Comparisons of Medical, Laser, and Incisional Surgical Treatments for Open-Angle Glaucoma in Adults Prepared for: Agency for Healthcare Research and Quality (AHRQ)

This presentation covers:  The comparative effectiveness review (CER) process used by the Agency for Healthcare Research and Quality  Background information  Clinical questions addressed in the CER  A summary of the CER results (Clinical Bottom Line) comparing medical, surgical, and medical versus surgical interventions for:  Lowering intraocular pressure  Optic nerve damage and/or visual field loss  Reducing visual impairment  Reported adverse effects  Gaps in knowledge  Resources for shared decisionmaking Outline of Material

 Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into a Clinician Research Summary and a Consumer Research Summary for use in decisionmaking and in discussions with patients. The Research Summaries and the full report are available at Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 The strength of evidence ratings only apply to the analysis of primary studies in this review and are classified into four broad ratings:  Systematic review data were included and were considered as the highest level of evidence for addressing questions of therapy, but it was not possible to adapt the evidence grading scheme to incorporate evidence from systematic reviews. Strength of Evidence Ratings AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at Owens DK, Lohr KN, Atkins D, et al. J Clin Epidemiol 2010;63(5): PMID:

 Glaucoma is a leading cause of irreversible visual impairment and blindness worldwide.  Glaucoma is an acquired disease of the optic nerve (neuropathy), characterized by a particular appearance of the optic nerve and by visual field defects that are usually midperipheral and in the nasal visual field.  If optic nerve damage is associated with an open or closed appearance to the drainage channels for aqueous humor in the front of the eye, the glaucoma is referred to as open angle (the subject of this report) or closed-angle, respectively. Background: Open-Angle Glaucoma Heijl A, Leske MC, Bengtsson B, et al. Arch Ophthalmol 2002;120(10): PMID: Kass MA, Heuer DK, Higginbotham EJ, et al. Arch Ophthalmol 2002;120(6):701-13; discussion PMID: Quigley HA, Boman AT. Br J Ophthalmol 2006;90(3): PMID: Quigley HA, Flower RW, Addicks EM, et al. Invest Ophthalmol Vis Sci 1980;19(5): PMID: Sommer A, Tielsch JM, Katz J, et al. Arch Ophthalmol 1991;109(8): PMID:

 In mild glaucoma, damage to the optic nerve may be asymptomatic.  If damage increases, patients may have difficulty with peripheral vision, contrast sensitivity, glare, adjustments between light and dark, and clear central vision.  Severe glaucoma can result in total, irreversible blindness. Pathophysiology of Glaucoma Heijl A, Leske MC, Bengtsson B, et al. Arch Ophthalmol 2002;120(10): PMID: Kass MA, Heuer DK, Higginbotham EJ, et al. Arch Ophthalmol 2002;120(6):701-13; discussion PMID: Quigley HA, Boman AT. Br J Ophthalmol 2006;90(3): PMID: Quigley HA, Flower RW, Addicks EM, et al. Invest Ophthalmol Vis Sci 1980;19(5): PMID: Sommer A, Tielsch JM, Katz J, et al. Arch Ophthalmol 1991;109(8): PMID:

 Treatments focus on reducing intraocular pressure (IOP), which may prevent the secondary worsening of visual field loss, visual impairment, and blindness.  Eye drops are currently the most common treatment, including prostaglandin analogs, beta-adrenergic antagonists, oral and topical carbonic anhydrase inhibitors, and alpha-adrenergic agonists.  Laser trabeculoplasty is an outpatient procedure that lowers IOP by increasing the outflow of aqueous humor from the eye.  Incisional surgeries include well-established techniques including trabeculectomy and aqueous drainage device surgery, as well as a host of newer procedures, such as nonpenetrating deep sclerectomy, canaloplasty, endoscopic cyclophotocoagulation, and alternative methods of trabecular bypass. Treatments for Open-Angle Glaucoma Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 What is the comparative effectiveness for medical, surgical, or medical versus surgical treatments for open- angle glaucoma in adults for these outcomes:  Lowering intraocular pressure?  Preventing or slowing the progression of optic nerve damage and visual field loss?  Reducing visual impairment?  Patient-related quality of life?  Adverse effects from treatments? Clinical Questions Addressed in the Comparative Effectiveness Review Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Overall, strong evidence from other systematic reviews (50 trials) found that:  As single agents, prostaglandin analogs are the most effective at lowering intraocular pressure (IOP).  Prostaglandin analogs appear to be similar in their ability to lower IOP.  Prostaglandin analogs lower IOP more than other agents, including:  Brimonidine (mean difference of 1.64 mmHg; 4 trials)  Dorzolamide (mean difference of 2.64 mmHg; 3 trials)  Timolol (5% greater at 6 months; 4 trials)  In combination, dorzolamide/timolol lowers IOP the same amount as a prostaglandin analog. Clinical Bottom Line: Lowering Intraocular Pressure—Medical Interventions Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Laser trabeculoplasty effectively lowers intraocular pressure (IOP) regardless of the type of laser used.  Strength of Evidence = Moderate  With regard to incisional surgery, trabeculectomy more effectively reduces IOP than nonpenetrating surgeries such as viscocanalostomy and deep sclerectomy.  Strength of Evidence = Moderate  Intraoperative mitomycin-C enhances IOP reduction when used with trabeculectomy but not when used with other surgical methods.  Strength of Evidence = Moderate Clinical Bottom Line: Lowering Intraocular Pressure—Surgical Interventions (1 of 3) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 These surgical comparisons demonstrated similar lowering effects on intraocular pressure (Strength of Evidence = Moderate):  Trabeculectomy performed at nasal, superior, or temporal ocular sites  Trabeculectomy with a fornix versus limbus conjunctival incision  Laser suture lysis versus adjustable sutures after fornix-based trabeculectomy  Fornix-based trabeculectomy plus either mitomycin-C (MMC) or an Ologen ™ implant  Limbus-based trabeculectomy with or without an intraoperative amniotic membrane graft  Trabeculectomy plus MMC with or without an Ex-PRESS ™ minishunt Clinical Bottom Line: Lowering Intraocular Pressure—Surgical Interventions (2 of 3) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Two-site versus one-site phacotrabeculectomy may be associated with greater reductions in intraocular pressure (IOP).  Strength of Evidence = Moderate  The IOP-lowering effect of phacotrabeculectomy is not affected by the location of the conjunctival incision or the presence or absence of a peripheral iridectomy.  Strength of Evidence = Moderate  Evidence was insufficient to determine the comparative effectiveness of aqueous drainage devices in treating open- angle glaucoma.  Strength of Evidence = Insufficient Clinical Bottom Line: Lowering Intraocular Pressure—Surgical Interventions (3 of 3) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Incisional surgery lowers intraocular pressure (IOP) more than laser surgery or medications.  Strength of Evidence = Low  Initial treatment with lasers tends to reduce the need for medications to achieve the same IOP.  Strength of Evidence = Low Clinical Bottom Line: Lowering Intraocular Pressure—Medical Versus Surgical Interventions Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 These medicines lower circadian intraocular pressure (IOP) throughout a 24-hour cycle:  Prostaglandin analogs (latanoprost, bimatoprost, travoprost)  Beta-adrenergic blocker (timolol)  Alpha-adrenergic agonist (brimonidine)  Carbonic anhydrase inhibitor (dorzolamide)  Strength of Evidence = Low  Over a 24-hour cycle, prostaglandin analogs (latanoprost, bimatoprost, and travoprost) appear to lower circadian IOP more than:  A beta-blocker (timolol)  A topical carbonic anhydrase inhibitor (dorzolamide)  An alpha-adrenergic agonist (brimonidine)  Strength of Evidence = Low  Results for comparisons among prostaglandins were inconsistent; however, the reported difference among prostaglandins in the magnitude of IOP lowering was about 1 mmHg.  Strength of Evidence = Low Clinical Bottom Line: Lowering Circadian Intraocular Pressure Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Overall, strong evidence from a Cochrane review (N = 4,979 patients; 26 trials) that included the Early Manifest Glaucoma Trial (n = 255 patients) and the Ocular Hypertension Treatment Study (n = 1,636 patients) found that medical treatment decreased the rate of visual field loss and progressive optic nerve damage. Clinical Bottom Line: Optic Nerve Damage and/or Visual Field Loss—Medical Interventions (Systematic Reviews) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at Heijl A, Leske MC, Bengtsson B, et al. Arch Ophthalmol 2002;120(10): PMID: Kass MA, Heuer DK, Higginbotham EJ, et al. Arch Ophthalmol 2002;120(6): PMID: Vass C, Him C, Sycha T, et al. Cochrane Database Syst Rev 2007 Oct 17;(4):CD PMID:

 Treatment of ocular hypertension with medicines preserves visual fields better than no treatment.  Strength of Evidence = Low  The Low-Pressure Glaucoma Treatment Study found that fewer patients treated with brimonidine (9.1%) had progression of visual field loss than those treated with timolol (39.2%; p = 0.001).  Strength of Evidence = Low  All other primary studies were of insufficient size or duration to provide additional evidence about the effects of medical treatments on the progression of optic nerve damage.  Strength of Evidence = Insufficient Clinical Bottom Line: Optic Nerve Damage and/or Visual Field Loss—Medical Interventions (Primary Studies) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at Krupin T, Liebmann JN, Greenfield DS, et al. Am J Ophthamol 2011;141(14): PMID:

 Studies comparing surgical interventions did not report outcomes related to optic nerve damage or visual field loss.  Outcomes related to optic nerve damage and visual field loss are discussed in reference to the effectiveness of medical versus surgical interventions. Clinical Bottom Line: Optic Nerve Damage and/or Visual Field Loss—Surgical Interventions Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Overall, strong evidence from three systematic reviews (10 trials) indicate:  Patients treated medically and/or surgically (trabeculoplasty or trabeculectomy) are less likely to experience progression of field loss and optic nerve damage versus those who received no treatment.  The two systematic reviews comparing medical versus surgical interventions did not include contemporary medications (e.g., prostaglandin analogs).  In four out of five trials, patients treated with older medications had more progression of visual field loss when compared with those randomized to laser trabeculoplasty or trabeculectomy.  These results should be interpreted cautiously in light of the increased effectiveness of prostaglandin analogs when compared with these medications. Clinical Bottom Line: Optic Nerve Damage and/or Visual Field Loss— Medical Versus Surgical Interventions (Systematic Reviews) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Evidence from included primary studies was insufficient to distinguish a difference in visual field loss between surgical techniques and medications.  Strength of Evidence = Insufficient  For advanced glaucoma, evidence from included primary studies was insufficient to guide clinical decisionmaking regarding initial trabeculectomy or medication.  Strength of Evidence = Insufficient Clinical Bottom Line: Optic Nerve Damage and/or Visual Field Loss—Medical Versus Surgical Interventions (Primary Studies) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Evidence was insufficient to determine any differences in the effects of medical, surgical, or medical versus surgical treatments on visual impairment.  Strength of Evidence = Insufficient  Secondary outcomes of visual acuity were similar for all laser and other surgical interventions studied.  Strength of Evidence = Low Clinical Bottom Line: Reducing Visual Impairment Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at Burr J, Azuara-Blanco A, Avenell A. Cochrane Database Syst Rev 2004 Apr 18;(2):CD PMID: de Jong LA. Adv Ther 2009;26(3): PMID: Mielke C, Dawda VK, Anand N. Br J Ophthalmol 2006;90(3): PMID: Russo V, Scott IU, Stella A, et al. Eur J Ophthalmol 2008;18(5): PMID: Shaarawy T, Mermoud A. Eye (Lond) 2005;19(3): PMID:

 Evidence from included studies did not address a direct link between treatments for open-angle glaucoma and relative changes in patient-reported outcomes such as vision-related quality of life due to the unavailability of studies with sufficiently long-term followup.  Included studies did find that:  Patients preferred the medication that was administered less frequently.  Fear of blindness in newly diagnosed patients (34%) was significantly reduced 5 years after medical or surgical treatments (11%) in the Collaborative Initial Glaucoma Treatment Study Patient-Related Quality of Life Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 The evidence did not permit an analysis of the strength of evidence for comparative adverse effects across interventions.  There were a number of issues with assessing adverse effects. For example, adverse effects were not the primary outcome for the studies, meaning that the studies were not powered to detect differences. Comparative Adverse Effects Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Conjunctival hyperemia (redness) is the most commonly reported adverse effect among the observational studies of medical treatment for open-angle glaucoma.  Latanoprost is less likely to cause ocular redness among the prostaglandin analogs; however, as a class, prostaglandins may produce more ocular redness than does timolol.  Timolol is more likely to result in systemic side effects like shortness of breath or bradycardia. Reported Adverse Effects: Medical Interventions Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Trabeculectomy produces more hypotony, hyphema, shallow anterior chambers, cataracts, and choroidal detachment than the nonpenetrating procedures of deep sclerectomy or viscocanalostomy.  The risk of epithelial toxicity was 5.85 times as great with the addition of postoperative 5-fluorouracil in participants receiving primary trabeculectomy. Reported Adverse Effects: Surgical Interventions (1 of 2) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 There is no clear difference in adverse effects between one-site versus two-site phacotrabeculectomy.  The adverse effects associated with glaucoma drainage devices have not been adequately compared with the adverse effects of other procedures used to treat open- angle glaucoma.  Adverse effects reported from aqueous shunts include choroidal hemorrhage, choroidal complications, corneal complications, strabismus, no light perception, phthisis, tube exposure, retinal detachment, and infection. Reported Adverse Effects: Surgical Interventions (2 of 2) Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Trabeculectomy is associated with worsening of cataracts and an increased need for cataract surgery over time when compared with medical treatments for glaucoma.  Intraocular surgery rarely results in severe vision loss due to infection and/or bleeding. These risks are not associated with medical or laser treatments. Reported Adverse Effects: Medical Versus Surgical Interventions Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Medications and laser and incisional surgeries are effective in lowering intraocular pressure (IOP).  Prostaglandin analogs are consistently superior to the other drug classes in terms of their IOP-lowering ability and adverse effect profile.  Laser trabeculoplasty lowers IOP regardless of the type of laser used.  For incisional surgeries, trabeculectomy lowers IOP more than nonpenetrating surgical procedures, and this effect may be enhanced with mitomycin-C.  Patients treated medically and/or surgically (trabeculoplasty or trabeculectomy) were less likely to experience progression of visual field loss and optic disc damage versus those who received no treatment. Conclusions: Outcomes Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 Harms from medications do not threaten vision and commonly consist of conjunctival hyperemia and ocular irritation.  Complications of surgery are more significant than medications and may include infection, bleeding, cataract formation, choroidal effusions, hyphema, and flattening of the anterior chamber.  Adverse effects are more common with trabeculectomy than with nonpenetrating surgeries and may be increased in the presence of mitomycin-C. Conclusions: Adverse Effects Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 While at this time current evidence does not address a direct link between reductions in intraocular pressure (IOP), visual field loss, or optic nerve damage and reductions in visual impairment or vision-related quality of life, this should not be interpreted to mean that reductions in IOP, visual field loss, or optic nerve damage are not important for reducing visual impairment or maintaining vision-related quality of life, but rather that studies demonstrating this direct linkage are not available.  Given the slow progression of glaucoma, even if left untreated, it is not surprising these studies were not identified.  The time required to establish relative differences in patient outcomes requires studies with lengthy followup, which are not currently available. Conclusions: Glaucoma Treatment and Visual Impairment or Vision-Related Quality of Life Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 The systematic review identified areas where more evidence is needed on:  A direct association between treatment for open-angle glaucoma (OAG) and visual impairment and/or patient- reported outcomes  The relative risks and benefits of current medical and surgical treatments for OAG Gaps in Knowledge Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

 The severity of the patient’s glaucoma and need for treatment  The different types of treatment for glaucoma  The benefits and adverse effects of medicines, laser treatments, and surgeries for open-angle glaucoma  Patient preferences regarding the types of treatment  The importance of adherence to medicine regimens  The importance of regular and consistent followup with an ophthalmologist or glaucoma specialist to monitor disease progression over time  The cost of medicines and surgical treatments Shared Decisionmaking: What To Discuss With Your Patients Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at

Resource for Patients  Treatments for Open-Angle Glaucoma, A Review of the Research for Adults is a free resource for patients. It can help patients talk with their health care professionals about the many options for treating open- angle glaucoma. It provides:  Explanations of glaucoma and its causes  Explanations of medical and surgical treatments  Current evidence of effectiveness and adverse effects  Questions for patients to ask their doctor Boland MV, Ervin AM, Friedman D, et al. Comparative Effectiveness Review No. 60. Available at