Some practitioners of alternative medicine (doctors, naturopaths, chiropractors and others) earn a lot of money with the claim that chelation therapy (an effective mainstream treatment for acute heavy metal poisoning) is an effective means to treat cardiovascular disease. However, the notion is controversial and implausible. Several systematic reviews of the best evidence concluded less than optimistically:
More recently, important new evidence has emerged. The largest study of chelation therapy (TACT) ever conducted cost ~ $ 30 million and concluded that among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.
At the time, the TACT trial was heavily and rightly criticised for a whole host of reasons. For instance, because of the result of the FDA inspection of the highest accruing TACT site:
- The investigators didn’t conduct the investigation in accordance with the signed statement and investigational plan. Several examples were given of shoddy procedures, prefilled forms, and failure to train personnel.
- Failure to report promptly to the IRB all unanticipated problems involving risk to human subjects or others. Examples are given, including failure to report the deaths of patients on the study in a timely fashion (in one case the death wasn’t reported to the IRB until four months later; in another case it was never reported at all). In other cases, adverse event reports were not submitted to the IRB.
- Failure to prepare or maintain adequate case histories with respect to observations and data pertinent to the investigation.
- Investigational drug disposition records are not adequate with respect to dates, quantity, and use by subjects.
Despite these problems, the study was published in JAMA, albeit with a very critical editorial:
Differential dropout in TACT suggests unmasking, but the problem of intentional unblinding is more concerning. The sponsors of the trial, the National Heart, Lung, and Blood Institute (NHLBI) and the National Center for Complementary and Alternative Medicine (NCCAM), were unblinded throughout the trial. The National Institutes of Health policy unwisely allows the sponsor access to unblinded trial data, and both organizations sent observers to the closed sessions of the data monitoring committee. This gave them access to confidential data during each of the 11 interim analyses. The unblinding of the study sponsor represents a serious deviation from acceptable standards of conduct for supervision of clinical trials. If a pharmaceutical company sponsoring a trial were allowed access to actual outcome data during the study, there would be major objections. Like any sponsor, the NHLBI and NCCAM cannot be considered unbiased observers. These agencies made major financial commitments to the trial and may intentionally or inadvertently influence study conduct if inappropriately unblinded during the study…
Given the numerous concerns with this expensive, federally funded clinical trial, including missing data, potential investigator or patient unmasking, use of subjective end points, and intentional unblinding of the sponsor, the results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy. The findings of TACT should not be used as a justification for increased use of this controversial therapy.
Orac, makes several further critical points about the published trial:
First, the primary endpoint (i.e., the aggregated serious cardiovascular events) did indeed show a modest difference, namely 30% of placebo subjects versus 26.5% of the EDTA chelation subjects (hazard ratio 0.82 for chelation). However, one notes that the result is just barely statistically significant, p = 0.035, with the 99% confidence interval for the hazard ratio ranging from 0.69 to 0.99. (The predetermined level for statistical significance for purposes of this study was 0.036; so this is statistically significant by the barest margin.) More importantly, if you look at the individual endpoints that make up that aggregate, there was no statistically significant difference in death, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. Subgroup analysis (always a questionable analysis that requires replication, even when preplanned, as in TACT) purported to show a much greater benefit for diabetics, with a hazard ratio of 0.61 (p=0.002), while patients without diabetes showed no statistically significant difference in any of the outcome measures, including the aggregated total bad outcomes.
Now a paper that has just emerged describes the intent-to-treat comparison of this trial in patients with diabetes.
This was a double-blind, placebo-controlled, 2 × 2 factorial multicenter randomized trial of 1,708 post-myocardial infarction (MI) patients ≥50 years of age and with creatinine ≤2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitamin-multimineral mixture or placebo. The primary end point was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina.
Median age was 65 years, 18% were female, 94% were Caucasian, 37% were diabetic, 83% had prior coronary revascularization, and 73% were on statins. Five-year Kaplan-Meier estimates for the primary end point was 31.9% in the chelation + high-dose vitamin group, 33.7% in the chelation + placebo vitamin group, 36.6% in the placebo infusion + active vitamin group, and 40.2% in the placebo infusions + placebo vitamin group. The reduction in primary end point by double active treatment compared with double placebo was significant (hazard ratio 0.74, 95% CI 0.57-0.95, P = .016). In patients with diabetes, the primary end point reduction of double active compared with double placebo was more pronounced (hazard ratio 0.49, 95% CI 0.33-0.75, P < .001).
The authors conclude that in stable post-MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance.
I fear that these conclusions are erroneous and misleading: the marginally positive finding might have nothing to do with chelation per se; most likely they are due to the fact that the ‘vitamin’ mixture administered along with chelation contained ingredients like heparin and procaine which are potentially beneficial for cardiovascular conditions. Moreover, the placebo contained a considerable amount of glucose which could easily explain the better outcome of the diabetic subgroup receiving the verum – in other words, the verum generated better results not because it was effective but because the ‘placebo’ had detrimental effects.