Recei ed: 27 Feb ua y 2023
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Accep ed: 5 July 2023
DOI: 10.1002/jm .28971
RESEARCH ARTICLE
Ou pa ien a o as a in use and se e e COVID‐19 ou comes:
A popula ion‐based s udy
I ene Visos‐Va ela
1
|Ma uxa Zapa a‐Cacha ei o
1,2,3
|
Samuel Pin os‐Rod íguez
1
|Rosendo Buga ín‐González
4
|
F ancisco Ja ie González‐Ba cala
5,6
|Ma ia T. He dei o
7
|
Ma ía Piñei o‐Lamas
3
|Adol o Figuei as
1,2,3
|Ángel Salgado‐Ba ei a
1,2,3
1
Depa men o P e en i e Medicine and
Public Heal h, Uni e si y o San iago de
Compos ela, San iago de Compos ela, Spain
2
Ins i u e o Heal h Resea ch o San iago de
Compos ela (IDIS), San iago de Compos ela,
Spain
3
Conso ium o Biomedical Resea ch in
Epidemiology & Public Heal h (CIBER en
Epidemiología y Salud Pública‐CIBERESP),
San iago de Compos ela, Spain
4
Mon o e de Lemos Heal h Cen e , Heal h
A ea o Lugo, A Ma iña and Mon o e de
Lemos, SERGAS, Mon o e de Lemos, Lugo,
Spain
5
Spanish Biomedical Resea ch Ne wo king
Cen e‐CIBERES, San iago de Compos ela,
Spain
6
Pneumoloxy Depa men , San iago de
Compos ela Uni e si y Hospi al Complex,
San iago de Compos ela, Spain
7
Depa men o Medical Sciences, iBiMED‐
Ins i u e o Biomedicine, Uni e si y o A ei o,
A ei o, Po ugal
Co espondence
Ma uxa Zapa a‐Cacha ei o, Depa men o
P e en i e Medicine and Public Heal h, C/San
F ancisco s/n, Uni e si y o San iago de
Compos ela, 15786 San iago de Compos ela,
A Co uña, Spain.
Email: [email p o ec ed]
Funding in o ma ion
Ins i u o de Salud Ca los III; Ca los III Ins i u e
o Heal h, G an /Awa d Numbe : COV20/
00470; Eu opean Regional De elopmen Fund
Abs ac
E idence o he e ec o s a ins on pa ien s wi h co ona i us disease (2019)
COVID‐19 is inconsis en . The aim o his s udy was o e alua e he associa ion
be ween ch onic use o s a ins—bo h o e all and by ac i e ing edien —and se e e
ou comes o COVID‐19 ( isk o hospi aliza ion and mo ali y), p og ession o
se e e ou comes, and suscep ibili y o he i us. We conduc ed a popula ion‐
based case–con ol s udy wi h da a om elec onic eco ds o assess he isk o
(1) hospi aliza ion: cases we e pa ien s admi ed due o COVID‐19 and con ols we e
subjec s wi hou COVID‐19; (2) mo ali y: cases we e hospi alized pa ien s who died
due o COVID‐19 and con ols we e subjec s wi hou COVID‐19; (3) p og ession:
cases we e hospi alized COVID‐19 subjec s and con ols we e nonhospi alized
COVID‐19 pa ien s; and (4) suscep ibili y: cases we e pa ien s wi h COVID‐19 (bo h
hospi alized and nonhospi alized) and con ols we e subjec s wi hou COVID‐19.
We collec ed da a on 2821 hospi alized cases, 26 996 nonhospi alized cases, and
52 318 con ols. Ch onic use o a o as a in was associa ed wi h a dec eased isk o
hospi aliza ion (adjus ed odds a ios [aOR] = 0.83; 95% con idence in e al [CI]:
0.74–0.92) and mo ali y (aOR = 0.70; 95% CI: 0.53–0.93), a ibu able in pa o a
lowe isk o suscep ibili y o he i us (aOR = 0.91; 95% CI: 0.86–0.96). Sim as a in
was associa ed wi h a educed isk o mo ali y (aOR = 0.59; 95% CI: 0.40–0.87). The
wide deg ee o he e ogenei y obse ed in he es ima ed odds a ios (ORs) o he
di e en s a ins sugges s ha he e is no class e ec . The esul s o his eal‐wo ld
s udy sugges ha ch onic use o a o as a in (and o a lesse deg ee, o sim as a in) is
associa ed wi h a dec ease in isk o se e e COVID‐19 ou comes.
KEYWORDS
a o as a in, COVID‐19, hospi aliza ion, mo ali y, ou pa ien , s a ins
J Med Vi ol. 2023;95:e28971. wileyonlinelib a y.com/jou nal/jm
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This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion‐NonComme cial‐NoDe i s License, which pe mi s use and dis ibu ion in any
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© 2023 The Au ho s. Jou nal o Medical Vi ology published by Wiley Pe iodicals LLC.
1|INTRODUCTION
In ecen decades, inc eased imbalances in he human–
animal–ecosys em in e ac ion,
1
d i en by clima e change, loss
o biodi e si y, he demog aphic explosion, globaliza ion, and/o
inc eased con ac wi h wildli e, ha e gi en ise o a signi ican
inc ease in eme ging in ec ious diseases, including he 2019
co ona i us disease (COVID‐19).
2
The consequences o he lack o esou ces o ackle
COVID‐19 ha e highligh ed he impo ance o ha ing adequa e
means o p epa e o new public heal h h ea s. In his
espec , he Wo ld Heal h O ganiza ion (WHO) conside s h ee
ac ion s a egies o comba p esen and u u e pandemics
e ec i ely, ha is, apid diagnos ic me hods, accina ion, and
he apeu ic ea men .
3
In he case o COVID‐19, challenges in
he dis ibu ion and accep ance o accines,
4,5
as well as he
ulne abili y o elde ly popula ions and/o popula ions wi h he
p esence o como bidi ies,
6
make i necessa y o ha e e ec i e
ea men s ha complemen he accina ion plan, o al e na-
i ely, o p o ide ea men co e age in popula ions wi hou
access o accina ion.
O e he cou se o he pandemic, a numbe o medica ions
indica ed o ch onic condi ions ha e a ac ed a en ion as
ega ds hei possible e ec on he suscep ibili y and se e i y o
COVID‐19.
7,8
In his same di ec ion, a numbe o s udies ha e
epo ed ha s a ins, which ank among he main enance d ugs
mos used by he elde ly popula ion and/o popula ions wi h
como bidi ies,
8
migh imp o e p ognosis o COVID‐19.
9,10
The
explana ion o his possible p o ec i e ac i i y o s a ins could lie
in hei many pleio opic (o noncholes e ol‐dependen ) e ec s,
which include an i‐in lamma o y,
11
immunomodula o ,
12
an i h-
ombo ic,
13
and an i i al p ope ies.
14
Indeed, hese medica ions
ha e shown an i i al capaci y in p e ious ou b eaks, such as he
H1N1/09 in luenza
15
and Ebola i us pandemics.
16,17
I has also
been sugges ed, on heo e ical g ounds, ha hey could be o use
in se e e acu e espi a o y synd ome co ona i us (SARS‐CoV)
and Middle Eas espi a o y synd ome co ona i us (MERS‐CoV)
in ec ions.
18
To da e, published s udies (bo h obse a ional and expe i-
men al) on he u ili y o s a ins in pa ien s wi h COVID‐19
epo inconsis en esul s.
10,19–22
One o he possible causes o
hese disc epancies may be due o he s uc u al di e si y o
s a ins, which endows hem wi h signi ican ly di e en p ope -
ies.
23,24
Mos o he s udies, howe e , examine he e ec s
o he pha macological g oup o s a ins in gene al, wi hou
analyzing he e ec o he ac i e ing edien s sepa a ely.
19
In he ew s udies o his ype a ailable, he esul s ob ained
also display inconsis encies.
25–27
Acco dingly, he aim o ou
s udy was o e alua e he associa ion be ween ch onic use o
s a ins—bo h o e all and by ac i e ing edien —and (1) se e e
COVID‐19 ou comes ( isk o hospi aliza ion and mo ali y);
(2) p og ession o se e e COVID‐19 ou comes; and (3) suscep i-
bili y o he i us.
2|METHODS
2.1 |S udy se ing and popula ion
The s udy popula ion comp ised all ci izens o Galicia o e 18 yea s o
age who we e bene icia ies o he Galician Heal h Se ice (GHS). This
egion, si ua ed in he no hwes o Spain, has a popula ion o almos 3
million inhabi an s, p ac ically all o whom (98%) a e co e ed by he GHS.
2.2 |Design
We used a popula ion‐based, case–con ol design. Cases (subjec s wi h
COVID‐19, hospi alized and nonhospi alized) we e selec ed by exhaus i e
sampling, and con ols we e d awn om he same popula ion as cases,
which enabled us o ob ain a alid es ima e o he p e alence o exposu e
and co a ia es in he sou ce popula ion. The s udy pe iod was om
Ma ch o Decembe 2020.
2.3 |Cases and con ols
We conduc ed a o al o ou subs udies, which di e ed in hei
de ini ions o cases and con ols (Figu e 1and Suppo ing In o ma-
ion: Table S1) o espond o each s udy's designa ed objec i es, ha
is, he associa ion be ween ch onic use o s a ins and (1) isk o
hospi aliza ion; (2) isk o mo ali y; (3) p og ession o se e e
ou comes o COVID‐19; and (4) suscep ibili y o he i us.
2.3.1 |Case–con ol 1: Se e e COVID‐19
ou comes—hospi aliza ion
To analyze he isk o hospi aliza ion due o COVID‐19, cases we e
de ined as all subjec s wi h a con i med diagnosis o COVID‐19
(polyme ase chain eac ion [PCR+]) wi h a maximum gap o 10 days
be ween PCR da e and hospi al admission and (1) wi h he eason o
admission COVID‐19 o (2) symp oma ology compa ible wi h
COVID‐19 ( espi a o y ac in ec ion, i al pneumonia, sho ness
o b ea h, cough, e e , e c.), because in he i s mon hs o he
pandemic, no speci ic coding was a ailable.
Con ols we e andomly selec ed om among he gene al popula-
ion ha had no diagnosis o COVID‐19 (no PCR+ es ) in 2020 and we e
ma ched (up o 20 con ols pe case) by age, sex, p ima y‐ca e se ice o
e e ence, pandemic wa e, and s a us o he heal h p o essional o
ensu e hesame isko exposu e oSARS‐CoV‐2.
2.3.2 |Case–con ol 2: Se e e COVID‐19
ou comes—mo ali y
To assess he isk o mo ali y due o COVID‐19, cases
we e de ined as all subjec s hospi alized o COVID‐19
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(Case–con ol 1) who died du ing admission o any o he GHS
hospi als in 2020.
The con ols we e he subg oup o con ols om he
case–con ol 1 subs udy who we e hen ma ched wi h cases om
his subs udy.
2.3.3 |Case–con ol 3: P og ession o se e e
COVID‐19 ou comes
To s udy he isk o p og ession o se e e COVID‐19 ou comes,
de ined as in ec ed pa ien s' need o hospi aliza ion due o
COVID‐19, cases we e de ined as all pa ien s wi h COVID‐19
(PCR+) hospi alized due o COVID in 2020 (Case–con ol 1).
Con ols we e all pa ien s wi h COVID‐19 (PCR+) who did no
equi e hospi al admission due o COVID‐19 in 2020. In his model,
he con ols a e no ma ched, so while a dec ease in he s udy's
e ec i eness is o be expec ed, i s alidi y is no a ec ed.
28,29
2.3.4 |Case–con ol 4: Suscep ibili y o he i us
To es ima e he isk o in ec ion, cases we e all subjec s ha had a
diagnosis o COVID‐19 (PCR+) in 2020, bo h hospi alized and
nonhospi alized.
As con ols, we used he sample o subjec s who had no
diagnosis o COVID‐19 (no PCR+) in 2020 (Case‐con ol 1). As in he
p og ession model, con ols we e also no ma ched.
28,29
2.4 |Da a sou ces and da a collec ion
Real‐wo ld da a we e ex ac ed om he Galician in eg a ed heal hca e
da abase, which combines GHS sys em heal h eco ds wi h o he heal h
da abases (p esc ip ion and dispensing o medica ions, labo a o y da a,
and Na ional Heal h Sys em hospi al‐discha ge egis e [Minimum Basic
Da a Se (MBDS)/Conjun o Mínimo Básico de Da os]). We collec ed
in o ma ion on he clinical cou se o he disease, exposu e o he d ug
unde s udy, and o he co a ia es. All da a we e ex ac ed by an
independen in o ma ion echnology company.
2.5 |Exposu e
The a iableo exposu ewasch onicuseo s a ins(ATCC10AAcode).
We eco ded da a on s a ins p esc ibed and dispensed du ing each
subjec 's ollow‐up pe iod, which co e ed he 3 mon hs immedia ely
p eceding he index da e. The index da e was de ined as 10 days be o e
diagnosis o COVID‐19 (PCR+ es da e), o p e en he p esence o
symp oms o he disease om al e ing exposu e o he medica ion. Fo
FIGURE 1 Popula ion‐based mul iple case–con ol design.
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con ols, he index da e was assumed o be he same as ha o he cases
wi h which hey we e ma ched.
Sepa a e analyses we e pe o med by pha macological subg oup
(C10AA) and by ac i e ing edien , ha is, sim as a in (C10AA01),
lo as a in (C10AA02), p a as a in (C10AA03), lu as a in (C10AA04),
a o as a in (C10AA05), osu as a in (C10AA07), and pi a as a in
(C10AA08).
S udy co a ia es included demog aphic and socioeconomic a i-
ables, hospi aliza ion da a and clinical a iables o COVID‐19 (whe e
applicable), como bidi ies (hype ension, diabe es melli us, ch onic
obs uc i e pulmona y disease, obesi y, ischaemic hea disease,
ce eb o ascula acciden , hea ailu e, a ial ib illa ion, ch onic enal
ailu e, cance , as hma, and cu en smoke ), and exposu e o medica-
ions o he han hose speci ically add essed by his s udy. To es ima e
pa ien s' deg ee o ch onici y, he numbe o di e en d ugs p esc ibed
anddispensedwasusedasap oxy.
30
All co a ia es we e eco ded
ac oss he 3 mon hs p eceding he index da e.
2.6 |S a is ical analysis
Owing o he s uc u e o he da a collec ed, we analyzed he ou come
a iables (se e e COVID‐19 ou comes, p og ession o se e e ou comes,
and suscep ibili y o he i us) using mul ile el logis ic eg ession.
31
These models ha e a numbe o ad an ages o e condi ional eg es-
sion,
31–33
since hey allow o (1) analysis o ma ched and unma ched
models; (2) he in oduc ion o andom e ms o con ol o he e oge-
nei y o ini ial clus e s and ime pe iods; and (3) s a a in which cases
coincide in exposu es wi h con ols con inue o coun as e en s o he
pu pose o calcula ion and es ima es.
To cons uc he models, he ollowing ou le els we e
conside ed: pa ien ; case and con ol s a a ( o he se e e
COVID‐19 ou comes models); heal h cen e ; and pandemic
wa e. We used andom e ec s o e alua e he e ec o he
pandemic wa e and nes ed andom e ec s o pa ien s, case and
con ol s a a, and heal h a ea. Resul s we e exp essed as adjus ed
odds a ios (aORs) wi h hei 95% con idence in e als (95% CIs),
wi h adjus men s being made o he abo e‐men ioned co a ia es.
We ob ained adjus ed es ima es o he e ec o ea men wi h
s a ins (i.e., ac ually dispensed) in compa ison wi h no lipid‐lowe ing
d ug ea men . S a is ical signi icance was se a 0.05, and all
s a is ical analyses we e pe o med using he ee R s a is ical
so wa e p og amme ( e sion 4.1.2).
3|RESULTS
The b eakdown o he 82 135 s udy pa ien s was as ollows: 2821
we e hospi alized cases (PCR+), 397 o whom died du ing admission;
26 996 we e nonhospi alized cases (PCR+); and 52 318 we e subjec s
who did no es PCR+ du ing 2020.
The coho 's cha ac e is ics a e de ined in Tables 1and 2.
TABLE 1 Demog aphic and clinical cha ac e is ics o COVID‐19 cases and ma ched con ols (se e e ou comes: hospi aliza ion and mo ali y).
Se e e COVID‐19 ou comes
Hospi aliza ion Mo ali y
Cha ac e is ic Cases (N= 2821) Con ols (N= 52 318) Cases (N= 397) Con ols (N= 7129)
Sex; n(%)
Male 1457 (51.6) 26 998 (51.6) 236 (59.4) 4274 (60.0)
Female 1364 (48.4) 25 320 (48.4) 161 (40.6) 2855 (40.0)
Age, median (IQR) 74 (60–85) 73 (60–84) 84 (77–89) 84 (75–88)
Heal h p o essional; n(%) 78 (2.8) 1203 (2.3) 0 (0.0) 0 (0.0)
Como bidi ies; n(%)
Hype ension 1639 (58.2) 26 292 (50.3) 295 (74.3) 4687 (65.7)
Diabe es 782 (27.8) 10 233 (19.6) 157 (39.5) 1760 (24.7)
COPD 369 (13.1) 4305 (8.2) 87 (21.9) 875 (12.3)
Obesi y 830 (29.5) 10 104 (19.3) 114 (28.7) 1536 (21.5)
Ischemic hea disease 326 (11.6) 4479 (8.6) 86 (21.7) 914 (12.8)
Ce eb o ascula acciden 277 (9.8) 3631 (6.9) 72 (18.1) 725 (10.2)
Hea ailu e 430 (15.3) 3780 (7.2) 106 (26.7) 796 (11.2)
A ial ib illa ion 425 (15.1) 5405 (10.3) 84 (21.2) 1137 (15.9)
Ch onic enal ailu e 403 (14.3) 4059 (7.8) 99 (24.9) 882 (12.4)
Cance 475 (16.9) 7277 (13.9) 98 (24.7) 1340 (18.8)
As hma 267 (9.5) 3070 (5.9) 25 (6.3) 368 (5.2)
Cu en smoke 737 (26.1) 7842 (15.0) 83 (20.9) 866 (12.1)
Abb e ia ions: COPD, ch onic obs uc i e pulmona y disease; IQR, in e qua ile ange.
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Among s a in use s, a o as a in was he mos popula , ollowed
by sim as a in (Tables 3and 4). In bo h cases, he doses mos
equen ly dispensed we e hose o mode a e in ensi y (68.0% and
62.1%, espec i ely).
3.1 |Se e e COVID‐19 ou comes—hospi aliza ion
E alua ion o he isk o hospi aliza ion was based on 2821 cases and
52 318 con ols (Table 3). S a ins as a whole displayed s a is ically
signi ican di e ences (aOR = 0.87; 95% CI: 0.79−0.96, p= 0.004). In
he analysis by ac i e ing edien , a o as a in (aOR = 0.83; 95% CI:
0.74–0.92, p< 0.001) showed a s a is ically signi ican educ ion in
he isk o hospi aliza ion.
3.2 |Se e e COVID‐19 ou comes—mo ali y
Assessmen o he isk o mo ali y was based on 397 cases and 7129
con ols (Table 3). S a is ically signi ican di e ences we e obse ed
o s a ins as a whole (aOR = 0.71; 95% CI: 0.56−0.90, p= 0.005). In
he analysis by ac i e ing edien , bo h a o as a in (aOR = 0.70; 95%
CI: 0.53 0.93, p= 0.014) and sim as a in (aOR = 0.59; 95% CI:
0.40−0.87, p= 0.008) showed a s a is ically signi ican educ ion in
isk o mo ali y.
3.3 |P og ession o se e e COVID‐19 ou comes
A o al o 2821 cases and 26 996 con ols (nonhospi alized cases)
we e used o asce ain he isk o p og essing o se e e ou comes o
COVID‐19 (Table 1). No s a is ically signi ican di e ences we e ound
o SSRIs o e all o o any o he ac i e ing edien s indi idually.
3.4 |Suscep ibili y o he i us
In he analysis o he isk o SARS‐CoV‐2 in ec ion, 82 315 pa ien s
we e included: o hese, 29 817 we e COVID‐19 cases (hospi alized
and nonhospi alized) and 52 318 we e con ols (Table 4). A small
signi ican educ ion in isk was obse ed o s a ins as a whole
(aOR = 0.94; 95% CI: 0.90−0.99, p= 0.013), and a educ ion in isk o
a sligh ly highe magni ude was obse ed o a o as a in (aOR =
0.91; 95% CI: 0.86−0.96, p< 0.001).
TABLE 2 Demog aphic and clinical cha ac e is ics o COVID‐19 cases and ma ched con ols (p og ession o se e e COVID‐19 ou comes
and suscep ibili y o he i us).
P og ession o se e e COVID‐19 ou comes Suscep ibili y o he i us
Cha ac e is ic Cases (N= 2821) Con ols (N= 26 996) Cases (N= 29 817) Con ols (N= 52 318)
Sex; n(%)
Male 1457 (51.6) 11 217 (41.6) 12 674 (42.5) 26 998 (51.6)
Female 1364 (48.4) 15 779 (58.4) 17 143 (57.5) 25320 (48.4)
Age, median (IQR) 74 (60–85) 47 (33–63) 49 (34–67) 73 (60–84)
Heal h p o essional; n(%) 78 (2.8) 1238 (4.6) 1316 (4.4) 1203 (2.3)
Como bidi ies; n(%)
Hype ension 1639 (58.2) 6208 (23.0) 7847 (26.3) 26 292 (50.3)
Diabe es 782 (27.8) 2519 (9.3) 3301 (11.1) 10 233 (19.6)
COPD 369 (13.1) 759 (2.8) 1128 (3.8) 4305 (8.2)
Obesi y 830 (29.5) 3960 (14.7) 4790 (16.1) 10 104 (19.3)
Ischemic hea disease 326 (11.6) 865 (3.2) 1191 (4.0) 4479 (8.6)
Ce eb o ascula acciden 277 (9.8) 867 (3.2) 1144 (3.8) 3631 (6.9)
Hea ailu e 430 (15.3) 678 (2.5) 1108 (3.7) 3780 (7.2)
A ial ib illa ion 425 (15.1) 1076 (4.0) 1501 (5.9) 5405 (10.3)
Ch onic enal ailu e 403 (14.3) 712 (2.6) 1115 (3.7) 4059 (7.8)
Cance 475 (16.9) 1755 (6.5) 2230 (7.5) 7277 (13.9)
As hma 267 (9.5) 2170 (8.0) 2437 (8.2) 3070 (5.9)
Cu en smoke 737 (26.1) 4108 (15.2) 4845 (16.2) 7842 (15.0)
Abb e ia ions: COPD, ch onic obs uc i e pulmona y disease; IQR, in e qua ile ange.
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TABLE 3 Se e e COVID‐19 ou comes: isk o hospi aliza ion and mo ali y.
Se e e COVID‐19 ou comes
Risk o hospi aliza ion Risk o mo ali y
CASES: PCR+ hospi alized
(N= 2821)
CONTROLS: no
PCR+(N= 52 318)
Adjus ed OR
a
(95%CI) pValue
CASES: PCR+
deceased (N = 397)
CONTROLS: no
PCR+ (N = 7129)
Adjus ed OR
a
(95%CI) pValue
S a ins (C10AA) 1009 (35.8)
b
18 207 (34.8)
b
0.87 (0.79–0.96) 0.004 164 (41.3)
b
2896 (40.6)
b
0.71 (0.56–0.90) 0.005
Sim as a in (C10AA01) 276 (9.8) 5272 (10.1) 0.91 (0.79–1.04) 0.168 33 (8.3) 824 (11.6) 0.59 (0.40–0.87) 0.008
Lo as a in (C10AA02) 4 (0.1) 54 (0.1) 1.21 (0.43–3.39) 0.721 2 (0.5) 8 (0.1) 3.65 (0.75–17.80) 0.109
P a as a in (C10AA03) 73 (2.6) 1220 (2.3) 0.95 (0.74–1.22) 0.692 13 (3.3) 199 (2.8) 0.82 (0.44–1.51) 0.524
Flu as a in (C10AA04) 17 (0.6) 205 (0.4) 1.40 (0.85–2.33) 0.190 5 (1.3) 34 (0.5) 2.14 (0.78–5.88) 0.141
A o as a in (C10AA05) 538 (19.1) 9732 (18.6) 0.83 (0.74–0.92) <0.001 95 (23.9) 1603 (22.5) 0.70 (0.53–0.93) 0.014
Rosu as a in (C10AA07) 83 (2.9) 1469 (2.8) 0.84 (0.66–1.06) 0.149 16 (4.0) 193 (2.7) 0.95 (0.54–1.69) 0.868
Pi a as a in (C10AA08) 29 (1.0) 420 (0.8) 1.10 (0.75–1.63) 0.615 4 (1.0) 67 (0.9) 0.84 (0.30–2.39) 0.750
Abb e ia ion: OR, odds a io.
a
Adjus ed o : sex, age, s a us o heal h p o essional, como bidi ies (hype ension, diabe es, COPD, obesi y, ischemic hea disease, ce eb o ascula acciden , hea ailu e, a ial ib illa ion, ch onic enal ailu e,
cance , as hma, cu en smoke ), cu en use o o he pha macological ea men , and numbe o ea men s o ch onic diseases. Addi ionally, he p ima y‐ca e se ice o e e ence and he pandemic wa e
we e included as andom e ec s.
b
The o e all numbe o subjec s exposed o s a ins (C10AA) is lowe han he sum o hose exposed o he ac i e ing edien s o indi idual s a ins (C10AA01, C10AA02, C10AA03, C10AA04, C10AA05,
C10AA07, C10AA08), due o he ac ha some subjec s we e exposed o mo e han one s a in ac oss he s udy pe iod.
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TABLE 4 P og ession o se e e COVID‐19 ou comes and suscep ibili y o he i us.
P og ession o se e e COVID‐19 ou comes Suscep ibili y o he i us
CASES: PCR+ cases
hospi alized (N= 2821)
CONTROLS: PCR+
nonhospi alized (N= 26 996)
Adjus ed OR
a
(95% CI) pValue
CASES: PCR+ hospi alized &
nonhospi alized (N= 29 817)
CONTROLS: no
PCR+ (N = 52 318)
Adjus ed OR
a
(95%CI) pValue
S a ins (C10AA) 1009 (35.8)
b
4181 (15.5)
b
0.95 (0.84–1.05) 0.332 5190 (17.4)
b
18 207 (34.8)
b
0.94 (0.90−0.99) 0.013
Sim as a in (C10AA01) 276 (9.8) 1202 (4.5) 0.94 (0.80–1.10) 0.422 1478 (5.0) 5272 (10.1) 0.98 (0.92−1.05) 0.623
Lo as a in (C10AA02) 4 (0.1) 6 (0.0) 1.22 (0.29–5.18) 0.784 10 (0.0) 54 (0.1) 0.94 (0.46−1.92) 0.862
P a as a in (C10AA03) 73 (2.6) 240 (0.9) 1.15 (0.84–1.56) 0.386 313 (1.0) 1220 (2.3) 0.88 (0.77−1.01) 0.073
Flu as a in (C10AA04) 17 (0.6) 27 (0.1) 1.93 (0.95–3.88) 0.067 44 (0.1) 205 (0.4) 0.95 (0.67−1.35) 0.774
A o as a in (C10AA05) 538 (19.1) 2204 (8.2) 0.95 (0.83–1.08) 0.411 2742 (9.2) 9732 (18.6) 0.91 (0.86−0.96) <0.001
Rosu as a in (C10AA07) 83 (2.9) 420 (1.6) 0.85 (0.65–1.12) 0.241 503 (1.7) 1469 (2.8) 0.97 (0.87−1.09) 0.635
Pi a as a in (C10AA08) 29 (1.0) 105 (0.4) 1.17 (0.74–1.86) 0.508 134 (0.4) 420 (0.8) 1.08 (0.88−1.34) 0.456
Abb e ia ion: OR, odds a io.
a
Adjus ed o : sex, age, s a us o heal h p o essional, como bidi ies (hype ension, diabe es, COPD, obesi y, ischemic hea disease, ce eb o ascula acciden , hea ailu e, a ial ib illa ion, ch onic enal ailu e,
cance , as hma, cu en smoke ), cu en use o o he pha macological ea men , and numbe o ea men s o ch onic diseases. Addi ionally, he p ima y‐ca e se ice o e e ence and he pandemic wa e
we e included as andom e ec s.
b
The o e all numbe o subjec s exposed o s a ins (C10AA) is lowe han he sum o hose exposed o he ac i e ing edien s o indi idual s a ins (C10AA01, C10AA02, C10AA03, C10AA04, C10AA05,
C10AA07, C10AA08), due o he ac ha some subjec s we e exposed o mo e han one s a in ac oss he s udy pe iod.
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4|DISCUSSION
In his la ge popula ion‐based case–con ol s udy, ch onic use o
a o as a in was associa ed wi h a lowe isk o hospi aliza ion
(aOR = 0.83; 95% CI: 0.74−0.92, p< 0.001) and mo ali y (aOR = 0.70;
95% CI: 0.53−0.93, p= 0.014), a ibu able in pa o a lowe isk o
suscep ibili y o SARS‐CoV‐2 (aOR = 0.91; 95% CI: 0.86−0.96,
p< 0.001). Ou esul s also indica e ha sim as a in appea s o be
associa ed wi h an impo an dec ease in isk o mo ali y (aOR =
0.59; 95% CI: 0.40−0.87, p= 0.008). The wide deg ee o he e ogene-
i y obse ed in he es ima ed ORs o he di e en s a ins sugges s
ha he e is no class e ec and ha he e ec o each s a in mus
he e o e be conside ed indi idually.
This s udy's la ge sample size enabled us o analyze he e ec o
s a ins by ac i e ing edien , on he ollowing ou come a iables:
(1) se e e COVID‐19 ou comes (de ined as isk o hospi aliza ion and
mo ali y); (2) p og ession o se e e ou comes; and (3) suscep ibili y
o he i us. We we e hus able o asce ain he ole played by each in
he clinical cou se o he disease. Speci ically, we ound ele an
esul s o a o as a in and sim as a in, he s a ins wi h he g ea es
p e alence o use in he s udy popula ion and o e all.
34,35
Ano he impo an inding o ou s udy is ha he clinical
bene i s o s a ins in COVID‐19 would no seem o be due o a class
e ec , in iew o he a iabili y obse ed in he es ima ed ORs o he
espec i e ac i e ing edien s. Indeed, he e is s ong e idence o
show ha s a ins display independen pleio opic e ec s o he
common lipid‐lowe ing mechanism o ac ion and ha hese di e
among he ac i e ing edien s.
36
Fu he mo e, pha macokine ic
cha ac e is ics migh also ha e an in luence on he p o ec i e
capaci y agains COVID‐19, since lipophilic s a ins, such as a o as-
a in and sim as a in, show a wide issue dis ibu ion and a e hus
able o exe p o ec i e e ec s on a g ea e numbe o issues.
37
Hence, we eel ha he esul s ob ained by ou s udy o s a ins as a
whole could be due o he educ ion in isk obse ed in he wo mos
used ac i e ing edien s (a o as a in and sim as a in).
The impo an educ ion in isk o mo ali y associa ed wi h
ch onic use o a o as a in (30%; 95% CI: 7%−47%) is in line wi h
p e ious obse a ional s udies.
37–41
Compa ison wi h expe imen al
s udies is mo e complica ed because, in hese ypes o s udies,
ea men commences when he disease has al eady been con-
ac ed, he eby ende ing i impossible (i) o assess he possible
e ec on suscep ibili y o he i us (some hing which, in he case o
ou s udy, is aken in o accoun by design) and (ii) o e alua e ch onic
use, which is p ecisely wha is hough o ha e a p o ec i e e ec
agains COVID‐19.
19,42,43
We ound only one s udy ha examined
he associa ion be ween a o as a in and isk o hospi aliza ion due
o COVID‐19,
38
and epo ed a e y simila e ec magni ude (0.89;
95% CI: 0.84–0.95) e sus (0.83; 95% CI: 0.74−0.92). Al hough
hospi aliza ion is mo e dependen on clinical c i e ia and he
a ailabili y o hospi al beds, i may be o g ea in e es in public
heal h.
44,45
Thus, ou indings ega ding he ma ked educ ion in isk
o hospi aliza ion and mo ali y associa ed wi h a o as a in, aken
oge he wi h i s bene i ‐ isk‐cos a io,
40
could imply ha
conside a ion should be gi en o a o as a in being ecommended
as a i s ‐line d ug o pa ien s wi h indica ion o lipid‐lowe ing
ea men , in si ua ions o high COVID‐19 incidence.
Inso a as sim as a in is conce ned, ou mo ali y esul s a e also
consis en wi h he scan li e a u e a ailable.
34,37,38
Due o his
d ug's po en ial as adju an ea men o COVID‐19 desc ibed in
p eclinical models,
46,47
we eel ha he mo ali y‐ ela ed esul s
ob ained by us should be he subjec o u he epidemiological
esea ch.
The main s eng hs o his s udy a e i s la ge sample size
(encompassing mo e han 82 000 subjec s) and adjus men o many
con ounding a iables, which enabled us o accu a ely es ima e he
possible associa ion be ween ch onic use o di e en s a ins
and p ognosis o COVID‐19 (suscep ibili y, p og ession o se e e
COVID‐19 ou comes, hospi aliza ion, and mo ali y). Fu he mo e,
exposu e o d ugs was based on dispensing da a (i.e., medica ions
eally acqui ed by pa ien s), unlike o he s udies which use
p esc ip ion‐based da a sou ces (p esc ip ions issued).
The s udy also has se e al limi a ions. Fi s , he ac o i being an
obse a ional s udy wi h seconda y da abases means ha one canno
ule ou he exis ence o esidual con ounding o unmeasu ed o
misclassi ied co a ia es, such as he absence o da a on he deg ee o
se e i y o he main como bidi ies associa ed wi h g ea e COVID‐19
se e i y. Second, he lack o ma ching in he subs udies on
suscep ibili y and p og ession o se e e COVID‐19 ou comes could
be conside ed a u he limi a ion. E en so, his ci cums ance has no
impac on he alidi y o he s udy, since he absence o ma ching
would only esul in lowe e ec i eness a he han a highe isk o
biases.
28,29
Finally, he da a a ailable o s udy pu poses pe ain o
2020, when he p edominan SARS‐CoV‐2 a ian s in his coun y
we e hose o he 19B clade.
48
Tha said, howe e , we ha e no
eason o belie e ha he e ec o a o as a in (and sim as a in)
agains COVID‐19 migh be in luenced by he p esence o dominan
a ian s.
5|CONCLUSIONS
Despi e no able scien i ic and medical ad ances, COVID‐19 con-
inues o be a public heal h h ea . In p esen and u u e pandemics
alike, apid iden i ica ion o known e ec i e he apies is undamen-
al,
49
and o his end, i is necessa y o dis inguish be ween d ug‐class
a ge s and molecule‐speci ic mechanisms. Ou esul s show ha
ch onic use o a o as a in (and possibly, o sim as a in) is associa ed
wi h a educ ion in se e e COVID‐19 ou comes. Gi en ha he
p e alence o s a in use is e y high in de eloped coun ies,
50
a g ea
numbe o people could be doubly bene i ed (i.e., COVID‐19 and
ca dio ascula p e en ion) by ea men wi h a o as a in.
AUTHOR CONTRIBUTIONS
I ene Visos‐Va ela: W i ing o iginal d a p epa a ion. Ma uxa
Zapa a‐Cacha ei o: Concep ualiza ion; me hodology; w i ing—
e iew and edi ing. Samuel Pin os‐Rod íguez: W i ing— e iew and
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edi ing. Rosendo Buga ín‐González: Me hodology; w i ing— e iew
and edi ing. F ancisco Ja ie González‐Ba cala: Me hodology;
w i ing— e iew and edi ing. Ma ia T. He dei o: Me hodology;
w i ing— e iew and edi ing. Ma ía Piñei o‐Lamas: Fo mal analysis.
Adol o Figuei as: Concep ualiza ion; me hodology; unding acquisi-
ion; w i ing— e iew and edi ing. Ángel Salgado‐Ba ei a: Concep-
ualiza ion; me hodology; w i ing— e iew and edi ing.
ACKNOWLEDGMENTS
The au ho s should like o hank he SERGAS Gene al Heal hca e
Di ec o a e o u nishing he da a needed o conduc his s udy,
DXC Technology o i s wo k in ex ac ing he s udy da a, and
Michael Benedic o e iewing and e ising he English. This s udy
was sponso ed by he Ca los III Ins i u e o Heal h ia he “COV20/
00470”p ojec (co unded by he Eu opean Regional De elopmen
Fund, “A way o make Eu ope”).
CONFLICT OF INTEREST STATEMENT
The au ho s decla e no con lic o in e es .
DATA AVAILABILITY STATEMENT
The da a se s gene a ed and analyzed du ing he cu en s udy a e no
publicly a ailable due o Galician Public Heal h Sys em es ic ions.
ETHICS STATEMENT
The s udy was app o ed by he Galician Clinical Resea ch E hics
Commi ee ( e e ence 2020‐349), ce i ied by he Spanish Agency o
Medicines and Medical De ices, and conduc ed in acco dance wi h
he Helsinki Decla a ion and Spanish legisla ion go e ning biomedical
s udies and espec o human igh s. The s udy p o ocol was
egis e ed a he Eu opean Union Elec onic Regis e o Pos ‐
Au ho isa ion S udies (EU PAS, eg. no. EUPAS44587) and is a ailable
online a h ps://www.encepp.eu/encepp/ iewResou ce.h m?id=
44588. Da a ex ac ion was au oma ed and anonymous o ensu e
subjec s' con iden iali y and p i acy.
ORCID
I ene Visos‐Va ela h p://o cid.o g/0000-0001-6466-6213
Ma uxa Zapa a‐Cacha ei o h p://o cid.o g/0000-0002-
0648-7716
Samuel Pin os‐Rod íguez h p://o cid.o g/0009-0007-8315-6463
F ancisco Ja ie González‐Ba cala h p://o cid.o g/0000-0001-
5847-4784
Ma ia T. He dei o h p://o cid.o g/0000-0002-0500-4049
Ma ía Piñei o‐Lamas h p://o cid.o g/0000-0003-3655-100X
Adol o Figuei as h p://o cid.o g/0000-0002-5766-8672
Ángel Salgado‐Ba ei a h p://o cid.o g/0000-0003-4349-4947
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