NEW YORK -- A leading light in interventional cardiology -- Martin B. Leon, M.D., of Columbia University -- may have leaked details of a major study weeks before it was scheduled to release.

A 番茄社区 investigation uncovered a pattern of leaks by Dr. Leon beginning March 7, three weeks before results of the trial were to be presented at the American College of Cardiology meeting and simultaneously published in the New England Journal of Medicine.

This breach of confidentiality involved the results of the COURAGE trial, which found that stents were essentially co-equal with medical therapy for stable angina.

Dr. Leon obtained access to the data when the journal sent him a pre-publication manuscript of the COURAGE results for review.

番茄社区 found that once Dr. Leon reviewed the unpublished COURAGE study manuscript and realized it was unfavorable, he pursued a pattern of dropping hints of the results that he accompanied with criticism of the study design.

William Boden, M.D., lead author of the COURAGE trial said the leaks that occurred during the weeks leading up to the study's planned release amounted to a "premeditated campaign to discredit the COURAGE findings."

Dr. Boden characterized Dr. Leon's actions as "academic misconduct of the highest order. By his actions he deprived me and my co-investigators of the opportunity to be the first to present our data to our colleagues." Usurping that right, Dr. Boden said, was especially vexing because he and his co-investigators "worked for 11 years on the design and conduct of this trial."

The motivations for Dr. Leon's alleged actions remain unclear, except that he might have been trying to undercut the study's conclusions by pre-emptive criticism.

Pre-publication knowledge of the COURAGE results allowed the interventional cardiology community -- investigators and industry -- to try to spin the results in a way that minimized any negative impact on the stent industry.

The need for proactive damage control can be best understood in the context of the ongoing issue of late-stent thrombosis, which emerged in a study reported at the ACC in 2006 and has dogged drug-eluting stents in a series of studies reported over the past 12 months. During that time in the U.S. the use of drug-eluting stents has declined from about 90% to roughly 60% to 70% of all stent implants.

Ironically, Dr. Boden and his colleagues had hoped to present the COURAGE findings at the American Heart Association last November, but the analysis was not completed in time. "If we had reported the findings then before the worst of the drug-eluting stent publicity, I doubt this [embargo break] would have occurred," he said.

NEJM peer review is carried out in strictest confidentiality. Peer reviewers agree that nothing they learn about the results of a study they review will be disclosed publicly ahead of publication or online release. Even the very identity of the reviewer must never be divulged.

The journal alleged that Dr. Leon violated that covenant when he divulged study findings during remarks made at an industry symposium 36 hours before the results were to be released. At that time Dr. Leon made it clear that he possessed confidential information that the COURAGE study results were null, rather than positive in favor of stent intervention. He allegedly also divulged that as a reviewer he was in a position to know. Both were violations of his status as a confidential NEJM peer reviewer.

But a timetable constructed by 番茄社区 suggests that the breach of confidentiality first occurred weeks earlier.

Dr. Boden submitted the COURAGE trial manuscript to NEJM on Feb. 6 and the journal editors immediately sent electronic copies of the COURAGE manuscript to five reviewers.

Each copy of the manuscript had a cover sheet stamped with these words in red: "CONFIDENTIAL Please destroy upon completion of review."

Additionally the instructions to reviewers warn that the manuscript should "be considered a privileged communication. You should not photocopy it, show it to another person without approval from the editorial office, or discuss your evaluation and recommendations with the author or any other person."

Dr. Boden said four of the five reviews were "glowing and one really attacked the study. We knew that review was from an interventionalist, but we didn't know who it was until Dr. Leon identified himself."

The manuscripts were returned to the authors by Feb. 14 and authors and editors signed off on the final version on Feb. 22.

On March 7 Dr. Leon presented unrelated data during a daylong workshop in Washington, sponsored by Cardiovascular Revascularization Therapies.

Before the meeting and again during the morning break, Dr. Leon discussed the COURAGE trial with a small group of interested spectators that included reporters and financial analyst Lawrence Biegelsen, who tracks the medical device industry for investors. Dr. Leon predicted that the COURAGE results were likely to have a negative impact on interventional cardiology.

After the break, Biegelsen told this reporter and another that he had just confirmed a Feb. 4 note to clients in which he suggested that the COURAGE results could have a negative impact on the stent industry. Biegelsen claimed that he was the only analyst to predict that COURAGE would be a negative trial.

On March 8, a day after Dr. Leon's Washington presentation and two weeks before the ACC meeting, Biegelsen sent out this email to clients:

"In our view, COURAGE represents downside risk for stent manufacturers because the patients in COURAGE (stable angina patients) are currently receiving stents and these patients account for ~40% of total stent procedures. Therefore, if COURAGE shows no benefit for stents over drugs, stent utilization will likely decline. If, however, COURAGE shows a benefit for stenting, utilization will not change."

In a telephone interview, Biegelsen said Dr. Leon was not a source for his March 8 report and he said the timing of the report -- a day after the March 7 meeting -- was coincidental.

Moreover, he said he had very little contact with either Dr. Leon or Dr. Leon's partner, Gregg Stone, M.D. Biegelsen said his reports were based on his own research and conversations with other physicians including Robert Califf, M.D., of Duke University. Dr. Califf was a panelist at the March 7 workshop.

On March 12, Forbes published an article by Matthew Herper, an article that predicted more trouble for the stent industry.

Herper quoted Dr. Stone, chairman and chief medical officer of the Cardiovascular Research Foundation, which was founded by Dr. Leon. Dr. Stone told Herper that he "wouldn't be surprised if COURAGE, as designed, is a negative trial." He noted that the "purpose of most stent procedures in patients with stable angina is to relieve chest pain and improve exercise capacity and quality of life."

Dr. Stone added that there was no prior evidence that angioplasty reduces deaths and/or events in patients with chronic stable angina. COURAGE, he said, "may tell us what we know already."

The COURAGE results confirmed these observations.

Dr. Boden said that when he read the Forbes article his reaction was immediate -- he considered it an embargo break. He said he believed that Dr. Stone had seen the COURAGE data. But on March 12, when he read the Forbes article, Dr. Boden didn't know that Dr. Leon, who is Dr. Stone's partner, was one of the reviewers.

On March 22 the NEJM released the embargoed COURAGE manuscript to a select list of journalists who agreed to withhold the findings until 9 a.m. on March 27, when Dr. Boden and his colleagues were slated to present the results at the ACC meeting.

On the evening of March 23, a day before the ACC convened its annual meeting, the Cardiovascular Research Foundation presented a satellite symposium titled "Enter the Drug-Eluting Stent Revolution IV: A Critical Appraisal."

Dr. Stone reiterated his criticism of the trial in discussions with journalists who attended the symposium. He suggested that he was a NEJM reviewer of COURAGE -- although he was not -- and said that he and other interventionalists had begun a post-hoc analysis of the COURAGE data and then scrapped it when they learned that the data in the published manuscript did not match data in the review copy.

The problem data, he said, involved U.S. non-VA patients versus VA patients.

Dr. Boden confirmed that there had been "minor changes" in the data tables from the review copy to the final copy, but those changes did not alter the significance. Raising questions about that population-380 patients in review copy, which increased to 387 in the final paper-was obfuscation.

"Interventionalists keep mentioning these data contending that the results would be different if we enrolled more of these patients," he said. "This is just another attempt to undermine the findings. You might as well say that we needed to enroll more blondes."

Boston Scientific, a leading maker of stents, hosted a luncheon for journalists on March 24, more than two days before the scheduled release of COURAGE. Next week's issue of Trends-in-Medicine describes how at that luncheon Donald Baim, M.D., chief medical officer of Boston Scientific, tried to persuade reporters to put a positive spin on the COURAGE data. Dr. Baim, the article said, suggested that instead of a headline such as "Yet Another Failure of Percutaneous Coronary Intervention," the headline could be "Another Study Saying for Stable Angina You Have PCI to Improve Symptoms."

At another Boston Scientific symposium on March 25, Dr. Leon said the COURAGE trial was "rigged to fail and it did." That quote and Dr. Leon's acknowledgement that he was a reviewer for the paper made headlines hours later in a story by reporter Keith J. Winstein appearing on .

Reaction was swift.

On the weekend of March 30-April 1, Jeffrey M. Drazen, M.D., NEJM's editor-in-chief, and Gregory D. Curfman, M.D., NEJM's executive editor, sent a letter to Dr. Leon and to Lee Goldman, M.D., dean of the faculties of health sciences and medicine at Columbia, stating that Dr. Leon would no longer be asked to participate in the journal's peer review process.

Additionally, the letter stated that the journal would no longer seek out Dr. Leon for commentaries, perspectives, or editorials. A journal source who spoke on the condition of anonymity said that when a reviewer violated the NEJM's strict peer review process, the journal "would, as a consequence, lose confidence in the reviewer's judgment."

And the NEJM's editors asked Dr. Goldman to consider academic sanctions against Dr. Leon. If the medical school were to agree to this request, the consequences for Dr. Leon could be significant. "No one likes to be banished, and academic banishment is a pretty harsh punishment," was the way the one source described potential actions that could be taken at an institutional level.

Academic institutions have a number of disciplinary actions available that include outright termination or more limited actions such as removing a faculty member from committee posts, or limiting research support.

After repeated requests for comment on the NEJM letter and this article a spokesperson for Columbia University Medical Center released this statement: "We greatly respect the New England Journal of Medicine and its peer review process. Our practice is not to comment publicly on issues of this type."

The same spokesperson said Dr. Leon also declined to comment.

On April 4, the ACC's executive committee met to consider disciplinary action against Dr. Leon.

In a letter sent to the executive committee, Dr. Leon maintained that he had intended his comments at the March 25 satellite symposium to be considered speculation. To support this contention, Dr. Leon solicited support from a reporter who attended the symposium but who did not report Dr. Leon's comment. As outlined in her letter to the ACC, the reporter said that Dr. Leon's comments did not, in her opinion, constitute an embargo break.

But Dr. Leon's explanation was challenged by ACC trustees who pointed out that Dr. Leon had identified himself as a reviewer of the paper. Once he made that admission, his remarks could not be interpreted as speculation, they said.

The ACC has since referred the matter to its ethics committee, which will decide whether Dr. Leon should be sanctioned and what those sanctions should be. Among the actions under consideration by the ACC are a move to block Dr. Leon from reporting research at scientific meetings of the ACC for a specified period, blocking Dr. Leon from ACC committees and/or leadership positions, and taking away Dr. Leon's fellow of the ACC (FACC) designation.

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