Given But Not Taken

A Tale of Drug Adherence

By Delia O’Hara / American Medical News correspondent

Thirty days into the anthrax scare the country faced this fall (2001), less than three-fourths of the roughly 10,000 people exposed to the bacteria and put on a course of antibiotics were still taking their pills.

Inhaled anthrax spores can stay in the body for long periods, and the treatment regimens recommended early in the crisis involved a 60-day course of antibiotics. Patients knew from the highly publicized outbreak that the sickness was life-threatening.

Still, at least a quarter of them stopped taking their pills. Some additional members of the cohort were “not taking them exactly as recommended,” says Nancy Rosenstein, MD, an epidemiologist with the Centers for Disease Control and Prevention’s National Center for Infectious Diseases.

Side effects that included nausea and diarrhea were blamed for the lack of compliance with the antibiotic regimens.

“It’s a struggle to take antibiotics for this long,” Dr. Rosenstein says. “For the CDC and the country in general, facing a bioterrorist event like this one, we’re on a steep learning curve about how to help people through a difficult course of antibiotics.”

An astonishing anecdote? On the contrary, the anthrax experience mirrors the preponderance of evidence piled up by a series of groundbreaking studies over the past dozen years, that only about 75% of prescribed drugs are taken as intended.

This experience also reflects the increasing recognition in the medical profession that the fair-to-poor complier is not just the patient with a sinus infection who stops taking his antibiotics when he begins to feel better, but also the one who knows that not taking his medicine as prescribed may result in death, blindness, incapacitation or the rejection of an organ prayed for for years. Noncompliance results in an estimated 125,000 deaths a year from cardiovascular disease alone, up to a quarter of nursing home admissions and an estimated 10% of hospital admissions.

“The leading cause of rejection episodes after [organ] transplant is poor compliance,” says Joyce Cramer, associate research scientist in the Dept. of Psychiatry at Yale University School of Medicine, New Haven, Conn., a pioneering researcher on compliance.

“Fifty percent to 60% of failures to control HIV are due to incomplete adherence,” says Dava Klirsfeld, MD, medical director of the HIV clinic at New York City’s Bellevue Hospital.

The problem is as old as medicine itself.  Hippocrates complained that his patients did not take their medicines the way he prescribed them, and thousands of professional papers have addressed the topic of “compliance,” a term that is being overtaken by the less judgmental “adherence,” preferred by physicians and patients who treat or live with HIV.

The tremendous efficacy of many drugs in use today “smokes out the compliance problem as never before,” says John Urquhart, MD, professor of phamaco-epidemiology at Maastricht University in the Netherlands. Dr. Urquhart also is an adjunct professor of biopharmaceutical sciences at the University of California, San Francisco.

Some drugs work so well that if the physician is not seeing something like the expected results in a particular patient, he or she quickly comes to wonder if the failure lies not with the drug but with “the quality of execution,” says Dr. Urquhart, co-founder of two companies, APREX Corp., Union City, Calif., and AARDEX Ltd., Zug, Switzerland, that develop electronic compliance monitoring systems.


These relatively new measurement tools have dramatically helped to quantify compliance. Cramer used an electronic monitoring device for a 1989 drug trial that bypassed traditional patient reporting to give a dated record of when pills were extracted from their packaging. When she reported her results in the Journal of the American Medical Association, poor compliance began to assume a shape.

It is now known that patients are likely to comply best for the five days before and after appointments with their doctors, a phenomenon known as “white-coat compliance,” and that many patients treat themselves to “drug holidays,” three days or more off their drugs, especially on weekends. When they restart their medications, patients may double-dose or otherwise extemporize on their prescriptions. Patients also don’t like to admit they don’t take their pills, which may lead them to fabricate a good compliance record.

All of these things can lead to serious problems, to recurrent “first dose” effects, to rebounds and to resistant microbes in the case of an infectious disease. More common and more important, this last instance can lead to a relapse that can turn the patient into a colonizer of resistant bacteria, which can then spread throughout the community.

The dissembling is especially pernicious. “If a physician is looking at uncontrolled hypertension and he doesn’t know that it’s caused by non-compliance, then he’ll add another drug, or he’ll go through the expensive exercise of an extra workup, to find a problem that isn’t the problem at all,” Cramer says.


It has long been thought that if side effects could be eliminated, if drug regimens could be reduced to once a day and if drug costs could be curbed, then people would take their pills. Now there are some “perfect” drugs, though, and researchers are finding that even with those regiments, compliance is not perfect.

Statin drugs for hypertension come as close as any to “perfect.” They are taken once a day, have few side effects and cost about $2 a day. Still, only about 30% of patients who haven’t had a heart attack stick with the regimen for at least a year. “That figure is about 70% for people who have had a heart attack,” says Dennis Sprecher, MD, section head of preventive cardiology and rehabilitation at the Cleveland Clinic. “People who experience heart failure suddenly find themselves very interested in taking their medication.”

Drug noncompliance results in 125,000 deaths a year from cardiovascular disease alone.

The bottom line is that physicians have no idea how well a drug regimen is working unless they can gauge a patient’s level of compliance.

The practice of treating healthy patients with long-term drug regimens is only 40 years old, dating from the first oral contraceptives, Dr. Urquhart notes. Getting healthy or at least symptom-free people to take pills every day for the rest of their lives to counteract such silent conditions as hypertension or osteoporosis is fairly new for the medical community, and no small task.

“You have to recognize when you start on a [long-term] drug program that there is a beginning, a middle and an end,” he says. That is, a patient might be among the 10% or more that never fills the prescription. Or, in the middle, he might not adhere to the prescribed regimen.

Says Cramer: “I don’t believe our target is 100% compliance. The patient needs to take enough of the medicine to achieve the desired outcome,” and that varies from drug to drug. Some drugs are more “forgiving” than others. That is, a patient can miss one or two doses without suffering any adverse effects.

Other drugs, such as oral contraceptives, are unforgiving. “You have to take them the same time day after day or you may find yourself living with the consequence for 25 years,” she says.

The last hurdle, Dr. Urquhart’s “end,” is whether the patient will “persist” in the regimen over time, or join the nearly half of all patients who have stopped taking pills to treat a chronic condition a year after they were prescribed.

It still goes back to how to get the patient to open up that pill bottle on time today. “You achieve persistence one dose at a time,” Dr. Urquhart says.

Says Cramer, “The issue is outcomes.”


Unfortunately, given the gravity of the disease, the drugs used to combat HIV are highly “unforgiving” — that is, a patient who misses a small number of doses can suffer a quick rise in viral loads and the possible emergence of drug-resistant HIV strains.

The virus has two qualities that contribute to this phenomenon. “It reproduces like mad, and it’s a real sloppy reproducer, so there are lots of mutations,” says J. Todd Weber, MD, senior medical officer at the National Center for Infectious Diseases in Atlanta.

Drug regimens that have “turned HIV into a chronic disease” rather than an automatic death sentence “require a tremendous amount of adherence … to be successful,” says Dava Klirsfeld, MD, medical director for the HIV clinic at Bellevue Hospital Center in New York.

But most HIV patients, like other patients, do not adhere perfectly to their drug regimens. With the drugs that treat HIV, an adherence rate of, say, 88%, which would be good enough for great efficacy with many other drugs, is a disaster.

In fact, patients who will take the combinations of drugs to combat HIV “for the rest of their lives, as far as we know,” are better off complying with the regimen only half the time, because at compliance rates of 80% to 90%, “they are exerting more selective pressure” on the virus, Dr. Klirsfeld says.

Even though the dosing frequency has come down to twice a day for most people, the “pill burden” for patients with HIV may be four pills per dose or even more.

When people miss doses, it’s for various reasons. “They say they can’t stand taking any more pills, or they don’t feel well on the medications,” Dr. Klirsfeld says. “Or they forget, or they’re in denial around their disease and taking the medications reminds them of it, or they have housing issues. Some people get into substance abuse, or they go off their psychiatric medications.”

Is that frustrating for Dr. Klirsfeld? “It isn’t, because we have a huge number of successes,” she says. “Most people are really doing very well. We’re not perfectly suppressing everybody, but they’re not getting as sick as they used to.”

Like other HIV programs, Bellevue has a 2 1/2-year-old treatment support program, designed to help patients manage lives and medications. “It’s the rare person who is 100% adherent. It’s human nature,” says Kate Berrien, director of the program.

Interestingly, HIV providers are learning to use patients’ lapses to combat the virus. For example, the three-day “drug holiday” that compliance researchers have discovered some patients take has been put to work in HIV treatment as a “structured treatment interruption,” a few days’ hiatus to let the virus reproduce, followed by a renewal of treatment, an attack with “a brisk immune response to the virus.”


Researcher Joyce Cramer at the Psychiatry Dept. at the Yale University School of Medicine, New Haven, Conn., has discovered that helping patients tie pill-taking to daily routines can dramatically improve compliance.

Working with mentally ill patients in the VA Connecticut Health Care System, Cramer and her assistants identified activities that patients did without fail every day — shaving, eating a meal, watching the evening news on television — and linked taking medications to those routines. They asked, “‘What time of day would be best for you to take your medications? What is the best cue to remind you to take your pills?’ Select a reminder — that engrains the behavior and creates a cue in the brain,” she says.

This method significantly improved the ability of previously poor compliers to improve. Specifically, 81% took their meds, compared with 68% from a control group who received a more general conversation about the importance of taking their drugs, she says.
It isn’t the number of pills that patients take that most affects adherence but rather the number of times a day patients have to remember to take their medications. Whatever the frequency, “cueing” doses to regular activities helps patients remember them, Cramer says. And plastic pill organizers can provide patients with “an objective report card” on how they are doing.

Physicians should spend less time “talking about the biology of the disease and more about how to treat it, how to ‘do it,’ how to take the medications,” she says. At follow-ups, “Ask, ‘How do you take your medication? When? With what?’ Reinforce what the patient is doing. People will realize that you really care about what you prescribe.”

    American Medical News  02/04/02

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