363
ORIGINAL SCIENTIFIC ARTICLE
Anticoagulant vs. antiplatelet therapy after endovascular lower limb revascularisation
Copyright (c) 2022 Slovenian Medical Journal. This work is licensed under a
Creative Commons Attribution-NonCommercial 4.0 International License.
Effectiveness and safety of anticoagulant versus antiplatelet 
therapy in patients after endovascular revascularisation of 
the lower limb
Primerjava učinkovitosti in varnosti antikoagulacijskega in antiagregacijskega 
zdravljenja pri bolnikih po znotrajžilnem posegu na spodnjem udu
Kevin Pelicon,1 Klemen Petek,1 Anja Boc,1,2 Vinko Boc,1 Nataša Kejžar,3 Tjaša Vižintin Cuderman,1 Aleš Blinc1
Abstract
Background: After revascularisation, patients with peripheral arterial disease (PAD) are routinely prescribed antiplatelet 
treatment (APT). Patients who receive anticoagulant treatment (ACT) due to comorbidity are an exception. We set out to 
determine possible differences in the effectiveness and safety between ACT and APT in patients after endovascular revas-
cularisation of the lower limb arteries.
Methods: In a single-centre retrospective cohort study, we analysed the data of 1,587 PAD patients who underwent suc-
cessful endovascular revascularisation of the lower limb arteries due to disabling intermittent claudication or chronic 
critical limb ischemia over a 5-year period. Patients were divided into the ACT and APT groups based on their prescribed 
treatment. After balancing both groups’ baseline characteristics with propensity score matching, we compared the effec-
tiveness and safety of both treatment regimens in the first year after revascularisation.
Results: Compared to patients with APT, patients with ACT were older, and more often reported arterial hypertension, 
diabetes, chronic kidney disease, congestive heart failure, ischaemic heart disease, and prior stroke or transient isch-
aemic attack. After matching, the odds ratio (OR) for an effective outcome with ACT versus APT was 0.78 (95% CI 0.39–1.59; 
p=0.502), while the OR for a safe outcome with ACT versus APT was 4.12 (95% CI 0.82–20.73; p=0.085).
1 Klinični oddelek za žilne bolezni, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenia
2 Inštitut za anatomijo, Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija
3 Inštitut za biostatistiko in medicinsko informatiko, Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija
Correspondence / Korespondenca: Aleš Blinc, e: ales.blinc@kclj.si
Key words: peripheral arterial disease; percutaneous transluminal angioplasty; antithrombotic agents; treatment outcome; propensity 
score matching
Ključne besede: periferna arterijska bolezen; znotrajžilna angioplastika skozi kožo; antitrombotična zdravila; izidi zdravljenja; 
uravnoteženje z nagnjenjem
Received / Prispelo: 23. 2. 2022 | Accepted / Sprejeto: 13. 4. 2022
Cite as / Citirajte kot: Pelicon K, Petek K, Boc A, Boc V, Kejžar N, Vižintin Cuderman T, et al. Effectiveness and safety of anticoagulant 
versus antiplatelet therapy in patients after endovascular revascularisation of the lower limb. Zdrav Vestn. 2022;91(9–10):363–72. DOI: 
https://doi.org/10.6016/ZdravVestn.3339
eng slo element
en article-lang
10.6016/ZdravVestn.3339 doi
23.2.2022 date-received
13.4.2022 date-accepted
Cardiovascular system Srce in ožilje discipline
Original scientific article Izvirni znanstveni članek article-type
Effectiveness and safety of anticoagulant 
versus antiplatelet therapy in patients after en-
dovascular revascularisation of the lower limb
Primerjava učinkovitosti in varnosti antikoagulaci-
jskega in antiagregacijskega zdravljenja pri bolni-
kih po znotrajžilnem posegu na spodnjem udu
article-title
Anticoagulant vs. antiplatelet therapy after en-
dovascular lower limb revascularisation
Antikoagulacijsko in antiagregacijsko zdravljenje 
po endovaskularnem posegu spodnjega uda alt-title
peripheral arterial disease, percutaneous 
transluminal angioplasty, antithrombotic 
agents, treatment outcome, propensity score 
matching
periferna arterijska bolezen, znotrajžilna angio-
plastika skozi kožo, antitrombotična zdravila, izidi 
zdravljenja, uravnoteženje z nagnjenjem
kwd-group
The authors declare that there are no conflicts 
of interest present.
Avtorji so izjavili, da ne obstajajo nobeni 
konkurenčni interesi. conflict
year volume first month last month first page last page
2022 91 9 10 363 372
name surname aff email
Aleš Blinc 1 ales.blinc@kclj.si
name surname aff
Klemen Petek 1
Anja Boc 1,2
Vinko Boc 1
Nataša Kejžar 3
Tjaša Vižintin Cuderman 1
Aleš Blinc 1
eng slo aff-id
Department of Vascular 
Diseases, University Medical 
Centre Ljubljana, Ljubljana, 
Slovenia
Klinični oddelek za žilne bolezni, 
Univerzitetni klinični center 
Ljubljana, Ljubljana, Slovenia
1
Institute of Anatomy, Faculty 
of Medicine, University of 
Ljubljana, Ljubljana, Slovenia
Inštitut za anatomijo, Medicinska 
fakulteta, Univerza v Ljubljani, 
Ljubljana, Slovenija
2
Institute for Biostatistics and 
Medical Informatics, Faculty 
of Medicine, University of 
Ljubljana, Ljubljana, Slovenia
Inštitut za biostatistiko in 
medicinsko informatiko, 
Medicinska fakulteta, Univerza v 
Ljubljani, Ljubljana, Slovenija
3
Slovenian Medical Journallovenian Medical Journal
364
CARDIOVASCULAR SYSTEM
Zdrav Vestn | September – October 2022 | Letnik 91 | https://doi.org/10.6016/ZdravVestn.3339
1 Introduction
Peripheral arterial disease (PAD) indicates severe 
systemic atherosclerotic involvement, resulting in 
an increased risk of both major adverse limb events 
(MALE) and major adverse cardiovascular events 
(MACE) (1). Patients with symptomatic PAD are rou-
tinely prescribed antithrombotic therapy to lower the 
risk of atherothrombotic events. Except for patients for 
whom anticoagulant therapy (ACT) is indicated due to 
concomitant illness, antiplatelet therapy (APT) is gen-
erally considered to be the treatment of choice (1,2).
In patients with advanced PAD, presenting as dis-
abling intermittent claudication or chronic critical 
limb ischaemia (CLI), a revascularisation procedure 
is usually performed to restore perfusion of the low-
er limb. At present, endovascular procedures, namely 
percutaneous transluminal angioplasty (PTA) with or 
without stent placement, are the preferred way of re-
vascularisation (1,2). After revascularisation, the risk 
of atherothrombotic events increases as the proce-
dure causes trauma to the vascular wall, exposes the 
endothelium, and induces a local inflammatory re-
sponse (3), which stimulates platelet adhesion and clot 
formation. Meanwhile, activated platelets are also likely 
to promote vascular smooth muscle cell proliferation 
and thus cause neointimal hyperplasia (4). Preventing 
reocclusion and thus reducing the need for additional 
revascularisations is therefore one of the aims of anti-
thrombotic treatment after endovascular procedures 
(1,2,5-7).
After revascularisation, the optimal antithrombotic 
treatment regimen is yet to be determined (1,2). While 
patients are mainly prescribed APT, the role of antico-
agulants has not yet been fully established. Recent stud-
ies suggest better efficacy of the combination of low-
dose rivaroxaban and acetylsalicylic acid compared to 
acetylsalicylic acid alone, but with an increased risk of 
bleeding (8,9). As some patients will continue to require 
therapeutic doses of anticoagulants after intervention-
al revascularisation due to comorbidities, understand-
ing their effectiveness and safety in preventing MACE 
and MALE is crucial. This retrospective cohort study 
compares the effectiveness and safety of ACT and APT 
in patients after endovascular revascularisation of the 
lower limb arteries.
Conclusions: Patients who required ACT were elderly, had more cardiovascular risk factors and had more advanced PAD 
than patients with APT. After matching, we found no statistically significant difference in the effectiveness and safety of 
both treatment regimens; however the wide OR confidence intervals warrant further research.
Izvleček
Izhodišča: Bolniki s periferno arterijsko boleznijo (PAB) po revaskularizaciji običajno prejemajo antiagregacijsko zdravlje-
nje. Izjema so bolniki, ki zaradi pridruženih bolezni potrebujejo antikoagulacijsko zdravljenje. Namen raziskave je bil pre-
poznati morebitne razlike v učinkovitosti in varnosti med antikoagulacijskim in antiagregacijskim zdravljenjem pri bolni-
kih po skozikožni znotrajžilni revaskularizaciji arterij spodnjega uda.
Metode: V enocentrični retrospektivni kohortni raziskavi smo analizirali podatke o 1.587 bolnikih s PAB, pri katerih je bila 
v 5-letnem obdobju zaradi omejujoče intermitentne klavdikacije ali kronične kritične ishemije uda opravljena uspešna 
znotrajžilna revaskularizacija arterij spodnjega uda. Bolnike smo na podlagi predpisanega zdravljenja razdelili v antikoa-
gulacijsko in antiagregacijsko skupino. Po usklajevanju osnovnih značilnosti obeh skupin z metodo usklajevanja nagnjenja 
smo primerjali učinkovitost in varnost obeh režimov zdravljenja v prvem letu po revaskularizaciji.
Rezultati: Bolniki v antikoagulacijski skupini so bili v primerjavi s tistimi v antiagregacijski skupini starejši ter so imeli 
pogosteje arterijsko hipertenzijo, sladkorno bolezen, kronično ledvično bolezen, zastojno srčno popuščanje, ishemično 
bolezen srca in anamnezo možganske kapi ali tranzitorne ishemične atake (TIA). Po usklajevanju je bilo razmerje obetov za 
uspešen izid ob antikoagulacijskem zdravljenju glede na antiagregacijsko zdravljenje 0,78 (95-odstotni interval zaupanja 
0,39–1,59; p=0,502), razmerje obetov za varen izid ob antikoagulacijskem glede na antiagregacijsko zdravljenje pa 4,12 
(95-odstotni interval zaupanja 0,82–20,73; p=0,085).
Zaključki: Bolniki, ki so potrebovali antikoagulacijsko zdravljenje, so bili starejši in so imeli bolj številčne srčno-žilne de-
javnike tveganja ter bolj napredovalo PAB kot bolniki z antiagregacijskim zdravljenjem. Po usklajevanju nismo ugotovili 
statistično pomembne razlike v učinkovitosti ali varnosti obeh režimov zdravljenja, vendar širina intervalov zaupanja za 
razmerje obetov zahteva nadaljnje raziskave.
365
ORIGINAL SCIENTIFIC ARTICLE
Anticoagulant vs. antiplatelet therapy after endovascular lower limb revascularisation
2 Methods
Included in this retrospective cohort study were all 
patients with advanced PAD presenting as disabling in-
termittent claudication or CLI who underwent success-
ful endovascular revascularisation at the Catheter Labo-
ratory of the Clinical Department of Vascular Diseases, 
University Medical Centre Ljubljana, between January 
2014 and December 2018. Patient data were non-con-
currently obtained from electronic hospital medical re-
cords and supplemented with information received from 
the patients’ primary care physicians, when available. We 
collected data on patient demographics, PAD character-
istics at the time of the procedure, comorbidities (cardio-
vascular risk factors and risk factors for bleeding), and 
procedural characteristics. Diagnoses of comorbidities 
were based on established diagnoses in the patients’ doc-
umentation, laboratory values, and prescribed medica-
tion. Data were matched by the hospitalisation identifier 
and anonymised for analysis.
The exclusion criteria were: a simultaneously per-
formed surgical bypass procedure, subsequently per-
formed additional procedures due to previously un-
detected stenosis of a more proximal arterial segment, 
and insufficient data on post-procedural antithrombotic 
therapy. Treatment protocols and post-procedural anti-
thrombotic treatment were based on the ESC guidelines 
(1). Patients were generally prescribed APT, while in 
patients with comorbidity, which called for therapeutic 
doses of anticoagulants, ACT was continued after the 
procedure, sometimes with the addition of an antiplatelet 
agent for a limited time of usually 1 or 3 months. Patients 
were divided into two groups based on their prescribed 
antithrombotic treatment upon discharge from the hos-
pital. Those who received ACT (excluding prophylac-
tic doses of anticoagulants and low-dose rivaroxaban) 
with or without APT comprised the ACT group, while 
patients who received APT alone comprised the APT 
group. Adherence and potential changes in therapy were 
not considered.
Outcomes were assessed during the first year after re-
vascularisation or until a second intervention on the same 
limb if performed sooner. If the only follow-ups were 
more than one year after the procedure, the earliest subse-
quent follow-up was used to assess the outcomes after one 
year. In this interval, all events were evaluated equally, re-
gardless of when in the observed interval they occurred. 
If the patient had no follow-ups or if it was not possible 
to assess the outcome one year after the procedure, the 
patient was excluded from further analysis (Figure 1).
We defined two observed outcomes – an effective-
ness outcome and a safety outcome. Treatment was con-
sidered effective if the patient experienced:
• an improvement of symptoms as defined by the Fon-
taine classification (10) or
• the successful healing of a stump after a previously 
Figure 1: Patient selection process and statistical analysis.
Legend: PTA – percutaneous transluminal angioplasty; PSM – propensity score matching.
N=1,612
Patients with successful PTA
between 2014 and 2018
N=1,587
Comparison of baseline
characteristics
N=1,587
Assessment of eectiveness
and safety outcomes
N=1,412
PSM and
outcome analysis
N=25
Exclusion of patients with:
a simultaneously performed
surgical bypass procedure,
previously undetected
stenosis of a more proximal
segment,
insuicient data on
post-procedural
antithrombotic therapy
N=175
Exclusion of patients
where both observed
outcomes could not be
determined
366
CARDIOVASCULAR SYSTEM
Zdrav Vestn | September – October 2022 | Letnik 91 | https://doi.org/10.6016/ZdravVestn.3339
planned amputation, performed shortly before or af-
ter the revascularisation.
If there was no improvement or symptoms worsened, 
if the patient required another procedure or even major 
amputation of the treated limb, or if the patient died re-
gardless of cause, treatment was deemed ineffective.
Safety of treatment was defined as the absence of ma-
jor bleeding according to the ISTH criteria (11).
Statistical analysis of baseline characteristics was per-
formed using the SPSS statistical package (version 25, 
IBM SPSS Statistics, USA). Propensity score matching 
(PSM) and logistic regression were performed in the R 
programming language (12). Descriptive statistics were 
used to report the patients’ baseline characteristics, with 
categorical variables presented as frequency and per-
centage, and continuous variables presented as mean 
and standard deviation. The groups’ characteristics were 
compared using Pearson’s χ2 or Fisher’s exact tests for 
categorical variables and independent samples t-tests 
for continuous variables. We used PSM to select the 
subgroup of patients whose baseline characteristics and 
risk were comparable, making the observed outcomes 
dependent only on the treatment group and not on the 
patients’ other characteristics. We matched the patients 
in the APT group to the patients in the ACT group. 
Included in the matching process were all patients for 
whom the effectiveness and safety outcomes could both 
be determined. A propensity score was calculated for 
each patient based on demographics, PAD severity, pro-
cedural characteristics, and comorbidities, signifying 
the probability that a patient would be prescribed ACT 
based on the included covariates (13). We also calcu-
lated the standardised mean differences (SMD) before 
and after matching, indicating an individual covariate’s 
balance between the treatment groups. Covariates were 
considered well balanced when SMD was <0.05. After 
calculating propensity scores, matching was performed 
with three matching algorithms (nearest neighbour, full, 
and optimal). The nearest neighbour 1:5 algorithm with 
replacement enabled the inclusion of a sufficient num-
ber of patients and yielded adequate balance. After ap-
plying this algorithm, the data had the smallest number 
of covariates where SMD was >0.05 and the largest final 
effective sample size (patients from the ACT group were 
matched to multiple patients from the APT group). Fur-
ther analysis was thus conducted using this method. The 
final sample included all patients from the ACT group 
and only the matched patients from the APT group. To 
assess the relative effectiveness and safety of both treat-
ment regimens, we fit two logistic models to the matched 
sample, with the treatment group, the calculated pro-
pensity scores, and atrial fibrillation (previously not in-
cluded in the PSM) as predictors, and the effectiveness 
or safety as the outcome. We then calculated the odds 
ratio (OR) and the corresponding confidence intervals 
(CI) for the effectiveness and safety outcomes for ACT 
versus APT.
The study was conducted according to the guidelines 
of the Declaration of Helsinki. The study design was 
approved by the National Medical Ethics Committee 
(0120-623/2019/4; February 10, 2020).
3 Results
We reviewed the data of all 1,612 patients who had 
undergone technically successful revascularisation be-
tween the years 2014 and 2018. After excluding ineligi-
ble patients, we included 1,587 patients in the analysis of 
baseline characteristics, 233 (14.7%) of whom received 
ACT. In the ACT group, the majority of patients (173; 
74.2%) were prescribed warfarin, 21 patients (9.0%) re-
ceived rivaroxaban, and 17 (7.3%) received dabigatran. 
The remaining patients received apixaban, low-molecu-
lar-weight heparin, or acenocoumarol. About two-thirds 
of patients in the ACT group (156; 67.0%) were tempo-
rarily prescribed antiplatelet agents in addition to ACT 
for an average duration of 2.3 months. The comparison 
of the patients’ baseline characteristics for the ACT and 
APT groups is presented in Table 1.
In the unmatched groups, the effectiveness of ACT 
was 58.5% (120/205 patients), while the effectiveness of 
APT was 77.3% (933/1,207 patients). Within one year 
after endovascular revascularisation, all-cause mortality 
was 22.4% in the ACT group (46/205 patients) and 7.9% 
in the APT group (95/1,207 patients). The incidence of 
major bleeding was 4.4% in the ACT group (9/205 pa-
tients) and 1.2% in the APT group (15/1,207 patients). 
Bleeding was fatal for one patient in the ACT group 
(0.5%) and two in the APT group (0.2%). Of the 24 ma-
jor haemorrhages recorded, 13 (54.2%) occurred with-
in the first two months after revascularisation. Three of 
them directly resulted from the procedure, as there was 
bleeding at the procedural access site.
For 175 patients, both the effectiveness and safety 
outcome could not be determined. After their exclusion 
from further analysis, PSM was performed on 1,412 
patients (Figure 1). The characteristics of both patient 
groups before and after matching are shown in Table 2. 
All variables presented in Table 2 were used as covariates 
in the PSM procedure. After matching, the sample size 
was 655 patients, namely 205 patients in the ACT group 
367
ORIGINAL SCIENTIFIC ARTICLE
Anticoagulant vs. antiplatelet therapy after endovascular lower limb revascularisation
Table 1: Comparison of baseline characteristics of the anticoagulant group and the antiplatelet group of patients.
 Anticoagulant group 
(N=233)
Antiplatelet group 
(N=1,354)
p value
Patient characteristics
Age (years) 76.1 ± 10.1 69.0 ± 10.4 <0.001
Female sex 93 (39.9) 569 (42.0) 0.546
Arterial hypertension 215 (92.3) 1,141 (84.3) 0.001
Dyslipidemia 154 (66.1) 1,077 (79.5) <0.001
Diabetes mellitus 122 (52.4) 581 (42.9) 0.007
Ischaemic heart disease 74 (31.8) 293 (21.6) 0.001
Atrial fibrillation 188 (80.7) 34 (2.5) <0.001
Congestive heart failure 103 (44.2) 133 (9.8) <0.001
History of stroke or TIA 54 (23.2) 150 (11.1) <0.001
Chronic kidney disease 91 (39.1) 292 (21.6) <0.001
Liver disease 3 (1.3) 6 (0.4) 0.134
Bleeding diathesis 9 (3.9) 38 (2.8) 0.380
Smoking   <0.001
current or abstinence of <1 year 26 (11.2) 534 (39.4)  
abstinence of >1 year 74 (31.8) 368 (27.2)  
Excessive alcohol intake 9 (3.9) 63 (4.7) 0.592
PAD characteristics and procedural characteristics
Fontaine classification grade <0.001
2b 96 (41.2) 996 (73.6)  
3 30 (12.9) 82 (6.1)  
4 107 (45.9) 276 (20.4)  
ABI before the procedure 0.61 ± 0.26 0.59 ± 0.21 0.267
TASC II classification* 0.001
A 36 (15.5) 382 (28.2)  
B 76 (32.6) 495 (36.6)  
C 60 (25.8) 333 (24.6)  
D 12 (5.2) 35 (2.6)  
Treated arterial segment† <0.001
infrapopliteal 46 (19.7) 98 (7.2)
femoropopliteal 85 (36.5) 616 (45.5)  
femoropopliteal and infrapopliteal 74 (31.8) 276 (20.4)  
iliac 25 (10.7) 352 (26.0)  
iliac and femoropopliteal 3 (1.3) 12 (0.9)  
368
CARDIOVASCULAR SYSTEM
Zdrav Vestn | September – October 2022 | Letnik 91 | https://doi.org/10.6016/ZdravVestn.3339
and 450 in the APT group. The effective sample size was 
430.6 patients.
We found no statistically significant difference be-
tween the matched ACT and APT groups, neither in the 
effectiveness outcome (OR for ACT versus APT 0.78; 
95% CI 0.39–1.59; p = 0.502) nor in the safety outcome 
(OR for ACT versus APT 4.12; 95% CI 0.82–20.73; p = 
0.085).
4 Discussion
Current recommendations for the antithrombotic 
treatment of PAD patients after endovascular procedures 
are mainly extrapolated from evidence-based recom-
mendations for the antithrombotic treatment of patients 
with coronary heart disease (5). Antiplatelet drugs rep-
resent a cornerstone of antithrombotic treatment after 
Data are shown as frequency and percentage (%) for categorical variables and as mean ± standard deviation for continuous 
variables (age and ankle-brachial index). Due to rounding, totals may be different from 100%. Bold values denote statistical 
significance at the p<0.05 level.*TASC II was not assessed if revascularisation was performed on the infrapopliteal segment 
only. †All groups include percutaneous transluminal angioplasty with or without stent placement.
Legend: ABI – ankle-brachial index; TIA – transient ischaemic attack.
 Anticoagulant group 
(N=233)
Antiplatelet group 
(N=1,354)
p value
Previous amputation 0.001
none 198 (85.0) 1,248 (92.2)
below the ankle 22 (9.4) 74 (5.5)  
above the ankle 13 (5.6) 32 (2.4)  
Previous revascularisation 0.754
of the same segment 39 (16.7) 211 (15.6)  
of a different segment 30 (12.9) 197 (14.5)
Table 2: Results of nearest neighbour 1:5 propensity score matching for the anticoagulant group and the antiplatelet 
group of patients.
Unmatched groups Matched groups
Anticoagulant 
group 
(N=205)
Antiplatelet 
group 
(N=1,207)
SMD Anticoagulant 
group 
(N=205)
Antiplatelet 
group 
(N=450)
SMD
Patient characteristics
Age (years) 76.1 ± 10.1 68.7 ± 10.3 0.727 76.1 ± 10.1 75.8 ± 9.6 0.026
Female sex 85 (41.5) 503 (41.7) 0.004 85.0 (41.5) 188.3 (41.9) 0.008
Arterial hypertension 189 (92.2) 1,020 (84.5) 0.241 189.0 (92.2) 407.4 (90.5) 0.059
Dyslipidemia 132 (64.4) 969 (80.3) 0.361 132.0 (64.4) 283.2 (62.9) 0.030
Diabetes mellitus 108 (52.7) 520 (43.1) 0.193 108.0 (52.7) 244.1 (54.2) 0.031
Ischaemic heart disease 63 (30.7) 262 (21.7) 0.206 63.0 (30.7) 150.6 (33.5) 0.059
Congestive heart failure 90 (43.9) 117 (9.7) 0.837 90.0 (43.9) 188.3 (41.9) 0.041
History of stroke or TIA 48 (23.4) 136 (11.3) 0.325 48.0 (23.4) 105.4 (23.4) <0.001
Chronic kidney disease 80 (39.0) 258 (21.4) 0.392 80.0 (39.0) 193.6 (43.0) 0.081
Liver disease 3 (1.5) 5 (0.4) 0.109 3.0 (1.5) 5.7 (1.3) 0.017
369
ORIGINAL SCIENTIFIC ARTICLE
Anticoagulant vs. antiplatelet therapy after endovascular lower limb revascularisation
Data are shown as frequency and percentage (%) for categorical variables and as mean ± standard deviation for continuous 
variables (age). Due to the selected algorithm, patient frequencies may be shown with decimals. Due to rounding, totals may 
be different from 100%. *All groups include percutaneous transluminal angioplasty with or without stent placement.
Legend: SMD – standardised mean difference.
Unmatched groups Matched groups
Anticoagulant 
group 
(N=205)
Antiplatelet 
group 
(N=1,207)
SMD Anticoagulant 
group 
(N=205)
Antiplatelet 
group 
(N=450)
SMD
Bleeding diathesis 9 (4.4) 35 (2.9) 0.080 9.0 (4.4) 21.1 (4.7) 0.014
Smoking   0.703   0.050
non-smoker 116 (56.6) 390 (32.3)  116.0 (56.6) 245.4 (54.5)  
current or abstinence of <1 year 25 (12.2) 487 (40.3)  25.0 (12.2) 53.6 (11.9)  
abstinence of >1 year 64 (31.2) 330 (27.3)  64.0 (31.2) 151.0 (33.6)  
Excessive alcohol intake 7 (3.4) 54 (4.5) 0.054 7.0 (3.4) 16.2 (3.6) 0.011
PAD characteristics and procedural characteristics
Fontaine classification stage 0.735 0.077
2b 83 (40.5) 900 (74.6) 83.0 (40.5) 166.8 (37.1)  
3 27 (13.2) 73 (6.0) 27.0 (13.2) 58.0 (12.9)  
4 95 (46.3) 234 (19.4) 95.0 (46.3) 225.2 (50.0)  
TASC II 0.509   0.059
A 30 (14.6) 344 (28.5) 30.0 (14.6) 61.0 (13.6)  
B 65 (31.7) 439 (36.4) 65.0 (31.7) 140.9 (31.3)  
C 55 (26.8) 299 (24.8) 55.0 (26.8) 126.9 (28.2)  
D 12 (5.9) 31 (2.6) 12.0 (5.9) 30.7 (6.8)  
TASC II was not assessed 43 (21.0) 94 (7.8) 43.0 (21.0) 90.4 (20.1)  
Treated arterial segment*  0.617   0.021
infrapopliteal 40 (19.5) 84 (7.0) 40.0 (19.5) 85.6 (19.0)  
femoropopliteal 76 (37.1) 558 (46.2)  76.0 (37.1) 165.1 (36.7)  
femoropopliteal+infrapopliteal 66 (32.2) 240 (19.9)  66.0 (32.2) 146.6 (32.6)  
iliac 20 (9.8) 314 (26.0) 20.0 (9.8) 46.1 (10.2)  
iliac+femoropopliteal 3 (1.5) 11 (0.9) 3.0 (1.5) 6.6 (1.5)
Previous amputation 0.263   0.101
none 174 (84.9) 1,117 (92.5) 174.0 (84.9) 365.3 (81.2)
below the ankle 21 (10.2) 67 (5.6) 21.0 (10.2) 58.8 (13.1)
above the ankle 10 (4.9) 23 (1.9) 10.0 (4.9) 25.9 (5.8)
Previous revascularisation 0.077   0.057
none 141 (68.8) 832 (68.9) 141.0 (68.8) 312.6 (69.5)
of the same segment 37 (18.0) 191 (15.8) 37.0 (18.0) 86.0 (19.1)
of a different segment 27 (13.2) 184 (15.2) 27.0 (13.2) 51.4 (11.4)
370
CARDIOVASCULAR SYSTEM
Zdrav Vestn | September – October 2022 | Letnik 91 | https://doi.org/10.6016/ZdravVestn.3339
revascularisation, while the role of anticoagulants has 
not yet been completely established. The COMPASS and 
VOYAGER-PAD trials found the addition of low-dose ri-
varoxaban to acetylsalicylic acid to reduce the incidence 
of MACE and MALE in patients with stable PAD as well 
as in patients after a revascularisation procedure. How-
ever, a slightly increased risk of bleeding, excluding fatal 
and intracranial haemorrhage, was noted in both trials 
(8,9). Other studies were less conclusive, with some of 
them failing to demonstrate any difference between the 
combination of ACT with APT and APT alone (14-17).
After an endovascular procedure, patients are gener-
ally prescribed APT. In patients who require therapeutic 
doses of anticoagulants due to comorbidity, transient 
addition of APT is always considered, with the final de-
cision hinging on the patient’s risk for bleeding (1,2). In 
our study, two-thirds of patients in the ACT group were 
simultaneously prescribed at least one antiplatelet drug. 
Atrial fibrillation is one of the most common indications 
for anticoagulant use (18), which explains why the prev-
alence of atrial fibrillation in our study was more than 
80% in the ACT group and only 2.5% in the APT group. 
The presence of atrial fibrillation typically indicates 
higher age, and, therefore, a higher probability of co-
morbidity, including a more severe course of PAD with 
a poorer outcome (19). Our results are in concordance 
with these expectations. Compared to patients in the 
APT group, patients with ACT were more than 7 years 
older and more likely to have arterial hypertension, di-
abetes mellitus, chronic kidney disease, ischaemic heart 
disease, congestive heart failure, and a history of stroke 
or TIA. As expected, the higher age and more frequent 
comorbidities of patients in the ACT group were also re-
flected in more advanced PAD in these patients. Patients 
with ACT had more complex atherosclerotic lesions ac-
cording to the TASC II classification. Furthermore, pre-
vious amputations were twice as common in the ACT 
group as in the APT group, while CLI was present in al-
most 60% of patients in the ACT group compared to just 
over a quarter of patients in the APT group.
Interestingly, despite a significantly higher prevalence 
of CLI in the ACT group, no difference in the pre-proce-
dural ankle-brachial index (ABI) was found. This could 
be explained by a potentially higher prevalence of me-
dial arterial calcification in ACT group patients, which 
was not yet as pronounced as to increase the ABI above 
1.4. Diabetes mellitus and chronic kidney disease, rele-
vant risk factors for the development of medial arterial 
calcification, were more common in our patients with 
ACT (2,20). Both diseases also are independent risk fac-
tors for infrapopliteal PAD (21,22). In our study, this is 
reflected in the higher frequency of treatment of infrap-
opliteal arteries in patients in the ACT group compared 
to those in the APT group.
Before matching, 175 patients for whom both ob-
served outcomes could not be determined were exclud-
ed. These were the patients who did not have a follow-up 
examination within one year of their procedure and did 
not die. Possibly, these patients did not attend follow-up 
examinations because their outcomes were favourable. 
However, other explanations, such as treatment in oth-
er institutions, are also possible. We excluded all of 
them from further analysis to prevent bias, which did 
not affect the two groups’ baseline characteristics (Ta-
ble 1 and the unmatched groups in Table 2). In order 
to evaluate the effectiveness and safety outcomes, the 
two groups were balanced using PSM, after which ad-
equate balance was achieved. PSM is increasingly used 
in observational studies, as it enables the comparison of 
groups of patients with radically different characteristics 
by preprocessing the groups and yielding data already 
controlled for the measured pre-treatment variables (i.e. 
confounding variables or variables that predict the out-
come) (23). Compared to multiple logistic regression, 
PSM is very tolerant regarding the number of includ-
ed covariates (24). Therefore, we were able to include a 
wide range of covariates that are associated with the pa-
tients’ treatment regimen and might affect the observed 
outcomes. Since we were comparing two very different 
groups, PSM allowed us to match patients in the APT 
group to patients in the ACT group and make the final 
estimate of the odds ratio for the population of interest 
more precise. In our study, patients in the APT group 
were matched to their counterparts in the ACT group, 
meaning our findings cannot be extrapolated to the en-
tire population but to the subset of patients with similar 
characteristics to those with ACT – older patients with 
more severe PAD and more comorbidities.
After matching, we found no statistically significant 
difference neither in the effectiveness, nor the safety 
of both treatment regimens. One can hypothesise that 
patients were already prescribed the most appropriate 
treatment considering their health status. However, our 
study cannot confirm the equivalence of the two treat-
ment regimens. A possible explanation for the lack of 
difference may also be an insufficient number of includ-
ed patients, considering that antithrombotic treatment 
is only one of many factors that influence the outcome 
of revascularisation. Furthermore, the vast majority of 
patients in our ACT group simultaneously received APT 
for a short duration, which may, to some extent, obscure 
the results.
371
ORIGINAL SCIENTIFIC ARTICLE
Anticoagulant vs. antiplatelet therapy after endovascular lower limb revascularisation
Comparable studies often focus on an individual 
arterial segment rather than the entire limb. The treat-
ed arterial segment can significantly impact treatment 
outcomes, as the long-term patency after percutaneous 
revascularisation of the iliac segment is known to be bet-
ter than that of the femoropopliteal and infrapopliteal 
segments (25,26).
According to previous research, increased bleeding 
risk would be expected in patients who received ACT 
(8,9,27,28). In our study, the safety analysis had a wide 
confidence interval, likely due to very rare bleeding 
events. The annual risk of major bleeding in patients 
with ACT is estimated at 2–5%, with fatal bleeding oc-
curring in 0.5–1% of patients (29). Our results are con-
sistent with these estimates as 4.4% of patients in the 
unmatched ACT group suffered major bleeding, with 
fatal bleeding occurring in 0.5% of patients. For APT, 
the annual risk of major bleeding is less than 0.5% (30). 
In our study, 1.2% of patients in the unmatched APT 
group suffered major bleeding in the observed period. It 
should be noted that these annual estimates were made 
for all patients who had been prescribed a specific anti-
thrombotic treatment, while in our study patients also 
underwent revascularisation, which itself poses a risk of 
bleeding. Thus, 3 of our patients experienced bleeding 
at the access site due to the procedure. The somewhat 
higher incidence of major bleeding in the APT group 
could also be explained by the fact that more than 60% 
of our patients in the APT group temporarily received 
dual antiplatelet therapy, which is known to increase the 
risk of major bleeding 2- to 3-fold (31). This is further 
supported by the fact that more than half of our patients 
who experienced major bleeding, did so in the first two 
months after revascularisation.
Our single-centre study has some limitations. Its ret-
rospective nature prevented us from assessing the pa-
tients’ possible poor adherence to their prescribed treat-
ment, which could affect the observed outcomes. In the 
ACT group, the majority of patients simultaneously re-
ceived an antiplatelet agent for a limited duration, which 
could affect both the effectiveness and safety outcome. 
Furthermore, only the antithrombotic treatment upon 
discharge from the hospital was considered in the anal-
ysis, without considering the treatment before the pro-
cedure or possible changes in treatment in the observed 
period. Another limitation was the number of included 
patients. Although we analysed all successful procedures 
in a 5-year period to include a sufficient number of pa-
tients, the ACT group was still relatively small and was 
even further reduced after patients without both out-
comes were excluded and PSM was performed.
5 Conclusion
Patients with PAD who required ACT significantly 
differed from patients in the APT group. In our study, 
they were 7 years older on average, had more advanced 
PAD, and had more comorbidities than patients in the 
APT group. After PSM, no statistically significant differ-
ence was found in the effectiveness and safety outcomes 
between the two groups. As we matched patients in the 
APT group to patients in the ACT group, our findings 
can only apply to the population of older patients with 
more comorbidities.
As the antithrombotic treatment patients are pre-
scribed after revascularisation is only one of many fac-
tors that influence the outcome, we cannot confirm the 
equivalence of both treatment regimens using this study 
design. In order to provide more precise data, a large 
prospective study of the effectiveness and safety of treat-
ment with therapeutical doses of anticoagulants in PAD 
patients after revascularisation would be required.
Conflict of interest
None declared.
Editors comment
This article is based on the award-winning student 
Prešeren research project in 2020/2021.
References
1. Aboyans V, Ricco JB, Bartelink ML, Björck M, Brodmann M, Cohnert 
T, et al.; The Task Force for the Diagnosis and Treatment of Peripheral 
Arterial Diseases ofthe European Society of Cardiology (ESC) and of the 
European Society for VascularSurgery (ESVS). 2017 ESC Guidelines on the 
Diagnosis and Treatment of Peripheral Arterial Diseases,in collaboration 
with the European Society for Vascular Surgery (ESVS): Document 
coveringatherosclerotic disease of extracranial carotid and vertebral, 
mesenteric, renal,upper and lower extremity arteries. Endorsed by: the 
European Stroke Organization(ESO). Eur Heart J. 2018;39(9):763-816. 
DOI: 10.1093/eurheartj/ehx095 PMID: 28886620
372
CARDIOVASCULAR SYSTEM
Zdrav Vestn | September – October 2022 | Letnik 91 | https://doi.org/10.6016/ZdravVestn.3339
2. Frank U, Nikol S, Belch J, Boc V, Brodmann M, Carpentier PH, et al. 
ESVM Guideline on peripheral arterial disease. Vasa. 2019;48:1-79. PMID: 
31789115
3. Schillinger M, Exner M, Mlekusch W, Haumer M, Ahmadi R, Rumpold 
H, et al. Balloon angioplasty and stent implantation induce a vascular 
inflammatory reaction. J Endovasc Ther. 2002;9(1):59-66. DOI: 
10.1177/152660280200900111 PMID: 11958327
4. Cornelissen A, Vogt FJ. The effects of stenting on coronary endothelium 
from a molecular biological view:time for improvement? J Cell Mol Med. 
2019;23(1):39-46. DOI: 10.1111/jcmm.13936 PMID: 30353645
5. Hess CN, Norgren L, Ansel GM, Capell WH, Fletcher JP, Fowkes FG, et al. A 
Structured Review of Antithrombotic Therapy in Peripheral Artery Disease 
With aFocus on Revascularization: A TASC (InterSociety Consensus for 
the Management of PeripheralArtery Disease) Initiative. Circulation. 
2017;135(25):2534-55. DOI: 10.1161/CIRCULATIONAHA.117.024469 PMID: 
28630267
6. Baumgartner I, Norgren L, Fowkes FG, Mulder H, Patel MR, Berger JS, 
et al.; Executive Committee and Investigators of the EUCLID Trial. 
Cardiovascular Outcomes After Lower Extremity Endovascular or Surgical 
Revascularization:the EUCLID Trial. J Am Coll Cardiol. 2018;72(14):1563-
72. DOI: 10.1016/j.jacc.2018.07.046 PMID: 30261955
7. Hess CN, Wang TY, Weleski Fu J, Gundrum J, Allen LaPointe NM, Rogers 
RK, et al. Long-Term Outcomes and Associations With Major Adverse 
Limb Events After PeripheralArtery Revascularization. J Am Coll Cardiol. 
2020;75(5):498-508. DOI: 10.1016/j.jacc.2019.11.050 PMID: 32029132
8. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, 
et al.; COMPASS Investigators. Rivaroxaban with or without aspirin in 
patients with stable peripheral or carotidartery disease: an international, 
randomised, double-blind, placebo-controlled trial. Lancet. 
2018;391(10117):219-29. DOI: 10.1016/S0140-6736(17)32409-1 PMID: 
29132880
9. Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, 
et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. 
N Engl J Med. 2020;382(21):1994-2004. DOI: 10.1056/NEJMoa2000052 
PMID: 32222135
10. Fontaine R, Kim M, Kieny R. Die chirurgische Behandlung der peripheren 
Durchblutungsstörungen. Helv Chir Acta. 1954;21(5-6):499-533. PMID: 
14366554
11. Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher 
W; Subcommittee on Control of Anticoagulation of the Scientific and 
Standardization Committeeof the International Society on Thrombosis 
and Haemostasis. Definition of major bleeding in clinical investigations 
of antihemostatic medicinalproducts in surgical patients. J Thromb 
Haemost. 2010;8(1):202-4. DOI: 10.1111/j.1538-7836.2009.03678.x PMID: 
19878532
12. Core R. A Language and Environment for Statistical Computing. Vienna: R 
Foundation for Statistical Computing; 2019 [cited 2022 Feb 21]. Available 
from: https://www.r-project.org/.
13. Austin PC. An Introduction to Propensity Score Methods for Reducing the 
Effects of Confoundingin Observational Studies. Multivariate Behav Res. 
2011;46(3):399-424. DOI: 10.1080/00273171.2011.568786 PMID: 21818162
14. Koppensteiner R, Spring S, Amann-Vesti BR, Meier T, Pfammatter T, 
Rousson V, et al. Low-molecular-weight heparin for prevention of 
restenosis after femoropopliteal percutaneoustransluminal angioplasty: 
a randomized controlled trial. J Vasc Surg. 2006;44(6):1247-53. DOI: 
10.1016/j.jvs.2006.07.044 PMID: 17145426
15. Moll F, Baumgartner I, Jaff M, Nwachuku C, Tangelder M, Ansel G, et al.; 
ePAD Investigators. Edoxaban Plus Aspirin vs Dual Antiplatelet Therapy 
in Endovascular Treatment of PatientsWith Peripheral Artery Disease: 
results of the ePAD Trial. J Endovasc Ther. 2018;25(2):158-68. DOI: 
10.1177/1526602818760488 PMID: 29552984
16. Do DD, Mahler F. Low-dose aspirin combined with dipyridamole 
versus anticoagulants after femoropoplitealpercutaneous 
transluminal angioplasty. Radiology. 1994;193(2):567-71. DOI: 10.1148/
radiology.193.2.7972781 PMID: 7972781
17. Pilger E, Lammer J, Bertuch H, Stark G, Decrinis M, Pfeiffer KP, et al. Nd:YAG 
laser with sapphire tip combined with balloon angioplasty in peripheral 
arterialocclusions. Long-term results. Circulation. 1991;83(1):141-7. DOI: 
10.1161/01.CIR.83.1.141 PMID: 1824621
18. Antonucci E, Poli D, Tosetto A, Pengo V, Tripodi A, Magrini N, et al.; START-
Register. The Italian START-Register on Anticoagulation with Focus on 
Atrial Fibrillation. PLoS One. 2015;10(5):e0124719. DOI: 10.1371/journal.
pone.0124719 PMID: 26001109
19. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. 
Prevalence of diagnosed atrial fibrillation in adults: national implications 
for rhythmmanagement and stroke prevention: the AnTicoagulation and 
Risk Factors in Atrial Fibrillation(ATRIA) Study. JAMA. 2001;285(18):2370-
5. DOI: 10.1001/jama.285.18.2370 PMID: 11343485
20. Hassan NA, D’Orsi ET, D’Orsi CJ, O’Neill WC. The risk for medial arterial 
calcification in CKD. Clin J Am Soc Nephrol. 2012;7(2):275-9. DOI: 10.2215/
CJN.06490711 PMID: 22156752
21. Davies MG, Saad WE, Peden EK, Mohiuddin IT, Naoum JJ, Lumsden AB. 
Percutaneous superficial femoral artery interventions for claudication—
does runoffmatter? Ann Vasc Surg. 2008;22(6):790-8. DOI: 10.1016/j.
avsg.2008.04.007 PMID: 18640817
22. Diehm N, Shang A, Silvestro A, Do DD, Dick F, Schmidli J, et al. Association 
of cardiovascular risk factors with pattern of lower limb atherosclerosisin 
2659 patients undergoing angioplasty. Eur J Vasc Endovasc Surg. 
2006;31(1):59-63. DOI: 10.1016/j.ejvs.2005.09.006 PMID: 16269257
23. Ho DE, Imai K, King G, Stuart EA. MatchIt: Nonparametric Preprocessing 
for Parametric Causal Inference. J Stat Softw. 2011;42(8):1-28. DOI: 
10.18637/jss.v042.i08
24. Ho DE, Imai K, King G, Stuart EA. Matching as Nonparametric 
Preprocessing for Reducing Model Dependence in ParametricCausal 
Inference. Polit Anal. 2007;15(3):199-236. DOI: 10.1093/pan/mpl013
25. Indes JE, Pfaff MJ, Farrokhyar F, Brown H, Hashim P, Cheung K, et al. 
Clinical outcomes of 5358 patients undergoing direct open bypass or 
endovascular treatmentfor aortoiliac occlusive disease: a systematic 
review and meta-analysis. J Endovasc Ther. 2013;20(4):443-55. DOI: 
10.1583/13-4242.1 PMID: 23914850
26. Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, et al.; Zilver 
PTX Investigators. Durable Clinical Effectiveness With Paclitaxel-Eluting 
Stents in the FemoropoplitealArtery: 5-Year Results of the Zilver PTX 
Randomized Trial. Circulation. 2016;133(15):1472-83. DOI: 10.1161/
CIRCULATIONAHA.115.016900 PMID: 26969758
27. Dagher NN, Modrall JG. Pharmacotherapy before and after 
revascularization: anticoagulation, antiplateletagents, and statins. Semin 
Vasc Surg. 2007;20(1):10-4. DOI: 10.1053/j.semvascsurg.2007.02.006 
PMID: 17386359
28. Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, et al.; Warfarin 
Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant 
and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 
2007;357(3):217-27. DOI: 10.1056/NEJMoa065959 PMID: 17634457
29. Stehle S, Kirchheiner J, Lazar A, Fuhr U. Pharmacogenetics of oral 
anticoagulants: a basis for dose individualization. Clin Pharmacokinet. 
2008;47(9):565-94. DOI: 10.2165/00003088-200847090-00002 PMID: 
18698879
30. Bouget J, Balusson F, Viglino D, Roy PM, Lacut K, Pavageau L, et 
al. Pharmacogenetics of oral anticoagulants: a basis for dose 
individualization. Clin Pharmacokinet. 2008;47(9):565-94. DOI: 
10.2165/00003088-200847090-00002 PMID: 18698879
31. Savarese G, Savonitto S, Lund LH, Paolillo S, Marciano C, Dellegrottaglie 
S, et al. Efficacy and safety of prolonged dual antiplatelet therapy: a 
meta-analysis of 15randomized trials enrolling 85 265 patients. Eur Heart 
J Cardiovasc Pharmacother. 2016;2(4):218-28. DOI: 10.1093/ehjcvp/
pvw011 PMID: 27533949