Risk o pneumonia associa ed wi h use o angio ensin
con e ing enzyme inhibi o s and angio ensin ecep o
blocke s: sys ema ic e iew and me a-analysis
OPEN ACCESS
Daniel Caldei a ca diologis esiden , assis an o clinical pha macology 1, Joana Ala cão scien i ic
consul an , assis an o clinical pha macology2, An ónio Vaz-Ca nei o clinical p o esso o medicine,
di ec o o he Cen e o E idence-Based Medicine2 3, João Cos a p o esso o clinical pha macology,
coo dina o o he Po uguese Coch ane Cen e 123
1Labo a o y o Clinical Pha macology and The apeu ics, Facul y o Medicine, Uni e si y o Lisbon; 2Cen e o E idence-Based Medicine, Facul y
o Medicine, Uni e si y o Lisbon, A enue P o esso Egas Moniz, 1649-028, Lisbon, Po ugal; 3Coch ane Coo dina ing Cen e Po ugal, Facul y o
Medicine, Uni e si y o Lisbon
Abs ac
Objec i e To sys ema ically e iew longi udinal s udies e alua ing use
o angio ensin con e ing enzyme (ACE) inhibi o s o angio ensin ecep o
blocke s (ARBs) and isk o pneumonia.
Design Sys ema ic e iew and me a-analysis.
Da a sou ces Medline h ough PubMed, Web o Science wi h con e ence
p oceedings (incep ion o June 2011), and US Food and D ug
Adminis a ion websi e (June 2011). Sys ema ic e iews and e e ences
o e ie ed a icles we e also sea ched.
S udy selec ion Two e iewe s independen ly selec ed andomised
con olled ials and coho and case-con ol s udies e alua ing he use
o ACE inhibi o s o ARBs and isk o pneumonia and e ie ed
cha ac e is ics o he s udies and da a es ima es.
Da a syn hesis The p ima y ou come was incidence o pneumonia and
he seconda y ou come was pneumonia ela ed mo ali y. Subg oup
analyses we e ca ied acco ding o baseline mo bidi ies (s oke, hea
ailu e, and ch onic kidney disease) and pa ien s’ cha ac e is ics (Asian
and non-Asian). Pooled es ima es o odds a ios and 95% con idence
in e als we e de i ed by andom e ec s me a-analysis. Adjus ed
equen is indi ec compa isons be ween ACE inhibi o s and ARBs we e
es ima ed and combined wi h di ec e idence whene e a ailable.
He e ogenei y was assessed using he I2 es .
Resul s 37 eligible s udies we e included. ACE inhibi o s we e associa ed
wi h a signi ican ly educed isk o pneumonia compa ed wi h con ol
ea men (19 s udies: odds a io 0.66, 95% con idence in e al 0.55 o
0.80; I2=79%) and ARBs (combined di ec and indi ec odds a io es ima e
0.69, 0.56 o 0.85). In pa ien s wi h s oke, he isk o pneumonia was
also lowe in hose ea ed wi h ACE inhibi o s compa ed wi h con ol
ea men (odds a io 0.46, 0.34 o 0.62) and ARBs (0.42, 0.22 o 0.80).
ACE inhibi o s we e associa ed wi h a signi ican ly educed isk o
pneumonia among Asian pa ien s (0.43, 0.34 o 0.54) compa ed wi h
non-Asian pa ien s (0.82, 0.67 o 1.00; P<0.001). Compa ed wi h con ol
ea men s, bo h ACE inhibi o s (se en s udies: odds a io 0.73, 0.58 o
0.92; I2=51%) and ARBs (one andomised con olled ial: 0.63, 0.40 o
1.00) we e associa ed wi h a dec ease in pneumonia ela ed mo ali y,
wi hou di e ences be ween in e en ions.
Conclusions The bes e idence a ailable poin s owa ds a pu a i e
p o ec i e ole o ACE inhibi o s bu no ARBs in isk o pneumonia.
Pa ien popula ions ha may bene i mos a e hose wi h p e ious s oke
and Asian pa ien s. ACE inhibi o s we e also associa ed wi h a dec ease
in pneumonia ela ed mo ali y, bu he da a lacked s eng h.
In oduc ion
Pneumonia ep esen s an impo an clinical condi ion because
o i s ela i ely high incidence (0.5% o 1.1% annually in he
Uni ed Kingdom) and associa ed mo bidi y and mo ali y.1 2
Suscep ibili y is highe among elde ly people (≥65 yea s), hose
wi h alcohol dependency, smoke s, and pa ien s wi h hea
ailu e, p e ious s oke, diabe es, ch onic kidney disease, and
ch onic lung disease.3-6 Pneumonia is a common eason o
hospi al admission and a isk ac o o p olonged hospi al s ay,
ca ying a conside able inancial bu den on heal hca e
esou ces.7 8
Co espondence o: J Cos a [email p o ec ed]
Ex a ma e ial supplied by he au ho (see h p://www.bmj.com/con en /345/bmj.e4260? ab= ela ed#webex a)
Sea ch s a egy
Supplemen a y igu es 1-13
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Resea ch
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Usage o some d ugs has been shown o modula e he isk o
pneumonia. Acid supp essan s can inc ease pa ien s’
suscep ibili y o pneumonia, whe eas s a ins may ha e a
p o ec i e ole.9 10 Angio ensin con e ing enzyme (ACE)
inhibi o s and angio ensin ecep o blocke s (ARBs) a e o en
used in pa ien s wi h ca dio ascula disease. ACE inhibi o s a e
known o ha e ad e se e ec s on he espi a o y sys em, in
pa icula an inc eased incidence o cough. Basic in es iga ion
has shown ha b adykinin and subs ance P sensi ise he senso y
ne es o he ai ways and enhance he cough e lex,11-13 which
may ha e a p o ec i e ole on he acheob onchial ee.14 15
These mechanisms also imp o e swallowing by a oiding he
exposu e o he espi a o y ee o o opha ynx sec e ions.11 14 16
Taken oge he , he pleio opic e ec s o ACE inhibi o s we e
sugges ed o educe he incidence o pneumonia, bu a ailable
clinical e idence lacks s eng h17-19 and published esul s ha e
been con adic o y.20-22
We sys ema ically e iewed and me a-analysed all s udies
(expe imen al and obse a ional) e alua ing he use o ACE
inhibi o s and incidence o pneumonia. Because he clinical
cha ac e is ics and isk ac o s o popula ions using ARBs a e
simila o hose o pa ien s using ACE inhibi o s, and he e o e
s udies e alua ing hese in e en ions sha e iden ical po en ial
clinical con ounde s, we also es ima ed he incidence o
pneumonia in s udies e alua ing ARBs. Mo eo e , pa ien s
ea ed wi h ARBs a e less likely o expe ience espi a o y
ad e se e en s,23 24 and he e o e ARBs may ha e a p o ec i e
ole.
Me hods
The sys ema ic e iew was ca ied ou in acco dance wi h he
me a-analysis o obse a ional s udies in epidemiology and
p e e ed epo ing i ems o sys ema ic e iews and
me a-analyses s a emen s.25 26
Ou p ima y ou come was he incidence o pneumonia. We
conside ed cases o pneumonia, lowe espi a o y ac
in ec ions, and admissions o hospi al due o lowe espi a o y
ac in ec ions. Da a we e ex ac ed i espec i e o whe he
hey had been epo ed as p ede ined ou comes o as ad e se
e ec s. I s udies epo ed da a o dea h om pneumonia only,
o a oid duplica ion we did no conside hese cases o he
p ima y ou come. The seconda y ou come was pneumonia
ela ed mo ali y, de ined as dea h di ec ly ela ed o his
condi ion o in-hospi al dea h o mo ali y wi hin 30 days a e
onse o pneumonia.27 Fo bo h ou comes, we did no conside
unde ined da a o da a on uppe espi a o y ac in ec ions.
We conside ed andomised con olled pa allel ials, coho
s udies, and case-con ol s udies wi h ACE inhibi o s o ARBs
as in e en ions and wi h p ede ined ou comes. T ea men a ms
could compa e ACE inhibi o s and ARBs wi h each o he o
wi h placebo o any o he ac i e d ug. Coho s udies could be
based on popula ions in he communi y o hose in ins i u ions
o hospi al and had o ollow pa ien s o de e mine pneumonia
ou comes.
In case-con ol s udies, cases had o be de ined as pa ien s wi h
new onse pneumonia iden i ied h ough clinical examina ion,
adiological me hods, o da abase codes. Con ols had o be
ma ched o cases, bu wi hou new onse pneumonia. Fo
pneumonia ela ed mo ali y, we allowed case-con ol s udies
wi h bo h cases and con ols ha ing pneumonia.
We allowed all pa icipan s, i espec i e o baseline diseases
and isk ac o s.
In o ma ion sou ces and sea ch me hod
We iden i ied po en ially eligible s udies h ough an elec onic
sea ch o bibliog aphic da abases om incep ion o June 2011
(Medline h ough PubMed and Web o Science wi h con e ence
p oceedings). See he supplemen a y ile o de ails o he sea ch
s a egy. No language es ic ions we e applied. We sc eened
and c oss checked iden i ied sys ema ic e iews and
me a-analyses e alua ing ACE inhibi o s o ARBs, as well as
e e ence lis s o pape s o po en ial addi ional s udies. We also
sea ched he Food and D ug Adminis a ion websi e (10 June
2011) o egula o y documen s wi h unpublished da a om
clinical ials.
S udy selec ion and da a collec ion p ocess
The i les and abs ac s o ob ained eco ds we e sc eened.
Doub s and disag eemen s we e esol ed by consensus. We
assessed he selec ed s udies in ull ex o de e mine
app op ia eness o inclusion. Two au ho s independen ly
ex ac ed da a on s udy design, loca ion, pe iod o s udy,
pa ien s’ cha ac e is ics, d ug use and how i was assessed,
p ima y ou comes, da a o equi ed ou comes, and adjus men s
o es ima es.
When s udies p esen ed di e en es ima es on p ima y ou comes
acco ding o he se e i y o pneumonia, we ex ac ed o analysis
only hose epo ing he mos se e e cases. Fo he p ima y
ou come we conside ed d ug wi hd awals due o pneumonia
only when no o he es ima es we e a ailable. When mo e han
one isk es ima e was a ailable om se e al sou ces, we used
only he mos p ecise o adjus ed measu es o associa ion om
each epo . O he wise we used he c ude odds a io o de i ed
i om he aw da a.
Two au ho s (DC and JA) independen ly analysed he quali y
o epo ing by using a quali a i e classi ica ion acco ding o
isk o bias (high, unclea , o low). Fo obse a ional s udies
we used a six i em classi ica ion based on he me a-analysis o
obse a ional s udies in epidemiology,25 he quali y assessmen
ool o sys ema ic e iews o obse a ional s udies,28 and
s eng hening he epo ing o obse a ional s udies in
epidemiology.29 This sys em was adap ed om a p e iously
published sys ema ic e iew30 31 and ook in o conside a ion he
pa icipan s (i any jus i ica ion was gi en o he coho and
he s udy epo ed app op ia e inclusion and exclusion c i e ia),
in e en ion (i d ug use was adequa ely assessed and no based
on sel epo ), ou come (i pneumonia was assessed by clinical
examina ion, adiological me hods, o da abase codes and no
based on sel epo ), and ou come adjus men s ( o bo h age
and a leas one o he ollowing: smoke o pulmona y disease,
ca dio ascula diseases o d ug use o ch onic kidney disease;
o he adjus men s). Fo andomised con olled ials we adap ed
he Coch ane Collabo a ion’s ool o assessing isk o bias o
e alua e he quali y o epo ing: andomisa ion me hod,
alloca ion concealmen , blinding o pa icipan s and s a ,
blinding o ou come assessmen , selec i e epo ing (i
pneumonia was a p especi ied ou come), and desc ip ion o
wi hd awals.32 F om hese ools we de i ed isk o bias g aphs.
S a is ical analysis
We used Re Man 5.1.4 so wa e o s a is ical analysis (No dic
Coch ane Cen e, Coch ane Collabo a ion, 2011) and o de i e
o es plo s showing he esul s o indi idual s udies and pooled
analysis.
We ca ied ou h ee analyses. Fi s ly, we compa ed ACE
inhibi o s and ARBs wi h each con ol g oup using andom
e ec s me a-analysis weigh ed by he in e se a iance me hod
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RESEARCH
o es ima e pooled odds a ios and 95% con idence in e als.
He e ogenei y was assessed wi h he I2 es , which measu es he
pe cen age o o al a ia ion be ween s udies due o
he e ogenei y.33 We used he andom e ec s model
independen ly o he exis ence (I2≥50%) o subs an ial
he e ogenei y be ween he esul s o ials, as we pooled he
esul s o s udies wi h di e en designs and pa ien s’
cha ac e is ics. We chose he odds a io as he measu emen
es ima e o e ec because ela i e es ima es a e mo e simila
han absolu e e ec s ac oss s udies wi h di e en designs,
popula ions, and leng hs o ollow-up.34 Raw da a we e i s
con e ed o odds a ios h ough classic me hods, o h ough
Pe o’s me hod i one a m had a ze o coun cell. When aw da a
o odds a ios we e no a ailable we ook he haza d a io o
isk a io o analysis. To explo e di e ences in es ima es o
ou comes we p esen ed he esul s s a i ied acco ding o s udy
design. Fo he pu pose o he analysis we ea ed nes ed
case-con ol s udies as coho s udies. We ca ied ou subg oup
analyses o pa ien s wi h p e ious s oke, hea ailu e, and
ch onic kidney disease because such pa ien s a e known o be
pa icula ly suscep ible o pneumonia and all indica ions a e
clinically app o ed o ea men wi h ACE inhibi o s and
ARBs.5 6 35 36 In iew o he sugges ion ha ACE inhibi o s may
be mo e e icien in educing he isk o pneumonia in Asian
pa ien s we also calcula ed es ima es o Asian and non-Asian
popula ions.37 We e alua ed di e ences be ween subg oups
wi h he me hod desc ibed by Deeks e al, based on he in e se
a iance me hod.33
In he second analysis we ca ied ou adjus ed indi ec
compa isons be ween he pooled es ima e o ACE inhibi o s
( e sus con ol) and ARBs ( e sus con ol) using he Buche
equen is me hod, which compa es di e en ea men s
adjus ed o he esul s o hei di ec compa ison wi h a common
con ol.38 This me hod pa ially o e comes he p oblem o
di e en p ognos ic cha ac e is ics be ween pa icipan s among
s udies, and i is belie ed o be alid assuming ha he ela i e
e ec o in e en ions is consis en ac oss di e en s udies, as
e i ied in ou case.39 By de aul we used he andom e ec s
model because adjus ed indi ec compa isons ha used he ixed
e ec s model end o unde es ima e he s anda d e o s o pooled
es ima es.39
Thi dly, we combined e idence gene a ed by indi ec
compa isons wi h e idence om head o head s udies compa ing
ACE inhibi o s wi h ARBs using he andom e ec s model o
quan i a i e pooling,40 41 and we de e mined he disc epancy
and he e ogenei y be ween di ec and indi ec es ima es.42
We also calcula ed he numbe needed o ea (NNT) and 95%
con idence in e als, aking in o accoun he baseline isk
(weigh ed p opo ion o e en a e in con ol g oup) because o
he di e ences in he p edic ed absolu e bene i o ea men
acco ding o a ia ion in baseline isk be ween g oups.34 43 In
ou case, he weigh ed isk o pneumonia in he con ol g oups
was 4.6% (95% con idence in e al 3.1% o 6.7%). Publica ion
bias was assessed h ough isual inspec ion o he asymme y
in unnel plo s.
Resul s
The sea ch o he elec onic da abases yielded 807 published
s udies. A e applying he inclusion and exclusion c i e ia 29
s udies we e included o analysis ( ig 1⇓). The esul s om
eigh addi ional s udies we e iden i ied in he FDA egula o y
documen s. O e all, da a we e ob ained om 37 s udies.20-22 44-79
Desc ip ion o s udies
The 37 s udies included 18 andomised con olled ials,20 44-61
11 coho s udies,62-73 wo nes ed case-con ol s udies,21 74 and
six case-con ol s udies.22 75-79
Among andomised con olled ials, eigh we e done
wo ldwide,47 48 51 52 55 57 58 61 six in Eu ope,44-46 53 56 60 h ee in
Asia,49 50 59, and one in Eu ope and he Uni ed S a es.54 Mos o
he andomised con olled ials we e mul icen e (n=16). Se en
andomised con olled ials compa ed ACE inhibi o s wi h
con ols,44-50 nine compa ed ARBs wi h con ols,51-59 and wo
compa ed ACE inhibi o s wi h ARBs.60 61 Se en ials epo ed
speci ic da a o se ious pneumonia, i e o a al pneumonia,
and eigh epo ed pneumonia wi hou speci ying he se e i y
o disease. In only wo ials was pneumonia a p especi ied
ou come.49 59
Among obse a ional s udies, 10 we e ca ied ou in Asia, i e
in he Uni ed S a es, and ou in Eu ope. Ele en s udies we e
e ospec i e and eigh we e p ospec i e. Se en een e alua ed
ACE inhibi o s, wo ARBs, and wo compa ed ACE inhibi o s
wi h ARBs.
Tables 1 o 3⇓⇓⇓ summa ise he main cha ac e is ics o he
included s udies.
The o e all quali y o he s udies was conside ed o be good.
All he andomised con olled ials, excep one,51 me he c i e ia
o andom sequence gene a ion and abou hal speci ically
epo ed adequa e alloca ion concealmen .46 48 50 54 55 57 58 61 Only
wo andomised con olled ials56 59 we e conside ed o be a
high isk o pe o mance bias. Adequa e blinding o ou come
assessmen 45-48 50 52-59 61 and ull desc ip ion o s udy
wi hd awals44-55 57 58 60 61 we e epo ed in 78% and 89% o
andomised con olled ials, espec i ely. The highes isk o
bias was ound o po en ial epo ing bias because only wo
andomised con olled ials p esen ed esul s o pneumonia
as a p especi ied ou come.49 59 Supplemen a y igu es 1 and 2
show he esul s o he quali y app aisal o he andomised
con olled ials.
All obse a ional s udies we e conside ed o ha e adequa e
inclusion and exclusion c i e ia and p o ided jus i ica ion o
he coho . Fi e s udies (26%)62-64 66 69 did no clea ly s a ed how
he d ug use was assessed, and ou s udies (21%)63 64 66 73 did
no p o ide de ails abou ou come assessmen . Ele en s udies
(58%)21 22 68 70-72 74 75 77 79 p o ided esul s a e adjus men o a
leas one po en ial a iable con ounde . In one s udy76 i was
unclea o which a iables he esul s we e adjus ed. Few
s udies (26%) epo ed esul s adjus ed o mul iple con ounde s,
and in se en s udies (37%) no ype o adjus men was
men ioned. Supplemen a y igu es 3 and 4 show he esul s o
he quali y o he obse a ional s udies.
P ima y ou come: incidence o pneumonia
P ima y ou come da a we e a ailable om 19 s udies compa ing
ACE inhibi o s wi h con ols ( i e andomised con olled ials,
eigh coho o nes ed case-con ol s udies, and six case-con ol
s udies), 11 s udies compa ing ARBs wi h con ols (nine
andomised con olled ials and wo coho o nes ed
case-con ol s udies), and wo s udies compa ing ACE inhibi o s
wi h ARBs (one andomised con olled ial and one coho
s udy).
Use o ACE inhibi o s was associa ed wi h a signi ican 34%
educ ion in isk o pneumonia compa ed wi h con ols (odds
a io 0.66, 95% con idence in e al 0.55 o 0.80; I2=79%). The
NNT o 2.0 yea s was 65 (48 o 112). The magni ude o he
isk educ ion was simila ac oss all s udy designs (P=0.78 o
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RESEARCH
subg oup di e ences). The odds a ios o andomised con olled
ials, coho o nes ed case-con ol s udies, and case-con ol
s udies we e 0.69 (0.56 o 0.85; I2=0%), 0.58 (0.38 o 0.88;
I2=79%), and 0.67 (0.49 o 0.93; I2=73%), espec i ely ( ig 2⇓).
The isk o pneumonia was no , howe e , di e en be ween
pa ien s who did o did no use ARBs (0.95, 0.87 o 1.04;
I2=14%). Odds a io es ima es o andomised con olled ials
(0.90, 0.79 o 1.01; I2=7%) and coho o nes ed case-con ol
s udies (1.01, 0.94 o 1.09; I2=0%) did no di e signi ican ly
(P=0.10; ig 3⇓).
Pooled esul s om he wo head o head s udies showed a
non-signi ican 37% educ ion in isk o pneumonia associa ed
wi h use o ACE inhibi o s (0.63, 0.28 o 1.44; I2=78%). In his
case, es ima es om he andomised con olled ial and coho
s udy di e ed signi ican ly (P=0.03) (see supplemen a y igu e
5).
Indi ec compa ison o ACE inhibi o s wi h ARBs showed a
signi ican 30% educ ion in isk o pneumonia associa ed wi h
use o ACE inhibi o s (0.70, 0.56 o 0.86). Simila esul s we e
ob ained om pooled di ec and indi ec es ima es (0.69, 0.56
o 0.85) wi hou disc epancy (P=0.82) o he e ogenei y (I2=0%)
be ween bo h es ima es ( ig 4⇓). The NNT o 2.2 yea s based
on his es ima e was 72 (51 o 147).
Subg oup analyses o p ima y ou come
Pa ien s wi h p e ious s oke
In pa ien s wi h p e ious s oke, use o ACE inhibi o s was
associa ed wi h a 54% educ ion in isk o pneumonia compa ed
wi h con ols (0.46, 0.34 o 0.62, I2=0%; se en s udies pooled)
(see supplemen a y igu e 6). In he same popula ion, howe e ,
use o ARBs was no associa ed wi h a signi ican educ ion in
isk (0.86, 0.67 o 1.09; I2=0%; wo s udies pooled) (see
supplemen a y igu e 7).
The pooled es ima e om indi ec (odds a io 0.53, 95%
con idence in e al 0.16 o 1.79) and di ec (0.38, 0.17 o 0.81)
e idence o ACE inhibi o s compa ed wi h ARBs showed a
signi ican 58% educ ion in isk o pneumonia (0.42, 0.22 o
0.80; ig 4), wi hou disc epancy (P=0.44) o he e ogenei y
(I2=0%) be ween indi ec and di ec es ima es.
Pa ien s wi h hea ailu e
In pa ien s wi h hea ailu e, wo s udies e alua ed he isk o
pneumonia in hose ea ed wi h ACE inhibi o s44 45 and wo
o he s udies epo ed da a o hose ea ed wi h ARBs.51 52 ACE
inhibi o s we e associa ed wi h a signi ican 37% educ ion in
isk o pneumonia (0.63, 0.47 o 0.84; I2=0%), whe eas ARBs
showed no signi ican e ec (0.85, 0.49 o 1.47; I2=15%) (see
supplemen a y igu e 8).
Pa ien s wi h ch onic kidney disease
In pa ien s wi h ch onic kidney disease, he esul s om one
andomised con olled ial o ACE inhibi o s46 (odds a io 0.15,
95% con idence in e al 0.00 o 7.70) and wo andomised
con olled ials o ARBs52 53 (1.21, 0.32 o 4.52; I2=77%) did
no di e signi ican ly when compa ed wi h con ols (see
supplemen a y igu e 9).
Asian and non-Asian pa ien s
Ele en s udies we e ca ied ou in Asian coun ies and 11 we e
done ou side o Asia. The PROGRESS20 s udy was he only
mul icen e s udy ca ied ou wo ldwide ha supplied sepa a e
da a o Asian and non-Asian pa ien s. To lowe analysis bias,
he o he s udies ca ied ou wo ldwide ha did no p o ide
sepa a e da a o bo h g oups we e excluded.
The educ ion in isk o pneumonia associa ed wi h ACE
inhibi o s was signi ican ly highe among Asian pa ien s (0.43,
0.34 o 0.54; I2=0%) compa ed wi h non-Asian pa ien s (0.82,
0.67 o 1.00, I2=80%, P<0.001 o subg oup di e ences) (see
supplemen a y igu e 10). ARBs, howe e , we e no associa ed
wi h a educ ion in isk o pneumonia in Asian pa ien s (1.04,
0.59 o 1.84; one andomised con olled ial HIJ-CREATE59)
o non-Asian pa ien s (0.97, 0.84 o 1.12; I2=27%; i e s udies
pooled; ig 4 and supplemen a y igu e 11).
Seconda y ou come: pneumonia ela ed
mo ali y
Da a o seconda y ou comes we e ex ac ed om se en s udies
compa ing ACE inhibi o s wi h con ols ( h ee andomised
con olled ials and ou coho s udies),20 49 50 68 70-72 one
andomised con olled ial compa ing ARBs wi h con ol,55 and
one head o head andomised con olled ial.60 Fi e s udies
compa ing ACE inhibi o s wi h con ols we e ca ied ou on an
en iched popula ion— ha is, en olled pa ien s wi h
pneumonia.49 68 70-72
T ea men wi h ACE inhibi o s was associa ed wi h a signi ican
27% educ ion in isk o pneumonia ela ed mo ali y compa ed
wi h con ols (0.73, 0.58 o 0.92; I2=51%), wi hou signi ican
di e ences be ween es ima es om andomised con olled ials
and obse a ional s udies (P=0.76). The pooled esul om
andomised con olled ials, howe e , ailed o each s a is ical
signi icance (0.61, 0.20 o 1.90; I2=61%) ( ig 5⇓).
Only one andomised con olled ial55 epo ed he e ec o
ea men wi h ARBs on pneumonia ela ed mo ali y (odds
a io 0.63, 95% con idence in e al 0.40 o 1.00) ( ig 5).
The isk o pneumonia ela ed mo ali y in indi ec (1.16, 0.69
o 1.94), di ec (HEAVEN andomised con olled ial60 7.29,
0.14 o 367.24), and pooled compa isons (1.19, 0.71 o 1.98)
did no di e be ween ACE inhibi o s and ARBs ( ig 4). The e
was no disc epancy (P=0.36) o he e ogenei y (I2=0%) be ween
indi ec and di ec es ima es.
Publica ion bias
Visual inspec ion o unnel plo s did no e eal any ob ious
asymme ical ail (see supplemen a y igu e 12). Publica ion
bias was no sugges ed by sensi i i y analysis aking in o accoun
published and unpublished ials (see supplemen a y igu e 13).
Discussion
In his sys ema ic e iew we ound ha ea men wi h
angio ensin con e ing enzyme (ACE) inhibi o s was associa ed
wi h a signi ican educ ion in isk o pneumonia compa ed wi h
con ol ea men and angio ensin ecep o blocke s (ARBs);
he magni ude o his educ ion (abou one hi d) was simila
ac oss s udies wi h di e en designs ( andomised con olled
ials, coho , and case-con ol s udies). The isk o pneumonia
was also educed in pa ien s ea ed wi h ACE inhibi o s who
we e a highe isk o pneumonia, in pa icula hose wi h s oke
and hea ailu e. Mos o he po en ial p o ec i e bene i om
ACE inhibi o s seemed o be in Asian pa ien s; i is unclea
whe he he me hodology o he s udies o he clinical and
gene ic cha ac e is ics o he pa ien s we e esponsible o his
inding. Use o ACE inhibi o s was also associa ed wi h a
educ ion in pneumonia ela ed mo ali y, al hough he esul s
we e less obus han o o e all isk o pneumonia; i is
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RESEARCH
unce ain i di e ences exis be ween ACE inhibi o s and ARBs
o his ou come.
The p esen e iew was designed o de e mine he e ec o
ea men wi h ACE inhibi o s and ARBs on isk o pneumonia.
We combined da a om bo h expe imen al and obse a ional
s udies o ob ain mo e obus esul s, mainly because no
andomised con olled ial was p ima ily designed wi h his
objec i e. Pneumonia is no a a e ou come (pa icula ly in
popula ions ea ed wi h ACE inhibi o s o ARBs) o an ou come
ha only occu s mon hs o yea s a e use o ACE inhibi o s o
ARBs. The e o e andomised con olled ials would ha e been
an app op ia e s udy design o deal wi h his p oblem. We ound
signi ican s a is ical he e ogenei y o ACE inhibi o s bu no
o ARB esul s. This was due o he esul s o obse a ional
s udies (no he e ogenei y was ound among andomised
con olled ials). Ne e heless, he obse ed s a is ical
he e ogenei y was mo e quan i a i e han quali a i e because
all es ima es o s udy designs sha e he same di ec ion. This
consis ency, as well as he obus ness o educ ion in he isk
o pneumonia ac oss all s udy designs, sugges s ha use o ACE
inhibi o s dese es a en ion. Fu he mo e, ha ACE inhibi o s
educed he isk o pneumonia compa ed no only wi h he
con ol g oup bu also wi h ARB ea men , is eassu ing because
pa ien s’ cha ac e is ics and isk ac o s, as well as o he
po en ial clinical and me hodological con ounde s a e p obably
simila be ween s udies on ARBs and hose on ACE inhibi o s.
We we e also conse a i e in ou analysis because we did no
conside unde ined da a o da a on uppe espi a o y ac
in ec ions, and when s udies p esen ed di e en es ima es
acco ding o he se e i y o pneumonia we ex ac ed hose
epo ing only he mos se e e cases and he mos p ecise o
adjus ed measu e.
Ou indings ha e po en ial clinical implica ions. ACE inhibi o s
a e widely p esc ibed and p esc ip ions may be in luenced by
conce ns abou po en ial ad e se e ec s, in pa icula cough,
which may be p o ec i e. The incidence o ACE inhibi o
induced cough has been epo ed o be in he ange o 5% o
35%.80 Ou esul s sugges ha pa ien s aking ACE inhibi o s
who de elop cough should, p o iding ha cough is ole able,
pe sis wi h ea men . Compliance and pe sis ence wi h
ea men is impo an . Fu he mo e, om an e idence based
pe spec i e, he e is li le o choose be ween ACE inhibi o s
and he mo e expensi e ARBs. Howe e , in he case o a
pa icula pa ien , in whom ACE inhibi o s and ARBs a e
p esumed o ha e simila clinical bene i , ou esul s may also
in luence he choice o p esc ip ion in hose a high isk o
pneumonia. The e o e pa ien s wi h isk ac o s o pneumonia
and mo bidi ies ha equi e ea men wi h ACE inhibi o s may
ha e an addi ional eason o con inue ea men .
A u he impo an aspec o ou esul s was he educ ion in
isk o pneumonia ac oss high isk pa ien s, which p o ided
consis ency o he o e all esul s. Pa ien s wi h p e ious s oke
ha e inc eased suscep ibili y o pneumonia owing o isk o
aspi a ion associa ed wi h dec eased p o ec i e e lexes o he
espi a o y sys em media ed by subs ance P and pos -s oke
dysphagia.14 81 Abou 20% o hese pa ien s will de elop
pneumonia,82 which is a p edic o o poo unc ional ou come83 84
and a ele an cause o dea h.84 85 The pu a i e p o ec i e e ec
o ACE inhibi o s in his popula ion was p edic able gi en he
impo ance o dysphagia and subs ance P in hese pa ien s.
Acco ding o one s udy, ARBs do no inc ease he le els o
subs ance P o imp o e asymp oma ic dysphagia.86 This
highligh s he impo ance o using ACE inhibi o s in pa ien s
wi h p e ious s oke who ha e como bidi ies o which ACE
inhibi o s a e ecommended.
Only a ew s udies e alua ed o he popula ions wi h inc eased
isk, such as pa ien s wi h hea ailu e o ch onic kidney disease.
Fo pa ien s wi h hea ailu e, he dec eased isk o pneumonia
was also ound in pa ien s ea ed wi h ACE inhibi o s. The
sugges ed e ec was signi ican bu his e alua ion lacked obus
da a. ARBs did no show any p o ec i e e ec .
The pu a i e p e en i e e ec o ACE inhibi o s on pneumonia
in Asian pa ien s has been sugges ed.37 We explo ed his
subg oup and compa ed he e ec wi h non-Asian pa ien s.
Fu he mo e, we ob ained a conside able weigh o e idence
om s udies ha e alua ed Asian pa ien s. ACE inhibi o s
signi ican ly educed he isk o pneumonia in bo h Asian and
non-Asian pa ien s, al hough he odds educ ion was
signi ican ly highe in Asian pa ien s (57% 12%; P<0.001).
ARBs did no educe he isk o pneumonia in ei he popula ion.
Gene ic di e ences in ACE polymo phisms be ween Asian and
non-Asian pa ien s ha e been sugges ed o explain he di e ence
in p o ec i e e ec s. Polymo phisms I/I and I/D, which a e mo e
p e alen in Asian popula ion, showed a p o ec i e end in he
pos -hoc analysis in PROGRESS, whe eas he D/D
polymo phism was less p o ec i e.20 77 87 This las polymo phism
is associa ed wi h acu e espi a o y dis ess synd ome,
pa icula ly in whi e popula ions.88 This po en ial loss o
p o ec i e e ec may be explained by inc eased le els o se um
ACE inhibi o s and ca abolism o kinins in pa ien s wi h he
D/D polymo phism.89 Howe e , gene ic e idence is equi ocal.
One s udy did no ind an associa ion be ween any speci ic
geno ype and pneumonia.90 O he ac o s should be explo ed o
explain hese di e ences in e hnic g oups o by geog aphical
loca ion o be e de ine hose who can bene i mo e.
Ou conclusions a e weake o pneumonia ela ed mo ali y
because ewe s udies p o ided da a o his ou come and
signi ican he e ogenei y exis ed o he esul s o ACE
inhibi o s. This unce ain y was e lec ed by he wide
con idence in e als. T ea men wi h ACE inhibi o s ( h ee
andomised con olled ials and ou coho s udies) and ARBs
(one andomised con olled ial) we e bo h associa ed wi h a
dec eased isk o pneumonia ela ed mo ali y. Explana ions o
such indings may ely on modula ion o ca dio ascula isk by
ACE inhibi o s and ARBs because dea hs due o ca dio ascula
disease a e no uncommon among pa ien s wi h pneumonia.27 91
Dec eased mo ali y may also be explained by he ole o ACE
inhibi o s in pulmona y inju y and p oduc ion o cy okines,
which may be ela ed o se e i y o pneumonia.92-94 ACE
inhibi o s may in luence he pa e n o elease o cy okines
exe ing an i-in lamma o y e ec s ha could educe he se e i y
o and mo ali y om pneumonia.95
The in luence o ACE inhibi o s on su i al in hese pa ien s
should be in e p e ed ca e ully because obse a ional s udies
wi h en iched popula ions accoun ed o mos o he weigh o
he pooled analysis, whe eas me a-analysis o h ee andomised
con olled ials (one wi h an en iched popula ion) did no show
di e ences be ween ACE inhibi o s and con ols. Howe e ,
he e was no signi ican di e ence in e ec s be ween o e all
andomised con olled ials and obse a ional s udies. Al hough
he da a we e no obus , hey did sugges ha he e ec s o
ea men wi h ACE inhibi o s on mo ali y we e mos ly
no iceable in pa ien s wi h pneumonia.
Limi a ions o he e iew
The esul s and conclusion o his e iew a e weakened by
limi a ions inhe en o me a-analysis and indi idual s udies. The
o e all quali y o included s udies was good. Howe e , epo ing
quali y o a ew s udies, pa icula ly obse a ional ones, was
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RESEARCH

low as some o hese we e abs ac ed om cha ac e limi ed
sec ions such as le e s o commen s.
The highe isk o bias was ound o po en ial selec i e
epo ing in andomised con olled ials and p esen a ion o
unadjus ed isk es ima es in obse a ional s udies. Bo h limi
he s eng h o ou conclusions. A key limi a ion is ha no one
andomised con olled ial was p ima ily designed o assess
he e ec s o ACE inhibi o s o ARBs on pneumonia. Al hough
we sea ched a la ge numbe o s udies, only a ew epo ed his
ou come. Among hese, only wo andomised con olled ials
(<25%) had pneumonia o pneumonia ela ed mo ali y as a
p ede ined ou come.49 59 As a consequence we we e able o
ex ac da a only om s udies whe e au ho s conside ed
pneumonia o be an impo an ou come, because o ei he
scien i ic in e es o s a is ical signi icance.
Obse a ional s udies had an impo an weigh in he esul s o
he p ima y ou come and his should be aken in o accoun when
in e p e ing he clinical implica ions o ou indings. Use o
ca dio ascula d ugs in obse a ional s udies could bias esul s,
because pa ien s using d ugs could be mo e conce ned o hei
heal h and mo e willing o ollow medical ad ice han con ols,
he so-called heal hy use e ec bias.96 Howe e , pa ien s wi h
pneumonia a e likely o ha e a highe isk o ca dio ascula
disease91 97 and a e mo e likely o be ea ed wi h ACE inhibi o s,
coun e balancing he bias om a heal hy use e ec .
Addi ionally, he magni ude o he odds isk educ ion was
simila o andomised con olled ials, coho s udies, and
case-con ol s udies.
Pooling da a om s udies wi h di e en designs (con ounding
bias in obse a ional s udies) ha e alua ed pa ien s in di e en
se ings (communi y based and hospi al based s udies; e e al
bias), as well as wi h di e en baseline mo bidi ies and
he e ogeneous isk (membe ship bias) o pneumonia, should
also be aken in o accoun as limi a ions o ou conclusions. The
deg ee o s a is ical he e ogenei y was in ac high in some
compa isons. Ne e heless, he pooled es ima es om
expe imen al and obse a ional s udies we e simila . In his
case, pooling expe imen al and obse a ional da a inc eased he
powe and ex e nal alidi y o he indings.
Included s udies compa ed di e en ACE inhibi o s and ARBs
wi h di e en con ols, such as placebo, calcium channel
blocke s, and β blocke s. In he p esen analysis we did no ca y
ou se ial subg oup analysis o explo e i he e ec was di e en
o a pa icula d ug because o he sca ci y o he da a and he
isk o ob aining a esul by chance.
Finally, we used adjus ed indi ec compa isons o es ima e he
e ec o ACE inhibi o s compa ed wi h ARBs. Al hough
combined indi ec and di ec e idence showed no disc epancies
o he e ogenei y, he esul s should no be hough as de ini i e
conclusions because o he possibili y o imbalanced da a om
s udies wi h di e en designs, baseline isk o pa ien s, and
leng h o ollow-up.
Conclusions
Ou esul s sugges an impo an ole o ACE inhibi o s, bu no
ARBs, in educing he isk o pneumonia. These da a may
discou age he wi hd awal o ACE inhibi o s in some pa ien s
wi h ole able ad e se e en s (namely, cough) who a e a
pa icula ly high isk o pneumonia. Speci ic designed
andomised con olled ials a e equi ed o es ablish de ini e
conclusions and o es ima e be e he ue magni ude o his
pu a i e p o ec i e e ec . Pa ien s wi h p e ious s oke and
Asian pa ien s a e pa ien popula ions ha could bene i mo e
om ea men wi h ACE inhibi o s. ACE inhibi o s also
lowe ed he isk o pneumonia ela ed mo ali y, mainly in
pa ien s wi h es ablished disease, bu he obus ness o he
e idence was weake .
We hank he Coch ane Coo dina ing Cen e in Po ugal.
Con ibu o s: DC and JA con ibu ed o he concep and design, da a
acquisi ion, da a analysis, and in e p e a ion o he da a; w o e he i s
d a o he manusc ip ; c i ically e ised he manusc ip ; and ga e inal
app o al o he submi ed manusc ip . AVC con ibu ed o he
in e p e a ion o da a, c i ically e ised he manusc ip , and ga e inal
app o al o he submi ed manusc ip . JC con ibu ed o he concep
and design, da a analysis, and in e p e a ion o he da a; w o e he i s
d a o he manusc ip ; c i ically e ised he manusc ip ; and ga e inal
app o al o he submi ed manusc ip . JC is he gua an o .
Funding: This was an academic p ojec no unded by go e nmen o
non-go e nmen g an s.
Compe ing in e es s: All au ho s ha e comple ed he ICMJE uni o m
disclosu e o m a www.icmje.o g/coi_disclosu e.pd (a ailable on
eques om he co esponding au ho ) and decla e: no suppo om
any o ganisa ion o he submi ed wo k; no inancial ela ionships wi h
any o ganisa ions ha migh ha e an in e es in he submi ed wo k in
he p e ious h ee yea s; and no o he ela ionships o ac i i ies ha
could appea o ha e in luenced he submi ed wo k.
E hical app o al: No equi ed.
Da a sha ing: No addi ional da a a ailable.
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BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012) Page 6 o 20
RESEARCH
Wha is al eady known on his opic
Angio ensin con e ing enzyme (ACE) inhibi o s educe mo bidi y and mo ali y in pa ien s wi h ca dio ascula disease
These d ugs also ha e seconda y e ec s on he espi a o y sys em, sugges ed o p o ec agains pneumonia
Mos o he da a on his issue a e p o ided by he e ogeneous obse a ional s udies wi h inconclusi e esul s
Wha his s udy adds
In pooled esul s om bo h in e en ional and obse a ional s udies, ACE inhibi o s, bu no angio ensin ecep o blocke s (ARBs),
showed a s a is ical and pu a i e clinically signi ican p o ec i e ole agains pneumonia
This esul may discou age he wi hd awal o ACE inhibi o s in pa ien s wi h ole able ad e se e en s—namely, cough
This p o ec i e e ec was highe among Asian pa ien s and in hose wi h p e ious s oke; pa ien popula ions ha may bene i mos
om ACE inhibi o s
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Accep ed: 10 May 2012
Ci e his as: BMJ 2012;345:e4260
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RESEARCH
Tables
Table 1| Main cha ac e is ics o andomised con olled ials included in e iew
Da a*
Ou comes
abs ac ed
P ima y
ou come
Mean
(SD)
ageNo ( o al)Compa isonPa ien s
Mean
ollow-up
(yea s)Loca ionS udy
ACE inhibi o s
con ol:
PublishedSe ious pneumonia†Assessmen o
changes in
exe cise
ole ance
57.5
(10)
200 48
(248)
Spi ap il o enalap il placeboPa ien s wi h
ch onic conges i e
hea ailu e
0.2Mul icen e
Czech
Republic
and
Slo akia
CASSIS
199544
PublishedPneumonia†Dea h om any
cause
67.5876 873
(1749)
T andolap il placeboPa ien s wi h le
en icula ejec ion
ac ion a e
myoca dial
in a c ion
4.0Mul icen e
Denma k
TRACE 199545
PublishedD ug wi hd awal due
o
b onchopneumonia†
Ra e o decline
in glome ula
il a ion
49.3
(13.6)
78 88
(166)
Ramip il placeboPa ien s wi h
ch onic
neph opa hy and
pe sis en
p o einu ia
1.3Mul icen e
I aly
GISEN 199746
UnpublishedSe ious pneumonia†Myoca dial
in a c ion,
s oke, o dea h
due o
ca dio ascula
disease
66 (7)4645 4652
(9297)
Ramip il placeboPa ien s a high
isk o de eloping
a majo
ca dio ascula
e en
4.0Mul icen e
wo ldwide
(no Asia)
HOPE 200047
PublishedFa al and non- a al
pneumonia
Fa al o
non- a al s oke
64
(10)
3051 3054
(6105)
Pe indop il placeboPa ien s wi h
p e ious s oke o
ansien
ischaemic a ack
3.9Mul icen e
wo ldwide
PROGRESS
200420 48
PublishedHospi al dea hIn-hospi al
mo ali y,
du a ion o
an ibio ic use,
and in ec ion
wi h MRSA
78 (8)33 35 (68)Imidap il+aman adine+s anda d
ca e s anda d ca e
Pa ien s aged ≥65
wi h his o y o
s oke and
admi ed wi h
communi y
acqui ed
pneumonia
4.0Single
cen e
Japan
Kanda 200449
PublishedPneumonia as cause
o mo ali y
Composi e o
doubling o
se um c ea inine
le el, end s age
enal disease,
and dea h
44.8
(14.6)
216 112
(328)
Benazep il placeboPa ien s wi h
non-diabe ic
ch onic kidney
disease
3.4Single
cen e
China
Hou 200650
ARBs con ol:
PublishedPneumonia†Ad e se e en s54125 29Losa an placeboPa ien s wi h
essen ial
hype ension and
hea ailu e
0.3Wo ldwideWebe 199751
UnpublishedPulmona y in ec ion†Time o i s
occu ence o
doubling o
baseline se um
c ea inine le el,
end s age enal
58.9
(7.8)
579 569
(placebo)
(1148)
I besa an placebo o
amlodipine
Pa ien s wi h
hype ension and
wi h ype 2
diabe es and o e
p o einu ia
4.8Mul icen e
wo ldwide
IDNT 200152
disease, o
dea h
UnpublishedPulmona y in ec ion†Time o
occu ence o
clinical o e
albuminu ia
58.0
(8.1)
389 201
(590)
I besa an 100 mg i besa an
300 mg placebo
Pa ien s wi h
hype ension and
wi h ype 2
diabe es,
mic oalbuminu ia,
and no mal enal
unc ion
2.0Mul icen e
Eu ope
IRMA-2 200153
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BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012) Page 9 o 20
RESEARCH
Figu es
Fig 1 Flow o s udies h ough e iew. ACE=angio ensin con e ing enzyme; ARBs=angio ensin ecep o blocke s
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RESEARCH

Fig 2 Risk o pneumonia wi h use o angio ensin con e ing enzyme (ACE) inhibi o s compa ed wi h con ol ea men
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BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012) Page 17 o 20
RESEARCH
Fig 3 Risk o pneumonia wi h use o angio ensin ecep o blocke s (ARBs) compa ed wi h con ol ea men
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BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012) Page 18 o 20
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Fig 4 Summa y o me a-analysis es ima es and subg oup analyses. ACE=angio ensin con e ing enzyme; ARBs=angio ensin
ecep o blocke s
No comme cial euse: See igh s and ep in s h p://www.bmj.com/pe missions Subsc ibe: h p://www.bmj.com/subsc ibe
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Fig 5 Pneumonia ela ed mo ali y in s udies compa ing angio ensin con e ing enzyme (ACE) inhibi o s o angio ensin
ecep o blocke s (ARBs) wi h con ol ea men
No comme cial euse: See igh s and ep in s h p://www.bmj.com/pe missions Subsc ibe: h p://www.bmj.com/subsc ibe
BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012) Page 20 o 20
RESEARCH