C U T T I N G - E D G E A D V A N C E M E N T S

By Nancy Groves; Reviewed by Jae Hee Kang, ScD

RECENT TOOTH LOSS—with or without periodontal disease—was associ-ated with a significantly increased risk of primary open-angle glaucoma (POAG), ac-cording to findings from a long-term pro-spective study of oral health in male health professionals.

“We observed that men who differed in number of natural teeth, in whether they had any periodontal disease, or in whether they had ever received root canal treatment, did not show differences in the risk of de-veloping POAG,” said Jae Hee Kang, ScD, co-author of the study recently published in Ophthalmology.1 “However, compared to men who reported no tooth loss, men who reported losing one or more teeth recently

(in the past 2 years) had a 45% increased risk of POAG (95% CI, 1.06-1.97) and men who reported having both periodontal dis-ease and had lost one or more teeth in the past 2 years had an 85% increased risk of POAG (95% CI, 1.07-3.18).”

This association did not differ by IOP at diagnosis, but other possible associations were identified, said Dr. Kang, assistant professor of medicine, Channing Division of Network Medicine, Department of Medi-cine, Brigham and Women’s Hospital and Harvard Medical School, Boston.

“We observed some suggestion that these relations were strongest in those whose para-central vision was primarily affected ver-sus those whose peripheral vision was pri-marily affected,” said Dr. Kang, adding that paracentral vision loss in POAG has been shown to be related to impaired blood flow.

CYCLOSPORINEFOR DRY EYE WITH ANTI-PD-1 THERAPY

IN THIS CASE, a 58-year-old man with metastatic melanoma from a primary nasal sinus tumor was referred for bi-lateral eye irritation. He was undergo-ing his sixth cycle of nivolumab (3 mg/kg) for treatment of melanoma, and his lesions had been regressing favor-ably in response. The patient was as-sessed to have dry eye syndrome for which he was started on drop therapy. He continued to experience persistent burning in both eyes and was referred to a cornea specialist.

( See story on page 6 : Resident Writer’s )

( Continues on page 12 : Oral health )

Poor oral health, POAG may be linkedStudy raises possibility of systemic adverse effects

January 2017 VOL. 42, NO. 1

FIVE ROADBLOCKS TO BEING HAPPIER IN OPHTHALMOLOGYSOME PHYSICIANS may have a pre-conceived notion that comparing them-selves with other physicians who may be better off will give them a state of contentment. This is but one example of how physicians may deprive them-selves of more contentment, said John S. Grande, CFP, Traudy F. Grande, CFP, and John J. Grande, CFP in this latest “Money Matters” column. Learn about some of the other stressors common to practicing ophthalmologists as they prepare for retirement.

( See story on page 37 : Happiness )

OphthalmologyTimes.com

WHAT IS IT LIKE WHEN AN ARTIST LOSES VISION? Individuals might express impact in unique way PAGE 4

increased risk of POAG in men who

reported losing one or more

teeth recently

increased risk of POAG in men who reported having both periodontal disease and

had lost one or more teeth in

the past 2 years

45%

85%

Advanced laser technology enables surgeons to perform a full range of anterior and posterior YAG laser procedures, as well as SLT. Surgeons can also toggle between on- and off-axis modes to better visualize � oaters and their position.(Image courtesy of Inder Paul Singh, MD)

READ THE ARTICLE ON PAGE 18

On- and off-axis visualization

C L I N I C A L D I A G N O S I S S U R G E R Y D R U G T H E R A P Y

Resident Writer's Award

Practice Management

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AND TAKE A PEEK INSIDE.

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CHECK IIT OUTat Xiidra-ECP.com

C U T T I N G - E D G E A D V A N C E M E N T S

By Nancy Groves; Reviewed by Jae Hee Kang, ScD

RECENT TOOTH LOSS—with or

without periodontal disease—was associ-

ated with a significantly increased risk of

primary open-angle glaucoma (POAG), ac-

cording to findings from a long-term pro-

spective study of oral health in male health

professionals.

“We observed that men who differed in

number of natural teeth, in whether they

had any periodontal disease, or in whether

they had ever received root canal treatment,

did not show differences in the risk of de-

veloping POAG,” said Jae Hee Kang, ScD,

co-author of the study recently published

in Ophthalmology.1 “However, compared to

men who reported no tooth loss, men who

reported losing one or more teeth recently

(in the past 2 years) had a 45% increased

risk of POAG (95% CI, 1.06-1.97) and men

who reported having both periodontal dis-

ease and had lost one or more teeth in the

past 2 years had an 85% increased risk of

POAG (95% CI, 1.07-3.18).”

This association did not differ by IOP at

diagnosis, but other possible associations

were identified, said Dr. Kang, assistant

professor of medicine, Channing Division

of Network Medicine, Department of Medi-

cine, Brigham and Women’s Hospital and

Harvard Medical School, Boston.

“We observed some suggestion that these

relations were strongest in those whose para-

central vision was primarily affected ver-

sus those whose peripheral vision was pri-

marily affected,” said Dr. Kang, adding that

paracentral vision loss in POAG has been

shown to be related to impaired blood flow.

CYCLOSPORINEFOR DRY EYE WITH ANTI-PD-1 THERAPY

IN THIS CASE, a 58-year-old man with

metastatic melanoma from a primary

nasal sinus tumor was referred for bi-

lateral eye irritation. He was undergo-

ing his sixth cycle of nivolumab (3 mg/

kg) for treatment of melanoma, and

his lesions had been regressing favor-

ably in response. The patient was as-

sessed to have dry eye syndrome for

which he was started on drop therapy.

He continued to experience persistent

burning in both eyes and was referred

to a cornea specialist.

( See story on page 6 : Resident Writer’s )

( Continues on page 12 : Oral health )

Poor oral health, POAG may be linkedStudy raises possibility of systemic adverse effects

January 2017 VOL. 42, NO. 1

FIVE ROADBLOCKS TO BEING HAPPIER IN OPHTHALMOLOGYSOME PHYSICIANS may have a pre-

conceived notion that comparing them-

selves with other physicians who may

be better off will give them a state of

contentment. This is but one example

of how physicians may deprive them-

selves of more contentment, said John

S. Grande, CFP, Traudy F. Grande, CFP,

and John J. Grande, CFP in this latest

“Money Matters” column. Learn about

some of the other stressors common

to practicing ophthalmologists as they

prepare for retirement.

( See story on page 37 : Happiness )

OphthalmologyTimes.com

WHAT IS IT LIKE WHEN AN ARTIST LOSES VISION? Individuals might express impact in unique way PAGE 4

increased

risk of POAG

in men who

reported losing

one or more

teeth recently

increased risk

of POAG in men

who reported

having both

periodontal

disease and

had lost one or

more teeth in

the past 2 years

45%

85%

Advanced laser technology

enables surgeons to perform

a full range of anterior and

posterior YAG laser procedures,

as well as SLT. Surgeons can

also toggle between on- and off-

axis modes to better visualize

fl oaters and their position.

(Image courtesy of Inder Paul Singh, MD)

READ THE ARTICLE ON PAGE 18

On- and

off-axis

visualization

C L I N I C A L D I A G N O S I S S U R G E R Y D R U G T H E R A P Y

Resident Writer's Award

Practice Management

http://Glaukos.com

3JANUARY 2017 :: Ophthalmology Times

contentscontents

In Th is Issue 4 EDITORIAL 35 MARKETPLACE

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See what the ophthalmic community

is reading on OphthalmologyTimes.com

What’s Trending

1 Top 16 stories of 2016OphthalmologyTimes.com/Top2016Stories

2 Drug therapies moving

beyond anti-VEGFsOphthalmologyTimes.com/BeyondAnti-VEGFs

3 News from pharmaceutical

forefront of cataract surgeryOphthalmologyTimes.com/Intracameral

4 How glucosamine supplements

may increase IOPOphthalmologyTimes.com/Glucosamine

Resident Writer’s Award

6 CYCLOSPORINE FOR DRY EYE WITH ANTI-PD-1 THERAPYIntense infl ammation treatment helpful

in dry eye disease, corneal perforation

Special Report

31 ADD-ON MODULE ENHANCES GLAUCOMA DIAGNOSTICSTechnology creates anatomic map

of eye by using two fi xed landmarks

Practice Management

37 TIPS TO BE A HAPPIER OPHTHALMOLOGISTChanging fi ve key lifestyle habits can

decrease stress, improve well-being

Find us on

4

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JANUARY 2017 :: Ophthalmology Times

editorialeditorial

JANUARY 2017 ◾ VOL. 42, NO. 1

How gifted individuals may express impact of losing sight

VISION PROBLEMS have no doubt been

fairly common throughout history. However,

the difficulties of prominent artists—celebri-

ties that they are—often receive great attention.

Claude Monet’s difficulty with cataracts, Mary

Cassatt’s diabetes and cataracts that caused her

to give up painting, and Jules Chéret’s (creator

of those joyful posters of Parisian women) bi-

lateral angle-closure glaucoma are the subjects

of books.

Recently, I learned about three famous art-

ists who went blind in the 1700s. John Milton

(the English poet famous for writing Paradise

Lost) was born in 1674, 11 years before Johann

Sebastian Bach (who composed the Branden-

burg Concertos among other classical treasures)

and Georg Friedrich Handel (perhaps most fa-

mous for the choral work Messiah).

Bach’s blindness and subsequent death, both

at the age of 65, were reported to be “the un-

happy consequences of a very unsuccessful eye

operation” by British eye surgeon John Taylor

(who performed two operations a month apart).1

In 1751, at the age of 66, Handel developed a

cataract and was operated upon by “the great

charlatan Chevalier Taylor.”2 Again, the surgery

was unsuccessful and he was completely blind

for the last 7 years of his life.

H O W A R T I S T S

E X P E R I E N C E D L O S S

Not all famous artists of this time became blind

after failed surgery. Milton is thought to have

had either bilateral retinal detachments or glau-

coma, and he spent the last 20 years of life

without vision. He remained an acclaimed au-

thor, dictating his verse to scribes.3

Milton addressed the topic of his blindness

through the biblical character of Samson in the

poem Samson Agonistes. Samson, you may re-

call, was betrayed by the temptress Delilah, im-

prisoned, blinded by his captors, and chained

to giant columns.

The suffering Samson describes his blind-

ness as being similar to a solar eclipse: “O dark,

dark, dark, amid the blaze of noon,/Irrevocably

dark, total eclipse.”

Once his hair regrew, Samsom used his re-

gained strength to pull down the columns to

which he was chained, ending the lives of his

enemies as well as his own and his suffering

with blindness.

Handel, in his opera entitled “Samson,” has

his lead character describe his blindness using

a similar experience (a solar eclipse) and simi-

lar words: “Total eclipse! No sun, no moon!/All

dark amidst the blaze of noon!”

Bach, who only lived a few months following

his disastrous couching procedures, apparently

did not have the opportunity to use his art to

describe the experience of becoming blind.

Much has been written about these great art-

ists and their visual challenges. What to me is

less clear is the inner reaction of these gifted

individuals to the challenge of losing their

sight.

While a recent poll revealed the possibility of

losing sight to be the number one health-related

fear of Americans,4 my imagination causes me

to think that artists might experience that loss

in particularly dramatic fashion and might be

able express the impact in a special way. Q

When an artist loses vision

By Peter J. McDonnell, MD

director of the Wilmer Eye Institute,

Johns Hopkins University School of

Medicine, Baltimore, and chief medical

editor of Ophthalmology Times.

He can be reached at 727 Maumenee Building

600 N. Wolfe St. Baltimore, MD 21287-9278

Phone: 443/287-1511 Fax: 443/287-1514

E-mail: pmcdonn1@jhmi.edu

References1. David, Mendel, and Wolff. The New Bach Reader: A Life of

Johann Sebastian Bach in Letters and Documents. New

York; W.W. Norton and Company. 1998, p. 188.

2. Hicks, Anthony 2013. “Handel, Georg Frideric,” Groves

Music Online, Oxford University Press.

3. Sorsby A. The Nature of Milton’s Blindness. Br J

Ophthalmol. 1930;14:339-354.

4. Scott AW, Bressler NM, Ffolkes S, Wittenborn JS,

Jorkasky J. Public Attitudes About Eye and Vision Health.

JAMA Ophthalmol. 2016;134:1111-1118.

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Retina/Vitreous

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JANUARY, 2014 :: Ophthalmology Times

editorial advisory boardeditorial advisory board5JANUARY 2017 :: Ophthalmology Times

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resident writer’s awardresident writer’s awardJANUARY 2017 :: Ophthalmology Times

sponsored by

A 58-YEAR-OLD MAN with metastatic

melanoma from a primary nasal sinus tumor

was referred to ophthalmology for bilateral eye

irritation. Around this time, he was undergo-

ing his sixth cycle of nivolumab (3 mg/kg) for

treatment of metastatic melanoma. His meta-

static lesions had been regressing favorably

in response to nivolumab, an immunomodu-

latory agent that upregulates host immunity.

The patient was assessed to have dry eye

syndrome for which he was started on pre-

servative-free artificial tears and lubricating

ointment at bedtime. For the next 2 weeks,

he continued to experience persistent burn-

ing in both eyes and was then referred to a

cornea specialist.

E X A M I N A T I O N

On presentation to the cornea service, his cor-

rected visual acuity was 20/30 in the right

eye and 20/25 in the left. His examination

was notable for a low tear meniscus and dif-

fusely distributed punctate epithelial erosions

in both eyes. A basic secretion test (Schirm-

er’s with anesthesia) was performed which

yielded values less than 4.0 mm from each eye.

T R E A T M E N T A N D

C L I N I C A L C O U R S E

The patient was recommended to intensify the

frequency of lubricant tear use to at least 6-8

times daily. Additionally, he received bilateral

lower eyelid punctum plugs and was started

on topical cyclosporine (0.05%) twice daily in

both eyes. However, due to overseas travel,

the patient reported difficulty adhering to this

medication regimen.

Two weeks later, he returned to the office

with a perforated cornea in the right eye. Ex-

amination of the right eye was notable then

for a 1.8- × 1.4-mm paracentral epithelial de-

fect within which there was variable corneal

thinning and a small focus of Seidel-positive

leakage. The chamber was shallow but with-

out iris plugging to the perforation site. This

was acutely managed with corneal glue and a

bandage contact lens. The left eye had a small

epithelial defect without associated stromal

thinning.

Further treatment with nivolumab was held

in light of this adverse event. In the weeks that

followed, the right eye was stabilized with ad-

herence to a regimen that included preserva-

tive-free artificial tears, daily topical lotepre-

dnol (0.5%), topical cyclosporine, autologous

serum tears, oral doxycycline, and vitamin C.

The left eye had exhibited areas of slight stro-

mal thinning (80-90% normal stromal thick-

ness) but it was similarly stabilized with lu-

bricating tears (artificial and serum), topical

cyclosporine, and a bandage contact lens. One

month after the cornea of the right eye was

glued, the full thickness defect had healed but

there remained a stromal scar with marked

corneal thinning (Figure 1 on Page 7).

One year after nivolumab was discontinued,

abdominal imaging revealed a pancreatic head

mass that was biopsy-positive for melanoma.

After additional imaging revealed further sites

Editor’s Note: Oph-

thalmology Times

is pleased to an-

nounce Alexander

T. Nguyen, MD,

and Jessica Chow,

MD, of Yale Univer-

sity School of Med-

icine, New Haven,

CT, as the second-

place winners of the

2016 Resident Writ-

er’s Award Program,

sponsored by Aller-

gan. Their entry is

featured here.

The Ophthalmol-

ogy Times Resident

Writer’s Award Program is a unique recog-

nition opportunity designed to promote ex-

cellence in ocular surface disease education.

It was created to acknowledge outstanding

case identification and written presentation

skills in ophthalmology residents.

This year’s third-place winners, Lekha

Mukkamala, MD, and Albert Khouri, MD,

of Rutgers New Jersey Medical School, New-

ark, NJ, submitted a case study, “Irritation

in a bottle: The intensity of glaucoma treat-

ment and ocular surface disease.”

Look for their case study submission in

a future issue of Ophthalmology Times.

PURPOSE: To present a clinical case of severe dry

eye associated with nivolumab (Opdivo, Bristol-Myers

Squibb) that progressed to corneal perforation.

BACKGROUND: Nivolumab is a PD-1 (programmed

cell death protein 1) antagonist that exerts its anti-tumor

effect by upregulating host T cell immunity.

CASE PRESENTATION: A 58-year-old man with

metastatic melanoma was referred for management

of severe bilateral dry eyes after undergoing his sixth

cycle of nivolumab. The right eye progressed to cor-

neal perforation that was acutely treated with corneal

gluing. Nivolumab therapy was subsequently discon-

tinued due to this adverse event. When the patient ex-

hibited evidence of recurrent metastases, nivolumab

was restarted. The patient’s ocular surface was able

to sustain continued therapy with nivolumab with an

intensive approach that included topical cyclosporine.

CONCLUSIONS: PD-1 antagonists can cause or worsen

dry eye disease to the point of corneal perforation.

Given that its anti-tumor effect is immune mediated,

therapies targeting ocular surface inflammation can

be effective for stabilizing dry eye disease in patients

who are treated with anti-PD-1 agents.

Abstract

Cyclosporine for dry eyewith anti-PD-1 therapyCase exemplifi es need of proper ophthalmic care for cancer patientsBy Alexander T. Nguyen, MD, and Jessica Chow, MD; Special to Ophthalmology Times

Dr. Nguyen

Dr. Chow

tR

ESI

DENT WRITER’S AW

AR

2nd

Dt

7JANUARY 2017 :: Ophthalmology Times

resident writer’s award

of probable metastases, a decision was reached

to restart nivolumab.

In a recent clinic visit, the patient has cleared

all sites of metastases with several additional

treatment cycles. His ocular surface has been

maintained bilaterally with scleral lenses, topi-

cal cyclosporine, frequent surface lubrication,

and cautery of both upper and lower lid puncta.

D I S C U S S I O N

The programmed cell death protein 1 (PD-1)

is a membrane receptor that is involved in down-

regulating host immunity.1-3 Activation of this

pathway promotes the apoptosis of antigen-

specific T cells, which serves to promote host

tolerance for self-antigens. Nivolumab is an

antibody capable of disrupting this pathway;

in doing so, it exerts anti-tumor activity by up-

regulating host T cell immunity. Expectedly,

many of the adverse effects associated with

nivolumab are immune-mediated.1-4

While there is not much written about the

ocular side-effects of this drug class, we hypoth-

esized that the upregulation of T cell activity

could be the cause of worsening dry eye dis-

ease.4 If this were true, it follows that a thera-

peutic strategy targeting T cells may be of ben-

efit. The utility of controlling ocular surface

inflammation for the treatment of dry eye has

been demonstrated by prior studies investigat-

ing the use of topical cyclosporine for this end.5

Cyclosporine functions as a calcineurin inhibi-

tor. In doing so, it downregulates the transcrip-

tion of interleukin-2. The downstream effect of

this inhibition is a reduction in T cell activation.

Dry eye patients treated with cyclosporine

have been shown to have reduced levels of

pro-inflammatory cytokines on the ocular sur-

face,6 which is presumably responsible for the

improvement in symptoms, surface staining,7

and conjunctival goblet cell density.8

Because cyclosporine exerts its effect by in-

hibiting the activation of relatively naïve T cells,

its peak effect is delayed given the presence of

mature T lymphocytes that are already activated.

For this reason, bridging patients with a mild

topical corticosteroid can be helpful.

The patient’s poor compliance with the ini-

tial medication regimen may have contributed

to the progression towards perforation. Medi-

cation adherence, though, was improved after

the right eye required corneal gluing.

However, this adverse event led to the with-

drawal of nivolumab therapy, which had been

highly effective at resolving the patient’s meta-

static disease. When follow-up imaging showed

recurrent metastases, treatment with nivolumab

was reconsidered.

Ocular surface stability was a prerequisite

for receiving continued anti-PD-1 therapy. This

was achieved with an intensive approach that

includes topical cyclosporine, which provides

local inhibition of T cell activity on the ocu-

lar surface.

C O N C L U S I O N

Topical cyclosporine may be useful for treat-

ing dry eyes associated with immunomodula-

tory agents like nivolumab, which markedly

upregulate T cell activation.

In caring for patients with ocular side ef-

fects associated with cancer treatment, the de-

livery of proper ophthalmic care is critical. ■

References1. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and

activity of anti-PD-L1 antibody in patients with

advanced cancer. N Engl J Med. 2012;366:2455-

2465.

2. Rizvi NA, Mazieres J, Planchard D, et al. Activity and

safety of nivolumab, an anti-PD-1 immune checkpoint

inhibitor, for patients with advanced, refractory

squamous non-small-cell lung cancer (Checkmate

063): a phase 2, single-arm trial. Lancet Oncol.

2015;16:257-265.

3. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab

plus Ipilimumab in advanced melanoma. N Engl J

Med. 2013;369:122-133.

4. Nguyen AT, Elia M, Materin MA, et al. Cyclosporine

for dry eye associated with Nivolumab: a case

progressing to corneal perforation. Cornea.

2016;35:399-401.

5. Roberts CW, Carniglia PE, Brazzo BG. Comparison

of topical cyclosporine, punctal occlusion, and a

combination for the treatment of dry eye. Cornea.

2007;26:805-809.

6. Pflugfelder SC, Jones D, Ji Z, et al. Altered cytokine

balance in the tear fluid and conjunctiva of patients

with Sjogren’s syndrome keratoconjunctivitis sicca.

Curr Eye Res. 1999;19:201-211.

7. Chen M, Gong L, Sun X, et al. A comparison of

cyclosporine 0.05% ophthalmic emulsion versus

vehicle in Chinese patients with moderate to severe

dry eye disease: an eight-week, multicenter,

randomized, double-blind, parallel-group trial. J Ocul

Pharmacol Ther. 2010;26:361-366.

8. Kunert KS, Tisdale AS, Gipson IK. Goblet cell

numbers and epithelial proliferation in the conjunctiva

of patients with dry eye syndrome treated with

cyclosporine. Arch Ophthalmol. 2002;120:330-337.

Read the first-place entry 10 Tips for OSD-associated toxic epidermal necrolysis (TEN) at OphthalmologyTimes.com/10TipsForTEN

(FIGURE 1) Patient presented with severe dry eye after his sixth cycle of nivolumab for metastatic melanoma. Discontinuing nivolumab after corneal perforation

led to recurrent metastases. The anti-PD-1 agent was restarted successfully with a cyclosporine regimen, which stabilized the dry eye disease.

(Photos courtesy of Yale University School of Medicine)

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Take it all in at Xiidra-ECP.com

Proven to treat the signs of inferior corneal staining in 12 weeks and symptoms of eye dryness in 12, 6, and as little as 2.

(QWT�TCPFQOK\GF��FQWDNG�OCUMGF�����YGGM�VTKCNU�GXCNWCVGF�VJG�GHƂ�ECE[�CPF�UCHGV[�QH�:KKFTC�XGTUWU�XGJKENG�CU�CUUGUUGF�D[�KORTQXGOGPV�KP�VJG�UKIPU�OGCUWTGF�D[�+PHGTKQT�%QTPGCN�5VCKPKPI�5EQTG��

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what Dry Eye patients have been waiting forOVER

Indication Xiidra®�NKƂ�VGITCUV�QRJVJCNOKE�UQNWVKQP�����KU�KPFKECVGF�HQT�VJG�VTGCVOGPV�QH�UKIPU�CPF�U[ORVQOU�QH�FT[�G[G�FKUGCUG�&'&��

Important Safety Information+P�ENKPKECN�VTKCNU��VJG�OQUV�EQOOQP�CFXGTUG�TGCEVKQPU�TGRQTVGF�KP�������QH�RCVKGPVU�YGTG�KPUVKNNCVKQP�UKVG�KTTKVCVKQP��F[UIGWUKC�CPF�TGFWEGF�XKUWCN�CEWKV[��1VJGT�CFXGTUG�TGCEVKQPU�TGRQTVGF�KP����VQ����QH�VJG�RCVKGPVU�YGTG�DNWTTGF�XKUKQP��EQPLWPEVKXCN�J[RGTGOKC��G[G�KTTKVCVKQP��JGCFCEJG��KPETGCUGF�NCETKOCVKQP��G[G�FKUEJCTIG��G[G�FKUEQOHQTV��G[G�RTWTKVWU�CPF�UKPWUKVKU�

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BRIEF SUMMARY:Consult the Full Prescribing Information for complete product information.

INDICATIONS AND USAGE:KKFTCv�NKƂVGITCUV�QRJVJCNOKE�UQNWVKQP�����KU�KPFKECVGF�for the treatment of the signs and symptoms of dry eye FKUGCUG�&'&��

DOSAGE AND ADMINISTRATIONInstill one drop of Xiidra twice daily (approximately 12 JQWTU�CRCTV��KPVQ�GCEJ�G[G�WUKPI�C�UKPING�WUG�EQPVCKPGT��Discard the single use container immediately after using in each eye. Contact lenses should be removed prior to VJG�CFOKPKUVTCVKQP�QH�:KKFTC�CPF�OC[�DG�TGKPUGTVGF����minutes following administration.

ADVERSE REACTIONSClinical Trials ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may PQV�TGƃGEV�VJG�TCVGU�QDUGTXGF�KP�RTCEVKEG��+P�ƂXG�ENKPKECN�UVWFKGU�QH�FT[�G[G�FKUGCUG�EQPFWEVGF�YKVJ�NKƂVGITCUV�ophthalmic solution, 1401 patients received at least ��FQUG�QH�NKƂVGITCUV������QH�YJKEJ�TGEGKXGF�NKƂVGITCUV������6JG�OCLQTKV[�QH�RCVKGPVU������JCF�Ű��OQPVJU�QH�VTGCVOGPV�GZRQUWTG������RCVKGPVU�YGTG�GZRQUGF�VQ�NKƂVGITCUV�HQT�CRRTQZKOCVGN[����OQPVJU��6JG�OCLQTKV[�QH�VJG�VTGCVGF�RCVKGPVU�YGTG�HGOCNG�������6JG�OQUV�EQOOQP�CFXGTUG�TGCEVKQPU�TGRQTVGF�KP��������QH�RCVKGPVU�were instillation site irritation, dysgeusia and reduced XKUWCN�CEWKV[��1VJGT�CFXGTUG�TGCEVKQPU�TGRQTVGF�KP����VQ����QH�VJG�RCVKGPVU�YGTG�DNWTTGF�XKUKQP��EQPLWPEVKXCN�hyperemia, eye irritation, headache, increased lacrimation, eye discharge, eye discomfort, eye pruritus and sinusitis.

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Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Animal studies have not been conducted VQ�FGVGTOKPG�VJG�ECTEKPQIGPKE�RQVGPVKCN�QH�NKƂVGITCUV� Mutagenesis: .KƂVGITCUV�YCU�PQV�OWVCIGPKE�KP�VJG�in vitro #OGU�CUUC[��.KƂVGITCUV�YCU�PQV�ENCUVQIGPKE�KP�VJG�in vivo mouse micronucleus assay. In an in vitro chromosomal aberration assay using mammalian cells (Chinese JCOUVGT�QXCT[�EGNNU���NKƂVGITCUV�YCU�RQUKVKXG�CV�VJG�JKIJGUV�concentration tested, without metabolic activation. Impairment of fertility: .KƂVGITCUV�CFOKPKUVGTGF�CV�KPVTCXGPQWU�+8��FQUGU�QH�WR�VQ����OI�MI�FC[� �����HQNF�VJG�JWOCP�RNCUOC�GZRQUWTG�CV�VJG�TGEQOOGPFGF�JWOCP�QRJVJCNOKE�FQUG�4*1&��QH�NKƂVGITCUV�QRJVJCNOKE�UQNWVKQP������JCF�PQ�GHHGEV�QP�fertility and reproductive performance in male and female treated rats.

latanoprost (Rhopressa, Aerie Pharmaceuti-

cals) show that netarsudil is additive to latano-

prost, he noted.

“In addition, there is evidence of additivity

when ripasudil, a rho kinase inhibitor that is

commercially available in Japan, is combined

with other glaucoma medications,” he said.

As ophthalmologists become more familiar

with the medication, they will probably begin

to consider using netarsudil as a standalone

agent, Dr. Bacharach said.

In the Mercury 1 trial, netarsudil demon-

strated non-inferiority to latanoprost in eyes

with baseline IOP ranging from >20 to <25

mm Hg.

W E L L T O L E R A T E D

The Rocket 4 study, which is still under way, was

designed to provide safety data for registration

filing with European regulatory authorities.

Data collected so far in Rocket 4 and other

clinical trials show that netarsudil has an ac-

ceptable safety profile in clinical trials.

So far, adverse events related to the medica-

tion have been limited to the eye. Erythema,

mostly mild, has been the most common ad-

verse event associated with netarsudil.

In addition, verticillata has developed in

some eyes, but these corneal deposits have not

interfered with vision and resolve when treat-

ment is discontinued, as does the erythema

“Most side effects in patients using netarsudil

during clinical trials were well-tolerated and

did not lead to treatment termination, and no

side effects were permanent in patients who

stopped the medication,” Dr. Bacharach said. ■

Rocket 4 randomly assigned about 700 pa-

tients 1:1 to once-daily netarsudil or twice-

daily timolol maleate 0.5%.

Netarsudil met the primary efficacy end-

point, achieving non-inferiority to timolol for

lowering IOP in eyes with baseline IOP rang-

ing from >20 to <25 mm Hg.

Netarsudil also met the secondary efficacy

endpoints by demonstrating non-inferiority to

timolol for lowering IOP in eyes with

baseline IOPs ranging from >20 to

<27 mm Hg and from >20 to <28

mm Hg.

“The 90-day topline efficacy re-

sults from Rocket 4 reiterated the

positive findings of Rocket 1 and

Rocket 2, the two phase III registra-

tion trials,” said Dr. Bacharach, who

was an investigator in the Rocket 2

and Rocket 4 trials and a glaucoma

specialist in private practice in So-

noma County, CA.

Collectively, the phase III clinical

trial program for netarsudil includes

a robust number of treated patients, with nearly

2,000 patients dosed, he noted.

“Approval of this rho kinase/norepineph-

rine transporter inhibitor would be an excit-

ing and welcome development considering

that it would be the first new class of IOP-

lowering agents to become available in over

20 years,” Dr. Bacharach said. “Based on the

clinical trial experience, I expect netarsudil

will be an important part of our armamen-

tarium, and I am looking forward to using it

in the clinical practice.”

Dr. Bacharach observed that in Rocket 4,

netarsudil performed better for lowering IOP

in eyes with the higher baseline levels than it

did in the Rocket 1 and Rocket 2 trials.

In addition, its activity for reducing IOP in

eyes with lower starting IOPs distinguishes it

from available ocular hypotensive

agents. Netarsudil’s broad efficacy

is probably explained by its multi-

modal mechanism of action that in-

volves increased trabecular outflow

facility and likely also reduction of

episcleral venous pressure, he said.

E X P L O R I N G

C L I N I C A L R O L E

Dr. Bacharach foresees that if net-

arsudil is approved, it likely will be

first adopted for use as an add-on

to a prostaglandin analogue in pa-

tients needing combination therapy.

“The fact that about 50% of patients with

glaucoma are on two IOP-lowering medications

clearly speaks to the need for having multi-

ple therapeutic options with different mecha-

nisms of action that can be used in combina-

tion therapy,” Dr. Bacharach said.

Results from a phase II study of netarsudil

and the phase III Mercury 1 trial investigat-

ing the fixed combination of netarsudil and

Topline results from data collected after 90 days in

the 6-month Rocket 4 phase III clinical trial confirm

that netarsudil ophthalmic solution 0.02% (formerly

AR-13324; Rhopressa, Aerie Pharmaceuticals) safely

and effectively lowers elevated IOP in eyes with ocu-

lar hypertension or open-angle glaucoma, said Jason

Bacharach, MD.

NOVEL OCULAR HYPOTENSIVE DRUG MEETS ENDPOINTSThird phase III trial findings add evidence of efficacy, safetyBy Cheryl Guttman Krader; Reviewed by Jason Bacharach, MD 

take-home Netarsudil

ophthalmic solution

0.02% met its primary

and secondary

efficacy endpoints in

a third phase III trial

investigating its non-

inferiority to timolol

maleate 0.05% for IOP

lowering.

JASON BACHARACH, MD

E: jbacharach@northbayeye.com

Dr. Bacharach is a consultant to Aerie Pharmaceuticals and to other companies that

market and are developing medications for treatment of glaucoma.

1111EVOLVING CLINICAL STRATEGIES IN

GLAUCOMASpecial Report )

JANUARY 2017 :: Ophthalmology Times

ADVANCES CONTINUE TO PROGRESS FOR PHYSICIANS, RESEARCHERS IN FINDING A CURE FOR THIS BLINDING DISEASE

To investigate the hypothesis that poor oral

health may have systemic effects on the eye, the

researchers analyzed 26 years of data from the

Health Professionals Follow-up Study (HPFS),

which was designed to determine what factors

contribute to long-term health in men. They

reviewed data of 40,536 participants who were

followed biennially from 1986 to 2012.

Using information from the 2-year updates,

such as reports of periodontal dis-

ease, the participants could be cat-

egorized as having good oral health

versus poor oral health. Research-

ers could then compare the rates of

development of POAG in the two

groups over time.

“We also had a wealth of informa-

tion on additional health variables,

such as body mass index, smoking,

and diabetes so that we could ac-

count for these factors in our analy-

ses,” Dr. Kang said.

The 485 cases of POAG that were confirmed

with medical records were classified into sub-

types defined by IOP ≥ or < 22 mm Hg and vi-

sual field loss pattern at diagnosis (peripheral

loss only or early paracentral loss). Multi variate

rate ratios adjusted for key covariates with 95%

confidence intervals were estimated.

Although a modest increased risk of POAG

was observed in this study, observational epide-

miologic studies alone cannot establish causal

relations, and any clinical recommendations are

inappropriate at this time, Dr. Kang said.

“Nevertheless, the findings of the study raise

the possibility that systemic adverse effects of

poor oral health may also impact eye health,

and more confirmatory studies are warranted,”

she said.

E A R L I E R R E S E A R C H

This study follows earlier published studies by

several of the co-authors of this paper (Les-

lie Hyman, PhD, and John Danias, MD, PhD),

which found that individuals with glaucoma

had higher bacterial loads and fewer teeth than

those without glaucoma. Because the earlier

work had a small sample size and was con-

ducted in a clinic-based rather than a popu-

lation-based study sample, the authors were

interested in collaborating on a

larger study using the HPFS data.

The proposed association be-

tween poor oral health and POAG

derives from the shared factors of

impaired blood flow and endothe-

lial dysfunction, as well as the ob-

servation that treatment of peri-

odontal disease has been shown to

improve systemic blood flow and

endothelial function, Dr. Kang said.

“Therefore, we hypothesized that

poor oral health, manifesting as peri-

odontal disease and tooth loss, may be associated

with POAG,” she said.

Although studies often evaluate both women

and men, the investigators decided to use data

from the male-only HPFS since oral health ques-

tions were asked much less frequently in a simi-

lar study in women (the Nurse’s Health Study).

“We speculate that there may not be large

differences by gender, as periodontal disease

has been associated with various systemic dis-

eases, such as diabetes, cardiovascular dis-

ease, rheumatoid arthritis, certain cancers,

and neuro degenerative diseases in a similar

manner for men and women,” Dr. Kang said.

She added that some prior small studies have

not observed any differences by gender. ■

Reference1. Pasquale LR et al. Ophthalmology. 2016;123:2318-

2327. Epub 2016 Aug 20.

ORAL HEALTH( Continued from page 1 )

WEIGHING ROLE OF IOP FLUCTUATION IN PROGRESSIONAVAILABLE EVIDENCE INDICATES that

long-term IOP fluctuation is an important

factor in glaucoma progression, said Joseph

Caprioli, MD. Based on this information he

encouraged ophthalmologists to consider

IOP “modulation” rather than “reduction.”

“This relates to the quality of IOP control,”

said Dr. Caprioli, professor of ophthalmology,

University of California, Los Angeles. “The

target for patients with progressing primary

open-angle glaucoma at high risk should

be a low mean IOP and fewer excursions of

pressures into a range that may be damaging.

Go to OphthalmologyTimes.com/FluctuatingIOP

OphthalmologyTimes.comOnline Exclusive

take-home Recent tooth loss

and periodontal

disease have been

linked to primary

open-angle glaucoma

in a large prospective

study of male health

professionals.

JAE HEE KANG, SCD

E: nhjhk@channing.harvard.edu

This article was adapted from a study published in Ophthalmology as well as a

presentation by principal investigator Louis Pasquale, MD, at the 2016 meeting of the

American Glaucoma Society. Dr. Kang did not report any relevant disclosures.

Biosensors in contact lenses advancing to monitor IOP, diabetesBy Laird Harrison

CONTACT LENSES that can monitor

biomarkers in tear film for IOP and diabetes

mellitus are continuing to advance.

“The widespread use of contact lens sen-

sors could provide a paradigm shift in clinical

management of a variety of diseases,” wrote

Chau-Minh Phan, BSc, MSc, and colleagues of

the Centre for Contact Lens Research, School

of Optometery and Vision Science, Waterloo,

Canada, in Optometry and Vision Science.

Sensimed launched the Triggerfish IOP-mon-

itoring contact lens, which has CE approval in

Europe, but has not yet been FDA approved.

It uses four circular strain gauges capable

of sensing circumferential changes at the lim-

bus, Phan and colleagues noted.

An embedded microprocessor and antenna in

the contact lens sensor transfer the data wire-

lessly to an external eyepiece, and the data are

stored on a portable unit worn on the waist.

In clinical trials, the results proved highly

reproducible, and because no force is needed

on the cornea, they are independent of the in-

vestigator and patient, the authors said.

However, validation between the contact

lens sensor and tonometry has proved diffi-

cult because of the impossibility of simultane-

ous measurement using the contact lens sen-

sor and tonometry on the same eye.

Despite its technological obstacles, the de-

vice may prove useful over a 24-hour period

to glean information about fluctuation in IOP,

the researchers noted. ■

12 JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

http://www.alcon.com/

GLUCOSAMINE SULFATE supplements

widely used as an osteoarthritis treatment ap-

pear to increase IOP, according to H. Esfandi-

ari, MD, of the University of Medical Sciences,

Tehran, Iran, and colleagues in the journal Eye

(http://go.nature.com/2igYKFX).

Though the study did not have enough glau-

coma patients to evaluate the effects of glucos-

amine in this population, “it’s a wise

practice that ophthalmologists di-

rectly ask patients about its usage

and carry out medication discontinu-

ation trial[s] in uncontrolled cases,”

the researchers wrote.

An amino monosccharide, glucos-

amine is an essential constituent of

cartilage. Though evidence is lack-

ing that it can improve symptoms

of osteoarthritis, radiographic stud-

ies have shown that it slows joint

space width loss. Since it appears to be safe, it

is popular as a treatment.

However, glucosamine is also abundant in

corneal stroma and plays a role in the mor-

phology and function of the trabecular mesh-

work. One small retrospective study showed an

association between glucosamine supplement

usage and IOP.

Other researchers have proposed that glucos-

amine could restore the extracellular matrix of

cartilage or halt additional cartilage degrada-

tion. “It’s no surprise” if changing glycosami-

noglycans could lead to changes in IOP or IOP

measurement, the authors wrote.

D I V I N G D E E P E R

To investigate this finding further, Dr. Esfandi-

ari and colleagues recruited 88 patients with os-

teoarthritis who attended a rheumatology clinic

from July 2014 to March 2015. They excluded

patients with ophthalmic diseases that might

affect the biomechanics of the cornea.

They randomly assigned 44 patients to take 750

mg glucosamine three times a day for 3 months

and 44 patients to take gelatinous capsules filled

with sugar as a placebo on the same schedule.

Sixty-seven of the patients were female and

21 were male. Their mean age was 57.7 years.

The mean IOP of the glucosamine group was

12.4 mm Hg at baseline and 13.0 mm Hg in the

placebo group, differences that were not statis-

tically significant (p = 0.329).

At month 1, IOP rose to 12.6 mm Hg in the

glucosamine group and fell to 12.9 mm Hg in

the placebo group. The differences were still not

statistically significant (p = 0.868).

At month 3, IOP rose to 13.5 mm Hg in the

glucosamine group and 13.0 mm Hg

in the placebo group. At that point,

the differences reached statistical sig-

nificance (p = 0.023). In the glucos-

amine group, 34% of patients had

an increase of more than 2 mm Hg

compared with 23.5% of patients in

the placebo group.

There were no significant differ-

ences between the groups in ocular

response analyser Goldmann-corre-

lated IOP, cornea-compensated IOP,

corneal hysteresis or corneal resistance factor.

The mean age in those with increases of 2

mm Hg IOP or more was 66 years, compared

with 57.7 years in patients who had increases

of <2 mm Hg.

A B O U T T H E F I N D I N G S

“The results of this study show that while glu-

cosamine causes statistically significant in-

crease in IOP in patients with [osteoarthritis],

corneal biomechanics remain unchanged within

3 months of glucosamine supplement therapy,”

the authors wrote.

Their results suggest that glucosamine sup-

plementation could be “pathological” in the tra-

becular meshwork after 3 months, they wrote.

Glycosaminoglycans constitute the ground

substance for the outermost part of the trabec-

ular meshwork. Long, flexible chains of glycos-

aminoglycans interact with each other to form

a system of entangled polyanionic macromole-

cules which act like a gel and contribute to out-

flow resistance.

Accumulated glycosaminoglycans in the ground

substance of the trabecular meshwork outflow

pathways, and increased constriction of the tra-

becular spaces could explain the rises in IOP

seen with even short courses of steroid treat-

ment, the authors wrote. ■

CyPass® Micro-StentIMPORTANT PRODUCT INFORMATION

CAUTION: FEDERAL (USA) LAW

RESTRICTS THIS DEVICE TO SALE BY OR

ON THE ORDER OF A PHYSICIAN.

INDICATION: The CyPass® Micro-Stent is indicated for use in conjunction with cataract surgery for the reduction of intraocular pressure (IOP) in adult patients with mild to moderate primary open-angle glaucoma (POAG).

CONTRAINDICATIONS: Use of the CyPass Mi-cro-Stent is contraindicated in the following circum-stances or conditions: (1) in eyes with angle-closure glaucoma; and (2) in eyes with traumatic, malignant, uveitic, or neovascular glaucoma or discernible con-genital anomalies of the anterior chamber angle.

MRI INFORMATION: The CyPass Micro-Stent is magnetic resonance (MR) Safe: the implant is constructed of polyimide material, a non-conducting, non-metallic, non-magnetic polymer that poses no known hazards in all magnetic resonance imaging environments.

WARNINGS: Gonioscopy should be performed prior to surgery to exclude peripheral anterior synechiae (PAS), rubeosis, and other angle abnormalities or conditions that would prohibit adequate visualization of the angle that could lead to improper placement of the stent and pose a hazard.

PRECAUTIONS: The surgeon should monitor the patient postoperatively for proper maintenance of intraocular pressure. The safety and effectiveness of the CyPass Micro-Stent has not been established as an alternative to the primary treatment of glaucoma with medications, in patients 21 years or younger, in eyes with significant prior trauma, chronic inflammation, eyes with an abnormal anterior segment, eyes with chronic inflammation, eyes with glaucoma associated with vascular disorders, pseudophakic eyes with glaucoma, eyes with uveitic glaucoma, eyes with pseudoexfoliative or pigmentary glaucoma, eyes with other secondary open-angle glaucomas, eyes that have undergone prior incisional glaucoma surgery or cilioablative procedures, eyes with laser trabeculoplasty performed ≤ 3 months prior to the surgical screening visit, eyes with unmedicated IOP less than 21 mmHg or greater than 33 mmHg, eyes with medicated IOP greater than 25 mmHg, in the setting of complicated cataract surgery with iatrogenic injury to the anterior or posterior segment, and when implantation is without concomitant cataract surgery with IOL implantation for visually significant cataract. The safety and effectiveness of use of more than a single CyPass Micro-Stent has not been established.

ADVERSE EVENTS: In a randomized, multicenter clinical trial comparing cataract surgery with the CyPass Micro-Stent to cataract surgery alone, the most common postoperative adverse events included: BCVA loss of 10 or more letters at 3 months after surgery (8.8% for the CyPass Micro-Stent vs. 15.3% for cataract surgery only); anterior chamber cell and flare requiring steroid treatment 30 or more days after surgery (8.6% vs. 3.8%); worsening of visual field mean deviation by 2.5 or more decibels (6.7% vs. 9.9%); IOP increase of 10 or more mmHg 30 or more days after surgery (4.3% vs. 2.3%); and corneal edema 30 or more days after surgery, or severe in nature (3.5% vs. 1.5%).

ATTENTION: PLEASE REFER TO THE

INSTRUCTIONS FOR A COMPLETE LIST

OF CONTRAINDICATIONS, WARNINGS,

PRECAUTIONS, AND ADVERSE EVENTS.

© 2016 Novartis 08/16 US-CYP-16-E-3239

Glucosamine supplements may increase IOPFinding raises questions about possible role in glaucomaBy Laird Harrison

take-home A study investigated

the ocular hypertensive

effect of exogenous

glucosamine in

comparison with

placebo in patients

with osteoarthritis.

JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN

GLAUCOMA

Intracameral prostaglandin analogue therapy delivers durable benefitAnalysis: Nine months after single dose in ongoing trial, potential for once-a-year therapyBy Cheryl Guttman Krader; Reviewed by Thomas Walters, MD

AN EXTENDED-RELEASE intracam-

eral implant loaded with travoprost (travoprost

XR; ENV515, Envisia Therapeutics) was found

to be well tolerated and effective for providing

sustained IOP-lowering, according to 9-month

interim analysis findings in an ongoing phase

II trial.

The study included 5 patients with bilateral

ocular hypertension or open-angle glaucoma

previously treated with a topical prostaglandin

analogue (PGA). They received a single dose

of a low-dose formulation of the travoprost XR

implant in one eye and used

topical timolol maleate oph-

thalmic solution 0.5% contra-

laterally, twice daily.

In October 2016, Envisia

Therapeutics announced that

in an interim analysis, the in-

vestigational product provided

clinically meaningful reduction in IOP through-

out 9 months of follow-up.

The magnitude of the effect was comparable

to that achieved prior to the study with topical

prostaglandin treatment and during the study

with topical timolol treatment in the fellow eye

of the same patients.

Anecdotally, the IOP-lowering effect with

the travoprost intracameral implant

has been maintained beyond the

9-month assessment and with-

out loss of clinical efficacy, noted

Thomas Walters, MD, study inves-

tigator and medical director, Key-

stone Research, Austin, TX.

“The ongoing efficacy of this

intracameral implant is quite re-

markable, and safety data indi-

cate that it minimizes or avoids

several of the side effects associ-

ated with the topical administra-

tion of a prostaglandin,” he said.

“Namely, hyperemia seems to be

reduced compared to daily topi-

cal PGA therapy.

“The experience is still very preliminary,

but suggests this product has the potential to

be a big game-changer in medical therapy for

ocular hypertension and glaucoma by taking

patient compliance with daily drops out of the

equation,” he added.

Prior to washout of existing IOP-lowering

medications, the 5 patients included in the

study were using topical latanoprost 0.005%

or travoprost 0.004%.

Their mean IOP mea-

sured at 8 a.m. while

on pre-study medica-

tion was 19.7 mm Hg

and was 26.1 mm Hg

after washout.

The travoprost XR

implant was already

observed to have an

IOP-lowering effect

when the first mea-

surement was taken on Day 3. At 9 months,

mean IOP was reduced by 6.7 ± 3.8 mm Hg

(-26%) from the post-washout level.

“Because of the steady release of travoprost

from the delivery system, the intracameral im-

plant also controls diurnal fluctuations in IOP

better than topical therapy,” Dr. Walters said.

Dr. Walters noted there is some anterior

chamber inflammation for about 2 days after

the implantation procedure, which is due in

part to the use of povidone-iodine for sterile

preparation.

“After that resolves, the eyes have

been very white and the anterior

chamber quiet,” he said. “Prob-

lems that patients had in associ-

ation with topical prostaglandin

use prestudy, such as blurred vi-

sion and conjunctival hyperemia,

largely abated.”

M O R E A B O U T

T H E P R O C E D U R E

The procedure for placing the in-

tracameral implant is easily done

under topical anesthesia. In addi-

tion to the povidone-iodine prepa-

ration, the lashes and lids are isolated with a

speculum and a surgical drape placed.

Placement of the implant is similar to in-

serting a paracentesis port. The device is in-

troduced into the anterior chamber in front of

the iris and settles itself down into the inferior

angle. The biodegradable device is rectilinear

in shape, but becomes more amorphous and

conforms to the angle as it dissolves over time,

Dr. Walters said.

Monitoring is ongoing to determine the lon-

gevity of the IOP-lowering benefit, although

variation among patients is expected consid-

ering the potential for the kinetics of the im-

plant’s degradation to differ in the eyes of dif-

ferent patients.

A third cohort of the ongoing clinical trial

investigating the travoprost XR implant was re-

cently launched in which a high dose of ENV515

is being studied with the expectation of provid-

ing an IOP-lowering treatment effect that will

extend beyond 12 months after a single dose.

“In patients, the low dose demonstrated 9

months of IOP lowering efficacy after a single

dose,” Dr. Walters said. “The high dose demon-

strated 3-month-longer IOP duration versus the

low dose in preclinical evaluations in Beagle

dogs, thus, supporting its potential for once-

a-year therapy.” ■

take-home Five patients

receiving an extended-

release travoprost

delivery system

(ENV515, Envisia

Therapeutics) in the

anterior chamber have

ongoing IOP-lowering

with follow-up to 9

months in an ongoing

study.

THOMAS WALTERS, MD

E: tom@nobhill.me

Dr. Walters is an investigator and consultant for Envisia Therapeutics and multiple other

companies with products for IOP lowering.

Dr. Walters

‘The experience is still very preliminary, but suggests this product has the potential to be a big game-changer.’ — Thomas Walters, MD

15JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

Exploring risk/reward in trabecular bypass, suprachoroidal devicesAdditions will provide more surgical options, allow surgeons to individualize treatmentsBy John Berdahl, MD, Special to Ophthalmology Times

MICROINVASIVE GLAUCOMA sur-

gery (MIGS) has revolutionized the treatment

of glaucoma. With compliance concerns re-

garding topical medications, the benefits of

MIGS may even outweigh those of medical

therapies in patients with pressures adequately

controlled on medications.

Several companies are currently striving to

add more tools to the MIGS armamentarium

(including Glaukos with the iStent Trabecular

Micro-Bypass device).

Past focus for stents has been in the tra-

becular meshwork. However, companies are

currently developing suprachoroidal devices,

which are in various stages of FDA review.

These include the iStent SUPRA (Glaukos), the

CyPass Micro-Stent (Alcon Laboratories), and

the Solx Gold Shunt (Solx). These additions

will provide more surgical options and allow

surgeons to individualize treatments to pa-

tients more effectively.

T R A B E C U L A R B Y P A S S S T E N T S

The eye has two outflow pathways: the tra-

becular outflow and the uveoscleral outflow

pathway. The trabecular outflow pathway is

more pressure dependent and is where 75% of

the aqueous humor outflow occurs,1 making

this area a logical place to insert a stent to

restore natural physiologic aqueous outflow.

The episcleral venous pressure present is in

the range of 6 to 12 mm Hg, and while distal

outflow resistance adds a few mm Hg to the

IOP,2 trabecular bypass stents are still capable

of producing effective IOP lowering. The es-

sential benefit of the episcleral venous pres-

sure is that it virtually ensures no hypotony

will occur.

The iStent has a strong safety and efficacy

profile, as proven in the pivotal FDA trial.3

Results have only improved with time as sur-

geons continually become more experienced

with the procedure.

In a recently published study,4 a single stent

in combination with cataract surgery resulted

in a post-treatment mean IOP of 14.9 mm Hg ±

2.3 mm Hg at 3 years, a 36% reduction in IOP

from medicated baseline and an 86% reduc-

tion in the mean number of medications. This

was accomplished with no cases of hypotony,

IOP spikes, or hyphema within 1 month. Simi-

lar studies have shown corroborating results.5

Further studies demonstrate the efficacy of

multiple stents in reducing IOP and medica-

tions, illustrating the possibility of titrating

treatment with the stent.5-7

Optimizing patient benefit-to-risk is the cor-

nerstone of every glaucoma clinician’s man-

agement of glaucoma disease and iStent has

arguably demonstrated the highest benefit-to-

risk profile of any MIGS device to date.

S U P R A C H O R O I D A L S H U N T S

Suprachoroidal devices bypass the episcleral

venous pressure system and shunt fluid directly

into the suprachoroidal space to be reabsorbed

into the body. The intrinsic pressure differ-

ential between the anterior chamber and the

suprachoroidal space may aid in transferring

(FIGURE 1)

The iStent

Micro-Bypass

(Glaukos) is

implanted

through the

trabecular

meshwork

and into the

Schlemm’s

canal. (Images

courtesy of

Glaukos)

(FIGURE 3) The iStent SUPRA (Glaukos) is

designed to reduce IOP by accessing the

suprachoroidal space.

(FIGURE 2) The iStent

is designed with a

self-trephinating tip

and retention arches.

The device is 1 mm

long and 0.33 mm

tall.

16 JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

aqueous from the anterior chamber.10 How-

ever, without the episcleral venous pressure

back-stop there may be a greater risk of hy-

potony. A 2-year study of the CyPass demon-

strated hypotony prior to 1 month in 15.4%

of patients and hypotony after 1

month in 1.9% of patients.9 With

suprachoroidal stents there is also

potential for corneal edema10 as

well as hyphema.10-12

Published clinical evidence on

suprachoroidal shunts has at best

shown comparable efficacy to a

single trabecular bypass stent. Ini-

tial data for a CyPass inserted at

the time of cataract surgery in

patients with an IOP of > 21 mm

Hg show a reduction from a base-

line mean IOP of 25.5 mm Hg to a

mean of 15.8 mm Hg at 24 months

which is meaningful10 and it is possible that

safety and efficacy rates will improve over

time as surgeons gain experience but further

long-term study will be needed.

Like trabecular stents, implanting supracho-

roidal shunts requires a good understanding

of the anatomy. Surgeons should be deliberate

about placing a shunt in such a highly vascu-

larized space as it does present the possibil-

ity of serious intraoperative complications.

Risks can include bleeding from the highly

vascular iris and ciliary body and from the

anterior ciliary arteries while unintended cy-

clodialysis clefts may result from implanta-

tion of suprachoroidal shunts.

Other possible complications include pe-

ripheral anterior sequelae (PAS), small areas

of scarring around the device, which could

impair long-term efficacy. The creation of pas-

sageways in the suprachoroidal space could

cause abrupt closures of the cleft, resulting in

high-pressure spikes. The CyCLE trial showed

PAS formation at 10%,10 while the COMPASS

trial showed PAS formation reducing to 3.1%

over a 2-year period.12

However, suprachoroidal shunts

may be a valuable tool, especially as

an adjunct to a trabecular outflow

procedure in cases where disease

progression required additional pres-

sure lowering. I would like to see a

diagnostic that could easily deter-

mine episcleral venous pressure.

For low episcleral venous pres-

sures, a trabecular meshwork stent

would be more logical, while higher

episcleral venous pressures might

yield better results with supracho-

roidal stents. Perhaps in the future

that technology will be available.

Our collective experience and the accu-

mulation of data will determine the best use

for suprachoroidal and trabecular stents. Ex-

ploiting both the conventional and uveoscleral

pathways will enable enhanced treatment of

patients with progressive glaucoma disease

who require lower target pressures than can

be obtained by trabecular bypass treatment

alone. ■

References 1. Grant WM. Further studies on facility of flow through

the trabecular meshwork. AMA Arch Ophthalmol.

1958;60(4 Part 1):523-533.

2. Rosenquist R, Epstein D, Melamed S, Johnson M,

Grant WM. Outflow resistance of enucleated human

eyes at two different perfusion pressures and

different extents of trabeculotomy. Curr Eye Res.

1989;8:1233-1240.

3. Samuelson TW, Katz LJ, Wells JM, Duh Y-J,

Giamporcaro JE. Randomized evaluation

of the trabecular micro-bypass stent with

phacoemulsification in patients with glaucoma and

cataract. Ophthalmology. 2011;118:459-467.

4. Neuhann TH. Trabecular micro-bypass stent

implantation during small-incision cataract surgery

for open-angle glaucoma or ocular hypertension:

Long-term results. J Cataract Refract Surg.

2015;41:2664–2671.

5. Katz LJ, Erb C, Carceller Guillamet AC, Fea

AM, Voskanyan L, Wells JM, Giamporcaro JE.

Prospective, randomized study of one, two, or three

trabecular bypass stents in open-angle glaucoma

subjects on topical hypotensive medication. Clinical

Ophthalmology. 2015;9:2313-2320.

6. Donnenfeld ED, Solomon KD, Voskanyan L, Chang

DF, et al. A prospective 3-year follow-up trial of

implantation of two trabecular microbypass stents

in open-angle glaucoma. Clinical Ophthalmology.

2015;9:2057–2065.

7. Ahmed II, Katz LJ, Chang DF, Donnenfeld ED,

Solomon KD, Voskanyan L, Samuelson TW.

Prospective evaluation of microinvasive glaucoma

surgery with trabecular microbypass stents and

prostaglandin in open-angle glaucoma. J Cataract

Refract Surg. 2014;40:1295–1300.

8. Emi K, Pederson JE, Toris CB. Hydrostatic pressure of

the suprachoroidal space. IOVS. 1989;30:233-238.

9. Höh H, Grisanti S, Grisanti S, Rau M, Ianchulev

S. Two-year clinical experience with the CyPass

micro-stent: safety and surgical outcomes of a novel

supraciliary micro-stent. Klin Monbl Augenheilkd,

2014. Vol. 231(4), pp. 377-81.

10. Grisanti et al. [Supraciliary microstent for open-angle

glaucoma: clinical results of a prospective multicenter

study]. Ophthalmology. 2014;111:548-552.

11. Brown R. Minimally invasive supraciliary microstent

for IOP control in combined POAG-Cataract surgery:

2-year COMPASS RCT results. Presented at the ASCRS

Symposium and Congress. May 7, 2016. New Orleans.

12. García-Feijoo J, Rau M, Grisanti S, Grisanti S, Höh H,

Erb C, Guguchkova P, Ahmed I, Grabner G, Reitsamer

H, Shaarawy T, Ianchulev T. Supraciliary Micro-stent

Implantation for Open-Angle Glaucoma Failing Topical

Therapy: 1-Year Results of a Multicenter Study. Am J

Ophthalmol. 2015;159:1075-1081.

take-home Though much focus

for stents has been

in the trabecular

meshwork, many

companies are

currently developing

suprachoroidal devices,

which are in various

stages of FDA review.

MANAGING THE GROWING BURDEN OF GLAUCOMATHE NUMBERS OF PATIENTS with glaucoma

will rise dramatically in the future because of

growth in both the size of the aged population

and in demographic groups at high risk for

the disease.

Ophthalmology, however, is not equipped to

handle the increasing demand for services

considering workforce projections and current

models of care.

Delivering the Robert N. Shaffer Lecture at

AAO 2016, George A. Cioffi, MD, proposed

potential solutions and offered some testable

hypotheses aimed at addressing the problem

of glaucoma population management.

Go to OphthalmologyTimes.com/GlaucomaBurden

OphthalmologyTimes.comOnline Exclusive

JOHN BERDAHL, MD

E: john.berdahl@vancethompsonvision.com

Dr. Berdahl is an ophthalmologist at Vance Thompson Vision, Sioux

Falls, SD. He is a consultant for Glaukos.

‘I would like to see a diagnostic that could easily determine episcleral venous pressure.’

‘Exploiting both the conventional and uveoscleral pathways will enable enhanced

treatment of patients with progressive glaucoma disease.’ — John Berdahl, MD

17JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

Laser technology offers multiple treatments in single deviceSystem designed to perform full range of anterior, posterior YAG laser procedures, plus SLTBy Laird Harrison; Reviewed by Inder Paul Singh, MD

NEW LASER TECHNOLOGY (Tango

Reflex, Ellex) combines specialized Nd:YAG

vitreolysis settings for floaters, with settings

for trabeculoplasty, capsulotomy, and iridotomy

in one unit.

“It’s an exciting time, because for so long

floaters have been ignored,” said Inder Paul

Singh, MD, glaucoma specialist, Eye Centers of

Racine and Kenosha, WI. “It is one of the most

common patient complaints I see in my office.”

In its YAG mode, the platform delivers a

truncated, ultra-Gaussian energy beam that can

vaporize floaters with less energy and it uses a

coaxial illumination configuration to maximize

visualization of the floaters, Dr. Singh said.

Though some clinicians fear a higher dose

of energy will cause damage to nearby struc-

tures in the eye, dispersion of energy does not

increase in proportion to the increase in in-

tensity, he said.

“I realized early on how much of

a misperception some people have

about the physics behind the YAG

laser,” Dr. Singh said. For exam-

ple, 1 mJ of laser energy disperses

in a convergence zone of 100 μm,

while the convergence zone of 5

mJ is 150 μm.

In addition, the platform features

a truncated energy beam. Since it

has a sharper rise and fall, 30% to

40% less energy is needed to treat

floaters when compared with stan-

dard lasers. It can vaporize floaters at 3 to 4

mJ, but Dr. Singh said he often uses settings

in the 5 to 6 mJ range.

He uses 200 to 800 shots per floater depend-

ing on the size and density of the floater. Since

the laser delivers a 4-nanosecond pulse, the

energy dissipates before the next shot is fired,

therefore preventing a build up of energy.

C O A X I A L I L L U M I N A T I O N

The system also situates the slit lamp light,

aiming beam, and laser all on the same opti-

cal pathway.

This allows the clinician to more effectively

visualize posterior floaters in relationship to

the retina, Dr. Singh said.

By contrast, the light source on most lasers

is inferior, superior, or to one side of the laser.

The coaxial position allows for a red reflex

and maximizes visualization of floaters in the

middle and posterior vitreous, he said.

Without this coaxial illumination, it is not

possible to identify many of the symptomatic

floaters and more importantly, provide spatial

context with the retina, he explained.

“If the floater is in focus and the retina is

in focus, that tells me it is not okay to fire,” he

said. “If the floater is in focus and the retina

is not, that tells me it is okay to fire.”

The clinician can also fire with the slit lamp

off-axis.

“When the slit lamp is in the oblique posi-

tion, it gives us an understanding of where the

floater is in relation to the posterior capsule,”

Dr. Singh said. “You lose the red reflex and

thus the floaters appear white behind a black

background.”

Because the illumination level

provided with Reflex Technology is

adjustable, it is possible to precisely

titrate the amount of coaxial illu-

mination as needed, Dr. Singh said.

For example, a floater in the mid-

dle-to-posterior vitreous requires

use of coaxial illumination for spa-

tial context with the retina.

However, if a surgeon finds the

lighting too bright and the floater

gets lost in the red reflex, it is pos-

sible to incrementally adjust the amount of co-

axial illumination by slowly moving the slit

lamp into the oblique position. This can be

done until the perfect level of lighting needed

to maximize the contrast of the floater—yet

keep the spatial context in relation to the ret-

ina—is achieved.

O T H E R I N N O V A T I O N S

A third advantage of the platform over some

other lasers is that the light source is a light-

emitting diode instead of a halogen globe.

“That allows for fewer and less intense back

reflections for the doctor,” Dr. Singh said. “An-

other benefit is that the light runs cool and

can be left on indefinitely without warming

the environment and putting strain on sur-

rounding components.”

The platform uses a green aiming beam for

YAG treatments, which improves contrast sen-

sitivity and visualization against the red reflex

of the retina, and differentiates from the red

aiming beam of the SLT mode, Dr. Singh said.

The increased possibilities with vitreoly-

sis have awakened interest in treating float-

ers, with a new international floater society,

the International Ophthalmic Floater Society,

launched at the 2016 meeting of the European

Society of Cataract and Refractive Surgeons,

Dr. Singh said.

This group has begun work on classifying

floaters, developing standardized protocols,

and creating a customized floater question-

naire. Their goal is to raise awareness and

push technology forward in this space.

Until now, clinicians have often dismissed pa-

tient’s complaints about floaters, Dr. Singh said.

“We told them, ‘Deal with it, it’s normal

part of life.’ Now we’re realizing it does have

an impact on their daily life,” he said. “If you

have a large clump of vitreous, how can it not

affect vision?”

O U T C O M E S M E A S U R E D

To quantify the effectiveness of the laser, Dr.

Singh and colleagues asked 362 patients whether

the procedure made a difference. Ninety-three

take-home New laser technology

in a single device offers

multiple treatment

platforms, including

SLT for glaucoma, laser

vitreolysis for floaters,

capsulotomy, and

iridotomy.

VIDEO Watch how coaxial position

allows for a red reflex and maximizes visualization

of floaters in the middle and posterior vitreous.

(Video courtesy of Inder Paul Singh, MD)

Go to OphthalmologyTimes.com/LaserPlatform

ON- AND OFF-AXIS

18 JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

percent said it did. Asked to rate the improve-

ment on a scale of 1 to 10, the patients gave it

a 7.2 on average after 1 session and a 8.9 after

multiple sessions.

The best results were with solitary Weiss

rings. These required an average of 1.3 sessions,

while “amorphous clouds” typically required

about 3 sessions to satisfy patients.

In addition, the researchers used a wave-

front aberrometer and corneal topographer

(iTrace, Tracey Technologies) to measure vi-

sion changes in the patients.

The device distinguishes between the contri-

butions of the corneal and internal aberrations

(including the lens, posterior cornea, macula,

and vitreous) and calculates a dysfunctional

lens index based on multiple factors, including

higher-order aberrations, analysis of contrast

sensitivity, and pupil size dynamics.

In one example, before vitreolysis, a patient

reported “blurry” vision, and had a dysfunc-

tional lens index score of 3.79 on a scale of zero

to 10. After vitreolysis, the patient’s score im-

proved to 10, which is the best possible score,

and the patient was “very happy.”

“They were saying, ‘Doc, I can see better,’

and ‘Doc, I can read now,’” Dr. Singh said. “We

knew patients were seeing with better quality

of vision, and now, with the aberrometer, we

can objectively demonstrate this improvement.”

Still, Dr. Singh does not recommend the pro-

cedure for all floaters, since there are risks and

not all floaters are amenable to this procedure.

Patients with floaters right behind the pha-

kic lens, or near the retina/optic nerve are not

good candidates, Dr. Singh said.

Those with asteroid hyalonosis and other

diffuse floaters also may not respond well.

“Some people do neuroadapt,” he said. “And

we don’t advocate this procedure for people

without symptoms.”

In more than 1,400 cases, Dr. Singh said,

1 patient had a peripheral retinal hemorrhage,

7 patients had spikes in IOP, and 2 patients’

lenses were affected. There were no retinal

detachments, anterior chamber or vitreous

reactions, and no vitreous hemorrhages. The

lenses were hit before Dr. Singh discovered

the importance of using both coaxial and off-

axis illumination, he said.

“I have not seen a detachment or tear,” he

said. “In fact, in a few patients with vitreo-

macular traction, we have seen improvement

in macular contour on optical coherence to-

mography and release of the traction because

the laser severed strands of adhesion.”

The IOP spikes are most common in pseu-

dophakic patients who have had previous pos-

terior YAG capsuloptomies, where the floaters

are very close to the capsule, Dr. Singh said.

“It might be the gas bubbles floating into

anterior chamber or debris blocking outflow,”

he speculated. “I limit the number of shots in

those patients because we have seen a corre-

lation with number of shots and IOP spikes in

these subset of patients.”

C L I N I C A L P E A R L S

The best candidates are pseudophakic because

“you have a clear view into the vitreous and

retina and you don’t have to worry about hit-

ting the lens,” Dr. Singh said.

And those with Weiss rings make ideal can-

didates because it is relatively easy to see a

floater that correlates with patients’ symptoms.

Weiss rings require fewer shots and sessions

to improve patients’ symptoms.

Dr. Singh recommends that clinicians prac-

tice visualizing a floater before the procedure.

Visualizing can be made easier with the use

of a specialized lens such as one of the vitre-

olysis lenses made by Ocular Instruments or

the Singh Midvitreous Lens, which Volk Op-

tical designed with Dr. Singh’s help (though

he does not have a financial interest in the

product), he said.

He also recommends waiting 4 to 6 months

after first examining patients with new symp-

toms to see if the condition improves through

neuroadaptation and to make sure there are

no tears or holes that might have been missed

or develop later.

“It’s important to involve retina specialists,”

Dr. Singh added. “If I’m concerned about the

retina, I’ll send them to the retina specialist to

make sure everything is okay preoperatively.”

Also, if the laser cannot sufficiently remove

the floaters, a vitrectomy is an option, he noted.

(FIGURE 1) On-axis picture of a Weiss ring—nice red reflex, no retina in focus,

so okay to fire.

(FIGURE 3) Off-axis floater. Phakic patient—

no red reflex, but the floater appears white

behind a dark background and can help

determine distance from posterior capsule.

(Images courtesy of Inder Paul Singh, MD)

(FIGURE 2) Partial off-axis—still see some red reflex, but partially off-axis to

decrease the amount of the red reflex more anteriorly and therefore increase

contrast.

19JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

Continues on page 25 : Options

Microstent demonstrates lowered IOP, use of fewer drugs in European studyData focus on patients with combined cataract surgery and device implantationBy Vanessa Caceres; Reviewed by Steven R. Sarkisian Jr., MD

THREE-YEAR RESULTS with the mi-

croinvasive glaucoma surgery (MIGS) device

(CyPass Micro-Stent, Alcon Laboratories) com-

bined with cataract surgery showed sustained

IOP control and a lower need for glaucoma

medications, said Steven R. Sarkisian Jr., MD.

The device is placed in the supraciliary space

and is implanted in an ab interno fashion via a

clear cornea incision. This approach spares the

conjunctiva, sclera, and trabecular meshwork.

T W O C O H O R T S

European data presented by Dr. Sarkisian from

the multicenter prospective CyCLE study fo-

cused on two patient cohorts (245 eyes) that

both had combined small-incision cataract sur-

gery and device implantation. In one cohort

(93 eyes), the patients had uncontrolled IOP

(21 mm Hg or greater) at baseline.

“The goal with this group was to lower the

IOP,” said Dr. Sarkisian, clinical professor and

Glaucoma Fellowship Director, Dean McGee

Eye Institute, University of Oklahoma, Okla-

homa City, OK.

In a second cohort of 152 eyes, the IOP was

controlled (21 mm Hg or lower), and the goal

was to lower the number of medications used.

The mean baseline IOP in cohort 1 was 25.3

mm Hg versus 16.4 mm Hg in cohort 2. At

baseline, both groups used about 2.1 medica-

tions on average.

Thirty-two patients in the study

had previous glaucoma surgery, Dr.

Sarkisian said

After implantation of the device,

the mean IOP in cohort 1 lowered

from 25.3 mm Hg to 17.2 mm Hg

at 3 years. At 12 and 24 months,

the mean IOP in cohort 1 had low-

ered by 34% and 30%, respectively,

he said.

In cohort 2, the mean IOP stayed

the same postoperatively. However, by month

36, the mean number of medications used had

dropped to 1.

“Of note, we see that the percentage of pa-

tients on 1 or fewer medications at baseline

was only 31.6% and then increased to 64.1%

by 36 months,” Dr. Sarkisian said. “If you sep-

arate out the patients in cohort 2 who were on

zero medications at 36 months, it was 45%.”

The most commonly seen adverse event was

device obstruction (9.4%).

“There were 2 reports of transient device

obstruction by blood within the first postop-

erative week,” Dr. Sarkisian said. “However,

in the vast majority of cases (n = 19), obstruc-

tion appeared to have been related to intra-

operative device positioning that

was more posterior than optimal

and, over time, iris tissue over-

grew some portion of the device

lumen, which was resolved by use

of a YAG laser.

“Also, retinal complications oc-

curred in 4.1% of patients, but only

one case was related to the [de-

vice], and was due to hypotony

that resolved after device explan-

tation,” he said.

Although visual loss occurred in some pa-

tients, none of it was related to the implant.

“The 3-year safety profile gives long-term

evidence of compatibility with cataract sur-

gery and the potential to employ this therapy

earlier in the glaucoma treatment paradigm,”

Dr. Sarkisian said. ■

take-home Patients with

cataract surgery and

microstent implantation

had a lowered IOP and

a reduced number of

medications used at 3

years postoperatively.

STEVEN R. SARKISIAN JR., MD

E: steven-sarkisian@dmei.org

This article was adapted from Dr. Sarkisian’s presentation at the 2016 meeting of

the American Academy of Ophthalmology. Dr. Sarkisian is a consultant for Alcon

Laboratories.

S E L E C T I V E L A S E R

T R A B E C U L O P L A S T Y

Combining YAG and selective laser trabeculo-

plasty (SLT) functions into one unit can make it

feasible for small ophthalmology offices to offer

both services, said Savak “Sev” Teymoorian,

MD, MBA, of Harvard Eye Associates in Or-

ange County, CA.

If that encourages more practitioners to offer

SLT to their patients, then everyone will ben-

efit, he noted.

“In our treatments for glaucoma we are al-

ways looking for medication, and the new hot

things is microinvasive glaucoma surgery, but

we’re really underutilizing the SLT,” he said.

Patients often opt to try eye drops first be-

cause it sounds like a more conservative ap-

proach, but after they realize the challenge

of applying drops every day and especially if

they experience adverse reactions, they be-

come more interested in SLT, he said.

The treatment is particularly helpful in pa-

tients who have difficulty putting in their eye

drops, he said.

And despite patients’ concerns, adverse events

are rare with SLT, he said.

“I haven’t come up with any of them, but

in the literature, in those who have heavy pig-

ment, such as pigment dispersion syndrome

and pseudoexfoliation glaucoma, their IOP can

be elevated.”

In these patients, clinicians should use fewer

doses or less energy, Dr. Teymoorian said.

Some patients need repeat treatments, and

it can be used in both eyes, he pointed out. ■

INDER PAUL SINGH, MD

E: ipsingh@amazingeye.com

Dr. Singh is a speaker and consultant for Ellex.

 

SAVAK “SEV” TEYMOORIAN, MD, MBA

E: sevakteymoorian@hotmail.com

Dr. Teymoorian is a consultant to Ellex.

25JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

OPTIONS( Continued from page 19 )

Pelvic organ prolapse may be clue to presence of exfoliation syndromeInvestigators hypothesize that LOXL1 dysregulation may be contributing factorBy Lynda Charters; Reviewed by Barbara M. Wirostko, MD

RESEARCHERS HAVE identified a link

between exfoliation syndrome, an inherited

systemic disorder of elastin and extracellu-

lar matrix (ECM) associated with the LOXL1

gene locus, and pelvic organ prolapse, a com-

monly diagnosed connective tissue disorder in

women. The identified association was highly

statistically significant and thus, unlikely to

be a chance finding.

The recent investigation found that women

in the study population with

a history of pelvic organ pro-

lapse had an increased risk of

about 50% of receiving a diag-

nosis of exfoliation syndrome.

In exfoliation syndrome,

noted Barbara M. Wirostko,

MD, lead author of the Utah

Project on Exfoliation Syndrome Study, exfo-

liative material is deposited in the anterior

ocular segment (which can result in exfolia-

tion glaucoma) as well as in the

heart, brain, lungs, and skin, with

the potential for the development

of cardiovascular and cerebrovas-

cular diseases and hearing loss,

among other conditions.

Pelvic organ prolapse is consid-

ered a major health issue for women,

noted Dr. Wirostko, clinical ad-

junct associate professor, Depart-

ment of Ophthalmology and Vi-

sual Sciences, John A. Moran Eye

Center, University of Utah School of Medicine,

Moran Eye Center, Salt Lake City.

Study investigators noted the prevalence es-

timates of symptomatic pelvic organ prolapse

have been reported to range between 3% and

11%. In addition, 11% to 19% of women have

been reported to need surgical intervention to

repair the pelvic organ prolapse during their

lifetimes.

“Pelvic organ prolapse is believed to be as-

sociated with defects produced by elastin and

connective tissue injury in conjunction with

abnormalities in pathways for ECM tissue re-

pair,” the investigators said.

The study team explained in their report

(JAMA Ophthalmol 2016;134:1-8; doi:10.1001/

jamaophthalmol.2016.3411; published online

Sept. 15, 2016) that “because both exfoliation

syndrome and pelvic organ prolapse are char-

acterized by changes in elastin-containing ECM

tissue, we hypothesized that women with pel-

vic organ prolapse are more likely to develop

exfoliation syndrome during their lifetime.”

S T U D Y D E S I G N ,

R E S U L T S

Using the Utah Population Database (http://

bit.ly/1xuTosW)—a research resource at the

University of Utah that contains medical, de-

mographic, and genealogical records—a two-

pronged approach of a cross-sectional analy-

sis in Medicare patients and a retrospective

cohort study in patients in the University of

Utah Healthcare system of hospitals and clin-

ics was employed.

Investigators first performed a cross-sectional

analysis (substudy A) of 132,772

Utah women aged more than 65

years, who were Medicare recipi-

ents for more than 3 consecutive

years from 1992 to 2009, to deter-

mine the association between pel-

vic organ prolapse and the exfolia-

tion syndrome.

Then, investigators estimated

the longitudinal risk of an incident

diagnosis of exfoliation syndrome

from Jan. 1, 1995, to Dec. 31, 2014,

in 5,130 women aged between 30 and 65 years

at baseline who had been diagnosed with pel-

vic organ prolapse compared with 15,338 age-

matched female controls—women who had not

ever received a diagnosis of pelvic organ pro-

lapse (substudy B), Dr. Wirostko noted.

The mean age of the women in substudy A

was 82 years during the last year of follow-up

in the respective Medicare record. In substudy

A, investigators reported that pelvic organ pro-

lapse was associated with a 56% increased risk

of a diagnosis history of exfoliation syndrome

in Medicare beneficiaries (odds ratio, 1.56; 95%

confidence interval [CI], 1.4-1.7)

In substudy B, the results showed a 48% in-

creased incident risk of receiving a subsequent

exfoliation syndrome diagnosis in women who

were aged 30 to 65 years at baseline when

they had been diagnosed with a pelvic organ

prolapse compared with age-matched controls

during 20 years of follow-up (hazard ratio,

1.48; 95% CI, 1.1-1.9).

“Systemic conditions with altered ECM me-

tabolism, such as pelvic organ prolapse, might

share common biological pathways with the

exfoliation syndrome,” Dr. Wirostko said. “It is

possible that the LOXL1 dysregulation, thought

to occur in the exfoliation syndrome, is a com-

mon contributing factor.”

She added that a better understanding of the

shared pathways will ultimately impact clini-

cal diagnosis, management, and treatments. ■

take-home Women with pelvic

organ prolapse were

diagnosed more

frequently with

exfoliation syndrome

in the Utah Population

Database.

Dr. Wirostko

Increased risk of receiving a

diagnosis of exfoliation syndrome,

in women with a history of pelvic

organ prolapse

50%

26 JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

BARBARA M. WIROSTKO, MD

E: barbara.wirostko@gmail.com

Dr. Wirostko has no financial interest in any aspect of this report. She was joined in

this study by Karen Curtin, PhD, Samuel Thomas, MD, Kristina Allen-Brady, PhD, Gregory

S. Hageman, PhD, and Ken R. Smith, PhD, from the University of Utah, Salt Lake City;

Robert Ritch, MD, New York Eye and Ear Infirmary of Mount Sinai, NY, and R. Rand

Allingham MD, Duke University, Durham, NC.

Tracking treatment, adherence in cases of newly diagnosed OAGClaims data point to significant gap between diagnosis, medical/surgical therapiesBy Lynda Charters; Reviewed by Gail F. Schwartz, MD

A SIGNIFICANT NUMBER of patients

(17%) remained untreated 4 years after their

initial open-angle glaucoma (OAG) diagnosis,

according to U.S. claims data that follow the

prescription of IOP-lowering medications and

performance of glaucoma procedures.

“For this patient population, IOP-lowering eye

drops are the most common initial therapy for

OAG,” said Gail F. Schwartz, MD. “The avail-

ability of ophthalmic fixed combinations has

simplified topical dosing regimens for many

patients.

“For selected patients, laser trabeculoplasty

is frequently an alternative first-line treatment,”

added Dr. Schwartz,

who is in private prac-

tice and assistant pro-

fessor, Wilmer Eye In-

stitute, Johns Hopkins

University School of

Medicine, Baltimore.

Despite this, little is

known about the treat-

ment numbers and the

sequence/ timing used

to manage these pa-

tients. Having this in-

formation available would facilitate more accu-

rate assessment of the patient burden and the

unmet need for innovative therapies, she noted.

C L A I M S A N A L Y S I S

Considering the need for specific prescribing

data, Dr. Schwartz and her colleagues con-

ducted a retrospective claims analysis using

the Truven MarketScan Commercial Claims

and Medicare Supplemental databases that

covered July 2007 to December 2014.

Patients were included if they had a mini-

mum of two diagnoses of OAG 7 or more days

apart and within 1 year, with the first diagno-

sis in 2010; 30 or more months of continuous

enrollment before the index diagnosis with

no OAG diagnosis or OAG medication (un-

less with an accompanying pre-index ocu-

lar hypertension diagnosis); and 48 or more

months of continuous enrollment after the

index diagnosis.

During the 4-year study period, investiga-

tors evaluated the use of glaucoma medications

and the procedures performed, the time from

diagnosis to first therapy with medication or

laser trabeculoplasty, the sequence of thera-

pies implemented, and the use of adjunctive

medications after laser trabeculoplasty.

The glaucoma procedures included laser tra-

beculoplasty, trabeculectomy, implantation of

glaucoma drainage device, and a small num-

ber of minimally invasive glaucoma surgeries.

Further analysis of the surgical procedures

is planned.

A total of 6,172 patients (53% women, 47%

men) met the study inclusion criteria. The mean

patient age was 64.1 years.

During the 4 years after the index OAG di-

agnosis, Dr. Schwartz noted that 5,120 (83.0%)

patients with OAG were treated medically, by

laser trabeculoplasty or surgically. This left a

take-home An analysis of U.S.

claims data reveals a

substantial proportion

of patients (17%)

remained untreated 4

years after their initial

diagnosis of open-angle

glaucoma (OAG).

Number of other medication classes used before this

drug/procedure

Number of medication classes used subsequently

(including this medication)

MEDICATION OR PROCEDURE N (%) MEAN (SD) MEDIAN MEAN (SD) MEDIAN

Prostaglandin analogue3885

(75.88)0.2 (0.5) 0 1.7 (1.0) 1

Laser trabeculoplasty1292

(25.23)0.9 (1.1) 0 1.0 (1.2) 1

Sympathomimetic 1 (0.2) 0 (0) 0 1 (0) 1

Beta-blocker1336

(26.09)0.7 (0.8) 1 2.1 (1.0) 2

Alpha agonist800

(15.63)1.0 (1.0) 1 2.4 (1.1) 2

Fixed-combination alpha

agonist—beta-blocker

(Combigan)

673

(13.14)0.9 (0.9) 1 2.4 (1.1) 2

Topical CAI520

(10.16)1.4 (1.1) 1 2.6 (1.1) 2

Fixed-combination

CAI–beta-blocker (generic)479 (9.36) 1.4 (1.1) 1 2.4 (1.1) 2

Cholinergic agent 47 (0.92) 1.9 (1.4) 2 2.8 (1.3) 3

Fixed-combination

CAI–alpha-agonist (Simbrinza)47 (0.92) 2.3 (1.2) 2 1.7 (0.7) 2

Fixed-combination

CAI–beta-blocker (Cosopt)45 (0.88) 2.3 (1.3) 2 2.2 (1.1) 2

CAI, carbonic anhydrase inhibitor; OAG, open-angle glaucoma

(Figure courtesy of Gail F. Schwartz, MD)

(FIGURE 1) Sequence of use of medications and laser trabeculoplasty in 48 months after initial OAG diagnosis

28 JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

Continues on page 30 : Analysis

NS

95 (18%)

G

79 <1%

N

69 (12%)

T

51 (2%)

NI

95 (18%)

TS

92 (2%)

TI

129 (7%)

substantial percentage (17%) of patients who

had not been treated by 4 years after they ini-

tially received the OAG diagnosis.

“The most common medical treatments

were a prostaglandin analogue prescribed in

75.9% of patients and a beta-blocker in 26.1%,”

she said. “Laser trabeculoplasty was the most

common procedure and used in 25.2% as the

first line.”

Patients who underwent laser trabeculoplasty

did so less than 5 months after receiving the

diagnosis of OAG.

Data also showed that 3,592 (70.2%) patients

who underwent treatment during the 4 years

after the initial diagnosis were treated with

anti-glaucoma medications eye drops only. Of

that group of patients, 58.7% had insurance

claims for only one class of medication dur-

ing that time.

In addition, of 4,332 (85%) treated-patients

received topical medications as their first ther-

apy, and in more than half (54%), the therapy

was not changes during the course of the study.

Of that last group of patients, only about 25%

continued to refill their prescriptions through

the end of the 4-year study.

The most frequently prescribed, second-line

medications were beta-blockers, alpha agonists,

and fixed combinations of these medications

(brimonidine–timolol) with a median of one

previously prescribed medication.

The median times from the initial OAG diag-

nosis to the first prescriptions of those medica-

tions were 184, 299, and 241 days, respectively,

according to Dr. Schwartz.

Study limitations were those that are often

associated with insurance claims data analy-

ses, such as whether patients received pre-

scriptions but did not fill them, or whether

they used their medications as prescribed,

she noted.

Regarding the large percentage of patients

who were untreated at the 4-year time point,

another study limitation was that the current

analysis does not include data from office vis-

its, and it is unknown whether the 17% of pa-

tients who were untreated missed visits or did

not pick up their medications, or if other fac-

tors played a role in their lack of treatment.

Future analysis will incorporate office visit

data and further characterize the untreated

patients, Dr. Schwartz noted.

“Even in the setting of continuous insur-

ance coverage, adherence with topical therapy

remained limited, which was consistent with

previous data,” Dr. Schwartz said. “Forty-five

percent of patients undergoing initial laser tra-

beculoplasty were not prescribed additional

topical medication.”

This study lends further data to support

the need for long-acting medication and/or

alternative procedures that reduce or elimi-

nate the adherence component, Dr. Schwartz

concluded. ■

GAIL F. SCHWARTZ, MD

E: schwartzgf@aol.com

Dr. Schwartz has received speaker honoraria and consulting fees from Allergan. This

study was sponsored by Allergan plc, Dublin, Ireland. Dr. Schwartz was joined in this

study by Degang Wang, Guo Li, and Hitesh Chandwani, who were employees of Allergan

at the time of the study.

(FIGURE 2) Median time from index OAG diagnosis to fi rst use of medication or laser trabeculoplasty

Median time to fi rst prescription fi ll or laser (days)CAI, carbonic anhydrase inhibitor; OAG, open-angle glaucomaaFDA approved in April 2013

Prostaglandin analogue

Laser trabeculoplasty

Beta-blocker

Sympathomimetic

Fixed-combination alpha agonist—beta-blocker (Combigan)

Alpha agonist

Fixed-combination CAI–beta-blocker (generic)

Topical CAI

Cholinergic agent

Fixed-combination CAI–beta-blocker (Cosopt)

Fixed-combination CAI–alpha-agonist (Simbrinza)a

were prescribed

prostaglandin analogue

were prescribed

a beta-blocker

had laser trabeculoplasty

as the fi rst-line treatment

75.9%

26.1%

25.2%

MOST COMMON MEDICAL TREATMENTS

BY THE NUMBERS

MOST COMMON PROCEDURE

did not have claims for IOP-lowering medication or a glaucoma procedure during the 4 years after initial OAG diagnosis17%

(Figure courtesy of Gail F. Schwartz, MD)

(in days)

30 JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

ANALYSIS( Continued from page 28 )

Add-on technology module enhances accuracy in glaucoma diagnosticsSystem creates patients’ anatomic map using center of fovea, Bruch’s membrane openingBy Nancy Groves; Reviewed by Donald C. Hood, PhD

GLAUCOMA SPECIALISTS have a

new tool in their clinical armamentarium via an

add-on module designed to improve diagnostic

accuracy through a comprehensive analysis of

the optic nerve head, retinal nerve fiber layer,

and ganglion cell layer, as well as the use of

an extensive reference database.

The technology (SPECTRALIS Glaucoma

Module Premium Edition, Heidelberg Engi-

neering) received FDA 510(k) clearance last

fall. The add-on module, which has been on the

market internationally for a number of years,

has several distinctive features, said Kester

Nahen, PhD, managing director, Heidelberg

Engineering.

“One is that for the first time we are cus-

tomizing or individualizing the scan proto-

col to the anatomy of the patient,” Dr. Nahen

said. “There’s quite a variation from patient

to patient in the way that the optic nerve

head is oriented, relative to the fovea, what

we call the fovea-to-Bruch’s membrane open-

ing angle.

“And the Bruch’s membrane opening center

is the center of the optic nerve head,” Dr. Nahen

added. “With the optical coherence tomography

(OCT), we’re able to identify those landmarks,

and we are then able to place any subsequent

OCT scan according to these coordinates.”

I N D I V I D U A L I Z E D M E D I C I N E

The glaucoma module’s anatomic positioning

system (APS) technology creates the

anatomic map based on the two fixed

landmarks.

“This is quite a unique feature

that we have on our OCT system,”

Dr. Nahen said. “This is individu-

alized medicine in glaucoma care.

We’re taking the anatomy of the in-

dividual patient into consideration,

and then we’re using optimized scan

protocols for the different anatomic

structures that we’re studying.”

One of the options in the new glau-

coma model is a star-pattern or ra-

dial scan that looks at the thickness

of the neuroretinal rim.

“We’re not using a standard pro-

tocol that could also be used in the

retina,” Dr. Nahen said. “We have

come up with a scan pattern that is specific

to glaucoma.”

The star-pattern scan is focused on the cen-

ter of the Bruch’s membrane opening, and the

end of the membrane opening is also identi-

fied on every scan, as it is a stable anatomic

structure that can then be used to take cross-

sectional measurements of the minimum rim

width of the neuronal tissue that

exits the eye.

Deterioration of the Bruch’s

membrane opening minimum rim

width is important in monitor-

ing glaucoma progression, and

the measurements from the scan

can be compared with a refer-

ence database included in the

module. In the United States,

this age- and disc-size adjusted

reference represents the racial

and ethnic mix of the popula-

tion, making it more valuable

to local clinicians.

The series of scan patterns in-

cluded in the module will provide

extensive information with mul-

tiple applications, said Donald C.

Hood, PhD, the James F. Bender Professor of

Psychology and Professor of Visual Sciences

take-home Heidelberg

Engineering has

launched the Spectralis

OCT Glaucoma Module

Premium Edition in the

United States, which

has the capability of

creating an anatomic

map of each patient’s

eye by using two

fixed landmarks. The

module also includes

an extensive reference

database.

The glaucoma module enables precise

examination of relevant structures and ensures

accurate comparisons with reference data.

(Images courtesy of Heidelberg Engineering)Analysis of the Bruch’s membrane opening-based minimum rim width (BMO-MRW) with the glaucoma

diagnostics technology (Glaucoma Module Premium Edition), including a color-coded classification chart.

31JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

Continues on page 32 : Module

Titrate therapy to master efficacy, maintain safetyConsider glaucoma severity, eye pigmentation, medication useBy Vanessa Caceres; Reviewed by Nathan Radcliffe, MD

THOUGH TECHNOLOGY (MicroPulse

P3 Glaucoma Device, Iridex) allows surgeons to

personalize glaucoma therapy and reduce IOP,

there are ways to work the laser effectively de-

pending on several patient factors, said Nathan

Radcliffe, MD.

The device is used in conjunction with the

CYCLO G6 Glaucoma Laser System (Iridex) in

the office or the operating room. This cyclo-

photocoagulation device controls thermal eleva-

tion by chopping a continuous-wave beam into

repetitive microsecond pulses (micropulses),

which allow the tissue to cool between pulses,

Dr. Radcliffe said.

The treatment is efficient, non-incisional, re-

peatable, titratable, and can help address com-

mon concerns about medication compliance.

“The laser itself is powerful enough to cause

side effects and risks and powerful enough to

induce profound IOP lowering,” said Dr. Rad-

cliffe, glaucoma surgeon, New York Eye Surgery

Center, New York.

“That’s where personalizing and appropriately

titrating it comes into play,” he added.

With use of the MicroPulse, the mean IOP

reduced from 38.1 mm Hg to 23.2 mm Hg in a

study reported at the American Glaucoma Society

meeting in 2015 from Marlene Moster, MD, Phil-

adelphia, according to Dr. Radcliffe. That same

study found that the mean number of medica-

tions used dropped from 2.54 to 1.77.

A 2014 study reported a 45% reduction in IOP

with use of the P3 and a 75% success rate at 12

months, with no cases of hypotony.1

With the 200 cases that Dr. Radcliffe has treated,

there has been a 30% to 80% reduction in IOP

with no cystoid macular edema or phthisis. There

has been one case of worsening cataract. Post-

operative inflammation can occur and mydri-

atic pupil has also been reported.

P E A R L S T O M A X I M I Z E U S E

> Titrate according to glaucoma severity. For ex-

ample, if Dr. Radcliffe sees a glaucoma patient

with 20/20 vision who is on one or two glaucoma

drops, he’ll treat with 2,000 mW delivered for

100 seconds—50 seconds to the top half of the

eye and 50 seconds to the bottom half (sparing

the neurovascular bundles at 3:00 and 9:00).

“You get a 30% pressure reduction and a very

good safety profile,” he said.

However, if a patient is using four or five eye

drops and has had failed surgeries and 20/200

visual acuity, he will likely increase the device’s

power setting. The strongest setting Dr. Radcliffe

uses is 2,500 mW, so he may select that power

setting in such a patient and deliver the energy

for the same amount of time.

> Consider eye pigmentation. As the laser is bet-

ter absorbed in eyes with a lot of pigment, Dr.

Radcliffe will use a lower setting, at least for

starters, in eyes that are dark brown. In a pa-

tient with very blue eyes, he may use 2,200 mW

for the initial treatment depending on other pa-

tient factors. Assess the patient’s willingness to

undergo a repeat procedure and treat conserva-

tively until you understand the laser–pigment

interaction.

> Go aggressive to reduce medication use. If a

patient uses three or four medications, includ-

ing oral Diamox, Dr. Radcliffe is more likely to

start them at 2,250 or 2,500 mW. “There’s more

room to go down in terms of IOP,” he said. “If

a patient is on four medications, the likelihood

of overtreating and inducing hypotony is low.

We can be more aggressive with laser power in

eyes that have worse visual acuity.”

In contrast, if a patient does not use any medi-

cations and has MicroPulse treatment, surgeons

would be more cautious with laser settings, typi-

cally starting with a power of 2,000 mW. For pa-

tients with an IOP of 55 or 60 mm Hg, Dr. Rad-

cliffe may treat in the 2,300 or 2,500 mW range

and be able to lower their IOP to the mid-teens. ■

Reference1. Aquino MC, Barton K, Tan AM, et al. Micropulse

versus continuous wave trans-scleral diode

cyclophotocoagulation in refractory glaucoma:

A randomised exploratory study. Clin Exp

Ophthalmol. 2015;43:40-46.

NATHAN RADCLIFFE, MD

E: drradcliffe@gmail.com

This article was adapted from an Iridex booth presentation by Dr. Radcliffe during the

2016 meeting of the American Academy of Ophthalmology. Dr. Radcliffe is a consultant

for Iridex and other ophthalmic companies.

(Ophthalmology), Columbia Univer-

sity, New York.

“If you complete the full package on

a patient from a clinical research or

clinical diagnosis point of view, you

have a lot of information as well as

high-quality scans,” he said.

“By having radial scans within the

disc, it allows you to take a close look

at the damaged regions around and

in the disc,” he added. “It also will

help differentiate damage due to glau-

coma from damage due to other optic

neuropathies.”

Dr. Hood tests patients and inter-

prets OCT images in his lab and also

conducts clinical research. His lab

uses different OCT systems and soft-

ware packages, including those from

Heidelberg Engineering, with the goal

of improving the use of this technol-

ogy for diagnosing and understand-

ing glaucomatous damage.

F I L L I N G T H E G A P

The new glaucoma module for the

Spectralis OCT may help eradicate

what Dr. Hood sees as a shortcom-

ing in glaucoma diagnosis.

“Glaucoma specialists, in general,

are underutilizing the OCT,” he ex-

plained. “They tend to look at sum-

mary statistics on commercial reports.

What I’ve been trying to do is get them

away from these summary statistics

and get them to look instead at the

scan images and thickness maps.”

The module for the Spectralis OCT

is set up so that users can both view

reports and look at individual scans.

However, Dr. Hood is also work-

ing with Heidelberg Engineering to

design an improved format for a one-

page summary in the glaucoma mod-

ule that will describe the key features

from an imaging session for the cli-

nicians who prefer to view a single

report. It will be included in the mod-

ule in the near future. ■

32 JANUARY 2017 :: Ophthalmology Times

Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA

DONALD C. HOOD, PHD

E: dch3@columbia.edu

Dr. Hood has received grants from Heidelberg Engineering of equip-

ment and support for his laboratory at Columbia University.

MODULE( Continued from page 31 )

A new 0.075% formulation of

brom fenac ophthalmic solu-

tion (BromSite, Sun Pharma)

could provide relief from pain

and inflammation associated

with cataract surgery, according

to Sheri Rowen, MD, of Nvision

Eye Centers, Newport Beach, CA.

Last April, the FDA approved

the nonsteroidal anti-inflam-

matory drug (NSAID) to pre-

vent pain and treat inflam-

mation associated with cat-

aract surgery, Sun Pharma

announced.

“According to the study data,

it has good aqueous concentrations of the mol-

ecule after 1 drop,” Dr. Rowen said. “So that is

an encouraging sign.”

Sun Pharma’s U.S. subsidiary, Sun Ophthal-

mics, began marketing BromSite in the United

States last fall.

H O W I T W O R K S

The agent delivers bromfenac in a synthetic

polymer of crosslinked polyacrylic acid devel-

oped as DuraSite by InSite Vision. DuraSite

is also the vehicle for Bausch + Lomb’s be-

sifloxacin ophthalmic suspen-

sion (Besivance) and Akorn’s

azithromycin ophthalmic so-

lution (AzaSite).

DuraSite is mucoadhesive and

“can be used to improve solubil-

ity, absorption, bioavailability

and residence time as compared

to conventional topical thera-

pies,” according to Sun Pharma.

Sun Pharma of Mumbai, India,

purchased InSite Vision of Al-

ameda, CA, in November 2015.

The active ingredient is sus-

pended in the DuraSite and is released in small

doses each time the patient blinks, Dr. Rowen

explained. The label calls for twice-daily dos-

ing, morning and evening, beginning 1 day

before surgery and ending 14 days after.

Bromfenac, the active ingredient of Brom-

Site, inhibits cyclooxygenase (cox) 1 and 2, en-

zymes responsible for forming prostaglandins.

P H A S E I I I S T U D I E S

In two multicenter phase III, randomized clini-

cal trials, a higher proportion of patients treated

with BromSite were pain-free a day after surgery

than patients treated with the vehicle alone,

according to Sun Pharma.

In one study, 77% of the BromSite group

was pain free versus 48% of the vehicle group.

In the other, 82% of the BromSite group was

pain free versus 62% of the vehicle group.

The differences were statistically significant

(p < 0.001).

Likewise, a higher proportion of subjects ad-

ministered BromSite were inflammation-free

15 days after cataract surgery compared to a

vehicle control.

The proportions were 57% versus 19% in

the first study (p < 0.001) and 38% versus

22% in the second study (p = 0.035).

Adverse reactions listed on the BromSite

label include slow or delayed healing, an ef-

fect common to all NSAIDS.

Dr. Rowen has just begun treating patients

with the product, but so far has a good im-

pression, she said.

“It’s very comfortable and

interestingly enough it doesn’t

have a prolonged blur, which

was one of our concerns,” she

said. “Vision seems to clear

within a few blinks.”

Bromfenac is already avail-

able in a more standard vehicle

in Bausch + Lomb’s Prolensa,

which is approved to reduce (as

opposed to prevent) ocular pain

and treat inflammation associ-

ated with cataract surgery.

Other alternatives include nepafenac ophthal-

mic suspensions by Alcon Laboratories in two

concentrations: 0.1% (Nevanac, which is dosed

three times daily) and 0.3% (Ilevro, which is

dosed once daily).

Ketorolac is available as a generic for the

same indication.

“You have to use it 4 times a day,” Dr. Rowen

said. “It can cause corneal toxicity. It can sting

quite a bit so patients end up not wanting to

take it.”

BromSite comes in a 5 cc bottle, which is

larger than the bottle size for most competing

medications, Dr. Rowen said.

L O O K I N G A H E A D

Other medications in Sun Pharma’s pipeline in-

clude latanoprost ophthalmic solution 0.005%

(Xelpros) for the reduction of elevated IOP in

patients with open-angle glaucoma or ocular

hypertension, cyclosporine A 0.09% ophthal-

mic solution (Seciera) for the treatment of dry

eye disease, and dexamethasone 0.1% (Dexa-

Site) for the treatment of blepharitis. ■

WE WANT TO HEAR FROM YOU

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Comment on this article online:

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.COM

Clinicians, patients welcome pain-preventing NSAIDMultiple clinical studies demonstrate drug’s efficacy in cataract surgeryBy Laird Harrison; Reviewed by Sheri Rowen, MD

SHERI ROWEN, MD

E: srowen10@gmail.com

Dr. Rowen is a consultant for Sun Pharma.

Dr. Rowen

‘Vision seems to clear within a few blinks.’ — Sheri Rowen, MD

The recent approval

of bromfenac

ophthalmic solution

0.075% marks the

first NSAID approved

for the prevention

of ocular pain in

patients undergoing

cataract surgery.

TAKE-HOME

drug therapydrug therapy34 JANUARY 2017 :: Ophthalmology Times

35JANUARY 2017 :: Ophthalmology Times

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After working with ophthal-mologists across the country for more than 20 years, we have heard from hundreds of physicians about what stresses them out and de-tracts from their happiness.

Here are five ways physicians deprive them-selves of more contentment.

1 ) C O M P A R I N G A N O T H E R ’ S‘ P E R C E I V E D N E T W O R T H '

Physicians have a preconceived notion that comparing themselves with other physicians who may be better off will give them a state of contentment. Ironically, most physicians who claim they are poor could not be more wrong.

Ophthalmologists are close in net worth and, in some instances, physicians who worry about not having enough success ac-tually have more than the average physi-cian. We frequently hear, “If only I had twice what I have now, I’d be okay.” There are some physicians who do have twice that amount saying exactly the same thing.

These are the same ophthalmologists whose short-, intermediate-, and long-term goals have been met—or will be met with a high probability of success. Yet, they insist on focusing on what they don’t have. What happened to living in appreciation and ac-knowledging oneself for “a job well-done”?

2 ) R E T I R I N G T O O Y O U N GWe cannot tell you how many physicians have fretted over the thought that they may run out of money if they retire at age 62.

Hundreds of clients in their 40s or 50s who insisted they would retire at age 62 started pushing retirement out year after year when the age of 62 drew near.

Overall, ophthalmologists love what they do. They love their specialty. They have at-tachments to their patients and colleagues. They do not want to retire at the age of 62.

We suggest physicians be realistic when

targeting a retirement age. Why save a lot of money to meet that target, then give up a rewarding working life? Seventy is the new 62. Don’t retire too early, then find yourself saying, “I feel like I don’t count anymore.”

3 ) L A M E N T I N G O V E RI N V E S T M E N T S

The best advice we can give to avoid this habit is to have a written plan. This includes a investment policy statement, a description of your goals and aspirations, a realistic ex-pectation for a rate of return on your invest-ment portfolio, and an analysis tracking the probability of success of your plan.

Ask—and have the answers to—the fol-lowing questions: How will I educate my children? Can I have a second home? How much will I need in retirement? How can I plan for long-term care? Am I taking suf-ficient risk in my portfolio? Is it diversi-fied properly? Am I saving too much or too little? Do I have a will? Is my estate set up properly?

Physicians don’t need to add another worry to their life. To avoid such worry, or-ganize your financial life. A month-long ef-fort should give a lifetime of security and peace of mind.

4 ) N O T S P E N D I N G T I M E O N P E R S O N A L D E V E L O P M E N T

We know physicians are busy, but there is nothing wrong with taking time to read material that is uplifting and inspirational. There are countless books and seminars that address how to live a full, enriched life.

Suffering is caused many times by only a thought or idea held in one’s head. Learn to be the author of these thoughts rather than “being thought” by your mind and think-ing these thoughts are who you are. Living a happy life is more of a learned art than something that just unfolds naturally.

Of our ophthalmology clients with the exact circumstances—money, success, fam-

Akorn Pharmaceuticals CV4267/483-4010www.akorn.com

Alcon Laboratories 13-14, 38, CV3800/862-5266www.alcon.com

Ellex 27855/767-5784www.ellex.com/tango-reflex

Glaukos CV2949/367-9600www.glaukos.com

Heidelberg Engineering 29800/931-2230www.HeidelbergEngineering.com

Rhein Medical 5727/209-2244www.RheinMedical.com

Shire Ophthalmic CVTIP, 8-10800/828-2088www.shire-eyes.com

This index is provided as an additional service.The publisher does not assume any liabilityfor errors or omissions.

Advertiser Page Advertiser Index

OPHTHALMOLOGY TIMES (Print ISSN 0193-032X, Digital ISSN 2150-7333) is published semimonthly except for one issue in Jan, May, Aug and Dec (20 issues yearly) by UBM Medica, 131 W First Street, Duluth, MN 55802-2065. Subscription rates: $200 for one year in the United States & Possessions, Canada and Mexico; all other countries $263 for one year. Pricing includes air-expedited service. Single copies (prepaid only): $13 in the United States & Possessions, Canada and Mexico; $20 all other countries. Back issues, if available are $25 in the U.S. $ Possessions; $30 in Canada and Mexico; $35 in all other countries. Include $6.50 per order plus $2 per additional copy for U.S. postage and handling. If shipping outside the U.S., include an additional $10 per order plus $5 per additional copy. Periodicals postage paid at Duluth, MN 55806 and additional mailing offices. POSTMASTER: Please send address changes to OPHTHALMOLOGY TIMES, P.O. Box 6009, Duluth, MN 55806-6009. Canadian G.S.T. number: R-124213133RT001, Publications Mail Agreement Number 40612608. Return undeliverable Canadian addresses to: IMEX Global Solutions, PO Box 25542 London, ON N6C 6B2 CANADA. Printed in the U.S.A.

© 2017 UBM. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal/educational or personal use of specific clients is granted by UBM for libraries and other users registered with the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://www.copyright.com online. For uses beyond those listed above, please direct your written request to Permission Dept. fax 440-756-5255 or email: mcannon@advanstar.com.

5 roadblocks from being happierMost common stressors: money, retirement planning, healthMoney Matters By John S. Grande, CFP, Traudy F. Grande, CFP, and John J. Grande, CFP

Continues on page 38 : Happier

37JANUARY 2017 :: Ophthalmology Times

practice managementpractice management

ily, etc.—some are very happy, and some are

so unhappy that it manifests in their ill health.

What is the difference between the happy

and the unhappy? Happy physicians are cel-

ebrating life and appreciating everything they

have. They are uplifting to be around, and you

can see the joy on their faces.

5 ) N E G L E C T I N G O N E ' S H E A L T H

We visited a wealthy client in Florida many

years ago for a financial review. This physi-

cian, in his mid-70s, showed us his fishing

rods, bike, and golf clubs. He then turned to

us and said: “I am going to give you the only

wisdom that I have learned in life that mat-

ters. See these wonderful toys I have to play

with? Well, I can’t ride my bike, golf, or fish.

I never took care of my body and now I am a

HAPPIER( Continued from page 37 )

This article was written by Wells Fargo Advisors and

provided courtesy of John S., Traudy F., and John J.

Grande, CFPs, editors of the Money Matters column.

They are owners and principals of Grande Financial

Services Inc., Oakhurst, NJ, (www.grandefs.com) and registered principals of Wells Fargo

and Co., member of SIPC. The Grandes advise physicians across the country on a diverse

range of investment and financial matters. Readers may submit their financial questions to

them at john.s.grande@wfafinet.com or call 800/722-1258.

The views expressed in the Money Matters column are the views of Grande Financial

Services, and should not be considered as investment advice. Grande Financial Services

does not provide tax or legal advice. All information is believed to be from reliable sources;

however, Grande Financial Services make no representation as to its completeness or

accuracy. Past performance does not guarantee future results. Investing involves risk

including the potential loss of principal.

Wells Fargo Advisors and its Financial Advisors provide non-fiduciary services only. They do

not provide investment advice [as defined under the Employee Retirement Income Security

Act of 1974 as amended (“ERISA”)], have any discretionary authority with respect to the

plan, make any investment or other decisions on behalf of the plan, or otherwise take any

action that would make them fiduciaries to the plan under ERISA.

Wells Fargo Advisors does not provide legal or tax advice. Be sure to consult with your tax

and legal advisors before taking any action that could have tax consequences.

Wells Fargo Advisors Financial Network, LLC, Member SIPC, is a registered broker-dealer and

a separate non-bank affiliate of Wells Fargo & Company.

Investments in securities and insurance products are: NOT FDIC-INSURED/NOT BANK-

GUARANTEED/MAY LOSE VALUE. Investment products and services are offered through Wells

Fargo Advisors Financial Network, LLC (WFAFN), Member SIPC. Grande Financial Services,

Inc. is a separate entity from WFAFN.

©2017 Wells Fargo Advisors, LLC. All rights reserved. 1015-05666 [86913-v6] 1115

e6830

prisoner here after earning my retirement.

Please, don’t do this to yourselves.”

You have one body. Many physicians

take better care of their cars, which they

can replace at will. We know firsthand

how busy physicians are, but even 20 min-

utes a day, five days a week will reduce

muscle atrophy and the aging process.

Today, we have healthy clients traveling

the world in their late 80s, exploring and

enjoying life like they did when they were

teenagers. We wish you all happiness and

health that life has to give. It is not about

how much money you have or don’t have.

Our quote is: “Those who are happiest in

life, win!” You deserve to win as you have

spent your life helping others see. Happiness

is a decision of sorts. Choose to be happy! ■

JANUARY 2017 :: Ophthalmology Times38

practice management

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE

SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA® Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA® Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. DOSAGE FORMS AND STRENGTHS Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate. CONTRAINDICATIONS Hypersensitivity - SIMBRINZA® Suspension is contraindicated in patients who are hypersensitive to any component of this product. Neonates and Infants (under the age of 2 years) - SIMBRINZA® Suspension is contraindicated in neonates and infants (under the age of 2 years) [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Sulfonamide Hypersensitivity Reactions - SIMBRINZA® Suspension contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA® Suspension. Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Patient Counseling Information]. Corneal Endothelium - Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA® Suspension to this group of patients.Severe Renal Impairment - SIMBRINZA® Suspension has not been specifically studied in patients with severe renal impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA® Suspension is not recommended in such patients.Acute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA® Suspension has not been studied in patients with acute angle-closure glaucoma.Contact Lens Wear - The preservative in SIMBRINZA® Suspension, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA® Suspension but may be reinserted 15 minutes after instillation [see Patient Counseling Information].Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZA® Suspension, has a less than 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease. Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA® Suspension, has not been studied in patients with hepatic impairment, caution should be exercised in such patients.Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZA® Suspension, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA® Suspension should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information].ADVERSE REACTIONS Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.SIMBRINZA® Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA® Suspension, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIMBRINZA® Suspension occurring in approximately 3 to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA® Suspension patients. Other adverse reactions that have been reported with the individual components during clinical trials are listed below.Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis.The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria.Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10 to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus.Reactions occurring in approximately 3 to 9% of the subjects, in descending order included corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain.The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope.Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications].DRUG INTERACTIONS Oral Carbonic Anhydrase Inhibitors - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA® Suspension. The concomitant administration of SIMBRINZA® Suspension and oral carbonic anhydrase inhibitors is not recommended.High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA® Suspension.CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA® Suspension, the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA® Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA® Suspension is advised.

Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA® Suspension in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral administration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent.There are no adequate and well-controlled studies in pregnant women. SIMBRINZA® Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk.It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use - The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA® Suspension is contraindicated in children under the age of 2 years [see Contraindications].Geriatric Use - No overall differences in safety or effectiveness have been observed between elderly and adult patients.OVERDOSAGE Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility - Brinzolamide caused urinary bladder tumors in female mice at oral doses of 10 mg/kg/day and in male rats at oral doses of 8 mg/kg/day in 2 year studies. Brinzolamide was not carcinogenic in male mice or female rats dosed orally for up to 2 years. The carcinogenicity appears secondary to kidney and urinary bladder toxicity. These levels of exposure cannot be achieved with topical ophthalmic dosing in humans.The following tests for mutagenic potential of brinzolamide were negative: (1) in vivo mouse micronucleus assay; (2) in vivo sister chromatid exchange assay; and (3) Ames E. coli test. The in vitro mouse lymphoma forward mutation assay was negative in the absence of activation, but positive in the presence of microsomal activation. In this assay, there was no consistent dose-response relationship to the increased mutation frequency and cytotoxicity likely contributed to the high mutation frequency. Carbonic anhydrase inhibitors, as a class, are not mutagenic and the weight of evidence supports that brinzolamide is consistent with the class. In reproduction studies of brinzolamide in rats, there were no adverse effects on the fertility or reproductive capacity of males or females at doses up to 18 mg/kg/day (180 times the recommended human ophthalmic dose).Brimonidine tartrate was not carcinogenic in either a 21-month mouse or 24-month rat study. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in rats resulted in plasma drug concentrations 80 and 120 times higher than the human plasma drug level at the recommended clinical dose, respectively. Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, a host-mediated assay and cytogenic studies in mice, and a dominant lethal assay. In reproductive studies performed in rats with oral doses of 0.66 mg brimonidine base/kg (approximately 100 times the plasma drug concentration level seen in humans following multiple ophthalmic doses), fertility was not impaired.PATIENT COUNSELING INFORMATION Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician.Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA® Suspension. Care should be exercised in operating machinery or driving a motor vehicle.Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA® Suspension may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness.Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.Contact Lens Wear - The preservative in SIMBRINZA® Suspension, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA® Suspension, but may be reinserted 15 minutes after instillation.©2013-2016 Novartis U.S. Patent No: 6,316,441

ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA1-800-757-9195 alcon.medinfo@alcon.com

© 2016 Novartis 6/16 US-SMB-16-E-2215

INDICATIONS AND USAGESIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension)

1%/0.2% is a fi xed combination indicated in the reduction of elevated intraocular

pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Dosage and Administration The recommended dose is one drop of SIMBRINZA® Suspension in the affected

eye(s) three times daily. Shake well before use. SIMBRINZA® Suspension may

be used concomitantly with other topical ophthalmic drug products to lower intraoc-

ular pressure. If more than one topical ophthalmic drug is being used,

the drugs should be administered at least fi ve (5) minutes apart.

IMPORTANT SAFETY INFORMATION Contraindications SIMBRINZA® Suspension is contraindicated in patients who are hypersensitive

to any component of this product and neonates and infants under the age

of 2 years.

Warnings and PrecautionsSulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, and

although administered topically, is absorbed systemically. Sulfonamide attributable

adverse reactions may occur. Fatalities have occurred due to severe reactions to

sulfonamides. Sensitization may recur when a sulfonamide is readministered irre-

spective of the route of administration. If signs of serious reactions or hypersensi-

tivity occur, discontinue the use of this preparation.

Corneal Endothelium—There is an increased potential for developing corneal

edema in patients with low endothelial cell counts.

Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA® Suspension

has not been specifi cally studied in these patients and is not recommended.

Contact Lens Wear—The preservative in SIMBRINZA® Suspension, benzalkonium

chloride, may be absorbed by soft contact lenses. Contact lenses should

be removed during instillation of SIMBRINZA® Suspension but may be reinserted

15 minutes after instillation.

Severe Cardiovascular Disease—Brimonidine tartrate, a component of SIMBRINZA®

Suspension, had a less than 5% mean decrease in blood pressure 2 hours after

dosing in clinical studies; caution should be exercised in treating patients with severe

cardiovascular disease.

Adverse ReactionsSIMBRINZA® Suspension In two clinical trials of 3 months’ duration with SIMBRINZA® Suspension, the most

frequent reactions associated with its use occurring in approximately 3-5%

of patients in descending order of incidence included: blurred vision, eye irritation,

dysgeusia (bad taste), dry mouth, and eye allergy. Adverse reaction rates with

SIMBRINZA® Suspension were comparable to those of the individual components.

Treatment discontinuation, mainly due to adverse reactions, was reported

in 11% of SIMBRINZA® Suspension patients.

Drug InteractionsConsider the following when prescribing SIMBRINZA® Suspension:

Concomitant administration with oral carbonic anhydrase inhibitors is not recom-

mended due to the potential additive effect. Use with high-dose salicylate

may result in acid-base and electrolyte alterations. Use with CNS depressants may

result in an additive or potentiating effect. Use with antihypertensives/cardiac glyco-

sides may result in additive or potentiating effect on lowering blood

pressure. Use with tricyclic antidepressants may blunt the hypotensive effect

of systemic clonidine and it is unknown if use with this class of drugs interferes

with IOP lowering. Use with monoamine oxidase inhibitors may result

in increased hypotension.

References: 1. Data on fi le, 2014. 2. SIMBRINZA® Suspension Package Insert.

24-hour IOP-lowering coverage, including the night — nocturnal effi cacy established through an 8 AM time point2

© 2016 Novartis 4/16 US-SMB-16-E-1229

Aim for Target IOPConsider Adding SIMBRINZA® Suspension to a PGASIMBRINZA® Suspension should be taken at least fi ve (5) minutes apart from other topical ophthalmic drugs

Up to 7.1 mm Hg additional IOP reduction from baseline when

added to a PGA1

5.6 mm Hg* additional mean diurnal IOP lowering observed from baseline when added to a PGA1

* Treatment difference (mm Hg) and P value at Week 6 was -3.7, P<0.0001.

Learn more at myalcon.com/simbrinza

For additional information about SIMBRINZA® Suspension, please refer to the brief summary of the full Prescribing Information on the following page.

Treatment Arm 8 AM 10 AM 3 PM 5 PM

PGA + SIMBRINZA®

Suspension (N=88)

PGA + Vehicle (N=94)

Baseline‡ 24.5 22.9 21.7 21.6Week 6 19.4 15.8 17.2 15.6

Baseline‡ 24.3 22.6 21.3 21.2

Week 6 21.5 20.3 20.0 20.1

† Differences (mm Hg) and P values at Week 6 time points between treatment groups

were -2.14, P=0.0002; -4.56, P<0.0001; -2.84, P<0.0001; -4.42, P<0.0001.‡Baseline (PGA Monotherapy).

Baseline|| 22.7Week 6 17.1

Baseline|| 22.4

Week 6 20.5

Treatment Arm

PGA + SIMBRINZA®

Suspension (N=83)

PGA + Vehicle (N=92)

§ Difference (mm Hg) and P value at Week 6 between treatment groups

were -3.44, P<0.0001.||Baseline (PGA Monotherapy).

IOP Daily Time Points (mm Hg)1† Mean Diurnal IOP (mm Hg)1§

Study Design: A prospective, randomized, multicenter, double-blind, parallel-group study of 189 patients with open-angle glaucoma and/or ocular hypertension receiving treatment

with a PGA. PGA treatment consisted of either travoprost, latanoprost, or bimatoprost. Patients in the study were randomized to adjunctive treatment with SIMBRINZA® Suspension

(N=88) or vehicle (N=94). The primary effi cacy endpoint was mean diurnal IOP (IOP averaged over all daily time points) at Week 6 between treatment groups. Key secondary

endpoints included IOP at Week 6 for each daily time point (8 AM, 10 AM, 3 PM, and 5 PM) and mean diurnal IOP change from baseline to Week 6 between treatment groups.1

PGA=prostaglandin analog.

ZIOPTAN is licensed by Santen Pharmaceutical Co., Ltd.

©2016 Akorn, Inc. All rights reserved. P641 Rev 09/16 (a)

Cosopt is a registered trademark of Merck Sharp & Dohme Corp and is used under license. ZIOPTAN is a registered trademark of Merck Sharp & Dohme Corp and is used under license.

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