Age-related macular degeneration (AMD) and diabetic retinopathy (DR) represent 2 of the leading causes of visual impairment and blindness in the United States.¹ As the population ages, the prevalence of both diseases continues to increase. According to the National Eye Institute, more than 5 million people will be affected by AMD by the year 2050 in the United States, a five-fold increase in the prevalence compared to the year 2000.² A similar upsurge is occurring with DR, for which the prevalence is expected to triple between 2005 and 2050, from 5.5 million to 16 million individuals.^3,4

DEFINING LOSS TO FOLLOW-UP

In the face of the growing burden of these diseases, improved access to care and prevention of patient attrition are critical. Loss to follow-up (LTFU) is defined by a significant gap in the treatment course when patients miss their scheduled appointments and return with a considerable delay or never return. Compared to clinical trials, which typically demonstrate strong patient adherence to visits, real-world studies reveal significant LTFU among patients with neovascular AMD (nAMD) or DR. Obeid et al found that 22.2% (2,003 of 9,007) of nAMD patients receiving intravitreal anti-VEGF injections had at least 1 12-month interval of LTFU over 4 years.⁵ Another study by Obeid et al showed a similar rate of attrition among those with proliferative diabetic retinopathy (PDR): 22.1% (228 of 1,030) of patients with PDR undergoing intravitreal injections and 28% (356 of 1,272) of patients with PDR who had received panretinal photocoagulation (PRP) were LTFU for more than 1 year.⁶ Likewise, Gao et al found that 25.3% (413 of 1,632) of patients with nonproliferative DR and DME did not show up for their scheduled appointment visit for more than 1 year.⁷

A GLOBAL HEALTH CHALLENGE

Although the previously mentioned studies evaluated patients from urban, private practices in the Northeast, LTFU seems to be a persistent problem across diverse regions and practices. Clinics in areas of the United States with a less insured population may be at higher risk. One study of patients from a safety-net hospital found that 61% of PDR patients were LTFU for more than 6 months.⁸ A retrospective cohort of PDR patients in Houston, Texas found a complete LTFU (patients who never returned to care) rate of 52.4% and interval LTFU (returned to care with a considerable gap) of 17.7% for 6 months and 10.6% for 12 months.⁹ Internationally, patients with nAMD and DR have high LTFU rates, as well. Boulanger-Scemama et al from France explored nonadherence to treatment in patients receiving ranibizumab for nAMD. Overall LTFU (patients who never returned) was 57% during the study period.¹⁰ Kelkar et al from India reported LTFU rates of 33.5% among patients with nAMD and 38% among patients with DME.¹¹ Differences in LTFU rates in these studies may also be related to variations in LTFU definition, study design, and the study population. However, regardless of geographic region, LTFU is a global public health problem that may impose irreversible effects on visual outcomes of patients with nAMD and DR, leading to not only a poorer quality of life but also increased societal costs. Patients with visual impairment may be unable to work or have difficulty performing activities of daily living, thereby relying on friends, family, or other social assistance that incurs additional cost.

EFFECTS ON VISUAL ACUITY

The effects of treatment interruption and discontinuation are detrimental to visual outcomes of nAMD patients (Figure 1). Kim et al showed that nAMD patients receiving anti-VEGF therapy who discontinued their treatment course despite intraretinal fluid exhibit significant deterioration in VA (approximately 6 lines of vision) by 24 months of follow-up.¹² Soares et al similarly investigated the functional and anatomic outcomes of LTFU in nAMD patients. Ninety-three eyes with at least 6 months of LTFU were evaluated after their return. Median VA significantly worsened from 20/80 at the visit before LTFU to 20/200 at the return visit (P<.001). Treatment with anti-VEGF injections was restarted after return, and patients were followed for a mean of 383 days. However, VA did not return to the level prior to LTFU despite restarting therapy. Median VA was significantly worse compared to the visit before LTFU at 12 months after return (20/100, P=.004) and at the final follow-up visit (20/200, P<.001). In terms of anatomic changes, a significant increase in mean central foveal thickness (CFT) occurred from 201 µm at the visit before LTFU to 240 µm at the return visit (P=.004). However, the final CFT decreased to 183 µm and was not significantly different from the mean CFT at the visit before LTFU (P=.10), suggesting that resuming anti-VEGF therapy was able to reduce edema but underlying retinal damage likely limited any visual recovery.¹³

Nonadherence to recommended care similarly affects outcomes in PDR patients (Figure 2). A series of 76 eyes from 59 patients with PDR were reviewed after a 6-month gap and subsequent return to the clinic. Of those patients, 20 (33.9%) had received only anti-VEGF and 39 (66.1%) had received only PRP prior to LTFU. In terms of VA, significant worsening of vision was found in both groups, but the intravitreal injection group was disproportionately affected. In the anti-VEGF group, VA changed from 20/54 at the visit before LTFU to 20/187 at the return visit (P=.001). Despite the initiation of treatment after return, VA remained significantly worse at the final visit (20/166) (P=.01, compared to the visit before LTFU). In the PRP group, VA changed from 20/53 at the visit before LTFU to 20/83 at the return visit (P=.03). However, after treatment initiation, VA rebounded to 20/58, a nonsignificant difference from the visit before LTFU (P=.38). Structurally, there was a significantly greater prevalence of DME at the return visit (P=.005) and the final visit (P=.04) in the anti-VEGF treatment group compared with the PRP group. Also, the prevalence of neovascularization of disc, neovascularization of iris, and tractional retinal detachment was significantly higher in the anti-VEGF group compared to the PRP group at the final follow-up visit (P=.005, P=.02, and P=.005, respectively). The authors concluded that eyes with PDR do worse anatomically and functionally after a period of LTFU, particularly if they had been treated exclusively with anti-VEGF injections with no prior PRP. These findings may be due to the greater durability of PRP compared to anti-VEGF agents. It is plausible that anti-VEGF agents’ protective effect is dependent on adherence to follow-up because these drugs have a limited duration of effect.¹⁴ Although randomized clinical trials in PDR patients have established noninferiority of visual outcomes of anti-VEGF injections compared to PRP at 1 year¹⁵ and 2 years,¹⁶ achieving these results in a real-world setting is highly dependent on strict adherence to follow-up visits.

INTERVENTIONS TO REDUCE LOSS TO FOLLOW-UP

Given the irreversible vision loss incurred by periods of LTFU, understanding and addressing the underlying causes of LTFU has become an important goal in the treatment of nAMD and DR. As seen in Table 1, consistent risk factors associated with LTFU include residence in a low-income community, non-White race or ethnicity, greater distance from clinic, and poor baseline vision. Given the chronic nature of both nAMD and DR and the prolonged and often lifelong need for maintenance treatment, thorough patient education is imperative for all. However, clinicians might consider a tailored approach to address a patient’s specific risk factors. Several interventions have been suggested. Ellish et al found equal effectiveness of newsletters tailored to the individual or targeted to a subgroup of patients in encouraging dilated fundus examinations in African American patients over the age of 65 years.¹⁷ Additionally, telephone-based reminders and tracking systems have been shown to increase care adherence independent of socioeconomic status, gender, and spoken language.^18,19 In a randomized controlled trial by Walker et al, a 74% increase in the rate of DR screening was observed compared to the control group (P<.0005).¹⁹ Anderson et al found that follow-up phone calls from clinic staff significantly improve the return rate after a missed ophthalmic appointment, as compared to a mailed reminder sent prior to the next visit. In this study, the return rate for the group that received personalized follow-up phone calls was 66% compared to the return rate of 35% in the standard follow-up group (P=.001).²⁰

Despite these efforts, perfect compliance is a near impossible goal. Most patients with nAMD and DR will have significant comorbidities, leading to hospitalizations or other illnesses that may delay their return as they are prioritizing which of their medical issues takes precedence. The generally younger DR population may find it difficult to take time off work for regular visits or have treatment gaps due to unforeseen job loss and/or health insurance issues. Some patients may have deductibles which, in combination with their other fixed costs, preclude them from affording to return as often as recommended. Older patients and those with visual impairment may need to rely on others to transport them to the clinic, which increases the barrier to returning regularly. It is important for physicians to keep these issues in mind when deciding on therapeutic options for each individual. No one metric can predict who will return on time and who may be delayed or LTFU.

One future possibility for mitigating the LTFU problem is the promise of longer-acting drugs and novel drug delivery systems. As these become available, physicians may be able to extend the follow-up intervals for various retinal diseases.²¹ Home-based OCT monitoring systems that are currently being developed may become another method to decrease treatment burden and number of clinic visits for patients. For example, this technology could allow patients to avoid clinic visits until specific OCT criteria are met, which then generates an alert to return for therapy.²² In combination with better risk assessment, greater education, and improved patient outreach, these potential long-acting therapeutics and home OCT monitoring technology offer greater hope for decreasing treatment burden and curtailing the adverse visual outcomes of LTFU. RP

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