ESC Guidelines on the diagnosis and treatment of peripheral artery ...

Page 32 of 56
improved prosthetic graft patency vs. anticoagulation. Notably, the
risk of major bleeding was two-fold higher in the anticoagulation
group. In another trial, 310 665 patients undergoing femoropopliteal
bypass were randomized to aspirin (325 mg/day) plus warfarin
(goal international normalized ratio 1.4–2.8) vs. aspirin (325 mg/
day) alone. This trial failed to demonstrate any improvement in
terms of graft patency with dual therapy. However, the results
were in favour of combination therapy for patients with prosthetic
bypasses. The haemorrhagic risk doubled when warfarin was
added to aspirin. In another randomized study, 311 warfarin (international
normalized ratio 2.0–3.0) plus aspirin (325 mg/day) was
compared with aspirin (325 mg/day) alone in 56 patients with highrisk
vein grafts (defined as poor arterial run-off, suboptimal vein
conduit, and repeat interventions). At 3 years, patency and limb
salvage rates were significantly higher in those receiving warfarin
and aspirin, with in turn higher bleeding rates with this combination.
Recently, the Clopidogrel and Acetylsalicylic Acid in
Bypass Surgery for Peripheral ARterial disease (CASPAR) randomized
double-blind trial assessed the efficacy of aspirin plus clopidogrel
vs. aspirin alone to increase primary patency, limb salvage, and
survival in patients receiving a below-knee bypass graft. 312 Among
the 851 patients enrolled, almost 70% had a venous graft and 30% a
prosthetic graft. After a mean follow-up of 1 year, no overall difference
was found regarding the combined primary outcome
between the two groups. Subgroup analysis was in favour of a beneficial
effect of clopidogrel in association with aspirin in prosthetic
grafts. The number needed to treat using the dual antiplatelet
therapy to save one limb after below-knee surgery was dramatically
low, estimated at 10.2 patients.
The role of anticoagulation after infrainguinal balloon PTA and
stenting has been assessed in three prospective randomized
trials. 313 None of these trials showed any significant improvement
in arterial patency with the use of anticoagulation therapy, while
bleeding complications increased. 313 Yet, anticoagulation therapy
cannot be recommended routinely after lower extremity PTA or
stenting.
4.5.3.4 Stem cell and gene therapy for revascularization
The development of novel therapies to stimulate neovascularization,
known as therapeutic angiogenesis, is based on the use of
angiogenic factors or stem cells to promote revascularization and
remodelling of collaterals with the aim of ameliorating symptoms
and preventing amputation.
While several trials reported relief of ischaemic symptoms, functional
improvement, and prevention of amputation, 314 – 317 others
318 – 320
failed to confirm this early promise of efficacy.
For autologous cell transplantation in humans, bone marrow and
peripheral blood are rich sources of stem and progenitor cells.
Bone marrow is currently the most frequent source of cells used
for clinical repair trials, because it is easy to obtain and no
complex purification steps are required. Another advantage is
that it contains a variety of stem and progenitor cells with
suggested superiority over one selected type of progenitor cell.
With the many different cell types that can be used for stem cell
therapy, it is not yet clear which ones are the most promising. 321
In a recent meta-analysis of 37 trials, autologous cell therapy was
effective in improving surrogate indexes of ischaemia, subjective
Recommendations for antiplatelet and anticoagulant
therapy after revascularization
Recommendations Class a Level b Ref c
Antiplatelet therapy with
aspirin is recommended in all
patients with angioplasty for
LEAD to reduce the risk of
systemic vascular events.
Dual antiplatelet therapy with
aspirin and a thienopyridine
for at least one month is
recommended after
infrainguinal bare-metal-stent
implantation.
Antiplatelet treatment with
aspirin or a combination
of aspirin and dipyridamole
is recommended after
infrainguinal bypass surgery.
Antithrombotic treatment
with vitamin K antagonists
may be considered after
autogenous vein infrainguinal
bypass.
Dual antiplatelet therapy
combining aspirin and
clopidogrel may be considered
in the case of below-knee
bypass with a prosthetic graft.
a
Class of recommendation.
b
Level of evidence.
c
References.
LEAD ¼ lower extremity artery disease.
I C
I C
I A 308
IIb B 309
IIb B 312
<strong>ESC</strong> <strong>Guidelines</strong>
symptoms, and hard endpoints (ulcer healing and amputation).
Patients with thromboangiitis obliterans showed larger benefits
than patients with atherosclerotic LEAD. The TAMARIS study is
the largest randomized placebo-controlled trial of gene therapy in
CLI, including .520 patients from 30 countries with CLI and skin
lesions, unsuitable for standard revascularization. This study found
no statistical difference between the two groups regarding the
primary efficacy endpoint of death or first major amputation on
the treated leg, whichever came first (37.0% vs. 33.2%, P ¼
0.48). 322 At present angiogenic gene and stem cell therapy are still
being investigated and it is too early to give firm recommendations.
4.5.4 Management of intermittent claudication
The management of intermittent claudication consists of optimal
risk factor control in order to improve the vital prognosis (see
Section 3.4) and the symptoms. Therapeutic options to relieve
symptoms are non-invasive (mostly exercise therapy and drug
therapy) or invasive (revascularization). An algorithm for the management
of intermittent claudication is proposed in Figure 3. With
the increasing use of endovascular therapy to improve walking distance,
there is an apparent need to compare it with ‘supervised
exercise training’. In a study of 51 patients with intermittent