This is a contribution from members of THINCS, 
The International Network of Cholesterol Skeptics


Letter; N Engl J Med 2005;353:94.

The authors´ response:

Our comments
(Unpublished because letters of more than 300 words are not accepted by The New England Journal of Medicine)

The authors failed to elaborate on their criteria for determining whether a side effect might have resulted from atorvastatin.  For instance, how can the authors conclude that the five cases of rhabdomyolysis occurring during treatment were not due to atorvastatin? Rhabdomyolysis is a recognized complication of statin therapy that led to the withdrawal of Baycol because it is otherwise extremely rare. The fact that the incidence was unrelated to dosage is hardly a supportive argument. To determine whether a side effect is dose-dependent is impossible judged from five cases only.

More specific information about other possible adverse responses to atorvastatin was not supplied either as requested. In particular, only the number of patients with persistent elevation of aminotransferases over three times the upper limit of normal were listed (eg. 51 more cases in the high-dose group).  Why not give the number of any persistent elevation as is customary in pharmaceutical trials? Could the explanation be that the number of patients with this indication of liver damage by far outweighted the benefit of 65 fewer non-fatal heart attacks?

Even if the number of side effects given were true, there is reason to believe that the number was much smaller than it would be in clinical practice. At first more than 3000 of the patients originally selected for the trial were excluded, some of them because they did not fulfil the criteria, others because of elevated aminotransferases, or because of cancer or another disease associated with a limited lifespan, or because of “other reasons”.

Following a 1-8 week period of treatment with low dose atorvastin, an additional 5461 patients were rejected, including 197 with adverse events, 70 who did not comply with the treatment, 195 who had ischemic events, 16 who died during this short period, and 349 “for other reasons”.   No information is provided on the nature of these side effects or causes of death.  Similarly, it is not clear what side effects “related to treatment" later caused 7.2%  to stop the treatment.  (The lack of elaboration on this is not unusual since in other statin trials up to a fourth of the patients stopped medication for reasons that were not disclosed.) 

Finally, of the 18,469 patients originally screened, only 10001 were selected, thus representing a cohort of much healthier participants than would be treated by clinicians.

In addition, atorvastin's manufacturer, Pfizer, funded the trial, analyzed the data, did not allow outside access to this information and one of the study authors was a Pfizer employee.  The FDA recently cited Pfizer for publishing the results of a valdecoxib trial in a manner that obscured the risks and the drug now has a black box warning.1 Pfizer also pleaded guilty on 13 May 2004 to numerous charges for illegally promoting the off-label use of gabapentin and agreed to pay  $430 million to satisfy criminal and civil penalties.2

It also seems strange that the methodology of the 5-year long TNT trial3 was not published at the start of the trial instead of four years later.  Even more amazing was the availability of the TNT trial report on the journal´s website on March 8 if all the eleven authors did not have access to the data until January 29?  To write this 11 page report, to check all the data, and to get it peer-reviewed and published in less than six weeks is simply a case for Guiness Book of Records.

1.       Lenzer J. Pfizer pleads guilty, but drug sales continue to soar. BMJ 2004;328:1217 

2.       Lenzer J. Pfizer criticised over delay in admitting drugs´ problems. BMJ 2004;329:935

3.       Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C; TNT Steering Committee Members and Investigators. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004 Jan 15;93(2):154-8.