November 19th, 2013
TACT Substudy Suggests Possible Strong Benefit for Chelation in Diabetics
One year ago the results of the TACT trial were published in JAMA, sparking an enormous controversy over the propriety of publishing a trial suggesting that chelation therapy might be beneficial in people with cardiovascular disease. Chelation therapy has long been a staple of alternative medicine, but until the publication of TACT it had received no credit whatsoever in mainstream medicine. TACT was supported by the NIH as part of an initiaitve to test the scientific basis of alternative medical therapies.
The JAMA paper reported positive results for the prespecified subgroup of patients who had diabetes at the start of the trial. Now a new paper, presented at the American Heart Association Scientific Sessions and published online in Circulation: Cardiovascular Quality and Outcomes, focuses on this important subgroup, and provides even stronger evidence for a possible benefit for chelation in patients with diabetes. The authors speculate that ethylene diamine tetra-acetic acid (EDTA) chelation might have an effect on metal-catalyzed oxidation reactions in the development of advanced glycation end-products, which appear to play a central role in diabetic complications.
The primary endpoint of the main trial – the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina – was significantly lowered from 30% in the placebo group to 26% in the chelation group (HR 0.82, 0.69-0.99, p=0.035). Patients with self-reported diabetes composed 31.5% of the study population, or 538 patients. In the new report, the definition of diabetes was changed to be more consistent with the latest guidelines and included patients with self-reported diabetes, taking oral or insulin treatment for diabetes, or with fasting blood glucose > 6.99 mmol/L at the start of the study. The study population thereby increased to 633 patients, or 37.1% of the entire population.
After 5 years of followup there was an absolute 15% difference between the groups in the primary endpoint (the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina), resulting in a highly significant 41% reduction in the chelation group (HR 0.59, CI 0.44-0.79, p<0.001). The finding remained highly significant after adjusting for multiple subgroups. The authors calculated that 6.5 patients would need to be treated for 5 years to prevent one event. There were no significant differences in the primary endpoint in the non-diabetes subgroup.
The investigators also observed reductions in the individual components of the endpoint, including recurrent MI, all-cause mortality, and coronary revascularizations, though these were no longer significant after adjusting for multiple subgroups.
During the course of the trial there were more patients who withdrew consent in the placebo arm. This was the subject of considerable criticism when the trial was first presented and published. However, sensitivity analyses performed by the investigators found that the results remained significant for all realistic scenarios. Furthermore, the findings were similar when the investigators defined diabetes using the trial’s original criteria.
In their discussion, the authors wrote:
“These findings, if replicable, would have an impact on the health of patients with diabetes. We emphasize, however, that these results are based on a subgroup of the overall trial, albeit prespecified, and therefore must be interpreted with caution.”
The findings, they wrote, may have “particular relevance when considering that patients were taking standard, evidence-based medications for post-MI patients, and patients with diabetes had a median LDL of 83 mg/dL.”
In addition, the authors write, the findings “support the initiation of clinical trials in patients with diabetes and vascular disease to replicate these findings, and define the mechanisms of benefit. They do not, however, constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI diabetic patients.”