Noncompliance with drug therapy of glaucoma : a review about intervening factors

Glaucoma is defined as an optic neuropathy, characterized for loss of visual field and injury of the optic nerve, being considered as the second cause of blindness in the world, which could be prevented by the use of antiglaucoma eyedrops. The lack of adhesion of the patient to the drug treatment can culminate with loss of the vision. The objective was to revise possible literature data regarding intervening factors for noncompliance and explain estimated rates of noncompliance. A systematic review about the subject was carried out in the period of January to June of 2006. Articles had been searched in two data bases, in the National Library of Medicine (PUBMED) and in the Literature Latin American and Caribbean Health Sciences (LILACS) using the following keywords: glaucoma, compliance of the patient, noncompliance of the patient, treatment and eyedrops. In PUBMED, 199 articles were collected, written in English and French languages. No article was found in LILACS. Considering the inclusion and exclusion criteria, 27 articles were selected, with 25 originals and two reviews. Twelve possible intervening factors for noncompliance were raised, as well as estimates for rates of noncompliance. The noncompliance rates varied from 4.6% up to 59%. Two factors, forgetfulness and inadequate between-doses interval, had been associated to noncompliance of the drug therapy. The factors race, adverse effects, treatment cost, number of instilled doses, coexisting illnesses and number of eyedrops used, had resulted contradictory, being impossible to affirm that they have contributed for noncompliance. Age, sex, educational level and loss of visual field, had not been associated with noncompliance. The glaucoma patients tended to disregard the drug treatment. The wide variation in noncompliance rates could be an influence from the authors’ difficulty to define the noncompliance and the variety of methodologies used to estimate it. More studies are necessary for a better evaluation of these 12 raised factors.


INTRODUCTION
The glaucoma is defined, currently, as an optic neuropathy, characterized for loss of visual field and injury of the optic nerve (Rait, 2000), being the increase of the intra-ocular pressure (IOP) considered as a risk factor (Quigley, 1996).According to World Health Organization (WHO), glaucoma is the second worldwide cause of blindness (Kingman, 2004), with about 5.2 million blind people (Wilensky, 1996).
The blindness caused for this disease is irreversible (Coleman, 1999), being possible to prevent it through drug treatment with the use of eyedrops or surgical intervention.Normally, the first line of treatment is the drug therapy (Tsai et al., 2003).
The success of the therapeutic drug depends strictly on the patient's compliance, that is, on the correspondence of patient's behavior when using the medicines, with the medical recommendations (Schwartz, 2005).The lack of fulfillment to the drug treatment can culminate with the patient's vision loss (Stewart, Konstas, Pfeiffer, 2004).This is a worrying fact, as Patel & Spaeth (1995) had found 59% of noncompliant patients.Some authors (Bloch et al., 1977;Kass et al., 1987;Patel, Spaeth, 1995;Nordström et al., 2005) have found possible intervening factors for noncompliance to antiglaucoma therapy, with quite changeable results.In such a way, the proposal of this article is to make a review of literature data regarding the possible intervening factors for noncompliance to therapeutic regime, as well as, to find estimated rates for noncompliance.

MATERIAL AND METHODS
A systematic review about the subject was carried out in the period of January to June of 2006.Articles have been searched in two data bases, in the National Library of Medicine (PUBMED) and in the Literature Latin American and Caribbean Health Sciences (LILACS).The key words used in the research was: glaucoma, compliance of the patient, noncompliance of the patient, treatment and eyedrops.The search has included articles written in the English, French, Spanish and Portuguese languages, obeying the following priority order: glaucoma and compliance of the patient; glaucoma and noncompliance of the patient; glaucoma, compliance of the patient and eyedrops; glaucoma, noncompliance of the patient and eyedrops; glaucoma, compliance of the patient and treatment; glaucoma, noncompliance of the patient and treatment; compliance of the patient, eyedrops and treatment, and noncompliance of the patient, eyedrops and treatment.Articles published in the last 30 years were raised; between June, 1976 andJune, 2006.This review has included articles dealing with causes or intervening factors in the compliance to glaucoma drug treatment and estimated rates of compliance and/or noncompliance to glaucoma drug treatment; these articles were indexed to the used data base and had their available summaries over there.Those using invasive methods (methods using needles and/or catheters for blood collection with purpose of drugs dosage) for evaluation of the compliance; analyzing compared antiglaucomatous effect; approaching exclusively the persistence to glaucoma drug treatment of; focusing the improvement or increase of compliance to glaucoma drug treatment ; and having no known authorship were excluded.The interest data were collected and presented as text and tables.
Initially, 199 articles in the PUBMED, in English and French languages were raised.Articles in the LILACS were not found.Based on the inclusion and exclusion criteria, 27 articles were selected, being 25 originals and two reviews (Table I.) The noncompliance rates found in this review varied from 4.6% to 59%, as demonstrated in Table II.
Twelve possible intervening factors had been found for noncompliance of glaucoma therapy: sex, age, race, adverse effect, number of instilled doses, number of used eyedrops, treatment cost, educational level, inadequate between doses interval, coexisting illnesses, forgetfulness and loss of visual field.The factors -forgetfulness and inadequate between doses interval-apparently contributed positively for noncompliance to glaucoma therapy.

Age
A study developed for Rocheblave (1983) in a French agricultural area, showed that patients aged more than 65 years cooperate better for the treatment, although the quantified data (in percentage) do not indicate this trend with precision.In another French work described for Bour;Blanchard and Segal (1993), the factor age does not significantly intervene with patient's noncompliance (p = 0.42).Gurwitz et al. (1993) didn´t find significant difference in noncompliance between patients of different age strata: 65-74 years, 75-84 years and 85 years or more.Rotchford and Murphy (1998), Kosoko et al. (1998), Gurwitz et al. (1998), Wane et al. (2003), Khandekar, Shama & Mohammed (2005) and Sleath et al. (2006), have also concluded that age is not significantly associated with noncompliance.
Race Gurwitz et al. (1993) divided the study participants in three racial groups: 'Caucasian', 'Afro-American' and 'others'.There was no difference in the compared noncompliance rates between the Caucasian and Afro-American groups.On the other hand, when these two groups were compared with the 'others' group, a longer and significant period of days without treatment was noticed in this last racial group.Patel & Spaeth (1995) compared the non-adhesion indexes between Caucasian and Afro-American, arriving at the conclusion that, statistically, the race would be a delinquent factor (limit) between compliance and noncompliance (χ2 = 1.22,p = 0.27).In another research of Kosoko et al. (1998), the races were compared in only two groups, black and nonblack people.Cumulative results were analyzed by means of multiple logistic regression.This work concluded that race wasn´t a factor for noncompliance risk .
Adverse effect Bloch et al. (1977) found that 7 (64%) not adherent and 9 (31%) adherent patients interrupted their treatment because of the adverse effect (χ2 = 3.53, p < 0.1).Granströn & Norell (1983) noticed the occurrence of adverse effect in 54 of 78 patients using pilocarpine, but the non-adhesion rate wasn't significantly higher between patients exhibiting adverse effect (p > 0.20).Another study developed for Kass et al. (1987) pointed a higher adhesion on the part of patients using timolol maleate, when compared with those making use of pilocarpine, a fact related to the lower incidence of adverse effects of timolol maleate.Similarly to Bloch et al. (1977) study, Patel & Spaeth (1995) compared the presence of adverse effects in compliant and noncompliant patients, but, no significant influence for noncompliance was noticed (χ2 = 1.42, p = 0.23).Gurwitz et al. (1998), Rotchford & Murphy (1998) and Taylor, Galbraith and Mills (2002) have not correlated the presence of adverse effects with adhesion problems.Taylor, Galbraith and Mills (2002) verified that almost 10% of patients (2 in 21) left to use the eyedrops due to adverse effects.In a study on the classification of barriers for adhesion to glaucoma treatment, 27% of patients told that adverse effects confused or became difficult the use of eyedrops (Tsai et al., 2003).Deokule, Sadiq and Shah (2004) noticed a prevalence of about 30% of adverse effects in the systemic level.Respiratory difficulty (14%), nocturnal dyspnea (7.6%), ankle edema (4%), and migraines (3.4%) were the most frequent events, suggesting that these effects could also have some contribution for noncompliance to the treatment.Sleath et al. (2006)pointed adverse effects as one of the main factors with respect to non-adhesion, being pointed by 16% of the patients.

Number of Instilled Doses
In a study of Norell (1981) where the patients used three times a day pilocarpine, it was noticed that evening doses were lost more frequently than morning (χ2 = 115.35,p ~ 0) and night doses (χ2 = 61.82,p ~ 0), indicating an adhe-χ2 = 61.82,p ~ 0), indicating an adhe-2 = 61.82,p ~ 0), indicating an adhesion improvement in drug regimens containing as a maximum two daily applications.Granström & Norell (1983) have found good treatment adhesion independently of the number of daily applications.A comparison of two works, Kass et al. (1986) and Kass et al. (1987), disclosed that patients using pilocarpine four times a day had a lower adhesion rate than patients instilling maleate of timolol two times a day, 76% vs. 82.7%,respectively.Patients using the eyedrops more times a day, had a higher trend to disregard the treatment, as proven for Gurwitz et al. (1993).In this study, the patients who instilled eyedrops three or more times a day, exhibited a significantly higher rate of non-adhesion, as compared with those dripping eyedrops one or two times a day.Gurwitz et al. (1998) haven`t proved a significant association between the administration protocols and noncompliance.

Number of eyedrops
Granström & Norell (1983) have shown that the number of used eyedrops didn´t intervene on treatment noncompliance (r = -0.04).Kass et al. (1987) verified a higher adhesion rate to treatment with timolol maleate associated with other antiglaucomatous medicines, than when used separately, 86.1% vs. 78.6%,respectively.Patients dealing with a single medication are significantly more inclined to be non-adherent (Gurwitz et al., 1993).In the Tsai et al. (2003) study, a half of patients stated that the application of a single eyedrops medication every day, does not facilitate the adhesion to therapeutic regimen.Amongst patients participating in this study, 86% had used more than one eyedrops medication every day.A study described by Robin & Covert (2005) concluded that the addition of a second medicine to therapeutics increased significantly the interval for the medicine dispensing, having a consequent decrease in adhesion (p < 0,0001).In a recent work, Sleath et al. (2006) got similar results as Granström and Norell (1983).
Treatment Cost Kosoko et al. (1998), in a case-control study, have found four patients pointing the cost as intervening factor for non-adhesion.Amongst these patients, three were nonadherent.The statistical comparison of data wasn't possible

Interview Prescription dispensing
Loss of 1 dose in 14 days Loss of 2 doses in 14 days Loss of more than 2 doses in 14 days To leave to get medicines for periods longer than 60 or 120 days (depending on the bottle size), in a period of 3 years.* Device connected to eyedrops bottles, which memorizes (electronically) the number of drops and times that the eyedrops were instilled by the patient, storing the instillation schedules as well.
due to small number of involved patients.Patients thought the cost for acquisition of antiglaucomatous eyedrops medication was high, but they didn`t leave to use it due to this factor (Granström, Norell, 1983).On the other hand, patients told to leave the use the eyedrops medication, if their health plans left to pay for it (Tsai et al., 2003).Khandekar, Shama and Mohammed (2005) verified that the treatment cost wasn`t a significant factor for noncompliance [RR =1.29;].Nordström et al. (2005) concluded that, despite the higher cost of the prostaglandin-analog eyedrops, the patients using these medicines exhibited better adhesion as compared to those using β-blocker, α-agonist, miotic and carbonic anhydrase inhibitor eyedrops.Sleath et al. (2006) shown that 41% of patients had difficulty to pay for their eyedrops, pointing the treatment cost as one of the main factors related to noncompliance to treatment.

Educational Level
Five studies have shown that educational level did not contribute for noncompliance to drug treatment (Patel, Spaeth, 1995;Kosoko et al., 1998;Wane et al., 2003;Khandekar, Shama, Mohammed, 2005;Sleath et al., 2006), in Wane et al. (2003) and Khandekar, Shama and Mohammed (2005) studies, it was noticed a considerable ratio of illiterates in the study samples, of 38.7% and 67.6%, respectively.Kass et al. (1982Kass et al. ( , 1986Kass et al. ( , 1987) ) and Granström (1982) have shown a trend of patients to instill eyedrops rejecting the schedules prescribed by doctors, with increase in the number instilled doses during the morning and evening periods.The inadequate interval between doses of antiglaucomatous eyedrops is a contributing factor for noncompliance, as disclosed for some studies (Patel, Spaeth, 1995;Kosoko et al., 1998;Wane et al., 2003;Khandekar, Shama, Mohammed, 2005).

Inadequate between doses interval
Coexisting illnesses Bloch et al. (1977) have significantly associated the presence of chronic illnesses, such as diabetes, hypertension, arthritis and atherosclerosis, with noncompliance to therapeutic drug (χ2 = 4.36, p < 0.05).Contrarily, Bour, Blanchard and Segal (1993) and Gurwitz et al. (1998) have not found significant differences correlating the presence of coexisting illnesses with noncompliance.
Forgetfulness Bour, Blanchard and Segal (1993) have shown that 52.9% of the patients did not follow the treatment because they forgot to drip the eyedrops.Patel & Spaeth (1995) have statistically compared the forgetfulness with adhesion, and haven`t found a positive association for noncompliance to therapeutic drug (p < 0.05).The work of Taylor, Galbraith and Mills (2002) pointed out forgetfulness as the main reason for noncompliance to pharmacological treatment, being also this factor considered as a barrier with respect to adhesion, for Tsai et al. (2003).Sleath et al. (2006) have also associated forgetfulness with treatment noncompliance.

Loss of Visual field
Granström (1985) hasn`t verified significant statistical difference between the progression of visual field loss and noncompliance to drug treatment (p = 0,54).Similar result was obtained by Gurwitz et al. (1998).

DISCUSSION
The cumulative rates of noncompliance exhibited values between 4.6% and 59%.This ample variation could be, in part, due to different concepts and methodologies applied for noncompliance evaluation, showing also a patients trend to disrespect the treatment with antiglaucomatous eyedrops.In accordance with data raised from literature, eight of 12 possible intervening factors exhibited at least a story in literature trending to drug noncompliance.The factors 'forgetfulness' and 'inadequate between doses interval' seemed to positively contribute for noncompliance to therapeutic drug for glaucoma.Age, sex, educational level and loss of visual field were not significantly associated with noncompliance to drug treatment.Olthoff et al. (2005), in a review article, have found similar results about these factors.
Other possible intervening factors -race, adverse effects, treatment cost , number of instilled doses, number of used eyedrops, coexisting illnesses -resulted contradictory, being impossible to determine their actual intervenience for noncompliance to treatment.Amongst these factors, the 'number of used eyedrops' was the more conflicting one.In two works, Sleath et al. (2006) and Taylor, Galbraith and Mills (2002), the number of instilled eyedrops did not intervene for noncompliance.In other three works, Tsai et al. (2003), Kass et al. (1987) and Bour, Blanchard and Segal (1993), better adhesion was associated to the use of more than one eyedrops.Contrarily, Robin and Covert (2005) have shown that the addition of one medicine to therapeutics decreased the compliance.Some considerations could still be made respecting the factors 'adverse effects' and 'cost of the treatment'.The factor 'adverse effects', although not statistically associated to noncompliance, was described in some works (Taylor, Galbraith, Mills, 2002;Tsai et al., 2003;Deokule, Sadiq, Shah, 2004;Sleath et al., 2006) as one of the main barriers for the eyedrops instillation.Respecting to 'treatment cost' , this factor does not statistically intervene significantly for noncompliance, as demonstrated by Khandekar, Shama, Mohammed (2005); however, as the supply of eyedrops medication was free of charge for individuals participating in this study, such situation could have influenced the statistical analysis of data.In the study developed for Sleath et al. (2006), where free of charge medicine supply didn't occur, 41% of the patients had difficulties to pay for their eyedrops.

CONCLUSIONS
The daily instillation of eyedrops is the main form of treatment of glaucoma, hindering the illness advance and preventing, consequently, the loss of vision in glaucomatous.Our literary review showed that glaucomatous patients have tended to do not fulfill adequately the drug treatment, as demonstrated by the found rates of noncompliance, which varied from 4.6% to 59%.This ample variation could be influenced by the difficulty, on the part of the authors, in defining noncompliance, and, even, by the variance of methodologies used for the determination of the noncompliance rates.Amongst the 12 possible factors raised as intervening for noncompliance, only two -'forgetfulness' and 'inadequate between doses interval' -seemed to significantly contribute for noncompliance.The factors -'treatment cost' and 'adverse effect' -although having not significantly been associated with noncompliance, have been pointed out as possible barriers the drug adhesion.It has been noticed that men tended to adhere little to treatment than women.More studies are necessary for a better evaluation of these possible intervening factors for noncompliance to glaucoma drug treatment.

TABLE I -
Selected articles for review study

TABLE II -
Rates of noncompliance to the drug treatment