Electronically monitored dosing histories can be used

Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by IBI Circulation - Ashley Publications Ltd on 08/05/14 For personal use only.

Review

Electronically monitored dosing histories can be used to develop a medication-taking habit and manage patient adherence Expert Rev. Clin. Pharmacol. Early online, 1–12 (2014)

Bernard Vrijens*1, John Urquhart1 and David White2 1 MWV Healthcare, Rue des Cyclistes Frontie`re 24, 4600 Vise´, Belgium 2 Clinical Lead for GU Medicine, Hawthorn house, Birmingham Heartlands hospital, Birmingham B9 5SS, UK *Author for correspondence: Tel.: +32 4374 8635 [email protected]

Nonadherence to prescribed medications can lead to medical complications, disease progression, hospitalizations, overestimated dosing requirements, impaired quality of life, and death, as well as incurring substantive costs for the healthcare system from suboptimal dosing during ambulatory pharmacotherapy. Adherence can be improved by helping patients build habits of taking prescribed medications, impacting day-to-day implementation of and persistence with rationally prescribed drug dosing regimens. Accurate, easily understood and personally relevant feedback is clearly relevant to many patients in this process. There is a clear-cut need for studies specifically designed to investigate interventions aimed at improving adherence, taking into account the sometimes complex nature of these interventions. Implementation of results from such studies can be expected to improve outcomes. For scientific progress to be maintained in this field, there is also a clear need for consistent use of a sound taxonomy for the dosing errors that comprise poor adherence (distinguishing between initiation, implementation and discontinuation), and for interventions performed to improve adherence. KEYWORDS: adherence • behavioral change • clinical pharmacology • habit • implementation • intervention • taxonomy

Adherence to prescribed medications is crucial for therapeutic success, because even the most potent pharmacotherapeutic interventions can be rendered ineffective by suboptimal adherence to rationally prescribed medications. As the burden of illness in a population continues to shift toward chronic diseases, the problems created by patient nonadherence to long-term pharmacotherapy gain in importance. Nonadherence to rationally prescribed drug dosing regimens is a widely prevalent problem; analysis of the electronically monitored dosing histories of approximately 17,000 clinical trial participants revealed that, during a year of observed treatment, almost 40% of participants had discontinued taking the prescribed drug (including 4% who never initiated their treatment), and in addition, 15% of participants were occasionally omitting some of their prescribed doses [1]. In clinical practice, WHO has

informahealthcare.com

10.1586/17512433.2014.940896

estimated that only half of the patients adhere to long-term therapy for chronic illnesses in developed countries [2]. Burnier et al. compared in-practice persistence with antihypertensive drugs, as assessed in four pharmacoepidemiological studies, with the aggregate results of 21 clinical trials, and observed no substantive difference between in-practice and in-trial persistence [3]. The commonly recurring patterns of nonadherent dosing create a catalog of therapeutic errors, for example, failed treatment, inappropriate drug escalation, emergence of drugresistant infectious microorganisms, hazardous rebound or recurrent first-dose effects, and misdiagnosis. Nonadherence to prescribed medications may also impact the results of clinical trials and may lead to erroneous conclusions, including underestimated efficacy, underestimated incidence of adverse effects, distorted pharmacoeconomic analyses and overestimated

Ó 2014 Informa UK Ltd

ISSN 1751-2433

1


Review

Vrijens, Urquhart & White

dosing requirements [1]. Each of these errors carries economic costs that vary widely, arising from varying degrees of delayed or unrealized recovery from the diseases that were the indications for prescribing. It has been estimated that patients who are not taking their medications as prescribed cost the US healthcare system approximately US$290 billion every year [4]. The need is indisputable for workable methods that can achieve and maintain adherence to prescribed medications. It has been suggested that increasing the effectiveness of methods for improving adherence may have a far greater positive impact on human health and its economics than any single improvement in medical treatment [5]. Yet, evidence to support the best way to maximize adherence is inconclusive: a 2008 Cochrane review of the literature [6] found that quantitative analyses could not be performed due to the large differences between published studies in terms of medical condition, patient population, intervention, measures of adherence and clinical outcomes. Effects were also inconsistent from study to study, and almost all interventions that were effective for long-term care were complex and included multiple components. Moreover, the situation is further complicated by the fact that patient nonadherence is sometimes intentional (patients who are exerting a control over their medication-taking) and sometimes nonintentional (e.g., forgetfulness). In this nonsystematic review, we discuss the need for individualized strategies to improve adherence and the evident importance of feedback to the patients about the specifics of their recent dosing patterns, and we provide a forecast of how the attainment of specific habits can improve adherence to medication. Finally, we propose a new evidence-based approach to effectively: implement multiple components of behavioral interventions; assess the effectiveness of each component; promote the most effective ones and scale-up an adherence management program. What is patient adherence?

Over time, a variety of terms have been used to define different aspects of the act of seeking medical attention, acquiring prescriptions and taking prescribed medicines appropriately. These terms include compliance, adherence, persistence and concordance. However, to allow for comparison in research concerning adherence and for being able to interpret the findings of this research, there is a need for a clearly described adherence-related terminology and for consistent use of this terminology [7]. In 2012, a European consensus on terminology was proposed by the EU-sponsored ‘Ascertaining Barriers for Compliance’ project [8], in which adherence to medications is defined as the process by which patients take their medications as prescribed; medication adherence consists of three elements: initiation, which occurs when the patient takes the first dose; implementation, which is the extent to which a patient’s actual dosing history corresponds to the prescribed dosing regimen from initiation until the last dose is taken and discontinuation, which occurs when the patient stops taking the prescribed medication. The length of time between initiation and discontinuation of dosing is termed persistence [8]. doi: 10.1586/17512433.2014.940896

Medication adherence is crucial for safe and effective use of drugs. The vast majority of errors in adherence involve net underdosing, which has three origins: delayed or neveroccurring initiation of dosing; intermittently missed doses during regimen implementation and short persistence. The relative importance of these varies with the therapeutic context. Nonadherence to the prescribed medication regimen can also lead to overdosing, whether unintentional (forgetting that a dose has already been taken) or intentional (e.g., overuse of bronchodilator inhalers by asthma patients because they offer quick relief of symptoms [9]). The EU consensus taxonomy defines management of adherence as the process of monitoring and supporting the patient’s adherence to medications by healthcare systems, providers, patients and their social networks. The objective of medication management is to achieve the best use of appropriately prescribed medicines by patients to maximize benefit and minimize the risk of harm [8]. Adherence to medications and management of adherence are the principal foci of the adherence-related sciences, which seek to understand the causes and consequences of differences between the prescribed medication and the patients’ actual exposures to medicines [8]. Medication adherence is influenced by multiple factors. A recent systematic literature review identified 771 individual factor items, of which most were determinants of implementation [10]. It is worth noting that this review encountered difficulties due to the lack of standardized definitions as well as the poor measurement methods used in the included studies. These difficulties emphasize the importance of consistent use of a carefully defined taxonomy to describe adherence, as well as the methods of measurement of adherence, and the interventions aimed at improving adherence. The determinants of adherence are different for initiation, implementation and discontinuation. One patient’s determinants of adherence can also change over time, for example, the beliefs of the patient concerning his/her disease and his/her trust in the therapy can evolve. Moreover, patient-related factors (e.g., age, gender, marital status) were found to have an inconsistent impact on the implementation of correct dosing, which is an important part of the overall process of adherence [10]. The prediction of nonadherence for individual patients is therefore difficult. Suitable measurements of the three elements of adherence, combined with multifaceted interventions, may provide the most effective means to improve adherence. Measurement of patient adherence

Various methods have been proposed to measure adherence, although many of these methods provide only fragmentary information on patients’ actual exposure to the prescribed drug(s), are nonspecific and tend to be inaccurate. Counts of returned, untaken dosage forms (‘pill counts’) and retrospective questionnaires have frequently been shown to be biased and to overestimate the patient’s adherence [11–18], at least in part because they allow patients the ability to modify the data. More fundamentally, counts of returned, untaken Expert Rev. Clin. Pharmacol.

Electronically compiled dosing histories

Review

Improved medication adherence

02:59 00:00


21:00 18:00 15:00 12:00 09:00 06:00 03:00 18.02.2006

11.03.2006

01.04.2006

22.04.2006

13.05.2006

03.06.2006

24.06.2006

15.07.2006

05.08.2006

26.08.2006

16.09.2006

07.10.2006

28.10.2006

Focused discussion between healthcare provider and patient based on reliable and detailed adherence data

Figure 1. Example of improved medication adherence after intervention. This dosing history shows a period of improved adherence after a focused discussion between the healthcare provider and the patient. The blue dots represent electronically captured dosing times and the vertical grey bars mark omitted doses. Adapted with permission from [26].

dosage forms provide no information on the timing of omitted doses. Data from prescription refills can provide information on short persistence, but information on the exact timing of discontinuation is absent [19] and its availability happens too late for effective management. Electronic methods for compiling drug dosing histories have emerged as the currently recognized standard for quantifying adherence. Electronically monitored packages detect and store the times and dates of package entry, which are validated [20] as a robust measure of when the prescribed dose of the drug was taken. Thus, electronically compiled dosing histories provide a high degree of temporal resolution of the timing of each dose. The most widely used electronic package is the Medication Event Monitoring System (MEMSÒ), which monitors the opening and closure of a drug container for solid oral forms. This principle can be extended to blisters [21], pumps [22], dose organizers [23] or needle disposal [24]. Electronically monitored dosing histories & feedback to patients

Patients’ awareness of their adherence patterns can change their dosing behavior. A review and meta-analysis of adherenceenhancing interventions in 79 randomized clinical trials (RCTs), in which electronically compiled drug dosing histories were assessed, showed that feedback to patients about their dosing patterns was the biggest factor influencing adherence. Interventional studies that included a focused discussion, with the patient being provided feedback on his/her recent electronically compiled dosing history data, were 8.8% more effective than interventional informahealthcare.com

strategies without such feedback (p < 0.01), resulting in an overall 20% (95% CI: 11–29%) improvement in adherence [25]. SUPPLEMENTARY TABLE 1 (supplementary material can be found online at www.informahealthcare.com/suppl/17512433.2014.940896) summarizes the 21 studies included in the meta-analysis that used electronic monitoring (EM) feedback as part of the intervention to improve adherence as well as five more recently published studies (discussed below). An individual example of improved adherence after a focused discussion between the healthcare provider and the patient, based on the patient’s own adherence data, can be found in FIGURE 1 [26]. In this individual example, one can see that after approximately 4 months, the effect of the feedback seems to wear off, indicating a lack of sustainability of the improved adherence after a single discussion between the healthcare provider and the patient. The frequency with which feedback sessions would need to be reiterated has not yet been established and may well need patient individualization. The effectiveness of using personal feedback to patients to improve their adherence has been confirmed by five recent studies published after the abovementioned meta-analysis. Gross and Reich showed effectiveness in managing HIV patients, which ultimately resulted in improved CD4 and viral control [27,28]. Wu showed that this approach improved medication adherence and outcomes in patients with heart failure [29]. Van Camp reported improved adherence and phosphatemia control in hemodialysis patients following a nurse-led intervention using EM feedback [30]. Moreover, the cases illustrated by Herzer suggest that EM feedback can be a clinically useful tool when used to supplement an empirically supported intervention delivered in doi: 10.1586/17512433.2014.940896

Review


Training Education knowledge

Motivation self efficacy


Management of adherence Package

Goals

Measurement awareness Figure 2. Elements for changing patient behavior. This figure illustrates the three elements that should be covered by adherence management: education, motivation and measurement. The tools to support these three elements are training, which supports education and motivation; goals, provided and assessed by measurement of adherence to support the patient’s motivation; and the medication package, providing measurement (electronic monitoring) and information for education.

standard psychological practice aimed at promoting adherence among chronically ill adolescents [31]. One could expect that EM alone, without feedback, can already improve adherence due to the patients’ knowing that they are being monitored. However, this view is contradicted by a recent trial showing that EM alone had no statistically significant increase in adherence when compared to standard packaging [32], supporting the importance of the feedback component. Adherence management: elements for changing patient behavior

It has to be noted that while EM feedback has been reported to have the strongest effect on adherence [25], most interventions also included education (to increase knowledge) and motivation (to increase self-efficacy). Thus, there appear to be three elements for changing patient behavior that should be covered by management of adherence: education, motivation and measurement. The tools to support these three elements are training, goals, and the medication package (FIGURE 2). Training can not only support education by improving the patient’s knowledge and teach him/her the importance of adhering to the prescribed dosing regimen, but can also help motivate the patient. Motivation can also be achieved by setting clear goals, and by improving patients’ self-efficacy, thus helping them to realize that they are capable of reaching these goals, while measurement is needed to see if the goals set for the patient are being achieved. Measurement of the patients’ adherence is also crucial for increasing their awareness, and can be achieved through measurements that aptly provide information on both the number of doses taken and the timing at which those doses are taken. Methods that purport to ‘measure adherence’ but which cannot supply information on both quantity and timing of doses are therefore inherently deficient. The medication package can provide adherence measurement through EM doi: 10.1586/17512433.2014.940896

while also supporting the patient’s education through leaflets or brochures provided with the package. Another factor to keep in mind is that different patients display various patterns of nonadherence, and will therefore require the feedback of different messages to improve their adherence. In FIGURE 3, electronically monitored dosing histories are shown for four patients, each of whom took 75% of their prescribed doses during a 3-month period, yet their dosing patterns differed considerably. The first three patients display suboptimal implementation: patient A mainly missed evening doses, patient B missed both evening and morning doses, and patient C displays a drug holiday (i.e., three or more consecutive days without a dose). The adherence of these patients, when dominated by suboptimal implementation, could be improved by making them aware of their adherence pattern during a discussion based on their personal dosing history data and by educating them on the importance of good medication adherence. In contrast, the fourth patient initially had a high level of implementation, but discontinued the treatment prematurely. For this last patient, it would be important to investigate the reasons for discontinuation (e.g., actual or feared side effects of the drug or economic problems) so that solutions to those problems can be discussed with the patient, preferably during the time that the patient’s motivation to continue the treatment persists so that discontinuation of dosing can be prevented. The power of habits

While nonadherence is pervasive across all areas of ambulatory therapeutics, there are some patients who adhere almost perfectly to their prescribed dosing regimens [33]. Two examples of patients showing excellent adherence to their prescribed twicedaily medication are shown in FIGURE 4. In FIGURE 4A, the patient has a perfect adherence pattern with little variability in time of drug intake, and exactly 12 hours between the morning and evening intake. In FIGURE 4B, another patient shows more variability in time of drug intake with a delayed intake of the morning dose during the weekends. These differences may or may not have therapeutic importance, depending on the forgiveness [34] of the drug(s) in question. Such patients as those illustrated in FIGURE 4 have at some point deliberately made the choice to adhere and then probably stopped thinking about it; yet, they still continue to take their medication every day. This change is prima facie evidence that these patients have built a habit. This idea is for example applied in the Medication Usage Skills for Effectiveness program, in which the patients are assisted to select cues that help them remember to take doses, such as a specific time, a meal or a dependable daily ritual [35]. The Medication Usage Skills for Effectiveness program has been used to enhance adherence with drug therapy for patients with severe, persistent mental illness; the rate of adherence was 82% in patients receiving the intervention versus 70% in the control group (p = 0.023) [36]. Most interventions intended to enhance patient adherence that are reported in the literature do not distinguish between the three elements of adherence, but short persistence accounts for the Expert Rev. Clin. Pharmacol.


C

24 h clock time

00

0

00

AM

AM

PM

PM

PM

PM

AM

AM

21/10/2002

17/6/2003

8/11/2002

5/7/2003

23/7/2003

26/11/2002

AM

AM

PM

PM

PM

PM

AM

AM

25/2/2000 Calender date in day/month/year

AM 00 8/2/2000 3:

00 6:

9:

00

0 :0 12

00 3:

00

6:

9:

00

0

:0

59

2: 12

D

20/12/1993

Calender date in day/month/year

AM 00 2/12/1993

3:

AM

AM

PM

PM

PM

PM

AM

AM

13/3/2000

7/1/1994

30/3/2000

25/1/1994

12/2/1994

16/4/2000

3/5/2000

2/3/1994

Patient 12902

Figure 3. Differences in adherence patterns. Electronically compiled drug dosing histories are shown for four patients, each of whom took 75% of their twice-daily prescribed doses during a 3-month period. The blue dots represent electronically captured dosing times and the vertical grey bars mark omitted doses. The first three patients display suboptimal implementation: (A) this patient mainly missed evening doses; (B) this patient missed both evening and morning doses; (C) this patient displays a drug holiday (i.e., three or more days without a dose). (D) This patient initially had a high level of adherence, but discontinued the treatment prematurely.


3/10/2002

30/5/2003

Patient 5044

3:

15/9/2002


12/5/2003

00

6:

9:

00

0

:0

12

00

3:

00

6:

9:

00

0

:0

59

2: 12

B

Treatment discontinuation

AM 00 28/8/2002

6:

00

9:

12

:0

3:

00

6:

00

9:

00

:0

0

59

3:

2:

AM

AM

PM

PM

PM

PM

AM

AM

AM 00 24/4/2003

6:

12

0

00

9:

12

:0

3:

00

6:

00

9:

00

:0

0

59

2:

12

N

24 h clock time

A

Patient 4834 24 h clock time

Patient 5631

24 h clock time



Review

doi: 10.1586/17512433.2014.940896

Review


24 h clock time 12 12 9: 6: 9: 3: 3: :0 :0 00 00 00 00 00 00 0 0 AM AM PM PM PM PM AM AM

3:

00

AM

6:

Patient 8005

4/5/2013

16/5/2013

28/5/2013

9/6/2013

21/6/2013

3/7/2013

25/9/1998

7/10/1998

19/10/1998

31/10/1998

Calendar date in day/month/year

24 h clock time 12 12 2: 9: 6: 9: 3: :0 :0 59 00 00 00 00 0 0 0 AM AM AM PM PM PM PM AM

B

1/9/1998

13/9/1998

3:

00

AM

6: 0

Patient 7971


A

Calendar date in day/month/year

Figure 4. Developing a habit of taking medication improves adherence. The dosing history data of patients who have developed a habit of taking their medications are shown. The blue dots represent electronically captured dosing times. (A) This patient displays a near-perfect adherence pattern. (B) Nevertheless, the pattern of this second patient, who has developed a habit of taking his morning dose upon awakening (as suggested by the later time of dosing during weekends), is probably sufficient for fully effective and safe action of the majority of pharmaceutical products.

doi: 10.1586/17512433.2014.940896

Expert Rev. Clin. Pharmacol.



biggest discrepancy between prescribed and actual drug intake [1,37]. Patients discontinue treatment for multiple reasons; most often this decision is often intentional. When the taking of a medication acquires automaticity, such as breathing, something one does without even thinking about it, then the emergence of a habit bypasses decision-making [38], and we can expect the likelihood of considering discontinuation of the treatment to be lowered. Therefore, building a habit may not only be useful for overcoming forgetfulness (nonintentional nonadherence) and for improving day-to-day dosing, but it may also lengthen persistence and thus overcome certain aspects of intentional nonadherence. In his book ‘The Power of Habit,’ Charles Duhigg defines a habit as a three-step loop comprising a cue, a routine and a reward (FIGURE 5) [38]. A cue is a trigger that tells the brain to go into an automated mode of habit execution and which habit to use. The cue immediately precedes an action and can be a specific location, time, emotional state, or person. However, the relevant cue may not always be obvious and its identification may require careful analysis of the process leading to medication-taking. One obvious clue to identify the cue is the fact that this cue was absent when the habit failed to trigger. A routine is typically physical and consists of the action of accessing the medication and taking it. A reward reinforces the routine. A reward can be financial, social (being able to participate in certain activities), emotional (feeling of pride), familial (seeing a child or grandchild grow up) or medical (longevity or improved quality of life). Strategies to support medication-taking habits

Some habits emerge outside of consciousness, but they can also be deliberately designed. To design or improve a patient’s habit of adhering to medications, the first step is making the patient aware of the habit by analyzing the habit loop (FIGURE 5), writing down plans and goals, finally measuring achievements and going back to analyzing the loop, if needed. This approach is parallel to other situations where habit formation is important, such as smoking cessation or weight loss. The theory of habit-building to improve medication adherence is supported by the success of the abovementioned feedback model and the usefulness of measuring and analyzing dosing histories; patients are often not aware of deviations in their dosing intake patterns, such as delaying or missing doses, which explains the effectiveness of making patients aware of their recent dosing history data. Electronic compilation of drug dosing history data is currently the only approach that allows one to reliably measure adherence to medications with enough detail to reveal the temporal sequences of transition through its three elements (initiation, implementation, discontinuation). These detailed data allow for a focused discussion between the healthcare provider and the patient to analyze the habit loop, identify specific problems, plan measurable objectives, measure achievements and build in sustainable rewards. This contact with the healthcare provider also allows reinforcement of the trust of the patient in the benefits of following the habit, improving his/her medication adherence and attaining an optimal outcome of the prescribed treatment. These discussions between the patient and the informahealthcare.com

Review

Routine

Cue

Reward

Figure 5. The habit loop. A habit has been defined by Charles Duhigg [38] as a three-step loop comprising a cue (immediately preceding the action), a routine (e.g., taking the medication) and a reward (reinforcing the routine).

healthcare provider provide support, feedback encouragement, and rewards to the patient for modifying his/her habit in a positive direction, comparable to the Weight Watchers weekly meetings for people seeking to lose weight. Because nonadherence is often due to a mix of intentional and nonintentional causes, periodic communication between the patient and the healthcare provider performs better in improving adherence than sole reliance on self-care through electronic devices such as electronic reminder devices, computer software or internet and mobile applications [39]. The frequency at which such contacts are needed is highly dependent on the medical situation and the network of the patient. Moreover, the interaction between the patient and the healthcare provider needs to be integrated in a more general behavioral approach such as managed problem-solving (in which the healthcare provider and the patient work together to solve specific adherence barriers) [27], motivational interviewing (designed to facilitate behavior change by resolving patient ambivalence about change) [40] or selfmanagement [41]. The various possibilities for patient–healthcare provider interactions, combined with the many possible combinations of interventions in the three elements of the habit loop, illustrate the need for individualization of supportive methods. Barriers to implementing EM systems in clinical practice

The EM-feedback approach has been proven effective in clinical trials [25], where adherence is directly relevant to measuring efficacy and safety and has been recommended by the US FDA draft guidance “Enrichment strategies for clinical trials to support approval of human drugs and biological products” [42]. In clinical trials, electronically compiled dosing histories enable a thorough characterization of adherence with clear distinctions between initiation, implementation and discontinuation of the test drugs [1]. The challenge will be to extend this monitoringfeedback approach from the controlled environment of clinical trials to that of clinical practice. Successful implementation of feedback on adherence in clinical practice will require interventions on multiple levels, involving healthcare providers, patients and their families, and the healthcare system, and may also require the development of new policies concerning access to patients’ dosing history data. While EM is the current gold standard to assess patient implementation of a dosing regimen over a defined period of time in clinical practice, the estimation of initiation and discontinuation of a treatment may depend on the use of EM within the healthcare system; not all patients necessarily doi: 10.1586/17512433.2014.940896


Review


need continuous monitoring for the entire treatment course. Depending on the then-prevailing comparative costs of the EM feedback and its implementation versus costs of nonadherence, and their associated clinical explanatory power, intermittent use of EM may be the optimal solution. Going toward a wider use of electronic adherence monitoring in medical practice, there is a need for better designed smart packages that fit patients’ needs and usability, for example, for patients with a high number of different medications. Smart packages also need to move toward maximizing feedback to the patient and the healthcare provider while reducing inconvenience compared with standard packaging. EM packages are continuously being further developed and refined to meet these challenges, as for instance illustrated by the recently developed Polymedication Electronic Monitoring System [23]. Moreover, further research will be needed to clarify the need for monitoring all medications, compared to the possibility to monitor only one or several of the patient’s drugs to gain insight into his/her overall adherence pattern. Additional tools & alternatives for EM packages

The continuous monitoring of all patients’ adherence during their entire treatment would require a large amount of resources, for instance, taking into account the time and effort needed to analyze the feedback patterns and provide regular feedback to the patient. However, it is likely that not all patients will need continuous monitoring for their entire treatment. Moreover, each person’s habits are driven by different cues, routines and rewards, further indicating the need for individualized treatment and intervention. It will therefore be important to present patients with a panel of tools, from which they can choose those best suited for their personal situation, and which can further support the patients’ adherence in between or after feedback sessions. One such tool is the calendared blister package, which has been shown to improve adherence [43–46]. Such calendared packages, as for example used for oral contraceptives, support adherence by revealing dose omissions to the patient. The calendared packaging can also help to prevent overdosing caused by accidentally repeating the habit, and to simplify the routine and increase the patient’s awareness of the habit loop. Confirmation that the prescribed dose has been taken can be especially useful when the patient has developed an unconscious habit of taking the medication; inability to recall whether or not the last dose was taken is an inherent property of a habit having been formed. Another way to support the patient’s adherence is to provide education and motivation to the patient, either directly on the package or by dispensing leaflets or brochures together with the medication. The provided information can further educate the patient on the importance of adherence, and can refer the patient to support programs, testimonials (strengthening the patient’s beliefs) or instructions to activate text message reminders (providing a cue to the medication-taking habit). In an internet era with availability of too much information, sometimes of questionable quality, the package is a unique communication tool to filter and doi: 10.1586/17512433.2014.940896

provide validated information to guide the patients. The development of adherence-prompting packaging is supported by the Healthcare Compliance Packaging Council, which also has a yearly “Compliance Packaging of the Year” competition. In a recent overview, the Healthcare Compliance Packaging Council provides a summary of studies showing improved patient adherence with calendared, adherence-prompting packaging [47]. Expert commentary

When the patient is responsible for drug administration, electronically monitored packages are widely accepted as the gold standard of reliable adherence measurements, providing useful, detailed information on the patients’ adherence patterns and their temporal sequences, which can be used as the basis for discussion between the patient and the healthcare provider. EM of drug dosing is generally well accepted by the patients when the EM system is well integrated into the medication package. In a questionnaire assessing patient perception and acceptance of MEMS, the patients held positive perceptions about their device; 75% liked the MEMS and used it every day [48]. Moreover, there are over 600 peer-reviewed publications describing the use of EM across many therapeutic areas and medical settings, illustrating the wide general acceptance of EM. When looking at the available literature, it is clear that EM is a useful tool to measure adherence, and that EM feedback can improve adherence. Now, the remaining challenge is how to implement these findings in clinical practice. It is interesting to note that there is a general need for more and better implementation research, not only concerning healthcare but also extending to various other fields [49]. An important remaining question is which patients need to be monitored, and when. To answer this question, one must recognize that the beginning is critical to the development of a habit of medication-taking and consequent good adherence to that medication. More effort and attention should be invested assuring good implementation during the first weeks after a new treatment is initiated. Electronically monitored packages could thus be particularly useful in the initial stages of treatment to ensure a good start with medication-taking, providing essential, detailed information on the patient’s individual dosing patterns; the feedback of the patient’s recent dosing history provides a logical starting point in recognizing inadequacies in adherence and the need for improvement. Feldman [33] suggests that adherence could be improved by a visit to the healthcare provider in the first few weeks after the initiation of treatment. The objectives of that visit are to check that the patient has initiated therapy and that there is no major barrier; the patient understands the dosing regimen and its proper implementation and there is no major adverse effect. A second time when adherence assessment may be critical occurs when a treatment fails. Burnier et al. [50] assessed patients who, based on clinical inference, were presumed to have drug-resistant hypertension, only to find that approximately half of them were not taking their drugs as prescribed. Marin et al. [51] showed that poor adherence is the Expert Rev. Clin. Pharmacol.



predominant reason for inability to obtain adequate molecular response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. There is thus strong evidence that many patients who consistently underdose or completely discontinue taking the drug without the care provider’s knowledge are usually misclassified as nonresponders. In this situation, reliable measurement of adherence can avoid treatment escalation, treatment switches, or irreversible surgical procedures, for example, renal denervation for so-called resistant hypertension. A third time where EM may be critical is with very high-cost medications, even if those are used relatively short term, such as the novel hepatitis C drugs or certain oral anticancer drugs. In taking the managed problem-solving approach, it could be useful not only to focus on existing adherence barriers but also try to anticipate and forestall possible interferences with the patient’s medication-taking habit. From personal observations, we have noted that patients with good long-term adherence not only had developed a medication-taking habit, but often also had a ‘back-up habit,’ such as routinely checking whether they had taken their evening dose when going to bed or waking up so that a missed dose could still be taken.

Review

Baseline Determine baseline adherence Implementation of the intervention or changes Description of the behavioral change techniques (BCT) Measure the 3 elements of adherence Analyze and monitor achievement Promote the most effective BCT components

Five-year view

The assessment of interventions to improve adherence in patients with chronic diseases should be continued over long periods of time. While head-to-head comparison of an intervention against a standard of care (SOC) in an RCT is considered to be the gold standard, such comparisons pose concerns and problems that can compromise the adoption of adherence management approaches in identifying the most effective adherence-enhancing interventions. • A double-blind design is difficult to implement, as it is obvious to both the healthcare provider and the patient that an intervention to improve adherence is performed instead of the SOC. • There is a large variability in SOC, making it difficult to compare healthcare providers or care sites [52]. • Cluster-randomized designs can be adopted to avoid contamination within a given center, but lack of interest is likely among healthcare providers who are randomized to the SOC. • The healthcare provider goes through a learning phase when adherence-improving interventions are introduced, which needs to be taken into account in the study design. While RCTs are well suited to study the effects of a drug, interventions for behavioral changes are much more complex: 93 components have been identified in behavioral interventions, which are also often combined [53]. With the traditional approach inspired from the drug development process, it would be too slow to test each possible combination and thus difficult to discern which component of the intervention (or which combination of components) is most effective for long-term effects. A traditional RCT approach will also not address the widely differing healthcare systems. Therefore, such a traditional approach would be ineffective to address the fast rising, serious and costly challenge of nonadherence to medications in the general population. informahealthcare.com

Adapt intervention in centers requiring it

Figure 6. Proposal for a new evidence-based approach to implement, evaluate, promote and scale-up adherence-enhancing interventions. A study design, adapted for the assessment of behavioral interventions to improve adherence, should begin with a baseline period, to determine a reference level of adherence for each study center. During the implementation phase, each healthcare center has the opportunity to explore various interventional methods, choose their preferred interventions and allow their healthcare providers to be familiarized with these interventions. The behavioral components of the interventions must be clearly described, using a consistent, coherent taxonomy. By measuring and analyzing the effects of the interventions, one can select the most promising ones and introduce them into the other participating centers, leading, one hopes, to improved adherence management across most, if not all participating centers.

In the coming years, it will therefore be critical to adopt a new type of study design in which the best performers are identified and their findings promoted to the other medical centers. A proposal for such an evidence-based approach is shown in FIGURE 6. All participating medical centers would first be enrolled in a baseline period with a limited number of control patients receiving well-described SOC. As such, a baseline level of adherence per study center can be determined to be used as a reference for later study stages and analysis. The baseline period is then followed by an implementation phase, in which the healthcare centers have the opportunity to explore the implementation of various intervention methods. Each center can then choose its preferred (combination of) interventions, based on available information and on what they see as best fit for their specific situation, as doi: 10.1586/17512433.2014.940896


Review


it is important that they have confidence in the effectiveness of the chosen intervention. During the implementation phase, the healthcare provider also has the opportunity to gain familiarity with the intervention and learn how the different components can best be applied. At this stage, it is important to describe precisely the behavioral components using a consistent taxonomy, as proposed by Michie et al. [53]. By using this taxonomy, the various interventions will be clearly described, which is important for replication of these interventions in other studies or in clinical practice. During the entire process, it will also be crucial to measure appropriately the three elements of medication adherence in terms of initiation, implementation and discontinuation. The continuous monitoring and analysis of reliable, longitudinal data will allow one to identify the most promising adherence-enhancing components of an intervention. Better-performing centers can, in principle, help poor-performing centers achieve better results. Such an approach is already commonplace in, for example, business fields, as illustrated by Charles DuHigg in his case studies addressing change in organizational habits [38]. Given the complexity of adherence intervention, the number of poorly designed, underpowered and too-short interventional, randomized studies is currently rising. This situation is economically not sustainable and is ethically unacceptable. The move toward large monitored organization-based and implementation-focused programs as described above should be encouraged and empowered as soon as possible by drug regulatory authorities. These programs could be supervised by governmental or other payer organizations that come to recognize the prevalence of nonadherence to otherwise effective

prescription drugs, and the magnitude of the costs incurred as a consequence of prevalent nonadherence. Various groups during at least the past 40 years have estimated the avoidable costs of healthcare based on prevailing distributions of adherent and variably nonadherent dosing. The credibility of these mostly top-down estimates has been limited, and the scope of trials and of epidemiological studies for bottom-up estimates have not yet reached a critical mass. With the recent growth in recognition of the ubiquity of nonadherence, we are probably approaching the point where bottom-up assessments of the economic costs of poor adherence will begin to attract serious attention from governmental agencies charged with the responsibility to pay for healthcare across large parts of their countries’ populations. At the moment, there is a degree of gridlock between insufficient hard evidence on costs and cost– effectiveness of adherence-enhancing interventions [54], funding for properly designed studies to provide such evidence and properly funded studies to quantify how much improvement is possible with presently available or soon-to-be-available new methods of measurement and management. Financial & competing interests disclosure

B Vrijens and J Urquhart are employees of MWV Healthcare. MEMS is a registered trademark of MeadWestvaco Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance provided by Joke Vandewalle and Melissa McNeely (XPE Pharma & Science) was utilized in the production of this manuscript.

Key issues • Medication adherence is crucial for safe and effective use of drugs. The vast majority of errors in adherence involve net underdosing, which has three origins: delayed or never-occurring initiation of dosing; intermittently missed doses during regimen implementation and short persistence. The relative importance of these varies with the therapeutic context. • The prevalent underdosing, created by nonadherence, leads to increased healthcare costs and can have important consequences for the patient, such as failed treatment, inappropriate escalation of drugs and their doses, emergence of drug-resistant infectious microorganisms, hazardous rebound or recurrent first-dose effects and misdiagnosis, and for the interpretation of the results of clinical trials, such as underestimation of efficacy, underestimation of the incidence of adverse effects, distorted pharmacoeconomic analyses and overestimation of dosing requirements. • Current reports on adherence management often lack a good description of the interventions that have been applied to maximize adherence, causing difficulties for replication of these interventions in other studies and in clinical practice. A clear and consistent taxonomy for both adherence and behavioral interventions needs to be adopted and implemented. • Electronic monitoring of drug dosing histories allows assessment of the three elements that comprise adherence: initiation, implementation and discontinuation; barriers related to each of these elements require different messages and interventions to overcome and thus improve adherence. • Feedback to patients about their adherence patterns is an important factor – perhaps the most important modifiable factor – influencing adherence. Thus, dosing histories can be a useful starting point for discussions between the patient and the healthcare provider. • Persistence with drugs intended for indefinitely long use appears to lengthen when the act of taking the medication is made into a habit. Habit formation seems to decrease the likelihood of early discontinuation. • Feedback to the patient of recent dosing history data can help the patient evaluate and improve the habit loop. • The need is urgent for novel system-based approaches to organize, evaluate, promote and scale-up evidence-based adherence-enhancing interventions.

doi: 10.1586/17512433.2014.940896



Papers of special note have been highlighted as: • of interest •• of considerable interest


1.

•

2.

3.

Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence. to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol 2012;52:275-301 Shows the overall importance of adherence for therapeutic success and for drug regimen optimization, along with the role of electronic monitoring in providing reliable measurements of drug exposure needed for achieving therapeutic success and drug regimen optimization. WHO. Adherence to long-term therapies: evidence for action. WHO; Geneva, Switzerland: 2003 Burnier M, Wuerzner G, Struijker-Boudier H, Urquhart J. Measuring, analyzing, and managing drug adherence in resistant hypertension. Hypertension 2013;62(2):218-25

4.

NEHI. Research brief: thinking outside the pillbox. New England Health Institute; Cambridge, UK: 2009

5.

Haynes RB, Montague P, Oliver T, et al. Interventions for helping patients to follow prescriptions for medications. Cochrane Database Syst Rev 2000(2):CD000011

6.

7.

Haynes RB, Ackloo E, Sahota N, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008(2):CD000011

Vrijens B, De Geest S, Hughes DA, et al. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012;73(5):691-705

•

Defines a European consensus on an optimal taxonomy for adherence.

9.

Cole S, Seale C, Griffiths C. The blue one takes a battering’ why do young adults with asthma overuse bronchodilator inhalers? A qualitative study. BMJ Open 2013;3:2

10.

11.

12.

Garber MC, Nau DP, Erickson SR, et al. The concordance of self-report with other measures of medication adherence: a summary of the literature. Med Care 2004;42(7):649-52

23.

Arnet I, Walter PN, Hersberger KE. Polymedication Electronic Monitoring System (POEMS) - a new technology for measuring adherence. Front Pharmacol 2013;4:26

13.

Carroll CL, Feldman SR, Camacho FT, et al. Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial: commonly used methods of measuring adherence to topical therapy overestimate actual use. J Am Acad Dermatol 2004;51(2):212-16

24.

Bruce JM, Hancock LM, Lynch SG. Objective adherence monitoring in multiple sclerosis: initial validation and association with self-report. Mult Scler 2010;16(1): 112-20

25.

Demonceau J, Ruppar T, Kristanto P, et al. Identification and assessment of adherence-enhancing interventions in studies assessing medication adherence through electronically compiled drug dosing histories: a systematic literature review and meta-analysis. Drugs 2013;73(6):545-62

••

A review of adherence-enhancing interventions showing the importance of prompt feedback of ambulatory patients’ electronically compiled dosing history data.

26.

Vrijens B, Belmans A, Matthys K, et al. Effect of intervention through a pharmaceutical care program on patient adherence with prescribed once-daily atorvastatin. Pharmacoepidemiol Drug Saf 2006;15(2):115-21

27.

Gross R, Bellamy SL, Chapman J, et al. Managed problem solving for antiretroviral therapy adherence: a randomized trial. JAMA Intern Med 2013;173(4):300-6

28.

Reich WA. Medication adherence feedback intervention predicts improved human immunodeficiency virus clinical markers. Int J Nurs Pract 2013;19(6):577-83

29.

Wu JR, Corley DJ, Lennie TA, Moser DK. Effect of a medication-taking behavior feedback theory-based intervention on outcomes in patients with heart failure. J Card Fail 2012;18(1):1-9

30.

Van Camp YP, Vrijens B, Abraham I, et al. Adherence to phosphate binders in hemodialysis patients: prevalence and determinants. J Nephrol 2014. In press

31.

Herzer M, Ramey C, Rohan J, Cortina S. Incorporating electronic monitoring feedback into clinical care: a novel and promising adherence promotion approach. Clin Child Psychol Psychiatry 2012;17(4): 505-18

32.

Sutton S, Kinmonth AL, Hardeman W, et al. Does Electronic Monitoring Influence Adherence to Medication? Randomized Controlled Trial of Measurement Reactivity. Ann Behav Med 2014. [Epub ahead of print]

14.

Stone AA, Shiffman S, Schwartz JE, et al. Patient non-compliance with paper diaries. BMJ 2002;324(7347):1193-4

15.

Arnsten JH, Demas PA, Farzadegan H, et al. Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis 2001; 33(8):1417-23

16.

17.

Kardas P, Lewek P, Matyjaszczyk M. Determinants of patient adherence: a review of systematic reviews. Front Pharmacol 2013;4:91 Gossec L, Tubach F, Dougados M, Ravaud P. Reporting of adherence to medication in recent randomized controlled trials of 6 chronic diseases: a systematic


Matsui D, Hermann C, Klein J, et al. Critical comparison of novel and existing methods of compliance assessment during a clinical trial of an oral iron chelator. J Clin Pharmacol 1994;34(9):944-9 Rudd P, Byyny RL, Zachary V, et al. The natural history of medication compliance in a drug trial: limitations of pill counts. Clin Pharmacol Ther 1989;46(2):169-76

18.

Pullar T, Kumar S, Tindall H, Feely M. Time to stop counting the tablets? Clin Pharmacol Ther 1989;46(2):163-8

19.

Halpern MT, Khan ZM, Schmier JK, et al. Recommendations for evaluating compliance and persistence with hypertension therapy using retrospective data. Hypertension 2006; 47(6):1039-48

Ahmed R, Aslani P. What is patient adherence? A terminology overview. Int J Clin Pharm 2014;36(1):4-7

8.

asthma control. PLoS One 2013;8(2): e55335

literature review. Am J Med Sci 2007; 334(4):248-54

References

Review

20.

Vrijens B, Tousset E, Rode R, et al. Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models. J Clin Pharmacol 2005;45(4):461-7

21.

Kuypers DR, Peeters PC, Sennesael JJ, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation 2013;95(2):333-40

22.

Van Sickle D, Magzamen S, Truelove S, Morrison T. Remote monitoring of inhaled bronchodilator use and weekly feedback about asthma management: an open-group, short-term pilot study of the impact on

doi: 10.1586/17512433.2014.940896


Review


33.

Feldman S. Overcoming the forgetfulness problem. PM360. 2013. Available from: www.pm360online.com/physician-povovercoming-the-forgetfulness-problem/

•

The first discussion on the role of habits in medication adherence.

34.

Osterberg LG, Urquhart J, Blaschke TF. Understanding forgiveness: minding and mining the gaps between pharmacokinetics and therapeutics. Clin Pharmacol Ther 2010;88(4):457-9

35.

Cramer JA. Enhancing patient compliance in the elderly. Role of packaging aids and monitoring. Drugs Aging 1998;12(1):7-15

36.

Cramer JA, Rosenheck R. Enhancing medication compliance for people with serious mental illness. J Nerv Ment Dis 1999;187(1):53-5

37.

Vrijens B, Vincze G, Kristanto P, et al. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 2008;336(7653):1114-17

38.

Duhigg C. Power of habit: why we do what we do in life and business. Random House Books; NY, USA: 2012

•

This book describes how habits are formed and how new habits can be developed.

39.

40.

41.

42.

counseling to enhance adherence among HIV-infected patients: a randomized controlled trial. Health Psychol 2010;29(4): 421-8

49.

El-Sadr WM, Philip NM, Justman J. Letting HIV transform academia–embracing implementation science. N Engl J Med 2014;370(18):1679-81

US FDA. Guidance for Industry. Enrichment strategies for clinical trials to support approval of human drugs and biological products. Available from: www. fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/ Guidances/UCM332181.pdf

50.

Burnier M, Schneider MP, Chiolero A, et al. Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions. J Hypertens 2001; 19(2):335-41

51.

Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28(14):2381-8

52.

de Bruin M, Viechtbauer W, Schaalma HP, et al. Standard care impact on effects of highly active antiretroviral therapy adherence interventions: a meta-analysis of randomized controlled trials. Arch Intern Med 2010; 170(3):240-50

53.

Michie S, Richardson M, Johnston M, et al. The behavior change technique taxonomy (v1) of 93 hierarchically clustered techniques: building an international consensus for the reporting of behavior change interventions. Ann Behav Med 2013;46(1):81-95

••

Presents the first version of a taxonomy for behavioral changes needed to achieve successful therapeutic outcomes.

54.

Oberje EJ, de Kinderen RJ, Evers SM, et al. Cost effectiveness of medication adherence-enhancing interventions: a systematic review of trial-based economic evaluations. Pharmacoeconomics 2013; 31(12):1155-68

43.

Mahtani KR, Heneghan CJ, Glasziou PP, Perera R. Reminder packaging for improving adherence to self-administered long-term medications. Cochrane Database Syst Rev 2011(9):CD005025

44.

Zedler BK, Kakad P, Colilla S, et al. Does packaging with a calendar feature improve adherence to self-administered medication for long-term use? A systematic review. Clin Ther 2011;33(1):62-73

45.

Zedler BK, Joyce A, Murrelle L, et al. A pharmacoepidemiologic analysis of the impact of calendar packaging on adherence to self-administered medications for long-term use. Clin Ther 2011;33(5): 581-97

46.

Dupclay L, Eaddy M, Jackson J, et al. Real-world impact of reminder packaging on antihypertensive treatment adherence and persistence. Patient Prefer Adherence 2012;6:499-507

Saberi P and Johnson MO. Technology-based self-care methods of improving antiretroviral adherence: a systematic review. PLoS One 2011;6(11): e27533

47.

Easthall C, Song F, Bhattacharya D. A meta-analysis of cognitive-based behaviour change techniques as interventions to improve medication adherence. BMJ Open 2013;3:8

HCPC. Improving medication adherence through packaging. Available from: www. hcpconline.org/member-news-document/ HCPC-White-Paper-Improving-MedicationAdherence-with-Packaging.pdf

48.

Schoenthaler A, Ogedegbe G. Patients’ perceptions of electronic monitoring devices affect medication adherence in hypertensive African Americans. Ann Pharmacother 2008;42(5):647-52

de Bruin M, Hospers HJ, van Breukelen GJ , et al. Electronic monitoring-based

doi: 10.1586/17512433.2014.940896
