A Canadian Cost-Utility Analysis of 2 Trabecular Microbypass Stents at Time of Cataract Surgery in Patients with Mild to Moderate Open-Angle Glaucoma

Journal Pre-proof A Canadian Cost-Utility Analysis of Two Trabecular Micro-Bypass Stents at Time of Cataract Surgery in Patients with Open-Angle Glaucoma Iqbal Ike K. Ahmed, MD, FRCSC, Dominik W. Podbielski, BSc, MSc, MD, FRCSC, Vardhaman Patel, PhD, Heather Falvey, MSc, Judith Murray, BA, Marc Botteman, MSc, Ron Goeree, MA PII:

S2589-4196(19)30350-3

DOI:

https://doi.org/10.1016/j.ogla.2019.11.009

Reference:

OGLA 129

To appear in:

OPHTHALMOLOGY GLAUCOMA

Received Date: 7 June 2019 Revised Date:

6 November 2019

Accepted Date: 25 November 2019

Please cite this article as: Ahmed IIK, Podbielski DW, Patel V, Falvey H, Murray J, Botteman M, Goeree R, A Canadian Cost-Utility Analysis of Two Trabecular Micro-Bypass Stents at Time of Cataract Surgery in Patients with Open-Angle Glaucoma, OPHTHALMOLOGY GLAUCOMA (2019), doi: https:// doi.org/10.1016/j.ogla.2019.11.009. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology

A Canadian Cost-Utility Analysis of Two Trabecular Micro-Bypass Stents at Time of Cataract Surgery in Patients with Open-Angle Glaucoma

Iqbal Ike K. Ahmed, MD, FRCSC,1,2 Dominik W. Podbielski, BSc, MSc, MD, FRCSC,2 Vardhaman Patel, PhD,3 Heather Falvey, MSc,4 Judith Murray, BA,5 Marc Botteman, MSc,3 Ron Goeree, MA6,7

1

University of Toronto, Toronto, ON, Canada; Trillium Health Partners, Mississauga, ON, Canada

2

Prism Eye Institute, Mississauga, ON, Canada

3

Pharmerit International, Bethesda, MD, United States

4

Glaukos, San Clemente, CA, United States

5

Glaukos, Richmond Hill, ON, Canada

6

Goeree Consulting Ltd, Hamilton, ON, Canada

7

Professor Emeritus, McMaster University, Hamilton, ON, Canada

Corresponding author: Marc Botteman, Pharmerit International, LP, Bethesda, MD, United States, [email protected]

Meeting presentation: An abstract of this research was presented as a poster at the 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Europe meeting in Barcelona, Spain (PMD109; Monday, November 12, 2018).

Financial support: Pharmerit International, LP received funding from Glaukos, San Clemente, CA, United States, to develop the economic model and manuscript. The sponsor participated in preparation, review and approval of the manuscript.

1

Conflict of interest: DP has served as a consultant to QuintilesIMS, Alcon, and Glaukos, and has received speaker’s honoraria from Alcon, Allergan, Johnson & Johnson and Novartis. IA has served as a consultant to Acucela, Aerie Pharmaceuticals, Aequus Pharma, Alcon, Allergan, ArcScan, Bausch and Lomb, Beaver Visitec, Camras Vision, Carl Zeiss Meditec, Centervue, CorNeat Vision, Ellex, ElutiMed, Equinox, ForSight Labs, Genentech, Glaukos, Gore, Iantech, InjectSense, Iridex, iStar, Ivantis, Johnson & Johnson Vision, KeLoTec, LayerBio, Leica Microsystems, MicroOptx, New World Medical, Omega Ophthalmics, PolyActiva, Sanoculis, Santen, Science Based Health, Sight Sciences, Stroma, TrueVision, and Vizzario, and has received speaker’s honoraria from Alcon, Allergan, Carl Zeiss Meditec, and Johnson & Johnson Vision. IA has received research grant from Aerie Pharmaceuticals, Alcon, Allergan, Camras Vision, Glaukos, Ivantis, Johnson & Johnson Vision, New World Medical, and Santen. RG has participated in paid advisory boards for Glaukos. HF and JM are employees of Glaukos Corporation. Pharmerit International received funding from Glaukos Corporation to conduct and report the research presented herein. MB is a shareholder and employee of Pharmerit International. VP was an employee of Pharmerit international when this research was conducted.

Running head: Economics of Trabecular Micro-Bypass Stents in Glaucoma

Abbreviations: AE, adverse event; C$, Canadian dollars; CADTH, Canadian Agency for Drugs and Technologies in Health; CEAC, cost-effectiveness acceptability curve; CNIB, Canadian National Institute for the Blind; DALY, disability-adjusted life-year; dB, decibel; DID, difference-in-difference; EMGT, Early Manifest Glaucoma Trial; HCRU, healthcare resource utilization; HUI-3, Health Utilities Index 3; ICER, incremental cost-effectiveness ratio; ICUR, incremental cost-utility ratio; IOP, intraocular pressure; MD, mean deviation; MIGS, microinvasive glaucoma surgery; NICE, National Institute for Health and Care Excellence; OAG, open-angle glaucoma; ODBF, Ontario Drug Benefit Formulary; OHIP, Ontario Health Insurance Plan; QALY, quality-adjusted life-year; RCT, randomized controlled trial; SLT, selective laser trabeculoplasty; SOB, schedule of benefits; TBS, trabecular bypass stent; US, United States; VF, visual field; WTP, willingness-to-pay.

2

Abstract

PURPOSE: To assess from the Canadian public payer perspective the cost-utility of implanting iStent Inject® trabecular bypass stent (TBS) devices in conjunction with cataract surgery versus cataract surgery alone in patients with open-angle glaucoma (OAG) and visually significant cataract. DESIGN: Cost-utility analysis using efficacy and safety results of pivotal randomized clinical trial. PARTICIPANTS: Modeled cohort of patients with OAG (83.1% mild, 16.9% moderate) and visually significant cataract. METHODS: OAG treatment costs and effects were projected over a 15-year time horizon using a Markov model with Hodapp-Parrish-Anderson glaucoma stages (mild, moderate, advanced, severe/blind) and death as health states. Patients in the mild or moderate OAG health state received implantation of iStent inject during cataract surgery vs cataract surgery alone. Upon worsening of visual field defect and optic disc damage, patients could receive selective laser trabeculoplasty and trabeculectomy. We measured treatment effect as reduction in intraocular pressure (IOP) and mean medication use, and estimated transition probabilities based on efficacy-adjusted visual field mean deviation decline per month. Healthcare resource utilization and utility scores were obtained from the literature. Cost inputs (2017 Canadian dollars [C$]) were derived using the Ontario Health Insurance Plan, expert opinion, medication claims datasets, and Ontario Drug Benefit Formulary medication consumption costs. We conducted deterministic and probabilistic sensitivity analyses to examine the impact of alternative model input values on results. MAIN OUTCOME MEASURE: Incremental cost per quality-adjusted life year (QALY) gained. RESULTS: Compared to cataract surgery alone, TBS + cataract surgery had a 99% probability of being more effective (+0.023 QALYs [95% CI: 0.004 to 0.044]) and a 73.7% probability of being cost-saving (net cost, -C$389.00 [95% CI: -C$1,712.00 to $850.70]). In 95% of all simulations, TBS + cataract surgery had a cost per QALY of ≤$62,366. Results were robust in additional sensitivity and scenario analyses. CONCLUSIONS: iStent inject TBS implantation during cataract surgery appears cost-effective for reducing IOP in patients with mild to moderate OAG vs cataract surgery alone.

Keywords: microinvasive glaucoma surgery; cost-effectiveness; trabecular micro-bypass; iStent Inject; glaucoma; glaucoma drainage implants; trabecular meshwork Taxonomy: Aqueous drainage devices; Cost Benefit Analysis; Cost Saving

3

1

Glaucoma is a neurodegenerative disease that affects approximately 70 million people worldwide and is

2

the leading cause of irreversible blindness.1 In Canada, more than 455,000 people had glaucoma in 2008

3

to 2009.2 In 2007, vision loss in Canada caused an estimated 77,000 disability-adjusted life-years

4

(DALYs), with glaucoma accounting for 3.1% of the vision loss.3 In 2008, the estimated total cost of

5

glaucoma in Canada was approximately C$269 million.4

6

If left untreated, open-angle glaucoma (OAG) causes slow progressive optic disc damage, vision

7

loss, and irreversible blindness.1 Reduction of intraocular pressure (IOP) is the most effective method of

8

OAG treatment.1 Topical hypotensive medications and laser trabeculoplasty can reduce IOP but are

9

associated with treatment-related side effects,1 suboptimal adherence,5 or the need for multiple rounds

10

of treatment,6 while invasive trabeculectomy has traditionally been reserved for patients with advanced

11

disease or those in whom non-invasive approaches have failed.7

12

Microinvasive glaucoma surgery (MIGS) with trabecular bypass stents (TBS) is an alternative

13

treatment modality for patients with mild to moderate glaucoma. Clinical trials have demonstrated that

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the TBS devices have favorable safety profiles and can reduce IOP, delay the initiation of medication,

15

and reduce the number of medications patients use following surgery.8-10 One such TBS device is the

16

iStent Inject® (Glaukos Corp., San Clemente, CA) that consists of an injector with two multi-directional

17

stents designed to facilitate the flow of aqueous fluid and reduce IOP.

18

Economic evaluations of TBS devices for the treatment of OAG in Canada are lacking. Therefore,

19

we carried out this evaluation to assess from the Canadian public payer perspective the cost-

20

effectiveness of implanting iStent Inject® devices in conjunction with cataract surgery compared to

21

cataract surgery alone in patients with OAG and visually significant cataract.

4

22

Methods

23

Model Overview

24

We developed a health-state transition Markov model—inspired in part by a National Institute

25

for Health and Care Excellence (NICE) model11—to estimate over a 15-year time horizon, and in monthly

26

increments, the costs and effects of implantation of iStent Inject TBS devices during cataract surgery

27

compared to cataract surgery alone (Error! Reference source not found.) in patients with OAG in one

28

eye. All patients entered the model at the time of cataract surgery in the mild or moderate OAG states.

29

All were assumed to be aged 65 years at baseline, after applying United States (US) glaucoma age-

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specific prevalence data to the age distribution of Canada (in the absence of Canada-specific

31

epidemiologic evidence) (Table 1).12,13 The baseline glaucoma severity distribution (83.1% mild, 16.9%

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moderate) was obtained from a large US claims database analysis (Table 1).14 Mean baseline

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unmedicated IOP (24.8 mm Hg) and mean baseline number of medications used (1.6) were obtained

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from a randomized clinical trial (RCT) evaluating the efficacy and safety of the iStent Inject system.15

35

In the model, patients were assumed to be at risk of irreversible progression along 4 increasingly

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severe discrete health states (plus death), defined according to an adapted Hodapp-Parrish-Anderson

37

scale: mild (0 to -6 decibels [dB]), moderate (-6.01 to -12 dB), advanced (-12.01 to -20 dB), severe/blind

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glaucoma (< -20 dB).16 In absence of any treatment, the mean (SD) change in mean deviation (MD) per

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month was assumed to be constant at -0.05 (0.07) dB, irrespective of severity, based on the no-

40

treatment arm (n = 126) of the Early Manifest Glaucoma Trial (EMGT) of newly diagnosed treatment-

41

naïve patients with OAG.17 This decline was used to estimate the transition probabilities from one health

42

state to the next, by taking the inverse time needed for the average patient to progress from one health

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state to the next.18 5

44

Treatment for cataract with or without TBS was assumed to modify the natural disease

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progression via IOP reductions in a time-dependent fashion based on data from a 2-year RCT15

46

comparing iStent Inject + cataract surgery (n = 380) versus cataract surgery alone (n = 118) in patients

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with mild to moderate glaucoma who were consuming 1 to 3 medications at the time of screening. The

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unmedicated IOP reduction in the cataract surgery alone arm was 5.4 mm Hg at 24 months.15 TBS

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provided an additional reduction of 1.6 mm Hg at 24 months.15 Similarly, TBS reduced medication use by

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an additional 0.5 units at 24 months compared to the cataract surgery alone arm.15 Medicated IOP

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reductions were used in the model to reflect the real-world setting. Extrapolation of efficacy beyond the

52

trial follow-up was conducted up to 15 years by assuming an annual decline in the treatment effect of

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both arms by 5% from the end of year 3 to the end of year 10, and reversion to baseline values

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thereafter. In addition, we assumed a 5% erosion or waning of medication reduction in both arms each

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year after the trial follow-up. These IOP reductions were converted to changes in dB using data from the

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EMGT.17 Specifically, relative to untreated patients (n = 126), patients treated with selective laser

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trabeculoplasty (SLT) and medication (n = 129) maintained an additional absolute 5.1 mm Hg IOP

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reduction during the follow-up while experiencing a 40% relative reduction in the decline in visual field

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(VF) defect (per month: -0.03 dB treated vs -0.05 dB untreated; P = .008). Based on this information, the

60

percentage reduction in MD decline per unit mm Hg reduction in IOP pressure was estimated at 9.5%

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(i.e., 1 - [1-40%][1/5.1 mm Hg]). These reductions were in turn converted into modified transition

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probabilities as described above. For example, the natural MD decline per month in the EMGT untreated

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arm was -0.05 dB.17 Assuming a treatment reduced IOP by 2.88 mm Hg,11 the efficacy-adjusted MD

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progression per month would equal -0.036 (i.e., -0.05 – [2.88 mm Hg × 9.5% × -0.05]). Assuming a

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baseline MD score of -7.5,19 the time needed to transition from moderate to severe OAG would be 125

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months (i.e., [12 - 7.5]/0.036) and the monthly transition probability would be 0.8% (i.e., 1/125).

67

Although a constant natural rate of progression (dB decline) was applied to all patients in a treatment 6

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arm regardless of glaucoma severity stage, the transition probabilities between health states varied

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because of the extent of dB that patients would need to progress (e.g., -6 dB for moderate-to-advanced

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vs -8 dB for advanced-to-severe).

71

Separately from the dB progression, patients were assumed to be at risk for worsening of VF

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defect and optic disc damage, based on the data from the EMGT. Upon such worsening, patients could

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receive subsequent interventions (i.e., 2 × 180° SLT followed by trabeculectomy), based on key expert

74

opinion. The methods for estimating time to subsequent interventions have been reported previously.20

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Briefly, using the time-to-progression (i.e., worsening) Kaplan-Meier survival curve for the EMGT control

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group, patient-level simulated data were generated via digitalization and the use of the Guyott et al.

77

algorithm.21 Since the treatments were associated with change in IOP, and in turn IOP would change the

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time to progression, the model includes a hazard ratio for time-to-progression per unit increase in IOP of

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1.13 (95% CI: 1.07-1.19), as estimated in the EMGT22 (the hazard ratio per unit decrease in IOP was 0.88,

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i.e., the inverse of 1.13). We based SLT efficacy on an RCT that found a 12-month IOP reduction of 6.01

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mm Hg for patients receiving 360° SLT.23 We applied a constant annual IOP reduction of 6.01 mm Hg for

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as long as a patient’s SLT was successful (assumption: 1 year). The efficacy of trabeculectomy was based

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on an indirect treatment comparison that found a mean annual IOP reduction of 6.5 mm Hg for

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trabeculectomy versus no treatment.11 We used this 6.5 mm Hg annual change in our model and

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assumed it was maintained indefinitely. We assumed that the extent of improvement in visual acuity

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due to the cataract surgery was similar in patients undergoing MIGS with TBS and patients not

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undergoing MIGS with TBS.

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Cost Inputs Estimated surgery costs included medical device, physician, and facility fees (Error! Reference

90

source not found.). Physician fees were obtained from the official Ontario Health Insurance Plan (OHIP)

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Schedule of Benefits (SOB)24 while facility fees were estimated via expert opinion at an ophthalmological

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surgical center in Ontario. We calculated medication costs using estimated market share in third-quarter

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2017 IQVIA Pharmastat dataset25 medication claims and monthly medication consumption costs in the

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Ontario Drug Benefit Formulary (ODBF),26 with an assumed 1-month shelf life for each medication bottle

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and assumed 21% wastage (Error! Reference source not found.).27 The weighted average cost per

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month of medication was C$29.40 plus a dispensing fee of C$8.83 and 8% markup; with wastage, the

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total average cost was C$49.20 per month.

98

We estimated the frequency of office visits and VF tests by glaucoma severity using an

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observational chart review study of US patients with OAG,28 which indicated a trend of increasing visits

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due to worsening glaucoma severity, explicitly assuming that US health state–related healthcare

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resource utilization (HCRU) was generalizable to the Canadian population. The mean annual frequency

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of ophthalmologist visits increased from 3.0 to 4.0 visits as patients progressed from early to end-stage

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glaucoma, and we used those estimates (3.0 mild, 3.5 moderate, 3.8 advanced, 4.0 severe/blind) in our

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model. The mean annual frequency of VF tests varied between 1.4 (moderate) and 1.5 (mild, advanced,

105

severe/blind). Adverse events (AEs) related to the primary intervention were assumed to be resolved

106

within 1 month and therefore costs were applied to the first month post-surgery.

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In a scenario analysis, we included productivity loss by multiplying the average number of hours

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worked per year in the employed population (1,703 hours)29 by the risk of losing employment in each

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glaucoma stage (35.2% mild and moderate; 45.1% advanced; 100% severe/blind).30 Productivity loss due

8

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to death (100%) was estimated using the friction method for a period of 6 months.31-34 We obtained the

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annual caregiver burden (0.0 hours for mild and moderate glaucoma, 803.0 hours for advanced and

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severe/blind states) from a study that examined burden and depression in visually impaired patients in

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Canada.35

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The unit costs for ophthalmologist consultation, optic disc imaging, VF test, and IOP

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measurement (Error! Reference source not found.) were obtained from the OHIP SOB for physician

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fees.24 The costs of low vision aids were obtained from the Canadian National Institute for the Blind

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(CNIB) and applied only once to patients who transitioned into the advanced glaucoma health state.

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Costs were reported in 2017 Canadian dollars (C$). Per Canadian Agency for Drugs and

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Technologies in Health (CADTH) guidelines,36 a 1.5% discount rate was applied to future costs.

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Utility Inputs

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We used patient utility values from a cross-sectional survey conducted in Dutch patients with

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OAG37 and measured health preference using the Health Utilities Index 3 (HUI-3) with tariffs for the

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Canadian population.37,38 We estimated utilities for each health state using midpoint MDs and presence

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of AEs in patients using medications. As noted previously, progression in terms of MDs was dependent

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on the IOP reductions observed in the trials. IOP reductions in turn may be assumed to be dependent on

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both the efficacy of surgery and any subsequent medication use. Reduction in utilities due to medication

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AEs that occurred with a ≥3% incidence difference between comparators were subtracted from the

128

health state utility and multiplied by the market-share-weighted prevalence of side effects (10.5%) and

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the proportion of patients consuming medications in each month.39

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All patients were assumed to be consuming medications at baseline. The proportions of patients

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on medication in each month were estimated as the percentage reduction in mean medication usage

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from baseline.

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Analysis

134

The primary outcomes were the incremental cost-utility ratio (ICUR; i.e., difference in costs

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divided by the difference in quality-adjusted life-years [QALYs]) for TBS + cataract surgery versus

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cataract surgery alone. An economically “dominant” treatment was defined as having lower expected

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costs but higher effectiveness (i.e., higher QALYs) than the alternative. We conducted probabilistic base

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case analysis using 1,000 iterations from random draws of the underlying parameter uncertainty and

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expressed the results as ICUR scatterplots and cost-effectiveness acceptability curves (CEACs).

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In addition to the above, we tested the impact of varying treatment efficacy, natural progression

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rate (dB decline), and the hazard ratio for time-to-progression reduction per unit IOP reduction between

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95% CI limits, and varied unit costs, resource utilization, utilities, baseline characteristics (e.g., age), and

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baseline mild and moderate OAG health state distribution of stages by ±25%.

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We conducted the following scenario analyses: (1) lifetime horizon to capture all downstream

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costs and consequences; (2) 5-year time horizon; (3-4) 0% and 3% discount rates; (5) medication

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discontinuation due to imperfect persistence and no additional IOP reduction from TBS implantation

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during cataract surgery; (6) no medication wastage; (7) societal perspective; and (8) stable medication

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use after the end of trial follow-up. In the medication discontinuation scenario, IOP was assumed to

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increase post discontinuation of medications. In order to identify the timing of this IOP increase, we first

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estimated the time-to-medication discontinuation. Separate time-to-discontinuation curves for 4 drug

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classes (beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, and prostaglandins) were obtained 10

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from Nordstrom et al.40 A market-share-weighted average time-to-discontinuation of 10 months was

153

estimated using the 4 curves. The extent of increase in IOP after medication discontinuation was

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assumed equal to the difference in baseline IOP with and without medications (7 mm Hg) from a recent

155

RCT.8 In the analysis from the societal perspective, loss of productivity was only applied to simulations

156

where the mean age at baseline was >18 but <65 years, and the accumulation of indirect costs were

157

stopped at follow-up when the mean age reached 65 years.

158

159

Results

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Probabilistic Base Case

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At the end of the 15-year time horizon, TBS + cataract surgery was statistically significantly more

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effective (QALYs: 9.428 [95% CI: 5.296 to 10.893] vs 9.405 [95% CI: 5.283 to 10.864], for a total

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difference of +0.023 [95% CI: 0.004 to 0.044]) and had similar total costs (C$21,284.90 [95% CI:

164

C$12,164.90 to C$27,664.50] vs C$21,773.10 [95% CI: C$11,999.80 to C$28,283.10] for a non-statistically

165

significant difference of -C$389.00 [95% CI: -C$1,712.00 to C$850.70]) compared to cataract surgery

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alone (Error! Reference source not found.). Medication and primary surgery costs were the main drivers

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behind the total cost difference. TBS + cataract surgery was cost-saving in 73.7% of iterations and

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produced higher QALYs in 98.8% of iterations (Error! Reference source not found.). TBS + cataract

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surgery cost per QALY was ≤$50,000 and ≤$100,000 in 94.1% and 97.0% of iterations (Error! Reference

170

source not found.). Overall, 95% of iterations had a cost per QALY of ≤$62,366.

11

171

One-way Sensitivity Analysis

172

The ICUR results were largely robust to the uncertainties associated with baseline age, baseline severity,

173

natural rate of glaucoma progression, resource utilization, cost of medication, efficacy, and utility (Error!

174

Reference source not found.). The model was also robust to the changes in assumptions regarding the

175

rates and costs of AEs (data not shown).

176

Scenario Analyses

177

TBS + cataract surgery was dominant in the lifetime horizon, no medication wastage, societal

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perspective, and stable medication use after trial follow-up scenarios, generating more mean QALYs and

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lower mean costs than cataract surgery alone (Error! Reference source not found.). In the medication

180

discontinuation scenario, TBS + cataract surgery generated a larger mean gain in QALYs (0.075)

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compared to cataract surgery alone but had higher costs (C$1,456.20); however, the TBS + cataract

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surgery arm was still cost-effective (ICUR: C$19,212.50/QALY) with a probability of >90% at a

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willingness-to-pay (WTP) threshold of C$50,000 per QALY. As noted previously, the medication

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discontinuation scenario captured the benefit of reduced medication use due to the implantation of TBS

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but ignored any potential IOP reduction benefits. A mean gain of 0.075 QALYs in the medication

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discontinuation scenario versus only 0.023 QALYs in the base case analysis elucidates the potential

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benefit that TBS may have in addition to the IOP reductions observed in the clinical trial.

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Discussion

189

Our results show that TBS device implantation during cataract surgery was cost-effective

190

compared to cataract surgery alone in patients with OAG and cataract, with a cost per QALY ≤C$62,366

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in 95% of iterations and a 73.7% probability of being cost-saving. The higher primary surgery costs for 12

192

TBS are offset by lower medication costs and higher QALYs compared to cataract surgery alone. TBS +

193

cataract surgery was dominant in the base case and 5 out of 7 scenario analyses. Even if real-world

194

medication persistence (i.e., discontinuation) is considered, TBS remained cost-effective (albeit not

195

dominant). Although reported in the iStent Inject pivotal RCT,15 AEs had minimal impact in our model

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due to their relatively low incidence and associated costs.

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The effect of cataract surgery alone on IOP control is modest in OAG patients,41 whereas real-

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world evidence shows that the effect of iStent is sustained for at least 5 years.42 Results of the iStent

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Inject pivotal RCT showed iStent Inject + cataract surgery led to clinically and statistically greater

200

unmedicated IOP reduction through 2 years compared to cataract surgery alone.15 Compared to cataract

201

surgery alone, prior US real-world study results have shown that iStent TBS + cataract surgery in OAG

202

patients significantly improves 1-year postoperative success (i.e., unmedicated IOP ≤18) and reduction in

203

the number of glaucoma medications.43 Real-world studies in US patients with OAG found iStent TBS +

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cataract surgery also leads to 2-year postoperative reductions in the number of glaucoma medications

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used and the proportion of patients using no medications.44

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To the best of our knowledge, no previous cost-utility analysis has compared TBS + cataract

207

surgery against cataract surgery alone in the Canadian patient population. However, our findings were

208

consistent with a previous cost analysis that estimated iStent surgery to have lower costs compared to

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using medication alone (cost savings against 2 medications: C$1,273; 3 medications: C$2,125) over a

210

period of 6 years.27 The study underestimated the cost savings from the use of iStent as it excluded the

211

impact of IOP reduction on HCRU. Medication costs were ignored in the iStent arm. Patel et al 2019

212

conducted a cost-utility analysis of TBS alone against medication alone in patients with mild-to-

213

moderate glaucoma.20 Consistent with our study, Patel et al 2019 observed TBS alone to be the

13

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dominant treatment (cost savings: C$2,908; gain in QALYs: 0.068) over a 15-year time horizon, with a

215

majority of the cost savings (C$5,185) generated from a reduction in medication use.

216

This study has several limitations. Due to a lack of evidence in the literature, we restricted the

217

extrapolated duration of treatment effect to 10 years. However, this is a conservative assumption, as

218

IOP reduction for cataract surgery alone is not expected to be sustained long-term. We applied a

219

constant rate of natural decline in dB from the EMGT trial to all patients regardless of glaucoma severity.

220

The cost-effectiveness of TBS devices would have improved had we applied faster MD decline for

221

patients reflecting the level of severity for moderate and advanced glaucoma instead the constant rate

222

of decline representative of newly diagnosed, milder patients enrolled in the EMGT. The 2009 Canadian

223

Ophthalmological Society recommendations45 were published before the availability of TBS, so the

224

sequence of subsequent treatments was based on the clinical experience of the lead authors (IA and

225

DP). Due to the absence of data specific to Canada, we used HCRU from a US observational chart review

226

study. However, the sensitivity analysis showed our results to be relatively robust to change in these

227

assumptions. Long-term estimates on the relative efficacy of comparators were not available in the

228

literature at the time of this study, and follow-up in the iStent Inject trial was limited to 2 years.

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However, single-arm observational study results have shown that the effect of iStent Inject on IOP

230

continues for more than 5 years42; there is no evidence to suggest that the efficacy of iStent is limited

231

only to the trial’s 2-year follow-up period. The real-world difference-in-difference (DID) between

232

treatments may be larger than observed with our conservative assumptions, as IOP reduction for

233

cataract surgery alone was not expected to be sustained long-term. Existing long-term follow-up studies

234

lack generalizability of results due to limited sample sizes or included comparators other than cataract

235

surgery with patients who were newly diagnosed with glaucoma who may not need cataract surgery.15

236

Arriola Villalobos 2016 followed 11 patients implanted with iStent Inject concurrently with cataract

14

237

surgery for 5 years.42 An IOP reduction of 4.18 mm Hg and medication use reduction of 0.5 was observed

238

at the end of follow-up. Twenty percent of patients continued to experience ≥20% reduction in IOP at 5

239

years. Another RCT study followed newly diagnosed treatment naïve patients up to 5 years after

240

implantation with two first generation iStents (54 eyes) or initiation of travoprost (47 eyes).46 Eyes

241

implanted with iStents experienced a 35.3% reduction in IOP, albeit with some medication use (22.2% of

242

eyes). Future research could focus on the long-term efficacy (i.e., 10-15 years) and impact of medication

243

adherence on IOP. Finally, since this analysis was developed specifically for Canada, using Canadian

244

inputs wherever possible, supplemented in part with US data, extrapolating the results to other

245

countries should be done with caution as difference in costs and other assumptions may apply.

246

Although prevalence data specific to the Canadian population are not available, the number of

247

people with OAG in North America has been projected to increase by 42.8% from 2013 to 2040.47 Vision

248

loss in Canada from cataract and glaucoma were projected to increase by 114% and 117%, respectively,

249

from 2007 to 2032, primarily due to the country’s rapidly aging population.3 These changes may lead to

250

increased economic burden, and iStent TBS devices may help cost-effectively reduce the overall burden

251

of OAG and improve quality of life. TBS implantation surgery performed coincident to cataract surgery

252

offers a cost-effective method for reducing IOP in patients with mild to moderate OAG compared to

253

cataract surgery alone, without disrupting the demonstrated IOP reduction associated with

254

phacoemulsification alone.8

15

Acknowledgements Catherine Mirvis of Pharmerit International, LP (Bethesda, MD, United States) prepared a manuscript draft for the authors to edit and provided editorial assistance for subsequent drafts.

16

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21

Figure Legends

Figure 1. Model Structure Patients may undergo subsequent treatments due to progression in VF defect. Markov model health states shown above are replicated for each line of subsequent treatment. Abbreviations: dB, decibel; OAG, open-angle glaucoma; VF, visual field.

Figure 2. ICUR Acceptability Curve for TBS + Cataract Surgery Versus Cataract Surgery Alone Abbreviations: ICUR, incremental cost-utility ratio; QALY, quality-adjusted life-year; TBS, trabecular bypass stent.

Figure 3. One-Way Sensitivity Analysis For ICUR: TBS + Cataract Surgery Versus Cataract Surgery Alone The top 10 most influential variables are shown above. Results were robust to the uncertainty in all other input parameters. The IOP and medication reductions were varied between the upper and lower limits of 95% CI whereas all other variables were varied ±25%. Abbreviations: ICUR, incremental cost-utility ratio; IOP, intraocular pressure; QALY, quality-adjusted life-year; TBS, trabecular bypass stent.

22

Table 1. Model Inputs Variable

Distribution

Mean

SE

Lognormal

65

0.13

Beta Not applicable -

83.1%

Alpha

Beta

Reference

Baseline characteristics Age, y

12, 13

Glaucoma severity Mild

7,906

14

1,608

16.9%

14

24.8

15

-

1.6

15

TBS + cataract surgery

Normal

1.3

0.05

Cataract surgery alone

Normal

0.9

0.09

TBS + cataract surgery

Normal

1.2

0.06

Cataract surgery alone

Normal

0.8

0.13

Moderate Unmedicated IOP, mm Hg Medications used, no. Efficacy estimates Medication reduction, no. Year 1

47 47

Year 2

Year 2-15

15 15

Assumption

See text

Adverse events Stent obstruction TBS + cataract surgery

6.2%

TBS + cataract surgery

Beta

0.8%

2

294

Cataract surgery alone

Beta

5.9%

4

67

TBS + cataract surgery

b

Gamma

C$2,721.60

C$347.10

61.5

44.3

c

Gamma

C$1,047.80

C$133.60

61.5

17.0

Gamma

C$205.60

C$26.20

61.5

3.3

24

Gamma

C$1,500.00

C$191.30

61.5

24.4

Expert opinion

1st ophthalmologist visit

Gamma

C$82.50

C$10.50

61.5

1.3

24

>1st ophthalmologist visit

Gamma

C$29.00

C$3.70

61.5

0.5

Optic disc imaging

Gamma

C$35.00

C$4.50

61.5

0.6

Visual field test

Gamma

C$40.30

C$5.10

61.5

0.7

IOP measurement

Gamma

C$5.10

C$0.70

61.5

0.1

Gamma

C$197.90

C$25.20

61.5

3.2

48, 49

Gamma

C$3,780.00

C$482.10

61.5

61.5

50

Gamma

C$35.00

C$4.50

61.5

0.6

51

Cataract surgery alone

18

15

Beta Not applicable

278

15

0.0%

Hyperemia

Surgery costs

15 15

a

Cataract surgery alone d

SLT

e

Trabeculectomy

24 24

, Expert opinion

a

Direct medical costs

Low vision aids (cane + magnifier) Indirect medical costs

24 24 24

a

Nursing care cost per month Transportation to clinic

f

24

g a

Indirect nonmedical costs

Variable

Distribution

Mean

SE

Alpha

Beta

Reference

Gamma

C$27.30

C$3.50

61.5

0.4

29

Gamma

C$217.10

C$27.70

61.5

3.5

24

Gamma

C$92.00

C$11.70

61.5

1.5

24

Mild

Beta

0.847

251

45

52, 11

Moderate

Beta

0.781

231

65

52, 11

Advanced

Beta

0.704

208

88

52, 11

Severe/blind

Beta

0.594

176

120

52, 11

Beta

0.007

2

294

37

266

52, 39

Wage per hour Adverse event costs

a h

Cost of stent obstruction Cost of hyperemia

i

Quality of life Health state utilities

Disutilities Trabeculectomy j

Medication-related side effects

Beta

0.101

30

Abbreviations: C$, Canadian dollars; IOP, intraocular pressure; ODBF, Ontario Drug Benefit Formulary; OHIP, Ontario Health Insurance Plan; SLT, selective laser trabeculoplasty; TBS, trabecular bypass stent. a Costs presented in 2017 Canadian dollars (C$). b TBS + surgery arm: Physician fees (E214 + E950) + facility fee + TBS device. c Cataract surgery alone arm: Physician fee (E140) + facility fee. d Cost of SLT includes physician fee (C$205.60; OHIP24). e Cost of trabeculectomy includes: Surgical unit cost (C$950.00; expert opinion) + Physician fee (E132 = C$550.00; OHIP24). f Assistive Devices Program pays 75% of the price of low vision aids such as a cane (C$31.95) and magnifier (C$231.95). g Midpoint of range C$20.00-C$50.00. h Unit costs (OHIP24): Laser retinopexy = C$750.00, argon laser = C$182.75. i Cost of hyperemia: Corticosteroid (C$9.70; ODBF26) + 1 ophthalmologist visit (A235 = C$82.30; OHIP24) j Disutility was multiplied by the proportion of patients consuming medication at each Markov cycle and the prevalence of side-effect. At each Markov cycle, this adjusted disutility was subtracted from the utility associated with the health states.

Table 2. Cost of Medication Per Month and Market Shares Product

Market Share

Lumigan RC 5 mL (bimatoprost)

15.6%

Cost Per Month, C$ 58.10

Lumigan RC 7 mL (bimatoprost)

1.4%

87.10

Vistitan

0.4%

46.00

Alphagan (brimonidine)

1.8%

11.60

Alphagan P (brimonidine P)

4.3%

17.30

Combigan (brimonidine-timolol)

6.1%

43.60

Simbrinza (brimonidine-brinzolamide)

2.1%

46.80

Azopt (brinzolamide)

5.5%

17.80

Azarga (brinzolamide-timolol)

4.8%

23.40

Trusopt (dorzolamide)

2.7%

15.40

Cosopt (dorzolamide-timolol)

8.8%

21.00

Xalatan (latanoprost)

19.2%

9.60

Xalacom (latanoprost-timolol)

4.1%

11.10

Betagan (levobunolol)

0.8%

35.30

Timolol, 0.25%

0.2%

9.70

Timolol XE, 0.25%

0.4%

29.50

Timolol, 0.50%

2.6%

12.10

Timolol XE, 0.50%

6.0%

27.30

Travatan (travaprost)

7.5%

20.10

Teva-Travoprost Z (travoprost)

0.0%

10.10

5.8%

68.10

DuoTrav (travoprost-timolol) c

Weighted average medication cost a

a,b

49.20

Costs presented in 2017 Canadian dollars (C$). b The cost and volume (mL) of the largest medication bottle size available for an active ingredient was used when >1 size was available. c The weighted average cost per month of medication was C$29.40 plus a dispensing fee of C$8.83 and 8% markup, with wastage.

Table 3. Expected Costs and Benefits of TBS in Combination with Cataract Surgery Versus Cataract Surgery Alone (Probabilistic Base Case) TBS + Cataract Surgery

Variable

Cataract Surgery Alone

Difference/ Incremental

Benefit QALYs

9.428

9.405

0.023

Average number of 1 blind eye per patient

0.0352

0.0354

0.00021

2,725.90

1,053.40

1,672.40

Surgery costs, C$

a

Primary surgery

363.60

364.60

-0.90

3,089.50

1,418.00

1,671.50

5,237.70

7,307.30

-2,069.60

Ophthalmologist visit

11,615.60

11,615.20

0.40

Visual field defect test

695.60

695.50

0.10

Optic disc imaging

606.80

606.80

0.00

IOP measurement

88.10

88.00

0.10

Low vision aids

36.60

36.90

-0.30

13,042.70

13,042.40

0.30

14.20

5.40

8.80

21,384.10

21,773.10

-389.00

Secondary surgeries Subtotal Medication costs, C$

a

Glaucoma-related healthcare resources, C$

Subtotal Adverse event costs, C$

a

a

Total costs, C$ a Cost-effectiveness ratios ICUR (Cost/QALY) ICER (Cost/blind eye avoided)

a

b

-C$16,691 (TBS arm dominates)

b

-C$1,302,385 (TBS arm dominates)

Abbreviations: ICER, incremental cost-effectiveness ratio; ICUR, incremental cost-utility ratio; IOP, intraocular pressure; TBS, trabecular bypass stent; QALY, quality-adjusted life-year. a All costs presented in 2017 Canadian dollars (C$). b Negative ratio was calculated for magnitude only and would normally not be calculated when there is dominance.

Table 1. Scenario Analyses Scenario Lifetime horizon

Result Total cost, C$

a

Total QALYs

TBS + Cataract Surgery 31,125.80

Cataract Surgery Alone 31,512.00

13.296

13.271

Total cost, C$

a

9,119.30

8,672.40

3.919

3.905

23,319.70

23,821.10

10.277

10.252

19,722.80

20,009.80

8.693

8.671

No medication wastage

Total cost, C$

Total QALYs

16,338.20

14,882.00

9.362

9.287

20,106.10

20,136.00

9.428

9.405

ICUR

0.023

TBS arm dominates (95 percentile: 72,445.80) a

93,263.80

93,909.40

9.428

9.405

-645.50 0.023 th

ICUR Total QALYs

-29.90 th

Total QALYs

Stable medication use after the end of follow-up

0.075

C$19,212.50 (TBS arm is cost-effective) (95 percentile: 60,735.61) a

ICUR

Total cost, C$

1,456.20 th

Total QALYs Total cost, C$

0.022

TBS arm dominates (95 percentile: 59,344.31) a

ICUR

Societal perspective

-287.00 th

ICUR Total cost, C$

0.025

TBS arm dominates (95 percentile: 46,219.36) a

Total QALYs Medication discontinuation with no IOP benefit by TBS implantation

-501.50 th

ICUR Total cost, C$

0.014

C$32,227.80 (TBS arm is cost-effective) (95 percentile: 125,941.37) a

Total QALYs 3% discount rate

446.90 th

ICUR Total cost, C$

0.025

TBS arm dominates (95 percentile: 55,952.02)

Total QALYs 0% discount rate

-386.20

th

ICUR 5-year time horizon

Point Estimate for Difference

TBS arm dominates (95 percentile: 86,638.05) a

20,426.50

21,185.30

9.438

9.410

-758.80 0.027 th

TBS arm dominates (95 percentile: 34,673.55)

Abbreviations: ICUR, incremental cost-utility ratio; IOP, intraocular pressure; TBS, trabecular bypass stent; QALY, quality-adjusted life-year. a All costs presented in 2017 Canadian dollars (C$). b Negative ratio was calculated for magnitude only and would normally not be calculated when there is dominance.

Précis: A cost-utility model found that iStent Inject® trabecular bypass stent implantation during cataract surgery appears to be a cost-effective strategy to reduce intraocular pressure in Canadian open-angle glaucoma patients.