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Editor's note: The results of the TACT trial came under fire after publication in JAMA over several concerns including lack of accounting for a high dropout rate, use of soft endpoints, and the potential for early unblinding of the data.
I have to admit that until 1999, I had no particular interest in studying a pariah therapy called EDTA chelation -- really just not my style.
I had started my experience in clinical trials with Marc Pfeffer at the Brigham, studying LV remodeling and being involved in the rats-to-bedside progression of post-MI ACE inhibitors. This is now called translational work, by the way.
I then applied to the pacemaker world what I had learned from Pfeffer about asking a question and designing a trial to answer it. Other studies followed -- not really based on an overriding topic, but selected based on clinical questions that were relevant to me as a clinician.
But I never had an interest in alternative medicine. At the Brigham, we knew it was bunk. An eccentric patient showed up on a slow clinic day and asked if he should receive chelation therapy. Obviously, I said, "no way!" But the question got me to rediscover the obvious: absence of evidence of efficacy is not the same as evidence of absence of efficacy.
I also rediscovered that the epidemiologic evidence that many metals have cardiovascular toxicity at barely measurable levels is robust, particularly for lead and cadmium (, , , , ), metals chelated by EDTA (, ).
Cadmium is a highly toxic metal widely distributed in the environment. A by-product of mining, smelting, and refining zinc, lead, and copper ores, its use substantially increased during the last decades of the 20th century, particularly in nickel-cadmium batteries and in coating plastic stabilizers. Soil contamination of cadmium is a significant environmental problem because vegetables and grains bio-concentrate cadmium from soil resulting in major cadmium exposure through diet and smoking (, ). Ambient air can also contribute to cadmium exposure, particularly in urban areas and in the vicinity of industrial sources. Cadmium biological half-life in humans is very long, about 15 to 30 years ().
Lead is another bad actor. Lead exposure is still two orders of magnitude higher today than prior to the 17th century (). Given continued uses of lead, primarily for batteries, and because of the persistence of past uses (house paint, plumbing, and soil contamination from past use in gasoline), lead exposure is still widespread (). Moreover, since lead accumulates in the skeleton (, , ), most adults carry some body lead burden from past exposures, and are at risk of present and future health effects. EDTA chelates lead and cadmium.
The Trial to Assess Chelation Therapy (TACT) started with a phone call to NHLBI. I asked a senior scientist if they were interested in a definitive double-blind trial of chelation for cardiovascular disease. Oddly enough, they were. So I recruited my usual cast of extraordinarily competent scientists at Duke, led by Kerry Lee and Dan Mark. We then cajoled hundreds of colleagues and we embarked on what will ultimately be a 20+ year quest.
Four years into the quest, patient one was randomized in the $30 million NCCAM/NHLBI-funded TACT. We are now entering year 16 and planning TACT2. It is not over, but we can see the horizon.
TACT enrolled 1,708 patients who were at least 50 years old and had a prior MI and creatinine 2.0 mg/dL or less. The proposed treatment was intensive -- a factorial trial with 2 randomizations, 40 intravenous Na2EDTA infusions versus IV placebo, and high dose oral multivitamins versus oral placebo. Overall, 1,708 patients received 55,222 IV infusions in 134 enrolling sites across the U.S. and Canada.
Nearly a decade later on Aug. 15, 2012, we received the unblinded results in a long, sparse conference room at the Duke Clinical Research Institute in Durham, N.C. About 10 researchers and NIH scientists sat on one side of the table facing the Duke statisticians.
When the Duke staff distributed the previously blinded analyses, all of us turned to the bottom line, wanting to know: Did chelation work to reduce cardiac events in post-MI patients?
Turns out, it did. This is why research is fun.
In November 2012, I presented the results to a packed house at the American Heart Association's Scientific Sessions in Los Angeles. Massive screens behind me showed my head and my slides. I heard the audience sucking in air when I presented our positive results. The commentator who took the stage after me did his best to discredit the results. The following day, the convention newsletter headline read "Dismay Greets Positive Chelation Trial." But we have published in major journals. We presented our results at Duke, Columbia, Harvard, Mayo, and NYU. The air was electric with interest -- and neither tomatoes nor shoes flew.
The final analysis of the study data demonstrated a significant 26% reduction in overall cardiac events -- including death, strokes, repeat MI, revascularizations, and hospitalizations for unstable angina – by EDTA-chelation plus oral vitamins, a completely generic treatment.
In patients with diabetes, the reduction with infusions alone was by 41% (Figure 2) and all-cause mortality was reduced by an incredible 43% over 5 years. With oral vitamins added, the reduction in the primary endpoint for diabetic patients was 51%. These data raised our classification by the ACC/AHA from Class 3 to 2b – the anteroom where other therapies in common practice also wait for more data, or to sink into the slough of despondency.
We presented our analyses to the FDA and they agreed that the trial was well-designed and positive, and the drug safe. But they requested a confirmatory study.
And so we sit, hopefully at the threshold of funding for TACT2, a simpler pragmatic trial, testing the most effective drug combination (chelation + oral vitamins) in the population that demonstrated the greatest benefit (post-MI diabetic patients).
TACT1 represents a rare occurrence in large randomized clinical trials, something very unexpected, which may have far-reaching consequences. In his book Nicholas Nassim Taleb termed such occurrences "black swan events" () and convincingly discussed how such events can alter the course of science.
If TACT2 replicates the results of TACT1, EDTA chelation therapy will become a novel guideline-supported therapeutic option for patients with CAD already on evidence-based medical therapy, an unexpected consequence of major significance.
, of Mount Sinai Medical Center in Miami. TACT2 is currently looking for trial sites to enroll, infuse, and follow patients. For more information, contact Lamas at gervasiolamas@gmail.com.