Respi a o y Medicine 178 (2021) 106220
A ailable online 12 No embe 2020
0954-6111/© 2020 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
O iginal Resea ch
Riocigua ea men in pa ien s wi h ch onic h omboembolic pulmona y
hype ension: Final sa e y da a om he EXPERT egis y
Hossein-A deschi Gho ani
a
,
b
,
*
, Miguel-Angel Gomez Sanchez
c
,
d
, Ma c Humbe
e
,
Da id Pi ow
, G´
e ald Simonneau
g
, Henning Gall
a
,
b
, Ekkeha d G ünig
h
, Hans Klose
i
,
Michael Halank
j
, Da id Langleben
k
, Repke J. Snijde
l
, Pila Esc ibano Subias
m
,
n
,
Lisa M. Mielniczuk
o
, Tobias J. Lange
p
, Jean-Luc Vachi´
e y
q
, Hube Wi z
,
Douglas S. Helme sen
s
, I aklis Tsanga is
, Joan A. Ba be ´
a
u
,
, Joanna Pepke-Zaba
w
,
Anco Boons a
x
, S ephan Rosenk anz
y
, Sil ia Ul ich
z
, Regina S e inge -Masche baue
aa
,
Ma ion Delc oix
ab
, Pa el Jansa
ac
, I e a ˇ
Simko ´
a
ad
, Geo ge Giannakoulas
ae
, Jens Klo sche
a
,
E genia Williams
ag
, Ch is ian Meie
ag
, Ma ius M. Hoepe
ah
, NEW COLLABORATORS LIST
a
Uni e si y o Giessen and Ma bu g Lung Cen e (UGMLC), Giessen, Ge many
b
Membe o he Ge man Cen e o Lung Resea ch (DZL), Giessen, Ge many
c
Respi a o y Depa men , Ram´
on y Cajal Uni e si y Hospi al (IRYCIS), Mad id, Spain
d
Biomedical Resea ch Ne wo king Cen e on Respi a o y Diseases (CIBERES), Spain
e
Uni e si ´
e Pa is-Saclay, Inse m U999, Se ice de Pneumologie e Soins In ensi s Respi a oi es, Hˆ
opi al Bicˆ
e e, Le K emlin-Bicˆ
e e, F ance
Ins i u e o Clinical Pha macology, Technical Uni e si y, D esden, Ge many
g
Uni e si ´
e Pa is-Sud, Le K emlin-Bicˆ
e e, Se ice de Pneumologie, Cen e de R´
e ´
e ence de l’Hype ension Pulmonai e S´
e `
e e, DHU Tho ax Inno a ion, Hˆ
opi al Bicˆ
e e,
Le K emlin-Bicˆ
e e, Pa is, F ance
h
Cen e o Pulmona y Hype ension, Tho axclinic a Heidelbe g Uni e si y Hospi al, Heidelbe g, Ge many
i
Depa men o Pneumology, Uni e si y Medical Cen e Hambu g-Eppendo , Hambu g, Ge many
j
Medical Clinic I, Depa men o Pneumology, Uni e si y Hospi al Ca l Gus a Ca us, D esden, Ge many
k
Cen e o Pulmona y Vascula Disease, Jewish Gene al Hospi al, McGill Uni e si y, Mon eal, Quebec, Canada
l
Depa men o Pulmonology, S An onius Ziekenhuis, Nieuwegein, he Ne he lands
m
Depa men o Ca diology, Hospi al 12 de Oc ub e, Mad id, Spain
n
CIBER-CV (CIBER o Ca dio ascula Disease), Hospi al 12 de Oc ub e, Mad id, Spain
o
Di ision o Ca diology, Depa men o Medicine, Uni e si y o O awa Hea Ins i u e, O awa, On a io, Canada
p
Depa men o In e nal Medicine II, Di ision o Pneumology, Uni e si y Medical Cen e , Regensbu g, Ge many
q
D´
epa emen de Ca diologie, Cliniques Uni e si ai es de B uxelles, Hˆ
opi al E asme, B ussels, Belgium
Depa men o Respi a o y Medicine, Uni e si y o Leipzig, Leipzig, Ge many
s
Albe a Heal h Se ices, Uni e si y o Calga y, Calga y, Albe a, Canada
Second Depa men o C i ical Ca e, Uni e si y Hospi al A ikon, Na ional and Kapodis ian Uni e si y o A hens, A hens, G eece
u
Hospi al Clínic-IDIBAPS, Uni e si y o Ba celona, Ba celona, Spain
Biomedical Resea ch Ne wo king Cen e on Respi a o y Diseases (CIBERES), Mad id, Spain
w
Pulmona y Vascula Disease Uni , Royal Papwo h Hospi al, Camb idge, UK
x
VU Medisch Cen um, Ams e dam, he Ne he lands
y
Depa men III o In e nal Medicine and Cologne Ca dio ascula Resea ch Cen e (CCRC), Cologne Uni e si y Hea Cen e , Cologne, Ge many
z
Clinic o Pulmonology, Uni e si y Hospi al Zu ich, Zu ich, Swi ze land
aa
Se ices elle ü klinische S udien, K ankenhaus de Elisabe hinen Linz GmbH, Linz, Aus ia
ab
Depa men o Respi a o y Diseases, Uni e si y Hospi als o Leu en, and Respi a o y Di ision, Depa men CHROMETA, KU Leu en – Uni e si y o Leu en, Leu en,
Belgium
ac
2
nd
Depa men o Medicine, Depa men o Ca dio ascula Medicine, Cha les Uni e si y in P ague, P ague, Czech Republic
ad
Depa men o Ca diology and Angiology, Facul y o Medicine, Slo ak Medical Uni e si y & Na ional Ins i u e o Ca dio ascula Diseases, B a isla a, Slo ak Republic
ae
Depa men o Ca diology I, A is o le Uni e si y o Thessaloniki, Thessaloniki, G eece
a
Ge man Rheuma ism Resea ch Cen e Be lin, Leibniz Ins i u e, Be lin, Ge many
ag
Baye AG, Global De elopmen , Global Medical A ai s, Be lin, Ge many
ah
Depa men o Respi a o y Medicine and he Ge man Cen e o Lung Resea ch, Hanno e Medical School, Hanno e , Ge many
* Co esponding au ho . Uni e si y o Giessen and Ma bu g Lung Cen e (UGMLC), Giessen, 35392, Ge many.
E-mail add ess: [email p o ec ed] (H.-A. Gho ani).
Con en s lis s a ailable a ScienceDi ec
Respi a o y Medicine
jou nal homepage: h p://www.else ie .com/loca e/ med
h ps://doi.o g/10.1016/j. med.2020.106220
Recei ed 17 May 2020; Recei ed in e ised o m 5 No embe 2020; Accep ed 6 No embe 2020
Respi a o y Medicine 178 (2021) 106220
2
ARTICLE INFO
Keywo ds:
Ch onic h omboembolic pulmona y
hype ension
Riocigua
Regis y
Real-wo ld
Clinical p ac ice
Sa e y
ABSTRACT
Objec i e: The soluble guanyla e cyclase s imula o iocigua is app o ed o he ea men o adul pa ien s wi h
pulmona y a e ial hype ension (PAH) and inope able o pe sis en / ecu en ch onic h omboembolic pul-
mona y hype ension (CTEPH) ollowing Phase 3 andomized ials. The EXPosu E Regis y RiociguaT in pa ien s
wi h pulmona y hype ension (EXPERT) s udy was designed o moni o he long- e m sa e y o iocigua in
clinical p ac ice.
Me hods: EXPERT was an in e na ional, mul icen e , p ospec i e, uncon olled, non-in e en ional coho s udy
o pa ien s ea ed wi h iocigua . Pa ien s we e ollowed o a leas 1 yea and up o 4 yea s om en ollmen o
un il 30 days a e s opping iocigua ea men . P ima y sa e y ou comes we e ad e se e en s (AEs) and se ious
ad e se e en s (SAEs) coded using Medical Dic iona y o Regula o y Ac i i ies p e e ed e ms and Sys em
O gan Classes e sion 21.0, collec ed du ing ou ine clinic isi s and colla ed ia case epo o ms.
Resul s: In o al, 956 pa ien s wi h CTEPH we e included in he analysis. The mos common AEs in hese pa ien s
we e pe iphe al edema/edema (11.7%), dizziness (7.5%), igh en icula (RV)/ca diac ailu e (7.7%), and
pneumonia (5.0%). The mos common SAEs we e RV/ca diac ailu e (7.4%), pneumonia (4.1%), dyspnea
(3.6%), and syncope (2.5%). Exposu e-adjus ed a es o hemop ysis/pulmona y hemo hage and hypo ension
we e low and compa able o hose in he long- e m ex ension s udy o iocigua (Ch onic Th omboembolic
Pulmona y Hype ension Soluble Guanyla e Cyclase–S imula o T ial [CHEST-2]).
Conclusion: Da a om EXPERT show ha in pa ien s wi h CTEPH, he sa e y o iocigua in ou ine p ac ice was
consis en wi h he known sa e y p o ile o he d ug, and no new sa e y conce ns we e iden i ied.
1. In oduc ion
Ch onic h omboembolic pulmona y hype ension (CTEPH) is a po en-
ially a al condi ion cha ac e ized by obs uc ion o he pulmona y ascu-
la u e by esidual o ganized h ombi esul ing in inc eased pulmona y
ascula esis ance (PVR), p og essi e ascula emodeling and pulmona y
hype ension (PH), and subsequen ly igh en icula (RV) ailu e [1–5].
The ea men o choice in CTEPH is pulmona y enda e ec omy (PEA),
which po en ially no malizes hemodynamics [5–8]. Up o 40% o pa ien s
a e inope able, howe e , and up o 51% exhibi pe sis en o ecu en
CTEPH a e PEA [6–14].
Riocigua is a i s -in-class soluble guanyla e cyclase s imula o ecom-
mended in Eu opean Respi a o y Socie y/Eu opean Socie y o Ca diology
guidelines o he ea men o pa ien s wi h inope able CTEPH o pe sis-
en / ecu en CTEPH a e su ge y [1]. I s e icacy and ole abili y ha e
been demons a ed in clinical ials [15,16]. Agen s ha ha e been app o ed
o pulmona y a e ial hype ension (PAH) include p os acyclin analogs,
endo helin ecep o an agonis s (ERAs), and phosphodies e ase ype 5 in-
hibi o s (PDE5i). Wi h he excep ion o ep os inil in selec ed pa ien s, hese
a e no licensed o use in he ea men o pa ien s wi h CTEPH, bu can be
adminis e ed o -label. Balloon pulmona y angioplas y (BPA) is a po en ially
e ec i e op ion o selec ed inope able pa ien s [1,17].
EXPosu E Regis y RiociguaT in pa ien s wi h PH (EXPERT) was a
p ospec i e, non-in e en ional egis y o moni o he long- e m sa e y
o iocigua in clinical p ac ice.
2. Me hods
2.1. S udy design
EXPERT (NCT02092818) was an in e na ional, mul icen e , p ospec-
i e, uncon olled, non-in e en ional coho s udy in pa ien s ea ed wi h
iocigua in 28 coun ies. The design is desc ibed in de ail elsewhe e [18].
EXPERT was linked wi h he Compa a i e, P ospec i e Regis y o Newly
Ini ia ed The apies o Pulmona y Hype ension (COMPERA [h ps://com
pe a.o g/]), one o he la ges global academic PH egis ies. This was
consis en wi h guidance om egula o y au ho i ies o use exis ing egis-
ies. EXPERT was conduc ed in acco dance wi h good pha maco igilance
p ac ices and was no eques ed, bu was accep ed, by he Eu opean Medi-
cines Agency o he collec ion o addi ional long- e m pos -app o al da a on
iocigua .
Pa ien s we e ollowed o 1–4 yea s om en ollmen (including pos -
ea men sa e y ollow-up) du ing a ec ui men pe iod o 3 yea s o un il
30 days a e s opping iocigua ea men . Da a—including pa ien
demog aphics, disease cha ac e is ics, iocigua dosing, hemodynamic pa-
ame e s, changes in ea men , bioma ke s, labo a o y a iables, ad e se
e en s (AEs) and se ious ad e se e en s (SAEs)—we e collec ed a baseline
and du ing ou ine clinical ollow-up isi s app oxima ely e e y
3–6 mon hs. Da a we e collec ed using a case epo o m (CRF) based on he
COMPERA CRF, ex ended o ob ain iocigua sa e y da a.
2.2. Pa ien s
Pa ien s who s a ed ea men o we e al eady being ea ed wi h io-
cigua we e eligible o inclusion. Pa ien s wi h disease du a ion ≥6 mon hs
we e de ined as p e alen , and hose diagnosed wi hin <6 mon hs o
en ollmen we e de ined as inciden . Pa ien s we e de ined as iocigua -
p e ea ed i hey had been ecei ing iocigua o ≥3 mon hs be o e eg-
is y en y and as iocigua -newly ea ed i hey had been ecei ing iocigua
o <3 mon hs be o e en y. Riocigua -newly ea ed pa ien s we e he e o e
no necessa ily inciden pa ien s and could ha e ecei ed PAH-app o ed
he apy be o e iocigua . Newly ea ed pa ien s we e u he ca ego ized
as swi ched o non-swi ched. Swi ched pa ien s we e newly ea ed pa ien s
who had s opped p io he apy ≤10 days be o e commencing iocigua .
2.3. Sa e y assessmen s
The p ima y sa e y ou comes we e AEs and SAEs, coded using Medical
Dic iona y o Regula o y Ac i i ies (MedDRA) p e e ed e ms and Sys-
em O gan Classes e sion 21.0. Seconda y sa e y ou comes included AEs
and SAEs o special in e es (hypo ension and hemop ysis/pulmona y
hemo hage). This epo ocuses on AEs and SAEs occu ing du ing he
ea men phase (onse da e ≤2 days a e he mos ecen dose o ioci-
gua ). An AE was conside ed se ious i i : esul ed in dea h, was li e-
h ea ening, equi ed inpa ien hospi aliza ion o p olonga ion o hos-
pi aliza ion (wi h speci ic excep ions, de ined in he p o ocol), esul ed in
pe sis en o signi ican disabili y o incapaci y, was a congeni al ab-
no mali y o bi h de ec , o was medically impo an . AEs and SAEs we e
classi ied as d ug- ela ed acco ding o he in es iga o ’s judgmen .
Dea hs we e analyzed in e ms o all SAEs wi h a a al ou come wi h onse
du ing he ea men phase and he pos - ea men phase (onse da e
>2 days a e discon inua ion un il he end o 30-day sa e y ollow-up).
2.4. S a is ical me hods and popula ions analyzed
EXPERT was an obse a ional s udy. All a iables and ou comes,
including compa isons be ween p ede ined g oups (such as newly
ea ed e sus p e ea ed pa ien s and p e alen e sus inciden
H.-A. Gho ani e al.
Respi a o y Medicine 178 (2021) 106220
3
pa ien s) we e analyzed desc ip i ely. S a is ical analyses o hese
compa isons we e no pe o med because hey would be o limi ed alue
wi hou adjus men o di e ences be ween he g oups. All analyses
we e pe o med wi h SAS 9.3. Ca ego ical a iables we e analyzed using
equency ables and con inuous a iables by summa y s a is ics (mean
±s anda d de ia ion [SD], median, and minimum–maximum ange).
The e aluable popula ion consis ed o all en olled pa ien s who did no
wi hd aw consen and had ecei ed a leas one dose o iocigua wi h
dosing da a a ailable. Summa y s a is ics and changes om baseline
we e calcula ed o 6-min walking dis ance (6MWD), Wo ld Heal h
O ganiza ion unc ional class (WHO FC), Bo g Dyspnea Index, Eu oQoL
5-dimensional Visual Analog Sco e (EQ-5D VAS), hemodynamic pa-
ame e s, and bioma ke s. This pape desc ibes he esul s in pa ien s
wi h CTEPH. Resul s in pa ien s wi h PAH a e desc ibed sepa a ely [18].
3. Resul s
3.1. Pa ien disposi ion
The e aluable popula ion wi h CTEPH consis ed o 956 pa ien s o
whom 537 (56.2%) we e iocigua -p e ea ed and 419 (43.8%) we e
iocigua -newly ea ed. App oxima ely 86% o pa ien s o e all
comple ed he s udy (Fig. 1).
3.2. Demog aphics and baseline cha ac e is ics
The mean age o he pa ien s was 66.3 ±13.7 yea s; 570 pa ien s
(59.6%) we e women. CTEPH was p e alen in 713 pa ien s (74.6%),
inciden in 197 (20.6%), and unknown in 46 (4.8%). A baseline, iocigua
was adminis e ed in combina ion wi h o he PH-app o ed he apy in 198
pa ien s (20.7%): wi h ERAs in 170 (17.8% [bosen an, 7.0%; maci en an,
7.0%; and amb isen an, 3.8%]), p os anoids in 9 (0.9% [ilop os , 0.6%;
in a enous ep os inil, 0.2%; and in a enous epop os enol, 0.1%]),
and bo h an ERA and p os anoid in 19 (2.0%). No pa ien ecei ed
concomi an PDE5i. A Visi 6 (mon h 33−<39), 27.9% o pa ien s we e
ecei ing combina ion he apy. In o al, 901 pa ien s (94.2%) had a leas
one como bidi y. O he baseline demog aphics a e shown in Table 1. The
ope abili y s a us o he pa ien s is shown in Fig. 2.
3.3. Riocigua sa e y
3.3.1. To al CTEPH popula ion
In he o al popula ion wi h CTEPH, he median ( ange) du a ion o
obse a ion and iocigua ea men was 504.0 (0.0–1367.0) days and
493.5 (0.0–1367.0) days, espec i ely. In o al, 615 pa ien s (64.3%)
expe ienced AEs and 365 (38.2%) expe ienced SAEs. These e en s we e
conside ed d ug- ela ed by he in es iga o in 148 (15.5%) and 34 (3.6%)
pa ien s, espec i ely. The mos common AEs and SAEs a e shown in
Table 2. Discon inua ion due o AEs and SAEs occu ed in 55 pa ien s
(5.8%) and 38 pa ien s (4.0%), espec i ely. The mos common AEs o
SAEs leading o discon inua ion a e shown in Supplemen a y Table 2.
Sa e y da a o pa ien s acco ding o use o iocigua as mono he apy o in
combina ion wi h o he PAH-app o ed d ugs a e shown in Supplemen-
a y Table 3. Ra es o AEs and SAEs (68.2–88.9% and 44.1–66.7%,
espec i ely) we e nume ically highe wi h p os anoid-con aining egi-
mens (78.9–88.9% and 57.9–66.7%, espec i ely) han wi h iocigua
mono he apy o iocigua +ERA (62.8–68.2% and 36.0–44.1%, espec-
i ely), bu he numbe s o pa ien s ecei ing p os anoids we e small.
Hemo hages we e epo ed in 110 pa ien s (11.5%) and se ious
hemo hages in 57 pa ien s (6.0%). These e en s we e conside ed by he
in es iga o o be ela ed o iocigua in nine (0.9%) and ou pa ien s
(0.4%), espec i ely. Th ee pa ien s (0.3%) discon inued iocigua as a
esul o a hemo hage. The mos equen ly occu ing hemo hages
we e epis axis in 30 pa ien s (3.1%) and hemop ysis in 26 pa ien s
(2.7%). The mos common se ious hemo hages we e hemop ysis in 16
pa ien s (1.7%) and gas oin es inal hemo hage in i e pa ien s (0.5%).
O all pa ien s who expe ienced a hemo hage, 78 we e eco ded as
ecei ing a i amin K an agonis (VKA) and 24 as ecei ing non-VKA
o al an icoagulan s (NOACs). Hemop ysis and pulmona y hemo hage
we e conside ed AEs o special in e es and a e discussed u he below.
3.3.2. Sa e y in p e alen s. inciden pa ien s
A pos hoc analysis compa ed p e alen pa ien s (disease du a ion ≥6
mon hs) (n =713) wi h inciden pa ien s (diagnosed wi hin <6 mon hs o
en ollmen ) (n =197) acco ding o disease du a ion da a a ailable a
baseline. Disease cha ac e is ics, including 6MWD and WHO FC, indi-
ca ed a mo e se e e disease s a us in inciden pa ien s compa ed wi h
p e alen pa ien s (da a no shown). Median disease du a ion was 1.8
( ange, 0.0–6.0) mon hs in inciden pa ien s and 3.2 ( ange, 0.5–39.7)
yea s in p e alen pa ien s. AEs we e epo ed in 471 p e alen pa ien s
(66.1%) and 119 inciden pa ien s (60.4%), and SAEs in 276 (38.7%) and
73 (37.1%) p e alen and inciden pa ien s, espec i ely.
3.3.3. Compa ison be ween iocigua -p e ea ed and iocigua -newly
ea ed pa ien s
Compa ed wi h iocigua -p e ea ed pa ien s, iocigua -newly
ea ed pa ien s had a nume ically sho e disease du a ion, sho e
6MWD, a highe p opo ion o WHO FC III/IV disease, and a g ea e
p opo ion o inciden disease (Table 3). Mo e han 90% o pa ien s in
bo h g oups had a leas one como bidi y. App oxima ely 89% o
iocigua -p e ea ed pa ien s and 83% o iocigua -newly ea ed pa-
ien s comple ed he s udy (Fig. 3). O he iocigua -newly ea ed pa-
ien s, 72 (17.2%) had swi ched om p e ious PAH-app o ed he apy:
65 (15.5%) om PDE5i, 5 (1.2%) om a p os anoid, and 12 (2.9%) om
an ERA (some pa ien s swi ched om mo e han one p io he apy).
AEs we e epo ed in 270 iocigua -newly ea ed pa ien s (64.4%) and
345 iocigua -p e ea ed pa ien s (64.2%). SAEs we e epo ed in 166
iocigua -newly ea ed pa ien s (39.6%) and 199 iocigua -p e ea ed
Fig. 1. Pa ien disposi ion.
CTEPH, ch onic h omboembolic pulmona y hype ension. The numbe s and
pe cen ages e e o he o al CTEPH popula ion en olled (n =969). Cha
shows p ima y eason o no comple ing pe p o ocol.
a
O he easons o discon inua ion a e shown in Supplemen a y Table 1.
H.-A. Gho ani e al.
Respi a o y Medicine 178 (2021) 106220
4
pa ien s (37.1%). Nume ically mo e AEs and SAEs in iocigua -newly
ea ed pa ien s we e conside ed d ug- ela ed and led o d ug discon inua-
ion han in iocigua -p e ea ed pa ien s (Table 4). The ypes o AEs and
SAEs we e gene ally simila be ween he wo g oups. The mos common AEs
o SAEs leading o discon inua ion a e shown in Supplemen a y Table 4.
Sa e y esul s in swi ched pa ien s we e gene ally simila o hose in non-
swi ched pa ien s (da a no shown). In iocigua -p e ea ed and iocigua -
newly ea ed pa ien s, AEs and SAEs we e mo e equen wi h combina-
ion he apy han wi h mono he apy (Supplemen a y Table 5).
3.4. AEs and SAEs o special in e es
In gene al, AEs and SAEs o special in e es we e in equen
(Table 5). All o he 16 pa ien s wi h se ious hemop ysis/pulmona y
hemo hage o e all we e eco ded as ecei ing concomi an an icoag-
ulan s, h ee as ecei ing concomi an an ipla ele he apy, and one as
ecei ing a concomi an p os anoid. The incidence o hypo ension was
low ac oss all subg oups (Supplemen a y Table 6).
3.5. AEs associa ed wi h PEA o BPA
In o al, 47 pa ien s (4.9%) unde wen PEA (one ope a ion in 44 pa ien s
[4.6%] and wo ope a ions in h ee pa ien s [0.3%]). Wi hin 10 days a e
PEA, nine o hese pa ien s (19.1%) had an AE, six (12.8%) had an SAE, and
one (2.1%) had an AE- ela ed dea h. No episode o hemop ysis was epo ed
wi hin 10 days ollowing PEA. Also, 89 pa ien s (9.3%) unde wen BPA
(mean: 2.1 ±1.4 sessions; median: 2; ange: 1–8) du ing he s udy. Wi hin
10 days a e BPA, six o hese pa ien s (6.7%) had an AE and six (6.7%) had
Table 1
Baseline demog aphics and disease cha ac e is ics in he o al CTEPH popula ion (n =956).
Cha ac e is ic Mean ±SD o n (%) Cha ac e is ic Mean ±SD o n (%)
Age, yea s 66.3 ±13.7 Riocigua daily dose a ini ial s udy isi , mg
Age g oup, yea s Mean 6.9 ±1.4 (n =934)
<65 366 (38.3) Median ( ange) 7.5 (1.5−7.5) (n =934)
65 o <75 260 (27.2)
≥75 330 (34.5)
BMI, kg/m
2
28.6 ±15.2 Riocigua median daily dose a ini ial s udy isi , mg
BMI ca ego y, kg/m
2
≤2.5 13 (1.4)
<18.5 24 (2.5) >2.5 o 4.5 108 (11.3)
18.5 o <25 290 (30.3) >4.5 o 6 90 (9.4)
25 o <30 348 (36.4) >6 o 7.5 723 (75.6)
≥30 294 (30.8) Missing 22 (2.3)
Smoking s a us Concomi an CCB 22 (2.3)
Ne e 602 (63.0)
Fo me 314 (32.8) Concomi an an icoagula ion he apy
Cu en 40 (4.2) O al an icoagula ion 861 (90.1)
Age a ini ial PH diagnosis, yea s 62.7 ±14.5 Vi amin K an agonis 506 (52.9)
Median (IQR) disease du a ion, yea s 2.1 (0.7−4.9) Di ec o al an icoagulan 190 (19.9)
O he o al an icoagula ion
b
159 (16.6)
O he an icoagulan
b
66 (6.9)
Concomi an an ipla ele agen s 44 (4.6)
WHO FC, % (I/II/III/IV/unknown) 4.0/38.2/50.1/3.0/4.7 Como bidi y
BNP, pg/mL (median, ange) 131 (5−5844) (n =148) A leas one medical his o y inding 901 (94.2)
NT-p oBNP, pg/mL (median, ange) 602 (16−177 759) (n =540) A e ial hype ension 445 (46.5)
6MWD, m 365 ±128 Venous h omboembolism 431 (45.1)
6MWD Thy oid disease 183 (19.1)
<320 m
a
290 (30.3) Diabe es melli us 123 (12.9)
≥320 m 521 (54.5) Cance 123 (12.9)
<380 m 421 (44.0) Co ona y hea disease 122 (12.8)
≥380 m
a
390 (40.8) Obs uc i e sleep apnea 99 (10.4)
Missing 145 (15.2) His o y o hemop ysis/lung bleeding 37 (3.9)
EQ-5D VAS 62.3 ±20.6 (n =229) O he 759 (79.4)
Bo g Dyspnea Index 3.8 ±2.2 (n =701)
mPAP, mmHg 43.0 ±11.5 (n =850)
PVR, dyn⋅s⋅cm
−5
652 ±502 (n =767)
PAWP, mmHg 11.1 ±5.0 (n =809)
Ca diac index, L/min/m
2
2.8 ±4.4 (n =756)
RAP, mmHg 9.0 ±5.6 (n =710)
S O
2
, % 63.7 ±9.2 (n =613)
6MWD, 6-minu e walking dis ance; BMI, body mass index; BNP, b ain na iu e ic pep ide; CCB, calcium channel blocke ; CTEPH, ch onic h omboembolic pulmona y
hype ension; EQ-5D VAS, Eu oQoL 5-dimensional Visual Analog Sco e; IQR, in e qua ile ange; mPAP, mean pulmona y a e y p essu e; NT-p oBNP, N- e minal
p oho mone o b ain na iu e ic pep ide; PAWP, pulmona y a e y wedge p essu e; PEA, pulmona y enda e ec omy; PH, pulmona y hype ension; PVR, pulmona y
ascula esis ance; RAP, igh a ial p essu e; SD, s anda d de ia ion; S O
2
, sa u a ed enous oxygen; WHO FC, Wo ld Heal h O ganiza ion unc ional class.
Da a a e mean ±SD o numbe (%) unless o he wise s a ed.
Resul s a e o all pa ien s (n =956) unless o he wise s a ed.
a
Th esholds chosen (380 m p especi ied) based on a ailable (6MWD) coho da a a he ime indica ing good o poo p ognosis in PAH.
b
As indica ed by he in es iga o on he CRF.
H.-A. Gho ani e al.
Respi a o y Medicine 178 (2021) 106220
5
an SAE. No AE- ela ed dea hs we e epo ed. The AEs included hemop ysis
in wo pa ien s. Bo h e en s esol ed, and nei he was conside ed ela ed o
iocigua . None o he AEs epo ed wi hin 10 days a e PEA o BPA was
conside ed ela ed o iocigua .
3.6. E icacy assessmen s
Resul s o indica o s o e icacy (6MWD, Bo g Dyspnea Index,
EQ-5D VAS, hemodynamic measu emen s, and bioma ke s) ha e no
been he ocus o his non-in e en ional s udy; many da a we e missing,
and alues a ied g ea ly be ween pa ien s. Selec ion bias o epea
e icacy assessmen s could con ound he esul s. These esul s a e
he e o e no shown o discussed he e.
3.7. Dea hs and a al SAEs
O he 956 pa ien s wi h CTEPH, 101 (10.6%) (44 iocigua -newly
ea ed pa ien s [10.5%] and 57 iocigua -p e ea ed pa ien s [10.6%])
died o expe ienced an SAE wi h a a al ou come wi h onse du ing he s udy.
These SAEs began du ing he ea men phase in 93 pa ien s (9.7%); 38
iocigua -newly ea ed pa ien s (9.1%) and 55 iocigua -p e ea ed pa ien s
(10.2%). Fa al SAEs wi h pos - ea men onse occu ed in six iocigua -
newly ea ed pa ien s (1.4%) and wo iocigua -p e ea ed pa ien s
(0.4%). The mos common a al SAEs in he o al CTEPH popula ion we e RV
ailu e/ca diac ailu e in 27 pa ien s (2.8%), ollowed by ca diac a es ,
pneumonia, sepsis, and hemop ysis, each in h ee pa ien s (0.3%). In 19
pa ien s (2.0%), he SAE was lis ed as dea h (cause unknown). Two dea hs
we e conside ed ela ed o iocigua by he in es iga o . In one case he cause
o dea h was hemop ysis, which occu ed mo e han 2 yea s a e he apy
was ini ia ed in a pa ien ecei ing concu en an icoagulan medica ion.
The o he case was dea h om RV ailu e/ca diac ailu e, which occu ed
10 days a e he las dose o iocigua and was a ibu ed o lack o e icacy o
iocigua a he han an AE o he d ug.
Es ima ed su i al a es in he o al CTEPH popula ion a 1, 2, and 3 yea s
we e 94.7% (95% CI, 92.9–96.0%), 85.7% (95% CI, 82.4–88.4%), and
79.3% (95% CI, 74.0–83.6%), espec i ely. Kaplan−Meie su i al cu es
o iocigua -newly ea ed and iocigua -p e ea ed pa ien s a e shown in
Fig. 4.
In he pos hoc analysis assessing pa ien s acco ding o disease du a-
ion, dea h du ing he ea men pe iod occu ed in 77 p e alen pa ien s
(10.8%) and 14 inciden pa ien s (7.1%). Fou p e alen pa ien s (0.6%)
and ou inciden pa ien s (2.0%) died du ing he 30-day sa e y ollow-up.
4. Discussion
4.1. Sa e y indings
EXPERT p o ided da a on he sa e y and ole abili y o iocigua in
mo e han 950 pa ien s wi h CTEPH in eal-wo ld clinical p ac ice. The
ypes o AEs obse ed we e consis en wi h hose epo ed in Ch onic
Th omboembolic Pulmona y Hype ension Soluble Guanyla e Cycla-
se–S imula o T ial-1 (CHEST-1) [15], CHEST-2 [16,19], and he CTEPH
Ea ly Access S udy [20], wi h no new sa e y signals iden i ied. The mos
common e en s (e.g., pe iphe al edema/edema, dizziness, and dyspnea)
we e consis en wi h symp oms o he unde lying disease o wi h
asodila a ion by iocigua . Al hough he numbe s o pa ien s unde -
going BPA o PEA we e small, he e was no e idence o an inc eased isk
o d ug- ela ed e en s sho ly a e hese p ocedu es. The
exposu e-adjus ed a e o hypo ension (2.7 e en s pe 100 pa ien -yea s)
was lowe han ha epo ed in CHEST-2 (4.0 e en s pe 100
pa ien -yea s) [19]. The a es o hemop ysis/pulmona y hemo hage
we e simila (2.2 and 2.8 e en s pe 100 pa ien -yea s in EXPERT and
CHEST-2 [19], espec i ely). Mos pa ien s we e ecei ing an icoagu-
lan s as equi ed by CTEPH ea men guidelines: hese may ha e
con ibu ed o he bleeding AEs. A sepa a e publica ion compa ing
hemo hagic and h ombo ic/embolic e en s in pa ien s ecei ing VKAs
o NOACs a baseline is in p epa a ion. In pa ien s ecei ing iocigua as
pa o a combina ion egimen, he incidences o AEs and SAEs we e
highe han in pa ien s ecei ing mono he apy. These da a should be
in e p e ed wi h cau ion as hey a e desc ip i e, hey a e no adjus ed
o di e ences be ween he combina ion and mono he apy g oups, hey
e e o ea men a baseline, and he numbe s o pa ien s ecei ing
p os anoids we e small. Clinical expe ience wi h iocigua shows an
inc eased equency o some AEs such as hypo ension, dizziness, and
edema du ing dose adjus men [21,22]. These e ec s, desc ibed in he
e e ence sa e y in o ma ion o he d ug, ha e been a ibu ed o he
asodila o y p ope ies o iocigua [21]. Al hough he o e all e-
quency o AEs o SAEs did no di e g ea ly be ween iocigua -newly
ea ed and iocigua -p e ea ed pa ien s, nume ically mo e e en s o
hypo ension we e epo ed in newly ea ed pa ien s, as was discon in-
ua ion because o AEs o SAEs. The highe equency o hypo ension
migh be pa ly explained by a mo e se e e disease s a e (as indica ed by
6MWD and WHO FC) and pa ly by mo e equen moni o ing du ing
dose-adjus men pe iods. Fo iocigua -p e ea ed pa ien s, bias may be
in oduced, because hose who had o discon inue he d ug because o
AEs, o who died, could no be documen ed in he s udy. Pa ien s
en olled in disease egis ies as p e alen cases may be mo e likely o
ha e s able disease han inciden pa ien s [23]. In ou pos hoc analysis,
Fig. 2. Ope abili y s a us.
BPA, balloon pulmona y angioplas y; CTEPH, ch onic h omboembolic pul-
mona y hype ension; PEA, pulmona y enda e ec omy. Pe sis en CTEPH a e
PEA o BPA we e de e mined by he in es iga o .
Table 2
Mos common AEs and SAEs in he o al CTEPH popula ion (n =956).
AEs
a
n (%)
Pe iphe al edema/edema 112 (11.7)
b
Dyspnea 81 (8.5)
RV ailu e/ca diac ailu e 74 (7.7)
c
Dizziness 72 (7.5)
Pneumonia 48 (5.0)
SAEs
d
RV ailu e/ca diac ailu e 71 (7.4)
e
Pneumonia 39 (4.1)
Dyspnea 34 (3.6)
Syncope 24 (2.5)
PH
22 (2.3)
AE, ad e se e en ; CTEPH, ch onic h omboembolic pulmona y hy-
pe ension; PH, pulmona y hype ension; RV, igh en icula ; SAE,
se ious ad e se e en .
No e. Pa ien s wi h pe iphe al edema/edema, o RV ailu e/ca diac
ailu e could ha e bo h e en s.
a
P e e ed- e m AEs epo ed in ≥5% o pa ien s.
b
Including pe iphe al edema in 73 pa ien s (7.6%) and edema in
42 pa ien s (4.4%).
c
Including RV ailu e in 61 pa ien s (6.4%) and ca diac ailu e in
16 pa ien s (1.7%).
d
P e e ed- e m SAEs epo ed in ≥2% o pa ien s.
e
Including RV ailu e in 59 pa ien s (6.2%) and ca diac ailu e in
15 pa ien s (1.6%).
P e e ed e m o wo sening o he condi ion.
H.-A. Gho ani e al.

Respi a o y Medicine 178 (2021) 106220
6
Table 3
Baseline demog aphics and disease cha ac e is ics o iocigua -p e ea ed and iocigua -newly ea ed pa ien s.
Riocigua -p e ea ed
a
(n =537) Riocigua -newly ea ed
b
(n =419)
Age, yea s 65.9 ±14.1 66.8 ±13.3
Age g oup, yea s, n (%)
<65 218 (40.6) 148 (35.3)
65 o <75 138 (25.7) 122 (29.1)
≥75 181 (33.7) 149 (35.6)
Female sex, n (%) 337 (62.8) 233 (55.6)
BMI, kg/m
2
29.1 ±19.5 28.0 ±6.3
BMI ca ego y, kg/m
2
, n (%)
<18.5 15 (2.8) 9 (2.1)
18.5 o <25 164 (30.5) 126 (30.1)
25 o <30 191 (35.6) 157 (37.5)
≥30 167 (31.1) 127 (30.3)
Smoking s a us, n (%)
Ne e 332 (61.8) 270 (64.4)
Fo me 181 (33.7) 133 (31.7)
Cu en 24 (4.5) 16 (3.8)
P e alen (disease du a ion ≥6 mon hs), n (%) 481 (89.6) 232 (55.4)
Inciden (disease du a ion <6 mon hs) 28 (5.2) 169 (40.3)
Du a ion s a us unknown, n (%) 28 (5.2) 18 (4.3)
Age a ini ial PH diagnosis, yea s 61.6 ±14.8 (n =509) 64.2 ±13.9 (n =403)
Median (IQR) PH disease du a ion, yea s 2.9 (1.5–5.6) 0.8 (0.2–4.0)
Pe sis en CTEPH ollowing PEA, n (%) 133 (24.8) 74 (17.7)
Pe sis en CTEPH ollowing BPA, n (%) 16 (3.0) 10 (2.4)
WHO FC, % (I/II/III/IV/unknown) 5.6/45.1/43.6/2.8/3.0 1.9/29.4/58.5/3.3/6.9
BNP, pg/mL (median, ange) 107 (5–3560) (n =79) 171 (6–5844) (n =69)
NT-p oBNP, pg/mL (median, ange) 483 (16–177 759) (n =320) 813 (17–48 858) (n =220)
6MWD, m 382 ±122 (n =477) 341 ±133 (n =334)
6MWD, n (%)
<320 m
c
152 (28.3) 138 (32.9)
≥320 m 325 (60.5) 196 (46.8)
<380 m 219 (40.8) 202 (48.2)
≥380 m
c
258 (48.0) 132 (31.5)
Missing 60 (11.2) 85 (20.3)
EQ-5D VAS 63.6 ±19.7 (n =144) 60.1 ±22.1 (n =85)
Bo g Dyspnea Index 3.7 ±2.2 (n =403) 4.0 ±2.3 (n =298)
mPAP, mmHg 43.3 ±11.8 (n =462) 42.8 ±11.2 (n =388)
PVR, dyn•s•cm
-5
675 ±575 (n =413) 626 ±400 (n =354)
PAWP, mmHg 11.2 ±5.0 (n =436) 10.9 ±4.9 (n =373)
Ca diac index, L/min/m
2
2.8 ±5.0 (n =409) 2.7 ±3.7 (n =347)
RAP, mmHg 9.3 ±5.9 (n =389) 8.6 ±5.1 (n =321)
S O
2
, % 63.6 ±9.5 (n =323) 63.9 ±8.9 (n =290)
Riocigua daily dose a ini ial s udy isi , mg
Mean 7.1 ±1.1 6.6 ±1.6 (n =397)
Median ( ange) 7.5 (1.5–7.5) 7.5 (1.5–7.5) (n =397)
(con inued on nex page)
H.-A. Gho ani e al.
Respi a o y Medicine 178 (2021) 106220
7
a es o AEs and SAEs we e simila be ween p e alen and inciden pa-
ien s, indica ing ha he highe p opo ion o inciden pa ien s in he
iocigua -newly ea ed g oup did no disad an age hem in e ms o
sa e y. The e is no explana ion o he g ea e numbe o dea hs in
p e alen pa ien s han inciden pa ien s bu i may be ela ed o he
longe CTEPH disease du a ion in he p e alen g oup.
4.2. Compa ison wi h o he s udies
Compa ed wi h he 247 non-ope able pa ien s desc ibed in he in-
e na ional p ospec i e CTEPH egis y [9,24], CTEPH pa ien s in
EXPERT had less se e e unc ional impai men , wi h 53.1% ca ego ized
as WHO FC III/IV a baseline e sus 83.0% and a sligh ly highe mean
6MWD a baseline (365 s. 315 m). The in e na ional egis y en olled
only inciden pa ien s, whe eas 74.6% o pa ien s wi h CTEPH in EXPERT
had p e alen disease. In a p ospec i e s udy o 392 pa ien s newly
diagnosed wi h CTEPH in Ge many, iocigua was he ini ial ea men in
81.1% o pa ien s who ecei ed medical he apy, illus a ing he impo -
ance o ob aining sa e y da a o iocigua [25]. The pa ien s in his s udy
had gene ally simila cha ac e is ics o hose in he EXPERT popula ion.
The es ima ed su i al a e in pa ien s wi h CTEPH in EXPERT (94.7%,
85.7%, and 79.3% a 1, 2, and 3 yea s, espec i ely) appea s o be highe
han in non-ope able pa ien s in he in e na ional CTEPH egis y (88%,
79%, and 70% a 1, 2, and 3 yea s, espec i ely) [24], non-PEA pa ien s in
he Giessen egis y (84.5% a 1 yea and 72.5% a
3 yea s) [26], US e e ans e alua ed in a e ospec i e analysis (89.2%,
81.4%, and 72.7% a 1, 3, and 5 yea s, espec i ely) [27], and pa ien s in
se e al o he egis ies [13,14,28–30]. In an analysis om COMPERA, 561
medically ea ed pa ien s wi h CTEPH we e g aded as a low, in e media e,
o high isk o dea h based on hei WHO FC, 6MWD, BNP/NT-p oBNP,
Table 3 (con inued)
Riocigua -p e ea ed
a
(n =537) Riocigua -newly ea ed
b
(n =419)
Riocigua median daily dose a ini ial s udy isi , mg, n (%)
≤2.5 6 (1.1) 7 (1.7)
>2.5 o 4.5 34 (6.3) 74 (17.7)
>4.5 o 6 51 (9.5) 39 (9.3)
>6 o 7.5 446 (83.1) 277 (66.1)
Missing 0 22 (5.3)
PAH-app o ed egimen a ini ial s udy isi , n (%)
Riocigua mono he apy
d
403 (75.1) 355 (84.7)
Riocigua combina ion he apy
e,
134 (25.0) 64 (15.3)
Riocigua +ERA 112 (20.9) 58 (13.8)
Riocigua +amb isen an 21 (3.9) 15 (3.6)
Riocigua +bosen an 47 (8.8) 20 (4.8)
Riocigua +maci en an 44 (8.2) 23 (5.5)
Riocigua +p os anoid 6 (1.1) 3 (0.7)
Riocigua +ilop os 3 (0.6) 3 (0.7)
Riocigua +in a enous ep os inil 2 (0.4) 0 (0.0)
Riocigua +in a enous epop os enol 1 (0.2) 0 (0.0)
Riocigua +ERA +p os anoid 16 (3.0) 3 (0.7)
Concomi an CCB, n (%) 13 (2.4) 9 (2.1)
Concomi an an icoagula ion, n (%)
O al an icoagula ion 482 (89.8) 379 (90.5)
Vi amin K an agonis 311 (57.9) 195 (46.5)
Di ec o al an icoagulan 84 (15.6) 106 (25.3)
O he o al an icoagula ion
g
87 (16.2) 72 (17.2)
O he an icoagulan
g
34 (6.3) 32 (7.6)
Concomi an an ipla ele agen s, n (%) 16 (3.0) 28 (6.7)
Como bidi y, n (%)
A leas one medical his o y inding 509 (94.8) 392 (93.6)
A e ial hype ension 231 (43.0) 214 (51.1)
Venous h omboembolism 223 (41.5) 208 (49.6)
Thy oid disease 100 (18.6) 83 (19.8)
Cance 67 (12.5) 56 (13.4)
Co ona y hea disease 67 (12.5) 55 (13.1)
Diabe es melli us 66 (12.3) 57 (13.6)
Obs uc i e sleep apnea 65 (12.1) 34 (8.1)
His o y o hemop ysis/lung bleeding 23 (4.3) 14 (3.3)
O he 428 (79.7) 331 (79.0)
6MWD, 6-min walking dis ance; BMI, body mass index; BNP, b ain na iu e ic pep ide; BPA, balloon pulmona y angioplas y; CCB, calcium channel blocke ; CTEPH,
ch onic h omboembolic pulmona y hype ension; EQ-5D VAS, Eu oQoL 5-dimensional Visual Analog Sco e; ERA, endo helin ecep o an agonis ; IQR, in e qua ile
ange; mPAP, mean pulmona y a e y p essu e; NT-p oBNP, N- e minal p oho mone o b ain na iu e ic pep ide; PAH, pulmona y a e ial hype ension; PAWP,
pulmona y a e y wedge p essu e; PEA, pulmona y enda e ec omy; PH, pulmona y hype ension; PVR, pulmona y ascula esis ance; RAP, igh a ial p essu e; SD,
s anda d de ia ion; S O
2
, sa u a ed enous oxygen; WHO FC, Wo ld Heal h O ganiza ion unc ional class.
Da a a e mean ±SD o numbe (%), unless o he wise s a ed.
a
Recei ing iocigua o ≥3 mon hs be o e en y (n =537 unless o he wise indica ed).
b
Recei ing iocigua o <3 mon hs be o e en y (n =419 unless o he wise indica ed).
c
Th esholds chosen (380 m p especi ied) based on a ailable (6MWD) coho da a a he ime indica ing good o poo p ognosis in PAH.
d
Pa ien s ecei ing iocigua bu no ERA o p os anoid.
e
Pa ien s ecei ing iocigua +ERA o p os anoid o bo h.
No pa ien ecei ed concomi an PDE5i du ing he s udy.
g
As indica ed by he in es iga o on he CRF.
H.-A. Gho ani e al.
Respi a o y Medicine 178 (2021) 106220
8
RAP, CI, and S O
2
[31]. The es ima ed 1-yea su i al a e was 98.6%,
94.9%, and 75.5% in he low-, in e media e-, and high- isk g oups, espec-
i ely. The baseline cha ac e is ics o CTEPH pa ien s in EXPERT and hei
es ima ed su i al we e closes o hose o he in e media e- isk COMPERA
g oup.
Regis ies p o ide impo an in o ma ion abou he sa e y o d ugs in
clinical p ac ice and hus supplemen he in o ma ion gained om
selec ed popula ions unde he closely con olled condi ions o clinical
ials. They may also de ec p e iously unsuspec ed sa e y signals. No
such signals we e iden i ied in EXPERT. Limi a ions inhe en in egis-
ies including con ounding, lack o andomiza ion, missing alues, and
he haza ds o gene alizing da a om he egis y popula ion o o he
popula ions [32], also apply o EXPERT. In addi ion, EXPERT was
designed o collec sa e y in o ma ion on iocigua ; i was no designed
o p o ide da a on he long- e m e icacy o his d ug. S eng hs o
EXPERT include he ela i ely long obse a ion ime (median:
504 days), he la ge numbe (956) o pa ien s wi h CTEPH, he la ge
p opo ion o pa ien s comple ing he s udy. The planned en ollmen o
he en i e s udy was 900 pa ien s o allow o de ec ion o ≥3 “un-
common” AEs wi h an incidence ≥0.5%. Gi en ha 956 pa ien s wi h
CTEPH we e en olled, he e we e enough pa ien s in he CTEPH coho
alone o achie e his powe le el. The a ailabili y o sa e y da a in
Fig. 3. Disposi ion o iocigua -p e ea ed and iocigua -newly ea ed pa ien s wi h CTEPH. Cha shows p ima y eason o discon inua ion.
a
O he easons o no comple ing he s udy a e lis ed in Supplemen a y Table 1.
Table 4
Sa e y summa y in iocigua -p e ea ed and iocigua -newly ea ed pa ien s wi h CTEPH.
Riocigua -p e ea ed
a
(n =537) Riocigua -newly ea ed
b
(n =419)
AEs, n (%)
Any AE 345 (64.2) 270 (64.4)
Mos common AEs
c
, n (%)
Pe iphe al edema/edema 73 (13.6)
d
39 (9.3)
e
Dyspnea 50 (9.3) 31 (7.4)
Dizziness 42 (7.8) 30 (7.2)
RV ailu e/ca diac ailu e 40 (7.4)
34 (8.1)
g
Pneumonia 31 (5.8) 17 (4.1)
Cough 27 (5.0) 16 (3.8)
Hypo ension 13 (2.4) 24 (5.7)
Dyspepsia 12 (2.2) 21 (5.0)
Any d ug- ela ed AE
h
53 (9.9) 95 (22.7)
Discon inua ion due o AE 21 (3.9) 34 (8.1)
SAEs, n (%)
Any SAE 199 (37.1) 166 (39.6)
Mos common SAEs
i
, n (%)
RV ailu e/ca diac ailu e 39 (7.3)
j
32 (7.6)
k
Pneumonia 26 (4.8) 13 (3.1)
Dyspnea 17 (3.2) 17 (4.1)
Syncope 14 (2.6) 10 (2.4)
PH
l
15 (2.8) 7 (1.7)
Pulmona y embolism 3 (0.6) 9 (2.1)
Any d ug- ela ed SAE
h
13 (2.4) 21 (5.0)
Discon inua ion due o SAE 17 (3.2) 21 (5.0)
AE, ad e se e en ; PH, pulmona y hype ension; RV, igh en icula ; SAE, se ious ad e se e en .
a
Recei ing iocigua o ≥3 mon hs be o e en y. Median ( ange) du a ion o obse a ion and iocigua ea men (days): 532.0 (0.0–1346.0); 506.0 (0.0–1346.0).
b
Recei ing iocigua o <3 mon hs be o e en y. Median ( ange) du a ion o obse a ion and iocigua ea men (days): 475.0 (0.0–1367.0); 455.0 (0.0–1367.0).
c
P e e ed- e m AEs epo ed in ≥5% o pa ien s in ei he g oup.
d
Pe iphe al edema in 46 pa ien s (8.6%) and edema in 30 pa ien s (5.6%).
e
Pe iphe al edema in 27 pa ien s (6.4%) and edema in 12 pa ien s (2.9%).
RV ailu e in 34 pa ien s (6.3%) and ca diac ailu e in 7 pa ien s (1.3%).
g
RV ailu e in 27 pa ien s (6.4%) and ca diac ailu e in 9 pa ien s (2.1%).
h
In es iga o ’s causali y assessmen .
i
P e e ed- e m SAEs epo ed in ≥2% o pa ien s in ei he g oup.
j
RV ailu e in 34 pa ien s (6.3%) and ca diac ailu e in 6 pa ien s (1.1%).
k
RV ailu e in 25 pa ien s (6.0%) and ca diac ailu e in 9 pa ien s (2.1%).
l
P e e ed e m o wo sening o he condi ion.No e. Pa ien s wi h pe iphe al edema/edema o RV ailu e/ca diac ailu e could ha e bo h e en s.
H.-A. Gho ani e al.
Respi a o y Medicine 178 (2021) 106220
9
pa ien s ecei ing iocigua ei he as mono he apy o as pa o a com-
bina ion egimen a baseline was also a s eng h o he s udy.
5. Conclusion
Final da a om he EXPERT egis y showed ha in pa ien s wi h
CTEPH, he long- e m sa e y o iocigua in ou ine p ac ice, was
consis en wi h clinical ials, wi h no new sa e y conce ns iden i ied.
Decla a ion o compe ing in e es
The au ho s decla e he ollowing inancial in e es s/pe sonal e-
la ionships which may be conside ed as po en ial compe ing in e es s:
P o Ma ius M. Hoepe epo s pe sonal ees om Baye AG, du ing he
conduc o he s udy; pe sonal ees om Ac elion, pe sonal ees om
Accele on, pe sonal ees om MSD, pe sonal ees om Jansen, pe sonal
ees om P ize , ou side he submi ed wo k. D Hans Klose epo s
speake and consul ancy ees om Ac elion, Baye AG, GSK, No a is,
P ize , and Uni ed The apeu ics and esea ch suppo om Ac elion,
Baye AG, GSK, P ize , and MSD. D Michael Halank epo s pe sonal
ees and non- inancial suppo om Ac elion, As aZeneca, Baye AG,
Be lin-Chemie, GSK, OMT, MSD, and No a is. D Geo ge Giannakoulas
epo s speake and consul ancy ees om Ac elion, Baye , ELPEN
Pha maceu icals, GSK, P ize , Lilly, and Uni ed The apeu ics, and
esea ch suppo om GSK, ELPEN Pha maceu icals, and Galenica. D
Henning Gall has ecei ed hono a ia and/o o he suppo om Ac e-
lion, As aZeneca, Baye , BMS, GSK, Janssen-Cilag, Lilly, MSD, No a is,
OMT, P ize , and Uni ed The apeu ics. D Pa el Jansa epo s consul-
ancy and speake ees om MSD, AOP O phan, and Ac elion. P o
Ekkeha d G ünig epo s esea ch g an s and speake hono a ia/con-
sul ancy ees om Ac elion and Baye /MSD, esea ch g an s om GSK,
Uni ed The apeu ics, Belle ophon, OMT GmbH, P ize , Rea a, and
No a is, and speake hono a ia om Bial, Medscape, and O Pha Swiss
GmbH. P o Da id Pi ow epo s pe sonal ees om Ac elion, Baye
AG, Aspen, Boeh inge Ingelheim, Sano i, Biogen, Shi e, and MSD
ou side he submi ed wo k. Sil ia Ul ich epo s esea ch g an s and
pe sonal ees om Ac elion, Baye , MSD, and O pha Swiss. Tobias J.
Lange has ecei ed pe sonal ees om Ac elion, MSD, P ize , and OMT
o phan. D I aklis Tsanga is epo s speake and consul ancy ees om
Ac elion, Baye AG, ELPEN, GSK, MSD, P ize , and Uni ed The apeu ics.
S ephan Rosenk anz epo s emune a ions o lec u es and/o consul-
ancy om Abbo , Ac elion, A ena, Baye , Fe e , GSK, MSD, No a is,
P ize , and Uni ed The apeu ics; and esea ch suppo o his ins i u ion
om Ac elion, Baye , No a is, P ize , and Uni ed The apeu ics. Repke
J. Snijde epo s g an s om P ize and Ac elion Pha maceu icals. P o
I e a ˇ
Simko ´
a epo s consul ancy and speake ees om MSD, AOP
O phan, and Ac elion. D Ma c Humbe epo s g an s and pe sonal ees
om Baye and GSK, and pe sonal ees om Ac elion, Me ck, and Uni ed
Table 5
AEs and SAEs o special in e es .
All CTEPH (n =956)
a
Riocigua -p e ea ed
b
(n =537) Riocigua -newly ea ed
c
(n =419)
Absolu e AE a es, n (%)
Hypo ension 37 (3.9) 13 (2.4) 24 (5.7)
Hemop ysis/pulmona y hemo hage 26 (2.7) 15 (2.8) 11 (2.6)
Exposu e-adjus ed AE a es (95% CI)
d
Hypo ension 2.7 (2.0–3.7) 1.7 (0.9–2.7) 4.3 (2.8–6.2)
Hemop ysis/pulmona y hemo hage 2.2 (1.5–3.0) 1.9 (1.1–3.0) 2.6 (1.5–4.1)
Absolu e SAE a es, n (%)
Hypo ension 4 (0.4) 3 (0.6) 1 (0.2)
Hemop ysis/pulmona y hemo hage 16 (1.7) 8 (1.5) 8 (1.9)
Exposu e-adjus ed SAE a es (95% CI)
d
Hypo ension 0.3 (0.1–0.7) 0.4 (0.1–0.9) 0.2 (0.0–0.8)
Hemop ysis/pulmona y hemo hage 1.4 (0.9–2.1) 1.1 (0.5–1.9) 1.9 (1.0–3.2)
AE, ad e se e en ; CI, con idence in e al; CTEPH, ch onic h omboembolic pulmona y hype ension; SAE, se ious ad e se e en .
a
Median ( ange) du a ion o obse a ion and iocigua ea men (days): 504.0 (0.0–1367.0); 493.5 (0.0–1367.0).
b
Recei ing iocigua o ≥3 mon hs be o e en y. Median ( ange) du a ion o obse a ion and iocigua ea men (days): 532.0 (0.0–1346.0); 506.0 (0.0–1346.0).
c
Recei ing iocigua o <3 mon hs be o e en y. Median ( ange) du a ion o obse a ion and iocigua ea men (days): 475.0 (0.0–1367.0); 455.0 (0.0–1367.0).
d
Ra e pe 100 pa ien -yea s, calcula ed by he numbe o e en s obse ed di ided by ( o al d ug exposu e in yea s/100).
Fig. 4. Kaplan−Meie su i al cu es o iocigua -newly ea ed and iocigua -p e ea ed pa ien s. CI, con idence in e al.
H.-A. Gho ani e al.