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1.  The Effect of an EDTA-based Chelation Regimen on Patients with Diabetes and Prior Myocardial Infarction in TACT 
The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an ethylene diamine tetraacetic acid (EDTA-based) infusion regimen in patients 50 years or older with prior myocardial infarction (MI). Diabetes prior to enrollment was a pre-specified subgroup.
Methods and Results
Patients received 40 infusions of EDTA chelation or placebo. 633 (37%) had diabetes (322 EDTA, 311 placebo). EDTA reduced the primary endpoint (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina) [25% vs 38%, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.44, 0.79), p<0.001] over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI (0.39, 0.88), adjusted p=0.002). All-cause mortality was reduced by EDTA chelation [10% vs 16%, HR 0.57, 95% CI (0.36, 0.88) p=0.011], as was the secondary endpoint (cardiovascular death, reinfarction, or stroke) [11% vs 17% HR 0.60, 95% CI (0.39, 0.91), p=0.017]. After adjusting for multiple subgroups, however, those results were no longer significant. The number needed to treat to reduce one primary endpoint was 6.5 over 5 years (95% CI (4.4, 12.7). There was no reduction in events in non-diabetics (n=1075, p=0.877), resulting in a treatment by diabetes interaction (p=0.004).
Post-MI diabetic patients age 50 or older demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts 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.
PMCID: PMC4111470  PMID: 24254885
myocardial Infarction; diabetes mellitus; secondary prevention
2.  Oral High-Dose Multivitamins and Minerals or Post Myocardial Infarction Patients in TACT 
Annals of internal medicine  2013;159(12):797-805.
Oral multivitamins and minerals are often used in conjunction with ethylenediamine tetra acetic acid infusions to treat atherosclerotic disease. Whether high-dose multivitamins are effective as secondary prevention of atherosclerotic disease, however, has not been established.
The vitamin component of the Trial to Assess Chelation Therapy assessed whether oral multivitamins reduced cardiovascular events, and were safe.
The Trial to Assess Chelation Therapy was designed as a double-blind placebo-controlled 2×2 factorial multicenter randomized trial.
134 US and Canadian academic and clinical sites participated.
1708 patients, age ≥50 years, ≥6 weeks post myocardial infarction, with creatinine level ≤ 176.8 µmol/L (2.0 mg/dL). ( NCT00044213).
Patients were randomly assigned to an oral 28-component high-dose multivitamin and multimineral mixture or placebo.
Study results were analyzed per randomized group. The primary endpoint was time to total mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina. Limited secondary endpoints and subgroup analyses were also pre-specified.
The median age was 65 years, 18% female. The qualifying myocardial infarction had occurred 4.6 (1.6, 9.2) years prior to enrollment. The median duration of follow-up was 55 months (IQR 26, 60) overall. The median number of months during which patients took their vitamins was 31 (13, 59) in the active treatment group, and 35 (13, 60) in the placebo group (p=0.65). There were 645 (76%) vitamin patients and 646 (76%) placebo patients who completed at least 1 year of oral therapy (p=0.98); and 400 (46.9%) vitamin patients and 426 (49.8%) placebo patients who completed at least 3 years of oral therapy (p=0.23). There were 783 (46%) of patients who discontinued their vitamin regimen (390 (46%) in placebo, 394 (46%) in active; p=0.67), and 17% of patients withdrew from the study. The primary endpoint occurred in 230 (27%) patients in the active vitamin group and 253 (30%) in the placebo group (hazard ratio 0.89, 95% CI 0.75–1.07, p=0.21). There was no evidence suggesting harm from vitamin therapy in any category of adverse events
The study had considerable non-compliance and drop-out. Thus, the ability to draw firm conclusions (particularly regarding safety) is limited.
High-dose oral multivitamins and multiminerals did not produce a statistically significant reduction in cardiovascular events in post-myocardial infarction patients on standard medications, but this conclusion has to be tempered by the non-compliance rate.
Primary Funding Source
National Institutes of Health.
PMCID: PMC4143134  PMID: 24490264
3.  Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: The TACT Randomized Trial 
Chelation therapy with disodium ethylene diamine tetraacetic acid (EDTA) has been used for over 50 years to treat atherosclerosis without proof of efficacy.
To determine if an EDTA-based chelation regimen reduces cardiovascular events.
Design and Setting
Double-blind placebo-controlled 2×2 factorial multicenter randomized trial. NIH Funding was approved in August 2002. The first patient was enrolled in September 2003, and the last follow-up took place in October 2011. Median follow-up was 55 months. Participants were recruited from 134 US and Canadian clinical sites.
1708 patients, age 50 or older and at least 6 weeks post myocardial infarction, with a serum creatinine <2.0 mg/dL. 289 patients (17% of total; 115 in the EDTA group and 174 in the placebo group) withdrew consent for continued follow-up over the course of the trial.
Patients were randomized to receive 40 infusions of a 500 mL chelation solution (containing 3 grams of disodium EDTA, 7 grams of ascorbate, B-vitamins, electrolytes, procaine, and heparin) versus placebo, and to an oral vitamin and mineral regimen or an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Patients received 55,222 infusions. 15% discontinued infusions for adverse events.
Main outcome measure
The pre-specified primary endpoint was a composite of total mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina. Followup for clinical events began upon randomization. This report describes the intent-to-treat comparison of EDTA chelation versus placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was p=0.036.
The qualifying myocardial infarction occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, 31% were diabetic. 83% had prior coronary revascularization, and 73% were on statins. The primary endpoint occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio 0.82, 95% confidence interval 0.69–0.99, p=0.035). There was no effect on total mortality (chelation: 87 deaths (10%) placebo 93 (11%): hazard ratio (HR) 0.93, 95% confidence interval 0.70–1.25, p=0.64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary endpoint other than death was of similar magnitude as its overall effect (myocardial infarction HR 0.77 95% confidence interval (0.54,1.11); stroke HR 0.77 95% confidence interval (0.34, 1.76); coronary revascularization HR 0.81 95% confidence interval (0.64, 1.02); hospitalization for angina HR 0.72 95% confidence interval (0.35, 1.47). Extensive sensitivity analyses examining the effect of patient drop out and varying treatment compliance did not alter the study’s conclusions.
Conclusions and Relevance
In stable patients with a history of MI, the use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of a composite of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not, by themselves, sufficient to support the routine use of chelation therapy for treatment of post-MI patients.
PMCID: PMC4066975  PMID: 23532240
chelation; EDTA; vitamin C; myocardial infarction; diabetes; alternative medicine
4.  Development of the adult and child complementary medicine questionnaires fielded on the National Health Interview Survey 
The 2002, 2007, and 2012 complementary medicine questionnaires fielded on the National Health Interview Survey provide the most comprehensive data on complementary medicine available for the United States. They filled the void for large-scale, nationally representative, publicly available datasets on the out-of-pocket costs, prevalence, and reasons for use of complementary medicine in the U.S. Despite their wide use, this is the first article describing the multi-faceted and largely qualitative processes undertaken to develop the surveys. We hope this in-depth description enables policy makers and researchers to better judge the content validity and utility of the questionnaires and their resultant publications.
PMCID: PMC3882880  PMID: 24267412
Complementary therapies; Complementary medicine; Questionnaire development; Cognitive interviewing; National Health Interview Survey (NHIS)
5.  Design and Methodology of the Trial to Assess Chelation Therapy (TACT) 
American heart journal  2012;163(1):7-12.
The Trial to Assess Chelation Therapy (TACT) is an NIH-sponsored, randomized, double blind, placebo-controlled, 2×2 factorial clinical trial testing the benefits and risks of 40 infusions of a multi-component Na2EDTA-chelation solution compared with placebo, and of an oral, high-dose multivitamin and mineral supplement. TACT has randomized and will follow 1708 patients for an average of approximately 4 years. The primary endpoint is a composite of all cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900 patient substudy will examine quality of life outcomes. The trial is designed to have >85% power to detect a 25% relative reduction in the primary endpoint for each treatment factor. Enrollment began in September 2003 and completed in October 2010.
PMCID: PMC3243954  PMID: 22172430
6.  Disease severity is associated with the use of complementary medicine to treat or manage type-2 diabetes: data from the 2002 and 2007 National Health Interview Survey 
The overall prevalence of complementary medicine (CM) use among adults in the United States with diabetes has been examined both in representative national samples and in more restricted populations. However, none of these earlier studies attempted to identify predictors of CM use to treat diabetes among the populations sampled, nor looked for a relationship between CM use and diabetes severity.
Combining data from the 2002 and 2007 National Health Interview Survey (NHIS), we constructed a nationally representative sample of 3,978 U.S. adults aged ≥18 years with self-reported diabetes. Both the 2002 and 2007 NHIS contained extensive questions on the use of CM. We used logistic regression to examine the association between diabetes severity and overall CM use, as well as the use of specific categories of CM.
In adults with type-2 diabetes, 30.9% used CM for any reason, but only 3.4% used CM to treat or manage their type-2 diabetes versus 7.1% of those with type-1 diabetes. Among those using CM to treat/manage their type-2 diabetes, 77% used both CM and conventional prescription medicine for their diabetes. The most prevalent types of CM therapies used were diet-based interventions (35.19%, S.E. 5.11) and non-vitamin/non-mineral dietary supplements (33.74%, S.E. 5.07). After controlling for sociodemographic factors, we found that, based on a count of measures of diabetes severity, persons with the most severe diabetes had nearly twice the odds of using CM as those with less severe disease (OR=1.9, 95%CI 1.2-3.01). Persons who had diabetes 10 years or more (OR=1.66, 95%CI 1.04-3.66) and those that had a functional limitation resulting from their diabetes (OR=1.74, 95%CI 1.09-2.8) had greater odds of using CM than those not reporting these measures. No significant associations were observed between overall CM use and other individual measures of diabetes severity: use of diabetic medications, weak or failing kidneys, coronary heart disease, or severe vision problems.
Our results demonstrate that individuals with more severe diabetes are more likely to use CM independent of sociodemographic factors. Further studies are essential to determine if CM therapies actually improve clinical outcomes when used to treat/manage diabetes.
PMCID: PMC3528411  PMID: 23088705
Complementary medicine; Diabetes; Disease severity; Logistic regression; Survey
7.  Applying Principles from Complex Systems to Studying the Efficacy of CAM Therapies 
In October 2007, a National Center for Complementary and Alternative Medicine (NCCAM)–sponsored workshop, entitled “Applying Principles from Complex Systems to Studying the Efficacy of CAM Therapies,” was held at Georgetown University in Washington, DC. Over a 2-day period, the workshop engaged a small group of experts from the fields of complementary and alternative medicine (CAM) research and complexity science to discuss and examine ways in which complexity science can be applied to CAM research. After didactic presentations and small-group discussions, a number of salient themes and ideas emerged. This paper article describes the workshop program and summarizes these emergent ideas, which are divided into five broad categories: (1) introduction to complexity; (2) challenges to CAM research; (3) applications of complexity science to CAM; (4) CAM as a model of complexity applied to medicine; and (5) future directions. This discusses possible benefits and challenges associated with applying complexity science to CAM research. By providing an introductory framework for this collaboration and exchange, it is hoped that this article may stimulate further inquiry into this largely unexplored area of research.
PMCID: PMC3110804  PMID: 20715978
8.  Ginkgo biloba and risk of cancer: Secondary Analysis of the Ginkgo Evaluation of Memory (GEM) Study 
Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.
A total of 3,069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.
During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.87–1.36; p=0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95% CI, 0.97–4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92–2.87; p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43–1.17; p=0.18).
Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.
PMCID: PMC2917376  PMID: 20582906
Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complimentary and alternative medicine
9.  Effect of ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women 
American journal of hypertension  2010;23(5):528-533.
Accumulating evidence suggests that ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure-lowering effects in humans is lacking.
We determined the effects of ginkgo biloba extract (240 mg/day) on blood pressure and incident hypertension in 3,069 participants (mean age, 79 yrs; 46% female; 96% White) from the Ginkgo Evaluation of Memory study. We also examined whether the treatment effects are modified by baseline hypertension status.
At baseline 54% of the study participants were hypertensive, 28% were pre-hypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in blood pressure and pulse pressure in the ginkgo biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of ginkgo biloba, it did influence the changes in blood pressure variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in pre-hypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the OR (95% CI) for being a never-user in the ginkgo biloba group was 0.75 (0.48–1.16). The rate of incident hypertension also did not differ between participants assigned to ginkgo biloba vs. placebo (HR, 0.99, 95% CI, 0.84–1.15).
Our data indicate that ginkgo biloba does not reduce blood pressure or the incidence of hypertension in elderly men and women.
PMCID: PMC2989407  PMID: 20168306
gingko biloba; blood pressure; hypertension; elderly
10.  Health need and the use of alternative medicine among adults who do not use conventional medicine 
We hypothesize that a substantial portion of individuals who forgo conventional care in a given year turn to some form of alternative medicine. This study also examines whether individuals who use only alternative medicine will differ substantially in health and sociodemographic status from individuals using neither alternative medicine nor conventional care in a given year. To identify those factors that predict alternative medicine use in those not using conventional care, we employed the socio-behavioral model of healthcare utilization.
The current study is a cross-sectional regression analysis using data from the 2002 National Health Interview Survey. Data were collected in-person from 31,044 adults throughout the 50 states and the District of Columbia.
19.3% of adults (38.3 million) did not use conventional care in a 12 month period, although 39.5% of these individuals (14.7 million) reported having one or more problems with their health. Of those not using conventional care, 24.8% (9.5 million) used alternative medicine. Users of alternative medicine had more health needs and were more likely to delay conventional care because of both cost and non-cost factors compared to those not using alternative medicine. While individual predisposing factors (gender, education) were positively associated with alternative medicine use, enabling factors (poverty status, insurance coverage) were not.
We found that a quarter of individuals who forgo conventional care in a given year turn towards alternative medicine. Our study suggests that the potential determinants of using only alternative medicine are multifactorial. Future research is needed to examine the decision process behind an individual's choice to use alternative medicine but not conventional medicine and the clinical outcomes of this choice.
PMCID: PMC2919531  PMID: 20670418
11.  Guidance from an NIH Workshop on Designing, Implementing, and Reporting Clinical Studies of Soy Interventions1–4 
The Journal of Nutrition  2010;140(6):1192S-1204S.
The NIH sponsored a scientific workshop, “Soy Protein/Isoflavone Research: Challenges in Designing and Evaluating Intervention Studies,” July 28–29, 2009. The workshop goal was to provide guidance for the next generation of soy protein/isoflavone human research. Session topics included population exposure to soy; the variability of the human response to soy; product composition; methods, tools, and resources available to estimate exposure and protocol adherence; and analytical methods to assess soy in foods and supplements and analytes in biologic fluids and other tissues. The intent of the workshop was to address the quality of soy studies, not the efficacy or safety of soy. Prior NIH workshops and an evidence-based review questioned the quality of data from human soy studies. If clinical studies are pursued, investigators need to ensure that the experimental designs are optimal and the studies properly executed. The workshop participants identified methodological issues that may confound study results and interpretation. Scientifically sound and useful options for dealing with these issues were discussed. The resulting guidance is presented in this document with a brief rationale. The guidance is specific to soy clinical research and does not address nonsoy-related factors that should also be considered in designing and reporting clinical studies. This guidance may be used by investigators, journal editors, study sponsors, and protocol reviewers for a variety of purposes, including designing and implementing trials, reporting results, and interpreting published epidemiological and clinical studies.
PMCID: PMC2869505  PMID: 20392880
12.  Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial 
Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G biloba on dementia incidence are lacking.
To determine effectiveness of G biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).
Design, Setting, and Participants
Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n=2587) or MCI (n=482) at study entry were assessed every 6 months for incident dementia.
Twice-daily dose of 120-mg extract of G biloba (n=1545) or placebo (n=1524).
Main Outcome Measures
Incident dementia and AD determined by expert panel consensus.
Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94–1.33; P=.21) and for AD, 1.16 (95% CI, 0.97–1.39; P=.11). G biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85–1.50; P=.39).
In this study, G biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI.
PMCID: PMC2823569  PMID: 19017911
13.  Health behaviors and risk factors in those who use complementary and alternative medicine 
BMC Public Health  2007;7:217.
Surveys have generally found that individuals more likely to use complementary and alternative medicine are female, live in the western United States, are likely to have a health complaint, and have a higher socioeconomic status than do nonusers. What is not known is the extent to which those who use complementary and alternative medicine also engage in positive health behaviors, such as smoking cessation or increased physical activity and/or exhibit fewer health risk factors such as obesity. This has been identified as a key research question in a recent Institute of Medicine report. In the present study we sought to determine whether the use of complementary and alternative medicine is associated with health behaviors or risk factors known to impact on health status.
The current study is a cross-sectional regression analysis using data from the 2002 National Health Interview Survey. Data were collected in-person from 31,044 adults throughout the 50 states and the District of Columbia.
After controlling for a range of other factors, we found that engaging in leisure-time physical activity, having consumed alcohol in one's life but not being a current heavy drinker, and being a former smoker are independently associated with the use of CAM. Obese individuals are slightly less likely to use CAM than individuals with a healthy body-mass index. No significant associations were observed between receipt of an influenza vaccine and CAM use.
Those engaging in positive health behaviors and exhibiting fewer health risk factors are more likely to use CAM than those who forgo positive health behaviors or exhibit more health risk factors. The fact that users of CAM tend to pursue generally healthy lifestyles suggests that they may be open to additional recommendations toward optimizing their health.
PMCID: PMC2031902  PMID: 17723149

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