Thursday, February 14, 2013

Another Industry Funded Statin Study That Smacks Of Bad Science and Bias

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Reposted from Dr. Briffa

‘JUPITER’ is the name given to a study which tested the effectiveness of the statin drug rosuvastatin (Crestor). The effects of rosuvastatin were compared with placebo in a large group of individuals free from a history of cardiovascular disease (such as previous heart attack or stroke) [1]. Testing in this setting (what is known as ‘primary prevention’) generally yields less beneficial results than in individuals with known cardiovascular disease (‘secondary prevention’). Despite being deemed at relatively low risk, the individuals treated with rosuvastatin saw significant improvements in some outcomes (more on this later), and the study got a lot of positive media and medical attention as a result.
One slight fly in the ointment that emerged from this study was the fact that those treated with a statin had a significantly increased risk of developing type 2 diabetes. Other studies have also found statins can up the risk of this condition. So, last week a study was published [2] in the Lancet medical journal, in which the original JUPITER authors looked again at their data to, supposedly, assess whether or not the benefits of rosuvastatin outweighed any risk from diabetes.
The authors found that the enhance risk of diabetes was only seen in individuals with at least one major risk factor diabetes. They go on to tell us that in this group, treatment with statins led to 54 new cases of diabetes being diagnosed. However, all is well because the group treated with statins also had 134 fewer ‘vascular events’.
The term ‘vascular’ event, however, covers a multitude of ills, including unstable angina (heart pain that comes on in an unpredictable fashion), non-fatal heart attacks, non-fatal strokes, fatal heart attacks, fatal strokes, and ‘revascularisations’ (e.g. insertion of a stent or bypass surgery). An outcome that is made up of lots of different outcomes is sometimes referred to as a ‘composite endpoint’. There is at least some doubt about the appropriateness of using composite endpoints to judge the effectiveness of medical interventions.
To begin with, the wider the net is cast, the more likely benefit will be seen, and the more likely the benefits will be deemed to be ‘statistically significant’. Also, some of the outcomes that are of limited relevance clinically (e.g. unstable angina) can occur frequently. This can skew the statistics in favour of finding ‘significant’ results, even though the clinical significance is debatable. The risk of the most important outcomes (such as fatal heart attacks and overall risk of death) may be reduced only a small amount or not at all.
Some researchers have raised the idea that drug companies and researchers may ‘game’ (deliberately manipulate) the design of studies by using composite endpoints in a way which inflates the apparent benefits of a drug [3].
In this latest regarding the impact of rosuvastatin on diabetes risk seen in the JUPITER study, the authors seem keen to remind us of the benefits of statins using a composite endpoint. However, analysis of adverse effects are limited to one outcome (diabetes). This basic technique really does much to stack the odds in favour of ending up a favourable end result.
I have seen many, many statin studies which use composite end points for benefits. Never, though, have I seen one which uses composite endpoints for adverse effects. In addition to increasing diabetes risk, statins have the potential to precipitate a range of other adverse effects including muscle pain, muscle damage, liver damage and kidney damage. How about lumping all those and other effects together to see how that ‘benefits’ and ‘risks’ stack up then?
There’s more than a whiff of bias here. Is there any other evidence that the authors of the study were biased and committed, perhaps, to finding positive results for rosuvastatin? I believe so.
In the abstract (summary) of the study, the authors are keen to point out that in individuals statins reduced the risk of venous thromboembolism (e.g. clots in the veins of the legs known as deep vein thrombosis) by about half. They also tell us that in people with or without risk factors for diabetes statins reduced overall risk of death by 17 and 22 per cent respectively. These are impressive statistics perhaps. But what the authors neglect to tell us, though, is that none of these outcomes was ‘statistically significant’, which means the ‘benefits’ the authors laud were much more likely to be due to chance than any genuine effect from taking statins.
It’s unlikely that any of us will be too surprised to learn that the original JUPITER study and this latest poor excuse of a paper were funded by the company that makes rosuvastatin (AstraZeneca).
1. Ridker PM, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207
2. Ridker PM, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. The Lancet 2012;380(9841):565-571
3. Kip KE, et al. The Problem With Composite End Points in Cardiovascular Studies – The Story of Major Adverse Cardiac Events and Percutaneous Coronary Intervention. J Am Coll Cardiol. 2008;51(7):701-707