Lipitor Study Creates More Doubts On CRP Study Used to Expand Crestor Label

A new analysis of a large European trial presented at the American Heart Association annual meeting has further damaged the case for using C-reactive protein levels as a guide for statin therapy.

A post hoc secondary analysis of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) has found that high sensitivity C-reactive protein (hsCRP) testing did not have added value for directing and monitoring high risk patients on Pfizer's statin Lipitor (atorvastatin).

That finding runs contrary to the results from the JUPITER trial that supported an expanded label for AstraZeneca's Crestor (rosuvastatin). Crestor received FDA approval in February for use in patients with no clinically evident heart disease but who are at an increased risk due to the combined effects of certain risk factors: age (over 50 years in men and over 60 years in women); elevated hsCRP (greater than 2 mg/L); and at least one additional CV risk factor, such as high blood pressure, low HDL-C, smoking, or a family history of premature heart disease.

JUPITER raised questions about whether CRP should be used to direct and monitor statin use. But the new analysis of data from ASCOT comparing the cholesterol-lowering effects of atorvastatin to placebo in about 4,800 patients suggests testing is not worthwhile. A first look at the ASCOT data showed LDL cholesterol and CRP levels were both predictive of cardiovascular events. But when researchers considered other risk factors at the start of the study, or in-trial changes in LDL, the changes in CRP were no longer linked to cardiovascular events.

"These results do not support current proposals to measure CRP in the clinical setting and to assign statins to individuals on the basis of an elevated CRP alone," said lead investigator Peter Sever, Imperial College of London, during a presentation of results at the AHA meeting on Nov. 17. In an AHA press statement, Sever said: "The message coming out of the JUPITER study was that we should be screening people for CRP irrespective of their other risk factors. That's very, very expensive and almost certainly not a cost-effective intervention, particularly given these findings that measurement of CRP doesn't add anything in a much more widely representative population."

In discussing the results during the AHA presentation, Donald Lloyd-Jones of Northwestern University said the findings add to a large body of evidence showing minimal clinical utility for CRP testing for guiding statin therapy. As for the JUPITER study, which did link the value of statins with elevated hsCRP, panelists at the AHA meeting pointed out that the patients in this trial were at lower risk than the ones in ASCOT. So there could still be a role for CRP in patients that are not clear candidates for statin therapy.

Some clinicians had never bought into the role of hsCRP in the JUPITER study. At the time of the approval, they said it was unclear whether the hsCRP levels had any relevance to the findings because the study excluded almost 30% of the 90,000 people screened to participate, those who had an hsCRP below 2 mg/L. Lloyd-Jones also pointed out the exclusion of people with low hsCRP in JUPITER during his discussion of the ASCOT results at the AHA meeting.

Without results for a range of hsCRP, it's impossible to know if patients with low levels would have had the same reduction in risk for events as those with higher levels. The JUPITER results could have been due to the value of reaching such low LDL levels. The commercial impact of the ASCOT trial is unclear. U.S. sales for Crestor amounted to about $1.68 billion in 2008, the year the JUPITER study was released, $2.1 billion in 2009 (a 25% increase) and $1.3 billion for the first three months of 2010.

It's difficult to estimate how much of the sales come from the new indication, commented Nikhil Mehta of Decision Resources. A significant percentage of the gain was related to a bump in the standard base of patients with high cholesterol at the expense of Merck 's Vytorin (ezetemibe/simvastatin), after the release of negative results from ENHANCE in 2008 ("Merck Revises Guidance To Include $700 Million Less In Vytorin/Zetia Sales," "The Pink Sheet," April 21, 2008).

Decision Resources estimates that Crestor's new indication contributed only single-digit percentage growth. As for the ASCOT data, Mehta predicts minimal effect. It isn't the first to question the value of hsCRP testing, nor will it be the last. It may fuel more debate about the value of hsCRP testing, but it's unlikely that the results will dissuade proponents of the test from continuing to use it, he said.

"It also remains to be seen whether the AHA presentations will be widely remembered in a year's time, whereas no doubt advertising and physician detailing from AstraZeneca will ensure that findings from JUPITER continue to be top-of-mind for patients and prescribers over the coming years," he said.

An important factor that will influence how widely hsCRP testing is used and how successful Crestor might be in gaining sales growth from its new indication will be the recommendations in new clinical practice guidelines from the National Cholesterol Education Program Adult Treatment Panel, which should be released next year, Mehta added.

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