Treatment Satisfaction Among Patients Using Anti-In Ammatory Topical Medications For Dry Eye Disease
Treatment Satisfaction Among Patients Using Anti-In Ammatory Topical Medications For Dry Eye Disease
Treatment Satisfaction Among Patients Using Anti-In Ammatory Topical Medications For Dry Eye Disease
Darrell E White 1 Purpose: To assess patient satisfaction among current and former users of the anti-
Yang Zhao 2 inflammatory topical medications, cyclosporine A 0.05% (CYC) and lifitegrast 5.0% (LIF),
3 for the management of dry eye disease (DED).
Hemalatha Jayapalan
Pattabhi Machiraju 3 Patients and Methods: Patients with DED were recruited via physician referral to
participate in a survey. Current users of CYC or LIF were asked to rate their experience in
Ramu Periyasamy 3
terms of satisfaction, side effects, and limitation of activities. Switchers of CYC to LIF or
Abayomi Ogundele 2
LIF to CYC were asked to rate the importance of potential reasons for switching.
1
SkyVision Centers, Westlake, OH, USA; Results: Surveys were completed by 207 patients currently treated with CYC (n=98), LIF
2
Sun Pharmaceutical Industries, Inc.,
Princeton, NJ, USA; 3Indegene, Inc., (n=96), or other DED medications (n=13). Although overall satisfaction with current treat-
Bangalore, India ment was high, current users of CYC and LIF reported ineffective relief of DED symptoms
(31% and 22%, respectively) and dissatisfaction with the time to onset of effect (29% and
11%). Substantial proportions of patients reported ‘sometimes’, “usually”, or ‘always’
experiencing the following side effects: burning sensation (72% CYC, 64% LIF), itching
(43% CYC, 44% LIF), altered sensation of taste (21% CYC, 56% LIF), blurred vision (37%
CYC, 50% LIF), and discharge (28% CYC, 30% LIF). Of the 30 switchers of CYC to LIF
and 31 switchers of LIF to CYC, the majority reported inability to relieve DED symptoms as
a very or extremely important switching reason. Despite switching, one in four patients were
somewhat dissatisfied or dissatisfied with their current medication, with 37% of patients
reporting ineffective symptom relief.
Conclusion: Although the rate of overall satisfaction was generally high with both LIF and
CYC, many patients were unable to achieve effective symptom relief and commonly
experienced side effects. The proportion of patients who were dissatisfied and/or unable to
achieve effective symptom relief even after switching suggests the need for additional
treatment options for managing DED.
Keywords: patient satisfaction, dry eye disease, cyclosporine, lifitegrast, ocular surface
Introduction
Dry eye disease (DED) is a chronic, multifactorial, progressive condition estimated
to affect around 16 million adults in the United States (US) alone,1 and with
a global prevalence of between 5% and 34%.2 DED is more common among
women than men, and prevalence increases with age.1 Other risk factors for DED
Correspondence: Abayomi Ogundele
Medical Affairs, Sun Pharmaceutical include wearing contact lenses, prolonged screen time, hormonal changes, auto-
Industries, Inc., 2 Independence Way, immune disease (e.g. Sjögren’s syndrome), environmental conditions such as low
Princeton, NJ 08540, USA
Email abayomi.ogundele@sunpharma.com humidity and pollution, and use of systemic medications that may affect tear
production and secretion.3 Ophthalmic and eyelid sur- experienced side effects considered possibly or probably
geries and post-procedural medications can also trigger drug-related, resulting in the discontinuation of LIF in
DED.3 Presenting symptoms vary between patients but 12.3% of patients.21
commonly include ocular discomfort, visual disturbances, The primary objectives of this study conducted among
and dryness that requires long-term treatment.3,4 patients with DED in a real-world setting were to assess
Quality of life (QoL) outcomes are a core component of treatment satisfaction among current users of CYC or LIF,
dry eye research and are of major importance to patients.5 and to assess reasons for treatment change among former
DED has been shown to contribute to limitations in daily users of CYC and LIF.
activities such as using a computer, reading, and driving,6
and also has detrimental effects on sleep7 and work produc-
Materials and Methods
tivity that increase with the severity of symptoms.8,9 Thus,
the goal of treatment in DED is to relieve symptoms and
Study Design and Patient Population
This was a cross-sectional survey study conducted
improve QoL by restoring normal homeostasis in the tear
between October 2018 and January 2019 at 20 centers in
film and ocular surface.10 Treatment options include artifi-
the US. Twenty-one physicians currently treating DED
cial tears, topical anti-inflammatory agents, immunosup-
patients with CYC and LIF were invited to refer patients
pressants, and antibiotics.10,11
eligible to take part in the survey. Participating patients
Only two topical anti-inflammatory agents for DED are
were able to access the surveys via a secure web-based
approved and commercially available in the US.
link and could complete the survey in intervals to reduce
Cyclosporine ophthalmic emulsion 0.05% (CYC) was
the burden of fatigue. The patient survey was co-
approved in 2003 for increasing tear production in patients
developed with clinicians. This study was Health
with reduced tear production presumed due to ocular
Insurance Portability and Accountability Act (HIPAA)
inflammation.12 Lifitegrast ophthalmic solution 5% (LIF)
compliant, approved by an institutional review board
was approved in July 2016 for the treatment of signs and
(Sterling Institutional Review Board, Atlanta, Georgia),
symptoms of DED.13 The 2019 American Academy of
and conducted in accordance with the Declaration of
Ophthalmology guidelines discussed both drugs as treatment
Helsinki.
options for the management of patients with dry eye.14 For
Patients with a diagnosis of DED who were current or
both drugs, the most common side effect is a burning or
recent users of either CYC or LIF were invited by their
stinging sensation upon instillation,15,16 and this outcome
physician to take part in a survey to assess their experi-
together with ocular discomfort and ocular pain has been
ences and satisfaction with treatment. The patient survey
identified in a global Delphi survey as being most important
aimed to enroll at least 200 patients with DED – around
to patients with dry eye.5 Dysgeusia is a unique side effect of
70% current users and 30% patients who had undergone
LIF, occurring in 14.5% of patients randomized to receive
a treatment change from CYC or from LIF in the past 6
this therapy across five clinical trials.16
months. Treatment change could be from either CYC or
To date, few studies have assessed patient satisfaction
LIF to other drugs, or from CYC to LIF or LIF to CYC.
with CYC and there are no published data on patient
Patients were required to provide written, informed con-
satisfaction with LIF.17–19 The largest of the studies in
sent prior to being enrolled in the study.
CYC was a 2006 survey of 3145 DED patients in the
US, which reported high treatment satisfaction and will-
ingness to continue treatment among the 79% of patients Survey
who adhered to the prescribed twice-daily dosing.18 In an A survey was developed to elicit patients’ perspectives on
open-label extension of the CYC Phase III clinical trials, treatment with either CYC or LIF. Each patient was asked
95% of patients reported that they would continue using to rate his or her experiences with their current treatment
CYC and 98% would recommend it to others with DED.17 (CYC or LIF) over three domains: satisfaction, frequency
One concern for patients taking CYC is that the onset of of side effects, and limited activities. Items in the satisfac-
efficacy can take 3–6 months.17 LIF tends to work more tion domain included onset of action, effectiveness of the
rapidly, with significant improvements from baseline evi- drug after onset, and ease of use (relating to the dosing and
dent after as little as 2 weeks.20 However, in one study packaging), each rated on a 5-point scale from 1 (“Very
47.3% of patients treated with LIF over 12 months dissatisfied”) to 5 (“Very satisfied”). Items in the
frequency of side effects domain included burning sensa- treatment (41% had been using CYC for >12 months,
tion, itching, altered sensation of taste (dysgeusia), blurred compared with 26% for LIF) (Table 3).
vision, and discharge, each rated on a 5-point scale from 1
(“Always”) to 5 (“Never”). Patients were also able to Treatment Satisfaction
specify other side effects not listed. The activities domain Treatment satisfaction was lowest for onset of effect: 51%
asked whether patients were limited by DED in their daily of current CYC users and 63% of current LIF users
lives while on medication with respect to reading, driving, reported being satisfied (grouped responses of “somewhat
working on the computer, watching TV, work productivity, satisfied” or “very satisfied”) with time to onset of effect
and social activities, rated on a 5-point scale from 1 (Figure 1). The majority of patients (78% of current CYC
(“Always”) to 5 (“Never”). If any activity was not applic- users and 77% of current LIF users) were satisfied with the
able to the patient (e.g. if they were retired or out of work), ability of CYC and LIF to manage DED after onset of
they were able to rate the activity 0 (“I do not do this effect. Satisfaction with ease of use was 78% among
activity”). current CYC users and 72% among current LIF users.
A subset of patients who recently switched from CYC Few patients reported being “very dissatisfied” with any
or from LIF (within the past 6 months) were also asked to of the three criteria. The highest proportion of patients
rate the importance of possible reasons for switching. who were “somewhat dissatisfied” or “very dissatisfied”
Reasons included inability to relieve dry eye symptoms, was reported for time to onset of effect (29% and 11% of
onset of action, effectiveness of the drug after onset, ease current users of CYC and LIF, respectively).
of use, limited visual tasking activities while on medica-
tion, and recommendation from their doctor. Patients were Side Effects
also able to specify their own reasons for switching. Burning sensation was the most frequently reported side
A 5-point scale was used, from 1 (“Not important at all”) effect of treatment: 21% of current CYC users and 22% of
to 5 (“Extremely important”). current LIF users “always” or “usually” experienced
a burning sensation on instillation (Figure 2). Consistent
with the known side effects of LIF, 29% of current users
Analysis
“always” or “usually” experienced dysgeusia; only 3% of
Patient demographics and responses were examined
current CYC users reported the same outcome. Over half
descriptively. Responses on the 5-point scales were con-
of current CYC users (54%) reported “never” experiencing
verted to a 3-point scale by combining the two least
dysgeusia, compared with 23% of current LIF users.
favorable categories (e.g., very dissatisfied and somewhat
Blurred vision “always” or “usually” occurred upon instil-
dissatisfied) and the two most favorable categories (e.g.,
lation in 16% of current LIF users and 4% of current CYC
very satisfied and somewhat satisfied) (Table 1).
users; 50% of current LIF users and 63% of current CYC
Continuous measures were presented as means and stan-
users said they “rarely” or “never” experienced blurred
dard deviations (SD); categorical measures were presented
vision. Itching and discharge were the least frequently
as counts and percentages.
reported side effects. The majority of patients in both
treatment groups “rarely” or “never” itching or discharge:
Results 57% and 72% of current CYC users and 56% and 70% of
Patient Characteristics current LIF users, respectively.
A total of 211 patients were referred by 21 physicians (13
general ophthalmologists, 4 optometrists, and 4 corneal Activity Limitations
specialists). Of these, 207 (98.1%) participated in the Working on the computer was the activity most frequently
survey: 98 were current users of CYC (22 recently limited by dry eye while on medication: 8% of current
switched from LIF), 96 were current users of LIF (26 CYC users and 11% of current LIF users reported
recently switched from CYC), and 13 were former users “always” or “usually” being limited (Figure 3). Reading
of CYC (n=4) or LIF (n=9) who were switched to other was the second most frequently limited activity; 8% of
treatments for DED (Table 2). Current users of CYC were current CYC users and 7% of current LIF users reported
older on average than current users of LIF (mean age: 58 “always” or “usually” being limited. Around half of
vs 55 years), and had a longer duration on their current patients reported that reading and working on the
IV. Switch reasons 1. Inability to relieve dry eye symptoms 1. Insignificant 1. Insignificant or somewhat insignificant
2. Onset of action 2. Somewhat significant 2. Significant
3. Effectiveness of the drug after onset 3. Significant 3. Highly or very highly significant
4. Ease of use 4. Highly significant
5. Side effect profile 5. Very highly significant
6. Limited visual tasking activities while
on medication
7. Recommended by your doctor
computer were “rarely” or “never” limited by dry eye contributing factor for both groups of switched patients.
while on medication (51% and 55% of current CYC Patients switched from CYC more frequently rated onset
users and 54% and 49% of current LIF users, respec- of effect, effectiveness of the drug after onset of effect, and
tively). For the other activities included in the survey limited activities as “very important” or “extremely impor-
(driving, watching TV, work productivity, and social activ- tant” reasons for switching than did patients switched from
ities) the majority of patients reported “rarely” or “never” LIF. Patients switched from LIF rated the importance of
being limited by dry eye while on medication (70–94% of side effect profile more highly than patients switched from
current CYC users and 69–91% of current LIF users), with CYC; however, 16 patients (6 [20%] in the switched from
driving most often affected and social activities least often CYC group and 10 [32%] in the switched from LIF group)
affected. did not provide a rating for the side effect profile domain.
Age, mean years (SD) 58.2 (15.7) 55.2 (14.3) 57.0 (14.6) 56.5 (14.8)
Gender, n (%)
onset of effect of CYC, and to a lesser extent of LIF, was ocular symptoms. The detrimental impact on visual function
viewed unfavorably by current users. Working on the and QoL is substantial and can interfere with a patient’s
computer and reading were the most affected activities ability to effectively carry out everyday activities.6,22 DED
among patients with DED. Patient responses for the side represents a growing global public health problem. Although
effects domain were consistent with the known tolerability the exact prevalence of DED is hard to measure due to
issues of CYC and LIF.15,16 Burning sensation was differences in diagnostic methods23 and lack of correlation
“always” or “usually” experienced by approximately one between clinical measures and patient-reported
24–26
in four patients upon treatment instillation. Notably, symptoms, the aging population and our increasing reli-
among current LIF users, the frequency of dysgeusia was ance upon digital devices are contributing to a rise in the
substantially higher in this real-world cohort than in the number of people living with a DED diagnosis. Several
pooled analysis of five LIF clinical trials.16 studies have established that long durations of computer
DED is a complex and chronic disease triggered and and smartphone use can trigger and/or exacerbate dry eye
exacerbated by inflammation and damage to the ocular sur- symptoms across all age groups.27–30 It is not unusual now
face that disturbs the dynamic equilibrium of the lacrimal for adults to spend more time looking at screens than
functional unit, resulting in tear film instability and a range of sleeping.31 Thus, whereas in the past the typical patient
80
Current CYC user (n=98)
60
% of patients
50
40
30
20
10
0
Onset time Continued management Ease of use
of DED
Figure 1 Percentage of patients who reported being “somewhat satisfied” or “very satisfied” with their current treatment.
Abbreviations: CYC, cyclosporine ophthalmic emulsion 0.05%; DED, dry eye disease; LIF, lifitegrast ophthalmic solution 5%.
20
% of patients
10
0
Burning sensation* Itching* Altered sensation of taste Blurred vision Discharge
Figure 2 Percentage of patients who reported always’ or “usually” experiencing side effects while on their current treatment.
Note: *One patient in the current LIF user group did not provide a response for this category.
Abbreviations: CYC, cyclosporine ophthalmic emulsion 0.05%; LIF, lifitegrast ophthalmic solution 5%.
with DED was likely to be a woman aged over 50 years,6 for 6 months or less. The implications of this should be
ophthalmologists can now expect to see younger patients of considered when interpreting the results, given that CYC
both sexes with “lifestyle-driven” DED.32,33 can take as long as 3–6 months of continued twice-daily
Although this survey did not directly evaluate treat- use to work, and that good compliance and persistence
ment persistence, it is worth noting that 31% of CYC users with CYC have been associated with greater treatment
and 40% of LIF users had been on their current treatment satisfaction in a larger patient sample.18
10
8
% of patients
0
Reading Driving Working on computer Watching TV Work productivity Social activities
Figure 3 Percentage of patients who reported that they “always” or “usually” experienced activity limitation while on their current treatment.
Notes: *An alternate response of “I do not do this activity” was provided by 1 patient for “Reading”, ’Driving’, and “Social activities”, and 5 patients for “Working on
computer” and “Work productivity”: **An alternate response of “I do not do this activity” was provided by 1 patient for “Reading”, 2 patients for “Driving”, 5 patients for
“Working on computer”, and 7 patients for “Work productivity”.
Abbreviations: CYC, cyclosporine ophthalmic emulsion 0.05%; LIF, lifitegrast ophthalmic solution 5%.
80
Switched from CYC (n=30)
Switched from LIF (n=31)
70
60
% of patients
50
40
30
20
10
0
Inability to relieve dry Onset of action* Effectiveness of the drug Ease of use (dosage, Side effect profile** Dry eye limited visual Doctor
eye symptoms* after onset of action* packaging)* tasking activities while recommendation*
on medication*
Figure 4 Percentage of patients who rated reasons for switching from CYC or LIF as “very important” or “extremely important”.
Notes: *No response was provided in this category by 1 patient in the switched from CYC group; **No response was provided in this category by 5 patients in the
switched from CYC group and 10 patients in the switched from LIF group.
Abbreviations: CYC, cyclosporine ophthalmic emulsion 0.05%; LIF, lifitegrast ophthalmic solution 5%.
Despite the many challenges in the management of gaps in dry eye management identified in this study
DED, disease control is possible with long-term use of demonstrate a need for additional options for long-term
topical anti-inflammatory agents, in accordance with cur- treatment of DED. In August 2018, a nanomicellar cyclos-
rent treatment guidelines. However, the patient-perceived porine ophthalmic solution 0.09% was approved in the US
16. Nichols KK, Donnenfeld ED, Karpecki PM, et al. Safety and toler- 27. Moschos MM, Chatziralli IP, Siasou G, et al. Visual problems in
ability of lifitegrast ophthalmic solution 5.0%: pooled analysis of five young adults due to computer use. Klin Monbl Augenheilkd.
randomized controlled trials in dry eye disease. Eur J Ophthalmol. 2012;229:379–381. doi:10.1055/s-0031-1299222
2019;29:394–401. doi:10.1177/1120672118791936 28. Ribelles A, Galbis-Estrada C, Parras MA, et al. Ocular surface and
17. Barber LD, Pflugfelder SC, Tauber J, et al. Phase III safety evaluation tear film changes in older women working with computers. Biomed
of cyclosporine 0.1% ophthalmic emulsion administered twice daily Res Int. 2015;2015:467039.
to dry eye disease patients for up to 3 years. Ophthalmology. 29. Moon JH, Kim KW, Moon NJ. Smartphone use is a risk factor for
2005;112:1790–1794. doi:10.1016/j.ophtha.2005.05.013 pediatric dry eye disease according to region and age: a case control
18. Trattler W, Katsev D, Kerney D. Self-reported compliance with study. BMC Ophthalmol. 2016;16:188. doi:10.1186/s12886-016-
topical cyclosporine emulsion 0.05% and onset of the effects of 0364-4
increased tear production as assessed through patient surveys. Clin 30. Jaiswal S, Asper L, Long J, et al. Ocular and visual discomfort
Ther. 2006;28:1848–1856. doi:10.1016/j.clinthera.2006.11.016 associated with smartphones, tablets and computers: what we do
19. Byun YS, Rho CR, Cho K, et al. Cyclosporine 0.05% ophthalmic and do not know. Clin Exp Optom. 2019;102:463–477. doi:10.1111/
emulsion for dry eye in Korea: a prospective, multicenter, open-label, cxo.v102.5
surveillance study. Korean J Ophthalmol. 2011;25:369–374. 31. Ofcom Communications Market Report 2016. Available from: www.
doi:10.3341/kjo.2011.25.6.369 ofcom.org.uk/research-and-data/multi-sector-research/cmr/cmr16.
20. Pepose JS, Qazi M, Devries DK. Longitudinal changes in dry eye Accessed September 17, 2019.
symptoms and signs following lifitegrast therapy and relationship to 32. Sheppard AL, Wolffsohn JS. Digital eye strain: prevalence, measure-
tear osmolarity. Clin Ophthalmol. 2019;13:571–579. doi:10.2147/ ment and amelioration. BMJ Open Ophthalmol. 2018;3:e000146.
OPTH.S196593 doi:10.1136/bmjophth-2018-000146
21. Donnenfeld ED, Karpecki PM, Majmudar PA, et al. Safety of lifite- 33. Courtin R, Pereira B, Naughton G, et al. Prevalence of dry eye
grast ophthalmic solution 5.0% in patients with dry eye disease: a disease in visual display terminal workers: a systematic review and
1-year, multicenter, randomized, placebo-controlled study. Cornea. meta-analysis. BMJ Open. 2016;6:e009675. doi:10.1136/bmjopen-
2016;35:741–748. doi:10.1097/ICO.0000000000000803 2015-009675
22. Li M, Gong L, Chapin WJ, et al. Assessment of vision-related quality 34. Karpecki PM, Weiss SL, Kramer WG, et al. A Phase 1, open-label,
of life in dry eye patients. Invest Ophthalmol Vis Sci. single-arm study evaluating the ocular safety of OTX-101 and sys-
2012;53:5722–5727. doi:10.1167/iovs.11-9094 temic absorption of cyclosporine in healthy human volunteers. Clin
23. Thulasi P, Djalilian AR. Update in current diagnostics and therapeu- Ophthalmol. 2019;13:591–596. doi:10.2147/OPTH.S187945
tics of dry eye disease. Ophthalmology. 2017;124:S27–S33. 35. Mandal A, Gote V, Pal D, et al. Ocular pharmacokinetics of a topical
doi:10.1016/j.ophtha.2017.07.022 ophthalmic nanomicellar solution of cyclosporine (Cequa®) for dry
24. Galor A, Felix ER, Feuer W, et al. Dry eye symptoms align more eye disease. Pharm Res. 2019;36:36. doi:10.1007/s11095-018-2556-5
closely to non-ocular conditions than to tear film parameters. Br 36. Goldberg DF, Malhotra RP, Schechter BA, et al. A Phase 3, rando-
J Ophthalmol. 2015;99:1126–1129. doi:10.1136/bjophthalmol-2014- mized, double-masked study of OTX-101 ophthalmic solution 0.09%
306481 in the treatment of dry eye disease. Ophthalmology.
25. Hua R, Yao K, Hu Y, et al. Discrepancy between subjectively 2019;126:1230–1237. doi:10.1016/j.ophtha.2019.03.050
reported symptoms and objectively measured clinical findings in 37. Kala Pharmaceuticals press release. August 8, 2019. Kala pharma-
dry eye: a population based analysis. BMJ Open. 2014;4:e005296. ceuticals receives FDA complete response letter for KPI-121 0.25%
doi:10.1136/bmjopen-2014-005296 NDA and plans to respond with data from STRIDE 3 trial. Available
26. Gomes JAP, Santo RM. The impact of dry eye disease treatment on from: http://investors.kalarx.com/news-releases/news-release-details
patient satisfaction and quality of life: a review. Ocul Surf. /kala-pharmaceuticals-receives-fda-complete-response-letter-kpi.
2019;17:9–19. doi:10.1016/j.jtos.2018.11.003 Accessed January 2, 2020.