstrate that increased expression of metallothionein decreases risk for tissue damage in diabetic rodents, and in some of these studies metallothionein expression was boosted by supplemental zinc. Zinc supplementation also modestly improves glycemic control in type 2 diabetics, and might reduce risk for diabetes by protecting pancreatic beta cells from oxidative stress. A long term study assessing the impact of supplementing diabetics with high-dose zinc, assessing risk for mortality, vascular events, and diabetic complications, may be warranted. Histidine, which readily forms complexes with copper that possess superoxide dismutase activity, also has potential for alleviating the contribution of loosely bound copper to AGE formation; moreover, in a recent clinical study, supplemental histidine improved insulin sensitivity and exerted anti-inflammatory and antioxidant effects in women with metabolic syndrome. Since ascorbate can reduce labile copper and thereby enhance its pathogenicity, the impact of high-dose ascorbate supplementation on cardiovascular risk in diabetics should receive further study.

Abstract 18819: Graded Benefit of EDTA Chelation in Post-MI Patients with Diabetes Treated with Different Hypoglycemic Strategies

Introduction: The NIH-funded Trial to Assess Chelation Therapy (TACT) reported a clinical benefit of EDTA-based chelation on cardiovascular (CV) outcomes in post-MI patients with diabetes (DM). We assessed the benefit of therapy by severity of diabetes. Methods: TACT, a multi-center, double-blind, placebo-controlled, 2 X 2 factorial trial of EDTA chelation and high-dose vitamins, enrolled pts age &gt; 50 years with an MI at least 6 weeks prior and creatinine &lt; 2.0. Median duration of follow-up was 55 months. The primary endpoint was death from any cause, MI, stroke, coronary revascularization, or hospitalization for angina. The major secondary clinical endpoint was cardiovascular death, MI, or stroke. The type of hypoglycemic therapy (insulin, oral, or none) was used as a surrogate for severity of diabetes. The log rank test and Cox model were used for treatment comparisons. This is a non-prespecified subgroup comparison. Results: TACT enrolled 1708 pts. Among the 633 (37%)with diabetes, 162 (26%) were on insulin, 301 (48%) not on insulin, but on oral hypoglycemic, and 170 (27%) on neither. For the overall subgroup of 633 pts with diabetes EDTA chelation significantly reduced the primary endpoint (HR 0.59 95% confidence intervals (CI) 0.44-0.79, p&lt;0.001). For pts on insulin, the benefit was qualitatively greatest (HR 0.42 95% CI 0.25-0.74, p=0.002), compared with the effect on patients receiving oral hypoglycemic therapy (HR 0.66 95% CI 0.43-1.01, p=0.053), or none (HR 0.69 95% CI (0.39-1.20), p=0.19). For the key secondary endpoint, the best results were in the patients on insulin (HR 0.53) or on oral drugs (HR 0.54), whereas the smallest effect was seen in the patients on neither type of medication (HR 0.82). Conclusions: In post-MI pts with DM treated with standard therapies, the clinical benefit of EDTA-based chelation therapy was most pronounced among the patients with the most severe diabetes, those on insulin therapy. Additional work to understand mechanisms will be necessary.