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Troubled study at heart of therapy debate

With $30 million of taxpayer money, researchers set out to conduct one of the largest studies ever of an alternative medical treatment, a controversial therapy for coronary artery disease.

The project was marred with problems from beginning to end.

Because the treatment was so out of step with mainstream medicine, it was difficult to find enough patients to take part.

The researchers failed to inform the subjects that one risk of the treatment was death. In consent form documents, they made a confusing statement about the study drug, implying it was safer than it was.

The researchers overseeing the study stepped up background checks on the doctors involved after some physicians ran into disciplinary problems unrelated to the chelation trial. Two doctors consulting on the trial have been convicted of crimes.

The troubles with the study, called the Trial to Assess Chelation Therapy or TACT, are emblematic of the difficulties faced by the National Center for Complementary and Alternative Medicine as it tries to study alternative treatments in a scientific way.

In its 12 years of existence, NCCAM has found itself funding clinical trials of therapies with weak scientific foundations, from distant prayer as a treatment for AIDS to a risky regimen for pancreatic cancer involving coffee enemas.

The chelation study was one of the center's biggest projects, launched about a decade ago with support from a powerful congressman. Funding came from NCCAM and a second organization within the federal National Institutes of Health, the National Heart, Lung, and Blood Institute.

The project was designed to assess whether intravenous chelation therapy, which helps expel metals from the body, can treat coronary artery disease. Tens of thousands of Americans are choosing to undergo such treatments, even though using chelating drugs as heart medicine originated in decades-old ideas about arterial plaques that have never been proved.

Chelating drugs also carry risks. In fact, the drug being studied, edetate disodium, turned out to be so risky that the U.S. Food and Drug Administration later withdrew its approval. Yet the study was not halted, and the volunteers were not immediately told.

"To subject human subjects to risks for no plausible benefit is really unethical," said Dr. Kimball Atwood, an anesthesiologist at the Newton-Wellesley Hospital in Newton, Mass., and first author of a lengthy critique of the study published in The Medscape Journal of Medicine in 2008.

A co-author of the critique, Liz Woeckner, said the trial is a black eye for the National Institutes of Health.

"(The NIH) is the nation's premier medical research facility. We look up to them. We put our hopes in them. We trust them," said Woeckner, president of Circare, a nonprofit that advocates for people enrolled in clinical trials. "For them to conduct a trial that is unethical and unscientific — and continue to conduct it? It is just mind-boggling."

The Medscape paper also questioned whether the results of the study would be valid, citing flaws that included wrong or incomplete information given to subjects and the tarnished professional records of some researchers.

"The trial's outcome will be unreliable and almost certainly equivocal, thus defeating its stated purpose," Atwood wrote in the paper. In an interview, he called the project "rotten to the core."

Dr. Josephine Briggs, head of NCCAM since 2008, declined to discuss the study in detail, saying her center no longer oversees it. She did say such research is difficult to conduct. "It has been hard to complete because of the fact that physicians are highly polarized in what they believe," Briggs said.

She referred questions to the National Heart, Lung, and Blood Institute, which was handed oversight of the trial in 2006. Dr. Susan Shurin, its acting director, said in a written statement that a well-designed, sufficiently large clinical trial was needed because so many people were choosing to receive the therapy.

"The lack of compelling evidence to support a widely practiced therapy is an argument FOR doing a randomized trial, not against it," wrote Shurin, who is board-certified in pediatric hematology-oncology.

TACT's principal investigator, cardiologist Gervasio Lamas, defended the project in a written statement and said researchers are committed to ensuring the highest level of patient safety. Lamas is chairman of medicine at Mount Sinai Medical Center in Miami Beach, Fla.

Lamas emphasized that the study operates under extensive oversight by multiple groups. "We are serious scientists trying to provide needed evidence to define whether chelation therapy for coronary heart disease should be part of the standard clinical armamentarium, or whether the risks of chelation outweigh any possible benefit," he wrote.

'Considered obsolete'

Problems with TACT start with the most basic of all: There was little scientific reason to believe the study drug, edetate disodium, could help treat coronary artery disease.

In fact, far from helping, edetate disodium can rapidly strip calcium from the body, which can cause an electrolyte imbalance and interfere with the beating of the heart, sometimes fatally.

In the 1950s, doctors hypothesized that the drug could yank calcium from the plaques that clog arteries, helping break them down, like Drano for blood vessels. The therapy has been promoted over the years in books like "Bypassing Bypass: The New Technique of Chelation Therapy" and on practitioners' websites.

But in a document submitted as part of the grant application, Lamas acknowledged there was "little data to support the decalcifying hypothesis." He listed six other possible explanations for how chelation therapy could help, but none had been proved.

Scientists say it's fine to study a potential treatment without knowing exactly how it works — but there needs to be compelling evidence to suggest that it does work.

Chelation to treat coronary artery disease didn't have that either. Three randomized, double-blind clinical trials found no meaningful difference between chelation therapy and a placebo.

Dr. Edzard Ernst, a retired professor of complementary and alternative medicine at University of Exeter, summed up the evidence in a 2000 review published in the American Heart Journal. "The most striking finding is the almost total lack of convincing evidence for efficacy," Ernst wrote. "Given the potential of chelation therapy to cause severe adverse effects, this treatment should now be considered obsolete."

Lamas wrote in an email that the study had a plausible hypothesis that deserved to be tested. "TACT was supported by Congress, reviewed by multiple peer-review committees and approved," he wrote.

Dr. Clyde W. Yancy, chief of the cardiology division at the Northwestern University Feinberg School of Medicine, agreed with Lamas. "It's time to either prove this to be a reasonable treatment or put it to rest," Yancy wrote in an email.

Yet this is a question cardiac researchers were not clamoring to answer. Over a period of 30 years, the NIH's National Heart, Lung, and Blood Institute received just three chelation-related research grant applications amid tens of thousands, according to congressional testimony. They were not funded.

"If the science is invalid," said Woeckner, who advocates for the rights of clinical trial patients, "it is unethical to expose human beings to any risk whatsoever."

Congressional push

With scant compelling evidence that chelation therapy might be safe and effective for coronary artery disease, why did the government spend $30 million of taxpayer money studying it?

The answer begins with a powerful politician.

In 1999, Rep. Dan Burton, R-Ind., held a congressional hearing titled "Cardiovascular Disease: Is the Government Doing More Harm Than Good? EDTA Chelation Therapy."

An advocate of alternative medicine, Burton wanted to know why NIH wasn't spending more of its taxpayer dollars studying such treatments.

He brought the director of the National Heart, Lung, and Blood Institute, Dr. Claude Lenfant, before the committee and pressed him to explain why the institute had not yet studied chelation therapy for coronary artery disease.

Then he asked proponents of chelation therapy to talk about how effective it was and how the therapy had not been given a fair shake.

One who spoke was Dr. Theodore Rozema, president-elect of the American College for Advancement in Medicine, the largest organization advocating for chelation therapy.

In 1978, the state Board of Medical Examiners in North Carolina disciplined Rozema's medical license after learning that in 1976 in Massachusetts, Rozema had pleaded guilty to and was convicted of the charge that he "did knowingly, willfully and feloniously extort by the use of force, violence and fear money," according to board records.

Medical boards in Illinois, South Carolina and Pennsylvania also disciplined his medical license, according to the North Carolina board. Rozema did not respond to requests for comment.

After Rozema and others spoke, Burton left officials with the NIH and other agencies in charge of medicine with an unambiguous message: "We are going to be hauling them before this committee on a regular basis — they will get sick of seeing my face before this is over — to make sure that we are not blocking something that is going to save lives."

In 2001, NCCAM and NHLBI issued a joint request for applications for a maximum $30 million federally funded grant to study chelation in people suffering from coronary artery disease. Lamas submitted an application that passed review by various NIH panels. TACT was a go.

More than 2,300 heart attack survivors older than 50 were sought, according to Lamas' 2003 protocol. Patients would be assigned randomly to one of four groups. Some would receive 40 infusions of the chelation solution recommended by the American College for Advancement in Medicine, plus either high or low doses of supplements. Others would receive 40 infusions of a placebo with either high or low doses of supplements. The study would be double-blinded, meaning neither volunteers nor researchers would know who got the treatment and who got the placebo.

"Welcome to the Trial To Assess Chelation Therapy!" Lamas wrote in a newsletter sent to study sites in 2003. "I am proud to welcome you to an elite group of physicians and coordinators who are committed to answering an important clinical question."

This group included many fine doctors who enrolled volunteers and ran study sites out of their own clinics.

But 13 of them have run afoul of state medical boards or health departments for actions unrelated to the chelation study, the Tribune found. Two physicians had their medical licenses revoked. Two others paid fines for placing misleading ads about the benefits of chelation therapy. One was issued two administrative complaints this year for allegedly running a clinic with unsanitary conditions linked to a hepatitis C outbreak.

Meanwhile, both consultants to the trial — each was paid more than $19,000 in taxpayer money, according to study records — were convicted of federal crimes, government records show.

One was Rozema, who also ran a study site and was among the first to enroll volunteers. The other was Dr. Martin Dayton. In 1986, a jury found Dayton guilty of mail fraud and conspiracy for his role in helping a family defraud an insurance company, according to U.S. Court of Appeals records. Dayton appealed, arguing, among other issues, that he had poor legal representation.

Today in a clinic in Sunny Isles Beach, Fla., Dayton offers several unproven remedies, including chelation and treatments with cell extracts made from pig fetuses and embryos, according to his website. His book "The Case for Intravenous EDTA Chelation Therapy" is available as a free download.

Dayton called his legal history "a distraction to your readership" and declined to discuss it further.

Lamas wrote in an email that only a small number of the physicians who participated in the study have troubled histories. "When these physicians joined the study, all had unrestricted licenses to practice medicine, granted by their state medical boards," he wrote.

Informed consent?

One of the most critical parts of a trial is a process known as informed consent. The aim is to ensure that patients who agree to enter a clinical trial understand what they are getting into, including the potential benefits and risks.

But the consent form for TACT was misleading and omitted important information. For example, it failed to tell volunteers that edetate disodium was never meant to treat coronary artery disease and that one risk of the drug is death, according to a 2009 letter from the federal Office for Human Research Protections, which looks out for the welfare of subjects in federally funded studies.

The form also included the information that "EDTA," or edetate, had been approved as a treatment for lead poisoning, according to the letter.

That's true of edetate calcium disodium. But the drug used in the study, edetate disodium, is a different medication not used for lead poisoning.

The FDA issued a public health advisory in 2008 to warn that children and adults had died because the two drugs had been confused or because edetate disodium had been used to treat conditions for which it wasn't approved.

After the FDA announced it would review edetate disodium's safety and efficacy, its manufacturers voluntarily recalled the drug in 2007 and 2008. The FDA removed it from the agency's list of approved drugs in 2008.

Yet the chelation study continued, and subjects were not immediately told that the FDA had delisted the drug over safety concerns.

After the Medscape critique came out in 2008, the Office for Human Research Protections told study coordinators they would have to change the consent form for new subjects and tell patients already enrolled what information had been left out.

The federal office said it was "concerning" that "several of the TACT study investigators have been accused of substandard practices by state medical boards, involved in insurance fraud, and at least three are convicted felons" but concluded that didn't necessarily mean subjects were put at risk.

The office recommended that institutional review boards overseeing the study re-examine the way they evaluate researchers signing on to the project.

Shurin, of the National Heart, Lung, and Blood Institute, told the Tribune that trial leaders have closed clinic sites or changed investigators at sites where concerns exist over medical licensing. In 2007, Lamas initiated a policy of checking regularly with medical boards for any concerns about active TACT investigators, she wrote.

In an email, Lamas wrote that researchers did not consider death to be a potential side effect of the therapy because the safety of clinical trials is closely monitored. "NIH, FDA and dozens of independent institutional review boards agreed and approved the form," he wrote. "In 2009, in an abundance of caution, OHRP asked us to revise the consent form, and, of course, we did."

The study continues, Lamas noted, despite scrutiny by the Office of Human Research Protections, the FDA, the NIH and other groups. A data safety monitoring board looks at data from TACT every six months, he wrote. "At every meeting, they have recommended continuing the trial," he wrote.

Shurin wrote that in the setting of a well-monitored trial, in which the infusion rate is tightly controlled, the disodium form of EDTA is very safe. "Our experience in TACT has reinforced our confidence in the safety of this drug in the setting of a well-conducted trial," she wrote.

In Melbourne, Fla., cardiologist Rajiv Chandra said he welcomes evidence that will help him decide whether to offer chelation therapy to heart patients or not.

Chandra, one of the most successful recruiters for TACT, had offered chelation therapy to some patients before the study began but suspended treatments until the results of the research come in.

"If it comes back negative, we ought to stop," he said.

But negative results may not sway heart patients who strongly believe chelation therapy helped them.

One is Chet Jenkins, a 76-year-old Korean War veteran who volunteered for TACT through Chandra's practice. Several years before joining TACT, Jenkins had undergone chelation and said he felt improvement.

"I don't know if it was psychological or not," he said. "But I am a believer."

Atwood, first author of the critique of TACT, said the Office of Human Research Protections and other oversight groups have let down volunteers like Jenkins and allowed a flawed study to continue even though the results will mean little or nothing. "They agreed with our points and then let everyone off the hook," he said.

"You still have criminals," he said. "You have the vast majority of subjects enrolled up to this point based on wildly inaccurate statements in the consent form, and you think it can proceed? … If you already have data from, say, 1,000 subjects and they all came in under false pretenses, that is it. It's over."

ttsouderos@tribune.com

Twitter @chicagoscience

Copyright © 2014, The Baltimore Sun
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