5.For at least the next several years, topical IOP-lowering medication will remain the mainstay for glaucoma treatment.

Comment: Despite limitations (inconvenience, dependence on the compliance of the patients and well-described adverse events in particular on the conjunctiva), topical anti-glaucomatous medication is (relatively) cheap, easily available, and generally safe, and it is reversible, should side effects arise.

6.A change in the preservatives of eye drops to a less toxic and more tis- sue-friendly formulation, and/or the development of preservative free drug delivery systems is needed to reduce the preservative related side-effects and tissue toxicity while delivering enough drug to control the intraocular pressure.

7.Non-IOP dependent therapy for glaucoma and also new drug delivery systems remain a high priority unmet medical need in glaucoma management.

Adherence/Perseverance/Dyscompliance

David Friedman, David Greenfield and Ivan Goldberg

Definitions

The literature on adherence to medical therapy has always suffered to some extent by an inconsistent use of terminology. What is meant by ‘compliance?’ What is the implication when this term is used as opposed to ‘adherence?’ These are not trivial questions since the nomenclature used influences how patients and doctors think about the issues involved and how they communicate with each other.

The most recent trend is to use the term adherence since this is less judgmental as it does not imply that the patient who fails to take medications is in some way failing to be a good person (as is implied with the term compliance). But what is adherence? Is it taking 100% of doses? Most clinicians would accept less than perfect drop taking as adherence, so when does a patient become ‘non-adherent’ or ‘poorly adherent.’ Unfortunately, there are no published studies documenting the level of adherence that are clinically important. We therefore rely on our clinical judgment about what is good enough to help keep our patients safe.

For the purposes of this discussion, we will define ‘adherence’ as the degree to which a patient follows the prescribed treatment instructions during a defined period of time. An alternative measure that has been used is ‘persistence.’ It is a measure of continuous use. Again, how do we know when a patient has run out of medication? In general the number of drops in a bottle are known, and therefore the number of days that a bottle can last can be calculated. However, some patients use more than one drop at each dosing, and this means that far fewer days are available in a bottle. Persistence is less frequently used as an indicator of overall drop taking behavior as many appear to stop for periods of time but still continue to use their medications. Another term used is the

‘medication possession ratio’ which is an indication of how much of the prescribed course of therapy was used. It is calculated by dividing the amount of medication the patient actually used by the total prescribed and is frequently applied to pharmacy claims data.

Strategies for determining adherence

Patient interviews

Several approaches have been used to identify patient adherence to treatment. One of the most common ones is to ask patients directly whether or not they take eyedrops as prescribed. Unfortunately, patients frequently overestimate their level of adherence. In one study, patients administered a mean of 76% of the prescribed pilocarpine doses, as recorded by an electronic eye drop monitoring device. However, when these patients were interviewed they reported administration of a mean of 97% of the prescribed doses.1 The authors also noted that ophthalmologists do a poor job of detecting which patients are poorly adherent. Similar discrepancy was also noted in a recent study using an electronic monitor in patients who knew they were being monitored:2 the mean adherence rate was 71% based on the monitoring device, compared to 95% according to patients self-report. Others also reported higher rates on non-adherence to timolol therapy using data on dispensed eye drops compared to data from questionnaires (51% and 24%, respectively).3 Researchers in other fields have also reported that electronic monitor data and patient self-report are poorly correlated.4 These findings call into question studies that rely on interviews with patients to determine which ones are adherent and which are not. That said, a recent study found that admitting to any missed doses in the last week was associated with lower refill rates and lower adherence when monitored electronically.6

Pharmacy claims data

Pharmacy claims data have limitations,7 especially when considering the use of eyedrops which do not come in fixed quantities as is the case with pills. Some patients are using medications in one eye, and may deliver more than one drop when putting drops in the eyes, and others may hoard medications or may rely on samples. Estimates based on pharmacy claims are likely only an approximation. However, pharmacy claims data are a reasonable estimate of drop taking behavior and should on average be able to separate those taking most of their drops from those taking far less.

Several studies using pharmacy claims data have reported on glaucoma therapy and in general report that about 70% of doses are taken.7,10-12 The first study of this type assessed Medicaid recipients in New Jersey, who were given free medications and reported that 23% had not refilled a prescription over a 12-month period.11 The same author reported that 25% of this population failed to fill 80% or more of their prescriptions over time. Others reported lower rates of

medication possession,10,12 at any given point in time, with rates being around 50%. Using the medication possession ratio, one group reported that about 65% of doses were available.7 These data and the large number of studies published on hypertension and lipid lowering therapies using pharmacy claims data indicate that a large proportion of doses are not taken.13

Electronic monitoring

Electronic monitoring allows researchers to know exactly how many doses are administered by the patient, although it does not confirm that the drops actually went into the eye. The use of monitoring devices to assess adherence was initially reported in the 1980s in studying adherence to pilocarpine treatment,14,15 and later in studies with timolol.1 More recently others have evaluated adherence to treatment with prostaglandin analogs using electronic monitors.2 In regard to pilocarpine, 41% of the patients omitted at least 10% of the prescribed doses, and 20% omitted at least 20% of the prescribed doses.14 Others reported that 34% of patients on pilocarpine omitted at least 25% of the prescribed doses, and 15% omitted at least 50% of the prescribed doses.15 Adherence to treatment by nonadherent patients tended to increase just before the return visit in this study and a more recent publication.2

Electronic monitoring studies of adherence to prostaglandin analogs have had variable findings. One study using a MemsCap device reported that 97% of doses were taken when patients were on monotherapy and this decreased to 86% when a second medication was required.5 In contrast, others using the Travatan Dosing Aid, reported that 44% of the patients used their eye drops less than 75% of the time. The overall mean adherence rate was 71%.2

Electronic monitoring remains a gold standard approach to monitoring adherence, but few methods exist for monitoring eye drops with this technology. Subjects being monitored are also frequently aware of this fact and this may influence drop taking behavior and this may bias the findings.

Prevalence and risk factors for less-than-ideal adherence

The title of this section is intentionally wordy and poorly stated, because we have almost no clear way to define what is ‘poor adherence.’ As noted above, several methods have been used to evaluate patients’ adherence to therapy: questionnaires, interviews, the use of health insurance claims data or health plan database, and the use of electronic dose-monitoring device. Regardless of the method used, all adherence studies show that many patients do not take their medications as prescribed. The prevalence of non-adherence varies considerably among studies, and ranges between 23-85% in the larger-scale studies. Electronic monitoring studies in glaucoma and most other chronic asymptomatic diseases find that on average patients take about 70% of prescribed doses.

There is a large literature in chronic disease on risk factors for low adherence. In addition, several reports in the last decade have looked at this specific ques-

tion. Unfortunately, many of those relied on self reported adherence and these studies suffer from two major design issues. First, those who admit to failing to take medications as prescribed may be different from those who do not take medications but refuse to admit they do not take them. What makes one person more willing to be honest with the interviewer than the other? This difference, and not the risk of not taking drops, may be what is being assessed in these interview-based studies. Second, the group identified as ‘adherent’ in these studies likely includes many who are not taking the medications as prescribed. This will tend to reduce the power that these studies have to detect real differences.

A major review summarized known associations with poor adherence in all chronic diseases and found depression and cognitive impairment were strongly associated.16 Adherence was worse with asymptomatic diseases and barriers to obtaining medications, complex treatments, high cost of medications, and a poor doctor-patient relationship were all found to be risk factors. Several of these have been found to be associated with lower adherence rates in glaucoma. A model for thinking about the issues that might influence adherence to therapy includes patient factors, medication factors, provider factors and environmental factors. Patient factors that have been associated with lower adherence include patient concern about glaucoma and those who are younger or older and African Americans.6 Medication factors include the cost of medications, depression, the complexity of the regimen, and side effects. Provider factors include communication and poor understanding of the consequences of glaucoma. Environmental factors include travel away from home and not having somebody to help with eye drops. Additionally, several studies have found that those who report missing drops are more likely to have poorer adherence.

Several previous reports have found that patients frequently fail to instill a drop in the eye when attempting to do so, and a recent report evaluated videotapes of patients experienced in using topical glaucoma drops and found that the majority touched the bottle to the eye, and the average number of drops administered at each dosing was 1.8, with nearly a quarter of the subjects squeezing a stream of medication on the eye.8 Furthermore, about 20% of patients completely failed to administer a drop to the eye.

References

1.Kass MA, Gordon M, Morley RE Jr, et al. Compliance with timolol treatment. Am J Ophthalmol 1987; 103: 188-193.

2.Okeke CN, Quigley HA, Jampel HD, Plyler RJ, Ying GS, Friedman DS. Adherence with Topical Glaucoma Medication Monitored Electronically: the Travatan Dosing Aid (TDA) Study. Ophthalmology 2009; 116: 191-199. Epub 2008 Dec 12.

3.Rotchford AP, Murphy KM. Compliance with timolol treatment in glaucoma. Eye 1998;

12:234-236.

4.Garber MC, Nau DP, Erickson SR, Aikens JE, Lawrence JB. The concordance of self-report with other measures of medication adherence: a summary of the literature. Med Care 2004;

42:649-652.