1. CONTEMPORARY GLAUCOMA CARE
Ron Melton, OD, FAAO
Randall Thomas, OD, MPH, FAAO
PENNSYLVANIA OPTOMETRIC ASSOCIATION
SPRING CONFERENCE
MAY 18, 2019
KALAHARI RESORT
MOUNT POCONO, PENNSYLVAINA
SECO International, LLC is committed to providing fair and unbiased continuing education.
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2. Financial Disclosure
Dr. Ron Melton and Dr. Randall Thomas are consultants to, on the speakers bureau of, on the advisory committee of, or involved in research for the following companies: ICARE, Valeant.

3. The Strength of Optometric Glaucoma Care
“Although highly desirable, physician-patient communication is an often overlooked but essential element in engaging patients in their own care.”
“When physicians communicate well, adherence rates are 19% higher than for patients whose physicians communicate less effectively.”
Who can spend more time with their patients, those seeing 20-some patients daily or those seeing 40-some patients daily? It’s simple arithmetic!
Ophthalmology. July 2015.

4. Systemic Medicines and Their Associations with Advanced Glaucoma
SSRI’s (selective serotonin reuptake inhibitors) and
Prozac®, Zoloft®, Paxil® and Lexapro®
SNRI’s (serotonin-norepinephrine reuptake inhibitors)
Effexor®, Cymbalta®
showed a 30% protective effect
Beta-blockers (mainly metoprolol); 20% protection
CCB (calcium channel blockers) (mainly amlodipine) (Norvasc®) have a strong harmful association with glaucoma.
Eye physicians need to be aware of these positive and negative influences on their patients with advancing, and advanced glaucoma.
Zheng W, Dryja TP, Wei Z, et al. Systemic Medication Associations with Presumed Advanced or Uncontrolled Primary Open-Angle Glaucoma. Ophthalmology 2018;125(7):
Ophthalmology, July, 2018

5. Sleeping Relationship on IOP
IOP is highest while we sleep
In Supine posture there is a hydrostatic increase in the pressure of the episcleral and orbital veins.
“The reason that nocturnal IOP elevation is so important is because: the increase is greater for glaucoma patients and the increase coincides with the time when our systemic blood pressure is the lowest. If IOP increases and BP decreases, the ocular perfusion pressure will decrease, leaving it at greater risk for glaucomatous damage.”
Doug Rett, OD, FAAO.
Primary Care Optometry News. March 28, 2018.

6. Glaucoma: Nocturnal Dip in Blood Pressure
Role of BP in glaucoma pathogenesis is critical
Extreme dipper (~20% of people) portend higher risk for glaucoma, esp. in normotensive patients
Antihypertensive meds need morning administration!
Relationship between IOP and POAG is weak with lower levels of IOP
Melgarejo JD, Lee JH, Petitto M, et al. Glaucomatous Optic Neuropathy Associated with Nocturnal Dip in Blood Pressure: Findings from the Maracaibo Aging Study. Ophthalmology 2018;125(6):
Ophthalmology, June, 2018

7. Head position effect on IOP
IOP is higher in recumbent than sitting posture
In the lateral decubitus position (laying on one’s side), the dependent (more downward) eye will have a relatively increased IOP.
“The IOP rise of the dependent eye in the lateral decubitus posture occurs despite IOP-lowering medical treatment.”
The difference between the two eyes is however small
For patients with more advanced glaucomatous optic neuropathy, counseling about sleeping posture could be important!
Lee T-E, Yoo C, Lin SC, Kim YY. Effect of Different Head Positions in Lateral Decubitus Posture on Intraocular Pressure in Treated Patients With Open-Angle Glaucoma. Am J Ophthalmol. 2015;160(5):
Am J Ophthalmol, Nov, 2015

8. Role of Cataract Extraction on IOP
“The role of cataract extraction in the alogorithm of glaucoma treatment is undeniable.”
“The latest studies to include washout in the context of MIGS show surprisingly large effects of phacoemulsification alone and relatively small incremental benefit of MIGS.”
(M+T: Don’t be “oversold” on hyped MIGS!)
Results of cataract extraction
For angle closure, reduction averaged 6.4 mm Hg
For open angle glaucoma, about 2.7 mm Hg reduction
Masis M, Mineault PJ, Phan E, Lin SC. The role of phacoemulsification in glaucoma therapy: A systematic review and meta-analysis. Survey Ophthalmol 2018;63(6):
Survey Ophthalmol. September - October, 2018

9. Perspective on Ocular Hypertension Treatment Study
About 5% of Americans over age 40 have OHT
Screening tests are RNFL assessment and VF testing
“Median time to develop POAG was 6.0 years in the observation group and 8.7 years in the medication group.”
“There is little absolute benefit of early treatment in low-risk OHT patients. Most OHT patients fall into this group and probably can be followed less frequently without treatment.”
5 Key Factors: Age, IOP, CCT, C/D ratio, and VF’s
Gordon MO, Kass MA. What We Have Learned From the Ocular Hypertension Treatment Study. Am J Ophthalmol. 2018;189:24-27.
Am J Ophthalmol, May, 2018

10. Regarding Treating Patients with OHT
“One approach would be to treat every individual with elevated IOP. However, the potential benefit of treatment would have to outweigh the low conversion rate to POAG, as well as the cost, inconvenience, and potential adverse effects of treatment.”
“Starting medical treatment after the development of early signs of POAG has only a modest impact on the rate of VF loss over the subsequent 5-year F/U. Some clinicians may choose not to treat any OHT patients until early glaucomatous damage is confirmed. However, this approach requires patients to return for F/U visits and appropriate diagnostic tests in a timely fashion.”
Gordon MO, Kass MA. What We Have Learned From the Ocular Hypertension Treatment Study. Am J Ophthalmol. 2018;189:24-27.
Am J Ophthalmol, May, 2018

11. β-Blockers Are Helpful In Patients with COPD!
“Conclusion: Treatment with β-blockers may reduce the risk of exacerbations and improve survival in patients with COPD, possibly as a result of dual cardiopulmonary protective properties.”1
“Patients with COPD often do not receive β-blockers because of concerns that they might exacerbate respiratory symptoms.”
“Beta-blocker users who subsequently received diagnosis of COPD didn’t have worse outcomes; indeed, outcomes were better in the beta-blocker cohort.”2
References:
Rutten F, et al. Arch Int Med ;170(10)
E-Clin Med, January, 2019 (as reported in Journal Watch , April 1, 2019.

12. New SITA-FASTER
Judging “rate of progression” is a critical step in managing glaucoma
New proposal protocol:
3 fields per year for the first 2 years
Then revert to annual testing
Known for over 2 decades: Overall SITA-Fast is just as good as SITA-Standard
SITA-Faster shaves about 2 minutes per eye off testing time, making more frequent testing more practical.
Heijl A, Patella VM, Chong LX, et al. A new SITA perimetric threshold testing algorithm: Construction and multicenter clinical study. Am J Ophthalmol. 2019;198:
Am J Ophthalmol. February 2019

13. The Optometric Perspective on Hysteresis
“Although research has a long way to go in better understanding CH’s role in glaucoma, clinicians may one day measure CH as part of routine glaucoma care and follow-up.”
Review of Optometry, June 15, 2018
Fisher B, Stursma A, Lifferth A, Carter S. Prepping Your Diagnostic Toolbox. Rev Optometry June 15, 2018.

14. Underdiagnosis of POAG
Population studies suggest over half of all glaucoma patients have not been diagnosed
From the Baltimore Eye Study: One-half of all people who were found to have glaucoma had seen an eye doctorwithin the past year and were unaware they had glaucoma!
“Despite all the progress being made in the field, it is sobering that ophthalmologists fail to diagnose more than 50% of cases of glaucoma.”
(Quigley, Ophthalmology Times)

15. Role of Self-IOP Measurements in Glaucoma Management
Home tonometry – logical step in understanding and management of glaucoma
Recent FDA approvals of devices
Triggerfish (Sensimed) – contact lens
ICARE Home (ICARE USA) – rebound tonometry requiring no anesthetic
Home tonometry helpful in better understanding the IOP changes and to support future glaucoma management

16. Literature on “HOME” Tonometry
“Up to 75% of individuals have peak IOP outside of office hours.”
“Most patients (73%) were able to accurately measure their own IOP after a short training session. Self-tonometry was deemed comfortable and relatively easy to perform and has the potential to improve patient engagement in their own care.”
“Patients with glaucoma may not only find self- monitoring of IOP acceptable, but also soon demand it.”
JAMA Ophthalmol, October, 2017
Pronin S, Brown L, Megaw R, et al. Measurement of Intraocular Pressure by Patients With Glaucoma. JAMA Ophthalmol. 2017;135(10):1-7.

17. Glaucoma Treatment Options
Pilocarpine derivatives
Epinephrine derivatives
Laser Trabeculoplasty
MIGS
Surgical Trabeculectomy
Nitric Oxide donating PGA
Rho-kinase Inhibitor
Prostaglandin Analogs
Beta-Adrenergic Blockers
Prostaglandin / Beta-Blocker combinations
Adrenergic Agonists
Adrenergic Agonist / Beta-Blocker combination
Carbonic Anhydrase Inhibitors (CAI’s)
CAI/Beta-Blocker combination

18. Compounding of Rx Glaucoma Meds
“Our compounded drugs are not FDA-approved as a whole, but each ingredient we use is FDA-approved. Since we are a compounding pharmacy, that is FDA-registered and inspected, we are able to compound these FDA-approved ingredients. Let me know if I need to explain a little clearer. If you have any other questions, please let me know. Thank you!”
Imprimis Pharmaceuticals

19. FDA Pregnancy Categories
A- Controlled studies show no risk
B- No evidence of risk in humans
Either animal studies show risk, human studies do not; or if no human studies, animal studies negative
C- Risk cannot be ruled out.
Human studies lacking, and animal studies positive for fetal risk or lacking. Potential benefits may justify potential risks
D- Positive evidence of risk post-marketing data show risk to fetus. If needed in life-threatening
Investigational or situation or serious disease, drug may be acceptable if safer drugs cannot be used
X- Contraindicated in pregnancy
Fetal risk clearly outweighs any benefit to patient

20. Treating During Pregnancy
6.3 million pregnancies reported in US each year
Pregnancy creates a natural reduction in IOP (19.6% reduction is normal; 24.4% decrease in OH)
Past FDA Pregnancy Categories no longer apply for drugs approved after June 30, 2015; Doctor must now read the package inserts and analyze the safety data to make an informed decision.
Until new drugs are approved, use the more familiar pregnancy category labeling
In glaucoma, brimonidine only category B (avoid during lactation- linked to CNS dedression)
Consult patient’s OB/GYN or PCP prior to treatment

21. Prostaglandin Receptor Agonists
Latanoprost (Xalatan and generic) 0.005%
Travoprost (Travatan Z and generic) 0.004%
Bimatoprost (Lumigan) 0.01%, and generic 0.03%
Tafluprost (Zioptan) %

22. Prostaglandins Pharmacology: prostaglandin analog
Mechanism: enhances uveoscleral outflow
Dosage: once daily, usually in the evening
Effectiveness: 30% reduction in IOP
Potential side effects: Iris darkening, hypertrichosis, CME, iritis, HSK activation, migraine headache, inflammatory bowel disease (IBS)
Xalatan 0.005% by Pfizer (and generic), Travatan (Z) 0.004% by Alcon, Lumigan 0.01% by Allergan, and Zioptan % by Akorn

23. Prostaglandin-Associated Periorbitopathy
A more newly recognized side effect of prostaglandin therapy
Periorbital fat atrophy gives rise to marked deepening of the superior lid sulcus, which can result in ptosis and enophthalmos
Beyond the obvious cosmetic concerns, such altered lid/orbital anatomy can make applanation tonometry quite challenging
Probably expressed more in middle-aged patients than in older patients
Tends to be at least partially reversible over a few months.
Advanced Ocular Care, July-August 2011

24. Latanoprostene Bunod 0.024%
FDA approved in November 2017
First nitric oxide – donating prostaglandin
One molecule – two mechanisms of action
Enhances uveoscleral outflow
Enhances trabecular meshwork outflow
Reduces IOP by 7.5 – 9.1 mm Hg
Perserved with 0.2% BAK
Used once daily in the evening (6% red eyes)
Comes in a 2.5 and 5 ml opaque bottle
Refrigerate until opened
Marketed as Vyzulta by Bausch & Lomb

25. Each Millimeter of IOP Reduction Matters
“Our current understanding of the relationship between IOP lowering and glaucoma onset or progression translates to the effect of each mm Hg IOP reduction on the development of progression of visual field loss.”
de Moraes CG, et al. Survey Ophthalmol 2016;61(5):
de Moraes CG, Liebmann JM, Medeiros FA, Weinreb RN. Management of advanced glaucoma: Characterization and monitoring. Survey Ophthalmol 2016;61(5):

26. “Glaucoma Treatment: by the Highest Level of Evidence”
The risk reduction could be about 19% per mm Hg, confirming results from the Early Manifest Glaucoma Trial and Canadian Glaucoma Study, and showing that IOP reduction is highly effective, and that every mm of pressure counts.
These results should serve as a stimulus to the pharmaceutical industry to continue development of new and even more potent drugs.
Heijl, A. The Lancet , April 5, 2015
Heijl A. Glaucoma treatment: by the highest level of evidence. The Lancet Volume 2015;385(9975):1264–1266.

27. Perspective on IOP and Progression on Glaucomatous Optic Neuropathy
“Progression was closely linked to the magnitude of the initial IOP reduction with treatment. The initial change in IOP (from baseline to the initial follow-up visit) was strongly associated with progression, with about a 10% lowering of the risk with each mm Hg of IOP reduction.”
Leske M, et al. Arch Ophthalmol, Jan 2003
“Elevated IOP is a strong risk factor for glaucoma progression, with hazard ratio increasing by 11% for every 1 mm Hg of higher IOP” Bengtsson B, et al. Ophthalmology, Feb 2007
Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E; Early Manifest Glaucoma Trial Group.
Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.
Arch Ophthalmol. 2003;121(1):48-56.

28. Xelpros™ (0.005% latanoprost)
Xelpros is non-BAK preserved latanoprost
Preservative is 0.47% potassium sorbate
(Zioptan® is the only preservative-free formulation of a prostaglandin)
Not available in retail pharmacies
Must be ordered through their contracted compounding pharmacies, and the requisite 3-month supply is shipped monthly directly to the patients
See Xelpros.com (Sun Pharmaceuticals) for details
Dosed once daily, exactly as any other latanoprost product

29. Rhopressa (netarsudil 0.02%)
FDA approved in December 2017
First rhokinase inhibitor
MOA purported to be enhancemen of conventional trabecular outflow
Use once daily in the evening
Reduces IOP about 4-5 mm Hg
Perserved with 0.015% BAK
Comes in a 2.5 ml bottle
Potential Side Effects:
In phase III, 53% experienced red eyes;
Can cause subconjunctival hemorrhages
Can cause an amiodarone-like vortex keratopathy
Marketed by Aerie Pharmaceuticals

30. Rocklatan™ Ophthalmic Solution
A combination of netarsudil 0.02% (Rhopressa) and latanoprost 0.005%
First combination drug of a prostaglandin and a rho-kinase inhibitor
Both ingredient drugs are “once daily” administration
As with new drugs, coupons may be essential to achieve cost-effectiveness
Conjunctival hyperemia (59%) may be a limiting factor
Marketed by Aerie Pharmaceuticals

31. Topical Beta-Andrenergic Receptor-Blocking Drugs
* Timolol (Timoptic and Timoptic XE / Betimol) 0.25% and 0.5%; (Istalol) 0.5%
* Levobunolol (Betagan) 0.25% and 0.5%
Metipranolol (Optipranolol) 0.3%
Carteolol (Ocupress) 1.0%
Betaxolol (Betoptic-S 0.25%)
* Have longer half-lives than other beta-blockers

32. Topical Beta-Blockers
Decrease aqueous production
Reduces IOP .25%; no response 15%
R/O asthma
Recommend monocular trial with lowest concentration once daily
Possible diminished effect if used with systemic beta- blockers
No advantage to gel-forming solution

33. Timoptic in OcuDose Only preservative-free glaucoma medicine
Niche product: indicated when ocular preservatives, particularly benzalkonium chloride (BAK), impair surface tissues of the eye
Available as .25% and .5% in .2mL individual units of solution from Valeant

34. Systemic Adverse Effects of Beta-adrenergic Blockers: An Evidence-based Assessment
“Ophthalmic beta-adrenergic blockers are effective in lowering IOP and have a long history of success and tolerability, despite the known contraindications. However, many of these beta-adrenergic blocker contraindications have been either disproven or there is no definite evidence to prove a casual link Wide acceptance of such traditionally purported side effects has been largely due to propagation of isolated case reports and short series as well as personal communication felt to reflect expert opinion. Based on published evidence many more patients are eligible for ophthalmic -adrenergic blockers than previously presumed. However, it remains incumbent on the clinician to elicit the appropriate history, check the pulse for bradycardia or arrhythmia, and refer for medical evaluation when appropriate before initiating ophthalmic - adrenergic blockers.”
Reference: Paul Lama, MD. AJO. November 2002

35. Beta Blockers and Chronic Heart failure
“Unless there is a specific contraindication, all patients with stable heart failure with reduced ejection fraction should receive a beta blocker in addition to an ACE inhibitor”
“A recent observational cohort study in patients with heart failure with preserved ejection fraction found that use of a beta blocker was associated with a decreased rate of all- cause mortality.”
Reference: The Medical Letter, Vol. 57 (1460). January 19, 2015

36. β-Blockers May Reduce Mortality and Risk of Exacerbations in Patients with Chronic Obstructive Pulmonary Disease
Conclusion: Treatment with β-blockers may reduce the risk of exacerbations and improve survival in patients with COPD, possibly as a result of dual cardiopulmonary protective properties.
Reference: F Rutten et al. Archives of Internal Medicine ;170(10)

37. Adrenergic-Receptor Agonists
Brimonidine
Apraclonidine
Dipivefrin
Epinephrine

38. Brimonidine Tartrate Alpha-2 adrenergic agonist; tid FDA approval
Acts by reducing aqueous production with some enhancement of uveoscleral outflow
Reduces IOP similar to timolol 0.5% bid
Side effects: fatigue and dry mouth most common side effects; uveitis reported; may reduce systolic BP 10 mmHg
Less tachyphylaxis or allergy development than the other alpha-2 agonists
Neuro-protective potential unknown
Alphagan (0.2%) by Allergan, and generic Alphagan P (0.15%) by Allergan and generic, and Alphagan P (0.1%) by Allergan

39. How important is “Preservative Free”?
“Published studies have not demonstrated any clear benefits of the BAK-Free formulations.”
“There is a lack of evidence of clinically significant harm from a small number of BAK preserved drops in patients without OSD. This means that generally more expensive PF glaucoma medications should only be recommended for those on poly pharmacy or those with OSD but are not necessarily required for all patients.”
Steven DW, Alaghband P, Lim KS. Preservatives in glaucoma medication. Br J Ophthalmol Epub ahead of print: 4 July doi: /bjophthalmol
Br J Ophthalmol, July, 2018

40. Lumify (brimonidine 0.025%) Ophthalmic Solution
FDA approved in December 2017 – OTC product
Major upgrade to help the chronic red eye
Superior to early generation vasoconstrictors
No rebound hyperemia
Used once or twice a day PRN
Marketed as Lumify OTC by Bausch & Lomb
To drug lecture

41. Neuroprotection
“Despite the long list of neuroprotective candidates, clinicians lack a proven neuroprotective agent with which to manage glaucoma.”
Glaucoma Today. November/December 2014.

42. Combigan Ophthalmic Solution
Combination of 0.2% brimonidine and 0.5% timolol
With ANY combination drug, always try one of the component drugs as monotherapy, and only use the combination product if or when the monotherapy drug comes close, but does not achieve target IOP
Remember, most all drugs have a non-response rate of about 10%, so there is a 20% chance that one of the components of any combination drug is not performing
Marketed as Combigan by Allergan in 5, 10, and 15 ml opaque white bottles, preserved with BAK .005%

43. Topical CAI’s Dorzolamide 2% sol. and Brinzolamide 1% susp.
Mechanism: decreases aqueous humor secretion
Reduces IOP approximately 15%
FDA dosage: tid, practical dosage bid
Contraindications: Allergy to sulfa and/or history of blood dyscrasias
Side effects: minimal; some burning, bitter taste, rare allergic reaction
Most all patients controlled with oral acetazolamide were successfully controlled with a topical CAI
Azopt 1% susp-Alcon; Trusopt 2% sol-Merck

44. Dorzolamide Hydrochloride 2% –Timolol Maleate .5% (Cosopt)
Both components decrease IOP by reducing aqueous humor secretion
Because of the CAI, must be used bid, which results in excessive beta-blocker therapy
Contraindications: patients with asthma, heart disease, or allergy to sulfa drugs
Ocular side effects: burning/stinging and perversion in taste
Marketed as Cosopt by Merck bottle, PF and generic

45. Simbrinza
Combination drug without a beta blocker where both ingredient drugs are dosed the same (b.i.d.)
Combines 1% brinzolamide (Azopt ophthalmic suspension) with 0.2% brimonidine
Offers a wide range of treatment possibilities due to its strong efficacy and ability to decrease elevated IOP by %
Marketed by Alcon under the brand name Simbrinza

46. Contemporary Glaucoma Medication Flow
1st Tier: Prostaglandin q d or timolol q am
2nd Tier: Topical CAI or brimonidine
3rd Tier: Combigan, Cosopt, Simbrinza, or
Prostaglandin/beta-blocker combination
4th Tier: Pilocarpine
Oral CAI (preferably methazolamide)

47. After a Prostaglandin; What to Add
Meta-analysis of studies regarding what drug to add to a prostaglandin
Is it brimonidine, a beta-blocker, or a CAI?
Conclusions: “All 3 classes are similarly effective in lowering mean diurnal IOP when used in combination with PGAs. Brimonidine is statistically less effective in reducing IOP at trough compared with the beta-blockers and CAI’s.”
Additional lowering of IOP was, on average, 2.5 to 3 mmHg for all 3.
Reference: Arch. Oph. July 2010

48. ALT vs SLT
“Selective laser trabeculoplasty almost certainly led to a marked increase in the use of trabeculoplasty in the first years of the 21st Century. However, careful, longitudinal trials suggest that it is no better than the argon laser.”
Ophthalmology, July 2015

49. Angle Closure Management Options
500 mg of acetazolamide in tablet form
Brimonidine q 15 min x 2 doses
A beta-blocker, q 15 min x 2 doses
Pilocarpine 2% once above steps completed
Potent steroid q 1h if there is much associated inflammation
YAG photoiridotomy once control is achieved

50. Alert on Topiramate (Topamax)
Approved for seizure disorders
Unapproved: Migraine HA, weight loss, depression, bipolar disorder
Mechanism of action is unknown
Because of a topiramate-associated risk for oral clefts, the FDA has now designated topiramate as a pregnancy category D drug.
Numerous reported cases of acute, bilateral, simultaneous angle- closure glaucoma
Onset usually within first 2 weeks of therapy
Most common presenting symptom: blurred vision
Exact mechanism of increased IOP is unknown
Tx: Stat consult with prescribing physician to begin to reduce topiramate dosage; then aqueous suppressants, oral CAI, cycloplegia (retracts ciliary body) - no miotics
IOP normalizes in 1-4 days, no laser treatment indicated

51. Topiramate (Topamax) and Vision
Uses: anticonvulsant, migraine prevention, bipolar disorder, obesity, OCD, IIH, neuropathic pain, essential tremor, post-herpetic neuralgia, and other esoteric uses.
Topiramate is a sulfa derivative (like CAI’s)
Idiosyncratic ciliochoroidal effusion is the most common ocular side effect, and most always results in a myopic shift with or without increased IOP
This rare event usually occurs within 2 weeks of initiation (or doubling) of dosing
First described in 2001 – 70% are female
Tx: D/C the medicine; use (PRN) beta-blocker, brimonidine, or in refractory case, oral prednisone or IV methylprednisolone. Also, instill cycloplegic agent, and do not use pilocarpine.
Reference: Clinical Ophthalmology. January 2012