JAMA. 2013;309(12):1241-1250Background Case reports as early as the 1950s suggested chelation of lead might reduce angina. The popularity of chelation accelerated around the turn of the century. Small underpowered trials of chelation were inconclusive. Mainstream medicine considered chelation unproven and potentially hazardous.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Chelation with disodium EDTA binds divalent and some trivalent cations, including calcium, magnesium, lead, cadmium, zinc, iron, aluminum, and copper, which facilitates their urinary excretion. High dose vitamins are often co-administered with chelation.The NIH-funded Trial to Assess Chelation Therapy (TACT) trial was conducted to respond to the public health problem posed by EDTA chelation therapy: namely, that large numbers of patients could be exposed to undefined risks for unproven benefits. TACT was a double-blind placebo-controlled 2x2 factorial randomized trial enrolling 1708 patients to test chelation therapy.Patients Eligibility for TACT required patients be older than 50 years, have a creatinine of < 2 mg/dl, and have survived a previous myocardial infarction. Exclusion criteria included platelet count less than 100 000/μL, abnormal liver function, BP > 160/100 mm Hg, past intolerance to the chelation or vitamin components, chelation therapy within 5 years, coronary or carotid revascularization planned or having taken place within 6 months, cigarette smoking within 3 months, active heart failure or heart failure hospitalization within 6 months, or inability to tolerate 500-mL infusions weekly. Enrollment began in 2003 and follow-up continued until 2011. There were 134 sites; 60% of which were established chelation centers.Baseline Characteristics The median age of patients was 65 years, 18% were women and the median body mass index was 30. More than 90% of patients had had either percutaneous coronary intervention or coronary bypass surgery. Approximately 31% of patients had diabetes. Use of guideline directed medications was typical of a well-treated population of post-MI patients. Procedures The active 10-component chelation solution consisted of up to 3 g of disodium EDTA; 7 g of ascorbic acid; 2 g of magnesium chloride; 100 mg of procaine; 2500 U of unfractionated heparin; 2 mEq of potassium chloride; 840 mg of sodium bicarbonate; 250 mg of pantothenic acid; 100 mg of thiamine; 100 mg of pyridoxine; and sterile water to make up 500 mL of solution. The identical-appearing placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total).The chelation or placebo infusions were administered through a peripheral intravenous line, weekly for the first 30 infusions, followed by an additional 10 infusions 2 to 8 weeks apart. Patient also received an oral vitamin-mineral regimen vs an oral placebo. In this review, we focus on the intention-to-treat comparison of EDTA chelation vs placebo.Endpoints The primary endpoint was a composite of death, reinfarction, stroke, coronary revascularization, or hospitalization for angina.TACT trialists had planned to enroll 2300 patients over three years with a follow-up of one year. Enrollment was slow, and with permission from the data safety monitoring board (DSMB) enrollment was decreased to 1700 patients and follow-up was extended. The resultant power was 85% to detect a 25% reduction in the primary endpoint assuming a 2.5% per year event rate in the placebo arm.Over the course of the trial, the DSMB requested 11 interim analyses of the data. Because of the increased monitoring, the level of statistical significance required for the primary endpoint was enhanced to a P value of less than 0.036.Results After a median follow-up of 55 months, a primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR]: 0.82 [95% CI: 0.69-0.99]; p= .035).