Chelation therapy linked with small reduction in cardiovascular outcomes

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1. For stable patients over age 50 with a history of MI, IV disodium EDTA, compared to placebo, moderately reduces the risk of a composite of cardiovascular outcomes. 

2. The results of the study are controversial due to the composite nature of the primary end point, high number of subject withdrawals, and possible unblinding; therefore, it should not be readily used to rationalize routine use of chelation.

In this study published today, infusions of disodium EDTA, as compared to placebo, was associated with a modest risk reduction of a composite index of cardiovascular outcomes for stable patients over age 50 with a history of MI. The most common reduction seems to occur in coronary revascularization procedures. Certain subgroups, including patients with a history of diabetes or anterior MI, appeared to show a greater benefit from chelation therapy.

This study was the first randomized trial of its kind to be able to assess EDTA-based chelation on clinical outcomes in patients with atherosclerosis. It should be noted, however, that the trial has been quite infamous over the past several years for a range of serious issues that may undermine the study findings (see accompanying editorials). While strengths of the study included the large number of patients to power the study, this was undermined with an over 17% drop-out rate. As described in an accompanying editorial, an even more alarming fact was a disproportionately high number of patients dropping out of the study from the placebo group, which suggests that there was possibly unblinding of treatment assignments. Another limitation of the study is the inclusion of subjective-based criteria such as revascularization and hospitalization for angina as adverse events in the primary composite outcome measure given that it made it easier to manipulate the data. Additionally, in the absence of a clearly understood mechanism of chelation in reducing cardiovascular adverse events, it may be difficult to properly contextualize these results. While this study may be a first step in understanding a possible role of EDTA-based chelation therapy in patients with atherosclerosis, methodological flaws cannot be ignored, and these results should not be used to change clinical practice at this time.

Click to read the study, published today in JAMA 

Click to read the first accompanying editorial in JAMA 

Click to read the second accompanying editorial in JAMA

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Image: PD

1. For stable patients over age 50 with a history of MI, IV disodium EDTA, compared to placebo, moderately reduces the risk of a composite of cardiovascular outcomes. 

2. The results of the study are controversial due to the composite nature of the primary end point, high number of subject withdrawals, and possible unblinding; therefore, it should not be readily used to rationalize routine use of chelation. 

This [double-blind, placebo-controlled, randomized] trial: The study included 1708 patients over age 50 who had a history of an MI. Patients were randomized into two study arms: either (1) 40 infusions of 10-component chelation solution with 3 g disodium EDTA or (2) placebo in addition to either oral high dose vitamin or placebo. The primary end point was a composite of all cause death, reinfarction, stroke, revascularization, or hospitalization for anginal symptoms.  By Kaplan-Meier estimates, the chelation group had a composite cardiovascular adverse outcome in 32.8% patients, the chelation group had it in 38.5% of patients. In subgroup analysis, patients with diabetes (HR 0.61) and those with anterior MI (HR 0.63) appeared to benefit more from chelation.

In sum:  In this study, infusions of disodium EDTA, compared to placebo, moderately reduced the risk of a composite of cardiovascular outcomes for stable patients over age 50 with a history of MI. The most common reduction seems to occur in coronary revascularization procedures. Certain subgroups, including patients with a history of diabetes or anterior MI, appeared to show a greater benefit from chelation therapy.

This study was the first randomized trial of its kind to be able to assess EDTA-based chelation on clinical outcomes in patients with atherosclerosis. It should be noted, however, that the trial has been quite infamous over the past several years for a range of serious issues that may undermine the study findings (see accompanying editorials). While strengths of the study included the large number of patients to power the study, this was undermined with an over 17% drop-out rate. As described in an accompanying editorial, an even more alarming fact was a disproportionately high number of patients dropping out of the study from the placebo group, which suggests that there was possibly unblinding of treatment assignments. Another limitation of the study is the inclusion of subjective-based criteria such as revascularization and hospitalization for angina as adverse events in the primary composite outcome measure given that it made it easier to manipulate the data. Additionally, in the absence of a clearly understood mechanism of chelation in reducing cardiovascular adverse events, it may be difficult to properly contextualize these results. While this study may be a first step in understanding a possible role of EDTA-based chelation therapy in patients with atherosclerosis, methodological flaws cannot be ignored, and these results should not be used to change clinical practice at this time.

Click to read the study, published today in JAMA 

Click to read the first accompanying editorial in JAMA 

Click to read the second accompanying editorial in JAMA

By Anne Marie Walters and Rif Rahman

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