Dr. Gervasio A Lamas, Director of Cardiology at Mount Sinai Medical College
Chelation refers to the chemical reaction of two or more coordination atoms of a multi-toothed ligand forming a chelating ring with the same metal ion. In living organisms, chelating agent-chelate complexes can be excreted from the body, and this chelation therapy is beneficial if the chelated is toxic metal ions.
Chelation therapy has been used to treat metal poisoning for decades. Do you remember the miracle drug known as the British anti-Lewy agent (dimercaptopropanol)? A chemical weapon used in the early days of World War II, dimercaptopropanol acts as a rescuer by chelating arsenic in Lewis' agent. EDTA is also a chelating agent and is often referred to as EDTA or edetate. EdTA was first synthesized in 1935, and its disodium calcium salt (disodium calcium edta) was approved by the U.S. FDA for the treatment of lead poisoning. Unlike this, disodium EDTA does not contain calcium, and if injected too quickly, it can cause severe hypocalcemia, which is the property of the drug, and in the 1950s, some clever doctors suggested that disodium EDTA may be used to treat atherosclerosis.
In 1956, the treatment for coronary artery disease (coronary heart disease) was too primitive to be said to have had little effect. Coronary artery disease progresses to advanced stages with severe arterial calcification. Clarke and his colleagues believe that perhaps disodium edta, atherosclerotic plaques can be relieved by infusing disodium edta. To their surprise, their "such prayer" actually alleviated the condition of 19 of the 20 patients with angina, but later studies did not have similar positive results. Due to the increasing toxicity of drugs caused by the irregular use of disodium edta, the traditional medical community has rejected the use of this therapy. But at that time, everyone forgot that although there was no evidence of the effectiveness of this therapy at that time, there was no evidence that the therapy was ineffective. So, in the 1960s, disodium EDTA left the stage of traditional and alternative medicine and spent 50 years less quietly. During this period, patients continued to seek doctors who were willing to use the therapy privately, and doctors were quietly trying disodium EDTA for chelation therapy for various indications, including atherosclerosis. The mainstream cardiovascular community conducted a small randomized trial of fewer than 300 patients with a short follow-up time and an alternative endpoint, but the trial did not yield a positive result, so chelation therapy was again considered to be clinically ineffective.
In 2001, the "Request for Applications" project jointly released by the National Center for Complementary Alternative Medicine (NCCAM) and the American Heart, Lung and Blood Institute (NHLBI) was a milestone event for disodium EDTA. We have secured a $30 million project fund to study the efficacy and safety of disodium edta in the treatment of patients with coronary heart disease. Until then, I thought chelation therapy for coronary heart disease would be lost in history. In clinical trials evaluating chelation therapy (TACT), patients enrolled for factorial analysis were randomly divided into four intersecting groups: disodium edta (40 infusions) or placebo injections, vitamins and trace elements (high-dose oral) or placebo2. The criteria for inclusion were: at least 6 weeks after myocardial infarction (MI), age of at least 50 years, and creatinine less than or equal to 2 mg/dL; finally a total of 1708 patients met the admission criteria, intravenous infusion (or placebo) for a total of 55222 cases, and the use of a large amount of vitamins (or placebo). The primary endpoints were death, recurrence of myocardial infarction, stroke, coronary revascularization, or hospitalization for angina. The median follow-up was 55 months. Every cardiologist involved in the trial, including me, the study chair, expected the final result to be likely to be negative before the results came out, and the study was blinded in 2012 and the results were positive. This once again explains the significance of conducting clinical trials.
The results of this test were extraordinary. In one subgroup, the mean age of patients was 65 years, > 90% of patients were taking aspirin, clopidogrel, or warfarin, 73% of patients were statins, mean LDL levels were 89, and the recurrence rate of coronary events in the disodium edta tetraacetate group alone was further reduced by 18% (P = 0.035; number of people requiring retreatment within 5 years [NNT] = 18). The disodium EDTA + vitamin regimen resulted in a 26% reduction in coronary events compared to the double placebo group (number of people requiring retreatment within 5 years = 12; P = 0.016). In the pre-set diabetes group (633 patients), disodium EDTA alone reduced coronary events by 41% (P = 0.0002; number of people requiring retreatment within 5 years = 7), all-cause mortality by 43% (P = 0.011; number requiring retreatment within 5 years = 12), while patients using disodium edtaate + vitamins reduced coronary events by 51% (P<0.001; number of people requiring retreatment within 5 years = 6). Currently, if drugs to treat diabetes do not increase mortality and cardiovascular events in patients, then almost can be approved by the U.S. Food and Drug Administration, in this context, there is no other drug that can beat disodium EDTA for the treatment of diabetics who are already taking statins. What's more, this chelation treatment was safe, and the incidence of serious adverse events was comparable to that of the placebo group.
So what is the mechanism of this? We don't know yet; but, on the other hand, aren't we just as unaware of the anti-inflammatory mechanism of action of statins and the mechanism of action of ivabradine in improving heart failure? We expected that the results of clinical trials (TACT) evaluating chelation therapy would most likely be negative, so no funds were allocated to study the relevant mechanisms of action. Nevertheless, epidemiological data already tells us that data from the Disease Registry of the Ministry of Health suggest that lead and cadmium are representatives of toxic substances, and lead and cadmium rank second and seventh respectively in the list of the top 10 toxic substances that affect human health, with significant implications for cardiovascular disease, peripheral arterial disease, hypertension, stroke and death. Disodium EDTA is an effective chelating agent for lead and cadmium that increases the urine output of lead and cadmium by hundreds of times.
How to grasp it clinically? Chelation therapy may be considered at least for patients with the highest risk of diabetic myocardial infarction; while waiting for PCSK9 inhibitors, these regimens are not the only "weapon" you have in your hands when waiting for PCSK9 inhibitors, not limited to statins, aspirin, and revascularization; while PCSK9 inhibitors may be effective for highly selective patients, these expensive biologics are only once again targeting an old mechanism of action — lowering LDL.
Clinical trials evaluating chelation therapy (TACT) tell us that environmental toxicants that are unavoidable in industrial societies are reversible risk factors for coronary events, which is also a new perspective on the treatment of atherosclerosis. In 2001 I was skeptical about the actual efficacy of chelation therapy, but in 2012 I was no longer skeptical. Based on this, I believe I can provide patients with the best treatment options of the 21st century.