Table 3:

Summary results of included economic evaluation studies

Study/citation	Mortality	Hospitalization	QALYs	LYQs	Annual cost	Total Cost	ICER	Threshold	Result
Ademi et.al, 2019	Icosapent + statin= 736.5 in 1000 individuals statin= 794.3 Difference=−57.8	Non-fatal MI/non-fatal Stroke: Icosapent + statin=877 statin= 1,147.8 Difference= −270.8 Serious Bleeding: Icosapent + statin= 220.6 statin= 208.2 Difference=12.4 Coronary Revascularization: Icosapent + statin= 772.4 statin= 1,068 Difference= −295.8 Hospitalization for AF: Icosapent + statin= 437.7 statin= 300.9 Difference= 136.8	Icosapent + statin =7.82 statin =7.53 Difference=0.28	Icosapent + statin=10.11 statin=9.78 Difference=0.33	Icosapent + statin= $1637 statin= $173	Icosapent + statin= $89,333 statin=$76,311	Cost per QALY gained (overall)= AUD $45,039 Cost per QALY gained (primary prevention) = $96,136 Cost per QALY gained (secondary prevention) = $35,935 Cost per YoLS (overall)= $38,480 Cost per YoLS (primary prevention) = $113,916 Cost per YoLS (secondary prevention) = $29,250	AUD50,000	Compared with statin alone, Icosapent ethyl in combination with statin therapy is likely to be cost-effective in the prevention of cardiovascular disease, especially in the secondary preventive setting.
Gao et.al, 2019	-	-	Icosapent = 10.57 Placebo= 10.28 Difference= 0.29	Icosapent = 12.78 Placebo= 12.47 Difference=0.31	AUD3768 per patient	Icosapent = $83,258 Placebo= $66,453 Difference= 16,805	Cost per QALY = $59,036 Cost per LYQs = $54,358	AUD50,000	Icosapent is not a cost-effective from an Australian healthcare system perspective. The government may consider subsidising this medication given the clinical need but at a discounted acquisition cost.
ICER, 2019	-	-	Icosapent =10.19 Statins=9.69 Difference=0.5	Icosapent =10.21 Statins=9.69 Difference=0.52	Net Price per Year Icosapent =$1,625	Icosapent: Total costs=$40,000 Intervention Costs=$15,000 Non-Intervention Costs=$25,000 Statins: Total costs=$31,000 Intervention Costs=$800 Non-Intervention Costs=$30,000 Difference=$9,000	$18,000 per QALY gained, $17,000 per LYQs and $53,000 per MACE avoided	$50,000, $100,000, and $150,000 per QALY	Results suggest that the use of icosapent ethyl (in patients receiving statins) provide clinical benefit in terms of gains in quality-adjusted survival and overall survival compared to optimal medical management alone in the adult,established CVD cohort, and adults without known CVD but at high risk for cardiovascular events.
Kodera, et.al 2018			primary prevention: Eicosapentaenoic + statin=18.8 statin=18.7 Difference=0.1 secondary prevention: Eicosapentaenoic + statin=18.1 statin=17.9 Difference=0.2	primary prevention: Eicosapentaenoic + statin=21.2 statin=21.1 Difference=0.1 secondary prevention: Eicosapentaenoic +statin=20.8 statin=20.6 Difference=0.2	A dose of 1,800mg costs ¥210.8 in Japan	primary prevention: Eicosapentaenoic + statin= ¥3,987,474 statin= ¥2,517,209 Difference= ¥1,470,265 secondary prevention: Eicosapentaenoic + statin= ¥6,551,407 statin= ¥5,281,864 Difference= ¥ 1,269,543	primary prevention: Cost per QALY = ¥29,567,364 Cost per LYQs = ¥32,198,787 secondary prevention: Cost per QALY = ¥5,450,831 Cost per LYQs = ¥5,410,598	¥5 million per QALY	Eicosapentaenoic +statin combination therapy showed acceptable cost-effectiveness for secondary prevention, but not primary prevention, of CVD in patients with hypercholesterolemia in Japan.
Philip et.al, 2016	-	-	Eicosapentaenoic+statin=3.627 statin=3.575 Difference=0.052	-	Eicosapentaenoic +Statin= $3,497 Statin= $994 Difference=$2503	Eicosapentaenoic +Statin= $29,377 Statin= $30,587 Difference=$−1210	-	-	Combining Eicosapentaenoic with statin therapy for secondary prevention of cardiovascular disease in the United States may be a cost-saving.
Weintraub et.al, 2020	-	-	-	-	-	$4.16 a day	primary prevention=$36,118/QALY	$50,000, $100,000, and $150,000 per QALY	In the United States, icosapent ethyl was shown to be dominant overall, cost-effective in primary prevention, and dominant in secondary prevention
Michaeli et.al, 2023	Primary prevention CVD death: 3.9 Non-CVD death: 41.7	Primary prevention 4.6	Primary prevention Incremental QALYs: 0.81	Primary prevention Incremental LYs: 0.97	Icosapent ethyl: €2,400	Primary prevention €14,732	Primary prevention ICER (costs/LY): 15,130 ICER (costs/QALY): 18,133	€20,000	For primary cardiovascular prevention, a combination therapy of icosapent ethyl plus statin is a cost-effective use of resources compared to statin monotherapy.
	Secondary prevention CVD death: 3.8 Non-CVD death: 48.8	Secondary prevention 4.3	Secondary prevention Incremental QALYs: 0.99	Secondary prevention Incremental LYs: 1.34	Statins: €131.62	Secondary prevention €14,333	Secondary prevention ICER (costs/LY): 10,695 ICER (costs/QALY): 14,485		For secondary prevention, icosapent ethyl increases atient benefit at different economic costs.
Michaeli et.al, 2022	Primary prevention CVD death: 3.9 Non-CVD death: 41.7	Primary prevention 4.6	Primary prevention Incremental QALYs: 0.79	Primary prevention Incremental LYs: 0.9	Icosapent ethyl + statin: £2064	---------------	Primary prevention ICER (costs/LY): 17,121 ICER (costs/QALY): 19,485	£17,000 per QALY	Icosapent ethyl is cost effective for primary and secondary cardiovascular prevention at an annual price of £2064 in the UK
	Secondary prevention CVD death: 3.8 Non-CVD death: 48.8	Secondary prevention 4.3	Secondary prevention Incremental QALYs: 0.98	Secondary prevention Incremental LYs: 1.25			Secondary prevention ICER (costs/LY): 10,409 ICER (costs/QALY): 13,285
Lachaine et.al, 2023	--------------	------------------	Icosapent ethyl: 9.88 (0.52) Placebo: 9.58 (0.49)	----------------	-----------------	Icosapent ethyl: $54.864 ($4483) Placebo: $42.341 ($4777)	$42,797 ($15,884)	$50,000/QALY	Icosapent ethyl could be a cost-effective strategy for treating these patients in Canada.
Weintraub et.al, 2022	• Death from any cause, nonfatal MI, or nonfatal stroke Icosapent ethyl: Trial:13.4 Model:13.6 Standard care: Trial: 16.9 Model:17.5	• During the trial period New heart failure Icosapent ethyl: 176 (4.30) Standard care: 167 (4.08) Atrial fibrillation/flutter Icosapent ethyl: 144 (3.52) Standard care: 105 (2.57)	In trial analysis Icosapent ethyl: SSR: 3.34 WAC: 3.34 Standard care: SSR: 3.27 WAC:3.27	In trial analysis Icosapent ethyl: SSR: 4.31 WAC: 4.31 Standard care: SSR: 4.25 WAC: 4.25	Icosapent ethyl: SSR: $1518 WAC: $3387	In trial analysis Icosapent ethyl: LY and QALY SSR: $18786 WAC: $24544 Standard care: SSR: $17273 WAC: $17273	In trial analysis SSR: $26,328 per LY WAC: $126,524 per LY SSR: $22311 Per QALY WAC: $107218 per QALY	$50,000	Both in-trial and over the lifetime, Icosapent ethyl offers better cardiovascular out-comes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.
	• Death from any cause Icosapent ethyl: Trial:6.7 Model: 6.9 Standard care: Trial: 7.6 Model:7.8	Ventricular tachycardia/fibrillation Icosapent ethyl: 35 (0.86) Standard care: 40 (0.98) Peripheral arterial disease Icosapent ethyl: 199 (4.87) Standard care: 206 (5.04) Unstable angina Icosapent ethyl: 132 (3.23) Standard care: 200 (4.89) • Over the lifetime New heart failure Icosapent ethyl: 513 (6.84) Standard care: 486 (6.48) Atrial fibrillation/flutter Icosapent ethyl: 428 (5.71) Standard care: 374 (4.99) Ventricular tachycardia/fibrillation Icosapent ethyl: 74 (0.99) Standard care: 76 (1.01) Peripheral arterial disease Icosapent ethyl: 475 (6.33) Standard care: 502 (6.69) Unstable angina Icosapent ethyl: 647 (8.63) Standard care: 982 (13.09)	Lifetime model Icosapent ethyl: SSR: 10.59 WAC:10.59 Standard care: SSR: 10.35 WAC:10.35	Lifetime model Icosapent ethyl: SSR: 14.08 WAC:14.08 Standard care: SSR: 13.94 WAC:13.94	Not reported for standard care	Lifetime model Icosapent ethyl: LY and QALY SSR: $195276 WAC: $202830 Standard care: SSR: $197064 WAC: $197064	Lifetime model SSR: Dominant WAC: $36042 per LY SSR: Dominant WAC: $23866 per QALY al.
Weintraub et.al, 2024	•Death from any cause, nonfatal MI, or nonfatal stroke Icosapent ethyl: Trial: 14.3 Model: 14.7 Standard care: Trial:19.3 Model:19.5 • Death from any cause Icosapent ethyl: Trial: 7.2 Model: 7.4 Standard care: Trial:9.8 Model:9.9	• During the trial period New heart failure Icosapent ethyl: 86 (5.6%) Standard care: 91 (5.7%) Atrial fibrillation/flutter Icosapent ethyl: 64 (4.1%) Standard care: 66 (4.1%) Ventricular tachycardia/fibrillation Icosapent ethyl: 17 (1.1%) Standard care: 20 (1.3%) Peripheral arterial disease Icosapent ethyl: 93 (6.0%) Standard care: 115 (7.2%) Unstable angina Icosapent ethyl: 49 (3.2%) Standard care: 94 (5.9%) • Over the lifetime New heart failure Icosapent ethyl: 428 (5.71%) Standard care: 374 (4.99%) Atrial fibrillation/flutter Icosapent ethyl: 74 (0.99%) Standard care: 76 (1.01%) Ventricular tachycardia/fibrillation Icosapent ethyl: 475 (6.33%) Standard care: 502 (6.69%) Peripheral arterial disease Icosapent ethyl: 647 (8.63%) Standard care: 982 (13.09%) Unstable angina Icosapent ethyl: 85 (1.13%) Standard care: 87 (1.16%)	In trial analysis Icosapent ethyl: Net cost: 3.28 WAC: 3.28 Standard care: Net cost: 3.13 WAC:3.13 Lifetime model Icosapent ethyl: Net cost:10.36 WAC:10.36 Standard care: Net cost: 9.83 WAC: 9.83	In trial analysis Icosapent ethyl: Net cost: 4.23 WAC: 4.23 Standard care: Net cost: 4.10 WAC: 4.10 Lifetime model Icosapent ethyl: Net cost: 13.68 WAC:13.68 Standard care: Net cost: 13.27 WAC:13.27	-----------------	In trial analysis Icosapent ethyl: LY Net cost: $33806 WAC: $41904 Standard care: Net cost: $35386 WAC: $35386 QALY Net cost: $29420 WAC: $36364 Standard care: Net cost: $30947 WAC: $30947 Lifetime model LY Icosapent ethyl: Net cost: $216243 WAC: $221403 Standard care: Net cost: $219212 WAC: $219212 QALY Icosapent ethyl: Net cost: $216243 WAC: $221403 Standard care: Net cost: $219212 WAC: $219212	In trial analysis LY Net cost: Dominant WAC: $48674 QALY Net cost: Dominant WAC: $36208 Lifetime model LY Net cost: Dominant WAC: $12385 QALY Net cost: Dominant WAC: $9582	$50,000	The REDUCE-IT USA cost effectiveness analysis has shown that IPE provides excellent value, even being cost saving (dominant) both in trial over the lifetime as well as in most sensitivity analyses and subgroups, and even within the conservative US WTP threshold of $50 000 per QALY gained, both in primary and secondary prevention.

Abbreviations: wholesale acquisition cost(WAC)