Lower extremity artery disease (LEAD) is a leading cause of atherosclerotic vascular morbidity in Europe, being even more
prevalent that coronary artery disease (CAD) [1]. Importantly, LEAD is an established independent risk factor for cardiovascular
(CV) mortality and morbidity [2-4], particularly in its advanced stages, i.e. in patients requiring lower limb revascularisation
[5, 6], and in patients suffering from chronic limb-threatening ischaemia (CLTI) [7]. The strong association between LEAD and
CAD, with at least one-third of LEAD patients having history and/or electrocardiographic signs of associated CAD, and with
up to 70% showing significant disease at coronary angiography [8, 9], has led to the identification of LEAD as a high-risk subgroup
in all randomised trials focussed on CAD [4, 10-14]. Given the great advances in the treatment of CAD over the last decades,
clinical research in this field is currently focussed on addressing “residual risk” in patients suffering from CAD. Therefore,
being a marker of worse prognosis in CAD patients, LEAD has attained a growing interest from the community of Cardiologists,
leading to the issue of guidelines on the management of peripheral arterial diseases from the European Society of Cardiology
(ESC), firstly in 2011 [15] and again in 2017 [16].
Most recently, LEAD attained the same “dignity” as CAD in the large randomised COMPASS (Cardiovascular Outcomes
for People Using Anti-coagulation Strategies) trial, where patients suffering from LEAD (or from carotid artery disease) were
enrolled independent of the presence of coexisting CAD, i.e. LEAD was not a subgroup of CAD but a distinct disease category
[17]. In COMPASS, rivaroxaban 2.5 mg twice daily on top of aspirin was more effective in reducing the risk of major CV
events in the peripheral artery disease population compared with the CAD population, and was also associated with an impressive
46% reduction in major adverse limb events (acute and chronic limb ischaemia including major amputation) [18]. On the
other hand, the risk of major bleeding was also increased with the dual antithrombotic regimen, highlighting the need for a careful
estimation of the bleeding risk of individual patients before embarking in more potent antithrombotic treatments. Based on
COMPASS results, low-dose rivaroxaban may soon be proposed as standard of care in patients with stable LEAD who are not
at high risk for bleeding. This may have a potentially huge impact on public healthcare costs, considering the current pricing of
the drug and the prevalence of LEAD in an ageing population. In this setting, cost-effectiveness analysis should be regarded as
a powerful tool in the hands of the clinicians when dealing with public health stakeholders and decisions bodies, because it enables
us to assess whether a new treatment is cost-effective - and thus affordable - for the community, on top of being clinically
effective [19]. As a matter of fact, two recent cost-effectiveness analyses of the COMPASS trial performed from an Australian
perspective showed that low-dose rivaroxaban is cost-effective in the vast majority of the scenarios explored, and even more so
in patients with LEAD [20] compared with patients with CAD [21].
A further source of interest for LEAD in recent years was represented by the rapid development of endovascular revascularisation
techniques, leading to an exponential increase in the number of patients undergoing lower limb revascularisation (currently
80% of cases undergo endovascular procedures) [22]. Such growth in the interventional treatment of LEAD was accompanied
by a large number of clinical studies, including randomised trials, enrolling patients with LEAD; however, the vast majority
of these trials are focussed on the evaluation of short-term outcomes of endovascular devices and techniques, leaving
wide gaps in evidence to be filled by future studies. In particular, very little evidence is available on the best antithrombotic
treatment following lower extremity revascularization.
In this context, it is my belief that it is now prime time for LEAD on the stages of both clinical research and clinical practice
in the field of atherothrombotic vascular diseases. A sign of these times is the quick growth of the Working Group on Aorta and
Peripheral Vascular Diseases of the ESC, which I had the honour to chair [23]. It was within this scientific community that the
idea of the present special issue of Current Vascular Pharmacology was conceived. This issue, dedicated to antithrombotic
therapy in patients with LEAD, represents a vehicle for the dissemination of knowledge in the field of LEAD, hopefully contributing
to a better understanding and management of LEAD patients in clinical practice. To increase the awareness and
knowledge of LEAD is actually the mission of the Working Group on Aorta and Peripheral Vascular Diseases of the ESC. The
need for an awareness campaign on LEAD is proven by recent epidemiologic studies, showing that a large proportion of patients
with LEAD does not yet receive guideline-recommended secondary prevention therapy, with antiplatelets and angiotensin-
converting enzyme inhibitors or angiotensin-receptor blockers being prescribed to <50% of the patients and statins to
only two thirds [24].
The mainstays of guideline-recommended pharmacological treatment of LEAD include antiplatelets (with clopidogrel as
first choice), statins, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers [16]. Antithrombotic therapy
was chosen as the topic of this special issue because of its prominent role in the prevention of CV events and of limb events
in patients suffering from LEAD, which is not associated with exhaustive evidence regarding the choice of drug(s) and treatment
duration in the numerous clinical settings that make up the wide spectrum of LEAD. In this issue of Current Vascular
Pharmacology we will cover all aspects of antithrombotic therapy in patients with LEAD, from the pathophysiology of thrombosis
to the assessment of the bleeding risk.
Habib, et al., provide a comprehensive description of the pathophysiology of vascular athero-thrombosis in LEAD, including
an in-depth analysis of the interplay between pro- and anti-thrombotic vascular receptors, and of the contribution of platelets and
circulating coagulation factors in triggering the pro-thrombotic response [25]. In particular, the role of nitric oxide, prostanoids and
endogenous purines is described with a translational approach, along with the consequences of the disruption of the protective
pathways and with the mechanisms of action of the numerous pharmacological agents that are active along these pathways.
Vrsalovic and Aboyans review the available clinical evidence on antithrombotic therapy in patients with LEAD [26]. This
review covers the full spectrum of clinical scenarios of LEAD, from asymptomatic to chronic limb-threatening ischaemia. In
particular, the role of single and dual antiplatelet treatment is discussed, as well as the role of oral anticoagulants, with a specific
focus on the results of the COMPASS trial with low-dose rivaroxaban. The authors also address the clinically relevant
issue of LEAD patients requiring antithrombotic regimens for concomitant CV diseases, such as atrial fibrillation and CAD,
offering a balanced point of view on the management of these patients.
The third paper, which I authored together with Angelillis and Liga, offers an updated overview of antithrombotic therapy
in patients undergoing peripheral revascularisation, both endovascular and surgical. We start with a description of the indications
and techniques of lower extremity revascularisation, and proceed with in-depth analysis of the available evidence regarding
type and duration of antiplatelet and anticoagulant treatment following endovascular and surgical revascularisation [27]. A
specific focus is dedicated to endovascular revascularisation, whose growth in numbers has not been accompanied by a parallel
growth in high-quality scientific evidence, particularly regarding antithrombotic therapy, which is substantially extrapolated
from the coronary field. Given the lack of randomised trials comparing different antithrombotic regimens and durations across
the wide range of indication, location and modality of peripheral revascularisation, we pragmatically analyse and compare the
antithrombotic strategies chosen by the experts leading the randomised trials dedicated to endovascular devices and techniques.
Lastly, Alatri and Mazzolai provide an in-depth review of how to assess the bleeding risk of our patients, in the era of precision
medicine [28]. In fact, while we strive to reduce local and systemic thrombotic events in patients with LEAD by using new antithrombotic
regimens, we should avoid exposing them to an excess in bleeding risk, tailoring antithrombotic regimen on the individual
patient’s clinical setting. It is therefore of the utmost importance to understand the numerous scores for the prediction of inhospital
and long-term bleeding events that have been developed in various clinical settings. In particular, the authors describe the
bleeding risk scores for patients receiving oral anticoagulants, single antiplatelet therapy and dual antiplatelet therapy.
In summary, I believe that the present special issue of Current Vascular Pharmacology may be useful as an ensemble, providing
a comprehensive outlook on all the aspects of antithrombotic therapy in patients with LEAD. On the other hand, each
review may be also regarded as a stand-alone expert advice on the specific topic covered, providing insights and guidance for
both researchers and clinicians.