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Why high-dose vitamin C kills cancer cells
Vitamin C has a patchy history as a cancer therapy, but researchers at the University of Iowa believe that is because it has often been used in a way that guarantees failure.
Most vitamin C therapies involve taking the substance orally. However, UI scientists have shown that giving vitamin C (also known as ascorbate) intravenously—thus bypassing normal gut metabolism and excretion pathways—creates blood levels that are 100 to 500 times higher than levels seen with oral ingestion. It is this super-high concentration in the blood that is crucial to vitamin C’s ability to attack cancer cells.
Earlier work by UI redox biology expert Garry Buettner found that at these extremely high levels (in the millimolar range), vitamin C selectively kills cancer cells but not normal cells both in the test tube and in mice. Physicians at UI Hospitals and Clinics are now testing the approach in clinical trials for pancreatic cancer and lung cancer that combine high-dose, intravenous vitamin C with standard chemotherapy or radiation. Earlier phase 1 trials indicated this treatment is safe and well-tolerated and hinted that the therapy improves patient outcomes. The current, larger trials aim to determine if the treatment improves survival.
In a new study published recently in the December issue of the journal Redox Biology, Buettner and his colleagues have homed in on the biological details of how high-dose vitamin C kills cancer cells.
The study shows that vitamin C breaks down easily, generating hydrogen peroxide, a so-called reactive oxygen species that can damage tissue and DNA. The study also shows that tumor cells are much less capable of removing the damaging hydrogen peroxide than normal cells.
“In this paper we demonstrate that cancer cells are much less efficient in removing hydrogen peroxide than normal cells. Thus, cancer cells are much more prone to damage and death from a high amount of hydrogen peroxide,” says Buettner, a professor of radiation oncology and a member of Holden Comprehensive Cancer Center at the University of Iowa. “This explains how the very, very high levels of vitamin C used in our clinical trials do not affect normal tissue, but can be damaging to tumor tissue.”
Normal cells have several ways to remove hydrogen peroxide, keeping it at very low levels so it does not cause damage. The new study shows that an enzyme called catalase is the central route for removing hydrogen peroxide generated by decomposing vitamin C. The researchers discovered that cells with lower amounts of catalase activity were more susceptible to damage and death when they were exposed to high amounts of vitamin C.
Buettner says this fundamental information might help determine which cancers and which therapies could be improved by including high-dose vitamin C in the treatment regimen.
“Our results suggest that cancers with low levels of catalase are likely to be the most responsive to high-dose vitamin C therapy, whereas cancers with relatively high levels of catalase may be the least responsive,” he explains.
A future goal of the research is to develop methods to measure catalase levels in tumors.
In addition to Buettner, the UI research team included Claire Doskey (now doing postdoctoral work at Michigan State University), Visarut Buranasudja, Brett Wagner, Justin Wilkes, Juan Du, and Joseph Cullen. The study was funded in part by grants from the National Institutes of Health and the Gateway for Cancer Research.
High-Dose Vitamin C (PDQ®)–Patient Version
- Vitamin C is a nutrient found in food and dietary supplements. It is an antioxidant and also plays a key role in making collagen (see Question 1).
- High-dose vitamin C may be taken by mouth or given by an intravenous (IV) infusion (through a vein into the bloodstream). When taken by IV infusion, vitamin C can reach higher levels in the blood than when the same amount is taken by mouth (see Question 2).
- Some studies of IV high-dose vitamin C in patients with cancer have shown improved quality of life, as well as fewer side effects (see Question 4).
- In general, high-dose vitamin C given by IV has caused very few side effects in clinical trials. However, IV vitamin C may cause serious side effects in patients with kidney disease, G6PD deficiency, or hemochromatosis (see Question 5).
- The U.S. Food and Drug Administration (FDA) has not approved the use of IV high-dose vitamin C as a treatment for cancer (see Question 7).
This cancer information summary provides an overview of the use of high-dose vitamin C (also known as ascorbate or L-ascorbic acid) as a treatment for people with cancer. This summary includes a brief history of early clinical trials of high-dose vitamin C; reviews of laboratory, animal, and human studies; and current clinical trials.
This summary contains the following key information:
- Vitamin C is an essential nutrient with redox functions at normal physiologicconcentrations.
- Case series and observational studies from the 1970’s of cancer patients who received high-dose oral and/or intravenous vitamin C seemed to indicate a clinical benefit.
- Two early randomized placebo-controlled trials of high-dose oral vitamin C (10 g/d) noted no significant differences between ascorbate-treated and placebo -treated groups for symptoms, performance status, or survival.
- Laboratory studies have reported that high-dose vitamin C has redox properties and decreased cell proliferation in prostate, pancreatic, hepatocellular, colon, mesothelioma, and neuroblastoma cell lines.
- Studies of vitamin C combined with other drugs in animal models have shown mixed results.
- Intravenous vitamin C has been generally well tolerated in clinical trials.
- Intravenous administration of vitamin C of doses over 500 mg produces much higher blood concentrations of ascorbate than oral administration of the same dose.
- Supplementation with vitamin C alone as ascorbate versus ascorbate formulations plus standard cancer therapies have been shown to be well tolerated in clinical trials.
- Two studies of high-dose vitamin C in cancer patients reported improved quality of life and decreases in cancer-related toxicities.
- Although early observations from preclinical and clinical trials of high-dose vitamin C with and without conventional cancer therapies appear promising and the therapy well tolerated, these studies have several limitations due to lack of rigor in trial design.
Magnesium Intake Associated with Decreased Arterial Calcification
A study published in November 2013 reports that increased magnesium intake is related to lower arterial calcification. Calcification within the arteries is a measure of the burden of atherosclerosis. Atherosclerosis is a systemic disease process in which fatty deposits, inflammation, cells and scar tissue build up within the walls of arteries, and is the underlying cause of the majority of clinical cardiovascular events.
Investigators evaluated 2,695 subjects with an average age of 53 years without cardiovascular disease using Multi-Detector Computed Tomography of the heart and abdomen to assess coronary artery and abdominal aortic calcification. The subjects completed food frequency questionnaires to determine magnesium intake as well as calcium, vitamins D, vitamin K, saturated fat, fiber, alcohol and energy intake.The researchers collected additional data including age, sex, body mass index (BMI), smoking status, blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy and menopausal status among women and treatment for high blood pressure and lipids, diabetes or cardiovascular disease prevention.
The researchers determined that a 50 mg per day increment in magnesium intake was associated with 22 percent lower coronary artery calcification and 12 percent lower abdominal aortic calcification. Additionally, the investigators showed that the subjects with the highest magnesium intake had 58 percent lower odds of having any coronary artery calcification and 34 percent lower likelihood of having abdominal aortic calcification compared to the subjects with the lowest magnesium intake. The researchers found that the association was stronger among women than in men.
The investigators stated, “In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium’s protective associations in stroke and fatal coronary heart disease.”
Hruby A, et al. JACC Cardiovasc Imaging. 2013 Nov 20. [Epub ahead of print.]
Magnesium Intake Related to Mortality in Subjects with High Cardiovascular Risk
The Journal of Nutrition reported in November 2013 that increased magnesium intake is associated with decreased mortality in subjects at high cardiovascular risk. The American Heart Association states that cardiovascular disease (CVD) accounts for 32.3 percent of all deaths in the U.S. equaling approximately one out of three deaths.
The subjects included 7,216 adults 55-80 years of age at high risk for cardiovascular disease with high average magnesium intake. The researchers assigned the subjects either a Mediterranean diet supplemented with nuts or olive oil or a low-fat control diet. The investigators followed the subjects for an average of 4.8 years to assess mortality.
During the follow-up period, the researchers identified 323 total deaths, including 81 cardiovascular deaths and 130 cancer deaths, as well as 277 cardiovascular events. The investigators determined that increased magnesium intake was associated with a reduced risk of cardiovascular, cancer and all-cause mortality. The subjects with the highest magnesium intake had a 34 percent reduction in mortality risk compared to the subjects with the lowest intake.
The study authors concluded, “Dietary magnesium intake was inversely associated with mortality risk in Mediterranean individuals at high risk of cardiovascular disease.”
Guasch-Ferre M, et al. J Nutr. 2013 Nov 20. [Epub ahead of print.]
Vitamin C (ascorbic acid, ascorbate) has a controversial history in cancer treatment. Emerging evidence indicates that ascorbate in cancer treatment deserves re-examination. As research results concerning ascorbate pharmacokinetics and its mechanisms of action against tumor cells have been published, and as evidence from case studies has continued to mount that ascorbate therapy could be effective if the right protocols were used, interest among physicians and scientists has increased. In this review, high-dose vitamin C therapy in cancer treatment is re-evaluated.
Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials
Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials.
Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with standard chemotherapies. This review assesses the evidence for safety and clinical effectiveness of intravenous (IV) ascorbate in treating various types of cancer.
Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to determine if they met inclusion criteria, and then summarized using a narrative approach.
A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or standard of care (chemotherapy). That trial reported an 8.75 month increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm.
Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer.
The Use of Intravenous Vitamin C as a Supportive Therapy for a Patient with Glioblastoma Multiforme.
Glioblastoma multiforme is a high grade malignant brain tumour with a poor prognosis. Here we report the case of a woman with glioblastoma who lived for over four years from diagnosis (median survival 12 months and 2% survival for three years), experiencing good quality of life for most of that time. She underwent initial debulking craniotomy, radiotherapy and chemotherapy, as well as having intravenous vitamin C infusions 2⁻3 times weekly over the four years from diagnosis. Her progress was monitored by blood tests, regular computerised tomography (CT) and magnetic resonance imaging (MRI) scans, clinical reviews and European Organization for the Research and Treatment of Cancer quality of life questionnaires (EORTC QLQ C30). Our case report highlights the benefits of intravenous vitamin C as a supportive therapy for patients with glioblastoma.
Potassium Ascorbate with Ribose: Promising Therapeutic Approach for Melanoma Treatment.
While surgery is the definitive treatment for early-stage melanoma, the current therapies against advanced melanoma do not yet provide an effective, long-lasting control of the lesions and a satisfactory impact on patient survival. Thus, research is also focused on novel treatments that could potentiate the current therapies. In the present study, we evaluated the effect of potassium ascorbate with ribose (PAR) treatment on the human melanoma cell line, A375, in 2D and 3D models. In the 2D model, in line with the current literature, the pharmacological treatment with PAR decreased cell proliferation and viability. In addition, an increase in Connexin 43 mRNA and protein was observed. This novel finding was confirmed in PAR-treated melanoma cells cultured in 3D, where an increase in functional gap junctions and a higher spheroid compactness were observed. Moreover, in the 3D model, a remarkable decrease in the size and volume of spheroids was observed, further supporting the treatment efficacy observed in the 2D model. In conclusion, our results suggest that PAR could be used as a safe adjuvant approach in support to conventional therapies for the treatment of melanoma.
Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, Part 2.
Some in the oncology community contend that patients undergoing chemotherapy and/or radiation therapy should not use food supplement antioxidants and other nutrients. Oncologists at an influential oncology institution contended that antioxidants interfere with radiation and some chemotherapies because those modalities kill by generating free radicals that are neutralized by antioxidants, and that folic acid interferes with methotrexate. This is despite the common use of amifostine and dexrazoxane, 2 prescription antioxidants, during chemotherapy and/or radiation therapy.
To assess all evidence concerning antioxidant and other nutrients used concomitantly with chemotherapy and/or radiation therapy. The MEDLINE and CANCERLIT databases were searched from 1965 to November 2003 using the words vitamins, antioxidants, chemotherapy, and radiation therapy. Bibliographies of articles were searched. All studies reporting concomitant nutrient use with chemotherapy and/or radiation therapy (280 peer-reviewed articles including 62 in vitro and 218 in vivo) were indiscriminately included.
Fifty human clinical randomized or observational trials have been conducted, involving 8,521 patients using beta-carotene; vitamins A, C, and E; selenium; cysteine; B vitamins; vitamin D3; vitamin K3; and glutathione as single agents or in combination.
Since the 1970s, 280 peer-reviewed in vitro and in vivo studies, including 50 human studies involving 8,521 patients, 5,081 of whom were given nutrients, have consistently shown that do not interfere with therapeutic modalities for cancer. Furthermore, non-prescription antioxidants and other nutrients enhance the killing of therapeutic modalities for cancer, decrease their side effects, and protect normal tissue. In 15 human studies, 3,738 patients who took non-prescription antioxidants and other nutrients actually had increased survival.
Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study.
A cohort of 11,580 residents of a retirement community initially free from cancer were followed from 1981 to 1989. A total of 1,335 incident cancer cases were diagnosed during the period. Relative risks of cancer were calculated for baseline consumption of vegetables, fruits, beta-carotene, dietary vitamin C, and vitamin supplements. After adjustment for age and smoking, no evidence of a protective effect was found for any of the dietary variables in men. However, an inverse association was observed between vitamin C supplement use and bladder cancer risk. In women, reduced cancer risks of all sites combined and of the colon were noted for combined intake of all vegetables and fruits, fruit intake alone, and dietary vitamin C. Supplemental use of vitamins A and C showed a protective effect on colon cancer risk in women. There was some suggestion that beta-carotene intake and supplemental use of vitamin A, C, and E were associated with reduced risk of lung cancer in women, but none of these results were statistically significant. These inverse associations observed in women seem to warrant further investigation, although there was inconsistency in results between the sexes.
High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.
Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.
Effects of N-acetyl-L-cysteine and ascorbic acid on mutagen-induced chromosomal sensitivity in patients with head and neck cancers.
The protective effect of N-acetyl-L-cysteine (NAC) and ascorbic acid on mutagen-induced chromosomal breakage was determined using human lymphoblastoid cell lines as well as freshly cultured lymphocytes from patients with head and neck malignancies and healthy control subjects. Mutagen sensitivity was determined using the previously described bleomycin exposure assay. The toxicities of different concentrations of NAC and ascorbic acid, as well as both the preincubation and dose-dependent protective effects of these two agents, were analyzed. Both test drugs proved to be effective in diminishing mutagen-induced chromatid breakage in established lymphocyte cell lines. In freshly cultured lymphocytes, NAC given in doses ranging from 0.1 to 10 mmol/L decreased the number of mutagen-induced breaks per cell in a range from 23% to 73%, and ascorbic acid decreased chromosomal breakage by 21% to 58% in a dose range from 0.01 to 1 mmol/L. The results of this study demonstrate the protective effect mediated in vitro by both NAC and ascorbic acid against mutagen-induced chromosomal damage. A similar in vivo phenomenon may explain the differences in occurrence of head and neck cancer between populations with different dietary backgrounds.
The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life.
Cancer patients commonly experience a number of symptoms of disease progression and the side-effects of radiation therapy and adjuvant chemotherapy, which adversely impact on their quality of life (QOL). Fatigue is one of the most common and debilitating symptom reported by cancer patients and can affect QOL more than pain. Several recent studies have indicated that intravenous (IV) vitamin C alleviates a number of cancer- and chemotherapy-related symptoms, such as fatigue, insomnia, loss of appetite, nausea, and pain. Improvements in physical, role, cognitive, emotional, and social functioning, as well as an improvement in overall health, were also observed. In this mini review, we briefly cover the methods commonly used to assess health-related QOL in cancer patients, and describe the few recent studies examining the effects of IV vitamin C on cancer- and chemotherapy-related QOL. We discuss potential mechanisms that might explain an improvement in QOL and also considerations for future studies.
Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledge.
The use of intravenous vitamin C (IVC) for cancer therapy has long been an area of intense controversy. Despite this, high dose IVC has been administered for decades by complementary health care practitioners and physicians, with little evidence base resulting in inconsistent clinical practice. In this review we pose a series of questions of relevance to both researchers and clinicians, and also patients themselves, in order to identify current gaps in our knowledge. These questions include: Do oncology patients have compromised vitamin C status? Is intravenous the optimal route of vitamin C administration? Is IVC safe? Does IVC interfere with chemotherapy or radiotherapy? Does IVC decrease the toxic side effects of chemotherapy and improve quality of life? What are the relevant mechanisms of action of IVC? What are the optimal doses, frequency, and duration of IVC therapy? Researchers have made massive strides over the last 20 years and have addressed many of these important aspects, such as the best route for administration, safety, interactions with chemotherapy, quality of life, and potential mechanisms of action. However, we still do not know the answers to a number of fundamental questions around best clinical practice, such as how much, how often and for how long to administer IVC to oncology patients. These questions point the way forward for both basic research and future clinical trials.
Intravenous vitamin C in the treatment of shingles: results of a multicenter prospective cohort study.
Vitamin C is an immune-relevant micronutrient, which is depleted in viral infections and this deficiency seems to play a critical role in the pathogenesis of herpes infections and in the development of postherpetic neuralgia. The objective of this observational multicenter study was to evaluate the utilization, safety and efficacy of intravenously administrated vitamin C in patients with shingles.
Between April 2009 and December 2010 16 general practitioners recorded data of 67 participants with symptomatic herpes zoster who received vitamin C intravenously (Pascorbin® 7.5 g/50 ml) for approximately 2 weeks in addition to standard treatment. The assessment of pain (VAS) and the dermatologic symptoms of shingles such as hemorrhagic lesions and the number of efflorescences were investigated in a follow-up observation phase of up to 12 weeks.
Mean declines of pain scores (VAS), number of affected dermatomes and efflorescences, and the presence of hemorrhagic vesicles between the baseline and follow-up assessments at 2 and 12 weeks were statistically significant. Overall, 6.4% of the participants experienced post-herpetic neuralgia. Common complaints such as general fatigue and impaired concentration also improved during the study. The effects and the tolerability of the treatment were evaluated positively by the physicians. The risk of developing PHN was reduced.
The data presented here provide evidence that concomitant use of intravenously administered ascorbic acid may have beneficial effects on herpes zoster-associated pain, dermatologic findings and accompanying common complaints. To confirm our findings, randomized, placebo-controlled clinical studies are necessary.
An Insight and Update on the Analgesic Properties of Vitamin C.
Pain is an unpleasant subjective feeling having implications on both physical and mental realm. Multiple dimensions of pain involving behavioral, spiritual, emotional, and cognitive changes have been studied and pathways elucidated. It is stressed that the nature in which pain is modulated and perceived at a higher center is a complex phenomenon. One of the main goals of pain modulation is to modify pain to a more tolerable level, rather than its complete eradication. Different pain management interventions were tried but have effects that are more adverse. Till date, the only reliable pain blockers are analgesics and anti-inflammatory drugs in the form of opioids and non-opioids. Despite this, most of the drugs are ineffective at various levels, furthermore, adding to complications. Thus, there is an urgent need for effective intervention with minimal side effects. Ascorbic acid, popularly known as vitamin C, has shown to exhibit promising analgesic properties. The literature is sparse with the usage of the drug in various forms of pain. This review focuses on the dynamics and kinetics of vitamin C and its usage in various forms of pain. With minimal adverse effects, the drug is shown to perform well in different types of pain disorders, thus paving way for alternative interventional agent for pain management.
Intravenous vitamin C in the treatment of allergies: an interim subgroup analysis of a long-term observational study.
Objective Oxidative stress appears to be a key factor in the pathogenesis of allergic diseases and a potential therapeutic target in allergy treatment. Allergic diseases are reportedly associated with reduced plasma levels of ascorbate, which is a key physiological antioxidant. Ascorbate prevents excessive inflammation without reducing the defensive capacity of the immune system. Methods An interim analysis of a multicenter, prospective, observational study was conducted to investigate the change in disease-specific and nonspecific symptoms (fatigue, sleep disorders, depression, and lack of mental concentration) during adjuvant treatment with intravenous vitamin C (Pascorbin®; Pascoe, Giessen, Germany) in 71 patients with allergy-related respiratory or cutaneous indications. Results Between the start and end of treatment, the mean sum score of three disease-specific symptoms decreased significantly by 4.71 points and that of four nonspecific symptoms decreased significantly by 4.84 points. More than 50% of patients took no other allergy-related medication besides vitamin C. Conclusions Our observations suggest that treatment with intravenous high-dose vitamin C reduces allergy-related symptoms. Our observations form a basis for planning a randomized controlled clinical trial to obtain more definitive evidence of the clinical relevance of our findings. We also obtained evidence of ascorbate deficiency in allergy-related diseases.
Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction
The TACT Randomized Trial
Importance Chelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis without proof of efficacy.
Objective To determine if an EDTA-based chelation regimen reduces cardiovascular events.
Design, Setting, and Participants Double-blind, placebo-controlled, 2 × 2 factorial randomized trial enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited at 134 US and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011 (median, 55 months). Two hundred eighty-nine patients (17% of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial.
Interventions Patients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs placebo (n=869) and an oral vitamin-mineral regimen vs an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events.
Main Outcome Measures The prespecified primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the intention-to-treat comparison of EDTA chelation vs placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was P = .036.
Results Qualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P = .64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results.
Conclusions and Relevance 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.
Trial Registration clinicaltrials.gov Identifier: NCT00044213
Treatment of lead toxicity with chelation was first reported with EDTA in the early 1950s.1 Apparent success in reducing metastatic calcium deposits2 led Clarke et al3 in 1956 to treat angina patients with EDTA, and others to use chelation for various forms of atherosclerotic disease.4– 6 Chelation therapy evolved to constitute infusions of vitamins and disodium EDTA, a drug that binds divalent and some trivalent cations, including calcium, magnesium, lead, cadmium, zinc, iron, aluminum, and copper, facilitating their urinary excretion.7,8
Over the next decades, based on favorable anecdotal and case report experience, chelation practitioners increased their use of EDTA for coronary and peripheral artery disease. The 2007 National Health Statistics Report compared chelation use since 2002 and noted an increase of 68%, from 66 000 to 111 000 adults using chelation therapy,9 although the indications for therapy were not clearly defined, and the prevalence of use of chelation therapy for cardiovascular disease is unknown.
Three small clinical trials have assessed the effects of chelation on surrogate outcomes, such as walking distance in patients with claudication (2 trials with 185 patients total) and time to exercise-induced ischemia in patients with coronary disease (1 trial with 84 patients). These studies did not find any evidence of treatment efficacy but were underpowered for evaluation of clinical events.10– 12As a consequence, mainstream medical organizations consider the therapeutic value of chelation for atherosclerotic vascular disease unproven13 and the use of this therapy potentially dangerous. Disodium EDTA, particularly when infused too rapidly, may cause hypocalcemia and death.14 The Trial to Assess Chelation Therapy (TACT) was conducted to respond to the public health problem posed by EDTA chelation therapy: large numbers of patients being exposed to undefined risks for unproven benefits.
TACT was a double-blind 2 × 2 factorial trial: patients were randomized to receive 40 infusions of disodium EDTA chelation or placebo and additionally to an oral high-dose vitamin and mineral regimen or placebo. Details of the study protocol have been published.15 This report describes the results of the EDTA chelation vs placebo comparison (Figure 1).
Figure 1. Participant Flow
aScreened patients not randomized because of inclusion/exclusion criteria, unwillingness to participate, or other reasons. Reasons for exclusions were not stored.
bAll patients were included in the primary “time to event” analysis for the duration of their follow-up, including patients who withdrew consent or were lost to follow-up.
The National Heart, Lung, and Blood Institute (NHLBI) and the National Center for Complementary and Alternative Medicine (NCCAM) provided sponsorship and oversight. The US Food and Drug Administration (FDA) approved an Investigational New Drug application for disodium EDTA for coronary artery disease. A data and safety monitoring board (DSMB), appointed by NCCAM (the primary institute at the time) and approved by directors of both sponsoring institutes, monitored patient safety, treatment effects, and the conduct of the trial. Institutional review boards approved the final protocol and provided ongoing oversight. All patients provided written informed consent. The Duke Clinical Research Institute (DCRI) performed data management and statistical analyses.
Eligible patients were at least 50 years old and had experienced a myocardial infarction (MI) 6 weeks or more prior to enrollment. Patients were ineligible if they were women of childbearing potential, had a serum creatinine level greater than 2.0 mg/dL, platelet count less than 100 000/μL, abnormal liver function studies, blood pressure greater than 160/100 mm Hg, past intolerance to the chelation or vitamin components, chelation therapy within 5 years, coronary or carotid revascularization planned or having taken place within 6 months, cigarette smoking within 3 months, active heart failure or heart failure hospitalization within 6 months, or inability to tolerate 500-mL infusions weekly.15 Patients were enrolled at 134 sites, of which 81 (60%) were sites in which chelation therapy was already practiced. Race and ethnicity were self-reported and collected as required in federally funded trials.
The refrigerated blinded active chelation solution was prepared by a central pharmacy with the ascorbate and EDTA in 2 separate syringes and shipped to arrive at the sites within 48 hours of preparation. Placebo infusions were shipped with identical packaging and 2 separate placebo syringes. Following mixing, the sites were instructed to infuse within 24 hours. The active, 10-component chelation solution was selected to most closely match the standard solution used by chelation practitioners16 and consisted of up to 3 g of disodium EDTA, adjusted downward based on estimated glomerular filtration rate; 7 g of ascorbic acid; 2 g of magnesium chloride; 100 mg of procaine hydrochloride; 2500 U of unfractionated heparin; 2 mEq of potassium chloride; 840 mg of sodium bicarbonate; 250 mg of pantothenic acid; 100 mg of thiamine; 100 mg of pyridoxine; and sterile water to make up 500 mL of solution. The identical-appearing placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total).
The chelation or placebo infusions were administered through a peripheral intravenous line, weekly for the first 30 infusions, followed by an additional 10 infusions 2 to 8 weeks apart. Infusions were administered over at least 3 hours unless serum calcium corrected for albumin concentration was between 8.0 and 8.5 mg/dL or the patient was unable to tolerate the 3-hour infusion because of heart failure. In those cases, the infusions were administered more slowly. During the infusion phase of the trial, all study patients, including those randomized to placebo infusions, received a daily low-dose vitamin regimen consisting of vitamin B6, 25 mg; zinc, 25 mg; copper, 2 mg; manganese, 15 mg; and chromium, 50 μg, to prevent potential depletion by the chelation regimen. Investigators were trained in and monitored for the use of evidence-based post-MI therapy.
Study follow-up for clinical events began at randomization. Patients were seen at baseline and at each of the 40 infusion visits. Following the infusion phase, patients were telephoned quarterly, attended annual clinic visits, and were seen at the end of the trial or at the 5-year follow-up, whichever was first. Patient follow-up continued without censoring if a nonfatal end point occurred.
Safety monitoring included periodic physical examinations and laboratory assessments. These included glucose, calcium, renal function, hepatic function, and hematologic parameters. Patients had body weight assessed prior to infusions to determine whether there was fluid retention. Infusions were delayed until specific abnormal physical or laboratory findings resolved. Rapid infusions were reported electronically to the coordinating centers. A medical monitor at the DCRI who was masked to patient treatment assignment reviewed deaths and unexpected serious adverse events.
The primary end point was a composite of death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina. The composite of cardiovascular death, reinfarction, or stroke was a prespecified secondary end point. A blinded independent clinical events committee at Brigham and Women’s Hospital adjudicated all nonprocedural components of the primary end point. The occurrence of coronary revascularizations was verified from the source medical record by the DCRI.
TACT prespecified several subgroups for analyses based on assessing underrepresented populations (women and minorities), elderly persons (aged >70 years), high-risk patients (MI location, diabetes, and metabolic syndrome), and other subgroups of interest (time from index MI to trial enrollment, patients in whom statin therapy was not being used). We also assessed any interaction of the infusion therapy with the oral high-dose vitamin and mineral component of the factorial trial and with the type of enrolling site (chelation practice vs not a chelation practice).
TACT originally planned to enroll 2372 patients over 3 years with a minimum follow-up of 1 year. This number provided 85% power for detecting a 25% relative reduction in the primary end point, assuming a 2.5-year event rate in the placebo group of 20% and a level of significance of .05. In July 2009, continued difficulties in recruitment of patients led the blinded investigators to request approval from the DSMB for a reduction of total enrollment to 1700, with a compensatory extension in the length of follow-up to maintain the same level of unconditional statistical power as described above for the original sample of 2372 patients. The DSMB approved the request, and 1708 patients were randomized. The follow-up period for the trial closed October 31, 2011, approximately 1 year after the last patient was enrolled (see eAppendix for additional details).
Secure web-based randomization was performed using permuted blocks stratified by clinical site. Time 0 was defined as the time of randomization. Treatment comparisons were performed according to the intention-to-treat principle and included all patients in the group to which they were randomized and all follow-up information that was available on each patient. Patients who withdrew consent or were lost to follow-up were included in the analysis with as much follow-up (person-time) as was available until they withdrew or were lost, including any events that occurred prior to their becoming lost or withdrawing from the study. The log-rank test17 was used for the statistical comparison of treatment. Although patients could experience more than 1 component of the primary and secondary end points, each patient was counted only once in the analysis using the time until the occurrence of their first event. All treatment comparisons were performed using 2-sided significance tests.
Cumulative event rates were calculated according to the Kaplan-Meier method.18Relative risks were expressed as hazard ratios (HRs) with associated 95% confidence intervals and were calculated using the Cox proportional hazards model.19 The Cox model was also used to assess the consistency of treatment effects by testing for interactions between treatment and the baseline characteristics prespecified for subgroup analyses as detailed in the previous section. Continuous variables are expressed as medians and interquartile ranges (IQRs) unless otherwise specified. Final statistical analyses were performed using SAS software, versions 8.2 and 9.2 (SAS Institute Inc).
Over the prolonged duration of the trial, the DSMB requested 11 interim analyses of the data. Interim treatment comparisons for the primary end point were monitored with the use of 2-sided symmetric O’Brien-Fleming–like boundaries generated with the Lan-DeMets α spending function approach to group-sequential testing.20,21The monitoring boundaries were based on an overall α=.05. Because of the sequential monitoring, the level of significance required for the primary 2-sided analysis at the completion of the study was P <.036 (eTable 1).
The primary treatment comparisons were performed without any imputation of outcomes in the patients for whom we did not have complete follow-up because of consent withdrawal or loss to follow-up. However, to assess the robustness of study findings, post hoc sensitivity analyses were performed with imputation of missing outcome data. These analyses incorporated event rate assumptions for withdrawn or lost patients in the placebo group that ranged from 10% to 30%. The differential event rate among withdrawn or lost patients in the chelation group was varied from 10% lower, or slightly favorable to chelation, to 25% higher, or moderately unfavorable to chelation. Using imputed event data among the withdrawn/lost patients combined with the actual follow-up data for all other patients, the treatments were then compared with respect to the primary end point. For each different event rate scenario, multiple replications (500) were performed and the results averaged to obtain the HR and confidence interval.
Between September 10, 2003, and October 4, 2010, 1708 patients were randomized, 839 patients to chelation, and 869 patients to placebo. The last infusion was administered on September 3, 2011, and the last follow-up visit completed on October 31, 2011. The median duration of follow-up was 55 (IQR, 26-60) months overall. Active treatment patients were followed up for 56 (IQR, 28-60) months and placebo patients were followed up for 53 (IQR, 24-60) months. The median time from randomization to first infusion was 8 (IQR, 6-12) days overall (8 [IQR, 6-12] days in the chelation group and 7 [IQR, 6-12) days in the placebo group).
Baseline characteristics were similar between treatment groups (Table 1). The median age was 65 (IQR, 59-72) years, 18% were women, 9% were minority, and the median body mass index was 30. The qualifying MI had occurred a median of 4.6 (IQR, 1.6-9.2) years prior to enrollment. The study population had a high prevalence of diabetes (31%), prior coronary revascularizations (83%), and guideline-recommended medication use of aspirin (84%), β-blockers (72%), and statins (73%). Patients had a median fasting glucose level of 102 (IQR, 92-121) mg/dL and a low-density lipoprotein cholesterol (LDL-C) level of 89 (IQR, 67-115) mg/dL.
Table 1. Baseline Characteristicsa
Patients received a total of 55 222 infusions. The median number of infusions received was 40 (IQR, 30-40); 76% of patients completed at least 30 infusions and 65% completed all 40 infusions, 30% discontinued study infusions (n=233 [28%] in the chelation group and n=281 [32%] in the placebo group), and 5% died or the study ended before infusions could be completed (n=41 [5%] in the chelation group and n=36 [4%] in the placebo group). Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events. The most common reason for discontinuation was patient refusal to continue treatment. There were a total of 289 patients (17% of total; n=115 in the chelation group and n=174 in the placebo group) who, during the course of the trial, withdrew consent for continued follow-up in the study. A plot of Kaplan-Meier curves depicting the pattern of consent withdrawals in the 2 randomized groups is presented in eFigure 1. An additional 22 patients were lost to follow-up (13 in the chelation group and 9 in the placebo group). With an average of approximately 3 years of follow-up in these patients, the loss of information was less than the loss among patients who withdrew consent (see eFigure 2, eFigure 3, eTable 2, and eTable 3 for additional details and analyses).
The Kaplan-Meier 5-year estimates for the primary end point were 32.8% (95% CI, 29.1%-36.5%) in the chelation group and 38.5% (95% CI, 34.6%-42.3%) in the placebo group (HR, 0.82; 95% CI, 0.69-0.99; P = .035) (Figure 2). Although treatment comparisons of the components of the primary end point were not individually significant, point estimates for the relative treatment effects (HRs from 0.72 to 0.81) were larger than that for the primary end point for all components except death (HR, 0.93) (Table 2). Revascularizations accounted for 45% of primary end point events; nonrevascularization events accounted for the other 55%. The composite of cardiovascular death, nonfatal MI, or nonfatal stroke occurred in 96 chelation patients (11%) and 113 placebo patients (13%) (HR, 0.84; 95% CI, 0.64-1.11; P = .22).
Figure 2. Kaplan-Meier Estimates of the Primary Composite End Point, EDTA Chelation Therapy vs Placebo
HR indicates hazard ratio. The primary end point was a composite of death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina.
Table 2. Clinical End Pointsa
Prespecified tests for treatment by covariate interactions (Figure 3) indicated statistically greater benefit in 2 subgroups: patients with prior anterior MI and those with diabetes (Figure 4). There was no significant interaction between treatment and type of enrolling practice (chelation site vs nonchelation, P =.28 for interaction) or between the high-dose oral vitamins and chelation therapy in the factorial design (P =.94 for interaction) (eTable 4).
Figure 3. Subgroup Analysis of the Primary Composite End Point, EDTA Chelation Therapy vs Placebo
The primary end point was a composite of death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina.
Figure 4. Kaplan-Meier Estimates of the Primary Composite End Point for the Diabetes and Anterior MI Subgroups, EDTA Chelation Therapy vs Placebo
HR indicates hazard ratio; MI, myocardial infarction. The primary end point was a composite of death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina.
Adverse Effects and Safety
Four unexpected severe adverse events occurred that were possibly or definitely attributed to study therapy, 2 in the chelation group (1 death) and 2 in the placebo group (1 death). Heart failure was reported in 57 chelation patients (7%) and 71 placebo patients (8%) (P = .28). There were 330 (0.60%) of 55 222 infusions administered at least 30 minutes too rapidly. Hypocalcemia, defined as calcium level less than 8.5 mg/dL prior to an infusion, was reported in 52 chelation patients (6.2%) and 30 placebo patients (3.5%) (P = .008). One patient had hypocalcemia associated with muscle cramping that led to an emergency department visit (see eTable 5, eTable 6, and eTable 7 for a complete list of adverse events).
In a sensitivity analysis, we assessed how the primary treatment comparison would be affected under a variety of assumptions regarding the occurrence of primary end point events among patients who withdrew consent or were lost to follow-up. The comparison of the 2 groups remained significant at the P <.036 level if the relative increase of events among the withdrawn/lost patients in the active group was as much as 20% higher than in the placebo group and even generally if the percentage of events among withdrawn/lost patients in the active group was 25% higher than in the placebo group. The HRs for all of these scenarios remained in the range of 0.80 to 0.84, and the significance of the treatment effect was maintained, not only for the scenarios for the withdrawn or lost patients that would be considered most plausible but also for scenarios that were unfavorable to EDTA chelation (eTable 8).
TACT is the first randomized trial, to our knowledge, designed and powered to evaluate the effects of an EDTA-based chelation regimen on clinical outcomes in patients with coronary disease. The trial randomized 1708 patients, administered more than 55 000 double-blind infusions, and accrued more than 6200 patient-years of follow-up experience. These data showed that among patients with a prior MI, a chelation regimen of 40 infusions of disodium EDTA, ascorbate, B vitamins, and other components resulted in a modest reduction in a composite outcome of cardiovascular events. The treatment effect persisted over the 5-year follow-up period without evident attenuation. There was no interaction of infusion therapy with the treatment assignment for the oral vitamin regimen. The study was not designed to ascertain mechanism of action or to identify which of the components of the infusions were responsible for the treatment effect observed.
The effect of EDTA chelation on the nonfatal components of the primary end point was quantitatively consistent with its overall effect. The most frequently occurring component was coronary revascularization. We saw no statistically significant treatment effect on all-cause mortality, but the trial had low statistical power for this evaluation. Likewise, the study was underpowered to detect a difference between groups for the secondary end point of cardiovascular death, MI, or stroke (P = .22). These results were observed against the background of modern evidence-based post-MI therapy given to the study patients: 83% had undergone revascularization with either coronary artery bypass grafting or percutaneous intervention, 84% were taking aspirin, 26% were taking clopidogrel, 72% were taking β-adrenergic blockers, and 73% were taking statins, with a median LDL-C level of 89 (IQR, 67-115) mg/dL.
Although the relative reduction in cardiovascular events (18%) was smaller than the effect hypothesized in the study design (25%), no prior effectiveness data were available with which to estimate the effect size. A 25% relative reduction in the event rate is included in the 95% CI around the measured treatment effect (HR, 0.69-0.99). Furthermore, an 18% relative treatment effect is within the range of effects that have been considered clinically important in prior trials, such as the use of clopidogrel for patients with acute coronary syndromes.22
Two prespecified subgroups appeared to receive particular benefit of therapy. Patients with diabetes had a reduction in risk (HR, 0.61; 95% CI, 0.45-0.83), and patients with anterior MI, as localized by site investigators, also had a reduction in risk of cardiovascular events (HR, 0.63; 95% CI, 0.47-0.86). Both of these subgroups were prespecified based on representing important high-risk subsets of patients but not because there was any specific biologic reason for suspecting that chelation would be uniquely beneficial for these patients. Whether the partitioning of treatment benefit evident in these subgroups will be replicable should be the subject of future investigation. Thus, at present our understanding of the significance of these subgroup findings is incomplete.
TACT is unique from a historical perspective. Chelation therapy with disodium EDTA has been in use to treat atherosclerotic disease for more than 50 years.23– 26 By 2007, the use of chelation had expanded in the United States to 111 000 adults, exposing this large group of patients to uncertain risks for unproven benefits. However, the prevalence of use of chelation therapy for atherosclerotic disease is not well documented.
The Centers for Disease Control and Prevention have reported deaths from misuse of EDTA chelation. In a June 2008 Federal Register notice, the FDA informed the public that edetate disodium was being withdrawn from the market27 Mainstream medical practitioners in general have been highly skeptical that chelation therapy provides any clinical benefit. The most recent American College of Physicians/American College of Cardiology/American Heart Association guideline for the management of stable ischemic heart disease gives chelation therapy a class III recommendation (not useful/effective and may be harmful).28 Disodium EDTA remains available through compounding pharmacies. Patients continue seeking out and receiving EDTA chelation therapy, and chelation practitioners continue to recommend this therapy. It is in the context of this half-century controversy that we carried out and now report TACT.
The interpretation of TACT is made more difficult by the absence of supporting research identifying the most plausible mechanism(s) of action. Although TACT was not a mechanistic study, the data obtained do allow some cautious conjectures regarding potential mechanisms meriting future investigation. Two, in particular, can be mentioned. Heavy metal exposure, particularly to lead, has been recognized as a risk for MI and stroke.29,30 The association of heavy metal pollutants with cardiovascular events extends to antimony, cadmium, cobalt, and tungsten.31 The continued separation of the Kaplan-Meier curves for chelation and placebo, after the infusions stop in year 2, might lend support to a hypothesis that removal of heavy metals has benefit beyond the active infusion phase.
Endothelial dysfunction is generally accepted as a common pathogenic abnormality in patients with atherosclerotic vascular disease. Improvement in endothelial function is a frequent finding with efficacious cardiovascular therapies. Disodium EDTA does not apparently show this effect.32 The chelation infusions, however, also contained 7 g of ascorbate, a vitamin that improves endothelium-dependent vasodilation.33,34 Yet clinical trials of oral antioxidant vitamins have been negative.35,36
Our use of repetitive intravenous infusions would have led tohigher ascorbate blood levels than that of any oral regimen previously studied in cardiovascular clinical trials.37 Thus, it is possible that improved endothelial function might account for some of the modest benefit observed. Oxidative LDL-C modification facilitated by transition metals is an interesting potential mechanism for the association of atherosclerosis with heavy metals. Transition metals are thought to promote LDL-C oxidation, while antioxidants are thought to retard it.38 Thus, a combination of EDTA and ascorbate might lead to a beneficial effect on oxidized LDL-C.
This study has several limitations. First, the necessity of using a composite end point as the primary outcome event in a clinical trial creates some unavoidable uncertainties about the actual treatment benefit because study power is insufficient to show an effect on any individual end point and the components are not all considered of equal clinical importance. In TACT, coronary revascularizations were the most frequently observed end point events. Revascularization events are considered “softer” because of the necessary element of physician decision making involved in the event, but such events are nonetheless commonly used in composite end points in cardiovascular trials. In TACT, the revascularization events were verified by staff masked to patient treatment assignment. The consistency of relative treatment effect on all individual nonfatal components of the primary end point provides some reassurance that the observed chelation benefits were not seen only because of some extratherapeutic effect on revascularization decisions.
Second, an unusually high number of patients in TACT withdrew consent, leading to some lost data. However, all patients had, with appropriate institutional review board approval to do so, their National Death Index status checked at the end of the study, and some patients withdrew after having a primary end point event. Post hoc sensitivity analyses with imputations for missing data, included in eTable 8, are consistent with our prespecified analyses.
Third, unblinding is a possible explanation for the observation that placebo patients were more likely to discontinue therapy, withdraw consent, or be lost to follow-up than chelation patients. Widespread unblinding of study patients is unlikely, however. There is no evidence from a review of adverse effects that patients perceived a difference between a saline infusion and a chelation infusion. Blinding of coordinators was maintained by the techniques developed to reproduce the viscosity and mask the color of the vitamin C syringes. In addition, there was no heterogeneity in the effect of chelation therapy based on whether a patient was enrolled and followed up at a chelation site or a conventional cardiology site. The imputations performed (eTable 8) support a modest benefit of chelation therapy.
Fourth, the study was initiated without a well-established hypothesis for the mechanism(s) of benefit, and this limits our ability to understand and use the results.
Fifth, the 40-infusion chelation regimen tested in TACT is not easy for patients to receive (each infusion takes about 3 hours and the first 30 infusions are administered at weekly intervals).
Finally, one trial, no matter how large or well conducted, cannot answer all the questions needed to transform a novel hypothesis into a clinical treatment that merits guideline endorsement. Moreover, as the first trial of a chelation regimen in this patient population, the possibility that the results represent chance findings must be considered, especially in light of the narrow difference between the significance level calculated and that prespecified for the analysis. Accordingly, the results of this study should be viewed as an important but single step on the long path toward better understanding the pathophysiologic and therapeutic implications of chelation therapy but do not provide evidence to support its routine use in clinical practice.
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 sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.
Corresponding Author: Gervasio A. Lamas, MD, Columbia University Division of Cardiology, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL 33140 (email@example.com).
Author Contributions: Dr Lamas had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lamas, Goertz, Boineau, Mark, Rozema, Nahin, Drisko, Lee.
Acquisition of data: Lamas, Rozema, Lewis, Drisko, Lee.
Analysis and interpretation of data: Lamas, Goertz, Boineau, Mark, Nahin, Lindblad, Lewis, Drisko, Lee.
Drafting of the manuscript: Lamas, Goertz, Boineau, Mark, Lindblad, Drisko, Lee.
Critical revision of the manuscript for important intellectual content: Lamas, Boineau, Mark, Rozema, Nahin, Lewis, Drisko, Lee.
Statistical analysis: Lamas, Lindblad, Lee.
Obtained funding: Lamas, Boineau, Mark, Lee.
Administrative, technical, or material support: Lamas, Boineau, Mark, Rozema, Nahin, Lewis, Drisko, Lee.
Study supervision: Lamas, Boineau, Mark, Nahin, Lewis, Lee.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lamas reports that from 2000 to 2003 he served as a consultant to OmniComm, the electronic data capture company used in the trial. No funds were received and all relationships were severed as of September 10, 2003. No other disclosures were reported.
Funding/Support: The NCCAM (grant U01AT001156) and the NHLBI (grant U01HL092607) provided sole support for this study.
Role of the Sponsor: Robin Boineau, MD, NHLBI, Richard Nahin, PhD, NCCAM, Mario Stylianou, PhD, NHLBI, and Yves Rosenberg, MD, NHLBI, respectively, were involved as part of the NIH Cooperative Agreement process, in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI, the NCCAM, or the National Institutes of Health.
Online-Only Material: The Author Video Interviewis available here.
Additional Contributions: We gratefully acknowledge the scientific contributions and support of Yves Rosenberg, MD, and Mario Stylianou, PhD, NHLBI; the organizational skills of Ana Mon, MPH, clinical coordinating center at Mt Sinai Medical Center; Alyssa Cotler, NCCAM, Susan Dambrauskas (formerly NHLBI), and Vivian Thompson, DCRI, for their competent professional assistance; and the Florida Heart Research Institute for supporting the pilot study. The above mentioned contributors received no compensation for their work other than their usual salary.
A complete list of the TACT Investigators appears in the eAppendix.
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High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.
Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail.
METHODS AND FINDINGS:
We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement.
Despite IVC’s biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC’s value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy regimen and IVC in which exceptional responses occur frequently enough to justify appropriately focused clinical trials.
Ascorbic Acid in Colon Cancer: From the Basic to the Clinical Applications.
Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type RAS. We perform a PubMed and Ovid MEDLINE search using ascorbic acid, intravenous vitamin C, KRAS mutation, BRAF mutation and colorectal cancer (CRC) as keywords. At the cellular level, colorectal cancer cells undergo a metabolic shift called the Warburg effect to allow for more glucose absorption and utilization of glycolysis. This shift also allows AA to enter which leads to a disruption in the Warburg effect and a shutdown of the downstream KRAS pathway in mutated KRAScolon cancer cells. At the clinical level, AA is associated with tumour regression in advanced disease and improved tolerability and side effects of standard therapy. Based on these findings, we conclude that further clinical trials are needed on a larger scale to examine the therapeutic benefits of AA in colon cancer.
Vitamin C (ascorbic acid) plays an important role in maintaining skin health and can promote the differentiation of keratinocytes and decrease melanin synthesis, leading to antioxidant protection against UV-induced photodamage. Normal skin needs high concentrations of vitamin C, which plays many roles in the skin, including the formation of the skin barrier and collagen in the dermis, the ability to counteract skin oxidation, and the modulation of cell signal pathways of cell growth and differentiation. However, vitamin C deficiency can cause or aggravate the occurrence and development of some skin diseases, such as atopic dermatitis (AD) and porphyria cutanea tarda (PCT). Levels of vitamin C in plasma are decreased in AD, and vitamin C deficiency may be one of the factors that contributes to the pathogenesis of PCT. On the other hand, high doses of vitamin C have significantly reduced cancer cell viability, as well as invasiveness, and induced apoptosis in human malignant melanoma. In this review, we will summarize the effects of vitamin C on four skin diseases (porphyria cutanea tarda, atopic dermatitis, malignant melanoma, and herpes zoster and postherpetic neuralgia) and highlight the potential of vitamin C as a therapeutic strategy to treat these diseases, emphasizing the clinical application of vitamin C as an adjuvant for drugs or physical therapy in other skin diseases.
IV Vitamin C Information
Vitamin C (as sodium ascorbate) administered intravenously has numerous benefits, such as improving immune function, improving antioxidant status, reducing oxidative damage, detoxification, decreasing bronchospasm, aids healing, especially after surgery, and many other benefits. As such, it is a useful adjunctive therapy for acute and chronic infections, Chronic Fatigue Syndrome, Lyme disease, asthma, and cancer patients and other diseases.
Serum ascorbate level above 4 mg/dl boosts interferon levels, which markedly improves immune response. This high serum level cannot be achieved with oral vitamin C due to gastrointestinal discomfort and diarrhea.
Additional nutrients (vitamins, minerals, amino acids, antioxidants) can also be added to this IV treatment to correct nutritional deficiencies or for synergistic effects. B vitamins, especially B-12, improves energy production. Correcting nutrition deficiencies intravenously markedly speeds up progress and improves outcomes. For example, magnesium deficiency causes migraine headaches, high blood pressure, and muscle spasms. IV magnesium can rapidly correct these issues.
The most common side effects that may accompany intravenous administration of nutrients include the following, however, most can be prevented or modulated by varying the rate of infusion:
-burning and stinging at the site of infusion or if IV infiltrates into surrounding tissue
-muscular spasms, weakness, or fatigue
-allergic reactions (rare)
-local vein irritation & thrombophlebitis (very rare)