Two years ago, a study called JUPITER looked at AstraZeneca’s Crestor cholesterol pill and measured levels of a protein called CRP that can indicate arteries are inflamed and point toward heart disease. But the results prompted debate over the extent to which CRP should be used as a guidepost for treating cholsterol and prescribing Crestor and other statins to people with low cholesterol (see here).
In June, a “critical reappraisal” appeared in The Archives of Internal Medicine calling the trial “flawed,” because there were various methodological problems and a “strong commercial interest” may have resulted in biased outcomes. Nine of 14 authors had ties to AstraZeneca and the principal investigator, Paul Ridker of Brigham and Women’s Hospital (pictured), is a co-holder of the patent for the CRP test and headed the Data Safety Monitoring Board (see here and here). Yet another analysis found no evidence that prescribing statins to patients at risk of heart disease reduces the chance of premature death in the short run (see this).
Now, Ridker and co-author Robert Glynn have published a response in the American Journal of Cardiology, since the other journal would only publish a "brief" letter, which they found insufficient to explain the complexities. And it is complex, but worth reading (here is the abstract). To summarize, they argue JUPITER "addressed the core clinical question posed using the most robust and widely accepted form of clinical scientific inquiry available, the randomized-placebo-controlled, double-blind trial."
They also insist the trial "used high levels of scientific rigor, achieved exemplary participant follow-up, used rigorous end point adjudication, prespecified a highly conservative monitoring plan in the charter of its Data and Safety Monitoring Board, and followed a prespecified analysis plan conducted exclusively on an intention-to-treat basis."
Then, they take aim at one criticism that suggested the decision by the DSMB to halt the trial early "substantially overestimated trial benefits," that the rules were not prespecified and that the end point used to define those rules was not defined. However, Ridker and Glynn maintain there was a specified charter that spelled out any stoppage "would require proof beyond reasonable doubt that prolonged use...was clearly indicated or clearly contra-indicated for all or some specific types of patients.”
They then criticize the critics for failing "to address the appropriateness of continuing a trial after the main study question has been answered definitively; trialists and study monitors have an ethical responsibility to stop experiments and inform their participants as well as society when uncertainty and equipoise no longer hold with respect to the question under evaluation."
Yet another point raised by their critics was the magnitude of the effect of stopping the trial early and whether that effect is large enough to alter clinical interpretation. To that, Ridker and Glynn write "there is no credible evidence that early stopping of the JUPITER trial had anything more than a marginal effect on the true estimates of efficacy. If anything, the magnitude of benefit in the trial was increasing over time, not decreasing."
As to conflicts and industry influence, they argue the critics did not provide any evidence to back up their claims, and goes on to assert that the trial was initiated by the study team, AstraZeneca did not play any role in analyzing the data and drafting the manuscript, or had access to the unblinded trial data until after the manuscript was submitted for publication. However, they do not address the individual ties between the study team and the drugmaker or how Ridker benefits from the CRP patent.
For those of you who read this far, one of the critics, Michel de Lorgeril, last June posted this question-and-answer on his website in response to questions from a journalist about the controversy.