October 2016

Comparative Effectiveness of Eye

Drops vs. Laser Trabeculoplasty

Final Report

Prepared for

Romana Hasnain-Wynia, PhD, MS Ayodola Anise, MHS

Patient-Centered Outcomes Research Institute

Addressing Disparities Program 1919 M Street, NW Suite 250

Washington, DC 20036

Prepared by

Shivani Reddy, MD MSc

Meera Viswanathan, PhD MA Andrew Kraska, BA

RTI International 3040 E. Cornwallis Road

Research Triangle Park, NC 27709

RTI Project Number 0214031.006.000.001

iii

CONTENTS

Section Page

1. Contributors 1

2. Introduction 1

3. Patient Centeredness 2

4. Burden of the Condition 2

5. Evidence Gaps 3

5.1 Literature Review ........................................................................................ 3

5.1.1 Systematic Review: “Laser Trabeculoplasty for Open-Angle Glaucoma” (Rolim de Moura et al., 2007)16 ........................................... 4

5.1.2 Systematic Review: “Treatment for Glaucoma: Comparative Effectiveness” (Boland et al., 2012)48 ................................................... 4

5.1.3 Meta-analysis of SLT versus Topical Medication in the Treatment of OAG (Li et al., 2015)49 ....................................................................... 5

5.1.4 Summary of Systematic Reviews ......................................................... 5

5.2 Limitations ................................................................................................. 5

5.2.1 Limitations in Comparative Effectiveness Research ................................ 5

5.2.2 Limited Research on Racial Disparities in Glaucoma Treatment ............... 5

5.2.3 Limited Reporting of Patient-Centered Outcomes ................................... 6

6. Guidelines 6

7. Ongoing Research 6

8. Likelihood of Implementation of Research Results in Practice 8

9. Durability of Information 8

10. Potential Research Questions 9

11. Conclusion 9

References 10

Appendix A: Key Informant Information A-1

Appendix B. Search Strategy B-2

iv

TABLES

Number Page

Table 1. Eligibility Criteria for Studies on the Comparative Effectiveness of Laser

Therapy versus Medical Therapy for Glaucoma ..................................................... 4

Table 2. Professional Health Organizations’ Guidelines for Treating OAG ........................... 6

Table 3. Ongoing Studies Comparing Laser Therapy with Medications ............................... 7

1

Topic: Comparative Effectiveness of Eye Drops vs. Laser Trabeculoplasty

Overall Comparative Research Question: What is the comparative effectiveness of eye drops versus

laser trabeculoplasty to reduce excess morbidity from open-angle glaucoma in black and Hispanic

individuals?

1. Contributors

PCORI Staff: Romana Hasnain-Wynia, PhD, MS; Ayodola Anise, MHS; Kaitlynn Robinson-Ector, MPH RTI: Shivani Reddy, MD, MSc; Meera Viswanathan, PhD, MA; Andrew Kraska, BA

2. Introduction

Glaucoma is a chronic, progressive eye disease characterized by optic nerve damage and visual

field loss. Glaucoma is classified into two broad categories: open-angle glaucoma (OAG) and angle-

closure glaucoma; more than 80% of cases are OAG.1 Glaucoma can progress without causing symptoms

until the disease is quite advanced, leading to visual impairment and blindness. The second leading

cause of blindness worldwide after cataracts,2 glaucoma’s risk factors include older age, family history of

glaucoma, elevated intraocular pressure (IOP), type 2 diabetes mellitus, and black race or Hispanic

ethnicity.3-5 Several trials have shown that treatments reducing IOP—medications, laser therapy, and

incisional surgery—can slow the progression of glaucoma.6-9 This topic brief focuses on medications and

laser therapy, two treatments that physicians can deliver in an outpatient setting and that do not carry

the surgical risks of infection and bleeding. Medical therapy with eye drops typically has been the first-

line treatment for glaucoma, although a growing body of evidence suggests that laser trabeculoplasty,

an office-based procedure that does not involve making an incision in the eye, can also be used as initial

therapy, particularly if a patient struggles with adherence to daily medications. Thus, glaucoma

treatment is a topic ripe for comparative effectiveness research—research that compares the benefits

and harms of two efficacious treatment options to help physicians and patients make clinical decisions

best suited for individual patients.

Glaucoma is characterized by a striking health disparity; black and Hispanic individuals are more

likely to have the disease than white individuals, and the onset of blindness starts 10 years earlier in

black individuals.10-12 In terms of the impact of health disparities on treatment, data on current

treatments of eye drops and laser trabeculoplasty are sparse. Older studies that compared surgery with

medications or laser therapy demonstrated that black and white individuals with medically uncontrolled

OAG have different outcomes.13,14 For example, in the Advanced Glaucoma Intervention Study, vision

was better preserved in black participants randomized to laser therapy compared with those

randomized to surgery; in contrast, white participants undergoing surgery had better visual outcomes.13

However, more recent comparative effectiveness research has not examined how the effectiveness of

current first-line treatment options used in practice—laser trabeculoplasty or eye drops—varies by

racial or ethnic subgroups. In this brief, we review the burden of glaucoma, the current evidence base

for glaucoma treatment, ongoing studies, and opportunities for new comparative effectiveness

research.

2

3. Patient Centeredness

In the face of clinical uncertainty, patient-centered care becomes essential to the management

of disease.15 Both medical and laser therapy are associated with slowing progression of disease.16,17

However, some patients may not opt for medical therapy because of the side effects and costs of daily

medication.18,19 The need for retreatment 5 to 10 years after laser therapy may pose a concern for other

patients.20 Patients can also find lifelong adherence to a chronic medication burdensome for several

reasons. Patients with deteriorating vision from glaucoma may be unable to self-administer

medications, or patients may struggle to comply with complex dosing schedules.21 Accordingly, some

experts suggest laser therapy as first-line treatment for patients who have difficulties with

adherence.22,23 Strong patient–provider communication and patient education can support decision

making about a therapy that promotes improved patient outcomes and takes into consideration

patients’ preferences.24 Patients and doctors should make treatment decisions in the context of the

patient’s age, preferences, and degree of ocular damage.22,25 Furthermore, as discussed in the sections

below, the impact of the disease and effect of treatment may vary by racial and ethnic subgroups,

emphasizing the importance of patient-centered care.

4. Burden of the Condition

Glaucoma affects an estimated 2.9 million individuals in the United States; over half (54.3%) are

unaware that they have the disease.10 The projected prevalence of OAG is expected to rise to 7.32

million by 2050.26 Glaucoma is the second leading cause of blindness worldwide.2 Furthermore,

glaucoma can have a profound effect on a patient’s quality of life (QOL). As visual loss progresses,

glaucoma patients can struggle with activities of daily living like walking, reading, and driving,27-29

although even patients early in disease can report reduced QOL.30

As noted above, glaucoma disproportionately affects black and Hispanic individuals. Studies

using the National Health and Nutrition Survey (NHANES) estimate the prevalence of glaucoma in black

individuals at 3.7% compared with 2% for white individuals.10 Black individuals have roughly 4.4 times

greater odds of having undiagnosed and untreated glaucoma than white individuals.11 Although rates of

blindness increase with age for all individuals, studies show that the onset of blindness starts 10 years

earlier for black individuals.12 Glaucoma is the leading cause of blindness in black individuals in the

United States,31 whereas age-related macular degeneration is the leading cause for white individuals.32

Estimates for glaucoma prevalence in Hispanic individuals range from 1.9% to 4.7%, and some

studies report prevalence comparable with blacks.10,33,34 Hispanic individuals have 2.5 times greater odds

of undiagnosed and untreated glaucoma than non-Hispanic whites in an NHANES study.11 In a study of

the National Health Interview Survey, Dominicans and Central and South Americans were among the

understudied racial and ethnic groups with high rates of self-reported visual impairment.35 Accounting

for future demographic shifts, Hispanic men are predicted to be the largest demographic group with

OAG in 2050.26

Few studies compare prevalence of glaucoma across racial and ethnic groups.36 Furthermore,

we do not have a clear understanding of the factors that underlie these observed health disparities; the

reasons are likely multifactorial and include biologic and social determinants of health.

3

Advances in genetics research have led to the identification of several genetic variants

associated with glaucoma.37 The African Descent and Glaucoma Evaluation Study (ADAGES) has

identified anatomic differences in the eyes of black and white participants38 and was the first study

powered to assess performance on several visual field-test variables.39 Whether these findings are

associated with early onset of disease or more rapidly progressive disease remains to be seen.

Some studies have shown that black and Hispanic patients are less likely to be seen by an eye

care provider40,41 and are less likely to undergo monitoring once diagnosed with glaucoma even when

they have insurance.42 These patients also have lower rates of medical and surgical treatment than

white patients.43,44 Patient factors such as poor understanding of disease, mistrust of the medical

community, limited financial resources, and poor adherence to therapy also serve as barriers to

diagnosis and treatment of glaucoma.45-48 Studies of patient–physician communication found that

although patient education could improve adherence to medical therapy for glaucoma,49 providers were

less likely to educate black patients about glaucoma than white patients.50

5. Evidence Gaps

We identified evidence gaps primarily through a review of peer-reviewed primary studies and

systematic reviews and supplemented our understanding through conversations with three key

informants. Our key informants are clinical investigators and practicing ophthalmologists with

appointments at major academic centers in the United States. They have led glaucoma studies with

funding from multiple sources, including the Centers for Disease Control and Prevention, the National

Eye Institute, and industry. (Appendix A lists our key informants.)

5.1 Literature Review

The mainstay of glaucoma treatment is reducing IOP, which can be achieved through

medications (eye drops), laser therapy, or incisional surgery. Eye drops and laser therapy are provided in

outpatient settings. The major classes of eye drops are prostaglandin analogues (e.g., latanoprost,

travoprost), beta adrenergic antagonists (e.g., timolol, betaxolol), carbonic anhydrase inhibitors (e.g.,

acetazolamide, dorzolamide), alpha2 adrenergic agonists, and combination treatments. Prostaglandins

lower IOP more than other classes of medications and are currently used as first-line therapy.51 Laser

therapies include argon laser trabeculoplasty (ALT) and more recently selective laser trabeculoplasty

(SLT). The effectiveness of laser therapy decreases over 5 years of follow-up.20 Incisional surgeries, such

as trabeculectomy, achieve the greatest reduction of IOP with longer lasting results compared with

medical or laser therapy.51 However, incisional surgery carries the rare risk of intraocular infection and

bleeding not present with medical or laser therapy51 and is outside the scope of the literature review for

this topic brief.

We performed a systematic search using the populations, interventions, comparators,

outcomes, timing, and setting (PICOTS) framework in Table 1 (Appendix B lists the search strategy). We

identified five comparative effectiveness systematic reviews.17,51-54 Three reviews included the same

primary studies,52-54 so we selected the review that included a meta-analysis to discuss below.52 The

remaining primary studies we identified from title and abstract review were (1) included in one of the

aforementioned systematic reviews, (2) protocols for ongoing studies discussed in Section 7, or (3)

exclusions for wrong comparator, primarily older eye drops that are no longer used in clinical practice or

no active comparator. We describe two major trials excluded for no active comparator below.

4

The Collaborative Normal Tension Glaucoma Study compared any treatment to reduce IOP (eye

drops, laser therapy, or incisional surgery) with observation; likewise, the Early Manifest Glaucoma Trial

compared a combination of laser therapy and eye drops with observation only. Both of these studies

reported a 50% reduction in the progression of glaucoma, finding that even small changes in IOP can

slow the progression of glaucoma.8,9 According to one key informant, the striking benefit of treatment

observed in these seminal studies shifted the treatment paradigm away from observation to providing

some form of IOP-lowering treatment when glaucoma is diagnosed. Thus, we did not include studies

with an inactive comparator in our literature review.

Table 1. Eligibility Criteria for Studies on the Comparative Effectiveness of Laser Therapy versus Medical Therapy for Glaucoma

PICOTS

Population Population: Adults >40 years with OAG

Intervention Laser trabeculoplasty or combination laser and medical therapy

Comparator Medical therapy (eye drops)

Outcomes Final health outcomes: Reduced visual impairment, patient-reported outcomes Intermediate health outcomes: Reduced IOP, visual field loss, optic nerve damage Harms: Adverse effects of eye drops or laser trabeculoplasty

Time frames All

Setting Outpatient settings

Study designs Randomized controlled trials (RCTs)

IOP= intraocular pressure; OAG = open-angle glaucoma; RCT = randomized controlled trial.

5.1.1 Systematic Review: “Laser Trabeculoplasty for Open-Angle Glaucoma” (Rolim de Moura et al.,

2007)17

A Cochrane meta-analysis of three trials comparing ALT with medications reported that ALT

reduced the chance of uncontrolled IOP at 6 months and 24 months (pooled relative risk [RR] 0.80, 95%

confidence interval [CI] 0.71 to 0.91, I2=0%). The review found a lower but not statistically significant

difference in the risk of visual field progression for ALT when compared with medications at the 2-year

follow-up (RR 0.70, 95% CI 0.42 to 1.16, I2 0%). The review also reported no differences in optic nerve

deterioration. Two older studies from the 1980s evaluated the effectiveness of ALT combined with

medications in patients already using medications; patients receiving combined ALT and medications

were less likely to fail therapy than those on medications alone.55,56 The review did not pool results

because of the underlying heterogeneity of interventions. In terms of harms, two studies reported

adverse effects of peripheral anterior synechiae in the ALT-treated patients (pooled RR 11.15, 95%CI

5.63 to 22.09, I2=0%) compared with medications. The primary outcomes of this review were all

intermediate visual outcomes (failure to control IOP, failure to stabilize visual field progression, and

failure to stabilize optic disc deterioration); authors found no evidence for outcomes related to visual

impairment or vision-related QOL.

5.1.2 Systematic Review: “Treatment for Glaucoma: Comparative Effectiveness” (Boland et al., 2012)51

Boland and associates,51 in a review for the Agency of Healthcare Research and Quality,

examined the effect of medical, laser, and surgical treatments for OAG on intermediate and final visual

health outcomes including harms. They report intermediate visual outcomes from Rolim de Moura et

al.17 and three additional primary studies in which laser therapy and medication groups did not differ

significantly in the change in IOP, visual field loss, and optic nerve deterioration.57-59 Regarding harms,

5

laser therapy did not carry the risk of ocular discomfort associated with medications. The reviewers

identified no evidence regarding visual impairment outcomes.

5.1.3 Meta-analysis of SLT versus Topical Medication in the Treatment of OAG (Li et al., 2015)52

A systematic review and meta-analysis by Li and associates52 included five studies comparing SLT

with medications. Of these, three studies compared SLT with prostaglandin eye drops (current first-line

therapy),60-62 and two studies compared SLT with medications from several classes.59,63 In the four

studies that reported percent IOP reduction (IOPR%) between the SLT and medication groups, the

pooled results showed no significant difference between the two groups (weighted mean difference in

IOPR%=-1.90, 95% CI -5% to 1.1%, I2=0%). The results were robust to sensitivity analyses of study type

(RCT only) and medication comparator (prostaglandin only). Li and associates also found no significant

difference in success rates between the two therapies, although the definition of success varied by

study. Three studies reported adverse events, but the review did not pool the results. The reviewers did

not report on visual impairment outcomes.

5.1.4 Summary of Systematic Reviews

In summary, the studies reviewed by Rolim de Moura and associates17 show that ALT or ALT in

combination with medications reduces the risk of some intermediate visual health outcomes in

glaucoma compared with medications alone. In comparison, results from Boland et al.51 and Li et al.52

show no significant differences in outcomes between medications and laser therapy. This difference

may be due to the use of older eye drops in the studies of the Cochrane Review by Rolim de Moura et

al.,17 which are not as effective as first-line medical therapy typically used today (e.g., prostaglandins).16

None of the reviews reported race or ethnicity subgroup analyses for studies comparing laser therapy

with medications.

5.2 Limitations

The authors of these reviews and our key informants highlighted several limitations in the body

of evidence for glaucoma treatments.

5.2.1 Limitations in Comparative Effectiveness Research

Reviewers and key informants agreed that the number of studies that adequately compare two

or more treatments over time is insufficient to draw conclusions about the comparative effectiveness of

most currently used therapies. Much of the evidence comparing laser therapy with medical therapy

relies on trials that used older medication therapies that do not have the improved clinical effectiveness

or milder side effect profile of current first-line treatment with prostaglandins.16 Glaucoma research

would also benefit from more rigorous study design, standardized diagnostic criteria for glaucoma and

severity of disease, and standardized reporting of outcomes using the World Glaucoma Association

guidelines.51,52,64

5.2.2 Limited Research on Racial Disparities in Glaucoma Treatment

Evidence for racial disparities in glaucoma treatment comes from older studies that were

excluded from our review for wrong intervention (e.g. surgery). The Advanced Glaucoma Study (2000–

2004) and the Collaborative Initial Glaucoma Treatment Study (CIGTS) (2001) compared incisional

surgery with laser therapy and medications, respectively. Both studies found that black participants had

6

worse outcomes than white participants who had surgery first.6,14 No studies on the differential impact

of treatment on racial subgroups have been published since these two studies. Key informants and

reviewers proposed additional RCTs to understand racial differences in response to laser therapy

compared with medications.17

5.2.3 Limited Reporting of Patient-Centered Outcomes

Most studies report intermediate outcomes but are not long enough to measure outcomes that

ultimately matter to patients—visual impairment, vision-related QOL, or pragmatic outcomes like

delaying the need for surgery.17,51 The minimal QOL data from treatment trials come from the CIGTS and

Early Manifest Glaucoma trials, which were excluded from our review because they used surgery as a

major intervention. Although ophthalmologic examination may show optic nerve deterioration, the

patient may not have any disability in activities of daily living for years,65 thus emphasizing the need for

data on patients’ experience of treatment to better tailor glaucoma management.

The challenges of measuring QOL in glaucoma lie in the chronic, indolent nature of the disease.

The most commonly used measure is the National Eye Institute Visual Function Questionnaire (NEI-VFQ-

25), which is not specific to glaucoma and may not capture the slow progressive changes in function in

glaucoma as compared with, say, cataract disease. Some have suggested modifying the NEI-VFQ-25 to

make it more glaucoma specific.66 Two key informants recommended developing better glaucoma-

sensitive QOL measures.

6. Guidelines

Table 2 lists professional health organizations that offer guidelines for glaucoma management.

In general, these guidelines recommend medications as first-line therapy, but none give a definitive

recommendation.

Table 2. Professional Health Organizations’ Guidelines for Treating OAG

Organization, Year Recommendations

American Academy of Ophthalmology, 201622

Medical treatment is the most common initial intervention. Laser trabeculoplasty can be considered as initial therapy in some specific patients or as an alternative for patients for whom adherence will be difficult.

American Academy of Family Physicians, 201667

Early treatment of patients with glaucoma is recommended to reduce the risk of visual field progression.

American Glaucoma Society, 201668

Treatment should be based on the therapy with the best chance of lowering the patient’s IOP.

Canadian Ophthalmological Society, 200969

The overarching aims of glaucoma management are to preserve visual function and maintain or enhance overall health-related QOL. This is achieved through a careful process of observing and monitoring visual function and providing patient education and support and medical, laser, or surgical intervention, as appropriate.

American Optometric Association, 201070

In the choice of a specific form of treatment or the decision to alter or provide additional therapy, the overriding consideration must be the risk or benefit to the patient. All forms of treatment for glaucoma have potential harms for the patient. The clinician must evaluate the possible impact of the treatment from a social, psychological, financial, and convenience standpoint.

IOP = intraocular pressure; OAG = open-angle glaucoma; QOL = quality of life.

7. Ongoing Research

We captured ongoing glaucoma research in our primary literature search and by searching

ClinicalTrials.gov,71 NIHRePORTER,72 and HRSProj,73 and National Institutes of Health funding.74 We

7

found four active comparative effectiveness treatment trials for glaucoma, summarized in Table 3. All of

these studies compare SLT to eye drops, specifically first-line medical therapy of prostaglandins or any

topical medication. All studies assess intermediate ocular outcomes, including IOP reduction, visual field

progression, and optic nerve deterioration; two are powered to examine health-related QOL as primary

outcomes. The first study is conducted in an African population, although study protocols or

descriptions did not include a subgroup analysis by race or ethnicity for any of the studies in Table 3.

Additionally, we identified a number of projects funded by the National Eye Institute aiming to

identify genetic markers associated with OAG in blacks and Mexican Americans,75-78 as well as a few

studies on aspects of glaucoma management in these subgroups (i.e., adherence in blacks with

glaucoma).79,80

Table 3. Ongoing Studies Comparing Laser Therapy with Medications

Study (Clinical Trial Identifier)

Funding Agency

Location Population; Size

Investigations Outcomes Duration

Status as of 2016

Primary Glaucoma Treatment Trial in Kenya and South Africa—SLT vs. Medication (NCT02774811)80

University College, London

UK, South Africa, Kenya

18 years or older, men and women, glaucoma, black African; 400

Multicenter RCT of SLT versus prostaglandin analogue therapy

IOP reduction 12 months

Recruiting

A Comparison of Bimatoprost SR to Selective Laser Trabeculoplasty in Patients With Open-Angle Glaucoma or Ocular Hypertension (NCT02636946)81

Allergan US 18 years or older, men and women with OAG; 160

RCT of SLT versus Bimatoprost SR

IOP reduction 24 weeks

Recruiting

Laser-1st versus Drops-1st for Glaucoma and Ocular Hypertension Trial (LiGHT)82 (ISRCTN32038223)83

National Institutes of Health, Research Health Technology Assessment Panel

UK 18 years or older, men and women newly diagnosed with OAG; 718

Multicenter RCT of SLT versus eye drops (any drug)

Health-related QOL Glaucoma-specific QOL measures IOP reduction Visual field progression Optic nerve progression Adverse effects Adherence Cost-effectiveness 36 months

Complete, results not published

The Glaucoma Initial Treatment Study (GITS)84

(ACTRN12611000720910)85

Australian National Health and Medical Research Council

Australia 18 years or older, newly diagnosed men and women, primary OAG or pseudo-exfoliation glaucoma; 400

Multicenter RCT of SLT versus eye drops (any drug)

Health-related QOL Glaucoma-specific QOL measures IOP reduction Visual field progression Optic nerve progression, Adverse effects Cost-effectiveness 24 months

Recruiting

IOP = intraocular pressure; OAG = open-angle glaucoma; QOL = quality of life; RCT = randomized controlled trial; SLT = selective laser trabeculoplasty; UK = United Kingdom; US = United States.

8

8. Likelihood of Implementation of Research Results in Practice

Our key informants did not identify practice-level barriers to implementation of comparative

effectiveness research on laser therapy versus eye drops. Although laser therapy is widely available in

ophthalmologic practices, provider-level and patient-level factors are barriers to its implementation.

One key informant noted that even after the trials of the 1980s and 1990s suggested comparable

efficacy of medications and laser therapy, laser therapy experienced limited uptake, even among

patients who may struggle with adherence to chronic treatment with eye drops. Another key informant

noted general clinical inertia to adopting new research.86 However, as discussed above, comparative

effectiveness research on laser trabeculoplasty and currently used eye drops is limited. Additionally,

comparative effectiveness research on racial differences in treatment is nearly nonexistent. Further

research in these areas can support provider–patient medical decision making.

Our key informants indicated a need for broader research into the contextual factors influencing

racial disparities. One informant noted the multiple ongoing glaucoma genetics studies funded by the

National Eye Institute, but he also pointed to the limited research in understanding and overcoming

barriers to accessing glaucoma care for black and Hispanic populations. Studies examining the reasons

for racial disparities could facilitate implementation of comparative effectiveness research and help

reduce health disparities. For example, the Philadelphia Glaucoma Detection and Treatment study is a

community-based intervention where educational workshops, screening, and treatment are offered on

site in underserved communities, in settings like churches and community centers. Twenty percent of

participants had suspected OAG and 9% received a diagnosis.87 Among newly diagnosed OAG patients

who attended a workshop that presented laser therapy and medications as first-line therapies, 20%

chose laser therapy over medications for initial treatment.87 This uptake was much higher than

expected, according to one of our key informants, indicating the role for improved patient education.

Project EQUALITY (Eye Care Quality and Accessibility Improvement in the Community), another

community-based intervention offering educational workshops, showed some improvement in

knowledge88 and offers glaucoma screening and treatment through community-based optometrists with

ophthalmology telemedicine support (results not yet available).

All key informants also noted the importance of patient-reported outcomes in supporting

implementation of research findings: information about patient experience and QOL with different

procedures could better guide medical decision making and facilitate implementation of comparative

effectiveness research.

9. Durability of Information

In the last few decades, research advances have solidified the practice paradigm of lowering IOP

to slow the progression of visual loss in glaucoma, using medical therapy, laser trabeculoplasty, or

incisional surgery. Our key informants did not anticipate new medical therapies that would make the

use of laser therapy or surgery obsolete. Even if a new medication came to market with better efficacy

and fewer side effects, adherence to medications for a chronic condition would remain an issue.

Minimally invasive glaucoma surgeries (MIGS) is an umbrella term applied to newly developed

surgical techniques using micro devices that aim to achieve the same IOP-lowering effects of surgery

without the less-than-ideal risk profile. Most studies of MIGS are of limited quality and duration and lack

9

study standardization, cost-effectiveness data, and information on ideal patient selection.89

Furthermore, many of these surgeries have been performed in patients with concurrent cataract

surgery; MIGS may be the more appropriate procedure in patients already undergoing surgery.89 Our

key informants had differing views on the future role of MIGS, particularly in racial and ethnic subgroup

populations. One downside of laser therapy is that the IOP-lowering effects generally dissipate after 5

years.20 One key informant suggested that if the promise of MIGS were realized—lower risk compared

with surgery and more durable reduction in IOP compared with laser therapy—then it would be

important to incorporate MIGS into future comparative effectiveness research. However, two other key

informants emphasized that incisional surgery, even minimally invasive surgery, still carries the risk of

intraocular infection, bleeding, and possible blindness that medical and laser therapy do not and that

the latter two will remain mainstays of initial treatment for glaucoma. Moreover, even if MIGS do show

comparable efficacy to laser or medical therapy, black patients may not benefit compared with white

patients as observed with past comparative effectiveness research on surgical treatment of

glaucoma.6,14

10. Potential Research Questions

The evidence gaps identified by our evidence review (Section 5) are not adequately addressed

by ongoing research (Section 7). We highlight comparative effectiveness research areas in which PCORI

can offer funding opportunities for impactful research for glaucoma treatments.

1) What is the comparative effectiveness of laser therapy versus eye drops on patient-centered

outcomes of visual impairment and quality of life?

Longer studies are required to study visual impairment, and further work in patient-

reported outcomes for glaucoma could help address this question. Studies will need to

address patient-level, provider-level, and system-level barriers to treatment that may help

facilitate implementation of comparative effectiveness research for high-risk populations.

2) What is the comparative effectiveness of laser therapy versus eye drops for black and

Hispanic individuals?

More comparative effectiveness studies are needed for all patients, but future studies

should be powered to measure differences in racial and ethnic subgroups. Studies will need

to address patient-level, provider-level, and system-level barriers to treatment that may

help facilitate implementation of comparative effectiveness research for high-risk

populations

11. Conclusion

Untreated, glaucoma silently leads to visual impairment and blindness. Black and Hispanic

individuals are disproportionately affected. Future comparative effectiveness research in glaucoma may

fill evidence gaps by focusing on patient-centered outcomes, outcomes by racial and ethnic subgroups,

and strategies for addressing barriers to treatment that can lead to a reduction in disparities.

10

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A-1

Appendix A: Key Informant Information

Michael Boland, MD, PhD Associate Professor of Ophthalmology Wilmer Eye Institute at Johns Hopkins University School of Medicine 600 N. Wolfe Street Baltimore, MD 21287 L. Jay Katz, MD

Glaucoma Service Director

Wills Eye Hospital

840 Walnut Street, Suite 1110

Philadelphia, PA 19107

Paul R. Lichter, MD, MS

Professor

Kellogg Eye Center at University of Michigan

1000 Wall Street

Ann Arbor, MI 48105

B-2

Appendix B. Search Strategy

B1. Search strategy for primary literature review.

PubMed – 232 records #1 (glaucoma*[Title] OR "Glaucoma"[Mesh:NoExp] OR "Glaucoma, Open-Angle"[Mesh]) AND (laser*[Title] OR "Laser Therapy"[Mesh] OR "Lasers"[Mesh] OR ("Trabeculectomy"[Mesh] AND laser*[Text Word]) OR "trabeculoplasty"[Title]) AND (eye drop*[Title] OR eyedrop*[Title] OR ophthalmic drop*[Title] OR eye solution*[Title] OR ophthalmic solution*[Title] OR ((topical*[Title] OR ophthalmic*[Title]) AND (drop*[Title] OR solution*[Title] OR administ*[Title])) OR "Administration, Ophthalmic"[Mesh] OR "Administration, Topical"[Mesh:NoExp] OR "Ophthalmic Solutions"[Mesh] OR "Ophthalmic Solutions"[Pharmacological Action] OR "Prostaglandins, Synthetic"[Mesh] OR prostaglandin analog*[Title] OR synthetic prostaglandin*[Title] OR Latanoprost[Title] OR Travoprost[Title] OR Tafluprost[Title] OR Unoprostone[Title] OR bimatoprost[Title] OR "latanoprost"[Supplementary Concept] OR "Travoprost"[Mesh] OR "tafluprost"[Supplementary Concept] OR "isopropyl unoprostone"[Supplementary Concept] OR "Bimatoprost"[Mesh] OR "Adrenergic beta-Antagonists"[Mesh] OR "Adrenergic beta-Antagonists"[Pharmacological Action] OR β-Adrenergic blocker*[Title] OR beta adrenergic blocker*[Title] OR Adrenergic beta-Antagonist*[Title] OR "Timolol"[Mesh] OR "Levobunolol"[Mesh] OR "Carteolol"[Mesh] OR "Metipranolol"[Mesh] OR "Betaxolol"[Mesh] OR Timolol[Title] OR Levobunolol[Title] OR Carteolol[Title] OR Metipranolol[Title] OR betaxolol[Title] OR "Adrenergic alpha-Agonists"[Mesh] OR "Adrenergic alpha-Agonists"[Pharmacological Action] OR Adrenergic alpha-Agonist*[Title] OR α-Adrenergic agonist*[Title] OR alpha Adrenergic agonist*[Title] OR Brimonidine[Title] OR apraclonidine[Title] OR "Brimonidine Tartrate"[Mesh] OR "apraclonidine"[Supplementary Concept] OR "Carbonic Anhydrase Inhibitors"[Mesh] OR "Carbonic Anhydrase Inhibitors"[Pharmacological Action] OR Carbonic anhydrase Inhibitor*[Title] OR Dorzolamide[Title] OR Brinzolamide[Title] OR acetazolamide[Title] OR "dorzolamide"[Supplementary Concept] OR "brinzolamide"[Supplementary Concept] OR "Acetazolamide"[Mesh] OR "Cholinergic Agonists"[Mesh] OR "Cholinergic Agonists"[Pharmacological Action] OR Cholinergic agonist*[Title] OR Pilocarpine[Title] OR carbachol[Title] OR "Pilocarpine"[Mesh] OR "Carbachol"[Mesh]) Filters: Publication date from 1990/01/01; English – 232 Embase – 58 records (29 records with duplicates removed) #1 (glaucoma*:ti OR ‘glaucoma’/mj OR ‘open angle glaucoma’/mj) AND (laser*:ti OR ‘laser’/mj OR ‘ophthalmic laser’/exp/mj OR ‘low level laser therapy’/mj OR (‘trabeculectomy’/mj AND laser*:ti,ab) OR trabeculoplasty:ti) AND ((eye NEXT/1 drop*):ti OR eyedrop*:ti OR (ophthalmic NEXT/1 drop*):ti OR (eye NEXT/1 solution*):ti OR (ophthalmic NEXT/1 solution*):ti OR ((topical* OR ophthalmic*) AND (drop* OR solution* OR administ*)):ti OR ‘intraocular drug administration’/exp/mj OR ‘prostaglandin derivative’/exp/mj OR (prostaglandin NEXT/1 analog*):ti OR (synthetic NEXT/1 prostaglandin*):ti OR Latanoprost:ti OR Travoprost:ti OR Tafluprost:ti OR Unoprostone:ti OR bimatoprost:ti OR ‘beta adrenergic receptor blocking agent’/exp/mj OR (‘β-Adrenergic’ NEXT/1 blocker*):ti OR (‘beta adrenergic’ NEXT/1 blocker*):ti OR (‘Adrenergic beta’ NEXT/1 Antagonist*):ti OR Timolol:ti OR Levobunolol:ti OR Carteolol:ti OR Metipranolol:ti OR betaxolol:ti OR ‘alpha adrenergic receptor stimulating agent’/exp/mj OR (‘Adrenergic alpha’ NEXT/1 Agonist*):ti OR (‘α-Adrenergic’ NEXT/1 agonist*):ti OR (‘alpha Adrenergic’ NEXT/1 agonist*):ti OR Brimonidine:ti OR apraclonidine:ti OR ‘carbonate dehydratase inhibitor’/exp/mj OR (‘Carbonic anhydrase’ NEXT/1 Inhibitor*):ti OR Dorzolamide:ti OR Brinzolamide:ti OR acetazolamide:ti OR ‘cholinergic receptor stimulating agent’/exp/mj OR (Cholinergic NEXT/1 agonist*):ti OR Pilocarpine:ti OR carbachol:ti) AND [english]/lim AND [1990-2016]/py 58

B-3

Web of Science - 122 records (93 records with duplicates removed) #3 122 #2 OR #1 #2 72 TITLE: (glaucoma* AND ("eye drop*" OR eyedrop* OR "ophthalmic drop*" OR "eye solution*" OR "ophthalmic solution*" OR ((topical* OR ophthalmic*) AND (drop* OR solution* OR administ*)) OR "prostaglandin analog*" OR "synthetic prostaglandin*" OR Latanoprost OR Travoprost OR Tafluprost OR Unoprostone OR bimatoprost OR "β-Adrenergic blocker*" OR "beta adrenergic blocker*" OR "Adrenergic beta-Antagonist*" OR Timolol OR Levobunolol OR Carteolol OR Metipranolol OR betaxolol OR "Adrenergic alpha-Agonist*" OR "α-Adrenergic agonist*" OR "alpha Adrenergic agonist*" OR Brimonidine OR apraclonidine OR "Carbonic anhydrase Inhibitor*" OR Dorzolamide OR Brinzolamide OR acetazolamide OR "Cholinergic agonist*" OR Pilocarpine OR carbachol)) AND TOPIC: ((laser* OR trabeculoplasty)) AND LANGUAGE: (English) Indexes=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=1990-2016 #1 59 TITLE: (glaucoma* AND (laser* OR trabeculoplasty)) AND TOPIC: (("eye drop*" OR eyedrop* OR "ophthalmic drop*" OR "eye solution*" OR "ophthalmic solution*" OR ((topical* OR ophthalmic*) NEAR/2 (drop* OR solution* OR administ*)) OR "prostaglandin analog*" OR "synthetic prostaglandin*" OR Latanoprost OR Travoprost OR Tafluprost OR Unoprostone OR bimatoprost OR "β-Adrenergic blocker*" OR "beta adrenergic blocker*" OR "Adrenergic beta-Antagonist*" OR Timolol OR Levobunolol OR Carteolol OR Metipranolol OR betaxolol OR "Adrenergic alpha-Agonist*" OR "α-Adrenergic agonist*" OR "alpha Adrenergic agonist*" OR Brimonidine OR apraclonidine OR "Carbonic anhydrase Inhibitor*" OR Dorzolamide OR Brinzolamide OR acetazolamide OR "Cholinergic agonist*" OR Pilocarpine OR carbachol)) AND LANGUAGE: (English) Indexes=SCI-EXPANDED, SSCI, CPCI-S, CPCI-SSH Timespan=1990-2016 Cochrane Library - 123 records (42 records with duplicates removed) #1 glaucoma*:ti or glaucoma*:kw Publication Year from 1990 to 2016 3627 #2 laser* or trabeculoplasty:ti or laser* or trabeculoplasty:kw Publication Year from 1990 to 2016 8752 #3 "eye drop*" or eyedrop* or "ophthalmic drop*" or "eye solution*" or "ophthalmic solution*" or ((topical* or ophthalmic*) and (drop* or solution* or administ*)) or "prostaglandin analog*" or "synthetic prostaglandin*" or Latanoprost or Travoprost or Tafluprost or Unoprostone or bimatoprost or "β-Adrenergic blocker*" or "beta adrenergic blocker*" or "Adrenergic beta-Antagonist*" or Timolol or Levobunolol or Carteolol or Metipranolol or betaxolol or "Adrenergic alpha-Agonist*" or "α-Adrenergic agonist*" or "alpha Adrenergic agonist*" or Brimonidine or apraclonidine or "Carbonic anhydrase Inhibitor*" or Dorzolamide or Brinzolamide or acetazolamide or "Cholinergic agonist*" or Pilocarpine or carbachol:ti or "eye drop*" or eyedrop* or "ophthalmic drop*" or "eye solution*" or "ophthalmic solution*" or ((topical* or ophthalmic*) and (drop* or solution* or administ*)) or "prostaglandin analog*" or "synthetic prostaglandin*" or Latanoprost or Travoprost or Tafluprost or Unoprostone or bimatoprost or "β-Adrenergic blocker*" or "beta adrenergic blocker*" or "Adrenergic beta-Antagonist*" or Timolol or Levobunolol or Carteolol or Metipranolol or betaxolol or "Adrenergic alpha-Agonist*" or "α-Adrenergic agonist*" or "alpha Adrenergic agonist*" or Brimonidine or apraclonidine or "Carbonic anhydrase Inhibitor*" or Dorzolamide or Brinzolamide or acetazolamide or "Cholinergic agonist*" or Pilocarpine or carbachol:kw Publication Year from 1990 to 2016 16108 #4 #1 and #2 and #3 123

B2. Search strategy for ongoing research studies.

Search terms: “trabeculoplasty” WITH Condition: glaucoma; “Medical therapy AND trabeculoplasty”

WITH Condition: Glaucoma