When evaluating a patient with inadequately controlled asthma symptoms despite appropriate therapy, one of the questions that need to be asked is whether the patient is actually taking the medication as prescribed. The causes of medication nonadherence are complex, and multiple clinic visits to address the issue may be needed. In addition, medication adherence may change over time. The term ‘nonadherence’ to asthma therapy includes several related, but separate issues, such as nonadherence of the ‘provider’ to asthma treatment and education guidelines, nonadherence of the ‘patient’ to prescribed medication(s) and improper inhaler technique, which are all frequent problems in asthma care. Here, in this review, we will focus specifically on patient medication nonadherence and review the current literature related to this topic published in the past 1–2 years.
METHODS OF EVALUATING MEDICATION ADHERENCE
It is important to reliably detect medication nonadherence because undetected poor adherence results in poor asthma outcomes (see the section below). However, detecting poor adherence can be a challenge in clinical practice, as there is no standardized method for its evaluation. The ideal method should be cost-effective, feasible to perform in clinical practice and easily interpretable with the capability of producing a regular feedback to the provider in a timely fashion. A summary of methods for evaluation of medication adherence is shown in Table 1.
The most cost-effective method is patient self-report, but it is well known that the patients frequently overreport their degree of adherence [1,2]. A recent study [3▪▪] from an ancillary study within a large, multicentre, placebo-controlled, randomized clinical trial in children (aged 5–12 years) confirmed that there was a substantial difference in subjective and objective adherence reporting, even in a clinical trial setting in which only the participants who are adherent to the study medication(s) are invited to participate. The investigators compared participant self-report study medication use recorded in a diary as subjective measurement with number of doses remaining on the dose counter of a participant's turbuhaler as the objective measurement. Objective measurement suggested that in 75% of 140 children adherence was less than 80%, but self-report suggested this was only in 6%. Objective measured adherence over 4 years was significantly lower than self-reported adherence (60.8 vs. 93.6%, P < 0.0001). The study further confirmed the need for using objective measurements for assessing medication adherence.
Apart from direct observed therapy, which is expensive and not practical for routine outpatient therapy, there are several options available for objective measurement. These alternatives include dose counters, use of biomarkers, assessment of prescription refill record and electronic monitoring devices. A dose counter is a mechanism on the inhaler device that shows the number of puffs remaining on the device and is available on many of the inhaled corticosteroid (ICS) medications (Advair, Symbicort, Durela, Asthmanex, Flovent HFA, Flovent DPI, Pulmicort Flexhaler). Use of dose counters on inhaler devices, however, has limited use in monitoring adherence in the clinic because they do not record date and time of each use. It is possible that the information from the dose counter can be altered, intentionally or unintentionally, by the patient. In addition, these devices do not have the capability to store the data beyond one canister/diskus. As a result, this method requires frequent assessment by the provider.
There are several biomarkers that can be measured to assess adherence such as measurement of serum cortisol levels for the detection of adrenal suppression in patients who are taking oral corticosteroids  and measurement of urine cortisol: creatinine ratio in patients who are on high-dose inhaled corticosteroids . There are several disadvantages to this strategy, which requires additional testing and cost. In addition, these tests are not routinely obtained and these data are unlikely to be available for the majority of patients.
With the dissemination of electronic medical records and prescription, assessing prescription refill record has become more available and is used frequently as a method of adherence assessment objectively in many studies [6–8]. The advantage is that the assessment can be done by other ancillary staff (i.e. pharmacy staff) in a standardized fashion with the possibility of providing feedback to the provider regularly. The disadvantage is that this method only records that the prescription was picked up at the pharmacy, but it does not guarantee that the patient actually has taken the medication. A recent study  examined the prevalence of nonadherence in 182 difficult-to-treat asthma patients assessed by prescription renewal records and found that 35% of patients picked up at the pharmacy only 50% or fewer of the medications that were prescribed: 88% of them initially denied their nonadherence, but later admitted to poor adherence. With electronic prescription systems being introduced more frequently in current practice, this method of reviewing the patient's prescription refill record may be practical for the clinician to implement.
The method that has emerged most recently is electronic monitoring. This method uses devices that attach to the inhalers with the capability of recording the actuation of the medication. Disadvantages of the system are the cost and the logistics of managing the data. There are several devices available on the market (DOSER and SmartInhaler) and several others are available for research use. DOSER (Meditrack, Hudson, Massachusetts, USA) attaches on the top of a metered dose inhaler (MDI) and is automatically activated to record each inhalation taken. It is inexpensive and easy to use, but only stores daily usage information for 30 days and does not have the capability of generating a report for review. The SmartInhaler (Nexus 6, Aukland, New Zealand) uses more advanced technology with the capability of storing the time and place of each inhaler use. Data can be downloaded from the device and wireless technology even allows for adherence data to be transmitted and monitored remotely. It also has the capability of giving reminders to the patients when the medication is not taken. Recently, the device has expanded its use not only to MDIs but also to diskus and turbuhalers. SmartInhaler has been used to directly monitor adherence in several clinical trials [9–11], and its reminder system has also been tested as an intervention, which we will review in a later section. Another advance monitoring device, Spiroscout (Asthmapolis, Madison, Wisconsin, USA), which uses wireless technology to remotely monitor adherence, is currently only available for research use and the use is only limited to MDIs.
PREVALENCE OF MEDICATION NONADHERENCE
The current National Asthma Education and Prevention Program (NAEPP) guideline stresses the importance of assessing and enhancing adherence to asthma treatment . However, medication adherence rates in asthma patients have consistently been shown to be only 30–40% in practice in previous studies [13–15] and may only be as high as 70% even in a well monitored clinical trial setting , which may deteriorate as the trial goes on [3▪▪].
This poor level of patient adherence has also been recently confirmed in two large studies using pharmacy refill records. The medication possession ratio (MPR) (percentage of days that the medication was filled/follow-up period) is one of the most commonly used measurements to quantify adherence using administrative medical records , and this was used in both studies. A study  involving 18 456 children on Medicaid in Florida and Texas showed that average MPR was only 20% for ICS and 28% for leukotriene inhibitors. Similarly, in a study in 3172 children (aged 0–18 years) registered with a primary care practice database in the UK, 15–39% (rate depending on the controller medication) of the patients had an adequate level of MPR (80–120%) . These results further confirmed that low medication adherence still remains a frequent problem even with its enhanced recognition in recent years.
CONSEQUENCES OF MEDICATION NONADHERENCE
Poor adherence to asthma therapy is associated with poor asthma control , increase in asthma exacerbations and healthcare utilization  and increased healthcare costs . This relationship has been confirmed in recent studies in various populations; however, Williams et al.[22▪▪] quantified the proportion of severe asthma exacerbations attributable to ICS nonadherence in a unique way accounting for changing pattern of ICS use over time. They utilized the data from 298 asthma patients (mainly African-Americans) who participated in a multicentre trial studying the phenotypes and pharmacogenomics in asthma. ICS adherence was estimated from electronic prescription and fill information, and to account for a change in ICS use, a moving 6-month average of medication use for each day of the study follow up was calculated. Asthma exacerbation was defined as either need for oral corticosteroids or emergency room visits for asthma or asthma-related hospitalization. They also included adjustments for underlying asthma severity (measured by short-acting beta agonist use). They demonstrated that ICS use began to increase before the exacerbation event and continued after the event. After adjustment with asthma severity, adherence was associated with a reduction in exacerbation only in those with adherence greater than 75% of the prescribed dose [hazard ratio, 0.61; 95% confidence interval (CI) 0.41–0.90], but not in those with adherence less than 25%. They estimated that 24% of asthma exacerbations were attributable to ICS nonadherence. This result suggests that high levels of adherence (>75%) are required to prevent asthma exacerbations.
INTERVENTIONS FOR MEDICATION NONADHERENCE
The barriers that patients face in taking their medication are complex [23,24], so the interventions that were shown to be effective for one population have not consistently been shown to be effective when tested in other populations. The published interventions on improving adherence in asthma patients during the past 2 years can be grouped into three general categories: (1) patient education programmes, (2) programmes to improve communication between clinicians and patients, and (3) use of remote wireless technologies.
One of the patient education programmes was conducted by Apter et al.[25▪▪], who assessed the effect of an individualized problem-solving intervention compared with standard asthma education for 3 months (both consisted of five 30-min sessions) in urban adults with moderate-to-severe asthma. The problem-solving intervention consisted of steps to define specific barriers, proposing and weighing the solution, choosing the best solution and trying out and revising the solution. The problem-solving approach did not show any advantage over standard asthma education on asthma outcomes, suggesting the difficulty of identifying the most effective education programme in the target population.
Wilson et al. tested whether a shared decision-making process on decision of treatment regimen can improve adherence and outcomes in poorly controlled asthma. A total of 612 adult asthma patients with poorly controlled asthma enrolled in a health maintenance organization (Kaiser Permanente) were randomized to receive shared decision-making, clinician decision-making and usual care. In the shared decision-making group, nonphysician clinicians negotiated a treatment regimen with the patient that reflected patient goals and preferences, whereas in the clinician decision-making group, treatment was prescribed taking only patient's clinical condition into account. The third control group received usual care. Adherence was measured by continuous medication acquisition (CMA) index for each year, defined as total days of supply acquired in a given year divided by 365 days. Shared decision-making compared with clinician decision-making resulted in better controller adherence (CMA, 0.67 vs. 0.46, P < 0.0001) and better clinical outcomes (quality of life, asthma control, healthcare utilization and lung function) over a 1-year period. The trial was a well designed study with much attention paid to the control group and to the execution of the intervention, which added significant evidence of the benefit of a shared decision-making process on improving adherence on asthma patients.
Emerging interventions include simpler methods utilizing electronic monitoring and feedback system and text messaging targeting mainly the younger populations, given the wide use of remote technologies. Use of reminder systems with Smartinhaler [26,27▪] and MDIlog II (Westmed, Inc, Engelwood, Colorado, USA) [28▪] has been shown to be well accepted by the patients and has good potential to improve adherence in both the paediatric and adult population. Another electronic device with remote capability, Spiroscout (Asthmapolis, Madison, Wisconsin, USA), has recently obtained U.S. Food and Drug Administration (FDA) approval for clinical use, and several studies are underway to evaluate its efficacy. Use of web-based programmes [29,30] and text messaging [31,32] has been shown to improve adherence at least during the study period mostly in paediatric and young adult asthmatic patients, but its longer benefit on overall asthma outcome is yet to be determined.
As there are different reasons for nonadherence, it may be important to tailor the potential intervention to the underlying reason for patient nonadherence. For example, ‘deliberate’ or ‘intelligent’ nonadherence is associated with patient lack of agreement or motivation . In this case, motivational interviewing or shared decision-making interventions may be more likely to be successful. ‘Unintentional’ or ‘unwitting’ nonadherence occurs when a patient incorrectly interprets medication instructions, which then leads to nonadherence. In this case, enhanced asthma education may be the most appropriate intervention. ‘Forgetful’ or ‘erratic’ nonadherence is associated with patient intent to take the medication, but the inability to remember to use the medication. In this case, a reminder system may be more likely to be more successful. Further research in tailoring interventions to the specific reasons for nonadherence is needed.
Nonadherence to prescribed treatment continues to be a frequent problem in patients with asthma. The recognition of the nonadherence is the important first step for the clinician to deal with this challenging problem. Objective measurement of adherence should be implemented whenever possible. Review of pharmacy refill data could be implemented for clinicians with access to electronic prescription data systems. Educational programmes should be specifically designed to the unmet need of the target population. The efficacy of devices with the capability of remote electronic monitoring and a reminder system awaits larger and longer studies. There is an urgent need for clinicians to have access to organized, proven methods to assess, tailor and treat medication nonadherence in asthma patients.
Conflicts of interest
No conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 87–88).
1. Milgrom H, Bender B, Ackerson L, et al. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol 1996; 98:1051–1057.
2. Krishnan JA, Riekert KA, McCoy JV, et al. Corticosteroid use after hospital discharge among high-risk adults with asthma. Am J Respir Crit Care Med 2004; 170:1281–1285.
3▪▪. Krishnan JA, Bender BG, Wamboldt FS, et al. Adherence to inhaled corticosteroids: an ancillary study of the Childhood Asthma Management Program clinical trial. J Allergy Clin Immunol 2012; 129:112–118.
This study demonstrated a gap in subjective and objective measurements of adherence even in the clinical trial setting.
4. Robinson DS, Campbell DA, Durham SR, et al. Systematic assessment of difficult-to-treat asthma. Eur Respir J 2003; 22:478–483.
5. Aburuz S, Heaney LG, Millership J, et al. A cross-sectional study evaluating the relationship between cortisol suppression and asthma control in patients with difficult asthma. Br J Clin Pharmacol 2007; 63:110–115.
6. Herndon JB, Mattke S, Evans Cuellar A, et al. Anti-inflammatory medication adherence, healthcare utilization and expenditures among Medicaid and children's health insurance program enrollees with asthma. Pharmacoeconomics 2012; 30:397–412.
7. Wilson SR, Strub P, Buist AS, et al. Shared treatment decision making improves adherence and outcomes in poorly controlled asthma. Am J Respir Crit Care Med 2010; 181:566–577.
8. Gamble J, Stevenson M, McClean E, et al. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med 2009; 180:817–822.
9. Turton JA, Glasgow NJ, Brannan JD. Feasibility and acceptability of using bronchial hyperresponsiveness to manage asthma in primary care: a pilot study. Prim Care Respir J 2012; 21:28–34.
10. Perrin K, Williams M, Wijesinghe M, et al. Randomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting beta-agonist inhaler therapy in asthma. J Allergy Clin Immunol 2010; 126:505–510.
11. Klok T, Kaptein AA, Duiverman EJ, Brand PL. High inhaled corticosteroids adherence in childhood asthma: the role of medication beliefs. Eur Respir J 2012; 40:1149–1155.
12. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma–summary report 2007. J Allergy Clin Immunol 2007; 120:S94–S138.
13. Bozek A, Jarzab J. Adherence to asthma therapy in elderly patients. J Asthma 2010; 47:162–165.
14. Latry P, Pinet M, Labat A, et al. Adherence to anti-inflammatory treatment for asthma in clinical practice in France. Clin Ther 2008; 30:1058–1068.
15. Jones C, Santanello NC, Boccuzzi SJ, et al. Adherence to prescribed treatment for asthma: evidence from pharmacy benefits data. J Asthma 2003; 40:93–101.
16. Clerisme-Beaty EM, Bartlett SJ, Teague WG, et al. The Madison Avenue effect: how drug presentation style influences adherence and outcome in patients with asthma. J Allergy Clin Immunol 2011; 127:406–411.
17. Hess LM, Raebel MA, Conner DA, et al. Measurement of adherence in pharmacy administrative databases: a proposal for standard definitions and preferred measures. Ann Pharmacother 2006; 40:1280–1288.
18. Elkout H, Helms PJ, Simpson CR, et al. Adequate levels of adherence with controller medication is associated with increased use of rescue medication in asthmatic children. PLoS One 2012; 7:e39130.
19. Lasmar L, Camargos P, Champs NS, et al. Adherence rate to inhaled corticosteroids and their impact on asthma control. Allergy 2009; 64:784–789.
20. Williams LK, Pladevall M, Xi H, et al. Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma. J Allergy Clin Immunol 2004; 114:1288–1293.
21. Bender BG, Rand C. Medication nonadherence and asthma treatment cost. Curr Opin Allergy Clin Immunol 2004; 4:191–195.
22▪▪. Williams LK, Peterson EL, Wells K, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol 2011; 128:1185–1191.
This study demonstrated that a large propotion of asthma exacerbations are attributable to nonadherence of ICS.
23. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353:487–497.
24. Weinstein AG. The potential of asthma adherence management to enhance asthma guidelines. Ann Allergy Asthma Immunol 2011; 106:283–291.
25▪▪. Apter AJ, Wang X, Bogen DK, et al. Problem solving to improve adherence and asthma outcomes in urban adults with moderate or severe asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128:516–523.
This study demonstrated that the problem-solving approach did not show any advantage over standard asthma education on asthma outcomes, highlighting the difficulty on identifying the most effective education programme in the target population.
26. Charles T, Quinn D, Weatherall M, et al. An audiovisual reminder function improves adherence with inhaled corticosteroid therapy in asthma. J Allergy Clin Immunol 2007; 119:811–816.
27▪. Foster JM, Smith L, Usherwood T, et al. The reliability and patient acceptability of the SmartTrack device: a new electronic monitor and reminder device for metered dose inhalers. J Asthma 2012; 49:657–662.
This study described that electronic monitoring and reminder system by SmartTrack device is well accepcted by the asthmatic patients.
28▪. Spaulding SA, Devine KA, Duncan CL, et al. Electronic monitoring and feedback to improve adherence in pediatric asthma. J Pediatr Psychol 2012; 37:64–74.
This study described that electronic monitoring by MDI log improved adherence.
29. Christakis DA, Garrison MM, Lozano P, et al. Improving parental adherence with asthma treatment guidelines: a randomized controlled trial of an interactive website. Acad Pediatr 2012; 12:302–311.
30. Halterman JS, Fagnano M, Montes G, et al.
The school-based preventive asthma care trial: results of a pilot study. J Pediatr 2012. [Epub ahead of print]
31. Strandbygaard U, Thomsen SF, Backer V. A daily SMS reminder increases adherence to asthma treatment: a three-month follow-up study. Respir Med 2010; 104:166–171.
32. Petrie KJ, Perry K, Broadbent E, et al. A text message programme designed to modify patients’ illness and treatment beliefs improves self-reported adherence to asthma preventer medication. Br J Health Psychol 2012; 17:74–84.
33. Rand C. Stone AA, Turkkan JS, Bachrach CA, et al. I took the medicine like you told me, doctor: self-report of adherence with medical regimens. The science of self-report. Mahwah, NJ:Lawrence Erlbaum Associates; 1999. 257–276.