4/06/2013. Medication Observation POAG. Proportion. Native American 0.1% 0.4%

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1 Clinical Research in Glaucoma: Putting Science into Practice J. James Thimons, O.D., FAAO Chairman, National Glaucoma Society Ocular Hypertension Treatment Study (OHTS) Primary Goals Evaluate the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the development of POAG in individuals with elevated IOP Identify baseline demographic and clinical factors that predict which participants will develop POAG The OHTS Exclusion Criteria VA worse than /40 in either eye Previous intraocular surgery other than uncomplicated CE with PCIOL Diabetic retinopathy Other disease capable of causing VF loss/ ON damage Baseline Characteristics by Randomization Group Self-designated Race Primary POAG Endpoints* Log Rank P-value <0.001, Hazard Ratio 0.40, 95% CI (0.27, 0.59) 0.15 Medication Observation Medication n=817 Observation n=819 Native American 0.1% 0.4% Asian 05% 0.5% 12% 1.2% African American 25.0% 25.0% Hispanic 2.9% 4.3% Caucasian 70.6% 68.4% Proportion POAG At 5 yrs, 4.4% of treated group and 9.5% observation group developed glaucoma Other 1.0% 0.7% Months *through 8 Nov 01 1

2 First POAG Endpoint (n=125) 10% 55% 35% Optic Disc VF Defect Concurrent VF and ON defect Includes all subjects in medication and observation group Treatment perhaps less protective in African Americans African Americans 12.7% POAG endpoints in observation group 69% 6.9% POAG endpoints in medication group Hazard Ratio 0.54 P value for interaction 0.26 Others 10.2% POAG endpoints in observation group 3.6% POAG endpoints in medication group Hazard Ratio 0.34 Significant Baseline Factors Predicting Progression to POAG Univariate Analysis Age Black race Male gender Heart disease Increased IOP Thinner CCT Greater PSD Horizontal C/D ratio Vertical C/D ratio Multivariate Analysis Age IOP CCT PSD Vertical C/D ratio POAG Endpoints by Central Corneal Thickness and Baseline IOP (mmhg) in Observation Group* Baseline IOP (mmhg) < >25.75 >23.75 to < % 13% 6% 12% 10% 7% 17% 9% 2% < 555 >555 to < 588 >588 Central Corneal Thickness (microns) POAG Endpoints by Central Corneal Thickness and Baseline Vertical C/D Ratio in Observation Group* Vertical C/D Ratio < 0.30 >0.50 >0.30 to < % % 8% 26% % 4% 15% 1% 4% < 555 >555 to < 588 >588 Central Corneal Thickness (microns) CCT vs IOP AJO 1997/ Wolfs RC et al. 395 subjects 352 controls 13 OHTN 30 COAg CCT Controls OHTN- microns thicker COAG 21 microns thinner 2

3 CCT vs Advanced Glaucoma Arch Ophth 04 / Herndon LW 350 eyes/190 patients age, sex, race, fam Hx, # meds, IOP, CCT, VF AA s 537 microns/ Whites 556 microns Lower CCT - increased risk of AGIS Increased C/D Increased MD Increased # COAG meds Peak IOP Outside Office Hours PURPOSE: To determine the relationship between office IOP and peak IOP METHODS (Study One) 1 : 42 patients with OAG Treated with 3 different IOP lowering eye drops 24 hr IOP values obtained in sitting position with Goldmann applanation tomography at 3 hr intervals METHODS (Study Two) 2 : 103 patients with OAG (including 35 untreated) 24 hr IOP values obtained at 2 hr intervals using a pneumatometer, in sitting and supine positions during the diurnal/wake period and in the supine position during the nocturnal/sleep period 1.Nakakura S, et al. J Glaucoma 07; (2): Mosaed S, et al. Am J Ophthalmol. 05; 139: Peak IOP Outside Office Hours IOP is Higher at Night of eyes Number o Study 1 Times at which maximum and minimum IOP occurred in a 24- hr period 1 : 40 3am 6am 28 9am 12pm pm 6pm pm 12am Time of minimum IOP in 24 hour Time of maximum IOP in 24 hour Study 2 67% of peak IOP occurs outside office hours 2 PURPOSE: To characterize the 24 hr pattern of IOP in untreated patients METHODS: 24 untreated patients with newly diagnosed glaucomatous optic discs and/or abnormal visual fields 24 hr IOP values obtained with a penumatonometer at 2 hr intervals, in the sitting and supine position during the diurnal/wake period and in the supine position during the nocturnal/sleep period 1.Nakakura S, et al. J Glaucoma 07; (2): Mosaed S, et al. Am J Ophthalmol. 05; 139: Liu JH et al. Invest Ophthalmol Vis Sci. 03; 44: IOP is Higher at Night Higher nocturnal supine IOP than diurnal sitting IOP (healthy and OAG) Supine IOP higher than sitting IOP, regardless of time of day Habitual IOP of healthy eyes Habitual IOP of glaucomatous eyes Diurnal Sitting Nocturn Diurnal Diurnal Sitting Noctur Diurnal al Sitting nal Sitting Supine 26 Supine 26 n= n= IOP (mm Hg) :30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM 1:30 AM 3:30 AM 5:30 AM 7:30 AM Clock Time Liu JH et al. Invest Ophthalmol Vis Sci. 03; 44: :30 AM 11:30 AM 1:30 PM IOP (mm Hg g) 15 3:30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM 1:30 AM 3:30 AM 5:30 AM 7:30 AM Clock Time *Error bars = SEM 9:30 AM 11:30 AM 1:30 PM Collaborative Normal Tension Methods One eye per each of 5 subjects with NTG was randomized either to 30% IOP reduction or to no treatment (control) Randomization criteria included documented progression of field defects, new disc hemorrhage, or field defects that threatened fixation 17 3

4 Collaborative Normal Tension Treatment for IOP reduction: medication (excluding beta- blockers or alpha2 adrenal receptor agonists due to concerns of vasoactivity), ALT, or filtration surgery Collaborative Normal Tension Survival analysis: time to visual field progression Findings At 5 years, treated patients showed overall survival of 80% compared with 40% in controls (P=.0018) The beneficial results of IOP reduction were found only when the impact of cataracts on visual field progression (caused mainly by filtration surgery) was removed The Collaborative Normal-Tension Clinical Pearls 1. Therapeutic intervention (30% IOP reduction) helped prevent visual field progression. However, one must adjust for the development of cataracts, which occur commonly after filtration surgery, to detect the therapeutic benefit of IOP reduction. The Collaborative Normal- Tension Clinical Pearls 2. 30% IOP reduction was achieved in 57% of patients receiving medical therapy with or without argon laser trabeculoplasty (ALT), which underscores the importance of conservative therapy. Since beta- blockers, alpha2 agonists, and prostaglandin analogs were not used in the study, currently available medical agents may achieve IOP reduction in a greater percentage of patients. The Collaborative Normal-Tension Clinical Pearls 3. Approximately 50% of eyes without a history of progression did not progress by 7 years when untreated. However, if progression has been documented in the past, future progression is highly likely, and IOP reduction is recommended. The Collaborative Normal-Tension Clinical Pearls 4. Confirmatory visual fields are essential for verifying suspected progression. For both visual function as well as structural tests, it is important to confirm suspected progression. 4

5 The Collaborative Normal-Tension Clinical Pearls 5. Disc hemorrhage is a strong, negative prognostic sign; other risk factors include migraine and female gender. Diurnal Fluctuations in IOP: Independent Risk Factor? PURPOSE: To study the risk associated with diurnal IOP variations in patients with OAG METHODS: 64 patients with OAG and IOP below 25 mm Hg (over 5 year follow up) Patients successfully performed tonometry with a self tonometer 5 times a day for 5 days Baseline status and time to progression of visual field loss identified from clinical charts Level and variability of diurnal IOP characterized and risk of progression analyzed using a nonparametric time to event model Asrani S, et al. J Glaucoma 00; 9: Diurnal Fluctuations Correlate with Visual Field Progression risk of disease on within 5 years Relative progressio Diurnal IOP range 3.1 mm Hg 5.76 Diurnal IOP range 5.4 mm Hg Habitual IO OP (mm Hg) Timolol: Nocturnal IOP N=18 Error bars = SEM Sitting Supine Sitting No treatment Timolol Hazard ratio between higher quartile and lower quartile for Range in Home IOP was PM 5.30PM 7.30PM 9.30PM 11.30PM 1.30AM 3.30AM 5.30AM Clock Time 7.30AM 9.30AM 11.30AM 1.30PM Asrani S, et al. J Glaucoma 00; 9: Liu JH, et al. Am J Ophthalmol. 04; 138: tual IOP (mmhg) Habit Effect of PGA s on Diurnal and Nocturnal IOP DIURNAL/WAKE 3:30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM Baseline NOCTURNAL/SLE EP Sit AJ, et al. Am J Ophthalmol. 06; 1(6): DIURNAL/WAKE 1:30 AM 3:30 AM 5:30 AM 7:30 AM 9:30 AM 11:30 AM 1:30 PM Clock Time On Treatment Error bars = SEM Measured in the usual habitual position of the patients during those time periods Diurnal period sitting Nocturnal period supine Early Manifest Glaucoma Trial Compared the effect of immediately lowering the IOP vs no treatment or later treatment, on the progression of newly detected open-angle glaucoma Heijl A. et al. Arch Ophthalmol. 02;1:

6 EMGT Participants 255 open angle glaucoma patients Ages (median 68 years) Early glaucoma Mild VF loss (median MD, 4dB) Median IOP of EMGT Excluded from trial Patients with IOP greater than 30 mmhg Patients with advanced VF loss Heijl A. et al. Arch Ophthalmol. 02;1: Heijl A. et al. Arch Ophthalmol. 02;1: EMGT - Interventions Subjects randomized to either Argon Trabeculoplasty + Betaxolol (n=129) OR No initial treatment (n=126) HVF 30-2 and IOP q 3 months for 10 years Optic nerve photos every 6 months Heijl A. et al. Arch Ophthalmol. 02;1: EMGT- Results 53 % of subjects progressed Progression 45 % of treated patients progressed (58/129) 62% of untreated patients progressed (78/126) Statistically significant (P=.007) This progression difference was evident at 11 months and increased steadily over time Leske MC et al. Arch Ophthalmol. 03 Jan;121(1): EMGT- Results In multivariate analyses, progression risk was halved by treatment Progression risk decreased by about 10% with each mm of HG of IOP reduction from baseline to the first follow-up visit Progression risk increased by about 10 % with each mm of HG of IOP increase from baseline at first follow-up visit Leske MC et al. Arch Ophthalmol. 03 Jan;121(1): EMGT- Summary Factors Increasing Risk of Progression Higher baseline IOP Exfoliation Bilateral disease Older age Worse MD on visual field Presence of disc hemorrhage Leske MC et al. Arch Ophthalmol. 03 Jan;121(1):

7 Collaborative Initial Glaucoma Treatment Study On ongoing study to determine if newly diagnosed open-angle glaucoma is better treated with initial medical therapy or immediate filtration surgery Different study design: Patient satisfaction and quality of life are determining factors in deciding patient care; enrolled patients interviewed before being assigned treatment then re- interviewed every 3-6 months Allows referring ophthals to remain primary caretaker; routine biannual visits conducted at clinical center CIGTS: Subjects Eligibility criteria years old Newly diagnosed glaucoma as determined by elevated IOP, glaucomatous optic disc damage and VF loss Must not have received any previous glaucoma treatment for longer than days CIGTS: Subjects 607 patients enrolled at centers Of the 607 patients enrolled: 90.6% had primary open angle glaucoma 4.6% pigmentary pg yg glaucoma 4.8% pseudoexfoliative glaucoma Subjects randomized to surgery or stepped medical therapy CIGTS: Subjects Medications: typically BB followed in order by other monotherapy, dual therapy, triple therapy, quad therapy, ALT, Trab, meds, trab+mmc, meds Surgical treatment arm: patients underwent immediate trab and, with documented failure, proceed to ALT, then conclude with medications CIGTS: Results Quality of life: Surgical vs. Medical The medical group reported a variety of systemic symptoms that were not consistent ste t over time, but were e clearly different from the symptoms reported by the surgical group CIGTS: Results Clinical Results: Surgery vs. Medicine Average pressure in the medically treated group mmhg Pressure in the surgical group was 3 points lower (-15) 15) Ophthalmology 01; 108: Ophthalmology 01; 108:

8 CIGTS: Results Clinical Results: Surgery vs. Medicine VF loss did not differ over 5 years between treatment groups VA was better for medically treated group over much of the study, but by 4 years, was no different than the surgical group Number progressing in both groups was low (15%) Ophthalmology 01; 108: CIGTS: Results Clinical Results: Surgery vs. Medicine THREE TIMES THE RATE of cataract in the surgical group Glaucoma Laser Trial 271 patients with previously untreated primary open angle glaucoma randomized to ALT or medication (Timolol) Through 2-year follow-up, ALT eyes had lower intraocular pressure (IOP) than medication-treated treated eyes; 25% did not require Rx At 7 years, in 3 of the original 271 patients, ALT-treated eyes had lower IOP, better visual field, and optic disc status than eyes in the medication group Glaucoma Laser Trial Glaucoma Laser Trial (GLT) Followed 3 patients 7 years randomized one eye to ALT and one eye to Timolol 0.5% twice daily ALT eye: 1.2mm Hg greater reduction in IOP 0.6 db better visual field slightly less optic nerve cupping (-0.01) Glaucoma Laser Trial Research Group, AJO Glaucoma Laser Trial (GLT) Results: Selective Laser Trabeculoplasty (SLT) Eyes treated initially with ALT had lower IOP (1.2 mmhg) and better VF and optic disc status ALT was as efficacious as medications in controlling pressure and preserving optic disc function 8

9 Selective Laser Trabeculoplasty Results comparable to ALT (argon laser trab.) 50 spots to nasal trabecular meshwork Less traumatic than ALT 70% of pts respond IOP reduced by > 3 mmhg, mean 23.5% ALT SLT SLT Effectivity International studies show IOP reductions of 22%-28% 28% with weeks follow-up In a prospective, randomized clinical trial, SLT and ALT were shown to have a similar effect on IOP reduction 85% Success on initial treatment 1-5 years of IOP control if initial success Glaucoma & Pregnancy BJO 09; JD Ho: 244 pregnant women treated for glaucoma analyzed for birth weight 1,952 age matched controls No significant difference between women on BB s vs: no Tx Herndon, L: D/C Brimonodine several weeks before d/t risk of apnea AGIS Patients enrolled patients 789 eyes 8 years of follow up Randomized to ALT or Trab first for COAG patients inadequately controlled with meds Main result: no difference between the two groups AGIS How effective is IOP lowering in preserving VF? Is there an ideal IOP that provides maximum benefit in reducing or eliminating pressure-related related component of damage? 9

10 defect score Mean change in visual d AGIS 7 Sustained IOP below 18 mm Hg: Positive Correlation with Stability of Visual Field 5 Percent of Visits with IOP Less Than 18 mm Hg 4 100% of visits % of visits it % of visits % of visits Follow-up (years) AGIS Investigators, 00, Am. J. Ophthalmol., 130, AGIS 7 Report Patients with IOP<18 on 100% of follow-up exams over 6 years had mean change from baseline VF close to ZERO. (Mean IOP=12.3 over 6 years) Patients with IOP<18 on 50% of follow-up exams showed progression Am J Ophthalmol 00;130: A message from AGIS and CIGTS Endoscopic CycloPhotocoagulation Aggressive IOP-lowering by any means is the best way to protect against further VF loss E2 Applications Ocular Endoscopy ECP Treatment Limbal Approach Posterior to Iris Zonules Dropped IOL Peripheral Retina 10

11 Incision Placement: Straight Endoscope Incision Size: Use at least a 2.6mm Keratome blade for ease of insertion to prevent corneal torquing. ECP Treatment Limbal Approach P L ECP for Refractory Glaucoma s Studies Alvarado et all AJO % patients with refractory glaucoma 35% avg drop in IOP 33% drop in medications 90% has IOP 21mm Hg Lima et all J of Glauc patients with refractory glaucoma 24 month follow up Randomized to ECP vs Ahmed Valve 73% success in both groups 2.9% choroidal effusion in ECP group 18% choroidal effusion and flat AC in Ahmed Group Hint: Surgeon s chair may be repositioned as needed. Studies Table 13 mmhg 19 Phaco-ECP vs Phaco Alone: Mean IOP Over Time 1.53 Meds Phaco-ECP Phaco Alone 1. Meds Meds Meds 15 Pre-Op 6 Months 1 Year 2 Years 3 Years Phaco-ECP Phaco Alone