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Can We Increase Patient Adherence with Intermittent Dosing?
By David Kiefer, MD. Dr. Kiefer is Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; and Adjunct Faculty, Bastyr University, Seattle; he reports no financial relationship to this field of study.
Having just glanced in the refrigerator and realized that, yet again, a week had passed and I had forgotten to take my omega-3 capsules, I wondered what I could do to develop a daily routine that would foster my good health. I am not alone in these musings and frustrations; patients recount to me daily that "Sorry, doc, I’ve been bad," or "I forgot to take my pills last night. I’m sure that’s why my blood pressure is up."
For example, from a recent clinic visit, Mr. Jones, in his 70s, presented with a diagnosis of prostate cancer from 3 years ago. After prostatectomy, having declined both radiation therapy and leuprolide, he was closely followed by his urologist with serial testing of prostate-specific antigen. He read about and started himself on a combination of eight dietary supplements, then consulted a naturopathic physician specializing in prostate health who added two additional herbal medicines to his regimen. Several months later, the patient's main complaint was that he only takes his vitamins, herbs, and prescription medications sporadically, finding it difficult to get into a routine, even with the use of a pill box and the placement of the bottles in a conspicuous place in his bathroom. He understood that he would likely have better health outcomes with the regular ingestion of his supplements, but still found it difficult to achieve 100% adherence. Does this sound familiar from your own clinical practice?
We're inundated with tasks to do every day, from flossing teeth, to eating five servings of fruits and veggies, to popping our pills morning, noon, and night. It's not easy to remember all of this with perfect accuracy. An argument could be made that humans are hard-wired for more sporadic behavior: Our ancestors probably ate certain foods when they were available, and then moved on to the next food supply, akin more to a feast-and-famine approach to life rather than a steady routine. Is this still relevant today, possibly indicating that intermittent health interventions are more likely to translate into optimal health? Wouldn't once monthly treatments be easier for all of us than once, twice, or three times daily? What does the research say?
This article will review the literature relevant to patient adherence, including strategies thought to improve adherence, as well as any studies relevant to the benefits or risks of alternatives to daily dosing regimens. As will become apparent later in this article, simply changing the dosing schedule only addresses one aspect of patient adherence, the optimization of which necessarily involves patient factors, provider factors, and aspects of the health care system as a whole (i.e., barriers to care and costs). Nonetheless, dosing regimens are an easily manipulated variable, apparent to both providers and patients, and so of particular interest in this topic.
As a preface to any scientific discussion of patient adherence, it is important to realize that there are challenges in this field, primarily because many of the results are dependent on the methods used to collect the data1,2; ways of measuring adherence vary considerably between studies, as do ways of identifying people at risk of nonadherence and who might be amenable to interventions.3 For example, there are direct methods of measuring adherence, such as observed therapy (thought to be very accurate), and indirect methods, such as pill counts, easy to perform but less accurate.1,4
That said, there are several terms used in the medical literature to describe the phenomenon by which patients do or do not behave according to how their health care provider wishes. The most common two terms used are adherence and compliance, the latter falling out of favor because it implies that patients passively follow (or ignore) a provider's treatment plan without any engagement or relationship with the provider in its development.4 One oft-cited definition of adherence is "...the extent to which a person's behavior taking medication, following a diet, and/or executing lifestyle changes corresponds with agreed recommendations from a health care provider."5 Regardless of the precise definition, there is a concern among researchers and clinicians about stigmatizing patients who are noncompliant or nonadherent, affecting their future interaction with the health care establishment.
Adherence rates vary, but have been reported to be 43%-78% for chronic conditions,4 though adherence rates between 4%-100% (median 76%) were reported by one review of 569 clinical trials.1 Medication adherence rates are estimated to be 26%-59% in older adults,6 approximately 50% in children with chronic illness,7 > 50% in chronic obstructive pulmonary disease (COPD),8 and 40%-60% in people with ulcerative colitis.3 An acceptable adherence rate is often deemed to be 80%, but some researchers prefer to reach 95% for serious medical conditions such as infection with human immunodeficiency virus.4
Benefits of Adherence
There are reasons to pay attention to patient adherence. For many medical conditions, patient adherence directly correlates with decreased morbidity and mortality.5 On the flip side, poorer adherence rates are associated with the worsening of disease and poorer prognoses, increased health care costs (as much as $100-$300 billion annually), higher hospital admission rates, and even death.4-6,8,9 Adherence to medication protocols is considered to be one of the most important and modifiable aspects of chronic disease management.6,10 One review of 19,000 patients from 63 studies found that 26% more patients had a good outcome if they adhered to their provider's recommendations when compared to people who didn't adhere to the recommended medical treatment.11
Strategies to Improve Adherence
As we strategize how to improve the likelihood that patients will follow through on treatment recommendations, it is useful to think about barriers that exist to 100% adherence. Part of this involves identifying the root causes of nonadherence, and addressing patients' attitudes and beliefs that may be involved.3,8 Some patients may be nonadherent merely because of forgetfulness or lack of information, though emotional factors, overly complex regimens, and poor provider communication also may be involved.4 In addition, not all approaches will be effective for all medical conditions or demographics, as demonstrated in one recent overview of 37 systematic reviews.12 That said, there are some general trends and specific successes identified in adherence research that are insightful (see Table 1), and one research team argues that with a variety of interventions it is possible to increase adherence by 4%-11%.9
Table 1: Strategies to Improve Adherence as per the Medical Literature
One meta-analysis compiled results from 33 research trials examining the effect sizes (ES) of interventions to increase adherence to medications in a total of 11,827 adults with a median age of 60 years.6 The various interventions increased adherence (ES = 0.33) and medication knowledge (ES = 0.48). In particular, medication package changes (including pill boxes), succinct written instructions, stimuli that remind patients to take their medications, dose modification, and having patients monitor medication-related symptoms seemed to make a significant difference in adherence, whereas teaching strategies, and physician medication reviews, interestingly, did not.
As mentioned above, there are specific considerations relevant to particular medical conditions or demographics.1 Management of hypertension remains substandard for many people, and various approaches are recommended to maintain long-term adherence, including changing to once-daily dosing when possible, and carefully monitoring for adverse medication effects as these can be a major deterrent to continued adherence.15 In children with chronic illnesses, one meta-analysis of 71 studies showed interventions to increase medication adherence were moderately effective (ES approximately 0.40) and yielded health benefits.7 Approaches generally involved a combination of behavioral, organization, psychological, and educational techniques, though one quarter of the studies used only one strategy to increase adherence; the most effective combination was behavioral and education, yielding better outcomes than either approach alone. Similar benefits with a combination of adherence interventions have been documented for people in need of hemodialysis.16 For COPD, proper patient education, provider-patient communication, and adjustment of medication dosing have all been shown to aid adherence and health outcomes.8 Chronic mental illness, such as bipolar disorder and schizophrenia, presents many adherence challenges, some of which can be improved by psychosocial and programmatic interventions, though a recent expert panel found that a switch to long-acting medications or the simplification of the medication regimen could benefit some patients.17 Adherence to lipid-lowering drugs, especially around the milestone of 6 months after the beginning of therapy, when adherence typically wanes, improves with patient reminders via telephone calls or pharmacist reviews.2
It is important to point out that adherence to a particular therapeutic intervention is not always a good thing. For example, we would not want patients to be adherent to a regimen that was imprecise, or incorrect and toxic.1 Hopefully situations in which it is ideal to be nonadherent are the exception, not the rule, focusing health care providers again on how to improve adherence.
A recent Cochrane review summarized eight patient-oriented interventions for improved adherence.12 There is some overlap between the categories for a few of the interventions (e.g., self-monitoring may be both "supporting behavior change" and "minimizing risks and harms;" see Table 2).
Finally returning to the premise of the initial patient case and the possible role of intermittent dosing in improved health outcomes, what do the data show? As mentioned above, simplification of medication regimens to improve adherence is a common conclusion from clinical trials and meta-analyses. Health care providers can simplify medications by changing to once-daily dosing, avoiding polypharmacy, using pill boxes, and incorporating dosing reminders into patient care, among other strategies. However, the literature is interestingly mute about medication adherence and intermittent or sporadic dosing. Of course, this is partly or completely due to the fact that only a few interventions are relevant to this issue. For example, with respect to appropriate use of contraception, there are clearly adherence benefits to once-weekly patches or every three month medroxyprogesterone injections over daily oral contraceptives; benefits from other longer-term options such as the intrauterine device or intradermal etonogestrel every three years are corroborated by the medical literature.18 Other examples of intermittently dosed pharmaceuticals are weekly or monthly dosing of bisphosphonates for osteoporosis and depot formulations of medications for prostate cancer. One review of the topic found 8.8%-12.0% higher adherence and higher patient preference for once-weekly dosed medications as compared to once-daily dosing in 11 studies.10 Once-monthly medications had similar adherence to once-daily medications, but this conclusion was based on only one head-to-head trial. This review brought up a very important concern specific to intermittent dosing: There is a greater risk of significant undertreatment and associated therapeutic ineffectiveness associated with missing one dose of a once-weekly medication vs missing one daily medication, and there is the increased chance of toxicity if patients attempt to make up for missed doses of intermittently dosed medications by taking extra doses.
In the realm of integrative medicine, there are a few examples of official recommendations that venture away from daily dosing, perhaps leading to a higher adherence benefit for this treatment approach. For example, repletion of vitamin D insufficiency with 50,000 IU once weekly of orally dosed vitamin D2 is practically standard of care,19 as is the prescription of twice-weekly fish intake for cardiovascular health.20 In addition, and thankfully for some of our patients, it is not necessary to exercise daily; rather "most days of the week" activity is sufficient for cardiovascular conditioning and weight loss. The new frontier of medicine may very well be epigenetics, and initial findings may have relevance for the issue of dietary supplements and nutrition, and regularity of dosing. One preliminary study noted that the ingestion of one cup of broccoli sprouts led to maintained hyperacetylation of histone (an epigenetic anticancer effect) in peripheral blood mononuclear cells for 48 hours.21 Does this mean that we only need to eat such vegetables every 2-3 days to receive optimal anticancer benefits? Perhaps, but such conclusions are still very premature and need to be corroborated.
The literature on patient adherence is extensive, providing many details about causes of nonadherence and approaches to maximize follow-through on medical treatment recommendations. Such strategies are extremely important; improved patient adherence absolutely correlates with better health outcomes on any of a variety of scales and measurements. Strategies to improve adherence should be tailored to each individual patient and diagnosis, and the best results usually incorporate a variety of approaches from improved provider communication to patient education and the simplification of medication regimens. Data on medication dosing definitely show improved patient adherence with once-daily dosing, and likely once-weekly dosing as per one literature review. There are some lifestyle, supplement, and nutrition recommendations that show health benefits when dosed intermittently, though the research remains to be done to show that these lead as well to improved adherence.
Improving patient adherence needs to be on the forefront of all clinician's minds, whether it involves medication prescriptions or the recommendation of complementary and alternative therapeutics. Many strategies exist that lead to an improvement in adherence, and therefore, health outcomes. One of these is the simplification of a patient's medication regimen, once-daily or even once-weekly being the preferred dosing frequency. As long as efficacy of a reduced dosing frequency has been ensured through clinical trials, realizing that this may not yet have been established for many dietary supplements, all clinicians should opt for supplement, medication, or lifestyle interventions that might be effective while requiring less frequent dosing strategies.
1. DiMatteo MR. Variations in patients' adherence to medical recommendations: A quantitative review of 50 years of research. Med Care 2004;42:200-209.
2. Schedlbauer A, et al. Interventions to improve adherence to lipid lowering medication. Cochrane Database Syst Rev 2010, Issue 3. Art. No.: CD004371.
3. Kane SV, Robinson A. Review article: Understanding adherence to medication in ulcerative colitis innovative thinking and evolving concepts. Aliment Pharmacol Ther 2010;32:1051-1058.
4. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487-497.
5. Sabaté E. Adherence to long-term therapies: Evidence for action. Geneva: World Health Organization; 2003.
6. Conn VS, et al. Interventions to improve medication adherence among older adults: Meta-analysis of adherence outcomes among randomized controlled trials. Gerontologist 2009;49:447-462.
7. Graves MM, et al. The efficacy of adherence interventions for chronically ill children: A meta-analytic review. J Pediatr Psychol 2010;35:368-382.
8. Lareau SC, Yawn BP. Improving adherence with inhaler therapy in COPD. Int J Chron Obstruct Pulmon Dis 2010;5:401-406.
9. Peterson AM, et al. Meta-analysis of trials of interventions to improve medication adherence. Am J Health System Pharm 2003;60:657-665.
10. Kruk ME, et al. The relation between intermittent dosing and adherence: Preliminary insights. Clin Ther 2006;28:1989-1995.
11. DiMatteo MR, et al. Patient adherence and medical treatment outcomes: A meta-anlaysis. Medical Care 2002;40:794-811.
12. Ryan R, et al. Consumer-oriented interventions for evidence-based prescribing and medicines use: An overview of systematic reviews. Cochrane Database Syst Rev 2011;5:CD007768.
13. Zolnierek KB, Dimatteo MR. Physician communication and patient adherence to treatment: A meta-analysis. Med Care 2009;47:826-834.
14. Morgado MP, et al. Pharmacist interventions to enhance blood pressure control and adherence to antihypertensive therapy: Review and meta-analysis. Am J Health Syst Pharm 2011;68:241-253.
15. Galzerano D, et al. Do we need more than just powerful blood pressure reductions? New paradigms in end-organ protection. Vasc Health Risk Manag 2010;6:479-494.
16. Matteson ML, Russell C. Interventions to improve hemodialysis adherence: A systematic review of randomized-controlled trials. Hemodial Int 2010;14:370-382.
17. Velligan DI, et al. Strategies for addressing adherence problems in patients with serious and persistent mental illness: Recommendations from the expert consensus guidelines. J Psychiatr Pract 2010;16:306-324.
18. Zibners A, et al. Comparison of continuation rates for hormonal contraception among adolescents. J Pediatr Adolesc Gynecol 1999;12:90-94.
19. Holick MF. The vitamin D epidemic and its health consequences. J Nutr 2005;135:2739S-2748S.
20. Covington MB. Omega-3 fatty acids. Am Fam Physician 2004;70:133-140.
21. Dashwood RH, Ho E. Dietary histone deacetylase inhibitors: From cells to mice to man. Semin Cancer Biol 2007;17:363-369.