Lancet retracts COOPERATE trial of dual RAS inhibition and spanks lead author for serious misconduct 3

The Lancet has published a retraction of COOPERATE (Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease) and reported that its lead author, Naoyuki Nakao, appears to have engaged in serious scientific misconduct.

COOPERATE was originally published in the Lancet in 2003, and concluded that combination therapy of an ACE inhibitor and an ARB was superior to an ACE inhibitor alone. Although several letters raised questions about the trial following its publication, a serious investigation ensued only after publication in 2008 of “a letter of concern” by Regina Kunz, Marcel Wolbers, Tracy Glass, and Johannes Mann, who published a meta-analysis that excluded COOPERATE. They wrote:

The number and seriousness of the inconsistencies found in the Nakao paper led us to wonder whether it is possible that this is only a case of extremely sloppy reporting or a hint towards more severe problems with the data. In fact we excluded the COOPERATE trial from our meta-analysis on the basis of the implausibility of the data and internal inconsistencies and we mentioned the reason for excluding the study in our review.

Now the Lancet has fully responded to these concerns. The Lancet retraction reports that an investigative committee led by Yutuka Sanada, the President of Showa University Fujigaoka Hospital found that:

  • the trial had not been approved by the hospital ethics committee,
  • proper consent from patients had not been obtained,
  • the involvement of a statistician could not be verified,
  • the trial was not a double-blind study, because Dr Nakao knew the treatment allocation, and
  • based on a sample of the medical records the authenticity of the data could not be proved.

Franz Messerli told CardioBrief about his long-standing concern over COOPERATE:

The story is simple and straight forward.  When COOPERATE was published the fad or fashion of using dual RAS blockade was in full swing and therefore COOPERATE just confirmed the dictum that since RAS blockade is good for you, more RAS blockade must be better.  However, the study looked too good to be true and the first person to notice this was Johannes Mann, who wrote a letter to the editor  to the Lancet.

Messerli said that Nakao subsequently presented another trial at the ASN in 2007 and 2008: “These data can be easily identified as a fake when the data are scrutinized,” says Messerli. Finally, following the publication of ONTARGET, dual RAS blockade fell out of fashion, as Messerli himself wrote in JACC. Messerli, along with George Bakris, subsequently wrote the editors of the Lancet requesting an investigation into COOPERATE. “The rest,” he says, “is history.”

Sanjay Kaul provided the following comment to CardioBrief:

We have met the enemy and he is us!

Is this a case of intellectual cretinism or moral turpitude? The smug insularity of academia that “truth is implied in research and it is rarely betrayed” has yet again been exposed!

One important lesson from this unfortunate episode is that reviewers and journal editors should be much more careful before publishing “too good to be true” results and much quicker to admit mistakes. The results, having been published in a prestigious medical journal, were accepted by specialists and rapidly incorporated into clinical practice. Nonetheless, the journal needs to be congratulated for their willingness to probe this matter and for retracting the article.

Personally, this sorry episode serves as a clarion call for public scrutiny of data bases of clinical trials.


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