Discussion
This register-based study following around 30 000 glaucoma patients over a period of 10 years between 2000 and 2018 demonstrated that increasing age, being a woman, and low CCI-score predisposed to being medical adherent to glaucoma treatment. Being adherent in the first and the first two years, respectively, increased the probability of being adherent after 5 and 10 years from index date, with the most profound association identified for those being adherent over the first two years. Finally, poor adherence was associated with increased healthcare costs in relation to hospital contacts, whereas high adherence was associated with higher costs to glaucoma-related medical treatment.
Around 60% of the highly adherent glaucoma patients were women and women in general were more likely to be adherent than men. These findings were in line with previous findings indicating a slight predominance of women.44 45 We further demonstrated that the vast majority of glaucoma patients were more than 60 years old (approx. 65%), which likewise corresponds to previous findings.44 45 Despite similar age distributions across the studies, an Italian study found a significantly higher average CCI score in their sample compared with the CCI score identified in this study.44 This discrepancy may be due to heterogeneity in the study designs but may also be due to national differences in disease occurrence and registration practices. Our findings further suggested that early adherence patterns were closely associated with adherence patterns in the longer term, and thus, early adherence behaviour may be a predictor for future adherence behaviour. This was supported by findings from a cohort study from the USA in which adherence patterns in the first year of treatment persisted in the subsequent three years of treatment.20
In general, poor adherence was related to younger age, men, and higher CCI score compared with the highly adherent patients. Glaucoma is often asymptomatic until advanced stages of the disease, and therefore, the consequences of not treating glaucoma may feel intangible.10 18–20 When looking at the patients who have poor adherence to medical treatment, one may wonder if the patients who have poor adherence are the less severe glaucoma cases, if they have been diagnosed at an earlier stage of the disease, or if their glaucoma disease is less progressive when initiating treatment compared with the highly adherent patients. In contrast, patients with more advanced glaucoma may be more motivated to be adherent since they may have already experienced negative visual symptoms from glaucoma. These speculations were supported in a cohort study demonstrating that patients with highest disease severity had the highest medication adherence, and that patients with greater adherence to glaucoma medication seem to have a slower deterioration in visual function over time compared with those with poor adherence.34 In accordance with this, we observed a reduction over time in the differences in costs to glaucoma-related medication between the patients with poor and high adherence. This may be explained by the poorly adherent group over time starting to experience an increase in disease severity (negative visual symptoms) and then may need more glaucoma medication or become more compliant which will increase their yearly cost for glaucoma-related medicines over time. However, it may also be explained by decreasing medication prices over time resulting in a lower absolute cost differences.
Finally, since some patients progress faster than others, the annual resource use would not only depend on disease severity but also on the progression rate.18 A Danish study of glaucoma costs demonstrated that glaucoma-related healthcare costs increased with the number of treatment changes indicating that the more intense treatment, the higher healthcare costs.46 Our findings suggested that patients with poor adherence in general were more costly in the longer perspective for the society in relation to overall healthcare services in the secondary sector compared with patients with high adherence, also after conditioning on age, sex, and comorbidities. This may reflect increased costs in relation to hospital contacts directly associated with glaucoma but also arising from glaucoma for example accidents, fractures, and concussions due to the increased risk of falling and unsafe driving among glaucoma patients, particularly among those with severe visual loss.47
Strengths and limitations
A strength of this study is that the applied data were based on national registers covering the full Danish population in which all Danish patients registered with at least one relevant ICD-10 diagnosis code of glaucoma or having at least three redemptions of glaucoma medicines in the period 2000–2009 were identified. Further, it is general practice in Denmark to record activities of healthcare services in the central administrative databases, why the registers have high validity and completeness.46 Another strength is that Danish data are available historically which ensured that all study participants were incident glaucoma patients, which we followed in relation to adherence patterns of the glaucoma patients and public costs over a period of 10 years.
There are, however, limitations to this study that need awareness in the interpretation of results. There is a risk of misclassification, as calculation of adherence was based on data of redeemed prescriptions, and we assumed that each patient was recommended to take one DDD of redeemed medication per day. However, the recommended dose may vary for each patient as may patients who received laser treatment or surgery not have needed eye drops for a certain period within a year, which may impact the classification of adherence. Furthermore, it is well-known that many glaucoma patients are struggling with instilling the eye drops properly,20 and for the calculations of adherence based on registry data, it is not possible to identify whether the patients were using the medication and whether the patient instilled the medication correctly. We do believe, however, that this potential misclassification is non-differential, and had no essential impact on the direction of effects. Furthermore, socioeconomic status is assumed to influence the likelihood of high adherence.25 For some of the analyses in this study, socioeconomic status may work as a confounder, and thus the estimates may be slightly overestimated since information on socioeconomic status was not available in the data at hand for this study. The same applies for other sociodemographic variables for example, civil status and residence. Finally, the study design forced all included patients to be followed for 10 years. In the selection process, we excluded individuals that were not alive in a period of 10 years from the time of glaucoma diagnosis, and thereby, we excluded the oldest people in the population, mostly men, and those with a high CCI score. Thus, women and individuals of younger age (ie, those being most likely to be adherent) were overrepresented in our sample. This selection may have introduced immortal time bias. Even though this might have impacted the results and that the proportion of poor adherent patients can be both overestimated and underestimated, we expect that the impact may profoundly be an issue in the oldest part of the population with the highest CCI score. Despite the age distribution in our study population is corresponding to findings from previous studies on glaucoma patients,44 45 this selection may thus have diluted the estimates against the null. Overall, balancing the advantages of using national patient data to estimate predictors, investigating adherence in a long-term perspective, and estimating the public economic burden of medical adherence among glaucoma patients over time, we believe the strengths of being able to include data on the entire Danish population and follow over 30 000 glaucoma patients for 10 years overseed the limitations of this work.
Conclusion
Increasing age, female sex, and low comorbidity score are correlated with high adherence to medical treatment for glaucoma. High adherence in the first years of glaucoma treatment, particularly over the first two years, may be a good predictor for persistent adherence in a five-year and 10-year perspective. This finding may be of importance for physicians informing of the clinical value of adherence in the first and the first two years of treatment and may lead physicians to investigate other IOP-lowering options sooner in patients with poor adherence, particularly among those that are progressing at unsafe rates. Finally, in the long term, patients with poor adherence are overall more expensive to society in terms of hospital contacts. Future studies exploring the direction of the association between severity and progression of glaucoma disease and poor adherence seem essential for enriching the interpretation of the findings from this study. The understanding of the interplay is likewise highly relevant for enhancing the glaucoma treatment, and thus, seeking to prevent the negative consequences of poor medical adherence to glaucoma treatment.