Landmark Trials in Ophthalmology

Herpetic Eye Disease Study — topical corticosteroids for stromal keratitis

Population

106 patients with active HSV stromal keratitis

Design

10-week topical prednisolone taper vs. placebo (both arms also received topical trifluridine)

Result

Steroids reduced persistent/progressive stromal keratouveitis by 68% and shortened time to resolution; no difference in 6-month visual outcome.

Conclusion

Topical corticosteroids are beneficial in HSV stromal keratitis when combined with antiviral prophylaxis.

Herpetic Eye Disease Study — oral acyclovir for stromal keratitis

Population

104 patients with HSV stromal keratitis

Design

10-week oral acyclovir 400 mg 5×/day vs. placebo (both arms on topical steroid + trifluridine)

Result

No significant difference in treatment failure, time to resolution, or 6-month visual acuity, though more acyclovir-group patients improved visually over 6 months.

Conclusion

Oral acyclovir added no measurable benefit as adjunctive therapy for stromal keratitis already being treated with steroids.

Herpetic Eye Disease Study — oral acyclovir for HSV iridocyclitis

Population

50 patients with HSV iridocyclitis (trial stopped early for slow enrollment)

Design

10-week oral acyclovir vs. placebo (both arms on topical steroid + trifluridine)

Result

Treatment failure was lower with acyclovir (50%) than placebo (68%), a trend that did not reach significance given the small sample.

Conclusion

Underpowered, but the trend suggested a possible benefit of oral acyclovir for HSV iridocyclitis.

Herpetic Eye Disease Study — acyclovir to prevent progression of epithelial keratitis

Population

287 patients with HSV epithelial keratitis

Design

3-week oral acyclovir vs. placebo (both arms on topical trifluridine)

Result

Stromal keratitis or iritis developed in 11% of the acyclovir group vs. 10% of placebo — no difference.

Conclusion

A 3-week course of oral acyclovir does not prevent progression from epithelial to stromal disease or iritis.

Herpetic Eye Disease Study — Acyclovir Prevention Trial

Population

703 patients with ocular HSV disease in the prior year, off treatment

Design

12-month oral acyclovir 400 mg BID vs. placebo

Result

Recurrence at 12 months: 19% with acyclovir vs. 32% with placebo — about a 50% relative reduction.

Conclusion

Long-term suppressive oral acyclovir meaningfully reduces recurrence of ocular HSV disease.

Herpetic Eye Disease Study — risk-factor study for recurrence

Population

308 patients with ocular HSV disease in the prior year

Design

Prospective cohort nested in the APT trial, tracking stress, illness, sunlight, menses, contact lens wear, and eye injury

Result

None of the tracked exposures (including psychological stress) was associated with recurrence once recall bias was accounted for.

Conclusion

No behavioral or environmental trigger reliably predicts ocular HSV recurrence; self-reported associations are largely recall bias.

Herpetic Eye Disease Study — predictors of recurrent keratitis

Population

346 placebo-arm patients from the Acyclovir Prevention Trial

Design

18-month observational follow-up comparing prior epithelial vs. prior stromal disease

Result

A history of epithelial keratitis did not predict recurrent epithelial disease, but a history of stromal keratitis increased the risk of recurrent stromal keratitis roughly tenfold.

Conclusion

Prior stromal — but not prior epithelial — disease is the strongest predictor of future stromal keratitis.

Steroids for Corneal Ulcers Trial

Population

500 patients with culture-positive bacterial corneal ulcers

Design

Adjunctive topical prednisolone 1% vs. placebo, both after 48h of moxifloxacin

Result

No overall difference in 3-month vision, scar size, or perforation; a subgroup with counting-fingers-or-worse vision or a central ulcer did significantly better with steroids.

Conclusion

Adjunctive corticosteroids are safe but show no overall benefit for bacterial keratitis, aside from a benefit in eyes presenting with severe vision loss or central ulcers.

Cornea Donor Study

Population

1,090 patients undergoing penetrating keratoplasty for endothelial disease

Design

Donor corneas aged 12–75, assigned without regard to recipient factors, followed up to 12 years

Result

10-year graft success was 77% for donors 12–65y vs. 71% for donors 66–75y — not significant overall, though continuous analysis showed higher donor age lowered success beyond year 5.

Conclusion

Donor age is not an important factor for most transplants, but there is a modest effect at the extremes of the donor age range.

Diabetic Retinopathy Study

Population

1,727 patients with severe NPDR or PDR in at least one eye

Design

One eye scatter (panretinal) photocoagulation vs. the fellow eye untreated

Result

Photocoagulation reduced severe visual loss by 50% or more, at the cost of some visual field constriction.

Conclusion

Established scatter laser as standard treatment for high-risk PDR (neovascularization of the disc, or hemorrhage with any neovascularization).

Branch Vein Occlusion Study

Population

139 eyes with macular edema from branch retinal vein occlusion

Design

Grid argon laser photocoagulation vs. untreated control

Result

Treated eyes gained significantly more visual acuity than controls over a mean 3.1-year follow-up.

Conclusion

Grid laser improves vision in eyes with macular edema and vision ≤20/40 from BRVO.

Diabetic Retinopathy Vitrectomy Study, report 5

Population

616 eyes with severe vitreous hemorrhage from diabetic retinopathy

Design

Early vitrectomy vs. deferral for 1 year

Result

Early vitrectomy increased the chance of 20/40 vision from 12% to 36% in type 1 diabetics; no advantage was seen in type 2 diabetics.

Conclusion

Early vitrectomy benefits type 1 diabetics (and monocular patients) with non-clearing vitreous hemorrhage.

Early Treatment Diabetic Retinopathy Study, report 9

Population

3,711 patients with mild-to-severe NPDR or early PDR

Design

One eye early photocoagulation vs. the fellow eye deferred until high-risk PDR appeared

Result

Early treatment gave a small reduction in severe visual loss; focal laser reduced moderate visual loss from macular edema, but scatter laser alone did not.

Conclusion

Focal laser is effective for macular edema; scatter laser should be reserved for eyes reaching the high-risk PDR stage rather than applied early for mild/moderate disease.

Diabetes Control and Complications Trial — glycemic exposure and retinopathy

Population

1,441 patients with type 1 diabetes

Design

Conventional vs. intensive glycemic control

Result

A 10% lower HbA1c (e.g., 8% vs. 7.2%) was associated with roughly a 43–45% lower risk of retinopathy progression, with no threshold below which risk stopped falling.

Conclusion

Intensive glycemic control substantially reduces retinopathy progression in type 1 diabetes.

Endophthalmitis Vitrectomy Study

Population

420 patients with post-cataract-surgery endophthalmitis

Design

2×2 design: immediate vitrectomy vs. tap/inject, with or without systemic antibiotics

Result

Systemic antibiotics added no benefit; immediate vitrectomy helped only the subgroup presenting with light-perception-only vision (a threefold increase in reaching 20/40 or better).

Conclusion

Skip routine systemic antibiotics; reserve immediate vitrectomy for eyes presenting with light-perception vision or worse.

Central Vein Occlusion Study

Population

181 eyes with ischemic central retinal vein occlusion

Design

Immediate prophylactic panretinal photocoagulation vs. close observation with PRP if neovascularization developed

Result

Prophylactic PRP did not significantly prevent iris/angle neovascularization, and regression was more likely when PRP was given only after neovascularization appeared.

Conclusion

Favor careful observation with prompt PRP at the first sign of neovascularization over prophylactic treatment.

Age-Related Eye Disease Study

Population

3,640 participants with a range of AMD severity

Design

Antioxidants (vitamin C/E, beta-carotene) + zinc vs. zinc alone vs. antioxidants alone vs. placebo

Result

Antioxidants plus zinc reduced progression to advanced AMD by roughly 25% in the higher-risk subgroup, and reduced moderate vision loss.

Conclusion

The AREDS formulation benefits patients with intermediate-to-advanced AMD, but not those with no or early (small-druse) AMD; caution with beta-carotene in smokers.

United Kingdom Prospective Diabetes Study, report 50

Population

1,919 patients with newly diagnosed type 2 diabetes

Design

Observational 6-year follow-up correlating glycemia and blood pressure with retinopathy incidence/progression

Result

Both hyperglycemia and hypertension independently predicted retinopathy incidence and progression.

Conclusion

Blood sugar and blood pressure control both meaningfully reduce diabetic retinopathy risk in type 2 diabetes.

Ranibizumab for neovascular AMD (minimally classic/occult CNV)

Population

716 patients with minimally classic or occult (no classic lesion) neovascular AMD

Design

Monthly ranibizumab 0.3 mg or 0.5 mg vs. sham injection

Result

94–95% of ranibizumab-treated patients lost fewer than 15 letters at 1 year, vs. 62% of sham; 25–34% gained 15+ letters vs. 5% with sham.

Conclusion

Anti-VEGF therapy with ranibizumab prevents vision loss and improves vision in neovascular AMD — the trial that established anti-VEGF as standard of care.

Ranibizumab vs. photodynamic therapy for predominantly classic CNV

Population

423 patients with predominantly classic subfoveal CNV

Design

Verteporfin PDT vs. ranibizumab 0.3 mg or 0.5 mg

Result

At 2 years, 90% of ranibizumab patients lost fewer than 15 letters (vs. 66% with PDT), and 34–41% gained 15+ letters (vs. 6% with PDT).

Conclusion

Ranibizumab is substantially more effective than photodynamic therapy for classic CNV in AMD.

Ranibizumab for macular edema after branch retinal vein occlusion

Population

397 patients with macular edema from BRVO

Design

Monthly ranibizumab 0.3 mg or 0.5 mg vs. sham

Result

55–61% of ranibizumab patients gained 15+ letters by 6 months vs. 29% of sham.

Conclusion

Ranibizumab rapidly and effectively improves vision and macular edema after BRVO.

Ranibizumab for macular edema after central retinal vein occlusion

Population

392 patients with macular edema from CRVO

Design

Monthly ranibizumab 0.3 mg or 0.5 mg vs. sham

Result

46–48% of ranibizumab patients gained 15+ letters by 6 months vs. 17% of sham.

Conclusion

Ranibizumab rapidly and effectively improves vision and macular edema after CRVO, mirroring the BRAVO results for BRVO.

Age-Related Eye Disease Study 2

Population

4,203 participants at risk of advanced AMD

Design

Adding lutein/zeaxanthin and/or omega-3 fatty acids to the AREDS formula; also testing removal of beta-carotene and lower-dose zinc

Result

Lutein/zeaxanthin and omega-3s did not further reduce progression versus the original formula; lutein/zeaxanthin appeared to be a safe substitute for beta-carotene (which raised lung cancer risk in former smokers).

Conclusion

Defined today's standard AREDS2 formulation: vitamin C, vitamin E, lutein, zeaxanthin, zinc, and copper — without beta-carotene.

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema

Population

660 patients with center-involved diabetic macular edema

Design

Intravitreal aflibercept vs. bevacizumab vs. ranibizumab

Result

All three improved vision; aflibercept had a clinically meaningful edge only in eyes with worse baseline vision (~20/50 or worse), not in mild vision loss.

Conclusion

Anti-VEGF choice for DME can be individualized — aflibercept's advantage is concentrated in eyes with worse baseline vision.

Panretinal photocoagulation vs. intravitreous ranibizumab for PDR

Population

305 patients (394 eyes) with proliferative diabetic retinopathy

Design

Panretinal photocoagulation vs. intravitreal ranibizumab 0.5 mg (with ranibizumab available to either arm for DME)

Result

Ranibizumab was non-inferior to PRP for 2-year visual acuity, with less peripheral field loss, fewer vitrectomies, and less DME development — at the cost of far more injections and visits.

Conclusion

Anti-VEGF is a reasonable alternative to PRP for PDR, provided patients can maintain a demanding treatment and follow-up schedule.

Aflibercept, bevacizumab, or ranibizumab for DME — 2-year results

Population

660 patients with center-involved diabetic macular edema

Design

Same three-arm anti-VEGF comparison as Protocol T, extended to 2 years

Result

Gains were sustained with fewer injections in year 2; aflibercept's advantage over bevacizumab persisted at 2 years in eyes with worse baseline vision, but its edge over ranibizumab seen at 1 year was no longer apparent.

Conclusion

Confirms durable benefit of anti-VEGF therapy for DME, with any drug-specific advantage narrowing over time.

Clear-lens extraction vs. laser iridotomy for primary angle-closure glaucoma

Population

419 patients aged 50+ with newly diagnosed primary angle closure or angle-closure glaucoma, no cataract

Design

Clear-lens extraction vs. standard care (laser peripheral iridotomy + medical therapy)

Result

Lens extraction gave better patient-reported health status and lower IOP at 36 months, and was more cost-effective, than standard care.

Conclusion

Early clear-lens extraction should be considered a first-line option in primary angle-closure glaucoma.

Bevacizumab vs. aflibercept for macular edema from central/hemiretinal vein occlusion

Population

362 patients with macular edema due to CRVO or hemi-CRVO

Design

Monthly bevacizumab 1.25 mg vs. aflibercept 2.0 mg through 6 months

Result

Bevacizumab was non-inferior to aflibercept for visual acuity gain at 6 months, despite aflibercept producing more complete anatomic drying.

Conclusion

Off-label bevacizumab is a reasonable, non-inferior alternative to aflibercept for CRVO-related macular edema.

Brolucizumab vs. aflibercept for neovascular AMD

Population

1,817 patients with treatment-naive neovascular AMD

Design

Brolucizumab 3 mg or 6 mg (HAWK only) or 6 mg (HARRIER) vs. aflibercept 2 mg, on a treat-and-extend-style q12w/q8w regimen

Result

Brolucizumab was non-inferior to aflibercept for vision at week 48, with over half of brolucizumab-treated eyes maintained on a 12-week interval and greater anatomic fluid reduction.

Conclusion

Brolucizumab offers durability comparable to or better than aflibercept, though later real-world data linked it to a distinct risk of intraocular inflammation requiring careful patient selection.

Intravitreal aflibercept for moderately severe to severe NPDR without DME

Population

402 adults with DRSS level 47 or 53 NPDR, no macular edema

Design

Aflibercept every 16 weeks vs. every 8 weeks (both after loading doses) vs. sham

Result

58% of combined aflibercept eyes improved ≥2 steps on the DRSS at 24 weeks vs. 6% of sham; aflibercept eyes also had far fewer vision-threatening complications through 100 weeks.

Conclusion

Proactive anti-VEGF treatment can reverse retinopathy severity and reduce progression risk even before DME or PDR develops — though the clinical significance of DRSS improvement alone remains debated.

Faricimab for neovascular AMD

Population

1,329 patients with treatment-naive neovascular AMD

Design

Faricimab 6 mg (extended up to every 16 weeks based on disease activity) vs. aflibercept 2 mg every 8 weeks

Result

Faricimab achieved non-inferior visual acuity gains to fixed-interval aflibercept, with comparable ocular safety.

Conclusion

Dual angiopoietin-2/VEGF-A blockade with faricimab allows extended, individualized dosing intervals without sacrificing efficacy in neovascular AMD.

Faricimab for diabetic macular edema

Population

1,891 patients with center-involving diabetic macular edema

Design

Faricimab 6 mg every 8 weeks or on a personalized treatment interval (up to every 16 weeks) vs. aflibercept 2 mg every 8 weeks

Result

Both faricimab regimens were non-inferior to aflibercept for 1-year visual acuity gain, with comparable safety.

Conclusion

Faricimab provides an extended-durability option for DME with efficacy on par with standard aflibercept dosing.

Glaucoma Laser Trial

Population

271 patients with newly diagnosed primary open-angle glaucoma

Design

Initial argon laser trabeculoplasty vs. initial topical medication

Result

Eyes started on ALT had 1.2 mmHg greater IOP reduction and slightly better visual fields over up to 9 years of follow-up.

Conclusion

Initial ALT was at least as effective as initial topical medication for newly diagnosed POAG.

Collaborative Normal-Tension Glaucoma Study

Population

140 patients with normal-tension glaucoma showing progression or high-risk field defects

Design

IOP lowered by 30% vs. untreated observation

Result

Progression occurred in 12% of the treated group vs. 35% of controls.

Conclusion

IOP is part of the pathogenic process in normal-tension glaucoma; a 30% IOP reduction meaningfully slows progression.

Ocular Hypertension Treatment Study

Population

1,636 patients with elevated IOP and no glaucomatous damage

Design

Topical hypotensive medication (target 20% IOP reduction) vs. observation

Result

5-year glaucoma incidence was 4.4% with medication vs. 9.5% with observation; thinner central corneal thickness was the strongest predictor of conversion.

Conclusion

Topical medication delays or prevents onset of POAG in ocular hypertensive patients; central corneal thickness is a key risk stratifier.

Early Manifest Glaucoma Trial

Population

255 patients (median age 68) with newly detected, mostly mild open-angle glaucoma

Design

Immediate laser trabeculoplasty + topical betaxolol vs. no initial treatment

Result

Progression occurred in 45% of the treated group vs. 62% of controls over a median 6-year follow-up; every 1 mmHg of IOP reduction cut progression risk by roughly 10%.

Conclusion

The first adequately powered placebo-controlled trial to show that lowering IOP slows glaucoma progression, across both high- and normal-tension disease.

Advanced Glaucoma Intervention Study, report 13

Population

581 patients (332 Black, 249 white) with medically uncontrolled glaucoma

Design

ALT→trabeculectomy→trabeculectomy (ATT) vs. trabeculectomy→ALT→trabeculectomy (TAT), followed up to 13 years

Result

Black patients did better long-term with the ATT sequence; white patients did better with the TAT sequence.

Conclusion

Optimal surgical sequencing for refractory glaucoma may differ by race — a finding that shaped subsequent surgical-sequencing discussions, though it should be weighed against later evidence and individual risk factors.

Collaborative Initial Glaucoma Treatment Study

Population

607 patients with newly diagnosed open-angle glaucoma

Design

Initial medical therapy vs. initial trabeculectomy, followed up to 9 years

Result

Overall visual field outcomes were similar between arms; initial surgery led to less progression in eyes with advanced baseline field loss, but more progression in patients with diabetes.

Conclusion

Initial medical and surgical treatment produce broadly similar long-term visual field outcomes for newly diagnosed glaucoma, with baseline severity and diabetes status informing the choice.

Tube Versus Trabeculectomy Study, 5-year results

Population

212 patients with uncontrolled glaucoma and prior cataract or trabeculectomy surgery

Design

Baerveldt tube shunt vs. trabeculectomy with mitomycin C

Result

5-year failure was lower with the tube (30%) than trabeculectomy (47%), with a similar IOP reduction and fewer reoperations in the tube group.

Conclusion

Tube shunt surgery has a higher long-term success rate than trabeculectomy in eyes with prior ocular surgery.

Ahmed versus Baerveldt Study, 3-year results

Population

238 patients with refractory glaucoma

Design

Ahmed FP7 valve vs. Baerveldt 350 implant

Result

3-year failure was 51% with Ahmed vs. 34% with Baerveldt, though Baerveldt had a higher rate of hypotony-related vision-threatening complications.

Conclusion

Both devices lower IOP effectively; Baerveldt has a lower failure rate but a distinct hypotony risk that must be weighed against it.

United Kingdom Glaucoma Treatment Study

Population

516 patients with newly diagnosed primary open-angle glaucoma

Design

Latanoprost vs. placebo drops

Result

Visual field preservation was significantly better with latanoprost (hazard ratio 0.44) alongside a 3.8 mmHg vs. 0.9 mmHg IOP reduction.

Conclusion

The first placebo-controlled trial to directly demonstrate that an IOP-lowering drug preserves visual field in open-angle glaucoma.

Clear-lens extraction vs. laser iridotomy for primary angle-closure glaucoma

Population

419 patients aged 50+ with newly diagnosed primary angle closure or angle-closure glaucoma, no cataract

Design

Clear-lens extraction vs. standard care (laser peripheral iridotomy + medical therapy)

Result

Lens extraction gave better patient-reported health status and lower IOP at 36 months, and was more cost-effective.

Conclusion

Early clear-lens extraction should be considered a first-line option in primary angle-closure glaucoma.

Selective laser trabeculoplasty vs. eye drops for first-line treatment

Population

718 treatment-naive patients with open-angle glaucoma or ocular hypertension

Design

Initial selective laser trabeculoplasty vs. initial topical medication, followed 36 months

Result

Quality of life was equivalent between arms; 74% of SLT patients remained drop-free at 3 years, needed no glaucoma surgery (vs. 11 patients in the drops arm), and SLT was more cost-effective.

Conclusion

SLT should be offered as first-line therapy for open-angle glaucoma and ocular hypertension, not reserved as a second-line option.

Ischemic Optic Neuropathy Decompression Trial

Population

244 patients with nonarteritic anterior ischemic optic neuropathy (NAION) and vision 20/64 or worse

Design

Optic nerve decompression surgery vs. careful follow-up

Result

Surgery patients did no better than observation (32.6% vs. 42.7% improved by 3+ lines) and had a significantly higher rate of vision loss (23.9% vs. 12.4%).

Conclusion

Optic nerve decompression surgery for NAION is not effective, may be harmful, and should be abandoned.

Corticosteroid Randomisation After Significant Head injury

Population

10,008 adults with head injury and GCS ≤14

Design

48-hour IV methylprednisolone infusion vs. placebo

Result

Risk of death was higher with corticosteroids (25.7% vs. 22.3%).

Conclusion

Corticosteroids should not be used routinely for head injury — directly relevant to traumatic optic neuropathy, where steroids lack proven benefit and carry this same risk.

Optic Neuritis Treatment Trial, 15-year follow-up

Population

389 patients with acute optic neuritis

Design

IV methylprednisolone → oral prednisone vs. oral prednisone alone vs. placebo, followed 15 years for MS risk

Result

IV steroids sped visual recovery but didn't change the final visual outcome; oral steroids alone increased recurrence risk. 15-year MS risk was 25% with no baseline brain MRI lesions vs. 72% with one or more lesions.

Conclusion

IV (not oral) steroids appropriately treat acute optic neuritis, and baseline brain MRI is the strongest predictor of long-term multiple sclerosis risk.

Idiopathic Intracranial Hypertension Treatment Trial

Population

165 patients with IIH and mild visual loss, on a low-sodium weight-reduction diet

Design

Acetazolamide (up to 4 g/day) vs. placebo

Result

Acetazolamide plus diet gave modestly better visual field improvement, papilledema grade, and quality of life than diet alone.

Conclusion

Acetazolamide is a reasonable adjunct to weight-reduction counseling for IIH with mild visual loss.

Pediatric Eye Disease Investigator Group — atropine vs. patching

Population

419 children under 7 with moderate amblyopia (20/40–20/100)

Design

Patching vs. atropine penalization

Result

Both groups improved similarly by 6 months (3.16 vs. 2.84 lines); patching worked slightly faster.

Conclusion

Atropine and patching are both appropriate first-line treatments for moderate amblyopia in children 3 to under 7.

Pediatric Eye Disease Investigator Group — amblyopia treatment in older children

Population

507 children aged 7–17 with amblyopia

Design

Patching + near activities (+ atropine for 7–12y) vs. optical correction alone

Result

53% of 7–12-year-olds responded to active treatment vs. 25% with correction alone; benefit in 13–17-year-olds was seen mainly in those not previously treated.

Conclusion

Amblyopia remains treatable well beyond the classic 'critical period,' though responsiveness declines with age and prior treatment history.

Contact lens vs. primary IOL for unilateral infantile cataract

Population

114 infants undergoing unilateral congenital cataract surgery at 1–6 months of age

Design

Primary intraocular lens implantation vs. aphakic contact lens correction

Result

No significant difference in 1-year grating acuity, but the IOL group needed additional intraocular surgery far more often (63% vs. 12%).

Conclusion

Contact lens correction is favored over primary IOL implantation in infants 6 months or younger, given no visual benefit and a much higher reoperation rate with IOLs.

Systemic Immunosuppressive Therapy and malignancy risk

Population

543 patients with severe ocular inflammatory disease (retrospective cohort)

Design

Systemic corticosteroids alone vs. immunosuppressive agents with or without corticosteroids

Result

Malignancy rates were not significantly different between groups over 1,261 person-years of follow-up.

Conclusion

No evidence that systemic immunosuppressive therapy for ocular inflammatory disease increases malignancy risk relative to corticosteroids alone.

Multicenter Uveitis Steroid Treatment Trial

Population

255 patients with active or recently active intermediate, posterior, or panuveitis

Design

Systemic corticosteroids ± immunosuppression vs. fluocinolone acetonide implant

Result

Visual acuity improved similarly in both arms at 24 months; the implant group had less residual active uveitis but far higher rates of cataract surgery and glaucoma.

Conclusion

Both systemic therapy and the fluocinolone implant are reasonable options for noninfectious uveitis; the choice should weigh implant-related cataract/glaucoma risk against systemic infection risk.