Should we all be on statins?

Well, probably not.

But a new review published earlier this month in the Cochrane Reviews looked at 14 different trials, with a total of 34,272 patients, in an attempt to answer this question, and came out with conflicting results. Scientific and medical experts looked at the review and have already reached diametrically opposed conclusions, reported in their blogs and in commentaries in several leading journals.

Everyone has heard of statins: they are a class of cholesterol-lowering drugs that offer clear benefits in people who already have suffered heart attacks or other serious cardiovascular problems. But what about the rest of us? If you have slightly elevated cholesterol, or even normal cholesterol, should you take statins? Drug companies would certainly like you too, and they have been pushing statins (such as Levacor, Zocor, Pravachol, Lipitor, and Crestor) for years in the U.S., through ad campaigns in print and on television. I wrote about a study of Crestor back in 2008, and I found serious problems with the study's design and conclusions.

First, what did this large-scale review find? All of the studies ran for at least a year, and all were randomized controlled trials, the most rigorous type of study. Overall risk of death was reduced by 17%, and the risk of a heart attack was reduced by 28%, which seem to be very positive results. None of the patients had previous history of cardiovascular disease, although most of the studies recruited patients with other risk factors such as high cholesterol, diabetes, or high blood pressure.

But - and this is a big but - the authors of the Cochrane review had big problems with the way these studies were run. They wrote in their conclusion that

"there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk."

So the review authors were not convinced that people without previous heart disease should all go on statins, even though their own numbers showed a decreased risk. I think their skepticism is justified, because the benefits they observed were very small. This means that subtle biases such as including people who did have cardiovascular disease, could create the appearance of a benefit even if there wasn't one. And 9 of the 14 studies were funded by pharmaceutical companies, which hints at possible bias.

Writing in the journal BMJ, Susan Mayor highlighted the skeptical interpretation. She quoted one of the study's authors, Shah Ibrahim, who said "Absolute benefits were small, and evidence of selective reporting of outcomes makes the evidence less robust.”

Over at Science-Based Medicine, neurologist and skeptic Steven Novella has a more positive interpretation. He concluded that

"there is solid evidence that statins have a real benefit for primary prevention. This benefit is small, which is exactly what I would predict for a preventive measure in a low-risk population. The data also show that statins are safe. ... For interventions that prevent death – that lower mortality – I think even small benefits are worthwhile."

However, he goes on to say that "it is still unclear where to draw the line in terms of which patients should receive statins."

I would love to believe that statins will reduce everyone's risk of heart disease, but I couldn't ignore one statistic: the "number needed to treat." Based on the new study's findings, you'd have to treat 1000 low-risk patients for one year to prevent one death. To put that another way, if you are at low risk of heart disease, then there is a 99.9% probability that taking statins for a year will give you no benefit. Even so, given that statins have minimal side effects, you might think it's a reasonable preventative treatment, even with such a small benefit. The skeptic in me says that if there was even a tiny amount of bias in some of the trials, that apparent benefit might actually be zero.

On this question, we need more data from completely unbiased studies. In an editorial for the Cochrane Reviews, Carl Heneghan wrote that "Interventions targeting CVD risk reduction in low-risk population should be undertaken in the context of a randomised controlled trial; preventing scarce healthcare resources going to waste."

He's right. Statins might have a small benefit, but before we start prescribing them to tens of millions of people - and before I start taking them myself - I'd like to see unbiased studies conducted exclusively in low-risk populations.

Searching for the cause of chronic fatigue syndrome: XMRV turns out to be another blind alley

Chronic fatigue syndrome (CFS) causes severe fatigue that can last for months at a time. CFS is difficult to diagnose and even more difficult to treat, and its cause has long been a mystery. In 2009, in an apparent breakthrough, scientists reported that a virus found in mice, called XMRV, might be the long-sought cause of chronic fatigue. Their results were reported, with great fanfare, by Judy Mikovits and colleagues in the journal Science (Lombardi et al., Science 2009;326:585), with reports in respected outlets such as the New York Times making it seem that the answer had been found.

Now it turns out that, like many initially exciting reports, this one has a much more mundane explanation: contamination.

As happens all too often when a "surprising" discovery is announced, the result turns out to be an experimental error. Contamination is a common type of error in modern molecular genetics, because nothing is actually visible to the naked eye, and we have to rely on very sensitive methods (such as PCR) to detect what is present. In this case, the experimenters had a common mouse cell line in their lab (not unusual), and it turns out these mouse cells were contaminated with a virus called MLV, which looks a lot like XMRV.

The new study by Hue et al. from University College London (Retrovirology 2010, 7:111) is titled "Disease-associated XMRV sequences are consistent with laboratory contamination." The title pretty much tells the story, but here's a brief synopsis.

XMRV (Xenotropic murine leukaemia virus-related virus) is the virus in question - the one that Mikovits claimed is the cause of chronic fatigue syndrome. It's a retrovirus, and it is very similar to another mouse virus called MLV-X. It turns out the the PCR method for detecting XMRV uses short DNA sequences ("primers") that will also detect MLV-X. These primers were previously believed to be specific to XMRV, but they're not. Therefore, if you are looking for XMRV in a tissue sample, and the sample contains MLV-X, you'll think you found XMRV. But what: why would human patients have MLV-X? Perhaps MLV-X is a cause of chronic fatigue? Good question.

Well, it turns out that a common tumor cell line called 22Rv1 is infected with MLV-X. It also turns out that all the XMRV sequences from human patients are far more similar to the exact same strain of MLV-X that is in the mouse cell line. The tumor cell line was in the lab doing the experiments: ergo, it's contamination. Elementary, my dear Watson. Or, as Hue et al put it:

"We provide several independent lines of evidence that XMRV detected by sensitive PCR methods in patient samples is the likely result of PCR contamination with mouse DNA.... We propose that XMRV might not be a genuine human pathogen."

The initial Science paper by Mikovits and colleagues generated three published "Comments" in the journal, an unusually high number, which alone is enough to raise some red flags. The comments pointed out multiple methodological problems, including the possibility of contamination. In one of them, the authors (van der Meet et al) warned that

"Over the past few decades, we have witnessed a long series of papers claiming the discovery of the cause of CFS. None of these claims has been confirmed. Each time, this gives false hopes to large numbers of patients who seek a solution for their suffering. Shortcomings in the study by Lombardiet al. now raise concerns about the role of XMRV in the pathogenesis of CFS."

After the 2009 Science paper, several other studies looked at patients with chronic fatigue syndrome and failed to find anyone with XMRV (for example, this study from the CDC last summer). This was strikingly different from Mikovits' report that 67% of patients had XMRV. The latest report, by explaining where the false positive results came from, should put the final nail in the coffin for the XMRV hypothesis.

In retrospect, Science shouldn't have published the flawed study, and you could argue that peer review failed. On the other hand, the final resolution illustrates the self-correcting mechanism of science at its best. All of this is very reminiscent of the scientific response to Andrew Wakefield's notorious 1998 study claiming that autism was associated with the MMR vaccine: multiple followup studies, most of them conducted far more carefully, failed to reproduce the results. But in that case, bad scientists (Wakefield) aided by gullible journalists and non-scientists (Jenny McCarthy, Jay Gordon) have kept the story alive, causing continuing damage to children in the form of preventable illnesses and even deaths. Even after the story last week in the journal BMJ that explained Wakefield's outright fraud, he continues to push his discredited notions. (I love the title of the BMJ's editorial: "Wakefield's article linking MMR vaccine and autism was fraudulent.")

CFS has less visibility than autism, so I hope that scientific evidence will carry the day here. We still need to find the cause of chronic fatigue syndrome, and there's no telling right now where the answer lies.