People who take their medication as directed are less likely to die - even when that "medication" is just a sugar pill.

This is the surprising finding of a paper just published,

Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST). 

BEST was a clinical trial of beta blockers, drugs used in certain kinds of heart disease. The patients were aged about 60 and they all suffered from heart failure. Everyone was randomly assigned to get a beta blocker or placebo, then followed up for 3 years to see how they did.

Here's the big finding: in the placebo group of 1174 patients, the people who took all of their placebo pills on time (the good adherers), were significantly less likely to die than the patients who missed lots of doses. People who took over 75% as directed were 40% less likely to die than those with less than 75% adherence:

That's pretty interesting. The pills were placebos - they can't have had any benefit. So what's going on?

It gets even better.

You might be tempted to write off these results as obvious: "Clearly, people who follow the study instructions are just 'healthy' people in other ways - maybe they take more exercise, eat better, etc. and that's what protects them."

Certainly, that's what I'd have said.

But what's remarkable is that when the authors corrected the statistics for all the confounding variables they measured - including things like age, gender, ethnicity, smoking, body mass index and blood pressure - it barely changed the effect. Some of the factors did correlate with adherence, but not in a way that it could explain the adherence effect on mortality.

This isn't the first study to find this effect. The authors themselves have already reported it, as have other researchers going back decades (many of which also tried, and failed, to explain it through confounding factors.) They say that it's unlikely to be a case of publication bias.

So what we have is a large effect, which cannot be causal, yet which can't be explained by any obvious confounds.

Logically then, it must be the result of a confound (or more than one) that aren't obvious.

This is an important lesson. It's common for someone to do a study and find an interesting / scary / controversial correlation between two things. Often one is some kind of lifestyle factor, diet, environmental exposure, or whatever, and the other is some nasty disease. "And it wasn't explained by confounds!", such studies often conclude.

What the placebo adherence effect demonstrates is that there may be confounds no-one has thought of. They might even be impossible to measure. And if these mystery confounds can literally kill you, they can probably cause all kinds of other effects too.

In other words this illustrates the truism that correlation is not causation - not even when you're really sure it is...

Pressman, A., Avins, A., Neuhaus, J., Ackerson, L., and Rudd, P. (2012). Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST) Contemporary Clinical Trials DOI: 10.1016/j.cct.2011.12.003