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Gervasio A. Lamas - One of the best experts on this subject based on the ideXlab platform.
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low level metal contamination and chelation in cardiovascular disease a ripe area for toxicology research
Toxicological Sciences, 2021Co-Authors: Francisco Ujueta, Gervasio A. Lamas, Ana Navasacien, Koren K Mann, Rakesh PrashadAbstract:Cardiovascular disease remains the leading cause of death worldwide. In spite of cardiovascular prevention, there is residual risk not explicable by traditional risk factors. Metal contamination even at levels previously considered safe in humans may be a potential risk factor for atherosclerosis. This review examines evidence that 2 metals, lead and cadmium, demonstrate sufficient toxicological and epidemiologic evidence to attribute causality for atherosclerotic disease. Basic science suggests that both metals have profound adverse effects on the human cardiovascular system, resulting in endothelial dysfunction, an increase in inflammatory markers, and reactive oxygen species, all of which are pro-atherosclerotic. Epidemiological studies have shown both metals to have an association with cardiovascular disease, such as peripheral arterial disease, ischemic heart disease and cardiovascular mortality. This review also examines Edetate Disodium-based chelation as a possible pharmacotherapy to reduce metal burden in patients with a history of cardiovascular disease and thus potentially reduce cardiovascular events.
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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
Journal of Diabetes and Its Complications, 2020Co-Authors: Esteban Escolar, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Francisco Ujueta, Kerry L Lee, Robin Boineau, Hwasoon Kim, Kevin J Anstrom, Gervasio A. LamasAbstract:Abstract Background The 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 Methods We 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. Results There 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). Conclusions Edetate 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 identifier Trial to Assess Chelation Therapy (TACT), NCT00044213.
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Urinary Metal Levels after Repeated Edetate Disodium Infusions: Preliminary Findings.
International journal of environmental research and public health, 2020Co-Authors: Zenith H. Alam, Ana Navas-acien, Francisco Ujueta, Ivan A. Arenas, Anne E. Nigra, Gervasio A. LamasAbstract:Environmentally acquired lead and cadmium are associated with increased cardiovascular disease risk. In the Trial to Assess Chelation Therapy, up to 40 infusions with Edetate Disodium over an approximately one-year period lowered the cardiovascular disease risk in patients with a prior myocardial infarction. We assessed whether a reduction in surrogate measures of total body lead and cadmium, post-Edetate Disodium urine lead and pre-Edetate urine cadmium, could be detected after repeated Edetate Disodium-based infusions compared to the baseline. Fourteen patients with coronary artery disease received multiple open-label Edetate Disodium infusions. The urine metals pre- and post-Edetate infusion, normalized for urine creatinine, were compared to urine levels pre and post final infusion by a paired t-test. Compared with the pre-Edetate values, post-Edetate urine lead and cadmium increased by 3581% and 802%, respectively, after the first infusion. Compared to baseline, post-Edetate lead decreased by 36% (p = 0.0004). A reduction in post-Edetate urine lead was observed in 84% of the patients after the final infusion. Pre-Edetate lead decreased by 60% (p = 0.003). Pre-Edetate lead excretion became undetectable in nearly 40% of patients. This study suggests that Edetate Disodium-based infusions may decrease the total body burden of lead. However, our data suggest no significant reduction in the body burden of cadmium.
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differential outcomes with Edetate Disodium based treatment among stable post anterior vs non anterior myocardial infarction patients
Cardiovascular Revascularization Medicine, 2020Co-Authors: Eldrin F. Lewis, Gervasio A. Lamas, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Francisco Ujueta, Rhonda S Roberts, Mario StylianouAbstract:Abstract Background The 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. Methods Patients (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. Results Among 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 Conclusions Edetate 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.
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Abstract P452: Urinary Metal Levels After Repeated Chelation With Edetate Disodium: Additional Evidence in Support of Metals as Cardiovascular Risk Factors
Circulation, 2020Co-Authors: Ana Navas-acien, Francisco Ujueta, Zenith Alam, Arce Domingo-relloso, Gervasio A. LamasAbstract: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 pri...
Francisco Ujueta - One of the best experts on this subject based on the ideXlab platform.
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low level metal contamination and chelation in cardiovascular disease a ripe area for toxicology research
Toxicological Sciences, 2021Co-Authors: Francisco Ujueta, Gervasio A. Lamas, Ana Navasacien, Koren K Mann, Rakesh PrashadAbstract:Cardiovascular disease remains the leading cause of death worldwide. In spite of cardiovascular prevention, there is residual risk not explicable by traditional risk factors. Metal contamination even at levels previously considered safe in humans may be a potential risk factor for atherosclerosis. This review examines evidence that 2 metals, lead and cadmium, demonstrate sufficient toxicological and epidemiologic evidence to attribute causality for atherosclerotic disease. Basic science suggests that both metals have profound adverse effects on the human cardiovascular system, resulting in endothelial dysfunction, an increase in inflammatory markers, and reactive oxygen species, all of which are pro-atherosclerotic. Epidemiological studies have shown both metals to have an association with cardiovascular disease, such as peripheral arterial disease, ischemic heart disease and cardiovascular mortality. This review also examines Edetate Disodium-based chelation as a possible pharmacotherapy to reduce metal burden in patients with a history of cardiovascular disease and thus potentially reduce cardiovascular events.
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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
Journal of Diabetes and Its Complications, 2020Co-Authors: Esteban Escolar, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Francisco Ujueta, Kerry L Lee, Robin Boineau, Hwasoon Kim, Kevin J Anstrom, Gervasio A. LamasAbstract:Abstract Background The 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 Methods We 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. Results There 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). Conclusions Edetate 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 identifier Trial to Assess Chelation Therapy (TACT), NCT00044213.
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Urinary Metal Levels after Repeated Edetate Disodium Infusions: Preliminary Findings.
International journal of environmental research and public health, 2020Co-Authors: Zenith H. Alam, Ana Navas-acien, Francisco Ujueta, Ivan A. Arenas, Anne E. Nigra, Gervasio A. LamasAbstract:Environmentally acquired lead and cadmium are associated with increased cardiovascular disease risk. In the Trial to Assess Chelation Therapy, up to 40 infusions with Edetate Disodium over an approximately one-year period lowered the cardiovascular disease risk in patients with a prior myocardial infarction. We assessed whether a reduction in surrogate measures of total body lead and cadmium, post-Edetate Disodium urine lead and pre-Edetate urine cadmium, could be detected after repeated Edetate Disodium-based infusions compared to the baseline. Fourteen patients with coronary artery disease received multiple open-label Edetate Disodium infusions. The urine metals pre- and post-Edetate infusion, normalized for urine creatinine, were compared to urine levels pre and post final infusion by a paired t-test. Compared with the pre-Edetate values, post-Edetate urine lead and cadmium increased by 3581% and 802%, respectively, after the first infusion. Compared to baseline, post-Edetate lead decreased by 36% (p = 0.0004). A reduction in post-Edetate urine lead was observed in 84% of the patients after the final infusion. Pre-Edetate lead decreased by 60% (p = 0.003). Pre-Edetate lead excretion became undetectable in nearly 40% of patients. This study suggests that Edetate Disodium-based infusions may decrease the total body burden of lead. However, our data suggest no significant reduction in the body burden of cadmium.
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differential outcomes with Edetate Disodium based treatment among stable post anterior vs non anterior myocardial infarction patients
Cardiovascular Revascularization Medicine, 2020Co-Authors: Eldrin F. Lewis, Gervasio A. Lamas, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Francisco Ujueta, Rhonda S Roberts, Mario StylianouAbstract:Abstract Background The 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. Methods Patients (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. Results Among 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 Conclusions Edetate 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.
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Abstract P452: Urinary Metal Levels After Repeated Chelation With Edetate Disodium: Additional Evidence in Support of Metals as Cardiovascular Risk Factors
Circulation, 2020Co-Authors: Ana Navas-acien, Francisco Ujueta, Zenith Alam, Arce Domingo-relloso, Gervasio A. LamasAbstract: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 pri...
Kerry L Lee - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Diabetes and Its Complications, 2020Co-Authors: Esteban Escolar, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Francisco Ujueta, Kerry L Lee, Robin Boineau, Hwasoon Kim, Kevin J Anstrom, Gervasio A. LamasAbstract:Abstract Background The 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 Methods We 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. Results There 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). Conclusions Edetate 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 identifier Trial to Assess Chelation Therapy (TACT), NCT00044213.
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the effect of edta based chelation on patients with diabetes and peripheral artery disease in the trial to assess chelation therapy tact
Journal of Diabetes and Its Complications, 2019Co-Authors: Francisco Ujueta, Daniel B. Mark, Esteban Escolar, Denisse Diaz, Ivan A. Arenas, Robin Boineau, Hwasoon Kim, Patrick Golden, Lauren Lindblad, Kerry L LeeAbstract:Abstract Objective Approximately 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 methods The 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. Results The 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). Conclusion Atherosclerotic 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.
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heavy metals cardiovascular disease and the unexpected benefits of chelation therapy
Journal of the American College of Cardiology, 2016Co-Authors: Gervasio A. Lamas, Daniel B. Mark, Ana Navasacien, Kerry L LeeAbstract:This review summarizes evidence from 2 lines of research previously thought to be unrelated: the unexpectedly positive results of TACT (Trial to Assess Chelation Therapy), and a body of epidemiological data showing that accumulation of biologically active metals, such as lead and cadmium, is an important risk factor for cardiovascular disease. Considering these 2 areas of work together may lead to the identification of new, modifiable risk factors for atherosclerotic cardiovascular disease. We examine the history of chelation up through the report of TACT. We then describe work connecting higher metal levels in the body with the future risk of cardiovascular disease. We conclude by presenting a brief overview of a newly planned National Institutes of Health trial, TACT2, in which we will attempt to replicate the findings of TACT and to establish that removal of toxic metal stores from the body is a plausible mechanistic explanation for the benefits of Edetate Disodium treatment.
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abstract 10466 post myocardial infarction treatment with Edetate Disodium was safe in the trial to assess chelation therapy
Circulation, 2015Co-Authors: Jeanne Drisko, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Karen P Alexander, Rhonda Roberts, Terry L Chappell, Kerry L Lee, Robin Boineau, Yves RosenbergAbstract: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 >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 (<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.
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Abstract 10466: Post-myocardial Infarction Treatment With Edetate Disodium was Safe in the Trial to Assess Chelation Therapy
Circulation, 2015Co-Authors: Jeanne Drisko, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Karen P Alexander, Rhonda Roberts, Kerry L Lee, Robin Boineau, L. Terry Chappell, Yves RosenbergAbstract: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 >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 (
Ana Navas-acien - One of the best experts on this subject based on the ideXlab platform.
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Urinary Metal Levels after Repeated Edetate Disodium Infusions: Preliminary Findings.
International journal of environmental research and public health, 2020Co-Authors: Zenith H. Alam, Ana Navas-acien, Francisco Ujueta, Ivan A. Arenas, Anne E. Nigra, Gervasio A. LamasAbstract:Environmentally acquired lead and cadmium are associated with increased cardiovascular disease risk. In the Trial to Assess Chelation Therapy, up to 40 infusions with Edetate Disodium over an approximately one-year period lowered the cardiovascular disease risk in patients with a prior myocardial infarction. We assessed whether a reduction in surrogate measures of total body lead and cadmium, post-Edetate Disodium urine lead and pre-Edetate urine cadmium, could be detected after repeated Edetate Disodium-based infusions compared to the baseline. Fourteen patients with coronary artery disease received multiple open-label Edetate Disodium infusions. The urine metals pre- and post-Edetate infusion, normalized for urine creatinine, were compared to urine levels pre and post final infusion by a paired t-test. Compared with the pre-Edetate values, post-Edetate urine lead and cadmium increased by 3581% and 802%, respectively, after the first infusion. Compared to baseline, post-Edetate lead decreased by 36% (p = 0.0004). A reduction in post-Edetate urine lead was observed in 84% of the patients after the final infusion. Pre-Edetate lead decreased by 60% (p = 0.003). Pre-Edetate lead excretion became undetectable in nearly 40% of patients. This study suggests that Edetate Disodium-based infusions may decrease the total body burden of lead. However, our data suggest no significant reduction in the body burden of cadmium.
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Abstract P452: Urinary Metal Levels After Repeated Chelation With Edetate Disodium: Additional Evidence in Support of Metals as Cardiovascular Risk Factors
Circulation, 2020Co-Authors: Ana Navas-acien, Francisco Ujueta, Zenith Alam, Arce Domingo-relloso, Gervasio A. LamasAbstract: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 pri...
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Potential Role of Metal Chelation to Prevent the Cardiovascular Complications of Diabetes.
The Journal of clinical endocrinology and metabolism, 2019Co-Authors: Rossana Calderon Moreno, Gervasio A. Lamas, Jonathan D Newman, Ana Navas-acien, Esteban Escolar, David M. Nathan, John F Schmedtje, Denisse Diaz, Vivian FonsecaAbstract:Context 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. Design 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. Results 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. Conclusions 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.
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Abstract 13005: Pilot Study of Edetate Disodium-Based Chelation in Diabetics With Critical Limb Ischemia
Circulation, 2018Co-Authors: Ivan A. Arenas, Ana Navas-acien, Denisse Diaz, Francisco Ujueta, Timothy Yates, Brandon Olivieri, Robert Beasley, Gervasio A. LamasAbstract:Critical limb ischemia (CLI) carries over a 60% risk of major events (death, major amputation, or myocardial infarction) at 1-year. The Trial to Assess Chelation Therapy (TACT), demonstrated a majo...
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Enhanced vasculotoxic metal excretion in post-myocardial infarction patients following a single Edetate Disodium-based infusion
Environmental research, 2017Co-Authors: Ivan A. Arenas, Ana Navas-acien, Ian Ergui, Gervasio A. LamasAbstract:Abstract 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. Methods Twenty 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. Results The 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 Conclusions Edetate 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.
Daniel B. Mark - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Diabetes and Its Complications, 2020Co-Authors: Esteban Escolar, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Francisco Ujueta, Kerry L Lee, Robin Boineau, Hwasoon Kim, Kevin J Anstrom, Gervasio A. LamasAbstract:Abstract Background The 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 Methods We 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. Results There 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). Conclusions Edetate 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 identifier Trial to Assess Chelation Therapy (TACT), NCT00044213.
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differential outcomes with Edetate Disodium based treatment among stable post anterior vs non anterior myocardial infarction patients
Cardiovascular Revascularization Medicine, 2020Co-Authors: Eldrin F. Lewis, Gervasio A. Lamas, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Francisco Ujueta, Rhonda S Roberts, Mario StylianouAbstract:Abstract Background The 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. Methods Patients (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. Results Among 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 Conclusions Edetate 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.
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the effect of edta based chelation on patients with diabetes and peripheral artery disease in the trial to assess chelation therapy tact
Journal of Diabetes and Its Complications, 2019Co-Authors: Francisco Ujueta, Daniel B. Mark, Esteban Escolar, Denisse Diaz, Ivan A. Arenas, Robin Boineau, Hwasoon Kim, Patrick Golden, Lauren Lindblad, Kerry L LeeAbstract:Abstract Objective Approximately 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 methods The 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. Results The 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). Conclusion Atherosclerotic 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.
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heavy metals cardiovascular disease and the unexpected benefits of chelation therapy
Journal of the American College of Cardiology, 2016Co-Authors: Gervasio A. Lamas, Daniel B. Mark, Ana Navasacien, Kerry L LeeAbstract:This review summarizes evidence from 2 lines of research previously thought to be unrelated: the unexpectedly positive results of TACT (Trial to Assess Chelation Therapy), and a body of epidemiological data showing that accumulation of biologically active metals, such as lead and cadmium, is an important risk factor for cardiovascular disease. Considering these 2 areas of work together may lead to the identification of new, modifiable risk factors for atherosclerotic cardiovascular disease. We examine the history of chelation up through the report of TACT. We then describe work connecting higher metal levels in the body with the future risk of cardiovascular disease. We conclude by presenting a brief overview of a newly planned National Institutes of Health trial, TACT2, in which we will attempt to replicate the findings of TACT and to establish that removal of toxic metal stores from the body is a plausible mechanistic explanation for the benefits of Edetate Disodium treatment.
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abstract 10466 post myocardial infarction treatment with Edetate Disodium was safe in the trial to assess chelation therapy
Circulation, 2015Co-Authors: Jeanne Drisko, Christine Goertz, Daniel B. Mark, Richard L. Nahin, Karen P Alexander, Rhonda Roberts, Terry L Chappell, Kerry L Lee, Robin Boineau, Yves RosenbergAbstract: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 >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 (<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.
