Clinical Events

Base case

Low value

High value

Distribution

References

Rate of SE on placebo (per 100 PY)
Rate of SE on Rivaroxaban (per 100 PY)

Severity (%)

Non-fatal
Fatal

0.05
0.01

91
9

0.038
0.008

68
7

0.063
0.013

114
11

Beta
Beta

27
28,29

25
25

Rate of IS on placebo (per 100 PY)
Rate of IS on Rivaroxaban (per 100 PY)

Severity (%)

Transient (< 24h)
Minor (mRS 0 - 2)
Major (mRS 3 – 5)
Fatal (mRS 6)

0.43
0.01

24
43
29
4

0.323
0.008

18
32.25
21.75
3

0.538
0.013

30
53.75
36.25
5

Beta
Beta

Beta
Beta
Beta
Beta

27
28,29

23
23
23
23

Rate of ICH on placebo (per 100 PY)
Rate of ICH on Rivaroxaban (per 100 PY)

Severity (%)

Minor (mRS 0 – 2)
Major (mRS 3 – 5)
Fatal (mRS 6)

0.15
0.4

17
37
46

0.113
0.3

13
28
35

0.188
0.5

21
46
58

Beta
Beta

Beta
Beta
Beta

27
28,29

25
25
25

Rate of MI on placebo (per 100 PY)
Rate of MI on Rivaroxaban (per 100 PY)

Severity (%)

Non-fatal
Fatal

0.016
0.4

89
11

0.012
0.3

67
8

0.02
0.5

111
14

Beta
Beta

23
28,29

25
25

Rate of MB on placebo (per 100 PY)
Rate of MB on Rivaroxaban (per 100 PY)

Severity (%)

Non-fatal
Fatal

0.0093
1.6

98
2

0.007
1.2

74
1

0.012
2

122
3

Beta
Beta

27
28-30

25
25

Rate of CRNMB on placebo (per 100 PY)
Rate of CRNMB on Rivaroxaban (per 100 PY)

2.63

12.8

1.973

9,6

3.288

16

Beta

27

28,29

Rate of CD on placebo (per 100 PY)
Rate of CD on Rivaroxaban (per 100 PY)

Hazard ratio (CHADS2-VASC = 0 - 1)

Severity (%) (all therapies):

Mild (CDR 0.5 - 1)
Moderate (CDR 2)
Severe (CDR 3)
Fatal

0.018

0.0114

0.85
77
16
1
6

0.013

0.0086

0.64
58
12
0.75
4

0.022

0.0143

1.06
96
20
1.25
8

Beta

Beta
Beta
Beta
Beta
Beta

31

24
24
24
24

Rate of death on placebo (per 100 PY)
Rate of death on Rivaroxaban (per 100 PY)

0.039
0.22

0.029
0.17

0.048
0.28

Beta
Beta

27
29

CD = cognitive decline; CDR = clinical dementia rating scale; CI = cognitive impairment; CRNMB = clinically relevant non-major bleed; ICH = intra=cranial hemorrhage; IS = ischemic stroke; MB = major bleed; MI = myocardial infarction; mRS = modified Rankin Scale adapted by the Oxfordshire Community Stroke Project to assess patient functional deficits at hospital discharge; PY = patient-years; SE = systemic embolism

Table 1: Base-case model variables and distributions used in the sensitivity analysis


Cost of Event	Adjusted Cost*	Lower/Upper Values	Probability Distribution	References
SE	$9,610.42	7,208 – 12,013	Gamma	42
IS
Fatal stroke	$19,200	14,400 – 24,000	Gamma	43
Minor stroke	$19,200	14,400 – 24,000	Gamma	43
Major stroke	$65,055.46	48,791 – 81,319	Gamma	43
Transient	$4,914.85	3,686 – 6,144	Gamma	43
ICH
Minor ICH	$18,944.38	14,208 – 23,680	Gamma	43
Major ICH	$37,865	28,399 – 47,331	Gamma	Assumption
Fatal ICH	$18,944.38	14,208 – 23,680	Gamma	43
Major bleed (extracranial)	$5,024.68	3,769 – 6,281	Gamma	43
CRNM bleed	$118.98	89 - 149	Gamma	43
MI fatal	$8,409.94	6,308 – 10,513	Gamma	43
MI non-fatal	$13,019.33	9,764 – 16,274	Gamma	43
Minor CD	$797 (3 months)	598 - 996	Gamma	44
Moderate CD	$1015 (3 months)	761 - 1268	Gamma	44
Severe CD	$16066 (3 months)	12,050 – 20,083	Gamma	44

Long Term Costs (per annum)
MI	$3,743.34	2,807 – 4,679	Gamma	43
Major stroke	$21,809.09	16,357 – 27,261	Gamma	43
Minor stroke	$9,033.45	6,775 – 11,292	Gamma	43
ICH	$9,033.45	6,775 – 11,292	Gamma	43
SE	$2,256.94	1,693 – 2,821	Gamma	42

Drug Treatment (per 3 months)**
Placebo	$0	-	-
Rivaroxaban 15 mg	$284	241 - 327	Fixed	46
* Cost estimated using 2020 inflation rate ** Cost of rivaroxaban is based on the “Liste des Médicaments - Régie de l’assurance maladie du Québec”, November 2020 with $8.50 dispensing fee and 8% mark-up. CD = cognitive decline; CRNM Bleed = clinically relevant non-major bleed; ICH = intracranial hemorrhages; IS = ischemic stroke; MI = myocardial infarction; SE = systemic embolism

Table 3: Cost of events and drugs

Parameter	ICER (With Parameter Low Value)	ICER (With Parameter High Value)
Base Case ± 15%
Cost of Rivaroxaban	$10,939	$11,884
Base Case ± 25%
Cost of Rivaroxaban	$10,624	$12,198
Base Case ± 25%
Cost of major IS	$11,617	$11,206
Cost of minor IS	$11,490	$11,333
Cost of fatal IS	$11,420	$11,403
Cost of ICH	$11,373	$11,450
Cost of minor ICH	$11,403	$11,420
Cost of fatal ICH	$11,384	$11,439
Cost of SE	$11,477	$11,345
Cost of MI	$11,664	$11,159
Cost of fatal MI	$11,430	$11,393
Cost of major bleed	$8701	$14,122
Cost of minor bleed	$11,405	$11,418
Cost of minor CD	$11,424	$11,399
Cost of moderate CD	$11,418	$11,405
Cost of severe CD	$11,453	$11,370
Base Case ± (CI)
Minor IS utility decrement	$11,410	$11,412
Major IS utility decrement	$11,409	$11,413
Minor ICH utility decrement	$11,412	$11,411
Major ICH utility decrement	$11,412	$11,411
SE utility decrement	$11,411	$11,414
MI utility decrement	$11,408	$11,416
Major bleed utility decrement	$11,584	$11,244
CRNMB utility decrement	$11,411	$11,411
Base Case ± 25%
Minor CD utility decrement	$11,406	$11,417
Moderate CD utility decrement	$11,406	$11,417
Severe CD utility decrement	$11,408	$11,415
Base Case ± 25%
Rate of IS with Rivaroxaban	$11,319	$11,876
Rate of IS with placebo	$11,919	$10,822
Rate of ICH with Rivaroxaban	$11,246	$11,583
Rate of ICH with placebo	$11,433	$11,376
Rate of SE with rivaroxaban	$11,388	$11,529
Rate of SE with placebo	$11,523	$11,284
Rate of MI with rivaroxaban	$11,136	$11,695
Rate of MI with placebo	$11,987	$10,926
Rate of MB with rivaroxaban	$7,972	$14,600
Rate of MB with placebo	$12,488	$10,418
Rate of CRNMB with rivaroxaban	$11,521	$11,303
Rate of CRNMB with placebo	$11,398	$11,426
Rate of CD with rivaroxaban	$11,360	$11,459
Rate of CD with placebo	$11,536	$11,303
Rate of death with rivaroxaban	$11,411	$11,412
Rate of death with placebo	$11,424	$11,400
Base case ± (low, high values)
Discount rate (low = 0, High = 3%)	$12,790	$10,028
Cycle length (1 month, 6months)	$22,769	$9,158
Time horizon 10 years 20 years 40 years	$-1,730 $3,627 $8,629
CI = Confidence interval; ICER = Incremental cost-effectiveness ratio CD= Cognitive decline; CRNMB = Clinically relevant non major bleed; ICH = Intracranial hemorrhage; IS = Ischemic stroke; MI = Myocardial infarction; MB = Major bleed; SE = Systemic embolism

Table A1: Results of One-Way Sensitivity Analyses


Health State	Utility/Decrement Base Case	Lower Value (2.5%)	Upper Value (97.5%)	Probability Distribution	References
NVAF	0.81000	0.67819	0.91373	Beta	35,64
SE	- 0.1199	-0.10224	-0.13880	Beta	35,64
IS Minor Major	- 0.1385 - 0.2958	- 0.1184 - 0.2372	- 0.1600 - 0.3554	Beta Beta	35,64 37,38
ICH Minor Major	- 0.1385 - 0.2958	- 0.1182 - 0.2372	- 0.1602 - 0.3554	Beta Beta	35,64 37,38
MI	- 0.1247	-0.10645	-0.14356	Beta	35,64
Major bleed (extracranial)	- 0.1814	-0.15476	-0.20899	Beta	35,64
CRNM bleed	- 0.0582	-0.02429	-0.09211	Beta	37,38
Cognitive decline Mild Moderate Severe	- 0.13 - 0.27 - 0.44	(Base Case -25%) - 0.01 - 0.11 - 0.31	(Base Case + 25%) - 0.29 - 0.51 - 0.56	Beta Beta Beta	40,41 40,41 40,41
CRNM Bleed = clinically relevant non-major bleed; ICH = intracranial hemorrhages; IS = ischemic stroke; MI = myocardial infarction; NVAF = non valvular atrial fibrillation; SE = systemic embolism


Strategy	Cost¨	D Cost¨	QALYs	D QALY	Incremental cost per QALY (ICER)
Placebo	$126,836		12.00
Rivaroxaban 15 mg	$255,379	$128,543	23.27	11.26	$11,411
¨ Canadian dollar ** rivaroxaban cost-effective (ICER below the willingness to pay value of $50K); Placebo undominated = less costly and less effective than rivaroxaban; Rivaroxaban undominated = more costly and more effective than placebo QALY = Quality adjusted life years; ICER = Incremental cost-effectiveness ratio

Tables at a glance

Figures at a glance