Clinical Outcomes following Selective Laser Trabeculoplasty in Afro-Caribbean Glaucoma Patients at High Risk for Progression

Abstract

Aim:

To characterize clinical outcomes following selective laser trabeculoplasty (SLT) in eyes of Afro-Caribbean open-angle glaucoma (OAG) patients at high risk for progression.

Methods:

In a prospective interventional case series, patients meeting high-risk criteria (advanced disease, unilateral glaucoma blindness, inadequate intraocular pressure [IOP] on ≥2 medications, recent progression on medications, inability to administer, afford or tolerate medications) underwent bilateral 360° SLT and managed based upon their subsequent clinical course. Patient-specific indications for SLT—IOP reduction (IOP group) or reduced reliance on medical therapy (MED group)—were recorded before treatment. IOP and medication use were recorded every 3–4 months through up to 24 months of follow-up. Outcomes were analyzed separately in the IOP and MED groups.

Results:

Among 33 right eyes (left eye outcomes were similar) in the IOP group, mean (standard deviation) IOP was significantly reduced from 21.7 (7.5) mmHg to 16.2–17.1 mmHg over follow-up (p≤0.0177); medication use remained unchanged (p>0.05) at all time points. Among 36 right eyes in the MED group, mean medication use was 1.9 (0.9) at baseline and ranged from 1.2–1.4 medications per eye through follow-up (p≤0.0033), and mean IOP was significantly reduced at Months 1–6 (to 13.1 [2.3] mmHg, p=0.0013) and Months 13–18 (to 14.3 [2.8], p=0.0136) and unchanged at other time points. No vision-threatening adverse events occurred.

Conclusions:

Afro-Caribbean patients with OAG at risk for progression can achieve clinically and statistically significant reductions in IOP or medications through up to 24 months following a single 360° SLT treatment.

Introduction

Glaucoma is an important cause of irreversible vision loss and blindness in Africa and in African-descended populations in the Caribbean and the United States.¹ The prevalence of glaucoma is particularly high among people of African descent. The prevalence of open-angle glaucoma in Caucasians has been estimated in various studies to range from 1–4%,^2–4 with a meta-analysis reporting a 1.86% prevalence of open-angle glaucoma in Americans aged 40 and older.⁵ In contrast, the prevalence of open-angle glaucoma in people of African descent ranges in various studies from 3–20%,^6–10 and has been estimated to be 4–5 times higher than for Caucasians in similar geographic regions.^8–10 In low-resource regions—common in sub-Saharan Africa and the Caribbean—significant barriers to care contribute to glaucoma-related vision loss, among them the availability and affordability of treatment and poor adherence to chronic medical therapy.¹¹

The West Indies Glaucoma Laser Study (WIGLS) was conducted to evaluate the role of selective laser trabeculoplasty (SLT) as sole therapy in Afro-Caribbean patients with primary open-angle glaucoma (POAG). Patients were medically-treated patients with POAG who underwent medication washout before bilateral 360° SLT. Twelve-month primary outcomes demonstrated meaningful IOP reductions of ∼30% with 78% of eyes remaining medication-free.¹² These findings were consistent with a prior report of SLT in Afro-Caribbean patients in Saint Lucia,¹³ and also with several reports of SLT in black African patients with POAG.^14–16 The broad goal of WIGLS was to establish SLT as a viable first-line therapy for glaucoma in low-resource regions populated by people of African descent.¹⁷

While WIGLS was designed to represent real-world clinical practice, eligibility criteria excluded high-risk patients, such as those with advanced disease, very high intraocular pressure (IOP), and unilateral blindness, among others. In these cases, the investigators felt that medication washout posed an unacceptable risk of progression, or SLT monotherapy was unlikely to achieve target IOP, or both. During the WIGLS screening process, such patents were identified and informed of non-eligibility. Through this process, it became clear that these excluded patients, who had the highest risk for glaucoma-related vision loss and blindness, were precisely the patients in whom SLT would have the greatest potential benefit. The protocol was revised to include a high-risk sample of patients in whom SLT could be applied in addition to existing therapy, without a washout, to characterize the efficacy and safety of adjunctive SLT in this population. The protocol for the primary WIGLS cohort—which mandated washout of IOP-lowering therapy and specified quantitative treatment goals and retreatment criteria—was not applied to these patients. Instead, they were managed as is customary in the real world, with management decisions based on clinical course.

In this report, we describe the clinical outcomes of SLT performed in ahigh-risk cohort of Afro-Caribbean patients with open-angle glaucoma.

Methods

This was a prospective interventional case series conducted between October 2015 and September 2018 at two sites in Saint Lucia and one site in Dominica in patients who did not or would not qualify for the WIGLS primary study and received SLT treatment as compassionate care. The protocol and all applicable revisions were deemed culturally appropriate by local authorities, were reviewed and approved by all applicable ethics committees, and the study was registered at www.ClinicalTrials.gov (NCT02375009). All patients provided written informed consent to participate.

Eligible patients were recruited from the WIGLS screen failure file, from referrals from eye care providers, and by general word of mouth in both Saint Lucia and Dominica. Patients were adults age 18 years or older with POAG who met one or more of the following high-risk criteria: advanced POAG (cup-disc ratio >0.9 and/or automated visual field defects within the central 10 degrees on automated perimetry if available), glaucoma-related low vision or blindness in one eye (20/400 or worse), IOP inadequately controlled (at the investigator’s discretion) on 2 or more medications, recent disease progression despite medical therapy based on communication with referring providers, inability to properly administer topical medical therapy (due to cognitive [e.g., dementia] òr physical [e.g., tremor] limitations), inability to afford medical therapy, or inability to tolerate medical therapy (the latter three ascertained primarily by patient report, with the exception that some patients manifested verifiable medication-related side effects at screening). Patients not considered candidates for SLT (those with forms of glaucoma not generally amenable to SLT therapy, including angle closure glaucoma, uveitic glaucoma, neovascular glaucoma, etc., and those with bilateral low vision [hand motions or worse]) were not treated. The indication for SLT (primarily for IOP reduction versus primarily for reduction of the medication burden) was determined in the investigator’s best judgment and documented at the time of screening.

After completing the consent process and undergoing an examination to evaluate eligibility, participants underwent SLT 360° in one or both eyes as applicable 1–3 days later. Baseline IOP was the mean of IOP at the eligibility visit and the SLT treatment visit. SLT laser energy was titrated as described by Latina et al:¹⁸ beginning at 0.8 mJ/spot, energy was adjusted upward or downward to the lowest level that produced fine champagne-like bubbles; energy was continuously titrated throughout the 360° treatment to account for sectoral variation in pigmentation patterns and laser absorption. Following SLT, patients were evaluated 1 hour, 1 week, 3 months, and every 3 months through January 2017 and every 4 months thereafter through up to 24 months of follow-up. At each study visit, visual acuity, IOP, and slit-lamp examination were performed; once annually, dilated fundus examination was performed and perimetry and optical coherence tomography of the retinal nerve fiber layer (RNFL) were performed if available (in this cohort of patients enrolled between October 2015 and January 2018, too few eyes had structural or functional testing over an adequate period of time to conduct meaningful analysis). As the primary outcome measure, IOP was measured by a single examiner using the same Perkins tonometer at the same time of day (± 2 hours) for each patient following a modified OHTS protocol as follows: the Perkins tonometer was set to 10 mmHg; the eye was applanated and the examiner adjusted the dial without looking at it to achieve applanation; the Perkins tonometer was removed from the eye, the IOP was read from the dial and recorded, and the dial was set back to 10 mmHg; a second reading from the same eye was obtained, again without looking at the dial, which was then read and recorded. A third reading was taken only if the first two differ by 4 mmHg or more. These two (or three) values were averaged. The procedure was repeated on the fellow eye. Determination of the number of medications used was by patient report at each visit.

In contrast to the WIGLS primary study reported previously,¹² this compassionate care cohort was not managed according to the primary WIGS study protocol but rather using real-word pragmatism. The patients whose data are presented in this report did not undergo medication washout before SLT (most were ineligible for WIGLS on the basis that washout would be unsafe), were not assigned specific quantitative treatment goals (e.g., achievement of a specific target IOP), and had no a priori rescue therapy or SLT retreatment criteria specified. Rather, these patients were managed using the real-world approach to clinical care: they were deemed to warrant treatment, were treated, were observed after treatment, and therapy was withdrawn, maintained, or advanced based on clinical course and the investigator’s discretion. They were seen on the primary WIGLS study visit schedule as a matter of convenience, and key clinical assessments (specifically IOP) were assessed using WIGLS methodology.

This was intended as a descriptive analysis and no specific hypothesis was established or tested. Data analysis consisted of comparing mean IOP and the mean number of IOP-lowering medications throughout follow-up in comparison to baseline values. This analysis was performed using paired t-tests with significance set at p=0.05. Data were analyzed using SAS version 9.4 (SAS Institute, Cary, NC, USA). To account for differences in absolute follow-up months between visits owing to the change in visit frequency mid-study, IOP data were binned into 6-month time intervals (0–6 months, 7–12 months, etc.), and values for each interval represent the mean of all visits occurring during the interval range. The study cohort was divided into two subgroups: those undergoing SLT with the primary indication of IOP reduction (the IOP group), and those undergoing SLT with the primary indication of medication reduction (the MED group). Patients with IOP deemed too high for the long-term health of the eye (those with advanced glaucoma, uncontrolled glaucoma, blindness in one eye due to glaucoma, or progressing glaucoma) were treated to lower IOP, while those who could not afford, administer or tolerate their existing therapy were treated to reduce their medication burden. These patient-specific indications were non-quantitative (no specific IOP or medication reduction goals were set) and designated at baseline prior to SLT treatment. Right and left eyes were analyzed separately. Right eye data are presented herein; left eye data were similar in all regards and are not presented herein.

Results

A total of 69 patients comprised the high-risk group, of whom 33 underwent SLT primarily for IOP reduction (the IOP group) and 36 for medication reduction (the MED group). Bilateral SLT was performed in all patients. Demographic data, baseline glaucoma characteristics, and laser treatment data are given in Table 1. Mean IOP was higher (21.7 vs 15.5 mmHg) and glaucoma more advanced in the IOP cohort compared to the MED cohort.

Table 1.

Demographic data, baseline glaucoma characteristics, and laser treatment data for the IOP and MED groups.

	IOP Cohort N=33 right eyes	Medication Cohort N=36 right eyes
Gender, n (%) male	17 (51.5)	20 (55.6)
	Mean (SD)	Mean (SD)
Age (yr)	62.5 (12.5)	60.5 (11.6)
IOP (mmHg)	21.6 (7.5)	15.5 (2.3)
Number of Medications	1.7 (1.2)	1.9 (0.9)
CDR	0.85 (0.1)	07 (0.2)
VF Mean Deviation (dB)	−10.5 (10.5)	−3.73 (3.3)
OCT RNFL Average Thickness (μm)	539 (61)	534 (46)
Total Power (mJ)	92.6 (19)	85.4 (19.2)
# of Laser Treatment Spots (n)	103 (3.1)	103 (2.0)

In the IOP group, mean (standard deviation) baseline IOP in 33 right eyes was 21.7 (7.5) mmHg and at the 1–6 month (n=30), 7–12 month (n=29), 13–18 month (n=24), and 19–24 month (n=17) time intervals, mean IOP was 16.2 (4.6) mmHg (p<0.0001), 16.9 (6.5) mmHg (p=0.0012), 16.9 (5.0) mmHg (p=0.0009), and 17.1 (5.2) mmHg (p=0.0177), respectively (Figure 1). The mean baseline number of IOP-lowering medications prescribed was 1.7 (1.2) and at the same time intervals was 1.7 (1.5), 1.7 (1.3), 1.5 (1.3), and 1.4 (1.3) medications, respectively, (p>0.05 at all time points; Figure 2). At baseline and at each time interval, the range of medications used per eye was 0–4. The proportions of IOP eyes using at least 1 fewer medication compared to baseline were 10.3%, 10.0%, 16.7%, and 29.4%, respectively, at the same time intervals (Table 2).

Figure 1.

IOP reductions at each time point in the IOP group (solid line) and in the MED group (dashed line). Error bars represent standard deviation.

Figure 2.

Medication reductions at each time point in the IOP group (solid line) and in the MED group (dashed line). Error bars represent standard deviation.

Table 2.

Proportions of eyes using ≥1 fewer medication compared to baseline by group and time point (%).

Group	1–6 Months	7–12 Months	13–18 Months	19–24 Months
IOP	10.3	10.0	16.7	29.4
MED	54.5	51.5	57.1	55.0

In the MED group, mean baseline IOP in 36 right eyes was 15.5 (2.3) mmHg and at the same time intervals, mean IOP was 13.1 (2.3) mmHg (p=0.0013), 14.6 (3.5) mmHg (p>0.05), 14.3 (2.8) mmHg (p=0.0136), and 14.9 (1.9) mmHg (p>0.05), respectively (Figure 1). The mean baseline number of IOP-lowering medications reported was 1.9 (0.9) and at the same time intervals was 1.2 (1.3) medications (p<0.0001), 1.3 (1.2) medications (p<0.0001), 1.4 (1.3) medications (p=0.0002), and 1.3 (1.4) medications (p=0.0033; Figure 2). At baseline and at each time interval, the range of medications used per eye was 0–4. The proportions of MED eyes using at least 1 fewer medication compared to baseline were 54.5%, 51.5%, 57.1%, and 55.5%, respectively, at the same time intervals (Table 2).

Adverse events included photophobia occurring in 20.3% of eyes, nonspecific eye pain in 10.1%, and IOP spikes >5 mmHg in 7 eyes (5.1%) of 4 (5.8%) patients.

Discussion

In Afro-Caribbean adults with medically-treated POAG at high risk for vision loss or blindness, SLT effectively achieved patient-specific goals (primarily IOP or medication reduction). Patients undergoing SLT for IOP reduction had significant IOP reductions from pre-SLT baseline at all time points through up to 2 years of follow-up, and patients undergoing SLT for reduction of the medication burden required significantly fewer topical medications at all follow-up time points as well.

Ideally, research is conducted dispassionately. The analysis presented in this report was conducted not on the basis of dispassionate research but rather of compassionate patient care. When it became clear during the WIGLS enrollment period that there was significant unmet need for advanced care among those deemed ineligible to participate, we amended the protocol and proactively obtained consent not for the purpose of conducting research in this cohort, but rather to ensure robust characterization of outcomes and permission to access the data with the foresight that these outcomes would be of value to report ancillary to the WIGLS primary study. This high-risk cohort of the WIGLS study represented patients with medically uncontrolled POAG who were at high risk for disease progression, vision loss, and possibly blindness. In contrast to the original WIGLS cohort—selected as a convenience sample to estimate the potential role of SLT as primary therapy in newly-diagnosed POAG in patients of African descent—this high-risk cohort represents POAG patients who were already diagnosed and failing existing medical therapy for a variety of reasons. In our IOP group, patients’ IOP was above target despite the use of medications, warranting further IOP reduction. These were generally patients at high risk for vision loss and blindness due to advanced disease, prior low vision or blindness in one eye, progressing glaucoma at current IOP, or any combination thereof. In our MED group, patients warranted a reduction in medication burden due to inability to administer, afford, or tolerate their prescribed medications. They did not follow the WIGLS protocol—which mandated washout of IOP-lowering therapy and specified quantitative therapeutic goals and criteria for retreatment—but were instead managed as we manage our patients in the real world. They underwent SLT in addition to their current medical regimen with the patient-specific indications of primarily IOP or medication reduction, with management dictated by clinical course rather than by protocol.

Generalizing the results of clinical studies to populations that differ in significant ways from study samples is not always possible. WIGLS was specifically designed to evaluate the role of SLT as sole therapy for OAG in patients of African descent,^12,19 with the long-term goal of positioning SLT as primary monotherapy for patients in regions and settings where the barriers to adherence with daily topical medical therapy limit its viability as a strategy for the prevention of glaucoma-related vision loss.^11,17 The original WIGLS protocol would have provided little or no insight into the value of SLT as adjunctive therapy in patients with medically-treated POAG. While the fullest impact of the findings of the primary WIGLS study will only be realized upon the development of viable screening techniques and expansion of clinical resources in low-resource areas to find and treat those with currently undiagnosed and untreated disease who would benefit from primary SLT, the findings of this analysis in our high-risk cohort are immediately applicable to the millions of African-derived patients already diagnosed and under medical treatment throughout the world.

The results of this analysis indicate that patients at high risk for glaucoma progression due either to uncontrolled IOP or shortcomings of medical therapy can benefit from SLT. Approximately half of patients with medically-controlled IOP who could not adequately administer, afford, or tolerate their topical therapy were able to reduce their medication burden without compromising IOP control. Similarly, patients with medically uncontrolled IOP reduced IOP by ∼20–25% on average with SLT. An incremental IOP reduction of this magnitude has been shown to reduce progression risk in glaucomatous eyes.^20,21 Clearly, based on these results, SLT will not suffice as sole rescue therapy for all high-risk patients, and even in eyes treated with SLT ongoing monitoring is necessary to assess efficacy over time. Communicating this need for ongoing monitoring to the patient is crucial for optimizing long-term outcomes. However, in regions where access to surgeons and surgery is limited and follow-up rates are suboptimal, a one-time in-office SLT treatment may prevent or delay glaucoma progression and glaucoma-related vision loss or blindness for 2 years or more in many patients with medically-uncontrolled glaucoma who otherwise would not undergo surgical interventions for IOP control.

The safety of SLT in this cohort was consistent with prior reports of SLT safety in this population. Photophobia—first reported in this population in our preliminary study of SLT in Saint Lucia¹³—was common and self-limited. Eye pain was also mild and transient. The incidence of IOP spikes in this cohort was identical to that in both WIGLS (2.8%) and our preliminary study (4.1%) among Afro-Caribbeans and is lower than the range in other studies with mixed-ethnicity samples (4.5–27%).²² A much lower incidence was reported in the recent Laser in Glaucoma and Ocular Hypertension Trial (LiGHT), albeit in a treatment-naïve sample with early glaucoma and likely less glaucoma-related and/or treatment-related damage to the trabecular outflow system.²³ Overall, the safety profile of SLT in this cohort offers no signals to dissuade from its use in similar patients.

This study is strengthened by its prospective nature and by designating the indication for SLT (IOP or medication reduction) before treatment. Limitations include its relatively small sample size (enrollment in this high-risk arm of the WIGLS study began well into the 5-year funding period, limiting the ultimate sample size and the follow-up period) and the lack of robust protocols governing treatment goals and retreatment criteria (as were in place for the primary WIGLS study). The patients analyzed in this data set were treated on a compassionate care basis and managed pragmatically post-SLT. These results thus represent real-world outcomes rather than those arising from a protocol-based clinical study. Follow-up was also limited by attrition attributable to referral for glaucoma surgery (these patients contributed data up to the point of referral, including the elevated IOP values prompting referral), and the emigration of 20–30% of Dominica’s population in September 2017 in the aftermath of Hurricane Maria, which struck the island as a category 5 storm, devastating infrastructure.²⁴

In summary, Afro-Caribbean patients with glaucoma at risk for progression can achieve clinically and statistically significant reductions in IOP or medications following a single 360° SLT treatment. In cases of medically-uncontrolled glaucoma in which surgery is unavailable, unaffordable, or declined by patients, SLT can achieve IOP reductions of a magnitude known to reduce the risk of further glaucoma progression.

Synopsis.

When patient-specific treatment goals are considered, selective laser trabeculoplasty performed in Afro-Caribbeans with medically-treated open-angle glaucoma significantly reduces IOP in patients seeking IOP reduction and significantly reduces the medication burden in patients seeking medication reduction