TACT: Heavy metal chelation for cardiovascular risk reduction

Lamas, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA 2013;309:1241-50.

Bottom line:

  • The role of chelation in cardiovascular disease is unproven & unclear;

  • The TACT trial, which has unclear risk of bias due to possible unblinding, demonstrated a reduction in cardiovascular events in patients with prior MI (mainly driven by coronary revascularization) with a complex regimen that includes a chelator, as well as pharmacologically-active agents such as heparin & procaine;

  • If a patient chooses to undergo chelation, clinicians should encourage ongoing adherence to evidence-based pharmacological therapies, & implement harm-minimization strategy (i.e. avoid use in those with contraindication to chelation or frequent IV infusions; monitor for fluid overload & hypocalcemia).


  • Chelation therapy (the act of administering a drug to bind metal ions) has been used in a non-evidence-based fashion to treat coronary artery disease (CAD) since the 1950s. The original rationale was to bind calcium and "decalcify the heart" following observations that autopsied hearts had heavily calcified coronary arteries.
    • Notably, we now know that calcification of arteries is a late consequence of atherosclerosis & not the direct cause of coronary events.
  • The rationale for chelation therapy in atherosclerotic CVD now centers around observations that increased exposure to heavy metals, particularly cadmium & lead, is associated with cardiovascular disease, possibly by causing endothelial dysfunction (cadmium), increased BP (lead), & inducing macrophage dysfunction & apoptosis (cadmium).
  • The only supporting evidence for chelation therapy in CAD prior to this trial came from uncontrolled case reports & case series.


  • 134 sites in US & Canada
  • 60% of sites already practiced chelation therapy (generally naturopathic & alternative medicine clinics)

Patients (n=1708)

  • Inclusion
    • Age >50 years
    • Prior MI (>6 weeks before enrollment)
  • Exclusion
    • Past intolerance to chelation or vitamin components
    • Inability to tolerate 500-mL infusions weekly
    • Chelation therapy within 5 years
    • Coronary/carotid revascularization planned or in prior 6 months
    • "Active" HF or HF hospitalization within 6 months
    • Current smoker or smoking in last 3 months
    • BP >160/100 mm Hg
    • SCr >170 umol/L
    • Plt <100
    • Abnormal LFTs
  • Baseline characteristics
    • 65 years
    • Female 18%
    • White 94%
    • CAD characteristics: Last MI 4.6 years ago, anterior MI 40%, angina 55%, prior CABG/PCI 83%
    • PMHx: Former smoker 56%, CHF 18%, diabetes 40%
    • BP 130/76
    • Meds: Antithrombotic 91% (ASA in 83%), ACEI/ARB 63%, beta-blocker 72%, statin 73%, multivitamin 44%, herbal products 34%
    • Labs: LDL 2.3 mmol/L, HDL 1.1 mmol/L, SCr 97 umol/L


  • Intervention: Chelation+ infusion
    • Each infusion consists of 10 components commonly combined by US chelation practitioners: Disodium EDTA (ethylene-diamine-tetracetic acid) 3 g (decreased based on eGFR), procaine hydrochloride 100 mg, heparin 2500 units, ascorbic acid (vitamin C) 7 g, magnesium chloride 2 g, potassium chloride 2 mEq, sodium bicarbonate 840 mg, pantothenic acid 250 mg, thiamine 100 mg, pyridoxine (vitamin B6) 100 mg, & sterile water to total 500 mL
    • Each infusion administered over minimum 3h (slower if HF or albumin-corrected serum Ca 2.0-2.12 mol/L)
    • 30 weekly infusions, followed by 10 infusions q2-8 weeks
  • Control: Placebo infusion (500 mL of NS & 1.2% dextrose)
  • Co-intervention: Daily vitamin containing vitamin B6 25 mg, chromium 50 ug, copper 2 mg, manganese 15 mg, zinc 25 mg

Results @ median 4.6 years


  • Chelation reduced the primary outcome (all-cause death, re-MI, stroke, coronary revascularization, angina hospitalization): Chelation 26% vs placebo 30% (hazard ratio [HR] 0.82, 0.69-0.99)
    • Driven by fewer coronary revascularizations: 15% vs 18% (HR 0.81, 0.64-1.02)
  • No significant difference in secondary outcome (CV death, re-MI, stroke): 11% vs 13% (HR 0.84, 0.64-1.02)
  • No significant difference in death (10% vs 11%), MI (6% vs 8%), stroke (1% vs 1%), or angina hospitalization (2% vs 2%)
  • No difference in quality of life scores at 2 years (in either cardiac functional status measured using Duke Activity Status Index, or SF-36 Mental Health Inventory-5) in subset of 911 patients


  • Serious adverse events: Chelation 12% vs placebo 15% (p=0.10)
  • Non-serious adverse events: 68% vs 67% (p=0.60)
  • Hypocalcemia (serum Ca <2.0 mmol/L): 6.2% vs 3.5% (p=0.008)

Subgroups: 9 subgroups evaluated, 2 had significant interaction p-value (diabetes, anterior MI) for primary outcome

  • iabetes status (p=0.02 for interaction)
    • Diabetes: HR 0.61, 0.45-0.83
    • No diabetes: HR 0.96, 0.77-1.20
  • MI distribution (p=0.03 for interaction)
    • Anterior MI: HR 0.63, 0.47-0.86
    • Non-anterior MI: HR 0.96 (0.77-1.20)
  • No difference between complementary/alternative sites vs others (p=0.28)

Generalizability & other considerations

  • Key characteristics of included patients
    • Several groups of patients with CAD were excluded, notably current smokers (rationale unclear), and those with "active" heart failure or recent hospitalization for HF, uncontrolled HTN or renal dysfunction (who may not tolerate the weekly fluid infusions)
    • Patients with chelation in the past 5 years were also excluded, likely to remove bias from including any patients with a potential preference for this therapy
    • Use of evidence-based therapies for CAD at baseline was low (particularly for statins; only used at any dose in 73%), & rates later in the trial are not reported. It is unclear if use of chelation, or practitioners of chelation themselves, may have influenced the use of proven, evidence-based therapies.
  • The chelation regimen includes a number of other pharmacologically-active components, including heparin (anticoagulant) and procaine (pro/antiarrhythmic, vasodilator). TACT used this combination as it is the most commonly used by chelationists in the US, but the actual therapeutic rationale is unclear. The apparent benefit in the primary outcome of TACT may be in part explained by these other components rather than chelation. Moreover, these extra components could be harmful.
  • The difference in the primary outcome is marginally statistically significant (p=0.035, just below the modified 0.036 threshold), & completely driven by coronary revascularization, the softest endpoint in the composite.
  • The findings from the subgroup analysis should be interpreted cautiously in context of the limitations: large # of subgroup analyses performed (9); the beneficial effect found in diabetes & anterior MI was not expected; no biologic rationale to explain the benefit in diabetics & those with anterior MI but not in others; no other RCT with which to compare.

Internal validity: Unclear risk of bias

  • Allocation: Web-based randomization with permuted blocks, allocation concealed.
  • Performance: Patients, clinicians blinded, matching placebo
    • Concern has been raised about possible unblinding of participants due to the higher withdrawal of consent in the placebo group, suggesting that patients were somehow told that they were receiving placebo and decided to leave the trial. This is not proven, but is one possible explanation for this finding, and would therefore introduce bias in the softer outcome of revascularization, which drove the difference in the primary outcome.
  • Detection: Blinded adjudication committee.
  • Attrition: Intention-to-treat analysis, but high loss-to-follow-up with differences between groups
    • 18% lost-to-follow-up, mainly due to withdrawal of consent, which was higher with placebo (20%) than chelation (13%). Usually, differences in loss-to-follow-up between groups are because of tolerability issues with 1 of the interventions, however, in this case those receiving placebo left the trial more often. As discussed above, this suggests unblinding. Other explanations would include chance (unlikely with such a large difference), people receiving chelation feeling better than placebo, thus being motivated to continue treatment (but this is not corroborated by the quality of life results).
  • Selective outcome reporting: Reporting of all clinical outcomes of interest for both efficacy & safety.
  • Others:
    • Trial initially planned to enroll ~2400 patients, but decreased to 1700 midway due to slow patient recruitment.
    • Data safety monitoring board performed 11 interim analyses prior to the final analysis.