Cost-effectiveness of ranibizumab versus aflibercept in the treatment of visual impairment due to diabetic macular edema: a UK healthcare perspective

Figures & data

Figure 1 Markov model structure showing health states and possible patient transitions between states.

Abbreviations: BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study.

Table 1 Baseline ocular characteristics of patients followed in the model

BCVA (letters)	Patients (%)
86–100	0
76–85	11
66–75	39
56–65	27
46–55	15
36–45	8
26–35	0
≤25 letters	0
Patients treated in both eyes	22
Patients treated in WSE	60
Patients treated in BSE	18

Abbreviations: BCVA, best-corrected visual acuity; WSE, worse-seeing eye; BSE, better-seeing eye.

Table 2 Utilities used by BCVA level and eye status

BCVA (letters)	BSE	WSE
86–100	0.850	0.8500
75–85	0.758	0.8357
66–75	0.685	0.8214
56–65	0.611	0.8071
46–55	0.537	0.7929
36–45	0.464	0.7786
26–35	0.390	0.7500
≤25 letters	0.353	0.7500

Notes: The utilities for the BSE were calculated using the following formula: Utilities =0.86–0.368* LogMar –0.001*age with the age set at 65 years.²⁷

Abbreviations: BCVA, best-corrected visual acuity; BSE, better-seeing eye; WSE, worse-seeing eye; LogMar, logarithm of the minimum angle of resolution.

Table 3 Key model inputs for the base-case scenario

Time period	Model input	Ranibizumab 0.5 mg PRN	Ranibizumab 0.5 mg T&E	Aflibercept 2q8
Year 1	BCVA data source for TPs Treatments (n) Monitoring visits (n)	RESTORE^Citation16 7.0 (RESTORE)^Citation16 12.0 (RESTORE)^Citation16	Network meta-analysis 7.7 (RETAIN)^Citation25 7.7 (assumptions)	Network meta-analysis + assumptions 8.5 (VIVID-DME/VISTA-DME)^Citation19 8.5 (VIVID-DME/VISTA-DME)^Citation19
Year 2	BCVA data source for TPs Treatments (n) Monitoring visits (n)	RESTORE extension^Citation40 3.9 (RESTORE extension)^Citation40 9.0 (DRCR.net^Citation29)a	Assumptions (same TPs as ranibizumab PRN) 5.1 (RETAIN)^Citation25 5.1 (assumptions)	Assumptions (same TPs as ranibizumab PRN) 5.1 (VISTA-DME)^Citation19,Citation42 5.1 (VISTA-DME)^Citation19,Citation42
Year 3	BCVA data source for TPs Treatments (n) Monitoring visits (n)	RESTORE extension^Citation40 2.9 (RESTORE extension)^Citation40 7.5 (DRCR.net^Citation29)a	Assumptions (same TPs as ranibizumab PRN) 5.1 (assumptions – same as in year 2) 5.1 (assumptions – same as in year 2)	Assumptions (same TPs as ranibizumab PRN) 5.1 (assumptions – same as in year 2) 5.1 (assumptions – same as in year 2)
Year 4+	BCVA data source Treatments (n) Monitoring visits (n)	Natural historyb 0 (assumption) 0 (assumption)	Natural historyb 0 (assumption) 0 (assumption)	Natural historyb 0 (assumption) 0 (assumption)

Notes:

a Average monitoring visits between ranibizumab plus prompt laser treatment and ranibizumab plus deferred laser treatment arms DRCR.net;²⁹

b natural history refers to the WESDR study.^22,23

Abbreviations: PRN, pro re nata; T&E, treat and extend; 2q8, 2 mg every 8 weeks after five initial monthly doses; BCVA, best-corrected visual acuity; TP, transition probability.

Table 4 Key treatment cost assumptions

	Cost (£)	Source
Ranibizumab price/vial	742.17	NICE^Citation28
Aflibercept price/vial	816.00	NICE^Citation28
Visit with injectiona	168.53	UK Department of Health^Citation43
Visit without injection (monitoring visit)	60.00	NICE^Citation28

Notes:

a Cost of optical coherence tomography (£51.27) + injection visit (£117.26); excludes drug costs. The cost of optical coherence tomography was estimated to be the same as an outpatient diagnostic procedure coded as an ultrasound scan of less than 20 minutes ie, £51.27 (HRG code, RA23Z). The ranibizumab injection administration visit was costed as an office-based outpatient procedure (£117.26 [HRG code, BZ23Z] Vitreous Retinal Procedures − category 1).

Abbreviations: NICE, National Institute for Health and Care Excellence; HRG, healthcare resource group.

Table 5 Base-case cost-effectiveness results per patient

Comparison	Total cost (£)	Total QALY	Incremental cost (£)	Incremental QALY	NMB (£)a
Aflibercept 2q8	25,859	8.54
Ranibizumab 0.5 mg PRN	20,019	8.59	−5,841	0.05	6,768
Ranibizumab 0.5 mg T&E	22,930	8.59	−2,930	0.05	3,934

Notes:

a Assumes willingness-to-pay threshold of £20,000/QALY.

Abbreviations: QALY, quality-adjusted life-year; NMB, net monetary benefit; 2q8, 2 mg every 8 weeks after five initial monthly doses; PRN, pro re nata; T&E, treat and extend.

Figure 2 Tornado plots of one-way sensitivity analyses for ranibizumab 0.5 mg PRN compared with aflibercept 2q8.

Assumptions used to determine the input range for the tornado plot: Ranibizumab PRN versus aflibercept OR values are based on the 95% CrI from the published network meta-analysis.²⁴ The range in the number of ranibizumab PRN injections over 3 years was based on the 95% confidence interval from the RESTORE 36-month data.⁴⁰ The range in the number of PRN injections in the first year was based on the weighted injection average across RESTORE¹⁶ and RESPOND.⁴¹ The lower value for the number of aflibercept injections assumed the same injection frequency as the ranibizumab PRN regimen. Ranibizumab maximal monitoring frequency assumed monthly monitoring (as described in the RESTORE protocol).¹⁶

Notes: The NMB in the base-case scenario is £6,768 for ranibizumab 0.5 mg PRN versus aflibercept. Model parameters varied in the sensitivity analyses are shown on the Y axis. The first model parameter in brackets was used to obtain the lower NMB while the second model parameter was used to obtain the higher NMB.
Abbreviations: PRN, pro re nata; 2q8, 2 mg every 8 weeks after five initial monthly doses; NMB, net monetary benefit; CrI, credible interval.

Figure 3 Scatter plots for probabilistic sensitivity analysis showing cost-effectiveness of (A) ranibizumab 0.5 mg PRN and (B) ranibizumab 0.5 mg T&E compared with aflibercept 2q8.

Abbreviations: QALY, quality-adjusted life-year; PRN, pro re nata; T&E, treat and extend; 2q8, 2 mg every 8 weeks after five initial monthly doses.

Figure 4 Cost-effectiveness acceptability curves for (A) ranibizumab 0.5 mg PRN and (B) ranibizumab 0.5 mg T&E compared with aflibercept 2q8.

Abbreviations: ICER, incremental cost-effectiveness ratio; PRN, pro re nata; T&E, treat and extend; 2q8, 2 mg every 8 weeks after five initial monthly doses.

Table S1 Calculation of aflibercept transition probabilities

	t <12 months	t ≥ 12 months
j > i +2	Aijt = Rijt =0%	Aijt = Rijt =0%
j = i +1 or j = i +2	(Aijt * [1 − Rijt])/(Rijt * [1 − Aijt]) = OR	Aijt = Rijt
j = i −1 or j = i − 2	Aijt = Rijt	Aijt = Rijt
j < i − 2	Aijt = Rijt =0%	Aijt = Rijt =0%
j = i	$A_{ijt}=1-{\displaystyle \sum _{j=1,j=i}^{j=8}{A}_{ijt}}$	Aijt = Rijt

Notes: R_ijt is the ranibizumab transition probability from state i (1≤ i ≤8) at time t (months) to state j at time t +1; A_ijt is the aflibercept transition probability from state i at time t to state j at time t + 1. OR is for the percentage of patients experiencing an improvement in BCVA of at least ten letters on the ETDRS scale, and is calculated so that, at month 12, the OR of gaining ten letters or more with ranibizumab (vs aflibercept) is equal to 1.59 (95% CrI, 0.61–5.37).²⁴

Abbreviations: BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; OR, odds ratio; CrI, credible interval.

Table S2 Costs of visual impairment

Item	Proportion of blind population requiring service (%)	Annual unit cost of service (£)	Mean cost per person (£)	Source calculations/assumptions
Low vision aids	33.0	167.38	55	• Shyangdan et al^Citation44 • 2003/04 cost inflated to 2010/11 cost using the HCHS index^Citation45 • Inflated cost is divided by two, assuming that the service applies every 2 years
Low vision rehabilitation	11.0	426.40	47	• PSSRU 2011^Citation46 • Community occupational therapist (local authority) • Cost per hour of client contact including training =£82 • Length of contact per care episode =5.2 hours (PSSRU 2003)^Citation47 • Inflated cost is divided by two, assuming that the service applies every 2 years
Residential care	30.0	51,090.00	15,327	• PSSRU 2011^Citation46 • Health authority residential care for older people • £982.50 establishment cost per permanent resident week • Costs assumed 52 weeks per year
Community care	6.0	10,005.84	600	• PSSRU 2011^Citation46 • Home care worker • Typical home care package =12.4 hours per week • Based on a study of community care packages, it has been estimated that 6.76 hours are worked, on average, during weekdays (6.6 between 9 am and 5 pm and 0.16 hours 5 pm). On average, 0.55 hours are worked each on Saturday and Sunday • Costs =£22 per hour face-to-face weekday contact (£27 per hour weekday evenings; £33 per hour Saturdays; £45 per hour Sundays) • Total annual cost per care package =£192.42 per week ×52
Depression	38.6	2,291.00	884	• McCrone et al^Citation48 • Cost per patient aged 65–74 = £2,000 per annum • 2005/06 cost inflated to 2010/11 cost using the HCHS index^Citation45
Hip replacement	5.0	6,617.00	331	• NHS reference costs 2010/11^Citation45 • NHS Trusts Elective Inpatient HRG data^Citation43 • HRG HB12B major hip procedures for non-trauma Category 1 with complications^Citation49
Blind registration	94.5	86.00	81	• Shyangdan et al^Citation44 • 2003/04 cost inflated to 2010/11 cost using the HCHS index^Citation45 • Inflated cost is divided by two, assuming that the service applies every 2 years
Total			17,325
Total in subsequent years			17,245

Abbreviations: HCHS, Hospital and Community Health Services; HRG, Health Care Resource Group; NHS, National Health Service; PSSRU, Personal Social Services Research Unit.

Table S3 Key variables with varying value in the probability sensitivity analysis

Variable	Base-case	Standard deviation	Distribution
OR of gaining ≥10 letters (ranibizumab PRN vs aflibercept 2q8)	1.59	1.21	Log normal
Transition probabilities
ranibizumab PRN – Yr 1–3	Varies by state	Varies by state	Gamma
Annual worsening after Yr 3	4.5%	alpha =5.5/beta =1	Gamma
No change after Yr 3	92%	alpha =92/beta =1	Gamma
Annual improvement after Yr 3	3.5%	alpha =4.5/beta =1	Gamma
Regression model for BSE utility
Constant	0.86	0.039	Normal
LogMAR coefficient	−0.368	0.045	Normal
Age coefficient	−0.001	0.002	Normal
Ranibizumab PRN injections
Year 1	7.0	0.26	Normal
Year 2	3.9	0.38	Normal
Year 3	2.9	0.32	Normal
Aflibercept 2q8 injections
Year 1	8.54	0.11	Normal
Year 2	5.10	0.38	Normal
Year 3	5.10	0.32	Normal
Costs of visual impairment
BCVA <35 letters	£17,326	£3,465	Gamma

Note: The transition probabilities in the probability sensitivity analysis are normalized, so that they equal 100%.

Abbreviations: OR, odds ratio; PRN, pro re nata; 2q8, 2 mg every 8 weeks after five initial monthly doses; BSE, better-seeing eye; LogMar, logarithm of the minimum angle of resolution.

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