Adherence: The difference between what is, and what ought to be

One of the most interesting aspects of working as a community-based pharmacist is the insight you gain into the actual effectiveness of the different health interventions. You can see the most elaborate medication regimens developed, and then see what happens when the “rubber really hits the road”: when patients are expected to manage their own treatment plan. Not only do we get feedback from patients, there’s a semi-objective measure we can use — the prescription refill history.

The clinical trial, from where we derive much of our evidence on treatments, is very much an idealized environment. The relationship to the “real world” may be tenuous. Patients in trials are usually highly selected, typically those that are able to comply with the intervention planned. They may need to be free of any other diseases which could complicate evaluation. Patients that qualify for enrollment enter an environment where active monitoring is the norm, and may be far more intense than normal clinical practice. All of these factors mean that trial results may be meaningful, but not completely generalizable to the patient that may eventually be given the intervention. It’s for this reason we use the term “efficacy” to describe clinical trial results, while “effectiveness” is what we’re more interested in: those real-word effects that are far more relevant, yet more elusive to our decision-making.  Efficacy measures a drug’s effect on an endpoint, and estimates risk and benefit in a particular setting. Effectiveness adds in real-world tolerance, the ability to tolerate the regimen, and all the other factors that are present when real patients take a drugs under less-than-ideal conditions. Consequently, effectiveness is a much more useful predictor of outcome than efficacy. Unfortunately, measurements of real-world effectiveness, possibly as a “phase 4″ or real-world trial, are rarely conducted.

But the gap between clinical trials and the real world is obvious: medications just aren’t taken regularly. The extent of non-compliance with prescribed therapy varies between reviews, but an estimate of about 25% is probably fair. Patient with HIV, arthritis, gastrointestinal disorders and cancer tend to be the most adherent to therapy — not surprising, perhaps because of the seriousness of the condition, or perhaps the responsiveness of symptoms to treatment. Least compliant are patients for treatments of lung disease, diabetes, and sleep disorders. In general, it’s safe to assume that if symptoms are mild or non-existent (e.g., high blood pressure or high cholesterol), compliance will be poor, compared to more symptomatic diseases.

Failing to adhere to a prescribed medication course is a significant challenge — after all, you won’t get the outcome you want if the medication isn’t taken. Or will you? The relationship between the two that has always been considered to be causal, but there is some evidence to suggest that adherence to a medication schedule may be a proxy for healthy lifestyles and generally healthy behaviours. I wanted to look closer into adherence after reading a paper highlighted by Mark Crislip a few weeks ago: Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST). This post-hoc analysis studied the placebo group of a double-blind, placebo-control trial that evaluated the drug bucindolol versus placebo. Those deemed “adherent” to their placebo (taking >75% of doses) were compared to the non-compliant  (who took <75% of doses). The authors adjusted for all known modifiable, non-modifiable and psychosocial variables. The surprising result?

Adherent participants had a significantly lower total mortality compared to less-adherent participants (HR = 0.61, 95% Confidence Interval: 0.46–0.82). Adjusting for available confounders did not change the magnitude or significance of the estimates. When considering cause-specific mortality, CVD and pump failure showed similar associations.

Those are impressive gains, apparently from a placebo. So what’s the cause? It’s not any confounding factor already explored by the authors. And we know the placebo has no meaningful physiologic effects. So by increasing adherence to prescribed medications, are we getting therapeutic effects from the intervention, or simply by modifying some other factor that affects outcomes? Or are there other factors at play? In the absence of a prospective randomized trial, we can’t say with any certainty.

While the correlation may not be understood yet, it seems reasonable to continue to promote adherence, given the relationship with improved outcomes. Surprisingly, despite the widespread nature of the problem, the literature base on interventions to improve adherence don’t paint a clear picture on how to change the situation. Well designed trials that evaluate interventions are rare. Probably the most comprehensive summary of the literature is from the Cochrane review, which concludes that even more effective interventions don’t lead to significant improvements in clinical outcomes. Before we get into what works, we should be clear on the terminology [PDF], as it can be source of confusion:

Adherence or Compliance refers to the act of following recommendations made by health professionals, with respect to drug, dose, and medication schedule. The ideal means of measuring adherence is with electronic devices that measure daily dosing. As these are usually not available, the prescription refill frequency is a useful, if imperfect, proxy.

Concordance is a related term used to describe a shared agreement between a health professional and a patient about therapeutic goals. It’s less a measure, and more a philosophical approach to implementing treatment plans.

Persistence refers to the duration of conformance to a particular treatment plan, and is usually defined by the interval between when therapy is started, and when it is discontinued. Adherence to the exact dosing schedule is not necessary in a measure of adherence.

Most research on adherence evaluates the effect of a specific intervention on some measure of medication-taking. In a few studies there are also evaluations of clinical outcomes that are a consequence of (non)adherence — which is far more relevant, but unfortunately, less frequently evaluated:

Technical interventions simplify dosing by modifying how medications are actually taken. You could reduce the number of daily doses (e.g., the extended-release tablet) or give a tablet or dosage form which contains two or more different drugs (e.g., many HIV medications). Technical interventions also include pharmacy-driven services like bubble-packing tablets, or by filling specialized pill “medication reminder” devices.

Technical interventions have been evaluated in multiple reviews. Obviously, blinding is a problem in these circumstances. In general, simplifying medication regimens helps with adherence: Taking one pill per day is easier and more acceptable than one pill every six hours.

Behavioural interventions prompt medication use through the use of memory aids, reminders (manual or electronic), monitoring, feedback and rewards. These types of interventions seem to have beneficial effects, an observation that’s been made in several different studies. There’s a lot of potential to use mobile technology to support medication use, now that smart phones are becoming ubiquitous.

Education interventions are the pharmacist’s bread and butter: patient teaching and knowledge. In general, there’s a positive correlation between patient knowledge, medication adherence, and outcomes, although the effects don’t seem as impressive as technical and behavioural interventions.

Social support interventions offer practical or emotional support to patients. While it sounds attractive, there’s less data available to describe which interventions are the most effective.

Structural interventions are more extensive tactics usually used to manage chronic disease. Workplace specialty care programs (e.g., hypertension) or disease management programs (e.g., diabetes) are examples of this intervention.

There are several caveats to keep in mind. Studies that have prospectively looked at adherence typically enroll patients that again, may not be fully representative of the general medication-taking population.  In addition, studies that have looked at adherence suggest that many interventions that work can be time consuming and expensive. Finally, the relevance to long-term medication use is unclear in some cases.


Adherence to therapy is a medical challenge, where the root causes are not always well understood. While the idea of a healthy patient effect seems real enough, the factors that lead to better outcomes in those that adhere to therapy isn’t clear. Given the importance of adherence to the treatment of most chronic diseases, it’s a unfortunate that strategies to improve adherence have not been more thoroughly evaluated. In the absence of good data, interventions to simplify medication schedules, provide education on the importance of adherence, and provide reminders on dosing make sense. When the “rubber hits the road” when planning treatments, it’s important to recognize that adherence may be one of the biggest influences on health outcomes.


Posted in: Science and Medicine

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13 thoughts on “Adherence: The difference between what is, and what ought to be

  1. DW says:

    I am not sure whether this is relevant or not, but it occurs to me there is sometimes a placebo effect even from medications not taken. I suffer episodic eczema, for instance, for which the doc will give me a steroid pak if it’s really bad. A number of times I’ve filled the Rx but not actually taken the meds – the condition, of course, has a stress-related component, and sometimes just knowing there is a pack of steroids in the medicine cabinet keeps me calm enough to endure the outbreak. Powerful drugs are sitting right there if I get really desperate … Presumably this only applies to conditions with some psychosomatic component. But what I’m wondering is whether sometimes “noncompliant” or “nonadherent” patients actually get a placebo effect from their prescribed-but-uningested meds.

  2. Bogeymama says:

    I find sometimes that no matter what we pharmacists do, the patient will refuse to take a particular med. Probably the category I see most often is statins, followed closely by BP meds. Yet the physician prescribes them every 3 months. (Refusal of inhaled steroids is actually #1, but cost is usually the culprit there.)

    I admit that I’ve notified the physician of a patient’s non-compliance before, but my colleagues are hesitant – they say it’s tattling. I remember a child’s mother coming in with a new script for Singulair, and was upset that her son’s asthma was not under control with the Advair disk that he was using (he was about 8). I spent a few minutes with the child and discovered that he was blowing INto his disk. When he was switched to the disk from an MDI with aerochamber (which they are allowed to breath normally with), no one told him to do it any differently. It made me realize that physicians don’t always know about a patient’s non-compliance, and that can greatly influence how they manage the patient’s care. I spoke with the doc, we agreed to hold off on the Singulair, and within weeks the boy’s asthma was under control.

    So how do we know if a patient is being honest with their physician about taking their meds properly? It is tattling for us to reveal it, or a duty as part of the health care team?

  3. cervantes says:

    Also important:

    Pruning medication regimens. Many people just have far too many prescriptions. They might take four different pills, but they won’t take 12.

    Making sure people understand the reasons for their prescriptions and why good adherence is important. This begins with physician-patient communication, which is highly deficient. (Doctors often just basically say, “Take these pills.” People often say okay, then they go home and never even fill the prescription in the first place.)

    Better physician-patient communication and relationships subsequently, so that people feel comfortable telling their docs if they aren’t taking their pills and why, or if they have (or believe they have) side effects; and so that physicians don’t respond with directiveness and scolding, but with a sympathetic dialog and mutual problem solving.

    Making sure meds are affordable for people. Sometimes people have trouble with the co-pays or have no insurance at all.

    Just for starters . . .

  4. cervantes says:

    Here’s a little something of ours, about people who are skeptical about their doctors’ prescriptions.

  5. nybgrus says:

    If the claim is that those in studies who are more adherent to the placebo regimen have better outcomes because they are more”healthy” in general (which makes sense to me), I do not think it logically follows that strategies which improve real world adherence would have the same effect.

    To me, the notion seems to be one of a global personality type. Changing a single attribute of a person, no mater how successfully, would not have this global effect. Especially since most initiatives to improve adherence are focused on mashing it easier for the patient to be afferent – in other words demanding less improvement of the same aspects which the study postulates are three true source of benefit (since we all, perhaps, can age that the placebo itself did not exert these physiologic changes).

    I fully agree that adherence is very important, that strategies to unitive it by any means are useful, and that those who are already likely to be more adherent will, in general, have better “health.” I just don’t see a path for taking someone with terrible adherence and intriguing that facet of their personality having particular benefit beyond simply taking the drug.

    *I put “healthy” in quotes since I didn’t want to get into a discussion of what it actually means. I was just interested in the concept of the correlation. Still a very useful thing to know, however, regardless of it applicability (or lack thereof).

  6. nybgrus says:


    I would actually postulate the more likely reason (or at least the stronger contributor here) is regression to the mean. eczema its a naturally waxing and waning disease. getting the steps can offer placebo based reduction of the perception of the symptoms, thus making it more tolerable and allowing it to wane on its own. Couple that with a post hoc fallacious memory that it was objectively better and shorter in duration because of the placebo induced reduction in perceived symptoms, toys in a little confirmation bias and voila!

    I’m sure it its possible that the decrease in stress could also contribute, but I just think its contribution would be minimal at best.

  7. Janet Camp says:

    I have no trouble taking my pills since I got a little container with the days of the week stamped on the lids. I used to actually forget if I had taken them or not and would then skip them in fear of double dosing, or dump them out and count them in an attempt to figure out how many were left from the date of refill. However, the reason I took action is because I know (from reading, not necessarily from interaction with doctors) that one of the most important things I can do to control my familial heart disease is to control my blood pressure.

    I also know that it’s a problem with no symptoms, so I simply have to take the pills and follow all the other advice–like losing the weight and maintaining it. I’m told that I’m an extremely compliant patient, but it simply makes sense to me to take the pills; otherwise, why even go to the doctor?

    In spite of that, I have an ongoing battle with the allergist about inhaled steroids. They stimulate my appetite significantly (she says this is a known effect but seems surprised I suspect it at the same time), so I don’t use them. Every time I see her, she wants to know if I’m using them, and every time I tell her that on balance, I think keeping the weight off is more important than perfect control of the asthma. She never disagrees.


    I think there is everything to be gained for patients by “tattling” to doctors. How else will they know? Who decided to turn this practice into something pejorative like “tattling” anyway?

    I didn’t take bp pills the first five years after they were initially prescribed because I fell victim to woo-thinking that the doc was trying to “push evil pharma” on me. I pretty much ignored it while trying a plethora of woo (I was skeptical, but like many I thought it wouldn’t hurt to try–embarrassing to think about now). One day I stopped at an event with one of those tables that offers bp checks or cholesterol screening. As soon as they got my reading a nurse Ratchet sort glared at me, told me to “sit down” and told me I was not leaving until I had a prescription which they would fill right next door. She called my doctor, I filled the rx and have been compliant ever since. My doctor had never followed up in any way even though I had been in a couple of times over the course of all this. I am now grateful that someone “tattled” on me. It was a turning point in many ways.

  8. DKlein says:

    Any time I haven’t been compliant was due to side effects. As an example, I, too, have eczema but cannot use any mineral oil-based topicals; they make my eczema worse and I’d end up washing it off with really hot water to quell the itch. Atarax is such a good sleeping pill for me that I cannot get up and do my job the next day, so I didn’t take that when it was prescribed. Just a few months ago I found a dermatologist who prescribed triamcinolone cream and this has been life-changing. If I needed an antibiotic, I would be very compliant now knowing more about how they work, though it seems whatever antibiotic was prescribed in the past gave me GI problems and I did not finish them as directed.

    My in-laws cut their statin pills in half out of fear of side effects. They say all their friends do the same. I wonder if drug commercials with the list of scary side effects at the end keep people from taking their medicine as directed.

    My husband has had a difficult year healthwise with symptoms finally being attributed to a dysautonomic disorder. He’s been on many different medications and has had side effects including sleepiness, dizziness, dry mouth, and even hallucinations. He’s not been compliant with most of them (other than a BP Rx) and stated he’d rather just be sick than feel so crummy.

  9. DW says:

    “eczema its a naturally waxing and waning disease.”

    I know, but my reaction to the meds is really dramatic – going from jumping out of my skin, intolerable itching to total peace in just a couple of hours. Maybe that was a placebo effect too? I don’t know, ‘cus I don’t have it nearly so bad anymore.

  10. nybgrus says:


    The needs are indeed powerful. All I am saying is that most likely, the times you fool the script but don’t take it and all is well likely reflects a bout that is not quite so bad, you tolerate it a little more and it wanes a little more rapidly than usual simply by natural variance. Then the confirmation bias kicks in and it genuinely seems that the placebo of filling but not taking the meds was more powerful than it really was. At least that’s my speculation.

  11. AlexisT says:

    I have found technical innovation to be the most helpful to me (just short of godsend). Extended-release formulations mean near-100% compliance for me. I can be relied on to take a pill at the same time every day. With a twice a day regime, it’s harder, especially with drugs that need to be taken with or after meals (metformin is a perennial problem) My mornings are rushed. Combo pills are also terrific–my BP meds are currently an ARB+HCTZ combo tablet. I take one a day, done. Dosing also matters for me: i find it easier to take fewer pills. Met XR was a problem because it only comes in 500s and I take 2000mg/day.

    When I did have a more complicated med regime one of the containers was a necessity, or I’d forget when and how many I’d taken. And I’m only 34, so I can’t blame age! I understand everything I take and why; that’s not an issue. For a patient like me, routine and ease of use raise compliance. I took to having my Synthroid and a glass of water next to my bed, so I would take it the second I woke up. I don’t forget now and I get it early enough that I can have breakfast.

  12. DugganSC says:

    Although, as a side note, it’s important for patients to raise questions on any and all potential side effects. One of my former co-workers was commenting how one of her sons was acting strange, going from a cheerful and pleasant child to one who was always angry and had a sudden fascination with violence and gore. Having read a comment line on Polite Dissent (the blog which brought me here, actually) in response to an article about a Claratin stealth ad in a Batman comic, I asked if he’d recently been put on Claratin and, surprised, she answered yes. Apparently, there is a rare side effect of Claratin use in children where they essentially go into rage states. I’ve never found it on the list of official side effects, although I suspect it comes under the “increased hyperactivity” and “increased irritability” bits. Anyhow, the story had a happy ending. She switched allergy medications for him and he returned to his regular personality within days. I’m just glad I happened to have read the article and noticed the similarities…

  13. JPZ says:

    Well, Scott passed the foolish skeptic test again.

    Walter Willett from Harvard ran the same statistics on general health-promoting behavior and clinical outcomes. You might learn a thing or two from his research.

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