Glaucoma For The Everyday Optometrist

Transcription

1 A Review Of Risk Factors Glaucoma For The Everyday Optometrist Eric E. Schmidt, O.D., F.A.A.O. Omni Eye Specialists Wilmington, NC FINDACAR Family history IOP Nearsightedness Diabetes/Vascular disease Age Corneal thickness Asymmetry Race A risk factor analysis is critical For the diagnosis To increase your level of suspicion For initiating therapy For changing therapy BUT are any of these more important than others? Glaucoma Risk Factors FINDACAR The more risk factors one has, the more likely one is to develop glaucoma The more risk factors one has, the lower the IOP target should be OHTS Goal of tx 20% drop in IOP - 24mm target IOP RESULTS: At 5 years 4.4% of tx group developed POAG 9.5% of no tx group developed POAG So - lowering IOP in Oc Hx reduced the likelihood of glaucoma by 50% - RIGHT? 1

2 OHTS A Closer Look 90% of untreated group did not progress 95.6% of tx group did not progress It proved that in those individuals who are going to progress to POAG lowering IOP by 22.4% will delay the onset by at least 5 yrs. Who are those individuals at risk? Juicy Data The pachymetry issue 36% of pxs w/ IOP >25.75 AND K thickness < 555 microns developed POAG 6% of pxs w/ same IOP but K thickness > 588 converted topoag Juicy Data II 15% pxs w/ C/D.3/.3 and K thickness < 555 microns converted but 4% of pxs w/ same disk parameters and K thickness> 588 microns converted OHTS The Nitty Gritty The most predictive factors for conversion: Older age 22% increase/ decade Larger horizontal and vertical C/D 32% increase/0.1 larger Higher baseline IOP 10% increase/ mm Hg Thinner corneas 71% increase in risk/ 40 microns thinner Risk Factors For Conversion 2

3 Corneal Thickness And Glaucoma The Latest Scoop CCT and VF loss CCT is a strong predictor for field loss in both NTG and POAG CCT-adjusted IOP does not predict VF loss Sullivan-Mee, Halverson, et.al. Optometry 2005;76: Corneal Thickness and Glaucoma CCT and Visual Function In OHT pxs OHT pxs with abnormal SWAP results had significantly thinner CCT than normals or OHT pxs with no VF defects Abnormal VF 545microns OHT w/ normal VF 572 microns Normals 557 microns Medeiros, Sample, Weinreb AJO Feb, ,No.2 So???? More Pachymetry Chatter African-Americans have thinner corneas Perhaps thin corneas translate to poor connective tissue at the disk as well Is there a fudge-factor for K thickness? Baseline of 545 microns Add or subtract 2.5mm Hg for every 50 microns deviation (Doughty and Zaman, Surv Ophthalmol, 2000). How should you use this data? CCT And Glaucoma- More latest scoop RNFL thickness and CCT in OHT pxs RNFL in OHT pxs with CCT < 555 was significantly thinner than in those with CCT >555. RNFL of normals and OHT pxs with CCT >555 were similar Points to an inherent structural predispositon to glaucomatous damage? Kaushik,S, et.al, AJO May 2006,

4 CCT and Treatment Response OHTS group AJO, November, 2004 Pxs with thinner corneas responded better to PGA and beta-blockers 1mm difference for beta-blockers mm difference for PGAs 550 microns was tipping point Fan and Camras reported similar results with brimonidine (ARVO, 2004) Why??? And what clinical implications are there? AGIS Results Pxs who achieved IOP < 18mm on 100% of f/up visits showed no VF progression (avg IOP 12.3mm) Pxs w/ IOP < 18mm on<50% of f/up visits showed VF progression (mean IOP 20.2mm) EMGT Conclusions 1) Reducing IOP (by 25%) prevents or slows VF defect and progression 2) For each 1mm of IOP reduction there is a 10% lower risk of VF loss 3) Study design and outcome show that these results are only due to IOP reduction (non IOP related factors showed difference between the 2 groups) 4) Tx effect was equal across age and glaucoma categories Low IOP Slows or Halts Vision Loss in Open-Angle Glaucoma Mao et al, AJO, 1991 Eric s spin on the EMGT 1-2 extra mm Hg may indeed be importantespecially in advanced cases. For those pxs who need treatment, aggressive therapy is warranted It is probably better to treat early than late You do not necessarily need to wait until the VF defects arise before therapy is initiated The benefit of treatment does last throughout the lifetime of the px just remember the risk/benefit Aggressive IOP Lowering Needed In Advanced POAG IOP <15 mm Hg Percentage of Eyes 100% 80% 60% 40% 20% 0% Stable Progressed Mean IOP Over 15 Years (mm Hg) Shirakashi et al, Ophthalmologica,

5 Diurnal IOP Fluctuations Speed Glaucomatous Progression Stable Visual Field Visual Field Loss Patients (%) Patients With Diurnal IOP Range >11.8 mm Hg Patients With Diurnal IOP Range <7.7 mm Hg Asrani et al, J Glauc, 2000 AGIS Results Diurnal Curve Is Real Important Avg IOP of 15mm with a curve btwn 13mm 17mm progresses less than if curve is btwn 11mm 19mm The peak IOP is important Which tx best affect the diurnal curve? Also remember risk/benefit ratio Consistently Low IOP Reduces Vision Loss Mean Change in Visual Defect Score All visits <18 75 to 100% of visits <18 50 to 75% of visits <18 0 to 50% of visits < Follow-up Visit (Months) Mean IOP 20.2 mm Hg 16.9 mm Hg 14.7 mm Hg 12.3 mm Hg AGIS 7, AJO,

6 CNTGS Results 35% untreated progressed over 3 yrs 7% of treated eyes progressed 30% IOP reduction achieved w/ drops, laser or surgery Showed that several VF were needed before progression was shown A very low IOP is beneficial Predictive Factors For Progressing POAG Older age Advanced VF damage Worsening MD (-4) Smaller neuroretinal im Larger zone Beta Martus, Jonas, et.al. AJO, June 2005 Baseline IOP, but not Mean IOP Martinez-Bello, et al, AJO March Lower CH SOOOO. How can we best determine IOP fluctuation? How can we plot a curve? Risk factors for progression Predictive Factors for Progressive Optic Nerve Damage in Various Types of Chronic Open-Angle Glaucoma - Martus, Budde, Jonas, et.al. AJO 6/05 POAG- Older age Advanced perimetric damage Smaller neuroretinal rim Larger Beta zone NTG- Baseline disk hemorrhage 6

7 When deciding to treat Identify Risk factors for conversion Risk factors for progression Risk factors for rate of progression Initial peak IOP Age C/D ratio Systemic/vascular status Noscitur a sociis! When Is The Peak IOP? 3,025 IOP readings on 1,072 eyes NTG, POAG, Pre-perimetric G, OHT Results: Peak IOP 7AM 20.4% Noon 17.8% 5PM % 9PM 26.7% Jonas, Budde, et al. AJO, June 2005;139: IOP and Glaucoma Which IOP is most important? Mean IOP Peak IOP Trough IOP IOP range Jonas study conclusion Any single IOP measurement taken between 7AM and 9PM has a higher than 75% chance to miss the highest point of the diurnal curve. Stresses the need for serial tonometry. For pxs who showed progression of glaucoma despite IOP at acceptable range 3% showed a peak IOP >21mm 35% showed a range of IOP >5mm Collaer, Caprioli, et.al, J Glaucoma 2005;14(3): Underscores the importance of serial tonometry even in well controlled pxs 7

8 IOP and Glaucoma Which IOP is most important? Mean IOP Peak IOP Trough IOP IOP range Intervisit IOP Range Using this marker: Doctors able to predict (estimate) peak IOP 70% of time Able to estimate IOP fluctuation ~50% of time Intervisit IOP Range A measure of long-term IOP fluctuation Intervisit IOP range calculated by: Highest IOP minus lowest IOP at 4 different measurements Calculated both pre- and post-treatment Range is considered high (> 6mm) 0r low (</ 6mm) High intervisit IOP range should be considered a risk factor for progression Varma et al AJO 2/09 IOP Standard Deviation Another predictor of progression Mean IOP 16.5mm Hg SD calculated to be 2.0 or 2.7mm Hg Each unit increase in SD results in a times higher risk for progression Clinically, what does this mean? Lee, Walt, et al AJO 7/07 Risk factors for high post-treatment IOP range High pre-treatment intervisit IOP range African-American Higher mean pretreatment IOP Longer time since diagnosis So What Do Standard Deviations Mean To Me? If mean IOP is 16 then: Acceptable range should be mm Hg If the IOP exceeds that by 1 SD ( mmhg) then the likelihood of progression increases by times Multiple pre and post-treatment readings are necessary to find the true level Further evidence to set a target IOP AND STICK TO IT!! 8

9 By The Way Latanoprost results in 6% of pxs with high IOP fluctuation Timolol ½% yields 11% with high IOP fluctuation So..????? What to do if IOP increases between visits? IOP fluctuation between 2 visits is not predictive of long term success or failure of medication. True whether using monocular trial or unadjusted IOP change Multiple pre-and post-treatment IOP readings are necessary Multiple VF and imaging studies are necessary Measuring IOP 5 methods: Goldmann applanation Tonopen Non-Contact Direct Applanation (Pascal) Pneumotonometry Is 1 method more accurate? What about telemetry? 9

10 New Goal of treatment in Glaucoma Low and Stable IOP Minimize the diurnal curve Prevent IOP peaks Recommendations Minimum initial target IOP reduction of 25% recommended for glaucoma patients More aggressive initial target IOP reductions of 30% or 35% recommended for most patients: especially those at higher risk Target IOP must be DYNAMIC, re-evaluated periodically, and lowered if patient progresses despite meeting the initial target IOP Re-evaluate and adjust patient s target IOP at least every 5 years, and in light of newest information The Delphi Panel. PDR Treatment Goals of Glaucoma Maximum IOP reduction achieve lower IOP to help preserve sight; historically physicians tried to achieve pressures below 20 mm Hg Maintaining low IOP over 24 hours avoid pressure spikes associated with visual field progression Ease of use patient compliance is best with simple, easy-to-use medication regimen (typical glaucoma patient uses at least 3 other systemic medicines); monotherapy is preferred Safety minimize systemic safety issues General Rule #1 30% decrease as an initial target Target decrease from highest untreated IOP CNTGS, OHTS Gottfredsdottir et al. J Glaucoma EMGT: Every mm Hg of IOP Lowering Matters Change in Risk (95% CI) 0% -2% -4% -6% -8% -10% -12% -14% -16% 10% Decrease in Risk of Progression For Each 1 mm Hg Decrease in IOP From Baseline to Month 3 General Rule #2 Mild glaucoma decrease IOP 30% Moderate glaucoma decrease IOP 40% Severe glaucoma decrease IOP 50% (at least) Leske et al. Arch Ophthalmol

11 When should the target IOP be changed? VF progression (even at target IOP) Neuroretinal rim recession (even at target IOP) Parametric changes Long term stability even if on multiple meds AGIS: Patients With Small IOP Variation Had Stable Fields Eyes with variation < 3 mm Hg: no average progression Eyes with variation 3 mm Hg: on average, significant progression Nouri-Mahdavi et al. Ophthalmology Importance of IOP Stability IOP variation is a risk factor for VF loss in glaucoma VF protected best when pressures are consistently kept under 18 mm Hg Wide swings in IOP during the day or from visit to visit should be avoided Stabilizing IOP is vital Visual Fields and Glaucoma Are they still cool? Are they considered the standard of care? How often? Do they better measure early detection or progression? AGIS: Need to Maintain Low IOP Over Time ALT or surgery in uncontrolled glaucoma Target IOP <18 mm Hg 100% of visits <18 mm Hg: on average no loss in VF Any visits with IOP target not met: on average significant VF loss 2-unit loss in VF over 7 years when target met at <75% of visits AGIS:7. Am J Ophthalmol Mean Change in VF Score All visits < to 75% of visits < to 100% of visits < 18 0 to 50% of visits < Follow-up Month CONCLUSION: Progression is minimized when IOP is kept consistently low (<18 mm Hg) Mean IOP 20.2 mm Hg 16.9 mm Hg 14.7 mm Hg 12.3 mm Hg Are certain VF parameters more predictive for progression? Johnson, Sample et al. AJO 8/ Highest predictors of conversion GHT outside normal limits 2 hemifield clusters worse than 5% level 4 abnormal (P<.05) locations on pattern deviation probability plot Specificity increased with 2 nd confirmatory VF test 11

12 Which VF instrument is best? SAP, SWAP or FDT FDT and SWAP similar in flagging abnormal locations FDT defects were more extensive in 62% SWAP more specific and accurate than SAP but harder to administer FDT questionable in end stage glaucoma Use 10-2 strategy in advanced glaucoma 12

13 MSOffice1 Primary Medical Therapy Building block approach Start with the STRONGEST FOUNDATION Efficacy Goals of Primary Therapy Achieve lowest IOP on single agent High response rate every mm Hg matters Maintain consistent long term and diurnal pressure lowering Regarding Visual Fields Are they more better for early glaucoma? OR Are they more better in established glaucomas? Eric s 7 Simple Rules For Treatment 1. Choose 30% IOP decrease as initial target 2. Squash the diurnal curve (Keep IOP peak <18mm) 3. Assess risk factors for progression and rate of progression (CT<555, IOP >26,C/D 0.5) Treatment Paradigm Summary Mean IOP in study populations Early treatment to lower IOP reduces and delays progression NEI trials show better outcomes at lowest IOP IOP in individual patient To preserve vision, every mm Hg matters Individualized, low target IOP recommended New predictors of progression Diurnal fluctuation and long-term variation in IOP within individual patients can cause glaucomatous damage Treatment goal: get IOP low, and keep it low Eric s Rules cont. 4. If you are going to treat; treat aggressively 5. KISS 6. Be mindful of perfusion issues 7. Above all, do no harm Heijl et al. Arch Ophthalmol. 2002; Kass et al. Arch Ophthalmol. 2002; Lichter et al. Ophthalmology. 2001; AGIS Investigators: 7. Am J Ophthalmol

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15 The Glaucoma Treatment Universe 2016 Bimatoprost vs Travoprost Prostaglandins Alpha agonist CAI Combo drugs Ginkgo, etc Beta-blockers Cardioselective betablockers SLT Trabeculectomy Nutrition issues Three clinical comparison studies in patients with elevated IOP Parrish et al, 2003 Noecker et al, 2003 Cantor et al, 2005 Sponsor Pharmacia Allergan Allergan Length 12 weeks 3 months 6 months Bimatoprost n=136 n=16 n=77 Travoprost (0.004%) n=138 n=15 n=81 Latanoprost n=136 Outcome Favored: Bimatoprost Bimatoprost Bimatoprost Study included latanoprost treatment arm, n=136 (see earlier slides). Study population comprised African-American patients. Mean IOP reduction. Significant difference between treatment groups. Parrish et al. Am J Ophthalmol. 2003; Noecker et al. Am J Ophthalmol. 2003; Cantor et al. ARVO Prostaglandins All decrease IOP by increasing uveoscleral outflow All are effective at squashing the diurnal curve They have either no effect or a positive effect on retinal perfusion But does 1 work better than the others? Patients Consistently Achieving a Mean Diurnal IOP <18 mm Hg At Every Visit Through 6 Months % of Patients 60% 50% 40% 30% 20% 10% 53.4% 37.5% 0% Bimatoprost Latanoprost P =.010 Choplin et al. IGS XLT Study: Mean IOP at Week 12 Mean IOP + SEM (mm Hg) AM 12 PM 4 PM 8 PM Study population: previously treated patients Approximately 50% on latanoprost at screening Consistently lower mean IOP with bimatoprost Statistical analysis not reported Parrish et al. Am J Ophthalmol Bimatoprost Latanoprost Travoprost Time of Day at Week 12 Mean IOP ± SEM (mm Hg) Walters et al. Surv Ophthalmol Circadian IOP Timolol Gel Latanoprost Bimatoprost 8 AM 12 PM 4 PM 8 PM 12 AM 4 AM 8 AM Day 28 Day 29 Time P.037 vs timolol 14

16 Majority of Patients on More Than One IOP-Lowering Medication What If: A patient failed on Xalatan? 3 Medications 4 or More Medications 22.8% 7.8% 1 Medication 27.1% 2 Medications 42.2% If switched to Lumigan, 57% achieved target IOP If switched to Travatan, 45.5% achieved target IOP SO? Schappert. National Center for Health Statistics Why Are so Many Patients on Multiple Medications? Latanoprost Non-Responders: Switch to Bimatoprost Target IOPs set lower than in the past As disease progresses, patients need even lower IOP Even the most effective IOP-lowering medications, the lipids, do not get all patients to low target IOPs Mean 16-Hour Diurnal IOP n = 15 Baseline (Untreated) After 30 Days Washout Between Treatments After 30 Days on Latanoprost After 30 Days on Bimatoprost P <.001 vs baseline, washout, and latanoprost Gandolfi, Cimino. Ophthalmology Choosing Therapy: Switch or Add? Target IOP should be reached with minimal number of medications Build strongest foundation prior to adjunctive therapy Switching to a more effective medication may be best course of action Differences within medication classes exist Potential benefits of monotherapy Improved patient compliance Decreased cost Reduced cumulative exposure to benzalkonium chloride Regarding Prostaglandins: Generally the 1 st line of treatment There are interindividual differences in efficacy Are there racial differences? If at first one fails; try, try, try again (with another prostaglandin) Why wouldn t you use a prostaglandin 1 st? 15

17 Prostaglandin Side Effects Conjunctival hyperemia: Severe hyperemia Lumigan 3.5% Travatan 1.5% Xalatan <1% Rescula 1% Is this a transient phenomenon? Is it an allergic conjunctivitis? Is it worth stopping the drop? Final prostaglandin thoughts They are additive to other G drugs but not with each other Travatan and Lumigan maintain target IOP 36hrs after instillation and significant IOP drop up to 84 hrs after instillation Prostaglandin Side Effects Iris pigmentation Is it reversible? Is it pre-cancerous? Xalatan 6mths 12mths Travatan 12 mths Lumigan 12mths Rescula 1 patient What if Target Pressure Is Not Reached With Even the Most Powerful Monotherapy? Add a second medication! SO? Other Prostaglandin side effects CME Uveitis Reactivation of HSK Hypertrichosis One must take into consideration the benefits of low IOP with the risks of the side effects Primary Considerations in Choosing Adjunctive Therapy Efficacy when used with the first-line medication IOP should be reduced by at least an additional 15% to a level as low as possible A medication that is effective monotherapy, or when added to one medication, may not be effective when added to a different medication! Safety Safety concerns increase with each additional medication: add the safest medication possible 16

18 Brimonidine vs Dorzolamide Added to Topical Beta-Blocker Patients Achieving Target 15% IOP Reduction (%) Brimonidine BID 86% 62% Dorzolamide TID Month 1 Month 3 Only patients who met target 15% IOP reduction were continued beyond 1 month 78% P < % Treatment paradigm, part IV If on 2 meds and target IOP not met 1. Consider 3 rd drop (Betoptic S or CAI) 2. Substitute combination drop for least successful drop 3. Consider SLT 4. Surgical intervention What is maximum medical therapy nowadays? SLT and trabeculectomy should not be considered weapons of last choice or last chance Simmons, Alphagan/Trusopt Study Group. Clin Ther Treatment paradigm Step 2 Prostaglandins 1 st If not successful try another agent by itself: Brimonidine bid or timolol QAM If neither of these get IOP to desired level then add Remember The Diurnal Curve!!! PGAs Trabeculectomy Brimonidine -TID CAI TID What about beta-blockers? BID vs QAM ½% vs ¼% Effect on diurnal curve Treatment Paradigm, Part III 1.Prostaglandins alone 2. Brimonidine or beta-blocker alone 3. Prostaglandin + beta-blocker or brimonidine (unless 1 of these absolutely sucked!) 4. Consider CAI or Cosopt if (3) is not successful 17

19 Safety Issues With Beta-Blockers For many years, timolol was the most effective IOPlowering agent available Widespread use revealed serious systemic adverse effects Exacerbation of reactive airway disease (asthma), exercise intolerance, impotence, depression, cardiopulmonary adverse events, etc Beta-blockers contraindicated or should be used with caution in many patients Up to 22% of patients may be unable to use nonselective beta-blockers due to contraindications or inability to tolerate side effects Kolker et al. Invest Ophthalmol Vis Sci Risk Factors For Conversion Systemic Adverse Effects of Beta-adrenergic Blockers: An Evidence-based Assessment (Lama, AJO Nov 2002) Many of the claimed adverse side effects of betablockers are not supported by clinical trials Most anectodal claims More patients may be eligible for beta-blockers Careful medical hx and checking pulse rate and rhythm should be sufficient What About Imaging Units? Are they essential? What do they do? What do they don t do? Are they the standard of care? 3 Questions For The Audience: 1. What is your definition of glaucoma? 2. What is the pathology of glaucoma? 3. Is retinal imaging the standard of care for treating glaucoma? 18

20 RNFL defects precede ONH changes 1 Glaucoma Early Detection The Macula Macula = central 20 Contains 50% of retinal ganglion cells Central 10 contains 23% of retinal ganglion cells Central 30 contains 58% of retinal ganglion cells GCC scan area 1 Quigley HA, et al Ophthalmology. 1992; 99: RNFL and Glaucoma Glaucoma: Where we scan Glaucoma is a disease of the RNFL Axons of retinal ganglion cells form the retinal nerve fiber layer (RNFL) Glaucoma is characterized by loss of ganglion cells leading to loss of retinal nerve fibers RNFL and Glaucoma RNFL changes are early to occur in glaucoma Up to 50% of the retinal nerve fibers may be lost before a visual field defect is detectable Early detection of glaucoma by RNFL imaging and analysis leads to early treatment, improving the chance to delay or halt the disease progression Imaging Overlay of the prnfl and GCC Related to OS 30-2 Visual Field prnfl GCC 19

21 Ganglion Cell Complex Analysis for earliest detection of structural change associated with glaucoma DIAGNOSE: Early is Better Inner retinal layer provides Ganglion cell assessment: Axons = nerve fiber layer Cell Body = ganglion cell layer Dendrites = inner plexiform layer Disc change precedes VF loss in most cases Imaging the GCC GCC Analysis may detect damage before RNFL GCC Full Retina Thickness Blood vessel ILM NFL GCL IPL INL OPL ONL PR IS/OS RPE Choriocapillaris and choroid GCC is inner retinal layers Nerve Fiber Layer Ganglion cell axons Ganglion cell layer Cell bodies Inner-Plexiform Layer - Dendrites GCC and RNFL analysis will be correlated, however GCC analysis may be more sensitive for detecting early damage in some patients GCC Thinning in Glaucoma Normal GCC Glaucoma with thinner GCC GCC 20

22 Comparing RNFL, GCC, and VF MANAGE: Topographic Change Analysis Inferior RNFL defect 24-2 Visual Field shows early superior VF defect Inferior GCC defect larger than RNFL and VF Images automatically aligned Areas with statistically significant change are highlighted Validated against a 10-year database of glaucoma progression cases Overlay of the RNFL and GCC (OS) with RTVue FD OCT prnfl GCC MANAGE: Looking for Progression Change is not always clear or certain The HRT does the math for you, pixel by pixel Significant change is marked and tracked 21