S e m i n a r s i n Va s c u l a r S u r g e ry 3 5 ( 2 0 2 2 ) 1 2 4 – 1 3 1

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Review article

A comprehensive review on antithrombotic

therapy for peripheral artery disease
Ryan Gupta a,1, Monica Majumdar b,1, Rabbia Imran c, Jeniann Yi b,∗
a Division of Vascular Surgery and Endovascular Therapy, University of Colorado Anschutz School of Medicine,
12631 E. 16th Avenue, Room 5415, MC C312, Aurora, CO 80045
b Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston,

MA
c University of Colorado Anschutz School of Medicine, Aurora, CO

a r t i c l e i n f o a b s t r a c t

Peripheral artery disease (PAD) is a morbid and costly disease that can result in loss of limb
and life if not managed appropriately with risk factor modification, antithrombotic therapy,
and revascularization when necessary. Antithrombotic therapy includes antiplatelet and
anticoagulant drugs. Antiplatelet agents used in PAD can include aspirin, reversible and
irreversible P2Y12 inhibitors, and PAR-1 antagonists. These drugs are prescribed as both
monotherapy or dual-antiplatelet therapy and are critical components of pre- and post-
revascularization maintenance. Anticoagulants, such as vitamin K antagonists and hep-
arin products, have long been used in cardiac disease; in patients with PAD, these drugs
have been largely supplanted by new direct factor Xa antagonists, which offer superior
safety profiles and reduced adverse events after revascularization. Anticoagulants are of-
ten used alongside antiplatelet medications after PAD revascularization; however, there is
a lack of guideline consensus about therapy selection and large regional disparity in re-
gard to antithrombotic prescribing patterns. In this review, we analyze the existing literature
and guidelines regarding the use of antithrombotic therapy in patients with PAD and offer
a framework to aid clinicians’ decision making regarding therapy selection and duration
based on current existing evidence.
© 2022 Elsevier Inc. All rights reserved.

amputation mortality rates reaching up to 50% at 1 year [2].

1. Introduction Although the sequelae of PAD itself can be destructive to a pa-
tient’s functional status and quality of life, patients with PAD
Peripheral artery disease (PAD) is endemic globally, with an
also experience increased rates of ischemic stroke, myocardial
estimated prevalence of 202 million, a number that is only
infarction (MI), and cardiovascular death [3–6].
increasing due to our aging population [1]. The morbidity
Risk factor modification and the use of cardioprotective
and mortality due to PAD can be devastating, with post-
medications generally supercede the role of operative inter-
vention as the initial recommended treatment in patients
∗
Corresponding author. with PAD to mitigate major adverse cardiovascular, cere-
E-mail address: jeniann.yi@cuanschutz.edu (J. Yi). brovascular, and limb events. Glycemic, blood pressure, and
1
Authors share co-first authorship.

https://doi.org/10.1053/j.semvascsurg.2022.04.004
0895-7967/$ – see front matter © 2022 Elsevier Inc. All rights reserved.
 S e m i n a r s i n Va s c u l a r S u r g e ry 3 5 ( 2 0 2 2 ) 1 2 4 – 1 3 1 125

Fig. 1 – Impact of antithrombotic therapies on coagulation cascade. ADP, Adenosine diphosphate; FVIIa, Coagulation Factor
7a; TF, Tissue Factor; TP, Thromboxane Receptor; TXA2, thromboxane A2; VKA, vitamin K antagonist.
Summary of recommendations (see Fig. 2):
• Asymptomatic peripheral artery disease (PAD)
◦ Consider antiplatelet monotherapy in those with concomitant coronary artery disease or cerebrovascular disease
• Symptomatic PAD
◦ Antiplatelet monotherapy
 Evidence suggests clopidogrel is more effective than aspirin; ticagrelor is an acceptable alternative in poor metabolizers of
clopidogrel
◦ Dual-antiplatelet therapy (DAPT) in patients with recent acute coronary syndrome → consider prolonged DAPT if high
risk
• Post-revascularization
◦ Endovascular: DAPT for 1 to 6 months followed by antiplatelet monotherapy or aspirin + rivaroxaban
◦ Open: aspirin monotherapy or aspirin + rivaroxaban
◦ Consider prolonged DAPT or intensified anticoagulation for high risk (defined by prosthetic graft, below-knee bypass,
poor arterial run-off, tissue loss, prior failed bypass prior myocardial infarction, uncontrolled diabetes mellitus,
or current smoker).

cholesterol management, in addition to smoking cessation
and exercise therapy, are integral to PAD treatment with well-
established impact on disease progression [7–10].
Numerous randomized trials regarding antithrombotic
therapy in patients with PAD have investigated medication-
related efficacy, bleeding safety profile, and incidence of major
adverse cardiac events (MACE), that is, cardiovascular death,
stroke, or MI. However, the optimal antithrombotic strategy
for patients with PAD is still characterized by a notable lack
of consensus within society guideline recommendations and
large variations in prescribing patterns [8,10,11]. The major-
ity of recommendations are derived from subgroup analysis
of randomized trials for coronary and cerebrovascular disease
patients [12]. This lack of consensus increases the likelihood
of those with PAD to be undertreated with antithrombotic
agents, as demonstrated in several studies [13–15].
The basis for current antithrombotic strategies within PAD
include antiplatelet (AP) and anticoagulant therapies, which
both act to attenuate platelet-fibrin clot formation, which
results in ischemic events (Fig. 1). Herein, we present an
126 S e m i n a r s i n Va s c u l a r S u r g e ry 3 5 ( 2 0 2 2 ) 1 2 4 – 1 3 1
evidence-based overview on the utilization of AP, anticoagu-
lant, and combination medication strategies for patients with
asymptomatic and symptomatic PAD.
2. Antiplatelet Therapy
PAD is the peripheral manifestation of atherosclerosis, which
is commonly present in multiple vascular beds in affected pa-
tients. Endothelial injury is the inciting factor to the develop-
ment of disease, to which platelet adhesion, activation, and
aggregation play a central role in both the progression of dis-
ease and the precipitation of acute arterial thrombotic events
[16,17]. Cassar et al [18] demonstrated abnormal platelet ac-
tivity in patients with PAD with increased expression of P-
selectin, a platelet surface protein that contributes to platelet
adhesion, and the degree platelet activation was shown to in-
crease with the severity of PAD [18,19]. Thus, antithrombotic
therapy aimed at reducing platelet activity is the cornerstone
of pharmacologic management in PAD, and AP medications
are the only antithrombotic drug type with class I recommen-
dations supported by level A evidence per the 2016 American
College of Cardiology/American Heart Association guidelines
[10].
2.1. Aspirin
The AP effect of aspirin results from the irreversible inhibi-
tion of COX activity to prevent the production of thromboxane
A2, thereby decreasing platelet aggregation. However, the an-
tithrombotic properties of aspirin span beyond platelet activ-
ity; by decreasing the phospholipid surface on which throm-
bin generation occurs, aspirin attenuates a key step of the
common pathway in the coagulation cascade [20].
In asymptomatic PAD, the largest randomized trial exam-
ining the use of aspirin was the Aspirin for Asymptomatic
Atherosclerosis Trial. The trial investigators compared 100
mg aspirin with placebo in 3,350 patients with a follow-
up of 8 years and found no significant reduction in cardio-
vascular events [21]. Although the American Heart Associa-
tion/American College of Cardiology recommendations still
consider AP therapy as a “reasonable” treatment choice for
all patients with an ankle-brachial index ≤0.90, the Euro-
pean Society of Cardiology recommends against routine AP
therapy in asymptomatic patients [8–10]. The US Preven-
tive Services Task Force recently modified its stance to sim-
ilarly recommend against routine aspirin use for primary
prevention of cardiovascular events in adults 60 years and
older without known atherosclerotic disease due to risk of
bleeding, while acknowledging that this represents level D
evidence [22].
In symptomatic PAD, aspirin has demonstrated benefit
for the reduction of MACE. The majority of evidence be-
hind the long-standing class I recommendations are the re-
sult of the Antiplatelet Trialists’ Collaboration and their 2002
meta-analysis of randomized trials of AP therapy for pro-
tection against MI, ischemia stroke, angina, PAD, or atrial
fibrillation [22]. The group concluded from the subset of
42 PAD trials including 9,214 patients that the use of AP
therapy resulted in a 23% proportional reduction in vascu-
lar events compared with control. However, the majority of
the PAD evidence was from subgroup analyses with multi-
ple studies using several AP agents other than aspirin, in-
cluding clopidogrel, ticlopidine, and picotamide [14–23]. The
Antiplatelet Trialists’ Collaboration trial was followed by the
Critical Leg Ischemia Prevention Study (CLIPS) in 2007, which
found a 64% relative risk reduction in MACE with 81 mg of as-
pirin compared with placebo, without an increase in adverse
events [24].
2.2. Clopidogrel
Clopidogrel is an irreversible P2Y12 inhibitor that blocks
adenosine diphosphate and its platelet activation pathway.
This results in diminished platelet aggregation as well as de-
creased platelet-fibrin cross-linking, which contributes to clot
strength and the platelet response to shear stress [16].
In symptomatic PAD, the use of clopidogrel compared
with aspirin was investigated within subgroup analysis of the
Clopidogrel Versus Aspirin in Patients at Risk for Ischemic
Events (CAPRIE) trial. The randomized, blinded trial enrolled
19,185 patients with known atherosclerotic cardiovascular
disease and found statistically significant relative risk reduc-
tion of MACE in favor of clopidogrel over aspirin, albeit with
similar event rates of 5.8% and 5.3% in the aspirin and clopi-
dogrel cohorts, respectively. Increased adverse effects were
noted with clopidogrel, including rash, diarrhea, and upper
gastrointestinal discomfort, but there was a reduced risk of in-
tracranial hemorrhage and gastrointestinal hemorrhage com-
pared with aspirin. The PAD group benefitted the most, with
a 25% reduction in the aggregate outcome of vascular death,
MI, and ischemic stroke in patients on 75 mg of clopidogrel
compared with 325 mg of aspirin [25]. However, given the un-
clear magnitude of benefit in clopidogrel patients, this recom-
mendation has not been integrated into the majority of soci-
ety guidelines [6].
2.3. Ticagrelor
Ticagrelor is a newer generation P2Y12 inhibitor with several
advantages over clopidogrel, including reversibility, rapid on-
set of action, and more potent platelet reactivity inhibition
with less inter-patient variability than clopidogrel [26,27].
In symptomatic PAD, the use of ticagrelor versus clopido-
grel as monotherapy in PAD was compared in the Examin-
ing the Use of Ticagrelor in Peripheral Artery Disease (EUCLID)
trial comprising 13,885 patients. Patients were eligible if they
had an ankle-brachial index of ≤0.80 or had undergone pre-
vious revascularization. The double-blind, event-driven trial
found no statistically significant difference between the two
groups for the primary efficacy end point of adjudicated car-
diovascular death, MI, or ischemic stroke. Similarly, there was
no difference in the secondary end points of acute limb is-
chemia and limb revascularization or major bleeding compli-
cation [16]. Despite its lack of superiority, some studies have
suggested the use of ticagrelor as an effective approach to
overcoming clopidogrel resistance, which can reach up to 65%
in the cardiovascular population [28,29].
 S e m i n a r s i n Va s c u l a r S u r g e ry 3 5 ( 2 0 2 2 ) 1 2 4 – 1 3 1
Fig. 2 – Summary of antithrombotic therapy selection in patients with peripheral artery disease [12,58]. BID, twice daily;
CAD, coronary artery disease; DAPT, dual-antiplatelet therapy.
2.4. Vorapaxar
Vorapaxar is a first-in-class protease-activated receptor-1 an-
tagonist, the primary thrombin receptor on platelets, and
thereby inhibits thrombin-related platelet aggregation [30,31].
The utility of vorapaxar in symptomatic PAD was assessed
using 10,000 patients in the Thrombin Receptor Antagonist in
Secondary Prevention of Atherothrombotic Ischemic Events-
Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50)
trial. The primary end point of cardiovascular death, MI, or is-
chemic stroke was not significantly different between patients
on vorapaxar versus placebo in the PAD cohort. However, the
rate of hospitalization for acute limb ischemia was decreased
by 41%, as well as the rate of peripheral artery revasculariza-
tion [30]. Of note, moderate to severe bleeding was found to
be increased with the use of vorapaxar and the trial’s Data
and Safety Monitoring Board recommended the interruption
of treatment for patients with a previous history of transient
ischemic attack or stroke due to an excess in intracranial hem-
orrhage. In addition, among patients with PAD assessed in
subgroup analysis, the use of concomitant aspirin was 81%.
In the subsequent Thrombin Receptor Antagonist for Clin-
ical Event Reduction in Acute Coronary Syndrome (TRACER)
trial, which investigated patients with symptomatic PAD plus
non-ST segment elevation acute coronary syndrome (ACS), re-
ductions in ischemic end points, peripheral revascularization,
and amputation with vorapaxar did not reach statistical sig-
nificance, and bleeding was again increased in the treatment
group [31].
2.5. Dual antiplatelet therapy
Given the key role of platelets in the pathogenesis of throm-
bosis and the utilization of multipathway AP therapy in coro-
nary artery disease (CAD) and cerebrovascular disease, dual-
AP therapy (DAPT) has also been investigated in PAD.
The Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management and Avoidance
(CHARISMA) trial compared DAPT with mono-AP therapy
127
via aspirin alone. The CHARISMA trial comprised 12,153
participants, 2,838 of which had documented symptomatic
PAD. In addition, 258 asymptomatic patients with PAD were
enrolled with an ankle-brachial index of <0.9 and multiple
risk factors for atherothrombotic events. Although there
was no significant decrease in the composite end point
of cardiovascular death, ischemic stroke, or MI, post-hoc
subgroup analysis of these 3,096 patients with symptomatic
and asymptomatic PAD showed that DAPT resulted in a
statistically significant reduction in the rate of MI compared
with aspirin alone (2.3% v 3.7%; hazard ratio, 0.63; P = .029), as
well as a significant reduction in the rate of hospitalization
for ischemic events, with no difference in moderate to severe
bleeding [32].
Given the poor prognosis of patients with concomitant PAD
and CAD, multiple trials have examined the benefit of DAPT in
this cohort. The efficacy of ticagrelor versus clopidogrel as an
additional agent to aspirin was examined in the Platelet In-
hibition and Patient Outcomes (PLATO) trial. The double-blind
trial randomized 18,624 patients with ACS. In the overall co-
hort, there was a reduction in the primary end point of car-
diovascular death, MI, or stroke in the ticagrelor treatment
group. However, on subgroup analysis, there was no differ-
ence in these events between the ticagrelor and clopidogrel
cohorts in patients with PAD (hazard ratio, 0.85; 95% CI, 0.64–
1.11). Patients with PAD were also noted to have higher rates of
cardiovascular and bleeding events compared with the overall
cohort [33].
The Prevention of Cardiovascular Events in Patients with
Prior Heart Attack Using Ticagrelor Compared to Placebo on
a Background of Aspirin-Thrombolysis in Myocardial Infarc-
tion 54 (PEGASUS-TIMI 54) trial further investigated the ben-
efit of ticagrelor and aspirin DAPT versus aspirin monother-
apy. Ticagrelor was found to confer a significant risk reduc-
tion in MACE. However, the subgroup analysis of more than
1,000 patients with symptomatic PAD and prior MI demon-
strated the greatest absolute risk reduction of 4.1% in MACE
on DAPT compared with aspirin alone. Moreover, there was an
additional relative risk reduction in both acute limb ischemia
128 S e m i n a r s i n Va s c u l a r S u r g e ry 3 5 ( 2 0 2 2 ) 1 2 4 – 1 3 1
and limb revascularization for patients with PAD on ticagrelor
[34].
There is no clear consensus and a lack of robust evidence
to define duration of DAPT regarding duration of therapy. De-
spite this, a general recommendation is using DAPT for at least
1 month after lower extremity endovascular revascularization
[8]. A retrospective analysis found that DAPT with aspirin and
clopidogrel for more than 6 months conferred a >50% lower
risk of MACE and major adverse limb events compared with
patients who received DAPT or mono-AP therapy for less than
6 months [35]. The conclusions of this study, however, have
been criticized due to the nonhomogenous treatment strat-
egy in the comparison group and a heterogeneous makeup of
comorbid conditions between groups [36]. A separate meta-
analysis of the use of DAPT beyond 1 year in all patients with
prior MI confirmed this decrease in ischemic events, but also
demonstrated an increase in major bleeding (1.9% v 1.1%; rela-
tive risk, 1.73; 95% CI, 1.19–2.50) [37]. Multiple scores have been
developed with the aim of defining the adequate patient to re-
ceive prolonged DAPT, including the DAPT and PRECISE-DAPT
score, however, there have been noted criticisms to the “one-
size fits all” approach of these tools [38,39].
Unfortunately, limited prospective randomized clinical
trial data exist to address the question of therapy dura-
tion. The Prolonged Dual Antiplatelet Treatment After Grad-
ing Stent-Induced Intimal Hyperplasia (PRODIGY) trial ana-
lyzed the use of aspirin plus clopidogrel for 24 months ver-
sus 6 months after coronary artery stent implantation. Al-
though the general study cohort showed no treatment benefit
between the short or long course of DAPT, subgroup analysis
of patients with PAD found a protective effect against MACE
and cerebrovascular events without a significant increase in
bleeding with longer DAPT duration [40]. The combination
of aspirin plus clopidogrel versus aspirin monotherapy after
below-knee bypass operations was evaluated with the Clopi-
dogrel and Acetylsalicylic Acid in Bypass Surgery for Periph-
eral Artery Disease (CASPAR) trial. There was no decrease in
limb or systemic outcomes overall between the two groups;
however, subgroup analysis of patients with prosthetic grafts
revealed a composite decrease in graft occlusion, major limb
amputation, and death [41].
2.6. Anticoagulation therapy
Anticoagulants, by preventing thrombus formation via the
coagulation cascade, have long been used successfully in
preventing MACE in CAD and patients post ST-elevation MI
[42,43]. Subsequent studies of anticoagulant use in patients
with PAD found minimal benefit over AP therapy alone, while
associated with greater bleeding risk [5]. However, newer an-
ticoagulants, such as direct factor Xa inhibitors, that inhibit
a single coagulation cascade factor have established better
safety profiles, while demonstrating promise in preventing
disease progression and adverse limb and cardiac events [44–
46].
2.7. Vitamin K antagonists
Vitamin K antagonists, such as warfarin, act on vitamin K
epoxide reductase complex 1 to inhibit activation of vitamin
K. The synthesis of coagulation factors II, VII, IX, and X, as well
as proteins C and S, require vitamin K as a co-factor; therefore,
these medications have an anticoagulant effect via limitation
of the factor-mediated clotting cascade. Because vitamin K an-
tagonists irreversibly inhibits its target receptor, supplemental
vitamin K or clotting factor infusions are required to reverse
its effects—an important point given the greater bleeding risk
associated with warfarin [47,48].
Previous studies assessing the use of warfarin in patients
with ACS found warfarin and aspirin in combination to be su-
perior to aspirin alone in preventing MACE; this subsequently
led to further investigation of vitamin K antagonist regimens
in the PAD population [49]. The 2007 Warfarin Antiplatelet
Vascular Evaluation (WAVE) trial explored the impact of AP
therapy alone compared with AP and warfarin in 2,161 pa-
tients with PAD at more than 80 international centers [49]. The
study found that patients taking warfarin in addition to AP
sustained an increase in major bleeding events, including in-
tracranial hemorrhage, with no reduction of adverse cardio-
vascular events [49]. Similarly, a meta-analysis of more than
25,000 patients with ACS found a greater risk of bleeding in
patients receiving warfarin rather than AP monotherapy [48].
The Dutch Bypass Oral Anticoagulants or Aspirin study offers
evidence for warfarin providing greater patency rates after in-
frainguinal vein graft bypass, albeit with greater bleeding risk
[50]. Currently, warfarin does not have a routine indication for
long-term use in most patients with PAD and has been largely
supplanted by newer, safer anticoagulants, such as direct fac-
tor Xa inhibitors [45,51].
2.8. Factor Xa inhibitors
Factor Xa inhibitors, such as rivaroxaban, are direct oral an-
ticoagulants that prevent thrombin generation, the result of
which is reduced clot generation and reduced downstream ac-
tivation of PAR-1, a protein responsible for inflammatory cy-
tokine secretion and cell adhesion molecule expression. Fac-
tor Xa inhibitor anticoagulants have become a popular target
of study after initial investigations demonstrated that patients
with ACS receiving Factor Xa inhibitors sustained less major
bleeding and mortality benefits compared with warfarin [49].
Although cost continues to be a concern for underresourced
patients, Factor Xa inhibitors offer patients the freedom of
fewer drug interactions, less risk of devastating bleeding, and
no need for periodic testing, as in the case of international
normalized ratio surveillance with warfarin therapy [45].
The ATLAS ACS-TIMI 46 (Rivaroxaban in Combination With
Aspirin Alone or With Aspirin and a Thienopyridine in Pa-
tients With Acute Coronary Syndromes) study established
dosing thresholds for rivaroxaban in patients with ACS with
bleeding noted in a dose-dependent manner, increasing haz-
ard ratio of major bleeding from 2.2 in 5-mg dose to 3.4
and 5.1 in 10- and 20-mg doses, respectively. The Cardio-
vascular Outcomes for People Using Anticoagulation Strate-
gies (COMPASS) trial evaluated the use of low-dose rivarox-
aban in more than 27,000 symptomatic patients with CAD
and PAD, demonstrating that the addition of rivaroxaban to
aspirin in patients with chronic vascular disease reduced
the incidence of cardiovascular death and stroke. The COM-
PASS study evaluated patients with CAD or PAD using the
 S e m i n a r s i n Va s c u l a r S u r g e ry 3 5 ( 2 0 2 2 ) 1 2 4 – 1 3 1
factor Xa inhibitor rivaroxaban alone, rivaroxaban with as-
pirin and aspirin alone [6]. Rivaroxaban alone and with as-
pirin was found to significantly reduce acute limb ischemic
events and improve mortality in patients with PAD com-
pared with aspirin alone. These results were not replicated in
patients older than 75 years, indicative of potentially lower
efficacy and higher risk of bleeding with rivaroxaban use
in geriatric populations [49]. In the PAD subgroup analysis,
the addition of rivaroxaban to aspirin was associated with
lower rates of MACE and major adverse limb events; rivarox-
aban was associated with higher rates of bleeding, predom-
inantly driven by gastrointestinal bleeds as opposed to in-
tracranial bleeding [49]. The VOYAGER PAD (Vascular Out-
comes Study of Acetylsalicylic Acid Along with Rivaroxaban
in Endovascular or Surgical Limb Revascularization for Periph-
eral Artery Disease) trial also demonstrated therapeutic bene-
fit and safety in 6,500 patients with PAD from 34 countries [44].
Patients received aspirin with or without rivaroxaban; combi-
nation patients experienced a 2.6% decrease in major adverse
limb events and MACE, while experiencing 1.8% more severe
bleeds. At median follow-up of more than 2 years, researchers
found that the addition of rivaroxaban to aspirin in patients
with PAD after intervention decreased disease progression
to acute limb ischemia, decreased reoperation for ampu-
tation, and decreased cardiovascular death, stroke, and MI
[46].
Other direct oral anticoagulants, such as edoxaban and
apixaban, have significantly less evidence supporting their
use in patients with PAD, although their safety and efficacy
have been supported for other indications, such as clot pre-
vention in patients with atrial fibrillation and ACS [52,53]. The
ePAD (Edoxaban in Peripheral Arterial Disease) study evalu-
ated edoxaban and aspirin therapy in patients undergoing
femoral-popliteal intervention for PAD. This study found sim-
ilar safety and lower restenosis rates in the edoxaban and
aspirin compared with DAPT, albeit in a trial with fewer pa-
tients and shorter follow-up than the COMPASS or VOYAGER
PAD trials. The use of apixaban with aspirin in infrapopliteal
critical limb ischemia is currently under investigation in
the ongoing AGRIPPA (Efficacy and Safety of Apixaban in
Reducing Restenosis and Limb Loss in PAD Patients) trial
[54].
2.9. Direct thrombin inhibitors
Direct thrombin inhibitors, such as dabigatran, are also avail-
able in an oral formulation without the need for periodic lab-
oratory testing. Dabigatran is predominantly used for pre-
vention of stroke and venous thromboembolism in patients
with arterial fibrillation [55]. An intravenous formulation, bi-
valirudin, is also available and used in cardiac patients under-
going percutaneous coronary intervention. The use of direct
thrombin inhibitors in patients with PAD is uncommon; Lopes
et al [56] presented an observational study in which a com-
bined cohort of patients with CAD and PAD had similar safety
and patency outcomes after receiving dabigatran compared
with other direct oral anticoagulants [56]. However, there is
limited long-term or randomized evidence supporting direct
thrombin inhibitors use in patients with PAD [55].
129
2.10. Heparin and low-molecular-weight heparin
Heparin products bind antithrombin III to activate it; in its ac-
tive form, this protein inhibits factor Xa and thrombin pro-
duction in the coagulation cascade [6]. The two predominant
roles for heparin products in patients with PAD are therapeu-
tic dosing to mitigate the impact of thromboembolic ischemia
or prophylactic dosing to prevent thromboembolism in the
perioperative period. Jivegård et al [57] examined whether
low-molecular-weight heparin can improve lower extremity
bypass graft patency, but found no benefit compared with
placebo at 1 year. Under current guidelines, there is no long-
term role for heparin in patients with PAD.
3. Conclusions
There is large variability within the PAD population, ranging
from asymptomatic disease to symptomatic patients with po-
tentially lifestyle-limiting claudication to finally critical limb-
threatening ischemia. Diversity in natural history and disease
progression is compounded further by a range of comorbid
risk factors, as well as variation in intervention type. Although
we present the current evidence for antithrombotic manage-
ment and suggest an approach to therapeutic management
of PAD (Fig. 2), the concern for major adverse limb, cardiovas-
cular, and cerebrovascular events must be weighed against
bleeding risk on a subject-specific level. The lack of consen-
sus guidelines and trial data on antithrombotic therapy selec-
tion, combinations, timing, and duration is representative of
the highly variable existing treatment paradigms, as well as
the need for individualized decision making based on disease
severity, patient factors, and overall goals of care.
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