Chelation Therapy in Patients With Cardiovascular Disease: A Systematic Review

Abstract

Background EDTA is an intravenous chelating agent with high affinity to divalent cations (lead, cadmium, and calcium) that may be beneficial in the treatment of cardiovascular disease (CVD). Although a large randomized clinical trial showed benefit, smaller studies were inconsistent. We conducted a systematic review of published studies to examine the effect of repeated EDTA on clinical outcomes in adults with CVD. Methods and Results We searched 3 databases (MEDLINE, Embase, and Cochrane) from database inception to October 2021 to identify all studies involving EDTA treatment in patients with CVD. Predetermined outcomes included mortality, disease severity, plasma biomarkers of disease chronicity, and quality of life. Twenty-four studies (4 randomized clinical trials, 15 prospective before/after studies, and 5 retrospective case series) assessed the use of repeated EDTA chelation treatment in patients with preexistent CVD. Of these, 17 studies (1 randomized clinical trial) found improvement in their respective outcomes following EDTA treatment. The largest improvements were observed in studies with high prevalence of participants with diabetes and/or severe occlusive arterial disease. A meta-analysis conducted with 4 studies reporting ankle-brachial index indicated an improvement of 0.08 (95% CI, 0.06-0.09) from baseline. Conclusions Overall, 17 studies suggested improved outcomes, 5 reported no statistically significant effect of treatment, and 2 reported no qualitative benefit. Repeated EDTA for CVD treatment may provide more benefit to patients with diabetes and severe peripheral arterial disease. Differences across infusion regimens, including dosage, solution components, and number of infusions, limit comparisons across studies. Additional research is necessary to confirm these findings and to evaluate the potential mediating role of metals. Registration URL: https://www.crd.york.ac.uk/; Unique identifier: CRD42020166505.

Keywords: EDTA; cardiovascular disease; diabetes; systematic review.

Figure 1. Flow diagram of study selection process.

Databases: Cochrane Central (https://www.cochranelibrary.com/central), EMBASE (http://www.embase.com/), and MEDLINE (www.pubmed.gov). CVD indicates cardiovascular disease.

Figure 2. Meta‐analysis for studies reporting ankle‐brachial index (ABI) outcome.

All studies measured the ABI at baseline and at the end of repeated chelation treatment with EDTA infusions. One study (*) did not report the SD or any other measure that would allow to estimate the SD and was not included in the meta‐analysis. In Guldager et al and Van Rij et al, only the active treatment arm was included in the analysis. A fixed‐effects meta‐analysis to estimate the common effect in ABI comparing follow‐up with baseline was conducted using the “meta” package version 5.1‐1 in R version 4.0.2., Because of differences in the compared studies, this meta‐analysis was done for descriptive purposes only, and no clear conclusions should be drawn from it. Square indicates size of weight; tick mark/circle, effect size; black horizontal line, CI; red diamond, common effect estimate and CI; and dashed vertical line, common effect estimate. MD indicates mean difference.

Figure 3. Kaplan‐Meier estimates of primary composite end point in patients with diabetes (n=633) (A) and without diabetes (n=1075) (B) following EDTA treatment in the TACT (Trial to Assess Chelation Therapy).

Adapted with permission from Escolar et al. ©2013, Wolters Kluwer Health, Inc. Med indicates medication.

Figure 4. Evolution of gangrene wound appearance at baseline (top) and following final EDTA infusion treatment (bottom).