Critics of EDTA Chelation Publish Deceptive Data in an Attempt to Discredit

CHELATION CRITICS PUBLISH DECEPTIVE DATA

by Elmer M. Cranton. M.D.

Mainstream medical journals refuse to publish positive research studies of EDTA chelation therapy for treatment of atherosclerosis, while at the same time printing poorly documented letters to the editor and editorials criticizing chelation. This type of editorial censorship has prevented easy access to favorable research. Literature searches usually begin and end with the United States Public Health Service, National Library of Medicine, Index Medicus, or its electronic counterpart, the MEDLINE PubMed computer database. Most studies showing benefit from chelation therapy have been excluded from those databases.

Physicians are often unaware that only approximately 15 of the world's total biomedical literature in all languages is indexed in the MEDLINE computer database. Many highly favorable research studies have been published that support chelation therapy as a treatment for atherosclerosis and age-related diseases, but they are often difficult to find. A MEDLINE computerized database search will point to only four misleading publications. For that reason the results of a computer search for studies of EDTA chelation therapy for treatment of atherosclerosis will be deceptively negative.

Critics of EDTA chelation therapy for treatment of atherosclerotic cardiovascular disease point to the following five studies as evidence that chelation is not effective. In actual fact, those studies all indicate benefit.

1) Kitchell JR, Palmon F, Aytan N, Meltzer LE: The treatment of coronary artery disease with disodium EDTA, a reappraisal. American Journal of Cardiology 1963;11:501-506.

2) Sloth-Nielsen J, Guldager B. Mouritzen C, Lund EB Egeblad M, Norregaard 0, Jorgensen SJ, Jelnes R: Arteriographic findings in EDTA chelation therapy on peripheral atherosclerosis. The American Journal of Surgery 1991; 162:122-125.

3) Guldager B, Jelnes R, Jorgensen SJ, Neilsen JS, et al: EDTA treatment of intermittent claudication—a double-blind, placebo-controlled study. Journal of Internal Medicine 1992;231:261-7.

4) Van Rij AM, Solomon C, Packer SG, Hopkins WG: Chelation therapy for intermittent claudication. A double-blind, randomized, controlled study. Circulation 1994 Sep;90(3):1194-1199.

4) Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy for ischemic heart disease. A randomized controlled trial. JAMA. 2002;287:481-6.

Anderson TJ, Hubacek J, Wyse DG, Knudtson ML. Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH substudy. J Am Coll Cardiol. 2003 Feb 5;41(3):420-5.

These studies (and one additional unpublished report) are analyzed separately and in detail below. The author’s negative conclusions are refuted.

CRITIQUE OF THE KITCHELL REAPPRAISAL STUDY

Kitchell JR, Palmon F, Aytan N, Meltzer LE: The treatment of coronary artery disease with disodium EDTA, a reappraisal. American Journal of Cardiology 1963;11:501-506.

This is a positive study with a mistaken negative conclusion.

This 1963 article by Kitchell, Palmon, Aytan and Meltzer, reappraising their data from an earlier study in 1960 with subsequent additional patients, has been cited for decades as disproving effectiveness of EDTA chelation therapy. However, the authors' conclusion is contrary to their published data.

A careful reading of the entire article reveals that the majority of patients did improve and they maintained that improvement for a considerable time following therapy. After 18 months, and with no stated changes in dietary or other risk factors such as smoking, 46% of the 28 patients remained improved. Twenty-three of the 28 patients (82%) had suffered myocardial infarctions before chelation, making this a high-risk group with any form of therapy.

The published conclusion that EDTA chelation therapy was not effective because some patients regressed after treatment is not justified. There is no other treatment about which that same statement cannot be made.

The 28 patients in this report were evaluated after only 20 treatments with EDTA. More than 64% were rated as improved by the authors. Seventy-one percent of patients had subjective improvement and 64% had objective improvement of measured exercise tolerance three months after chelation. Eighteen months following therapy, 46% remained improved. These results were quite favorable for EDTA and contradict the authors' published conclusions to the contrary.

In retrospect, the unsupported negative summary in this "reappraisal" article was largely responsible for subsequent opposition by mainstream medicine.

This "reappraisal" article refers to ten patients described by the same authors in an earlier publication edited by Drs. Seven and Johnson. Dr. Seven was an ardent enthusiast of EDTA therapy. He suffered an untimely death shortly after publication of his monograph containing the proceedings of the First International Conference on Chelation Therapy. Dr. Seven's death is another factor leading to reduced interest in EDTA chelation therapy and lack of wider acceptance. The Proceedings edited by Seven and Johnson were published in limited numbers and were not readily available to physicians. (Seven MJ, Johnson LA, editors: Metal Binding in Medicine, Philadelphia, J.B. Lippincott Co. 1960.)

A careful review of the original article in those Proceedings, which studied the ten original patients updated in the "reappraisal" article, reveals significant contradictions. The later article states, ". . . The original ten patients received additional courses of treatment and have also been followed continuously." Careful comparison of the two articles reveals that 30% of those original patients received no additional treatment (or, in one case, only one additional infusion). Thirty percent of the original ten patients were therefore misrepresented in the later paper.

Descriptions of the initial patients state, ". . . we selected ten patients referred to us because of severe angina. The patients had previously been treated with most of the accepted methods, and their inclusion in this study resulted from wholly unsuccessful courses. Each of the patients was considered disabled at the start of therapy." It’s obvious that the original ten patients studied were quite sick and were very high-risk patients. Despite that fact, 50% were still alive, three of whom remained improved while the other two were physically active, and no worse when compared to their pre-treatment status at the end of 44 months. That shows quite a remarkable benefit and further refutes the negative conclusion.

A practicing physician first introduced to chelation therapy by reading this "reappraisal" article would most likely have read only the summary and not the entire report. It’s a time-consuming process to extract and summarize all the data. It’s also unlikely that interested physicians would have had access to the original article published in Seven's monograph. The contradictions between actual data and conclusion and the misstatements in the "reappraisal" article are not apparent without time-consuming analysis.

It’s tragic that acceptance of the remarkable benefits of EDTA chelation therapy was seriously delayed by such a flawed report. EDTA therapy, as used now, is vastly more effective than those pioneering investigations first indicated. The outlook has greatly improved. Many complexities and problems of chelation therapy are now better understood and the protocol for administration has been upgraded.

In the early days of chelation therapy, magnesium, manganese, zinc, copper, pyridoxine and other essential nutrients, which are removed by EDTA, were not replaced. No consideration was given to modification of risk factors such as cigarette smoking or diet.

CRITIQUE OF DANISH CHELATION STUDY

Sloth-Nielsen J, Guldager B. Mouritzen C, Lund EB Egeblad M, Norregaard 0, Jorgensen SJ, Jelnes R: Arteriographic findings in EDTA chelation therapy on peripheral atherosclerosis. The American Journal of Surgery 1991; 162:122-125.

Guldager B, Jelnes R, Jorgensen SJ, Neilsen JS, et al: EDTA treatment of intermittent claudication—a double-blind, placebo-controlled study. Journal of Internal Medicine 1992; 231:261-7.

This Was Not a blinded study.

This was a study of EDTA chelation for treatment for intermittent claudication, defined as leg pain on walking caused by atherosclerotic plaque and blockage to blood flow.

The study was published and widely represented as being double blind, which it was not. In that regard it suffered from the same flaw that critics use to discredit many other studies showing benefit from EDTA. Bypass surgeons, who performed this study, broke the blind prior to final assessment. It’s well known that surgeons are often biased against EDTA chelation therapy. When follow-up exercise testing was done, surgeons doing the testing knew who received placebo and who received EDTA. Sixty-four percent of patients were also told which group they were in before follow-up assessments.

Serious methodological errors.

Study subjects underwent only one qualifying exercise test to determine baseline walking distance before stopping with pain. No effort was made to establish reproducibility. It’s well known and published (2-4) that some individuals with claudication can exhibit wide variations in walking distance on repeat testing, even under identical conditions. Scientifically accepted and published procedures for exactly this type of study require that subjects with widely variable walking distance on repeat testing be excluded from the study. (4) Otherwise, changes in walking distance could be caused by the training effect of repeat testing or by the inherent variability of that person, and not be related to treatment. The two groups were very different in that regard.

The average baseline walking distance before stopping from leg pain (absolute claudication distance, ACD) for the EDTA group was 119 meters, with a standard deviation of plus or minus (+/-) 38 meters. The average baseline absolute claudication distance for the placebo group was 157 +/- 266 meters. The EDTA group therefore suffered more severe disease at baseline than the placebo group (25% worse) and the placebo group exhibited a much wider variability (+/- 266 meters compared with +/- 38 meters, a 700% difference). The two study groups were therefore not properly matched at baseline. The EDTA group obviously started out with more severe disease.

The protocol required that all subjects, both placebo and EDTA, develop symptoms of claudication between 50 and 200 meters for entry into the study. A standard deviation of 266 meters in the placebo group indicates that many of the placebo subjects must have continued to walk for hundreds of more meters, before stopping with pain. The placebo group therefore had significantly less disease than in the EDTA group. This was contrary to protocol and biased the study against EDTA. Wide variability made follow-up testing of the placebo group almost totally unreliable.

Confounding variables were not accounted for.

Patients were counseled on dietary change, exercise programs, lifestyle factors, and were advised to stop smoking, but no effort was reported to track differences in compliance between the two groups. Adherence or non-adherence to those factors could cause significant differences in the final observations.

Insufficient numbers of study subjects.

There were insufficient numbers of patients, making the study severely under-powered in statistical terms. Statistically significant improvements could not be computed without enormous and unrealistic benefits in the EDTA group.

The Vascular Clinical Trialists, a group of investigators who are members of the Society for Vascular Medicine and Biology, have established sample size requirements when studying pharmacological agents in treatment of intermittent claudication (4). In studies of exactly this type, for a statistical significance to p< 0.05 (less than 5% probability that the difference is random chance and unrelated to the agent under study), with a 25% difference in walking distance between the treated and control groups, would require 98 patients in each group, for a total of 196 subjects. A key piece of information required, however, is the standard deviation of the baseline ACD. The extremely wide variation of baseline walking distances in the control group must be considered. This gave a pooled standard deviation of 191.8 meters. When that figure is entered into the equation, it would require 462 patients in each study group to yield a difference of 25 meters with statistical significance to p<0.05. The number of subjects required to detect a statistically significant difference of 50 meters walking distance between the groups would be 116 subjects in each group, for a total of 232. Only 51 subjects completed this study in the EDTA group and 56 in the control group, for a total of 107.

High rate of dropout.

Subject dropout was not accounted for in detail by the Danish investigators. The initial dropout rate during the treatment phase was 3.8%, but five EDTA subjects dropped out, compared with only one placebo subject. Between the end of the treatment phase and the 6-month post-treatment evaluations, nine more subjects dropped out. Sixteen other patients were not included in the data for 6-month post infusion exercise testing. The number of dropouts acknowledged by the investigators does not account for the reduced numbers of subjects in each group at the conclusion of the trial. The EDTA group lost 36.8%, decreasing from 80 to 51 subjects. The placebo group lost 29.1%, decreasing from 79 to 56 subjects. The authors accounted for only 34 of the 52 subjects who did not complete the trial. It’s not known whether the missing subjects received EDTA and became completely well, not returning for that reason. That’s a distinct possibility, based on the experience of a large group of chelation physicians. If that is what occurred, the post-infusion testing of EDTA subjects would have selectively excluded those with most improvement. (5) We’ll never know because the investigators refuse access to their study records. What are they attempting to hide? Why don’t they open their records to an audit and independent statistical analysis?

The Danish surgeons said that a number of patients did not complete the post treatment exercise test for reasons other than leg pain. What reasons? If claudication was completely relieved, as is quite possible in the EDTA group, they could have simply stopped because of exhaustion, no longer limited by leg pain from claudication. Why was the total walking distance of those subjects not included in the final data. It’s merely stated that they were censured out of the trial without further explanation. That violates accepted scientific and statistical procedures.

A research study this severely under-powered at the outset suffered even further compromise and became even more ineffective from dropouts. The study began with little likelihood of detecting a significant difference between the groups and became progressively inadequate to the task as subjects left the study.

Data manipulation and statistical irregularities.

The investigators manipulated their observations very deceptively by taking the observed percentage change at the end and calculating the ratio of that percentage change in the EDTA group to the percentage change in the placebo group, relative to the pre-treatment distance. This maneuver served to minimize observed differences between the two groups. Proper statistical procedure would require that a comparison be made between differences in walking distance in each group before and after therapy, and then determining whether a statistically significant change occurred.

The usual statistical t-test is not possible in this study because of the large number of dropouts. Such a situation called for an "intention-to-treat analysis," using non-parametric analysis of covariance. Subjects who stopped for reasons other than intermittent claudication on their follow-up exercise tests should have been assigned their total exercise distance in place of the ACD. For example, a subject could have stopped exercise for another reason because leg pain of claudication was completely resolved. If such a subject were in the EDTA group, failure to include that observation would introduce bias against EDTA. Statistical analysis should have included dropout patients. It did not! Patients who died, or went on to surgery in the control group could indicate benefit in the EDTA group. Any primary statistical analysis that did not include those subjects is potentially biased.

Iron neutralizes EDTA but was given to all patients daily.

It’s scientifically proven that EDTA preferentially binds to iron.(6) By giving all patients in the study daily iron supplementation, potential benefit from EDTA was reduced.

Data do show benefit from EDTA.

At 6 months, the EDTA group had an increase in absolute claudication distance (distance walked before stopping with pain) of 51.3%, from 119 to 180 meters. The placebo group had an increase of only 23%, from 157 to 194 meters. EDTA treated subjects demonstrated twice as much improvement. The investigators refused to divulge data for individual test subjects, so it’s not possible to analyze this difference for statistical significance. One wonders why they keep their data secret.

By way of comparison, in the study that resulted in FDA approval of pentoxifylline (Trental®) for the treatment of claudication, walking distance increased by only 25% over baseline. Because the number of patients was sufficiently large, that amount of improvement was statistically significant and the FDA approved Trental® for marketing.

REFERENCES

1) Guldager B, Jelnes R, Jorgensen SJ, Neilsen JS, et al: EDTA treatment of intermittent claudication—a double blind, placebo-controlled study. Journal of Internal Medicine 1992;231:261-7.

2) Ad Hoc Committee on Clinical Research. Proposed design for a double blind trial to evaluate medications for treatment of intermittent claudication. J Vasc Surg 1992;15:882-884.

3) Committee for Proprietary Medicinal Products. Efficacy Working Party. Guidelines for clinical investigations of medicinal products in the treatment of chronic peripheral arterial occlusive disease. III/5936/94 (revision) Draft 3. Brussels: European Commission, Directorate General III; 1994.

4) Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP, and the Vascular Clinical Trialists. Clinical trials for claudication. Assessment of exercise performance, functional status, and clinical end points. Circulation 1995;92:614-621.

5) Sloth-Nielsen J, Guldager B. Mouritzen C, Lund EB Egeblad M, Norregaard 0, Jorgensen SJ, Jelnes R: Arteriographic findings in EDTA chelation therapy on peripheral atherosclerosis. The American Journal of Surgery 1991; 162:122-125.

6) Skoog DA, West DM, Volumetric methods based on complex-formation reactions in Fundamentals of Analytical Chemistry, New York, Holt, Rinehart and Winston, Inc., 1969, 338-360.

CRITIQUE OF NEW ZEALAND CHELATION STUDY

Van Rij AM, Solomon C, Packer SG, Hopkins WG: Chelation therapy for intermittent claudication. A double blind, randomized, controlled study. Circulation 1994 Sep;90(3):1194-1199.

This is another positive study with a mistaken negative conclusion.

It’s probably no coincidence that cardiovascular bypass surgeons, with an obvious conflict of interest, and who had no prior experience with EDTA chelation therapy, published negative conclusions in both the Danish and New Zealand studies. Those studies were also performed in small countries where resources for scientific oversight are limited.

The New Zealand study was even more severely underpowered in statistical terms than the Danish study. In studies of exactly this type, for a statistical significance to p< 0.05 with a 25% difference in walking distance between the treated and control groups, it would require 98 patients in each group, or 196 total subjects. Only 32 subjects entered this trial.

Despite the small number of subjects, the resting ankle/arm Doppler blood pressure index and also the pulsatility index in the femoral artery of the worst leg improved with statistical significance in the EDTA group, p<.001 (less than 1% probability that the difference is random chance and unrelated to EDTA). (1)

One placebo subject improved far more than any other subject, showing lack of reproducibility on repeat testing. When that outlier was omitted from the final data, the EDTA group improved considerably more in comparison, with an increased walking distance to 230 meters at 90 days after treatment, compared to 185 meters for the control group. When smokers were eliminated from the study, non-smoking EDTA subjects increased walking distance to an average of 325 meters compared with 225 meters for non-smoking placebo subjects, a 70% difference. This was a positive study.

Raw data was subsequently evaluated independently by two highly qualified statisticians who concluded that improvement in the EDTA treated group was statistically significant, p<0.001. (1) The probability that this improvement could have been from random chance instead of EDTA was less than one in one thousand. This improvement occurred despite the fact that most patients in the study were smokers. Although a corrected analysis showing statistically significant benefit from EDTA was subsequently published (1), the mainstream medical journal that published the original report refused to publish a retraction or correction.

1. Chappell LT: Disputes author's conclusions on effectiveness of EDTA chelation therapy. Alternative Therapies Sep 1996;2(5):16-17.

CRITIQUE OF HEIDELBERG CHELATION STUDY
(PRESENTED FROM THE PODIUM, NEVER PUBLISHED)

(Adapted from: Carter JP. If chelation therapy is so good, why is it not more widely accepted? Journal of Advancement in Medicine 1989;2(1/2):213-226.)

This randomized, double blind, placebo controlled study of EDTA chelation therapy for treatment of atherosclerosis was conducted by Professor Doctor Schettler and associates in the clinics of the University Medical School in Heidelberg, Germany. Dr. Schettler was Chairman of the Department of Internal Medicine and President of the International Atherosclerosis Research Association. The study was funded by Thiemann Pharmaceutical Company, manufacturers of the platelet inhibitor, bencyclan, marketed as Fludilat®. Bencyclan is widely prescribed in Europe to treat atherosclerosis. EDTA chelation therapy was compared with bencyclan.

It’s unknown why a pharmaceutical company would fund a study of EDTA, a generic drug for which the patent had expired. It’s possible that Thiemann believed mainstream propaganda that EDTA is ineffective. Why else would Thiemann put EDTA up against their own Fludilat®, a proven effective drug?

Thiemann did take precautions, however. When the grant was awarded, Thiemann reserved the right in its written contract with Schettler to edit any published reports of the study. Thiemann reserved the right to interpret the final data for publication and to do the statistical analysis themselves. It was also agreed that Thiemann would retain all data at the end of the study. Such a contract seems to eliminate the possibility of unbiased research.

Approximately 48 patients were treated, 24 in the bencyclan group and 24 in the EDTA group. Treatments were given five days each week for a total of four weeks. Each patient received 20 infusions. Only patients with peripheral vascular disease who could not walk 200 meters without leg pain of claudication (caused by atherosclerotic blockage of blood flow) were included in the study. Pain-free walking distance was measured before, during and three months after therapy on a treadmill set at 3.5 km/hr with a 10% uphill gradient.

The measured results showed a 250% increase in distance walked before onset of claudication pain in the EDTA-treated group immediately after four weeks of therapy. By comparison, there was only a 60% increase in the bencyclan group. Bencyclan, however, is a drug proven to be of benefit in this disease and is widely prescribed in Europe.

Four patients in the EDTA group experienced more than a 1,000-meter increase in pain-free walking distance. This highly favorable data from those four patients mysteriously disappeared when the final results were made public. Thiemann, of course, had a legal right under terms of their contract to censor and misrepresent the final results and to interpret the data in any way that suited them. Their final report contained data that reduced observed benefit from EDTA immediately after the infusions from 250% increase to only 70%. The fact that data from the best EDTA responders were deleted wouldn’t have been known if scientists from Heidelberg with intimate knowledge of the study had not been shocked by what they considered unethical and dishonest scientific conduct. The original raw data from the study, as described here, were personally delivered to an official of American College of Advancement in Medicine in the United States for independent analysis.

Results of the Heidelberg study were reported verbally from the podium at the Seventh Atherosclerosis Congress in Melbourne, Australia, 1985. The presentation in Australia described only a 70% average increase in pain-free walking distance in the EDTA-treated group (instead of the 250% increase indicated by the raw data), which was compared to a 76% increase in the group treated with bencyclan. The only patient death was in the bencyclan group. No serious side effects were observed from EDTA. An attachment to the abstract of that presentation, available at the meeting, contained a graphic plot of pain-free walking distance extending out to three months after the end of therapy. When the original data from deleted EDTA-treated subjects was added back (including those with maximum relief of symptoms), average walking distance increased by more than 400% three months following EDTA chelation therapy.

Deceptively negative interpretations of this study received widespread coverage in the news media, but results were never published in a scientific medical journal. Furthermore, press releases stated that "EDTA was no better than a placebo," without mentioning that the so-called "placebo" was a proven effective drug.

By way of comparison, in the study that resulted in FDA approval of pentoxifylline (Trental®) for the treatment of claudication, walking distance increased by only 25% over baseline. Because the number of patients was sufficiently large, that amount of improvement was statistically significant and the FDA approved Trental® for marketing.

REFERENCES

Diehm C, Wilhelm C, Poeschl J. Effects of EDTA-Chelation Therapy in Patients with Peripheral Vascular Fisease--A Double-Blind Study. An unpublished study performed by the Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany in 1985. Presented as a paper before the International Symposium of Atherosclerosis, Melbourne, Australia, October 14, 1985.

Diehm C. Zeit Deutsch Herzstiftung. Vol 10, July 1986

CRITIQUE OF CALGARY PATCH STUDY

Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy for ischemic heart disease. A randomized controlled trial. JAMA. 2002;287:481-6.

There is also a more detailed and scientific critique of this study with references. A brief summary is presented below.

In January, 2002, the American Medical Association published a deceptively worded and highly unscientific study alleging to disprove benefit from EDTA chelation as a treatment for heart disease—the so-called Calgary PATCH study. Nowhere do they actually claim to have disproven chelation, although that is implied. They merely state that they found, “no evidence to support a beneficial effect.” In their final sentence they reiterate that conclusion: “Larger trails with a broader range of patients will be needed to assess the safety and impact of EDTA chelation therapy on clinical event rates.” That conclusion is not surprising, since a careful reading of the published report clearly shows that this study was too small, too flawed, and too poorly designed in many ways to produce anything of significance, beneficial or otherwise. It is puzzling that the American Medical Association, with its reputation for scientific integrity to uphold, would publish such sham science in its flagship journal.

The study seems carefully designed as an attempt to disprove chelation from the outset. Only one-fourth the number of patients needed for statistical significance was included. Patients most likely to benefit were selectively excluded. Most patients in the study had only minor symptoms, and 30% had no symptoms at all. It is not possible to study a treatment for angina in patients who do not have angina.

Twice as many patients in the EDTA-treated group had previously experienced myocardial infarctions.

The exercise protocol was bizarre. They failed to screen for reproducibility as a condition for entry. Accepted scientific guidelines were ignored. The primary endpoint was not clearly defined. The type of electrocardiographic ST-depression used as an endpoint is now considered non-specific and is no longer accepted as diagnostic for coronary disease.

Approximately twice as many patients in the misrepresented “placebo” group were given potent anti-anginal drugs. That would obscure comparative improvement in EDTA-treated patients, who received only half as much anti-anginal drug therapy. There was therefore no true “placebo” group. The F.D.A. in the United States. has never approved a new drug to treat angina without first requiring trials wherein all other anti-anginal medications had been discontinued.

Four patients in the placebo group and none in the EDTA-treated group underwent angioplasty during the one-year follow-up after chelation, suggesting that EDTA chelation reduces the need for invasive procedures. EDTA-treated patients also showed more improvement in maximal oxygen consumption.