Vol.:(0123456789)
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The Eu opean Jou nal o Heal h Economics (2023) 24:621–632
h ps://doi.o g/10.1007/s10198-022-01495-1
ORIGINAL PAPER
Modeling hepo en ial e iciency o ablood bioma ke ‑based ool
oguide p e‑hospi al h omboly ic he apy ins oke pa ien s
Elizabe hPa ody‑Rua1,2 · Alejand oBus aman e3 · JoanMon ane 4,5 · Ma iaRubio‑Vale a6,7 ·
Da idSe ano8· SoledadPé ez‑Sánchez5 · AlbaSánchez‑Viñas1 · Césa Gue a a‑Cuella 9 ·
An oniSe ano‑Blanco7,10,11
Recei ed: 18 Oc obe 2021 / Accep ed: 21 June 2022 / Published online: 27 July 2022
© The Au ho (s) 2022
Abs ac
Objec i es S oke ea men wi h in a enous issue- ype plasminogen ac i a o ( PA) is e ec i e and e icien , bu as i s
bene i s a e highly ime dependen , i is essen ial o ea he pa ien p omp ly a e symp om onse . This s udy e alua es he
cos -e ec i eness o a blood bioma ke es o di e en ia e ischemic and hemo hagic s oke o guide p e-hospi al ea men
wi h PA in pa ien s wi h suspec ed s oke, compa ed wi h s anda d hospi al managemen . The s anda d ca e o pa ien s
su e ing s oke consis s mainly in diagnosis, ea men , hospi aliza ion and moni o ing.
Me hods A Ma ko model was buil wi h ou heal h s a es acco ding o he modi ied Rankin scale, in adul pa ien s wi h
suspec ed mode a e o se e e s oke (NIHSS 4-22) wi hin 4.5 hou s a e symp om onse . A Spanish Heal h Sys em pe spec-
i e was used. The ime ho izon was 15 yea s.Quali y-adjus ed li e-yea s (QALYs) and li e-yea s gained (LYGs) we e used
as a measu e o e ec i eness. Sho - and long- e m di ec heal h cos s we e included. Cos s we e exp essed in Eu os (2022).
A discoun a e o 3% was used. P obabilis ic sensi i i y analysis and se e al one-way sensi i i y analyses we e conduc ed.
Resul s The use o a blood- es bioma ke compa ed wi h s anda d ca e was associa ed wi h mo e QALYs (4.87 s. 4.77),
mo e LYGs (7.18 s. 7.07), and g ea e cos s (12,807€ s. 12,713€). The ICER was 881€/QALY. P obabilis ic sensi i i y
analysis showed ha he bioma ke es was cos -e ec i e in 82% o i e a ions using a h eshold o 24,000€/QALY.
Conclusions The use o a blood bioma ke es o guide p e-hospi al h ombolysis is cos -e ec i e compa ed wi h s anda d
hospi al ca e in pa ien s wi h ischemic s oke.
Keywo ds S oke· Bioma ke s· PA· Cos -e ec i eness
* An oni Se ano-Blanco
an oni.se [email p o ec ed]
1 Teaching, Resea ch andInno a ion Uni , Pa c Sani a i San
Joan de Déu, San BoideLlob ega , Spain
2 P ima y Ca e P e en ion andHeal h P omo ion Ne wo k
( edIAPP), Ba celona, Spain
3 S oke Uni , Hospi al Uni e si a i Ge mans T ias i Pujol,
Badalona, Spain
4 Neu o ascula Resea ch Labo a o y, Vall d’Heb on Ins i u e
o Resea ch (VHIR), Ba celona, Spain
5 Ins i u e de Biomedicine o Se ille, IBiS/Hospi al
Uni e si a io Vi gen del Rocío/CSIC/Uni e si y o Se ille
andDepa men o Neu ology, Hospi al Uni e si a io Vi gen
Maca ena, Se ille, Spain
6 Head o Quali y andPa ien Sa e y, Pa c Sani a i San
Joan de Déu. Ins i u de Rece ca San Joan de Déu,
San BoideLlob ega , Spain
7 CIBER o Epidemiology andPublic Heal h (CIBERESP),
Mad id, Spain
8 F eelance Heal h Economis , Ba celona, Spain
9 Facul ad de Ciencias de la Salud, Uni e sidad Icesi, Cali,
Colombia
10 Pa c Sani a i San Joan de Déu. Ins i u de Rece ca San
Joan de Déu, Men al Heal h Di ec o a e, C/Camí Vell de la
Colònia, 25, 08830San BoideLlob ega , Ba celona, Spain
11 Depa amen de Medicina. Facul a de Medicina i Ciències
de la Salu , Uni e si a de Ba celona, Ba celona, Spain
622 E.Pa ody-Rua e al.
1 3
In oduc ion
S oke is one o he leading causes o dea h and disabil-
i y wo ldwide [1, 2]. Addi ionally, s oke a ec s pa ien s’
quali y o li e [3] and in ol es a conside able economic
bu den du ing hospi aliza ion and subsequen discha ge
[3–5], mainly due o hospi al s ays and ehabili a ion [5].
Th ombolysis wi h ecombinan issue plasminogen ac i-
a o ( PA) o ischemic s oke (IS) is e ec i e [6, 7] and,
acco ding o a li e a u e e iew, is an e icien ea men
[8]. Howe e , i has a educed he apeu ic window (4.5h
a e s oke onse ) and i s bene i s a e highly ime depend-
en . The e o e, i is essen ial o con i m IS diagnosis and
o ea pa ien s p omp ly a e symp om onse . Delays in
diagnosis con i ma ion, which depend on neu oimaging
echniques conduc ed on admission, a e among he ba -
ie s o imely acu e s oke ea men [9] and a e associ-
a ed wi h low a es o PA ea men and poo e s oke
ou comes [10]. Howe e , symp om ecogni ion and ime
o anspo o hospi al/accessibili y o expe ise would
appea o g ea e ba ie s [11].
To educe ea men delays, s udies ha e assessed p e-
hospi al h ombolysis. S udies in mobile s oke uni s
(MSUs) sugges ha p e-hospi al commencemen o in a-
enous h ombolysis can imp o e unc ional ou comes
in s oke pa ien s [12–14]. MSUs a e equipped wi h a
compu e omog aphy scanne , poin -o -ca e labo a o y,
elemedicine [15, 16], s oke iden i ica ion algo i hm a
dispa che le el, and a p e-hospi al s oke eam [13]. How-
e e , al hough MSUs ha e shown o be cos -e ec i e in
some s udies, hei g ea cos a ound 1M€/yea is una -
o dable o mos heal hca e sys ems [17].
Using blood bioma ke s in he ambulance o di e en ia e
s oke ypes wi hou special equipmen o medical pe sonnel
would be a mo e p ac ical and cheape al e na i e o MSUs
[14, 18]. Howe e , he e iciency o hese bioma ke s is s ill
unknown. In a ecen s udy, ou g oup showed he easibili y
o his me hod by using highly speci ic blood es s o de ec
an IS pa ien subg oup ha migh bene i om p e-hospi al
in e en ions, such as in a enous h ombolysis, e en wi h-
ou neu oimaging [19]. A wo-bioma ke panel including
e inol-binding p o ein and N- e minal p o-B- ype na iu-
e ic pep ide iden i ied IS pa ien s wi h 100% speci ici y and
sensi i i y a es a ound 20%. Mo eo e , a h ee-bioma ke
panel also including glial ib illa y acid p o ein, measu ed
wi h a high-sensi i i y assay, imp o ed sensi i i y o 50%,
main aining 100% speci ici y. These esul s a e cu en ly
unde e alua ion in he BIOFAST s udy (Bioma ke s o
Ini ia ing Onsi e and Fas e Ambulance S oke The apies,
ClinicalT ials.go iden i ie : NCT04612218 s udy), which
measu es hese bioma ke s in he p e-hospi al scena io wi h
poin -o -ca e es de ices.
This s udy de eloped a hypo he ical economic model
o e alua e he cos -e ec i eness o hese blood bioma ke
es s o guide p e-hospi al PA ea men s. s anda d ca e
( h ombolysis a he hospi al) in pa ien s wi h suspec ed IS.
Me hods
App oach
A cos -e ec i eness s udy based on a Ma ko model was
conduc ed in pa ien s wi h suspec ed s oke wi h < 4.5h
om symp om onse and wi h a Na ional Ins i u es o Heal h
S oke Scale sco e o 4–22 (mode a e o se e e s oke). A
Spanish Heal h Sys em pe spec i e was adop ed. The Span-
ish public heal hca e sys em p o ides uni e sal co e age o
ci izens and o eign na ionals and is mainly unded h ough
axes. I is a decen alized sys em and he 17 Spanish egions
con ol heal h planning, public heal h, and heal h se ice
managemen [20]. Na ional and in e na ional economic
e alua ion me hodological guidelines we e ollowed [21,
22]. The 15-yea ime ho izon was based on he mean age
o s oke diagnosis (70yea s) and li e expec ancy in Spain
(85yea s). A discoun a e o 3% was used o bo h cos s
and ou comes [21].
In e en ion
The in e en ion was a bioma ke es om he s udy by
Bus aman e e al. [19], consis ing o he combina ion o e i-
nol-binding p o ein > 52µg/mL and N- e minal p o-B- ype
na iu e ic pep ide > 4062pg/mL, p o iding 20% sensi i i y
and 100% speci ici y o IS (Table1S Supplemen al Ma e-
ial). This bioma ke combina ion was used as base-case in
he economic model. Sensi i i y analyses we e conduc ed
wi h a h ee-bioma ke panel including glial ib illa y acid
p o ein, desc ibed in he same s udy wi h 51.5% sensi i i y
and 100% speci ici y o IS.
Compa a o
The s anda d ca e o pa ien s su e ing s oke consis s
mainly in diagnosis, ea men , hospi aliza ion, and moni-
o ing. Ini ially, a neu oimaging es is conduc ed o ule ou
hemo hage. In addi ion, analy ical es s and complemen a y
es s a e done. I he s oke is ischemic and he pa ien mee s
he h ombolysis c i e ia, PA IV is adminis e ed.
Heal h ou comes
The main heal h ou come was measu ed in quali y-adjus ed
li e-yea s (QALYs) gained. This e ec i eness measu e was
chosen because s oke pa ien s’ unc ional s a us ypically
623
Modeling hepo en ial e iciency o ablood bioma ke ‑based ool oguide p e‑hospi al…
1 3
wo sens conside ably, which educes heal h- ela ed qual-
i y o li e. Deg ee o disabili y o dependence in he daily
ac i i ies o people who ha e su e ed a s oke was meas-
u ed using he modi ied Rankin scale (mRS) o neu ologic
disabili y. The p obabili ies o mRS o IS we e ob ained
om pooled andomized con olled ials [7] ha e alua ed
he use o PA s. placebo. In ace eb al hemo hagic (ICH)
mRS p obabili ies came om a clinical ial [23]. Rega d-
ing he bioma ke es , mRS alues we e es ima ed om an
MSUs s udy [15]. This s udy compa ed 3-mon h unc ional
ou comes a e in a enous h ombolysis in pa ien s wi h
acu e ischemic s oke who had ecei ed eme gency mobile
ca e o con en ional ca e. P e iously published da a on u ili-
ies we e used o de e mine he QALY o each mRS le el
[24, 25].
All-cause mo ali y p obabili ies we e de e mined by
gende and age and applied o pa ien s in he long- e m
phase one yea a e s oke, acco ding o Spanish mo ali y
ables, om he Na ional S a is ics Ins i u e [26], adjus ed
o he ela i e isk o ha ing a p e ious s oke. The Na ional
S a is ics Ins i u e a es we e con e ed in o p obabili ies.
Addi ionally, we adjus ed mo ali y p obabili ies by p opo -
ion o men (0.58) and women (0.42) su e ing s oke. This
in o ma ion was ob ained om RENISEN (Na ional S oke
Regis y o he Spanish Socie y o Neu ology) [27, 28], a
s oke egis y om 42 cen e s in Spain. We also used LYGs
as an e ec i eness measu e.
Decision model
The model was designed based on p e ious published
model-based economic e alua ions in s oke [29, 30]. We
combine a decision ee wi h a Ma ko model. The model
was alida ed by clinical expe s. Ma ko s a es ep esen
ou come ca ego ies acco ding o mRS. Fou mRS ca ego-
ies we e used acco ding o pa ien s’ measu emen equi e-
men s: mRS 0–1 (non-disabled pa ien , equi ing only sec-
onda y p e en ion s a egies), mRS 2–3 (disabled pa ien s
also equi ing ehabili a ion), mRS 4–5 (se e ely disabled
pa ien s, equi ing long- e m nu sing ca e), and mRS 6
(s oke dea h). Figu e1 shows model s uc u e and possible
ansi ions be ween heal h s a es. The di e en heal h s a es
we e de ined o be clinically and economically ele an .
The model has a wo-phase s uc u e: acu e (sho un ep-
esen ed by a decision ee model) and long e m (Ma ko
model). The acu e phase consis s o pa ien managemen
and ou comes om s oke onse o 90days. The model hen
ollows a long- e m phase wi h wo di e en cycle leng hs:
91days o a yea a e s oke and om one yea o 15yea s
wi h an annual cycle leng h; he e o e, a hal -cycle co ec-
ion was made.
The model was es ed o cons uc alida ion, e i i-
ca ion, and c oss- alida ion by clinical expe s (JM, AB)
and e alua ed using a i s -o de Mon e Ca lo simula ion in
Mic oso Excel 2016.
Model assump ions we e as ollows: (1) he p opo ion
o pa ien s unde going s anda d ca e s. es bioma ke was
50%; (2) when he es bioma ke is posi i e o IS, heo e i-
cally, PA could be applied in he ambulance i he pa ien
mee s he c i e ia o h ombolysis. Subsequen ly, he pa ien
would be ans e ed o he hospi al o con inue wi h s and-
a d ca e; (3) p obabili ies o heal h-s a e ansi ion we e
he same o bo h g oups; (4) a e he i s yea o s oke,
pa ien s emained in he same mRS unless hey had a ecu -
en s oke o died; (5) in case o ecu ence, he same ype
o s oke was assigned; and (6) a conse a i e isk op ion o
annual ecu ence was adop ed and we assumed ha ecu -
en s oke a es we e equal ac oss all ca ego ies o mRS, in
acco dance wi h p e ious s udies [24, 25].
Table1 shows he model pa ame e s and dis ibu ions.
Use o  esou ces andcos s
In line wi h he s udy pe spec i e, di ec heal h cos s we e
included using a mic o-cos ing s a egy. Fi e aspec s we e
conside ed o cos es ima ions: (1) Compa ison o he
al e na i es. The bioma ke es was he di e en ia ing
cos . All o he esou ces we e conside ed o be he same,
excep o he p opo ion o esou ces used; (2) Type: IS
o ICH; (3) Func ional s a us acco ding o mRS; (4) Cos -
alloca ion ime: acu e phase, discha ge a e h ee mon hs,
h ee mon hs du ing he i s yea and i s yea , long- e m;
and (5) Des ina ion a discha ge, o alloca e co esponding
cos s o ins i u ionalized pa ien s.
Clinical and economic e alua ion s udies on s oke
we e used as a basis o esou ce use acco ding o he i e
a o emen ioned aspec s. An elec onic su ey was used o
de e mine he use o clinical esou ces in di e en Span-
ish hospi als. Twen y-eigh neu ologis s om eigh egions
pa icipa ed, o whom 13 answe ed all he ques ions.
Finally, ou s oke neu ologis s alida ed he in o ma ion
on esou ce use.
Acu e phase cos s we e as ollows: neu oimaging, labo a-
o y es s, leng h-o -s ay including inpa ien ca e, pha ma-
cological ea men ( PA and o he d ugs acco ding o s oke
ype), and ehabili a ion (physio he apy, speech he apy
and occupa ional he apy, he p opo ion o pa ien s, and
he numbe o sessions). We included he cos o ea men
o symp oma ic hemo hagic ans o ma ion as an ad e se
e en om PA adminis a ion (2% o pa ien s, acco ding o
da a om Ca alonia’s Da abase-CICAT).
Cos s included om discha ge o 90days and om
90days o one yea we e: ollow-up ou pa ien isi s wi h
he neu ologis and/o p ima y ca e physician, ehabili-
a ion, addi ional o hopedic esou ces co e ed by he
heal h sys em (wheelchai , walke , o cane), ollow-up
624 E.Pa ody-Rua e al.
1 3
neu oimaging, and labo a o y es s. Fo cos s om one
yea onwa d, we conside ed he cos o s oke ecu ence
and ollow-up ou pa ien isi s whe e necessa y, acco ding
o su ey esul s and alida ion by s oke physicians/clini-
cal expe s. I was assumed ha pa ien s a e p esc ibed an
annual blood es .
Leng h-o -s ay cos s we e included o pa ien s whose
des ina ion a discha ge was a con alescen acili y o
long- e m s ay. Pa ien s in a long- e m ca e acili y one
yea a e he s oke we e assumed o emain he e o he
es o hei li es.
To al cos was calcula ed by mul iplying he p opo -
ion o esou ces used by hei uni cos and by he uni s
equi ed o each esou ce. Public heal h se ice a i s
a e published in Regional Go e nmen O icial Bulle ins,
upda ed o 2022 using he speci ic egional heal hca e con-
sume p ice index. D ug cos s we e ob ained om Boo -
Plus 2022. Cos s we e exp essed in eu os (2022). Table2
shows he cos s pe heal h s a e.
De e minis ic andp obabilis ic sensi i i y analysis
We conduc ed an analysis o de e mine he inc emen al cos -
e ec i eness a io (ICER).
ICER is exp essed ma hema ically in he ollowing
exp ession:
In his s udy, B is he in e en ion and A he compa a o .
De e minis ic one-way sensi i i y analyses we e pe -
o med o iden i y a iables signi ican ly in luencing model
ou comes: (1) es sensi i i y and speci ici y, (2) using a
h ee-bioma ke panel which includes glial ib illa y acid
p o ein, (3) es cos , and (4) changing h ombolysis ea -
men ( PA o enec eplase—TNK). This en ailed modi ica-
ions in mRS p obabili ies and cos s in he economic model.
TNK is non-in e io o PA as a ea men o s oke pa ien s
ICER
=
Inc emen alcos
Inc emen alQALYs
=
Cos
B−
Cos
A
QALY
B
−QALY
A
.
Fig. 1 Model S uc u e. A Sho - e m decision analy ic ee s uc u e
o clinical ial ou comes. Ou comes we e: non-disabled pa ien , only
equi ing seconda y p e en ion s a egies (modi ied Rankin scale
[mRS 0–1]), disabled pa ien s also equi ing ehabili a ion (mRS
2–3), se e ely disabled pa ien s, equi ing long- e m nu sing ca e
(mRS 4–5) and dea h (mRS 6) om s oke onse o 90days. Pa ien s
en e he model wi h suspec ed s oke wi h < 4.5 h om symp om
onse and wi h a Na ional Ins i u es o Heal h S oke Scale sco e
be ween 4 and 22 (mode a e o se e e s oke). B Long- e m Ma ko
model used o simula e li e ime pa ien ou comes. Pa ien s ansi ion
be ween he di e en heal h s a es as indica ed by he a ows
625
Modeling hepo en ial e iciency o ablood bioma ke ‑based ool oguide p e‑hospi al…
1 3
Table 1 Model inpu pa ame e s wi h base-case alues and dis ibu ion p obabili ies used in he sensi i i y analysis
Pa ame e Base-case
alue
Type o dis i-
bu ion
Pa ame e 1 o dis ibu ionaPa ame e 2 o dis ibu ionbSou ce(s)
S anda d
ca e p ob-
abili ies IS a
3mon hs
mRS 0–1 0.42 β 194 269 [7]
mRS 2–3 0.21 β 97 366
mRS 4–5 0.19 β 88 375
mRS 6 0.18 β 83 380
Bioma ke es
al e na i e
p ob-
abili ies IS a
3mon hs
mRS 0–1 0.50 β 220 218 [15]
mRS 2–3 0.25 β 110 328
mRS 4–5 0.14 β 61 377
mRS 6 0.11 β 48 390
Bo h al e na-
i es p ob-
abili ies ICH
a 3mon hs
mRS 0–1 0.10 β 9 84 [23]
mRS 2–3 0.34 β 32 61
mRS 4–5 0.33 β 31 62
mRS 6 0.23 β 21 72
Annual p ob-
abili y o
ecu en
s oke
0.05 β 5 95 [32]
P obabili ies o ansi ion in he
i s yea
P obabili y
om mRS
0–1 o:
mRS 0–1 0.70 β 66 28 [33]
mRS 2–3 0.07 β 7 87
mRS 4–5 0.09 β 8 86
mRS 6 0.14 β 13 81
P obabili y
om mRS
2–3 o:
mRS 2–3 0.33 β 24 48 [33]
mRS 4–5 0.13 β 9 63
mRS 6 0.14 β 10 62
mRS 0–1 0.40 β 29 43
P obabili y
om mRS
4–5 o:
mRS 4–5 0.55 β 31 25 [33]
mRS 6 0.30 β 17 39
mRS 0–1 0.02 β 1 55
mRS 2–3 0.13 β 7 49
U ili ies

626 E.Pa ody-Rua e al.
1 3
[35] wi h simila sa e y p o iles [38]. We used mRS p ob-
abili ies wi h TNK om a me a-analysis [37] compa ed wi h
s anda d ca e. Fo he bioma ke es s a egy, we es ima ed
he p obabili ies om Kunz e al. [15].
A p obabilis ic sensi i i y analysis (PAS) wi h second-
o de Mon e Ca lo simula ion wi h 1000 i e a ions was pe -
o med. A willingness- o-pay h eshold o 24,000€/QALY
was conside ed consis en wi h na ional ecommenda ions
[39]. The e iciency h eshold in he PAS has been changed,
using alues o 22, 25, 30, and 60 housand €/QALY [39,
40].
Resul s
Table3 shows he de e minis ic cos -e ec i eness analysis
and one-way sensi i i y analysis. The blood es bioma ke
used o guide p e-hospi al PA adminis a ion compa ed wi h
s anda d ca e was associa ed wi h mo e QALYs (4.87 s.
4.77), mo e LYGs (7.18 s. 7.07), and g ea e cos s (12,807€
s. 12,713€). The ICER was 881€/QALY in he base-case
scena io.
The uni a ia e sensi i i y analysis e ealed ha when
es sensi i i y inc eased (e.g., o 30%), QALY and LYG
Table 1 (con inued)
Pa ame e Base-case
alue
Type o dis i-
bu ion
Pa ame e 1 o dis ibu ionaPa ame e 2 o dis ibu ionbSou ce(s)
mRS 0–1 0.84 β 85 15 [25]
mRS 2–3 0.72cβ 73 27 [24]
mRS 4–5 0.45cβ 41 58 [24]
Cos sd
mRS 0–1 IS 8,101. 51 γ 81,015.10 0.1 Regional Go e n-
men O icial
Bulle ins;
Ca alonia hos-
pi al; Andalucia
hospi al; Bo Plus
2019; [34]; [35]
mRS 2–3 IS 11,099.88 γ 110,991.80 0.1
mRS 4–5 IS 16,257.44 γ 162,574.40 0.1
mRS 6 ISe6,787.84 γ 67,878.40 0.1
mRS 0–1 ICH 7,992.68 γ 79,926.80 0.1 Regional Go e n-
men O icial
Bulle ins,
Ca alonia hos-
pi al; Andalucia
hospi al; Bo Plus
2019; [35]; [36]
mRS 2–3 ICH 14,048.47 γ 140,484.70 0.1
mRS 4–5 ICH 16,758.86 γ 167,588.60 0.1
mRS 6 ICHe10,172.30 γ 101,723.00 0.1
Bioma ke
blood es
101.04 γ 1,010.40 0.1 BIOFAST
IS ischemic s oke, ICH in ace eb al hemo hagic
a Pa ame e 1 is: alpha (be a and gamma dis ibu ion), lowe alue (uni o m dis ibu ion)
b Pa ame e 2 is: be a (be a and gamma dis ibu ion), uppe alue (uni o m dis ibu ion)
c U ili y by ime ade-o (TTO) me hod
d Eu os 2022
e Only hospi aliza ion cos s
Table 2 Cos s o ea men (in 2022 eu os) pe s oke sub ype and
modi ied Rankin scale (mRS)
mRS/ esou ce Ischemic s oke In ace eb al
hemo hagic
mRS 0–1
Acu e phase 6651.39 6410.48
Discha ge o 90days 759.88 821.94
90days o one yea 495.78 558.78
A e one yea 194.46 201.48
S oke ecu ence 4500.60 5739.49
mRS 2–3
Acu e phase 8019.64 10,438.20
Discha ge o 90days 2139.85 2637.23
90days o one yea 694.88 715.20
A e one yea 244.81 257.84
S oke ecu ence 6053.03 9824.67
mRS 4–5
Acu e phase 10,067.72 10,589.38
Discha ge o 90days 4433.52 4624.48
90days o one yea 941.03 1090.78
A e one yea 444.69 454.22
S oke ecu ence 8168.39 9925.05
627
Modeling hepo en ial e iciency o ablood bioma ke ‑based ool oguide p e‑hospi al…
1 3
also inc eased. The es was cos -e ec i e in all scena ios,
excep when es sensi i i y was 56.5% and es speci ici y
was 68%. In his case, he bioma ke es had an ICER o
33,045€/QALYs and was a domina ed s a egy (mo e cos ly
and ewe LYGs compa ed wi h s anda d ca e). Using h ee
bioma ke s (52% sensi i i y and 100% speci ici y), he ICER
was 820€/QALYs.
Figu e2 ep esen s he cos -e ec i eness accep abili y
cu e. The es bioma ke p esen ed a g ea e p obabili y o
being cos -e ec i e o willingness- o-pay h esholds highe
han 10,000€/QALY. Fo a willingness- o-pay o 24,000€/
QALY, he es bioma ke p esen ed an 82.5% p obabili y o
being cos -e ec i e.
We an se e al models applying di e en blood es sen-
si i i y and speci ici y. The highe he sensi i i y o he es ,
he lowe he ICER (Fig.1S Supplemen al Ma e ial) and
QALYs anged om 0.06 o 0.52 wi h es sensi i i ies o
10% and 99%, espec i ely (Fig.2S Supplemen al Ma e-
ial). When he cos o he es was changed using di e en
sensi i i y and speci ici y alues (acco ding o Bus aman e’s
s udy [19] and hypo he ical alues), he es was cos -e ec-
i e when i s uni p ice was 10,000€ and had a sensi i i y o
99% and speci ici y o 100%. As he sensi i i y dec eases,
he ICER is no longe cos -e ec i e despi e lowe ing he
cos o he es ; o ins ance, a es wi h a sensi i i y o 10%
ha cos s 2000€ would no longe be e ec i e (Table4).
Table2S (Supplemen al Ma e ial) shows he maximum
indi idual cos o he es o make i a cos -e ec i e al e na-
i e; i is obse ed ha his cos a ies om 874 o 13,986€,
alues ha depend on he diagnos ic alidi y used.
The inc emen al cos -e ec i eness plane is p o ided
in Supplemen a y Ma e ials (Fig.3S). The Mon e Ca lo
simula ion shows ha mos o he simula ions a e wi hin
he con idence ellipse, showing ha he esul s a e qui e
obus o changes in he alues o he di e en a iables
simul aneously.
The bioma ke es was cos -e ec i e in 82.4%, 82.5%,
82.8%, and 83.1% o in e ac ions when he willingness- o-
pay h eshold was changed by 22,000, 25,000, 30,000, and
60,000 €/QALY, espec i ely.
Table 3 Cos -e ec i eness analyses o he bioma ke es o guide p e-hospi al PA: base-case scena io and sensi i i y analyses
S sensi i i y, E speci ici y, QALY quali y adjus ed-li e yea , ICER inc emen al cos -e ec i eness a io, LYG li e-yea gained
a P e alence o ischemic s oke was 81.9% and o hemo hagic s oke was 18.1%. Speci ici y = 100%
b P e alence o ischemic s oke was 49.3% and o hemo hagic s oke was 50.7%
Al e na i es Cos s (€) Inc emen al Cos QALY Inc emen al
QALY
ICER (€/QALY) LYG Inc emen al LYG ICER
(€/LYG)
Base-case scena io (S = 20%)a
S anda d ca e 12,713 4.77 7.07
Bioma ke es 12,807 94 4.87 0.11 881 7.18 0.11 822
Tes sensi i i y = 30% a
S anda d ca e 12,713 4.77 7.07
Bioma ke es 12,818 105 4.92 0.16 662 7.24 0.17 618
Tes Sensi i i y = 10% a (hypo he ical wo s scene y)
S anda d ca e 12,713 4.77 7.07
Bioma ke es 12,794 81 4.83 0.06 1369 7.13 0.06 1286
Tes sensi i i y = 60% a (hypo he ical bes scene y)
S anda d ca e 12,713 4.77 7.07
Bioma ke es 12,862 139 5.09 0.32 433 7.41 0.34 404
Tes sensi i i y = 56.5% and Speci ici y = 68%b
S anda d ca e 12,713 4.77 7.07
Bioma ke es 14,692 1979 4.83 0.06 33,045 6.99 -0.07 Domina ed
Using h ee bioma ke s (Sensi i i y = 52%; Speci ici y = 100%)
S anda d ca e 13,611 4.45 6.86
Bioma ke es 13,742 130 4.61 0.16 820 7.04 0.17 760
Doubling he cos o he es (200€)a
S anda d ca e 12,713 4.77 7.07
Bioma ke es 12,893 180 4.87 0.11 1576 7.18 0.11 1689
Changing al eplase o enec eplase (TNK)a
S anda d ca e 13,089 5.66 7.99
Bioma ke es 13,156 67 5.73 0.07 956 8.05 0.07 1027
628 E.Pa ody-Rua e al.
1 3
Discussion
Ou s udy shows ha using a p e-hospi al blood es o guide
PA may be a cos -e ec i e s a egy in a hypo he ical coho
o pa ien s wi h suspec ed mode a e o se e e s oke (NIHSS
4-22) wi hin 4.5h a e symp om onse om he Spanish
Heal h Sys em pe spec i e.
This is among he i s economic e alua ions o bio-
ma ke es s o guiding PA in he ambulance in pa ien s
wi h IS. Howe e , p e ious s udies showed he e iciency
o p e-hospi al ea men o acu e s oke. An economic
model s udy ound ha he MSUs s a egy could be cos -
e ec i e in di e en scena ios, al hough e iciency was
ela ed o popula ion densi y [41]. The MSUs s a egy led o
a highe equency o h ombolysis and a highe p opo ion
o pa ien s in he ea ly ime in e al (wi hin 90min: 48.1%
s. 37.4%; 91–180min: 37.4% s. 50%; 181–270min: 14.5%
s. 12.8%), which esul ed in 32,456€/QALY [42].
In he MSUs s a egy, he ambulance was equipped wi h
a scanne , a poin -o -ca e labo a o y, and elemedicine
capabili ies, making he cos p ohibi i e o ou ine clinical
implemen a ion in many coun ies [42]. In ou economic
model, he ambulance cos is he same as in usual ca e, and
he bioma ke cos (a ound 100€/uni ) is easily a o dable.
Adminis a ion o PA in ambulances is a usual p ac ice in
he d ip-and-ship model [43], wi h he excep ion ha PA is
ini ia ed a p ima y s oke cen e s, while he 1-h in a enous
in usion is con inued a he ambulance. The e o e, pa a-
medics a e amilia wi h PA in usion and able o ecognize
PA- ela ed complica ions, such as bleedings o angioedema.
Howe e , PA ini ia ion a con en ional ambulances migh
equi e an ex a in e sion in educa ional aspec s. This educa-
ion would also imp o e one o he g ea e ba ie s o ea ly
ea men s, which is s oke symp oms’ ecogni ion. In he
sensi i i y analysis, when he es uni p ice was doubled, i
was s ill an e icien al e na i e.
In he base-case and all one-way sensi i i y analyses in
his s udy, QALYs we e highe o he bioma ke s a egy s.
s anda d ca e, mainly due o sho ening o PA adminis a-
ion ime, esul ing in mo e pa ien s wi h a a o able mRS
[16]. Acco dingly, a s udy showed ha in acu e IS pa ien s
who we e ea ed wi h PA, sho e doo - o-needle imes
(wi hin 45min) we e associa ed wi h lowe all-cause mo -
ali y and lowe all-cause eadmission a 1yea [44].
The economic model used p elimina y sensi i i y (20%)
and speci ici y (100%) esul s om he bioma ke s udy [20].
When he sensi i i y is low, pa ien s who a e no diagnosed
in he ambulance a e no comp omised, as hey ollow he
same cu en s oke pa hways and would be ans e ed o a
hospi al whe e s oke diagnosis is made by neu oimaging.
The es (which akes abou 15min) needs no addi ional ime
as i is pe o med du ing he ans e . On he o he hand,
when speci ici y alues we e dec eased, he numbe o alse
posi i es inc eases; in hese cases, pa ien s wi h IH a e
Fig. 2 Cos -e ec i eness accep abili y cu e
629
Modeling hepo en ial e iciency o ablood bioma ke ‑based ool oguide p e‑hospi al…
1 3
ea ed wi h PA wi h he isk o wo sening. Lowe speci ic-
i y alues we e included in he model in sensi i i y analysis.
I is impo an o no e ha in addi ion o clinical en o cemen
and economic impac , e hical dilemmas would a ise. Rega d-
ing he sensi i i y analysis wi h he h ee-bioma ke panel,
esul s should be ca e ully in e p e ed, as his subs udy was
Table 4 Inc emen al cos -e ec i eness a io (ICER) acco ding o cos , sensi i i y, and speci ici y o he bioma ke es
Tes cos (eu os)
50 100 200 500 1000 2000 3000 4000 5000 6000 7000 8000 9000 10,000
Speci ici y 100% ICER
Sensi i i y 99% 254 339 510 1021 1873 3577 5281 6985 8689 10,392 12,096 13,800 15,504 17,208
Sensi i i y 60% 294 431 703 1521 2884 5610 8335 11,061 13,787 16,513 19,238 21,964 24,690
Sensi i i y 50% 301 464 789 1766 3394 6650 9905 13,161 16,417 19,673 22,928 26,184
Sensi i i y 40% 324 525 926 2131 4139 8154 12,170 16,185 20,201 24,216
Sensi i i y 30% 385 665 1195 2814 5512 10,910 16,307 21,705 27,102
Sensi i i y 20% 472 870 1666 4055 8036 15,998 23,960 31,923
Sensi i i y 10% 636 1349 2775 7055 14,188 28,454
Speci ici y 97% ICER
Sensi i i y 99% 569 685 916 1608 2763 5072 7381 9690 11,999 14,308 16,617 18,926 21,235 23,544
Sensi i i y 60% 792 981 1359 2494 4384 8166 11,948 15,729 19,511 23,293 27,074
Sensi i i y 50% 951 1183 1646 3035 5351 9982 14,613 19,244 23,875 60,582
Sensi i i y 40% 1103 1390 1963 3684 6550 12,284 18,018 23,751 5849,2
Tes cos (eu os)
50 100 200 500 1000 2000 3000 4000 5000 6000 7000 8000 900010,000
Sensi i i y 30% 1460 1858 2655 5044 9027 16,993 24,958
Sensi i i y 20% 2207 2839 4104 789914,222 26,870
Sensi i i y 10% 5158 6715 9828 19,169 34,737
Speci ici y 94%
Sensi i i y 99% 907 1055 1351 2239 3720 66819642 12,602 15,563 18,52421,485 24,446
Sensi i i y 60% 1465 1722 2236 3776 6344 11,480 16,615 21,751 7886,2
Sensi i i y 50% 1713 2025 2650 4525 7651 13,901 20,152 3046,2
Sensi i i y 40% 2166 2572 3382 5812 986217,963 26,064
Sensi i i y 30% 3094 3689 4877 8442 14,384 26,267
Sensi i i y 20% 5735 6844 9061 15,714 26,801
Sensi i i y 10% 31,190
Speci ici y 68% ICER
Sensi i i y 56.5% 29,740
Values in ed a e no cos -e ec i e
ICER: inc emen al cos -e ec i eness a io