The original “Expression of Concern” editorial over the VIGOR Vioxx trial in the New England Journal of Medicine was an odd enough document already. But today brought an “Expression of Concern Reaffirmed” in the journal, along with replies from the VIGOR authors.
It’s going to take some doing to get these folks together, as you’ll see. The NEJM’s editors, in their “reaffirmation”, add a few details to their December 8th expression. Their position is still that there were three heart attacks in the Vioxx treatment group that were not in the data submitted to the journal. And they’re not buying the explanation that these took place after the end of the study, either:
“The authors state that these events did occur during the trial but did not qualify for inclusion in the article because they were reported after a “prespecified cutoff date” for the reporting of cardiovascular events. This date, which the sponsor selected shortly before the trial ended, was one month earlier than the cutoff date for the reporting of adverse gastrointestinal events. This untenable feature of trial design, which inevitably skewed the results, was not disclosed to the editors or the academic authors of the study.”
Those academic authors (11 of them from seven different countries, led by Claire Bombardier of Toronto) have a reply to all this in the same issue. Regarding those three MI events, they say:
“The VIGOR study was a double-blind, randomized outcomes study of upper gastrointestinal clinical events. We, as members of the steering committee, approved the study termination date of February 10, 2000, and the cutoff date of March 9, 2000, for reporting of gastrointestinal events to be included in the final analysis. Comparison of cardiovascular events was not a prespecified analysis for the VIGOR study. . .the independent committee charged with overseeing any potential safety concerns recommended to Merck that a data analysis plan be developed for serious cardiovascular events. . .As a result, a cardiovascular data analysis plan was developed by Merck. Merck indicated that they chose the study termination date of February 10, 2000, as the cutoff date. . .to allow sufficient time to adjudicate these events. . . (The three events) were neither in the locked database used in the analysis for the VIGOR paper no known to us during the review process. However, changing the analysis post hoc and after unblinding would not have been appropriate.”
The authors go on to say that including the three heart attacks does not, in their view, change the interpretation of the safety data. They also take issue with the journal’s contention that the three events were deleted from the manuscript, saying that the table of cardiovascular events in the presubmission draft of the paper never included them in the first place.
The two Merck authors on the paper, in a separate letter, make the same point, and also mention that there was an additional stroke in the naproxen-treated group that didn’t make the paper for the same reasons. They reiterate that including the three heart attacks wouldn’t have changed anything:
“. . .The article clearly disclosed that there was a significant different in the rates of myocardial infarction in the Vioxx and naproxen arms of the study and reported these rates as 0.4 and 0.1, respectively, with a relative risk reported as 0.2. The inclusion of the post-cutoff data myocardial infarctions changes the Vioxx rate to 0.5 but does not meaningfully change the relative risk or the conclusion that there was a significant difference between the two arms of the study. Indeed, with such a small number of events (which were not a primary end point of the study) – and with such wide confidence intervals around them – it is difficult to imagine that this small numerical change could affect the interpretation of the data.”
Looking at everything together, I’m still coming down on the side of Merck and their academic collaborators in this part of the fight. The post-launch cardiovascular data on Vioxx and its advertising and promotion are worth debating separately, but as for the VIGOR study, I think the NEJM is overreaching. Still, from Merck’s viewpoint, I think the damage has already been done. . .
Update: Y’know, it occurs to me that there are a few people who aren’t as upset about all this editorial wrangling: the editors of JAMA and the other top-ranked medical journals. They’ll be getting some manuscripts that otherwise would have gone to NEJM.