Results of trial to assess chelation therapy (TACT) study presented

The Trial to Assess Chelation Therapy (TACT) was the first large-scale, multicenter study designed to determine the safety and efficacy of ethylenediaminetetraacetic acid (EDTA) chelation therapy for individuals with coronary artery disease (CAD) and prior myocardial infarction (MI).

The National Institutes of Health's National Heart, Lung, and Blood Institute (NHLBI) and National Center for Complementary and Alternative Medicine (NCCAM) cosponsored the study, and the results were presented at the American Heart Association Scientific Sessions in November 2012. Principal investigator at Mayo Clinic in Rochester, Minn., was Gerald T. Gau, M.D.

Rationale

"Chelation is a process in which a substance is used to bind molecules, such as minerals, and remove them from the body. Its use grew by nearly 68 percent between 2002 and 2007 in the United States, to 111,000 people, despite there being no evidence of its safety, efficacy or mechanism of action," according to Stephen L. Kopecky, M.D., a cardiologist at Mayo Clinic in Rochester. It was this rise in use nationwide that led the NHLBI and NCCAM to evaluate the efficacy of disodium EDTA chelation in the treatment CAD.

Methods

For the TACT study, the protocol specified 40 infusions of at least three hours each — 30 weekly infusions followed by 10 maintenance infusions two to eight weeks apart. For the active chelation arm, a 10-component chelation solution was selected to match most closely the standard solution used by chelation practitioners. The solution contained up to 3 g of disodium EDTA, 7 g of ascorbic acid, 2 g of magnesium chloride, 100 mg of procaine hydrochloride, 2,500 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, 100 mg of procaine, and sterile water to make up 500 mL of solution. The placebo solution consisted of 500 mL of normal saline and 1.2 percent dextrose.

The study was conducted at 134 research sites in the United States and Canada. The research sites represented a mix of clinical settings — university or teaching hospitals, clinical practices or cardiology research centers, and chelation practices. A total of 1,708 patients were randomized — 839 patients to chelation and 869 patients to placebo. Participants were at least 50 years old, had a myocardial infarction (MI) at least six weeks prior to enrollment, and had not had coronary or carotid revascularization procedures within the past six months or smoked cigarettes within the past three months.

On average, TACT participants were 65 years old, 8 percent were women, and 9 percent were minorities. Participant MI had, on average, occurred 4.6 years before enrollment. The study population had:

  • A high rate of diabetes (31 percent)
  • Prior coronary revascularizations (83 percent)
  • Use of medications, such as aspirin (84 percent), beta blockers (72 percent) and statins (73 percent)

A total of 55,222 infusions were completed in the study, with 65 percent of patients completing all 40 infusions and 76 percent completing at least 30 infusions. Thirty percent of those enrolled discontinued infusions due to:

  • Subject refusal (53 percent)
  • Adverse event (12 percent)
  • Open-label chelation (11 percent)
  • IV access problems (10 percent)
  • Other reasons (10 percent)

Seventeen percent of patients withdrew consent, therefore precluding any follow-up for events.

Results

Over the four-year follow-up, the difference in the primary endpoint, 26.5 percent in the EDTA group vs 30.0 percent in the placebo group, just reached statistical significance at P=.035, with a hazard ratio (HR) of 0.82 (95 percent confidence interval, or CI, 0.69- 0.99).

Subjects randomly assigned to active chelation infusions showed an 18 percent drop in the trial's primary endpoint — a composite of:

  • All-cause mortality (10.4 percent vs. 10.7 percent)
  • MI (6.2 percent vs. 7.7 percent)
  • Stroke (1.2 percent vs. 1.5 percent)
  • Coronary revascularization (15.5 percent vs. 18.1 percent)
  • Hospitalization for angina (1.5 percent vs. 2.1 percent)

There were no significant differences in the individual components of the primary endpoint in chelation patients vs. controls although there seemed to be a trend toward benefit for coronary revascularization (P=.076).

In a prespecified subgroup analysis, the 31 percent of the study population with diabetes showed greater benefit for the primary endpoint compared with nondiabetic patients with an HR of 0.61 (95 percent CI, 0.45-0.83; P=.002); in nondiabetic patients, the HR was 0.96 (95 percent CI, 0.77-1.20; P=.725).

Also, anterior MI patients showed benefit vs. other MI locations (P=.03). Possibly due to the fact that 83 percent of patients had previously undergone revascularization and 80 percent had no anginal symptoms at baseline, chelation therapy had minimal effect on standard measures of quality of life at 6, 12, and 24 months, with the exception of slight improvement in self-reported anginal symptoms at 1 year (P=.016). Adverse effects were similar in both groups.

More questions

"The trial results were the focus of much discussion at the recent 2012 AHA annual meeting in Los Angeles, where the TACT results were presented, with multiple reasons being offered," says Dr. Kopecky. The usual answer in randomized placebo-controlled clinical trials — that the active treatment (chelation) is better than placebo — was not believed by most in attendance to be the cause. Other possible reasons were offered, including:

  • Difference in low-density lipoprotein cholesterol levels at baseline. Subjects randomly assigned to active chelation therapy had a lower baseline LDL than the placebo group (87 mg/dL vs. 90 mg/dL). This level of difference would be expected to result in 3 percent less major cardiovascular events after five years, very close to the 3.5 percent actually seen in the study.
  • Placebo glucose infusion in the diabetic group. Since most of the benefit of chelation was seen in diabetic patients, some postulated that the placebo glucose infusion may have led to increased adverse outcomes in this subset.
  • Incomplete data due to dropout. Seventeen percent of patients withdrew consent (3 percent-5 percent is common in large trials), which prohibited investigators from ascertaining any endpoint data, thereby potentially missing some major cardiovascular events.

While being provocative, due to its borderline significance and the above-mentioned reasons, the TACT study is not conclusive and should not change clinical practice. The results do warrant further study, especially in patients with diabetes or prior anterior MI, due to a signal of benefit in these subgroups. "For now, we should await complete review and vetting of the data via the publication process before making final decisions on the role of chelation therapy in the treatment of CAD," says Dr. Kopecky.