ACCORD Lipid, performed in patients with type 2 diabetes being treated with simvastatin, compared adding fenofibrate or placebo. I realized as I read the title and saw the methods in the abstract that I had a rooting interest in the results.
In the past few years, I have written about lipid management, argued about it, and had my judgments vociferously called into question. I've posited that whether or not LDL is important in the pathogenesis of coronary heart disease (CHD), what we really know is that statins reduce adverse cardiovascular outcomes and mortality, and further that we have little evidence that any other lipid-lowering agent (with the possible exception of niacin) actually reduces mortality.
While I'm certainly not alone in questioning the efficacy of non-statin lipid agents, my position has been outside the mainstream. I'd made this point publicly and specifically about ezetimibe at a time when there were no data on clinical endpoints. That position became more mainstream after the ENHANCE trial was published (though it too looked only at a surrogate endpoint), but most experts seemed to feel that ENHANCE only cast doubt on ezetimibe and not on the larger group of non-statin agents. Three days before ACCORD Lipid was published, I was making this argument yet again in a resident journal club meeting, where the article being discussed was analyzing a statin-centric approach to lipids that the article credited, at least in part, to me.
So, within that context of being publicly identified with one position in the argument, and a minority position at that, I read the abstract of ACCORD hoping that it would show no benefit from adding a fibrate to statin therapy, since, if adding a fibrate worked, much of what I had been arguing was likely wrong.
It probably goes without saying -- but I'll say it anyway -- that this is no way to approach a scientific result. The best way to approach a result in a paper and fit it into prior evidence is from a position of disinterest. It allows you to realize that peptic ulcer disease is an infectious disease and estrogen supplementation causes heart attacks, even if, prior to the pivotal publications, you had been treating PUD as a psychological disorder or recommending that female friends and family members take estrogen supplementation.
Yet, when I got to the results of ACCORD Lipid, even though it might have been better for my patients had fenofibrate been of benefit, I was clearly pleased to see that the conclusion was negative:
The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes.
But, of course, nothing is ever that clear cut. The authors suggested that fenofibrate might have been of benefit in the subgroup of patients with both high triglycerides and a low HDL-C. In these patients, mortality was 5% lower with fenofibrate with an interaction p value that was borderline significant at 0.06. They even were allowed to make this point within the abstract.
To me, that this seemed like a stretch would be putting it mildly. The paper had looked at at least 10 subgroups, suggesting that even a statistically significant p value in a subgroup would be dubious. Furthermore, fenofibrate had shown no hint of additional benefit in patients with high triglycerides or low HDL-C, but only in patients with both.
Yet, the authors argued that this subgroup result was consistent with post-hoc analyses of a number of prior trials, and the editorial accompanying the paper took the argument quite seriously and stated that the value of fenofibrate in such patients remained unsettled.
So, was I right dismissing this subgroup analysis as likely no more than a statistical blip, or were these others right in thinking it pointed toward an important subgroup of patients who could benefit from fibrate therapy?
I'd like to know that in thinking about this, I had approached the data from a position of objective neutrality, but as I discussed above, I already knew I hadn't. I also knew that the authors of the paper and editorial all had their own intellectual agendas as well.
Conflicts of interest come in many shapes and sizes. But even without such conflicts influencing the interpretation of results, the desire to have been right in the past, and for their current research to have been of value, causes important, and perhaps overriding, biases in experts as they confront and interpret new evidence.