Compliance – The Hidden Challenge of Glaucoma Management

Determining medication compliance in glaucoma patients is a significant problem faced by ophthalmologists. Non-compliance can be an important cause of visual loss in patients with glaucoma. EuroTimes talked to five leading glaucoma specialists about the prevalence of non-compliance among their patients, the effect of non-compliance on the progression of the disease and strategies for increasing the level of patient compliance.

Do you think clinicians are truly aware of the real level of compliance among their glaucoma patients? If not, what accounts for this discrepancy?

William Stewart
I do not think clinicians are truly aware of the real level of compliance among their patients. In a recent survey, sponsored by the International Glaucoma Association (IGA) and Pharmacia, one of the questions asked of both physicians and patients related to the level of non-compliance (internal data, Pharmacia). They indicated that in the prior month, non-compliance had occurred in between 20% and 30% of individuals. Kass has previously shown, using a microchip counter inside a medicine bottle, that in reality patients are non-compliant much more than the level indicated in the IGA survey. Even if a physician does ask a patient they generally indicate that they are taking the medication. Compliance needs to be dealt with on an individual basis and treatment depends on the specific patient’s lifestyle and psychological profile.

Renato De Natale
I believe clinicians are not aware of the real level of compliance of their patients. Patients tend to hide or to underestimate their mistakes in following the prescribed therapeutic regimen. It may be very hard for the clinician to detect patients who comply poorly.

Tasos Konstas
Sadly, the magnitude of the problem of non-compliance often eludes clinicians. It has been shown that clinicians cannot predict accurately the behaviour of the average glaucoma patient and therefore are often unable to distinguish between the compliant and non-compliant glaucoma patient. The problem may be compounded when the ophthalmologist mistakes non-compliance as ineffectiveness of a given glaucoma medication and prescribes more potent medications.

Peter Phelan
I think a lot of younger clinicians who are not actively involved in research do not necessarily know or appreciate the level of non-compliance among their own patients. The most obvious and simple question is sometimes never asked " Are you using your drops exactly as instructed, all the time?"

Norbert Pfeiffer
I am sure clinicians are very much unaware of the level of compliance among their glaucoma patients. The problems are obvious. If we ask the patient whether he does so, we already imply that he does not. Therefore we often just do not ask. But if we do, most patients won’t tell us the truth, or, more correctly, will tell us what they believe to be the truth.

How prevalent do you feel non-compliance is among glaucoma patients?

William Stewart
Completely accurate numbers for compliance are very difficult to obtain. There are three types of non-compliance and prevalence rates might differ among these populations:
a) Missed medications
b) Inadequate spacing between medications
c) Inadequate instillation of the drops

Renato De Natale
Prevalence of non-compliance may vary very much according to the different type of patient - i.e. age, general health conditions, level of education, economic conditions, knowledge and awareness of the disease, motivation and confidence in their own doctor.The complexity of the therapeutic regimen - type of drugs, number of administrations - plays an important role in determining poor compliance. There are simply too many factors to make the job straightforward. This is probably the reason we find varying evaluations in the literature.

Tasos Konstas
The available literature (which is by no means sufficient) suggests that between 28% and 58% of glaucoma patients do not use their medications as prescribed. However, even this figure may be a conservative estimate because the true extent of non-compliance remains unknown in many ethnic cohorts and our compliance data may be partially flawed. The latter point was illustrated in a study by Novack who found that the participation of glaucoma patients in a study investigating compliance may improve their compliance by up to 30%.

Peter Phelan
This is a very difficult question to answer because it depends on so many different factors. The education the patient has received from the doctor/clinic about glaucoma is extremely important. Without due emphasis and education non-compliance is probably 30% to 40%.

Norbert Pfeiffer
There are but a few studies about compliance in glaucoma patients. All studies suggest that compliance among glaucoma patients is rather poor. Moreover, even those patients selected for such studies will probably be more compliant than others.

How significant a factor is non-compliance in the treatment of the disease?

William Stewart
The effect of non-compliance on the long-term outcome of ocular hypertension or glaucoma progression is not known. Considering the prevalence of non-compliance, the impact is probably clinically important

Renato De Natale
Very significant. Non-compliance is a frequent cause of apparently non-responding therapy. It may induce inaccurate clinical evaluations and therefore result in heavy consequences for both patient and physician.

Tasos Konstas
In my mind very significant indeed! Over the last few years we have been privileged to have at our disposal numerous new efficacious anti-glaucoma medications. However, all these innovative drugs will not impact the long-term prognosis of our patients if they are not used properly!

Peter Phelan
If non-compliance is not recognised it will lead to unnecessary operations with some associated morbidity. It is a very important factor which must be emphasised to all carers and patients so they understand its importance.

Norbert Pfeiffer
There are different kinds of non-compliance. Some patients just forget the occasional drop, while others never take any drops at all. A third group starts applying their drops faithfully but forgets it more and more often and before seeing the doctor again, re-commences with excessive treatment. Obviously, these forms of non-compliance affect the treatment in different ways in connection with different medications.

What is the impact of non-compliance on the efficacy of glaucoma treatments and the long-term health of patients?

William Stewart
The impact of non-compliance on long-term glaucoma is not precisely known. Washout times differ for each treatment medication, which generally fall into two groups:
Group 1 medications have longer washout times including the prostaglandin analogue medications and timolol maleate. Consequently, if the patient forgets their medication, then the effect goes beyond 24 hours.
Group 2 medications have less effect after 24 hours and must be dosed multiple times during the day to maintain efficacy. These medications include topical anhydrase inhibitors, alpha-agonists, beta-blockers and pilocarpine. Consequently, if a patient forgets the medication the pressure is more likely to return towards baseline levels within the 24-hour period.

Renato De Natale
Non-compliance, if undetected, forces the ophthalmologist to frequently change therapy in an attempt to find the best possible treatment. For the physicians this causes a waste of time and energy due to many wrong conclusions concerning the apparent non-effectiveness of different prescribed therapies in the short-term. For the patient, non-compliance may cause a loss of confidence in the specialist who is switching from drug to drug without appreciable clinical results.

Tasos Konstas
To date, this topic has not been addressed by controlled studies. Interestingly, in our Greek compliance study we did document, for the first time to the best of my knowledge, that non-compliant patients exhibited higher mean treated IOP and worse mean visual field loss compared with compliant patients.

Peter Phelan
If glaucoma medication is not used as directed it will cause a lot of problems. If the compliance is variable and the patient only uses the drops for a few days before he visits the surgery then the glaucoma will suffer between visits but every time the patient is seen, the IOP is well controlled. The doctor will be thinking of atypical normal tension glaucoma. If the patient doesn’t use the drops at all, the doctor will be trying more and more medication with seemingly no effect. Surgery may be the next unnecessary option. However if the patient isn’t using the drops perhaps surgery is a necessary option.

Norbert Pfeiffer
All recent studies have shown that the lowering of IOP is effective in preventing the advancement of glaucoma. This is true for early glaucoma, advanced glaucoma and also for normal tension glaucoma. Thus, it is reasonable to assume that non-compliance will influence the outcome of the disease negatively.

Is it possible to predict which patients are more or less likely to be compliant?

William Stewart
It is very difficult to predict which patients are more likely to be non-compliant. Rarely do patients admit to non-compliance. Kass has shown that physician assessments of compliance including weighing the bottles, checking pupillary diameter, physician and patient personal assessment, as well as patient log of medication usage were only mildly statistically associated with predicting non-compliance.

Renato De Natale
It is usually possible to tell those who are unlikely to fully comply:
•Those who are not aware of glaucoma because the eye specialist has not dedicated enough time to make clear the severity of the disease and the role of its treatment.
• Those who are too old to follow a complicated anti-glaucoma regimen.
• Those who are obliged to follow therapies for general diseases and glaucoma at the same time.
• Those who can’t afford to pay for their anti-glaucoma therapy.

Tasos Konstas
In our compliance study males and those using eyedrops more than four times a day were more likely to default. Previous research also suggests that non-compliance may be more common in patients receiving many medications and beyond a certain point there is a correlation between the rate of non-compliance and the frequency of administration of anti-glaucoma medications. Keeping glaucoma regimens as simple as possible, using once-a-day regimens and longer acting anti-glaucoma eye drops may diminish the rate of non-compliance in the future.

Peter Phelan
I don’t think one can always tell. People who are well motivated and want to know more about their disease rarely fail to comply. Elderly confused patients will fail unless help is sought from a carer. Patients who seem vague and don’t want to understand glaucoma and don’t want any further information are, I feel, high risk non-compliant patients.

Norbert Pfeiffer
It is fair to assume that those patients who understand the nature of the disease and who have trust in the recommendations of their doctor are more likely to be compliant.

What are the primary reasons for patients’ non-compliance with their glaucoma treatments?

William Stewart
Four general categories influencing non-compliance have been shown in the literature.
First, glaucoma as a disease encourages non-compliance. Blackwell indicated that chronic diseases, without pain, which require suppressive therapy, are associated with non-compliance. This definition fits glaucoma very well
Second, the medicine may influence compliance. With four times a day dosing, Kass showed that 55% of patients missed at least 10% of the doses.
Third, the patient may influence non-compliance because of mental errors. Lehto indicated that forgetfulness was the main problem. However, a patient’s psychological profile may also influence compliance.
Fourth, physicians may influence compliance. Blackwell has stated that the physician first must be aware that compliance is a problem. The physician may then promote compliance by demonstrating a positive attitude towards the treatment as well as a good personal relationship and communication with the patient and family.

Renato De Natale
In order of importance I would say:
•Complexity of glaucoma regimen - too many drugs with too many administrations.
•Lack of education on consequences of non-compliance.
•Physical barriers (difficulty instilling the drop(s) in the eye properly, difficulty opening and/or squeezing the bottle.
•Psychological barriers (complacency, polypharmacy, general unwillingness to take chronic medications).
•Cost.

Tasos Konstas
In our patients the most common reason quoted for non-compliance is the perceived lack of visual symptoms with glaucoma. Thus, in our cohort non-compliance was generally associated with lack of insight into the nature of glaucoma. Riffenburgh has emphasised that glaucoma is the most important area where the patient’s viewpoint can alter the clinical outcome. Poor understanding of the disease and its treatment may lead to a higher degree of non-compliance.
It is also clear, I think, that a significant proportion of our patients unintentionally default from the prescribed treatment. Unintentional non-compliance is an unexpected but clinically significant problem in many patients. Increased vigilance is required to identify patients who cannot instil their drops properly. It is probably a worthwhile step for all ophthalmologists to ask their patients to demonstrate how they instil their eye drops and if necessary to emphasise proper application techniques, including nasolacrimal occlusion.

Peter Phelan
People on multiple dosages such as four times a day are more likely not to comply. "Let somebody else help me. I am too old. Leave me alone." This type of patient will not comply unless forced to.

Norbert Pfeiffer
In Germany, cost is the only factor that probably does not lead to non-compliance. Almost everybody is insured and will receive glaucoma medication at no personal cost but a very minor basic fee which is the same for all medications. German patients tend to be rather disciplined but also very critical with medical care and medications. Generally, there is the feeling that the less medication you take the better.

Can you comment on the impact of non-compliance on ‘real-world’ effectiveness - that is the impact of IOP fluctuations on the progression of the disease?

William Stewart
This cannot yet be determined accurately. Stewart has demonstrated a long-term effect of non-compliance on vision. Further, these patients had greater fluctuations of pressure. Ziemer and O’Brien have shown greater fluctuations of pressure in progressed glaucomatous eyes.

Renato De Natale
Generally speaking, non-compliance represents a potential great cause of blindness. The IOP fluctuations surely lead to a progression of the disease. In developed countries poor compliance may result in a waste of human and economic resources. In countries with poor health care, blindness is the immediate consequence of non-compliance to glaucoma therapy.

Tasos Konstas
It is not unusual to encounter in the ‘real world’ of glaucoma management reduced or varied efficacy of many medications, compared to the previously reported level of efficacy in regulatory studies which are performed in more ‘sterile’ clinical environments. This discrepancy is, by and large, due to non-compliance. Naturally, the impact of non-compliance will vary greatly depending on the daily dosing of a given drug and will be far greater with short-acting drugs.

Peter Phelan
I feel the AGIS study has shown that if the IOP is kept below 16 mm Hg and maintained at a low level at every visit the loss of visual field is halted. This would emphasise, I feel, the importance of compliance as a major factor in the prevention of visual loss..

Norbert Pfeiffer
There are some studies which indicate that high fluctuations in IOP are more dangerous to the optic nerve than the uniformly high pressure. That would mean that the "area under the curve" is less important than the smoothness of the curve.

Both frequency of administration and the number of different drops have been shown to influence compliance. Can you comment on the impact a once-a-day, single-drop combination product such as Xalacom could have on patient compliance?

William Stewart
Although, Kass and Granström have demonstrated the improvement of compliance by reducing dosing from four to twice-a-day therapy, to my knowledge no study indicates a further advantage to once-a-day therapy. This is despite the concept of once-a-day therapy shown by the recent IGA survey performed in Europe being very popular with both physicians and patients. Physicians especially believed that once-a-day therapy would increase compliance. The survey indicated once-a-day therapies are popular with patients because of the increased convenience. Further, once-a-day dosing eliminates one type of non-compliance, the inadequate spacing between medications. In addition, with Xalacom specifically, which contains medications with the longest washout times, the effect of mistimed dosages may also be reduced because of the prolonged effect of these medications.

Renato De Natale
A therapeutic regimen of a once-a-day, single-drop product like Xalacom surely decreases dramatically the possibility of patient non-compliance. Two different drugs combined in one preparation ensures better therapeutic effectiveness and compliance.

Tasos Konstas
One may expect better compliance from the use of a fixed combination like Xalacom with the use of a once-a day regime instead of two separate medications and three drops a day. Clearly most of our patients would have preferred, if asked, a once-a-day dosing regime and the use of a single medication (indeed, patients would have also preferred a once-a-week or once-a-month medication, if available). To my mind, in the future we need a carefully conducted compliance study which will compare the rate of compliance with a once-a-day regime versus a twice-a-day regime.

Peter Phelan
Xalacom as a single-dose once-a-day drop should obviously improve patient compliance. If the patient only has to remember once a day, rather than twice or four times a day, then statistically the chances of missing a dose are halved or quartered. I know in my practice that a once-a-day dosage has, anecdotally at any rate, improved compliance. Lots of patients volunteer to tell me now that they don’t forget to put in their drops like they used to when they were more frequent.

Norbert Pfeiffer
I very much see the advantage of a once daily dosing regime in the context of the underlying pharmacological basis that a drug which is enough once a day has a minimal duration of action of 24 hours. A beta blocker such as Timolol and a prostaglandine such as Latanoprost have a much longer duration of action. Thus, even a mild non-compliance, the occasional "forgotten drop", will not change the level of IOP very much. Therefore a medication "once a day" is advantageous.

Do you think Xalacom is particularly useful for any specific patient type such as young vs old and so on?

William Stewart
Theoretically, Xalacom could improve compliance particularly in several types of patients:
• Patients with polypharmacy who are more apt to mix up or lose medication bottles.
• Older patients who are more likely to forget how frequently they are supposed to administer drops.
• Business people who are less likely to take medications during the daytime.
• Patients who have no other diseases and easily forget to dose.

Renato De Natale
It is no matter of age. Any patient, whatever his age, sex, educational, economical or social level wants a simple but effective treatment for his disease, whatever it is.

Tasos Konstas
From my personal experience Xalacom is particularly useful with younger, busy patients with active lifestyles, who greatly appreciate the opportunity to use a once-a-day fixed combination.

Peter Phelan
I feel Xalacom is ideal for the younger patient with high IOP and no contraindication to beta blockers.

Norbert Pfeiffer
For the reasons mentioned above, a once-daily drug would be beneficial in almost all patients.

Xalacom is considered the most powerful single-drop glaucoma agent on the market today. Where does/will this medication fit into your practice?

William Stewart
Unfortunately, we do not have Xalacom in the US. If I had it, I would use it as a second line therapy following Xalatan, which I most often use as first line therapy. Xalacom is a practical next step.

Renato De Natale
I am actually prescribing Xalacom to:
•Patients under treatment with Latanoprost alone who did not reach their target IOP.
•Patients who already received Timolol and Latanoprost separately.
• Patients under multi-drops regimen with different drugs.

Tasos Konstas
It is ideal for those patients with relatively high pressures (like patients with exfoliation glaucoma), or those with advanced damage who often require a 30% to 40% IOP reduction to arrest visual field progression. In these patients Xalacom may be an excellent first line indication.
In other patients where target pressure reduction is between 20% and 30% it may be a good indication for early adjunctive therapy after the use of either Xalatan or Timolol as monotherapy. If non-compliance is suspected Xalacom may offer a good clinical tool to evaluate whether compliance can be improved with less frequent dosing.

Peter Phelan
I use Xalacom in patients who are already on Xalatan and the IOP is still not quite as low as I want but has shown a good response to Xalatan, as long as there are no beta blocker contraindications. I also use it first line in patients who present with POAG and IOPs in the high 30s. I would also consider changing patients who are on beta blocker with good effect but not quite good enough IOP.

Norbert Pfeiffer
I would start any patient on a single medication, even if presenting IOPs are very high. However, if IOP-lowering is not sufficient on one drug and switching to another would not improve the situation, I use combination therapy. Two medications in one drop is advantageous when compared with treatments consisting of several drops. Therefore, a powerful combination therapy such as Xalacom will be an important drug in the armamentarium of glaucoma therapy.