The most severe manifestation of peripheral artery disease (PAD), critical limb ischemia (CLI) results in up to 75,000 major amputations per year. Patients with CLI and diabetes have a 25% annual risk of cardiovascular death, 20% risk of myocardial infarction (MI), 10% risk of stroke, and a 30% risk of amputation. The Trial to Assess Chelation Therapy (TACT) demonstrated a reduction in cardiovascular risk with an edetate disodium-based chelation regimen. Edetate disodium is a chelator with high affinity for lead and cadmium. We offered a regimen of 50 TACT infusions to an individual with ‘no treatment option’ for revascularization and scheduled for major amputation. The patient was able to avoid the scheduled amputation with improvement in his quality of life as measured by the SF-36 and PAD Questionnaires. Although this is a single case report, it may illustrate the potential importance of environmentally acquired toxic metals as a modifiable risk factor for CLI, and a novel therapy to promote limb salvage. Ongoing studies such as TACT2 in post-MI patients with diabetes and TACT3a in patients with diabetes and CLI will give more insight into this hypothesis.
Key words: critical limb ischemia, Trial to Assess Chelation Therapy (TACT), edetate disodium–based chelation
Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD) and results in up to 75,000 major amputations per year.1 Patients with CLI and diabetes have a 25% annual risk of cardiovascular death, 20% risk of myocardial infarction, 10% risk of stroke, and 30% risk of amputation.2,3 Optimal medical therapy in conjunction with hyperbaric oxygen therapy, endovascular revascularization, and lower extremity bypass grafting have led efforts towards limb salvage. Even though much success has been achieved, mortality remains high in patients with CLI, only trailing mortality rates in lung and breast cancer.
The Trial to Assess Chelation Therapy (TACT) demonstrated a reduction in cardiovascular risk with an edetate disodium–based chelation regimen.4 Although we do not fully understand the mechanism of chelation benefit or how it relates to risk, one striking finding from TACT was that chelation strategy in patients with diabetes reduced the risk of major adverse cardiovascular events to the level of patients without diabetes. Diabetes mellitus had been pre-specified as a subgroup for analysis in TACT and consisted of a total of 633 (37%) patients. Treatment with edetate disodium–based infusions reduced combined cardiovascular events (edetate disodium-based chelation vs placebo, 25% vs 38%, respectively; hazard ratio, 0.59; 95% CI, 0.44-0.79; P = .0002).5 A follow-up post-hoc analysis of 162 TACT patients with diabetes and PAD revealed an even greater benefit from edetate disodium-based chelation compared with placebo, with a 48% relative reduction in risk (P = .0069) of the TACT primary endpoint.
Edetate disodium is a chelator with high affinity for lead and cadmium. Cadmium is a highly toxic metal widely distributed in the environment. It is mostly concentrated in the soil and ingested through dietary vegetables and grains, as well as inhaled by smoking tobacco leaf. Lead is more commonly recognized as a cardiovascular toxicant and is encountered primarily through auto batteries, house paint, plumbing, and leaded gasoline.
Arenas and colleagues used the affinity of edetate disodium to toxic metals in explaining the positive results of TACT.6 Twenty-six post–myocardial infarction patients with similar enrollment criteria to TACT were offered a single infusion of edetate disodium chelation. Urinary levels of toxic metals were measured at baseline in overnight urine collections, for 6 hours following placebo infusion of normal saline, and for 6 hours following a TACT edetate disodium–based infusion. The study found an increase of 71% in total urinary metal after edetate disodium–based infusion compared with baseline (1500 vs 2580 μg/g creatinine; P < .0001). In particular, edetate disodium increased lead by 3835% and cadmium by 633%.6
We offered a regimen of 50 TACT infusions to an individual who had no treatment option for revascularization and was scheduled for for major amputation (below the knee amputation). The patient, an 81-year-old man with a long history of insulin dependent diabetes and 20-pack per year smoking, presented to the vascular surgery service with Rutherford 5 CLI.7 Prior to starting the chelation treatment, the patient underwent lower extremity angiography that revealed total occlusions of the left external iliac, left superficial femoral, distal right superficial, and right popliteal arteries (Figure 1). A vascular surgeon performed a left femoral thrombo-endarterectomy and patch angioplasty followed by a left ilio-femoral endarterectomy with vein patch repair of the left common femoral artery. Non-healing ulcers and dry gangrene progressed despite several sessions of hyperbaric oxygen therapy.
Amputation of the affected toes was discussed as the only treatment option. Treatment with edetate disodium–based chelation was initiated and was well-tolerated by the patient. After the 50 edetate disodium–based infusions, the non-healed ulcers and dry gangrene healed completely (Figure 2). The patient was able to avoid the scheduled amputation with improvement in his quality of life as measured by the SF-36 and PAD Questionnaires. Measurement for urinary excretion of cadmium and lead demonstrated a 428% and 2773% increase, respectively, after a single edetate disodium infusion. No adverse events were encountered during the 50 infusions, which was consistent with the safety results of TACT. This individual was part of a 10-patient open label pilot study in patients with diabetes and CLI.8
Although this is a single case report, it may illustrate the potential importance of environmentally acquired toxic metals as a modifiable risk factor for CLI and a novel therapy to promote limb salvage. We hypothesize that edetate disodium–based chelation depletes body stores of toxic metal pollutants acquired from the environment over time and reduces or reverses vascular toxicity.9 This hypothesis is based on extensive epidemiologic research. Tellez-Plaza and colleagues have reported the association of cadmium exposure with PAD.10 In 2018, two large epidemiologic reports gave further weight to the association of toxic metals with cardiovascular disease. A meta-analysis encompassing over 300 000 individual patients demonstrated that urine cadmium was an independent predictor of cardiovascular risk with a dose-response relationship.11,12 Zhuang and colleagues analyzed the National Health and Nutrition Examination Survey (NHANES) data for predictors of PAD within over 400 measured and self-reported variables.13 They reported that cadmium exposure was 1 out of 4 independently predictive variables. NHANES is an ongoing epidemiologic survey of a sample that is selected to be representative of the US population.
Our group performed a cross-sectional study of individuals who underwent edetate disodium treatment at our institution. Eligible patients participated in studies of toxic metals in vascular disease. All patients had a history of coronary artery disease (CAD) with varying severity of PAD: CAD without PAD, CAD with PAD (no CLI) and CAD with CLI. Baseline urinary cadmium levels were lowest in patients with CAD without evidence of PAD (0.37 ± 0.19), higher in CAD-PAD (no CLI) (0.56 ± 0.34), and highest in the CLI subgroup (1.56 ± 2.33), with an approximately four-fold increase in urinary cadmium levels compared to those without PAD (P = 0.009).14
In contrast to coronary arteries, lower extremity atheroma causes symptoms by obstruction rather than plaque rupture. Thus, any benefit of metal chelation most likely reduces atherosclerotic burden, or possibly improves microvascular flow, rather than stabilizes plaque. This mechanistic hypothesis may be supported by a previous study in animal models that demonstrated chronic cadmium exposure accelerated atherosclerosis and increased total cholesterol levels.15 Our working hypothesis is that edetate disodium chelation decreases vascular stores of cadmium levels and lead, thus improving vascular health. Ongoing studies such as TACT2 in post-MI patients with diabetes and TACT3a in patients with diabetes and CLI will give more insight into this hypothesis.
Advances in the management of PAD with endovascular and surgical therapies have given patients and practitioners more options in the treatment of CLI. Evidence is growing that environmentally-acquired toxic metals, particularly cadmium, may play a role in PAD. Limb salvage was attained and quality of life improved in our patient, even though no options for revascularization were available. It is important to note that although our patient demonstrated improvement from edetate disodium–based chelation, a larger placebo-controlled trial is needed to suggest it as a potential salvage therapy before amputation. TACT3a, a randomized, double-blind, placebo-controlled clinical trial, will further test the effects of edetate disodium-based chelation in patients with diabetes and CLI.
Disclosure: Drs Ujueta and Lamas have no disclosures to report.
Manuscript submitted on April 1, 2019; accepted on April 20, 2019.
Address for correspondence: Gervasio A. Lamas, MD, Columbia University Division of Cardiology, Mount Sinai Medical Center, 4300 Alton Road, Suite 2070A, Miami Beach, Florida, 33140. Tel: (305) 674 2260; email: email@example.com
1. Ponticello M, Andersen CA, Marmolejo VL. Limb salvage versus amputation: A closer look at the evidence, costs and long-term outcomes. Podiatry Today. 2016;29(3):30-39.
2. Terra M, Conte MS, Moll FL, Verhaar MC. Critical limb ischemia: current trends and future directions. J Am Heart Assoc. 2016;5(2): e002938.
3. Iida O, Takahara M, Soga Y, et al. Prognostic impact of revascularization in poor-risk patients with critical limb ischemia. JACC Cardiovasc Interv. 2017;10(11):1147-1157.
4. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309(12):1241-1250.
5. Escolar E, Lamas GA, Mark DB, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the trial to assess chelation therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014;7(1):15-24.
6. Arenas IA, Navas-Acien A, Ergui I, Lamas GA. Enhanced vasculotoxic metal excretion in post-myocardial infarction patients following a single edetate disodium-based infusion. Environ Res. 2017;158:443-449.
7. Ujueta F, Arenas IA, Yates T, Beasley R, Diaz D, Lamas GL. Edetate disodium–based treatment in a patient with diabetes and critical limb ischemia after unsuccessful peripheral arterial revascularization: A case report. Clinical Diabetes. 2019. doi:https://doi.org/10.2337/cd18-0059.
8. Arenas IA, Ujueta F, Diaz D, et al. Pilot study of edetate disodium-based chelation in diabetics with critical limb ischemia [American Heart Association abstract 13005]. Circulation. 2018;138:A13005.
9. Lamas GA, Navas-Acien A, Mark DB, Lee KL. Heavy metals, cardiovascular disease, and the unexpected benefits of chelation therapy. J Am Coll Cardiol. 2016;67(20):2411-2418.
10. Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E. Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. Environ Health Perspect. 2012;120(7):1017-1022.
11. Chowdhury R, Ramond A, O’Keeffe LM, Shahzad S, Kunutsor SK, Muka T, Gregson J, Willeit P, Warnakula S, et al. Environmental toxic metal contaminants and risk of cardiovascular outcomes: systematic review and meta-analysis. BMJ. 2018;362:k3310.
12. Tellez-Plaza M, Guallar E, Navas-Acien A. Environmental metals and cardiovascular disease. BMJ. 2018;362:k3436.
13. Zhuang X, Ni A, Liao L, et al. Environment-wide association study to identify novel factors associated with peripheral arterial disease: evidence from the National Health and Nutrition Examination Survey (1999-2004). 2018;269:172-177.
14. Ujueta F, Arenas IA, Diaz D, Yates T, Beasley R, Navas-Acien A, Lamas GA. Cadmium level and severity of peripheral artery disease in patients with coronary artery disease. Eur J Prev Cardiol. 2018;2047487318796585.
15. Oliviera TF, Batista PR, Leal MA, et al. Chronic cadmium exposure accelerates the development of atherosclerosis and induces vascular dysfunction in the aorta of ApoE-/- mice. Biol Trace Elem Res. 2018;187(1):163-171.