We’ve all seen the headlines.  Statins improve bone health.  Statins prevent cancer.  Statins make us smarter.  Low-fat diets improve longevity.  All these headlines and others like them are followed by articles describing studies seeming to show that subjects taking certain medications (usually statin drugs, it seems) or following a particular diet have improvements in health and/or longevity.  The promise of these articles is that if we all take the medication or follow the lifestyle choice, we, too, will reduce our risk of [fill in the blank] or live longer.  But will we?

Maybe so.  But not for the reason most people think.

The adherer effect demonstrates that people who adhere to medical or lifestyle regimens end up with better outcomes than those who don’t…even if the regimens are nothing but placebo.

I mentioned this phenomenon in an earlier post.

Almost thirty years ago a study was published in the New England Journal of Medicine looking at this very idea. [The adherer effect]  The study that inspired the article didn’t start out looking at this idea, but one of the investigators noted a key piece of the data and published on it.  The study was looking at clofibrate, a pre-statin cholesterol lowering drug,  and all cause mortality.  Subjects were randomized into two groups – those in one group got the drug, those in the other got the placebo.  After the subjects were on either the drug or the placebo for five years, researchers calculated the mortality from the number of deaths in each group.  Turned out that the five-year mortality of those on clofibrate was 20.0 percent whereas the five-year mortality of those on the placebo was 20.9 percent, or essentially the same.  Taking the drug was no different than taking the placebo, i.e., the drug was worthless. Had one of the researchers not looked a little closer, that would have been the end of the story.

When the data were looked at from the perspective of how many people actually took the drug as prescribed, the researcher discovered that those subjects who took at least 80 percent or more of their clofibrate had a five year mortality of only 15.0 percent, substantially less than the overall five-year mortality.  Those who took their clofibrate sporadically had a five-year mortality of 24.6 percent, significantly higher than those who took it as directed, a piece of data that would seem to confirm the efficacy of clofibrate.  Right?  Not necessarily.  Let’s look at compliance with the placebo.

Turns out that those subjects on the placebo who regularly took their placebo had a five-year mortality of 15.1 percent while those who took their placebo sporadically had a five-year mortality of 28.3 percent.  What this study really showed was that there is something intrinsic to people who religiously take their medicine that makes them live longer.  There was no difference between the drug and placebo in either those who took them regularly or those who took them sporadically, but there was a huge difference in mortality between those who took either drug or placebo on schedule and those who didn’t.

Gary Taubes discussed this same study and the adherer effect in  a long article he wrote for the New York Times Magazine a few years ago:

A still more subtle component of healthy-user bias has to be confronted. This is the compliance or adherer effect. Quite simply, people who comply with their doctors’ orders when given a prescription are different and healthier than people who don’t. This difference may be ultimately unquantifiable. The compliance effect is another plausible explanation for many of the beneficial associations that epidemiologists commonly report, which means this alone is a reason to wonder if much of what we hear about what constitutes a healthful diet and lifestyle is misconceived.

The lesson comes from an ambitious clinical trial called the Coronary Drug Project that set out in the 1970s to test whether any of five different drugs might prevent heart attacks. The subjects were some 8,500 middle-aged men with established heart problems. Two-thirds of them were randomly assigned to take one of the five drugs and the other third a placebo. Because one of the drugs, clofibrate, lowered cholesterol levels, the researchers had high hopes that it would ward off heart disease. But when the results were tabulated after five years, clofibrate showed no beneficial effect. The researchers then considered the possibility that clofibrate appeared to fail only because the subjects failed to faithfully take their prescriptions.

As it turned out, those men who said they took more than 80 percent of the pills prescribed fared substantially better than those who didn’t. Only 15 percent of these faithful “adherers” died, compared with almost 25 percent of what the project researchers called “poor adherers.” This might have been taken as reason to believe that clofibrate actually did cut heart-disease deaths almost by half, but then the researchers looked at those men who faithfully took their placebos. And those men, too, seemed to benefit from adhering closely to their prescription: only 15 percent of them died compared with 28 percent who were less conscientious. “So faithfully taking the placebo cuts the death rate by a factor of two,” says David Freedman, a professor of statistics at the University of California, Berkeley. “How can this be? Well, people who take their placebo regularly are just different than the others. The rest is a little speculative. Maybe they take better care of themselves in general. But this compliance effect is quite a big effect.”

In the same blog post of mine I linked to above, I wrote about another study showing the adherer effect, showing graphically how potent the phenomenon is.

Previously, the study of the adherer effect has been a secondary finding in studies of various drug regimens, but now comes a paper in which the adherer effect is the primary focus of the investigation.  Based on the data in this recent paper, the effect is robust and should be accounted for in the analysis of any data generated when subjects following a particular treatment are compared to those who don’t.

The authors lay out the problem:

The healthy-user effect [the adherer effect] is a hypothetical source of confounding bias that is thought to affect observational studies of drugs, diets, screening procedures, and other health-related behaviors. This bias presumes that patients who initiate and adhere to preventive therapies are more likely to engage in behaviors consistent with a healthy lifestyle than are patients who do not initiate or adhere to such treatments. Aspects of a healthy lifestyle could include diet, exercise, moderation of alcohol, and avoidance of risky behaviors. These characteristics, which are unmeasured in typical pharmacoepidemiological databases, may be associated with morbidity and mortality outcomes in observational studies. Thus, failure to adjust for them can lead to bias in studies of preventive therapies.

The healthy-user bias has been suggested as an explanation for the discrepancy between several experimental and observational studies, including studies of the effects of long-term use of estrogen therapy and vitamin E. It has also been discussed as a potential source of bias in observational studies of the effectiveness of influenza vaccines in the elderly  and the association between use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and reduced risk of hip fracture,  Alzheimer disease,  sepsis,  cancer,  and mortality.  This bias has also been observed in randomized controlled trials in which adherence to placebo was found to be associated with decreased mortality.  Although long suspected as a source of bias, a paucity of empirical data exists on the healthy-user effect.

Here’s how the study was set up.

It was really pretty simple.  The researchers looked at a group of patients who had been prescribed one of a variety of statin drugs and followed their compliance by looking at how many times these subjects picked up their medicines in the year following their prescription.  The typical statin prescription was for 60 days worth of the medication, and all subjects had available to them a full year’s worth of medicines.  The researchers grouped subjects into two groups: one group who took the trouble to go get over 120 day’s worth of the medication (the “more adherent”) and one group of subjects who were dispensed under 120 days of meds (the “less adherent”).

All subjects entered into the study were evaluated after the one year baseline study period during which their effort to follow their prescribed statin regimen sorted them into the categories of more adherent or less adherent.  The researchers were looking to see which subjects – the adherers or the non-adherers – would develop problems that had nothing to do with the statin drugs.

We evaluated a spectrum of events after the 1-year baseline period to assess the healthy-adherer bias. The outcomes were grouped into 4 broad categories: accident events, screening events, other events not expected to be associated with statin exposure, and other events for which a possible association with statin exposure could be expected. We included inpatient and outpatient events as well as primary and secondary diagnoses.

When the data on these 141,086 subjects was crunched, it turned out that the more adherent subjects had significantly fewer accidents, especially motor vehicle and workplace accidents.  The more adherent also had a lower likelihood of developing other disorders that were not likely to be attributed to the effect of the statin drugs.

In other words, whatever characteristic it was that made subjects hang in there with their statin prescriptions also made them less likely to indulge in risky behaviors and less likely to develop all kinds of medical problems.  Why?  Probably because these people were simply more health conscious, kept themselves in better shape, and didn’t act impulsively.

The real take-home message from this study is that the adherer effect significantly affects the outcome of drug and lifestyle intervention studies.  If you see a study that says those subjects using statin drugs developed 20 percent fewer problems (of whatever kind are being studied) than those who don’t use statins, you can be sure that the adherer effect is at work.  This adherer effect is why randomized, double-blind, placebo-controlled studies are needed to determine the efficacy of any drug, and even then the adherer effect should be controlled for.

There is a big note, enclosed in a box and titled Clinical Perspective, at the end of this study that exhorts doctors to consider this adherer effect when looking at data from observational studies.  Here is the note in full.

Clinicians need to read observational studies reporting surprising benefits of drug therapy with a healthy skepticism. Observational studies of preventive medications and health behaviors are susceptible to various sources of bias, including the so-called healthy-user and healthy-adherer biases. In this article, evidence of the healthy-adherer effect is demonstrated by showing that adherence to statins is associated with a reduction in the risk of accidents (eg, workplace or motor vehicle), outcomes that would not be expected to be affected by a statin. The approximate magnitude of the adherer effect was a 15% relative risk reduction. The most likely explanation for this association is that good adherence to statin therapy is a marker for other healthy behaviors, most of which cannot be accounted for in this type of study. In keeping with this explanation, the study also shows that adherence predicts a 7% to 17% increased incidence of medical screening procedures (eg, fecal occult blood testing, mammography). Risk of myocardial infarction, which has been demonstrated to be reduced by statin therapy in randomized placebo-controlled trials, was found in this study to be reduced by 28%. This observed relative reduction must be interpreted as reflecting a combination of the healthy-adherer effect and the drug effect. Clinicians can also learn from this study that patients who follow their advice are also likely to have other healthy behaviors and a lower risk of adverse events.

It is unfortunate, but I doubt that many doctors (or researchers, for that matter) will consider the adherer effect when they read these studies.  I would bet that we will continue to see studies reported as if the positive effects found were a function of the drug or lifestyle regimen studied and not the adherer effect.

To me the saddest part of this study was the statistic that of the 141,086 subjects in this study, 49 percent were women.  The randomized, double-blind, placebo-controlled studies of statins have never shown a benefit in terms of decreased all-cause mortality in women of any age.  Which means that over 70,000 women in this study took a drug that would do them no good, but which could well cause them significant and harmful side effects.

In this study, those who dropped out of their statin regimen because of intolerable side effects would be considered to be less adherent or non adherers.  My guess is that many of these ‘non adherers’ who dropped out because of side effects were really ‘adherers’ by nature.  Had these drop outs due to side effects been controlled for, I would bet that the difference between the less adherent and the more adherent would have been much larger than the data showed.