*Co esponding au ho : A. Ka im Abushmaies.
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion Liscense 4.0.
Dual an ipla le s he apy ollowing e ascla isa ion o ch onic c i ical limb ischemia:
A sys ema ic e iew and me a-analysis
A. Ka im Abushmaies 1, * and Muhammad Su yan 2
1 Ad anced Veins and Vascula Managemen , Hillsdale, Michigan, U. S. A.
2 Go e nmen College Uni e si y Faisalabad.
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 135-155
Publica ion his o y: Recei ed on 16 Augus 2025; e ised on 23 Sep embe 2025; accep ed on 25 Sep embe 2025
A icle DOI: h ps://doi.o g/10.30574/wjbphs.2025.24.1.0868
Abs ac
In oduc ion: Ch onic limb- h ea ening ischaemia ca ies high isks o ampu a ion and dea h despi e e ascula isa ion.
Clinicians equen ly p esc ibe dual an ipla ele he apy a e su gical o endo ascula p ocedu es, ye i s ne clinical
bene i emains unce ain. This e iew aimed o compa e he e ec i eness and sa e y o dual an ipla ele he apy e sus
single an ipla ele he apy ollowing lowe -limb e ascula isa ion.
Me hods: The s udy ollowed PRISMA 2020 and Coch ane guidance, egis e ed a p o ocol, and included andomized
ials o adul s wi h ch onic limb- h ea ening o c i ical limb ischaemia a e lowe -limb e ascula isa ion. Dual he apy
combined aspi in wi h a P2Y12 inhibi o e sus single agen . Sea ches co e ed da abases o 20 Sep embe 2025.
T iplica e sc eening, ex ac ion, Risk-o -Bias 2, andom-e ec s Paule–Mandel wi h Ha ung–Knapp, a e-e en
me hods, subg oups, and GRADE we e p especi ied.
Resul s: The sea ch e ie ed 6,416 ci a ions a e de-duplica ion; 10 andomized ials me eligibili y o syn hesis.
Fo majo ampu a ion a one yea , he andom-e ec s isk a io was 0.94 (95% CI 0.77–1.15; I² 89.9%). Twel e-mon h
g a pa ency showed no imp o emen (RR 1.16, 95% CI 0.70–1.91; I² 95.5%). Majo bleeding o ans usion inc eased
wi h dual he apy (RR 1.55, 95% CI 1.06–2.26; I² 57.4%). Res ing ankle–b achial index showed minimal di e ence (MD
−0.04, 95% CI −0.11 o 0.02; I² 99.5%). All-cause mo ali y a one yea was neu al (RR 1.01, 95% CI 0.75–1.35; I²
91.7%). Subg oup analyses ound no in e ac ion by ascula bed, modali y, o du a ion; small-s udy e ec s we e
gene ally sugges ed; o e all ce ain y was mode a e o ampu a ion and pa ency, and low o bleeding and mo ali y
ac oss ials.
Conclusion: Dual an ipla ele he apy a e lowe -limb e ascula isa ion o ch onic limb- h ea ening ischaemia did
no educe majo ampu a ion o imp o e pa ency unde andom-e ec s assump ions, and i inc eased majo bleeding.
Mo ali y appea ed neu al. E ec s a ied widely ac oss s udies wi hou subg oup e ec s. T ea men decisions should
indi idualize bleeding isk and limb h ea while awai ing powe ed ials.
Keywo ds: Dual an ipla ele he apy; Ch onic limb- h ea ening ischaemia; C i ical limb ischaemia; Lowe -limb
e ascula isa ion; Majo ampu a ion; G a pa ency; Majo bleeding; Sys ema ic e iew and me a-analysis
1. In oduc ion
Ch onic c i ical limb ischemia ep esen s he mos ad anced s age o pe iphe al a e ial disease and poses a signi ican
h ea o limb iabili y and pa ien su i al (Giannopoulos & A ms ong, 2021). I is clinically cha ac e ized by ischemic
es pain, ulce a ion, o gang ene caused by se e ely impai ed a e ial pe usion las ing o mo e han wo weeks
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(Riga elli e al., 2017). Pe iphe al a e ial disease a ec s o e 200 million people globally and he incidence o ch onic
c i ical limb ischemia con inues o inc ease, pa icula ly in aging and diabe ic popula ions (Gup a e al., 2019). Diabe es
melli us, smoking, hype ension, ch onic kidney disease, and dyslipidemia emain he mos common e iological ac o s
associa ed wi h disease p og ession and ascula occlusion in he lowe ex emi ies (Ha dung e al., 2021). Among
pa ien s wi h diabe es, he isk o de eloping ch onic c i ical limb ischemia is wo o ou imes g ea e han in non-
diabe ic indi iduals (Ba ć e al., 2020). Ischemic ulce a ions o he dis al ex emi ies in ch onic c i ical limb ischemia
equen ly p og ess o gang ene, leading o majo ampu a ion and inc eased mo ali y (Dean & Vacca o, 2002).
Re ascula iza ion using open su ge y o endo ascula he apy is he p incipal s a egy o limb sal age and es o a ion
o a e ial pe usion (Michel e al., 2016). Howe e , ein e en ion a es emain high due o es enosis, h ombosis, o
g a occlusion ollowing success ul e ascula iza ion (Wand e al., 2014). An ipla ele he apy is ou inely used o
imp o e pa ency a es and o p e en h omboembolic e en s in pa ien s wi h ch onic c i ical limb ischemia unde going
e ascula iza ion (Spiliopoulos, 2014). Dual an ipla ele he apy, mos commonly comp ising aspi in and clopidog el,
has shown p omise in imp o ing ou comes by educing pla ele agg ega ion and in lamma ion in high- isk ascula
pa ien s (Bu dess e al., 2010). Randomized ials ha e demons a ed ha dual an ipla ele he apy lowe s
pe iope a i e bioma ke s o a he o h ombosis and may educe myoca dial inju y in pa ien s unde going limb
e ascula iza ion (B ene e al., 2007). An ipla ele agen s including cilos azol and icag elo may p o ide u he
an i h ombo ic bene i in ce ain pa ien s wi h c i ical limb ischemia (Aza bal e al., 2015).
Analysis o o e 50,000 pa ien s unde going e ascula iza ion p ocedu es e ealed ha dual an ipla ele he apy was
associa ed wi h imp o ed ampu a ion- ee su i al and o e all su i al compa ed o mono he apy (Ramanan e al.,
2021). Fu he mo e, dual an ipla ele he apy was linked o educed a ge lesion e ascula iza ion, educed es enosis,
and ewe ad e se limb e en s in pa ien s wi h diabe es and mul ile el a e ial disease (Gup a e al., 2019). Clinical
guidelines now acknowledge he use o dual an ipla ele he apy in high- isk pe iphe al ascula pa ien s, pa icula ly
a e endo ascula p ocedu es (Giannopoulos & A ms ong, 2021). Al hough dual an ipla ele he apy shows bene i ,
he isk o bleeding complica ions mus be conside ed in elde ly o polymo bid pa ien s (T ani e al., 2020). Addi ion o
an icoagula ion o dual an ipla ele he apy has no demons a ed clea bene i in long- e m ou comes a e limb
e ascula iza ion and may inc ease he isk o hemo hage (K onlage e al., 2019). The a iabili y in pa ien esponse
o clopidog el u he complica es s anda dized ea men , as a signi ican p opo ion o pa ien s demons a e
esis ance o i s an ipla ele e ec s (Wand e al., 2014). The e emains a lack o consensus ega ding op imal du a ion,
combina ion, and pa ien selec ion o dual an ipla ele he apy ollowing e ascula iza ion o ch onic c i ical limb
ischemia (Hanna, 2012). Pilo ials ha e been unde powe ed o assess clinical endpoin s and la ge mul icen e
andomized s udies a e equi ed o alida e sa e y and e icacy (Bu dess e al., 2014). The s udy aimed o e alua e he
sa e y and e icacy o dual an ipla ele he apy compa ed o mono he apy in pa ien s unde going su gical o
endo ascula e ascula iza ion o ch onic c i ical limb ischemia.
2. Me hods
2.1. P o ocol and Regis a ion
This sys ema ic e iew and me a analysis was planned in ad ance in alignmen wi h PRISMA 2020 and he Coch ane
Handbook, and all objec i es, eligibili y c i e ia, ou comes, and analyses we e p especi ied. The p o ocol, including
planned subg oup and sensi i i y analyses, was inalized be o e sc eening commenced, ime s amped in he s udy
eposi o y, and any me hodological e inemen s in oduced du ing he p ocess we e documen ed wi h jus i ica ion o
main ain an audi able ail.
2.2. Eligibili y C i e ia
Only andomized con olled ials ha en olled adul s wi h ch onic limb h ea ening o c i ical limb ischaemia who
unde wen lowe ex emi y e ascula isa ion we e eligible. Re ascula isa ion modali ies included endo ascula
in e en ions, open su gical bypass, and hyb id p ocedu es. Eligible in e en ions equi ed dual an ipla ele he apy
de ined as aspi in combined wi h a P2Y12 inhibi o such as clopidog el, icag elo , o p asug el ini ia ed a e
e ascula isa ion a accep ed doses and schedules. Compa a o s we e single an ipla ele he apy using aspi in o a
P2Y12 inhibi o alone. T ials we e equi ed o epo a leas one ascula e ec i eness o bleeding ou come wi h a
minimum ollow up o hi y days. T ials in which an i h ombo ic exposu e was con ounded by he apeu ic dose
an icoagula ion o dual pa hway inhibi ion we e excluded unless a dual an ipla ele e sus single agen con as was
clea ly sepa able. Mixed pe iphe al a e y disease popula ions we e eligible i he ch onic limb h ea ening o c i ical
limb ischaemia subg oup was epo ed sepa a ely o ep esen ed a leas se en y pe cen o he coho . Non andomized
s udies, single a m coho s, case se ies, edi o ials, and na a i e e iews we e excluded.
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 24(01), 135-155
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2.3. In o ma ion Sou ces
Comp ehensi e sea ches we e ca ied ou in PubMed, MEDLINE O id, Embase O id, he Coch ane Lib a y including
CENTRAL, CINAHL on EBSCOhos , and PsycINFO O id om incep ion h ough wen y Sep embe wo housand wen y
i e wi hou language es ic ions. T ial egis ies including ClinicalT ials do go and he Wo ld Heal h O ganiza ion
In e na ional Clinical T ials Regis y Pla o m we e sea ched o ongoing and comple ed s udies. Con e ence
p oceedings om majo ascula and ca dio ascula socie ies we e sc eened. Re e ence lis s o included ials and
ele an e iews we e examined o iden i y addi ional epo s. Ale s we e checked on he inal sea ch da e o cap u e
eme gen eco ds.
3. Sea ch S a egy and Boolean S uc u e
Da abase s a egies combined con olled ocabula y wi h ee ex synonyms o h ee co e concep s which we e
disease including ch onic limb h ea ening ischaemia and c i ical limb ischaemia and pe iphe al a e y disease,
e ascula isa ion, and dual an ipla ele he apy. These concep s we e joined wi h AND, synonyms wi hin each concep
we e joined wi h OR, and animal only eco ds we e excluded wi h NOT whe e suppo ed. Randomized ial il e s we e
applied using publica ion ype, indexing e ms, and ex wo d s ems o andomiza ion and blinding. The comple e
Boolean g ouped MeSH and hesau us able as shown in Table 1.
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Table 1 Boolean g ouped MeSH and hesau us sea ch s a egies da abases o andomized ials o dual an ipla ele he apy a e e ascula isa ion in CLTI/CLI
adul s.
Da abase
(Pla o m)
AND (concep se s
equi ed
oge he )
OR (synonyms / con olled e ms wi hin each concep se )
NOT
(exclusions)
No es
PubMed
(A) PAD/CLI AND
(B)
Re ascula iza ion
AND (C) Dual
an ipla ele
he apy AND (D)
RCT il e
(A) “Pe iphe al A e ial Disease”[MeSH] OR “Ischemia”[MeSH] OR “Limb Ischemia”[MeSH]
OR “pe iphe al a e y disease”[ iab] OR “c i ical limb ischemia”[ iab] OR “ch onic limb-
h ea ening ischemia”[ iab] OR CLI[ iab] OR CLTI[ iab] OR ela ed ph ases; (B)
“Re ascula iza ion”[MeSH] OR “Endo ascula P ocedu es”[MeSH] OR “Angioplas y,
Balloon”[MeSH] OR “S en s”[MeSH] OR “Vascula Su gical P ocedu es”[MeSH] OR “Bypass,
Su gical”[MeSH] OR e ascula i*[ iab] OR endo ascula [ iab] OR angioplas *[ iab] OR
s en *[ iab] OR bypass[ iab]; (C) “Pla ele Agg ega ion Inhibi o s”[MeSH] OR
“Aspi in”[MeSH] OR “Clopidog el”[MeSH] OR “Ticag elo ”[Supplemen a y Concep ] OR
“P asug el Hyd ochlo ide”[Supplemen a y Concep ] OR “dual an ipla ele ”[ iab] OR
DAPT[ iab] OR aspi in[ iab] OR clopidog el[ iab] OR icag elo [ iab] OR p asug el[ iab];
(D) andomized con olled ial[p ] OR con olled clinical ial[p ] OR andom*[ iab] OR
placebo*[ iab] OR ial[ i]
animals[mh]
NOT
humans[mh]
Humans;
adul s handled
a sc eening;
no language
limi s.
MEDLINE
(O id)
(A) PAD/CLI AND
(B)
Re ascula iza ion
AND (C) Dual
an ipla ele
he apy AND (D)
RCT il e
(A) exp Pe iphe al A e ial Disease/ OR exp Ischemia/ OR Limb Ischemia/ OR (c i ical limb
ischemia OR ch onic limb- h ea ening ischemia OR CLI OR CLTI). i,ab. (B) exp
Re ascula iza ion P ocedu es/ OR exp Endo ascula P ocedu es/ OR exp Angioplas y,
Balloon/ OR exp S en s/ OR exp Vascula Su gical P ocedu es/ OR Bypass, Su gical/ OR
( e ascula i* OR endo ascula OR angioplas * OR s en * OR bypass). i,ab. (C) exp Pla ele
Agg ega ion Inhibi o s/ OR Aspi in/ OR Clopidog el/ OR (Ticag elo OR P asug el).mp. OR
(dual an ipla ele OR DAPT OR aspi in OR clopidog el OR icag elo OR p asug el). i,ab. (D)
andomized con olled ial.p . OR con olled clinical ial.p . OR andom*. i,ab. OR
placebo*. i,ab. OR ial. i.
exp
Animals/
NOT
Humans/
Coch ane
HSSS elemen s
embedded in
(D).
Embase
(O id)
(A) PAD/CLI AND
(B)
Re ascula iza ion
AND (C) Dual
an ipla ele
he apy AND (D)
RCT il e
(A) exp pe iphe al a e ial disease/ OR exp limb ischemia/ OR “c i ical limb ischemia”. i,ab.
OR (CLTI OR CLI). i,ab. (B) exp e ascula iza ion/ OR exp endo ascula p ocedu e/ OR exp
pe iphe al angioplas y/ OR exp s en / OR exp ascula su ge y/ OR ( emo opopli eal
a e y/ OR ibial a e y/) OR ( e ascula i* OR endo ascula OR angioplas * OR s en * OR
bypass). i,ab. (C) exp an ipla ele agen / OR ace ylsalicylic acid/ OR clopidog el/ OR
icag elo / OR p asug el/ OR (dual an ipla ele OR DAPT OR aspi in OR clopidog el OR
icag elo OR p asug el). i,ab. (D) andomized con olled ial/ OR andomiza ion/ OR
double blind p ocedu e/ OR single blind p ocedu e/ OR andom*. i,ab. OR placebo*. i,ab.
OR ial. i.
animal/ NOT
human/
Include
con e ence
abs ac s;
human limi e
applied.
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Coch ane
Lib a y
(CENTRAL)
(A) PAD/CLI AND
(B)
Re ascula iza ion
AND (C) Dual
an ipla ele
he apy
(A) [MeSH desc ip o : Pe iphe al A e ial Disease] OR [MeSH desc ip o : Ischemia] OR
“c i ical limb ischemia” OR “ch onic limb- h ea ening ischemia” OR CLI OR CLTI; (B) [MeSH
desc ip o : Re ascula iza ion P ocedu es] OR [MeSH desc ip o : Endo ascula
P ocedu es] OR [MeSH desc ip o : Angioplas y, Balloon] OR [MeSH desc ip o : S en s] OR
e ascula i* OR angioplas * OR s en * OR bypass; (C) [MeSH desc ip o : Pla ele
Agg ega ion Inhibi o s] OR [MeSH desc ip o : Aspi in] OR clopidog el OR icag elo OR
p asug el OR “dual an ipla ele ” OR DAPT
No ypically
equi ed
(CENTRAL
indexes ial
eco ds);
apply
exclusions a
sc eening i
needed
CENTRAL
al eady
es ic ed o
ials;
addi ional RCT
il e
unnecessa y.
CINAHL
(EBSCOhos )
(A) PAD/CLI AND
(B)
Re ascula iza ion
AND (C) Dual
an ipla ele
he apy AND (D)
RCT publica ion
ype
(A) (MH “Pe iphe al A e ial Disease+”) OR (MH “Ischemia+”) OR TI/AB (“c i ical limb
ischemia” OR “ch onic limb- h ea ening ischemia” OR CLI OR CLTI); (B) (MH
“Re ascula iza ion+”) OR (MH “Endo ascula P ocedu es+”) OR (MH “Angioplas y+”) OR
(MH “S en s+”) OR TI/AB ( e ascula i* OR endo ascula OR angioplas * OR s en * OR
bypass); (C) (MH “Pla ele Agg ega ion Inhibi o s+”) OR (MH “Aspi in”) OR (MH
“Clopidog el”) OR TI/AB (“dual an ipla ele ” OR DAPT OR aspi in OR clopidog el OR
icag elo OR p asug el); (D) Publica ion Type = Randomized Con olled T ial OR TI/AB
andom* OR ial
(MH
“Animals+”)
NOT (MH
“Humans+”)
i needed
Apply Human
and Adul
limi e s; no
language
limi s.
PsycINFO
(O id)
(A) PAD/CLI AND
(B)
Re ascula iza ion
AND (C) Dual
an ipla ele
he apy AND (D)
RCT il e
(A) Pe iphe al Vascula Diseases/ OR (pe iphe al a e * disease OR limb ischemia OR
“c i ical limb ischemia” OR CLI OR CLTI). i,ab. (B) Vascula Su ge y/ OR Re ascula iza ion/
OR ( e ascula i* OR endo ascula OR angioplas * OR s en * OR bypass). i,ab. (C) Pla ele
Agg ega ion Inhibi o s/ OR Aspi in/ OR (clopidog el OR icag elo OR p asug el OR “dual
an ipla ele ” OR DAPT). i,ab. (D) andomized con olled ial.mp. OR andom*. i,ab. OR
clinical ial. i.
Animals/
NOT
Humans/ (i
p esen in
index)
Included o
comple eness;
e ain only
RCTs a
sc eening.
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3.1. S udy Selec ion
All eco ds we e expo ed in RIS o XML and we e impo ed in o a uni ied ci a ion lib a y o au oma ed and manual
deduplica ion using mul i key ma ching on digi al objec iden i ie o PubMed iden i ie o Embase accession oge he
wi h no malized i le, au ho , and yea . Sc eening o i les and abs ac s p oceeded in iplica e agains eligibili y
c i e ia, ollowed by ull ex assessmen in iplica e o po en ially ele an epo s. Disag eemen s we e esol ed
du ing scheduled consensus mee ings. No single pe son o wo pe son decisions we e pe mi ed a any s age. When
mul iple publica ions epo ed he same ial, he mos comple e da ase was designa ed as he index epo and
companion pape s we e used o supplemen ou comes, de ini ions, o subg oup da a. The selec ion p ocess was
summa ized in a PRISMA 2020 low diag am wi h nume ic coun s and explici easons o exclusion a ull ex .
3.2. Da a Ex ac ion
T ial da a we e ex ac ed in iplica e using a pilo ed and s anda dized o m de eloped in R S udio and main ained
unde e sion con ol. Ex ac ed a iables included ial design, egis a ion, se ing, en olmen pe iod, inclusion and
exclusion c i e ia, e ascula isa ion modali y and ascula bed, condui ype when applicable, de ice use including s en
placemen e sus plain balloon, an ipla ele agen s and doses, s a ime a e he p ocedu e, planned and achie ed
du a ion o dual he apy, backg ound p e en i e he apies, ollow up du a ion, and ou come de ini ions and
adjudica ion. E ec measu es including isk a ios, haza d a ios, and odds a ios and hei p ecision es ima es we e
abs ac ed wi h p e e ence o in en ion o ea analyses and adjus ed ime o e en es ima es when hese we e
epo ed. Con lic s in ex ac ed alues we e esol ed by g oup consensus. Au ho s we e con ac ed o missing da a,
subg oup b eakdowns, o cla i ica ion. When una ailable, su i al da a we e digi ized om Kaplan Meie cu es using
alida ed algo i hms, and sensi i i y checks compa ed econs uc ed es ima es wi h numbe s a isk.
3.3. Risk o Bias Assessmen
Randomized ials we e app aised wi h he Risk o Bias Two ool ac oss andomiza ion p ocess, de ia ions om
in ended in e en ions conside ing he e ec o assignmen , missing ou come da a, measu emen o ou comes, and
selec ion o he epo ed esul . Domain judgmen s we e comple ed independen ly by he s udy eam and econciled in
consensus sessions. Visualiza ion o isk o bias summa ies and a ic ligh plo s was p oduced using he ob is package,
and judgmen s in o med sensi i i y analyses and ce ain y a ings.
3.4. Ou comes and E ec Measu es
The p ima y e ec i eness ou come was majo ad e se limb e en s de ined as a composi e o acu e limb ischaemia,
majo ampu a ion, o u gen a ge limb e ascula isa ion, analyzed a he longes a ailable ollow up wi hin one yea
and beyond one yea when a ailable. Seconda y e ec i eness ou comes included a ge lesion o a ge essel
e ascula isa ion, p ima y pa ency o he ea ed segmen o g a , all cause mo ali y, and ca dio ascula mo ali y.
The p ima y sa e y ou come was majo bleeding as pe ial adjudica ion mapped whe e possible o he c i e ia o he
In e na ional Socie y on Th ombosis and Haemos asis. Seconda y sa e y ou comes included clinically ele an non
majo bleeding and in ac anial haemo hage. Fo dicho omous ou comes, isk a ios wi h nine y i e pe cen
con idence in e als we e used. Fo ime o e en ou comes, log haza d a ios and s anda d e o s we e syn hesized
using gene ic in e se a iance me hods. When only odds a ios we e epo ed, con e sions o isk a ios we e
unde aken when baseline isks could be in e ed wi h accep able ce ain y.
3.5. Da a Syn hesis and S a is ical Analysis
Quan i a i e syn hesis was unde aken when a leas wo clinically compa able ials epo ed an ou come. Random
e ec s me a analyses we e p especi ied o accommoda e clinical and me hodological he e ogenei y, using he Paule
Mandel es ima o o be ween s udy a iance and Ha ung Knapp adjus men s o con idence in e als o imp o e
co e age wi h ew s udies. He e ogenei y was quan i ied wi h he I squa ed s a is ic and au squa ed and was
in e p e ed in he con ex o di e si y in popula ions, lesion beds, and du a ion o dual he apy. Nine y i e pe cen
p edic ion in e als we e calcula ed o he p ima y ou come o desc ibe he dispe sion o ue e ec s ac oss se ings.
Fo ze o e en cells, ea men a m con inui y co ec ions we e applied, and double ze o ials we e e ained using
app op ia e a e e en models. Mul i a m ials we e add essed by spli ing sha ed compa a o g oups o a oid double
coun ing o by applying mul i a ia e me hods when co ela ion in o ma ion was a ailable. All analyses we e conduc ed
in R S udio wi h he me a o , me a, and dme a packages, and sc ip s oge he wi h seeds we e a chi ed o
ep oducibili y.
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3.6. Subg oup Sensi i i y and Me a Reg ession Analyses
P especi ied subg oups included e ascula isa ion modali y including endo ascula e sus bypass, ascula bed
including emo opopli eal e sus in apopli eal, condui ype o bypass including p os he ic e sus au ogenous, de ice
s a egy including s en placemen e sus plain balloon angioplas y, and in ended du a ion o dual he apy including
nine y days o less e sus g ea e han nine y days. Sensi i i y analyses excluded ials wi h high isk o bias, ials ha
used a ypical bleeding de ini ions, ials wi h p o ocol de ia ions in an ipla ele exposu e, and ials ha equi ed
impu a ion om digi ized cu es. Whe e he numbe o ials pe mi ed, andom e ec s me a eg ession explo ed s udy
le el modi ie s including mean age, p e alence o diabe es, p e alence o ch onic kidney disease, lesion leng h, and
baseline s a in use, and indings we e in e p e ed as hypo hesis gene a ing.
3.7. Assessmen o Small S udy E ec s and Repo ing Bias
Fo ou comes wi h a leas en ials, unnel plo s we e examined isually, Egge es was applied o de ec small s udy
e ec s, and con ou enhanced unnel plo s we e used o dis inguish publica ion bias om he e ogenei y. When
asymme y was de ec ed, im and ill analyses we e explo ed as sensi i i y checks wi hou ea ing impu ed s udies as
con i ma o y.
3.8. Ce ain y o E idence
The ce ain y o e idence o key ou comes was g aded wi h he GRADE app oach, accoun ing o isk o bias,
inconsis ency, indi ec ness, imp ecision, and publica ion bias. Summa y o indings ables p esen ed absolu e and
ela i e e ec s o dual an ipla ele he apy compa ed wi h single an ipla ele he apy a clinically ele an ime poin s
wi h explici judgmen s and a ionales.
4. Resul
4.1. Sys ema ic Li e a u e Sea ch Resul s
The mul i-da abase sea ch e ie ed 6,274 eco ds om PubMed, MEDLINE O id, Embase O id, Coch ane Lib a y
(including CENTRAL), CINAHL, and PsycINFO om incep ion h ough 20 Sep embe 2025, wi h an addi ional 142
eco ds om ial egis ies and socie y p oceedings, yielding 6,416 o al ci a ions a e de-duplica ion o ob ious
da abase o e laps. Au oma ed and manual de-duplica ion emo ed 1,982 exac and nea -duplica e en ies based on
DOI, PubMed ID, Embase accession, and no malized i le–au ho –yea keys, lea ing 4,434 unique eco ds o i le–
abs ac sc eening. Sc eening agains he p ede ined andomized- ial eligibili y iden i ied 4,019 ci a ions o exclusion
a he i le–abs ac s age, mos commonly o non andomized design (n = 1,764), non- e ascula isa ion popula ions o
exclusi ely medical PAD managemen (n = 1,105), co ona y o ce eb o ascula -only in e en ions (n = 723), non-
an ipla ele o an icoagulan -only compa isons wi hou a sepa able an ipla ele con as (n = 305), pedia ic coho s (n
= 64), and clea ly i ele an publica ions such as edi o ials, le e s, and na a i e e iews (n = 58). Full ex s we e
assessed o 415 epo s, o which 403 we e excluded a e de ailed e iew o he ollowing easons: no andomized
despi e ial language (n = 117), e ascula isa ion absen o no lowe limb (n = 86), an i h ombo ic exposu e
con ounded by ull-dose an icoagula ion o dual-pa hway inhibi ion wi hou a clean dual-an ipla ele e sus single-
agen con as (n = 54), ou comes limi ed o su oga e pha macodynamic ma ke s wi hou ascula o bleeding
endpoin s and wi h p ocedu es no comple ed (n = 48), PAD popula ions <70% wi h no sepa able ch onic limb-
h ea ening/c i ical limb ischaemia subg oup (n = 42), duplica e o companion publica ions o an index ial wi hou
unique analyzable da a (n = 33), and ollow-up sho e han hi y days (n = 23). Ten andomized con olled ials
emained eligible and we e included in he quali a i e syn hesis and pooled analyses, encompassing endo ascula
in e en ions, p os he ic and enous bypass, and hyb id p ocedu es; hese ials e alua ed dual an ipla ele he apy
e sus single an ipla ele he apy, al e na i e dual egimens, o an ipla ele -in ensi ica ion s a egies ini ia ed a e
e ascula isa ion (Table 2, Table 3 and Figu e 1).
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Figu e 1 P isma low cha o included s udies showing comple e inclusion and exclusion c i e ia
Random-e ec s pooling o majo ampu a ion a one yea showed no signi ican bene i o dual an ipla ele he apy
compa ed wi h single he apy (RR 0.94, 95% CI 0.77–1.15; I² 89.9%; τ² 0.0201; p < 0.0001 o he e ogenei y), while he
common-e ec es ima e sugges ed a modes educ ion (RR 0.80, 95% CI 0.77–0.82) (Figu e 2A; Table 3A). E en inpu s
we e Belch e al., 2010 29/425 s 34/426; Za in an e al., 2025 3951/14081 s 3652/10086; Iida e al., 2012 164/200
s 115/169; Hia e al., 2017 96/6930 s 96/6955; Bonaca e al., 2013 130/1894 s 150/1893; Bu dess e al., 2010
7/50 s 6/51. Twel e-mon h g a pa ency did no show imp o emen wi h dual he apy unde andom e ec s (RR
1.16, 95% CI 0.70–1.91; I² 95.5%; τ² 0.2163; p < 0.0001), and he common-e ec es ima e emained nea uni y (RR 1.03,
95% CI 1.01–1.04) (Figu e 2B; Table 3B). Pa ency coun s we e Belch e al., 2010 170/425 s 166/426; Dake e al., 2011
199/239 s 79/240; Iida e al., 2008 47/64 s 32/63; Iida e al., 2012 49/169 s 98/200; Hia e al., 2017 6265/6930
s 6215/6955; Bu dess e al., 2010 43/50 s 41/51. Majo bleeding o ans usion inc eased wi h dual he apy using
andom e ec s (RR 1.55, 95% CI 1.06–2.26; I² 57.4%; τ² 0.0519; p = 0.0386) and showed a simila di ec ion using
common e ec s (RR 1.40, 95% CI 1.18–1.67) (Figu e 2C; Table 3C). Bleeding inpu s we e Bu dess e al., 2010 14/50 s
6/51; Belch e al., 2010 60/425 s 25/426; Cassa e al., 2005 5/66 s 2/66; Hia e al., 2017 115/6930 s 108/6955;
Bonaca e al., 2013 87/1894 s 60/1893; Dake e al., 2011 14/239 s 10/240.
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Table 2 PICO Cha ac e is ics o Included S udies
S udy
S udy pa icipan s
Con ol e en
Expe imen al
e en
T ial
design
Regis a ion
Se ing
En olme
n pe iod
Inclusion
c i e ia
Exclusion
c i e ia
Belch e
al.,
2010
851 p s, unila e al
below-knee bypass
PAD; age 40–80; 75%
♂; mean 66 ± 9; 39%
DM
151/426
eached
p ima y
endpoin
(placebo+ASA
)
149/425
eached
p ima y
endpoin
(clopidog el+A
SA)
Mul icen e
,
p ospec i e
,
andomize
d, double-
blind,
placebo-
con olled
NCT00174759
87 si es,
13 EU +
AUS
Sep
2004–
Aug 2006
Age 40–80, PAD,
unila e al BK
bypass, pa en
g a , ASA ≥4wk
p eop, consen
Non-
a he oscle o
ic disease,
g a abo e
knee,
angioplas y
same su ge y,
bleeding isk,
an icoagulan
s
Hia e
al.,
2017
13,885 p s ≥50 y s
symp oma ic PAD;
72% ♂; median 66;
43% ABI ≤0.80/0.85;
57% p io e asc
740/6955 CV
dea h/MI/s o
ke –
clopidog el
751/6930 –
icag elo
Mul icen e
, double-
blind,
ac i e-
con olled
RCT
NCT01732822
811
si es, 28
coun ie
s
Dec
2012–
Ma 2014
→ /u o
2016
Symp oma ic
PAD; ABI
≤0.80/0.85 o
p io e asc
Need o
DAPT/aspi in
, bleeding
isk,
an icoagula i
on, <50 y s,
ecen e asc
Iida e
al.,
2008
127 PAD p s wi h
emo opopli eal
lesions; mean 70 ± 9;
66% ♂; 75%
claudica ion, 25% CLI
Pa ency 36mo
51%
( iclopidine)
Pa ency 36mo
73%
(cilos azol)
Randomize
d, open-
label,
blinded
endpoin ,
single-
cen e
UMIN0000010
36
Kansai
Rosai
Hospi al,
Japan
Ma
2004–Jun
2005
Symp oma ic
PAD (Fon aine
II–IV), ≥50% FP
s enosis
Acu e CLI,
p io FP
bypass, pel ic
in low lesion,
alle gies
Dake e
al.,
2011
479 PAD p s
Ru he o d ≥2, de
no o/ es eno ic
lesions ≤14 cm; mean
68; 65% ♂; 91%
claudica ion
Pa ency 12mo
32.8% (PTA,
ITT)
Pa ency 12mo
83.1% (DES)
P ospec i e
,
mul ina ion
al RCT
NCT00120406
55
cen es
(USA,
Japan,
Ge many
)
Ma
2005–
Aug 2008
≥1 symp oma ic
lesion (≤14 cm),
ABI <0.9
In low
s enosis >50
%, p io
s en , >14 cm
lesion
Za in
an e al.,
2025
24,167 p s
unde going
in ainguinal ET o
1-y AFS
63.7%; 5-y
24.6% (SAPT)
1-y AFS
67.9%; 5-y
30.4% (DAPT)
Re ospec i
e
mul icen e
No egis e ed
VQI +
Medica
e (USA)
2011–
2019
Adul s wi h CLTI
in ainguinal ET
Missing
an ipla ele
da a
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150
Figu e 5 A. Funnel plo assessing small-s udy e ec s o majo ampu a ion. B. Con ou -enhanced unnel plo
dis inguishing asymme y wi hin signi icance con ou s. C. T im-and- ill adjus ed o es plo epo ing s udy log isk
a ios and he adjus ed pooled e ec . D. T im-and- ill adjus ed unnel plo showing impu ed s udies and educed
asymme y
Figu e 6A summa ized ce ain y ac oss ou comes using GRADE. Majo ampu a ion a 1 yea and 12-mon h g a pa ency
we e a ed mode a e ce ain y, e lec ing easonable con idence in he di ec ion o e ec a e downg ading. Majo
bleeding o ans usion and all-cause mo ali y a 1 yea we e a ed low ce ain y owing o imp ecision and suspec ed
epo ing bias. Figu e 6B de ailed domain-le el judgmen s. Majo ampu a ion was downg aded o isk o bias (se ious)
wi h inconsis ency, indi ec ness, imp ecision, and publica ion bias assessed as no se ious. G a pa ency was
downg aded o inconsis ency (se ious) wi h o he domains no se ious.
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Figu e 6 A. GRADE summa y plo showing o e all ce ain y by ou come (ampu a ion, pa ency, bleeding, mo ali y). B.
GRADE domain ma ix showing isk o bias, inconsis ency, indi ec ness, imp ecision, and publica ion bias a ings pe
ou come
4.4. Risk o Bias Summa y Ac oss T ials
Figu e 7A showed p edominan ly low isk ac oss domains, wi h smalle p opo ions a ed some conce ns and isola ed
high isk con ined o andomiza ion. Figu e 7B con i med o e all low isk in 9/10 ials and some conce ns in 1/10
(Iida e al, 2008). Domain coun s we e: andomiza ion high isk in 2 (Za in an e al, 2025; Iida e al, 2012), some
conce ns in 1 (Iida e al, 2008); de ia ions om in ended in e en ions some conce ns in 1–2 (no ably Dake e al, 2011;
Iida e al, 2008), o he s low; missing ou come da a low in all; measu emen o ou come low in all; selec ion o epo ed
esul some conce ns in 3 (Bu dess e al, 2010; Cassa e al, 2005; Iida e al, 2008). Belch e al, 2010; Hia e al, 2017;
Bonaca e al, 2013; Belch e al, 2008 emained low ac oss all domains.
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Figu e 7 A. Risk-o -bias summa y ba cha showing p opo ions o low isk, some conce ns, and high isk ac oss
domains. B. Risk-o -bias a ic-ligh able showing pe -s udy domain judgmen s and o e all isk assessmen s
5. Discussion
Ch onic limb- h ea ening ischemia (CLTI) ep esen s he end s age o pe iphe al a e y disease and ca ies high isks
o ampu a ion, ca dio ascula e en s, and mo ali y. Re ascula iza ion, whe he su gical o endo ascula , emains he
mains ay o ea men o es o e pe usion. An ipla ele he apy is c i ical pos -p ocedu e o main ain pa ency and
educe h ombo ic complica ions. Howe e , he op imal egimen single an ipla ele he apy (SAPT) e sus dual
an ipla ele he apy (DAPT) emains con o e sial. P e ious s udies ha e ocused on co ona y o ce eb o ascula
se ings, lea ing a gap in dedica ed andomized e idence o CLTI pa ien s. This has led o a iable clinical p ac ice and
unce ain bene i – isk p o iles ega ding in ensi ied an ipla ele egimens ollowing limb sal age p ocedu es. Ten
andomized con olled ials e alua ed DAPT compa ed o SAPT a e e ascula iza ion o CLTI. Majo ampu a ion a
1 yea showed no signi ican bene i wi h DAPT unde andom e ec s (RR 0.94, 95% CI 0.77–1.15; I² 89.9%), despi e a
modes educ ion in common-e ec es ima es (RR 0.80, 95% CI 0.77–0.82). Twel e-mon h g a pa ency also a o ed
DAPT in common-e ec analysis (RR 1.03, 95% CI 1.01–1.04) bu was inconclusi e unde andom e ec s (RR 1.16, 95%
CI 0.70–1.91; I² 95.5%). Majo bleeding inc eased wi h DAPT (RR 1.55, 95% CI 1.06–2.26; I² 57.4%), and his pa e n
was consis en ac oss analy ical models. No clinically impo an imp o emen was seen in ankle–b achial index (MD
−0.04, 95% CI −0.11 o 0.02; I² 99.5%). All-cause mo ali y showed neu al e ec s unde andom e ec s (RR 1.01, 95%
CI 0.75–1.35) bu a po en ial bene i unde common-e ec s (RR 0.90, 95% CI 0.87–0.94). Subg oup analyses did no
iden i y signi ican in e ac ions by ascula bed, e ascula iza ion modali y, o he apy du a ion. GRADE assessmen
a ed e idence o ampu a ion and pa ency ou comes as mode a e ce ain y, while bleeding and mo ali y e idence was
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low ce ain y. Funnel plo asymme y sugges ed missing small s udies wi h null esul s. Ou indings a e consis en wi h
obse a ional egis y da a sugges ing DAPT imp o es ampu a ion- ee su i al bu does no educe majo ampu a ions
a e e ascula iza ion (Ramanan e al., 2021) . Simila ly, Bu dess e al. (2010) showed DAPT imp o ed bioma ke s o
h ombosis wi hou educing myoca dial inju y o limb loss, while bleeding isk inc eased modes ly (Bu dess e al.,
2010). Ma caccio e al. (2022) epo ed no di e ence in 3-yea ou comes be ween SAPT, DAPT, o an ipla ele -
an icoagulan combina ions a e in apopli eal bypass (Ma caccio e al., 2022). Chinai e al. (2020) ound no bene i o
3-mon h DAPT o ampu a ion- ee su i al a e endo ascula in e en ion (Chinai e al., 2020). A Eu opean su ey
e ealed conside able a ia ion in DAPT use due o lack o s ong e idence, emphasizing he need o s anda dized
p o ocols (De Ca lo e al., 2022). Re iews by Gup a e al. (2019) and Spiliopoulos (2014) also con i m ha while DAPT
may imp o e pa ency in some endo ascula con ex s, bene i s a e inconsis en and bleeding isks mus be weighed
ca e ully (Gup a e al., 2019); (Spiliopoulos, 2014). O he s udies no e high p e alence o non- esponse o clopidog el,
highligh ing po en ial o esis ance- ela ed ea men ailu e (Wand e al., 2014). This me a-analysis was s eng hened
by s ic inclusion o andomized con olled ials wi h p especi ied ou comes and adhe ence o PRISMA and Coch ane
s anda ds. The comp ehensi e sea ch s a egy, iple da a ex ac ion, and ad anced s a is ical modeling ensu ed obus
indings. He e ogenei y was explo ed wi h subg oup and me a- eg ession analyses. Quali y assessmen wi h he GRADE
amewo k and isual explo a ion o publica ion bias added anspa ency and in e p e abili y. Fu he mo e, he use o
andom-e ec s and common-e ec models p o ided a comp ehensi e unde s anding o e ec dis ibu ions ac oss
di e se se ings.
Howe e , impo an limi a ions mus be conside ed. High be ween-s udy he e ogenei y was obse ed o all p ima y
ou comes, limi ing he gene alizabili y o pooled es ima es. De ini ions and du a ions o DAPT a ied ac oss ials, and
bleeding endpoin s lacked s anda dized adjudica ion. Se e al analyses elied on econs uc ed su i al da a om
digi ized Kaplan-Meie cu es, which may in oduce bias. Some ials ca ied isks o bias in andomiza ion o selec i e
epo ing. Mo eo e , po en ial small-s udy e ec s and unnel plo asymme y sugges ed ha neu al o nega i e s udies
migh be unde ep esen ed in he published li e a u e. The esul s imply ha DAPT a e e ascula iza ion o CLTI
does no signi ican ly educe majo ampu a ion o enhance g a pa ency compa ed o SAPT, while inc easing bleeding
isk. Cu en clinical p ac ice should a oid ou ine DAPT unless indi idualized bene i ou weighs he isks. Risk
s a i ica ion ools and sha ed decision-making should guide he apy. Clinicians should weigh ac o s such as p ocedu al
ype, ascula bed, and como bidi y bu den when selec ing an ipla ele egimens. Guidelines should emphasize
pe sonalized ea men a he han uni o m DAPT p esc ip ion. Fu u e s udies should explo e an ipla ele s a egies
s a i ied by e ascula iza ion ype and pa ien isk, using s anda dized de ini ions and adequa ely powe ed endpoin s.
T ials inco po a ing pha macogenomic p o iling o iden i y non- esponde s o clopidog el may o e mo e
indi idualized app oaches o he apy in CLTI. Clinicians should limi DAPT use o ca e ully selec ed pa ien s wi h high
ischemic bu low bleeding isk. Rou ine use pos - e ascula iza ion in CLTI is no suppo ed by cu en e idence.
T ea men plans should be eassessed a ollow-up and adjus ed based on e ol ing clinical s a us and bleeding his o y.
Policymake s should suppo de elopmen o e idence-based guidelines ha p omo e indi idualized an i h ombo ic
s a egies. Reimbu semen amewo ks should no incen i ize blanke DAPT use. Na ional ascula egis ies should
collec g anula ou come da a o guide u u e esea ch and e ine quali y me ics in CLTI ca e.
6. Conclusion
Dual an ipla ele he apy did no signi ican ly educe majo ampu a ion o imp o e g a pa ency a e e ascula iza ion
o ch onic limb- h ea ening ischemia when compa ed wi h single an ipla ele he apy. The bleeding isk was
consis en ly highe in pa ien s ecei ing dual he apy. No subs an ial bene i was obse ed in pe usion indices o all-
cause mo ali y. Subg oup and sensi i i y analyses did no iden i y ea men e ec modi ie s. Be ween-s udy
he e ogenei y and low ce ain y o e idence o sa e y ou comes u he limi ed con idence. Rou ine dual he apy canno
be ecommended o all pa ien s a e e ascula iza ion in his se ing.
Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
No con lic o in e es o be disclosed.
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154
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