Cost-effectiveness of sequential urate lowering therapies for the management of gout in Singapore

Figures & data

Figure 1. Abbreviations. SUA, serum uric acid; ULT, urate lowering therapy. Individuals can die in any of the health states.

Table 1. Treatment sequences included in the model.

No.	Treatment sequence
Base-case cohort
1	No ULT
2	ALLO300 → ALLO600 → PROB
3	ALLO300 → ALLO600 → FEB
4	ALLO300 → ALLO600 → PROB → FEB
5	FEB
6	HLA-B*58:01 positive: PROB → FEB
	HLA-B*58:01 negative: ALLO300 → ALLO600 → PROB
7	HLA-B*58:01 positive : PROB → FEB
	HLA-B*58:01 negative: ALLO300 → ALLO600 → PROB → FEB
Subgroup with concomitant moderate to severe renal impairment
8	No ULT
9	ALLO300 → FEB
10	HLA-B*58:01 positive: FEB
	HLA-B*58:01 negative: ALLO300 → FEB
11	FEB
12	ALLO300

Abbreviations. ALLO300, allopurinol 300 mg/day; ALLO600, allopurinol 600 mg/day; FEB, febuxostat 80 mg/day; PROB, probenecid 2 g/day; ULT, urate lowering therapy.

Table 2. Model inputs: clinical parameters.

Model parameter		Base-case value (95% CI)						Source
Probability of achieving response (SUA <6mg/dL)
Non-renal impaired patients
FEB vs ALLO300		RR 1.830 (1.60–2.09)						NMA
ALLO300		0.318 (0.25–0.39)						NMA
ALLO600		0.76 (0.4–0.85)						Reinders et al.^20
FEB		0.582						Derived using RR
PROB		0.65 (0.45–0.81)						Reinders et al.^21
Renal-impaired patients
FEB vs ALLO300		RR 2.26 (1.72–2.95)						Indirect treatment comparison
ALLO300		0.316 (0.24–0.39)						Becker et al.^18
FEB		0.715						Derived using RR
Distribution of non-responders across SUA levels (%)
SUA		No ULT		ALLO300		FEB	PROB	Source
>6 to ≤ 8 mg/dL		0		79.0		74.1	79.0	Beard et al.^27, Schumacher et al.^23, Becker et al.^16
> 8 to ≤ 10 mg/dL		63.4		17.5		21.3	17.5
>10 mg/dL		36.6		3.5		4.6	3.5
Acute flare probabilities
Initiation phase
FEB vs ALLO300		RR 1.313 (0.973–1.772)						Plumpton et al.^28
ALLO300		0.1402 (0.1210–0.1605)						Plumpton et al.^28
FEB		0.1840						Derived using RR, Tayar et al.^29
PROB		0.1402 (0.1210–0.1605)						Assumption
Maintenance phase^a
≤6 mg/dL		0.2622						Beard et al.^27, IMS^30
6–8 mg/dL		0.2967
8–10 mg/dL		0.3284
>10 mg/dL		0.3480
Treatment discontinuation/dropout rates (%)
		ALLO300			FEB	PROB		Source
Initiation		0.051			0.053	0.051		NMA and assumptions
Maintenance, annual average		14.45			12.20	14.45		Beard et al.^27, Schumacher et al.^23, Becker et al.^16, Becker et al.^32
Incidence of SCAR (%)
			ALLO			FEB		Source
SJS/TEN	All patients		0.20			0.01		Sensitivity and specificity of HLA-B 58:01 genotyping were assumed to be 100%. 18.5% of Singaporeans were assumed to have HLA-B 58:01 allele. Plumpton et al.^28, Somkrua et al.^36
	HLA-B*58:01 (+)		1.020			0.05
	HLA-B*58:01 (−)		0.014			0.0006
DRESS	All patients		0.08			0.01
	HLA-B*58:01 (+)		0.41			0.05
	HLA-B*58:01 (−)		0.005			0.0006
Mortality rate for SJS/TEN (%)
SJS			5					Roujeau et al.^4, Revuz et al.^34, Schopf et al.^35
SJS/TEN overlap			15
TEN			30
HRQoL utility weights
SUA^Δ			Base-case value (95% CI)					Source
<6mg/dL (responder)			0.7463					Beard et al.^27, IMS^30
>6 mg/dl ≤ 8mg/dL			0.7120
>8mg/dL≤ 10mg/dL			0.6777
>10mg/dL			0.6435
Disutility of acute flare lasting for 7 days			0.0097					Beard et al.^27, IMS^30
SJS/TEN			0.14					Oster et al.^38
DRESS			0.1430					Hofhuis et al.^37
Severe dry eye syndrome			0.68					Schiffman et al.^40

Abbreviations. ALLO, allopurinol; ALLO300, allopurinol 300 mg/day; ALLO600, allopurinol 600 mg/day; CI, confidence interval; DRESS, drug reaction with eosinophilia and systemic symptoms; FEB, febuxostat 80 mg/day; HRQoL, health-related quality of life; NMA, network meta-analysis; PROB, probenecid 2 g/day; RR, relative risk; SCAR, severe cutaneous adverse reaction; SJS, Stevens-Johnson syndrome; SUA, serum uric acid; TEN, toxic epidermal necrolysis; ULT, urate-lowering therapy; Δ, The utility values for patients with concomitant renal impairment is assumed to be similar to patients without renal impairment; ^Conditional probability of an acute flare episode amongst patients who experience flares, derived by multiplying the cumulative incidence of flares in Table 1 of Beard et al with the mean number of acute flare episodes per 3 months model cycle (0.1354*3).

Table 3. Model inputs: cost parameters.

ULT		Initiation^1,2		Maintenance^2,3		Unit	Source
		Primary	Tertiary	Primary	Tertiary
Treatment costs with ULT (SGD)
ALLO	300 mg/day	291	1,036	58	138	Per 3-month model cycle	National drug utilization data from public sector (2016–2018)
	600 mg/day			72	152
FEB		526	1,023	337	417
PROB		287	826	92	172
Treatment costs for acute flare (SGD)^4
Acute flare		113				Per episode	National drug utilization data from public sector (2016–2018)
HLA-B*58:01 genotyping cost		$280 (Mean)					Public health care institutions
Treatment costs for SJS, TEN and DRESS during acute phase (SGD)
SCAR		Survival		Death		Unit	Source
Acute phase	SJS	21,663		63,457		Per episode	MOH Casemix & Subvention data 2012–2017 (Retrieved March 2018)
	SJS/TEN overlap	45,337		86,324
	TEN	59,523		88,470
	DRESS	6,740		–
Chronic phase	Ocular complications	2,505		717		Once-off: Per episode Recurring: Per cycle	MOH Casemix & Subvention data 2017 (Retrieved March 2018)

Abbreviations. ALLO, allopurinol; DRESS, drug reaction with eosinophilia and systemic symptoms; FEB, febuxostat 80 mg/day; MOH, Ministry of Health, Singapore; PROB, probenecid 2 g/day; SCAR, severe cutaneous adverse reaction; SGD, Singapore dollars; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; ULT, urate-lowering therapy.

Notes: 1. Dosing regimen.     • Allopurinol: 100 mg/day (week 1), 200 mg/day (week 3), 300 mg/day (week 7 or 12 onwards)     • If serum uric acid remained >6 mg/dL with 300 mg, dose was titrated to 600 mg.     • Febuxostat (only used in tertiary care): 40 mg/day (week 1) and 80 mg/day (week 5 onwards).     • Probenecid: 250 mg/day (week 1), 500 mg/day (week 5), and 2g/day (week 9 onwards).     • Prophylactic colchicine: 0.5 mg daily for 30–90 days after initiation of ULT. 2. Treatment costs include costs for ULT flare prophylaxis, blood tests and consultations. • Blood test and consultation: 3 times/3-month cycle, except patients on allopurinol managed at tertiary care (4 times/cycle). • Prophylaxis: Once-off cost of colchicine applied to all patients starting ULT. 3. 6-monthly consultation and blood test. 4. Treatment cost for acute flares included costs for consultation, blood tests and medication. Costs for patients treated at primary care were based on the assumption that all patients, including those managed at tertiary care, would have any acute flare episodes managed in a primary care setting.

Table 4. Results from the base-case analysis (SGD).

Treatment strategy		Total costs	Total QALYs	ICER
				ΔC	ΔQ	ICER
Main population
1	Supportive treatment without ULT	7,079	11.91	–	–	–
2	ALLO300 → ALLO600 → PROB	7,845	12.39	766	0.48	1,584
4	ALLO300 → ALLO600 → PROB → FEB	8,370	12.44	524	0.05	11,398
6	HLA-B*58:01 positive: PROB → FEB HLA-B*58:01 negative: ALLO300 → ALLO600 → PROB	8,532	12.37	163	−0.06	Dominated
3	ALLO300 → ALLO600 → FEB	8,859	12.40	489	−0.04	Dominated
7	HLA-B*58:01 positive: PROB → FEB HLA-B*58:01 negative: ALLO300 → ALLO600 → PROB → FEB	8,916	12.40	547	−0.04	Dominated
5	FEB	13,421	12.31	5,051	−0.13	Dominated
ICER relative to standard of care (Strategy 2)
2	ALLO300 → ALLO600 → PROB	7,845	12.39	–	–	–
3	ALLO300 → ALLO600 → FEB	8,859	12.40	1,014	0.01	142,301
Population with renal impairment
8	No ULT	6,951	11.69	–	–	–
12	ALLO300	7,562	12.02	611	0.32	1,953
9	ALLO300 → FEB	11,720	12.14	4,158	0.12	33,396
10	HLA-B*58:01 positive: FEB HLA-B*58:01 negative: ALLO300 → FEB	12,090	12.12	370	−0.02	Dominated
11	FEB	13,111	12.10	1,391	−0.04	Dominated

Abbreviations. ALLO300, allopurinol 300 mg/day; ALLO600, allopurinol 600 mg/day; FEB, febuxostat 80 mg/day; ΔC, incremental cost; ΔQ, incremental QALYs; ICER, incremental cost-effectiveness ratio; PROB, probenecid 2 g/day; SGD, Singapore dollars; QALYs, quality adjusted life-years; ULT, urate lowering therapy.

Figure 2. (a) Top 5 parameters in the one-way sensitivity analysis for second-line febuxostat (Strategy 3) vs standard of care (Strategy 2): Base case SGD142,301/QALY. (b) Top 5 parameters in the one-way sensitivity analysis for third-line febuxostat (Strategy 4) vs standard of care (Strategy 2): Base case SGD11,398/QALY.

Figure 3. Abbreviations. SGD, Singapore dollars; ALLO, allopurinol; ALLO300, allopurinol 300 mg/day; ALLO600, allopurinol 600 mg/day; PROB, probenecid 2 g/day; FEB, febuxostat 80 mg/day; ULT, urate lowering therapy; G, genotyping test.

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