Keywords
Critical limb ischemia - peripheral artery disease - revascularization
Introduction
Critical limb ischemia (CLI) represents the most advanced form of peripheral artery
disease (PAD) with high rates of cardiovascular events, amputations, and even death.[[1]] Economical impact of the condition is immense with frequent hospital visits. Varied
treatment strategies have been employed in the management of CLI with the primary
aim of revascularization whenever feasible, though optimal revascularization strategy
is still uncertain due to the lack of sufficient clinical evidence.[[2]] Medical therapy is highly important for the optimization of cardiovascular risk
factors as these factors are responsible for considerable mortality and morbidity.
Further angiogenesis promoting therapies, such as gene or cell-based treatments appear
promising emerging options in nonrevascularizable CLI.
Definition
Use of CLI term in clinical practice is highly variable with different definitions
in use, thus causing variable research reporting in this subset of patients. A uniform
strict definition, including hemodynamic assessment is important to improve standardize
reporting on CLI. Earlier definitions lack the hemodynamic assessment, as proposed
by Fontaine et al. for the first time in 1954. As per current consensus definition, CLI is largely
defined by a clinical constellation of symptoms including ischemic rest pain, ulcer,
or gangrene in the context of objective hemodynamic evidence of manifest arterial
insufficiency.[[3],[4],[5]] As CLI represents the most advanced form of PAD, it is usually classified in the
higher stages or grades of the Fontaine classification (stage III-IV) or the Rutherford
classification (grades 4–6). The Society for Vascular Surgery has also created a CLI
staging scheme recently, which is according to wound extent, ischemia, and degree
of concomitant foot infection. This system defines four clinical stages of threatened
limb and helps in risk stratification, guiding treatment strategy, and predicting
the benefit of revascularization in these patients.[[6],[7]]
Epidemiology
PAD constitutes a common cause of vascular morbidity. It affects nearly 200 million
people worldwide and is associated with 3 to 6-fold increased risk of cardiovascular
mortality and morbidity as compared to patients without PAD.[[8],[9],[10]] CLI constitutes nearly 1% of the adult population and up to 10% of patients with
PAD with an annual estimated incidence of 220–3500 new cases per million population.[[2],[11],[12],[13]] Moreover, approximately 5%–10% patients with asymptomatic PAD or intermittent claudication
generally progress to CLI in a period of 5 years.[[2]] CLI is associated with high mortality rates (nearly 16–20%, 50% and 70% at 1, 5,
and 10 years, respectively),[[14],[15],[16]] and the prognosis with respect to limb salvage is generally poor with amputation
rates as high as 12% and 25% at 6 months and 1 year, respectively.[[17],[18]] Particularly, in no option CLI patients, 6 months amputation rates may range from
10% to 40%. Moreover, higher amputation rates have been shown in CLI patients (12%),
1 year after lower extremity bypass as compared to patients with claudication (1%).[[19]] Coexistent atherosclerosis in other vascular territories is also commonly seen
in these patients; significant coronary artery disease on angiograms in nearly two-third
patients with CLI and significant carotid stenosis in approximately a quarter of patients
with PAD,[[20],[21]] which is largely responsible for high mortality (13.4%, 19–25%, >60% at 6 months,
1 year and 5 years, respectively) and morbidity in these patients.[[17],[22],[23]] There is high likelihood (annual rate 5% –7%) of adverse cardiovascular events
(myocardial infarction, stroke, or death) in PAD patients, which is likely to be higher
in patients with CLI.
Pathophysiology
CLI is generally caused by diffuse, progressive, multilevel, obstructive atherosclerosis.
In minority of cases, CLI can also be secondary to hypercoagulable states, thromboembolism,
vasculitis, Burger disease, trauma, cystic adventitial disease, and popliteal entrapment
syndrome. The pathophysiology of CLI is a complex process and involves both macro-
and micro-vascular changes leading to reduced perfusion to the extremities.[[18],[24]] Angiogenesis, an adaptive response occurs, thereby promoting enlargement of pre-existing
collateral vessels to increase the blood flow to the critically ischemic limb. Distal
arterioles further adapt to this chronic ischemic process by decreasing wall thickness,
wall-to-lumen ratio, cross-sectional area, and with maximal vasodilatation, thus producing
a state of vasomotor paralysis, causing an orthostatic-dependent increase in the hydrostatic
pressure, thereby producing distal edema. In addition to this, microvascular dysfunction
occurs with endothelial damage resulting in inappropriate platelet activation, leukocyte
adhesion, and increased free radical production, leading to microthrombi formation
and causing impaired tissue oxygen exchange at the capillary level.
Diagnosis
CLI is largely a clinical diagnosis, which must be supported by objective hemodynamic
criteria. These patients usually have diminished or absent distal pulses, thin/dry
or shiny skin, loss of hair, dependent rubor or elevation pallor, or non-healing ulcer,
and increased capillary refill time. Multiple noninvasive tests (including ankle pressure,
toe pressure, pulse volume recordings, transcutaneous oxygen pressure, and Doppler
evaluation) can be used to establish the diagnosis of CLI, assess foot perfusion,
and predict wound healing. Ankle-brachial index (ABI) remains the simplest method,
which provides important diagnostic and prognostic information in such patients.[[25]] An ABI value less than 0.9 is indicative of PAD, while a value less than 0.4 is
consistent with CLI.[[3]] However, ABI assessment is limited in patients with renal failure or diabetes,
where it may remain spuriously high or within the normal range, due to impaired vessel
compressibility owing to medial calcinosis. In such cases, toe pressure readings may
provide an optimal assessment of the distal perfusion.[[26]] Various imaging modalities (including Doppler, computerized tomography, or magnetic
resonance angiography) have been used to assess the complete anatomical extent of
the disease; however, digital subtraction angiography is still considered as the gold
standard imaging evaluation, often providing a definitive treatment plan in these
patients.[[27]]
Management Options
Multiple treatment strategies [[Table 1]] have been employed in the management of CLI patients by different specialists involved
in patient care, however, definite optimal revascularization remains uncertain. Therapeutic
goals of treatment include optimization of coexistent cardiovascular risk factors,
ischemic pain relief, ulcer healing, major amputation prevention, quality of life
improvement, and patient survival. These aims can be achieved through optimal medical
therapy, revascularization (surgical or endovascular), or amputation.
Table 1
Key points with management options in critical limb ischemia
|
ABI=Ankle-brachial index, SAFARI=Subintimal antegrade flossing using antegrade and
retrograde intervention, TAMI=Tibio-pedal arterial minimally invasive retrograde revascularization
|
|
Classification/Categorization
|
|
|
Therapeutic goals
|
-
Optimization of coexistent cardiovascular risk factors
-
Ischemic pain relief
-
Ulcer care & infection control
-
Major amputation prevention
-
Quality of life improvement and patient survival.
|
|
Management options
|
|
|
Evolving treatment options
|
-
Gene and cell based therapies
-
Platelet rich plasma
-
Deep venous arterialization
-
Stem cell or growth factor eluting stents
-
Bilayered stents (paclitaxel & growth factor)
-
Advancements in atherectomy devices and angioplasty balloons (cryoplasty, laser or
vibrational angioplasty)
|
Medical therapy
Coexisting cerebrovascular and coronary artery disease accounts for considerable mortality
and morbidity in CLI patients; hence, optimization of risk factors is of prime importance
in the management of these patients. Medical therapy is primarily used to optimize
these cardiovascular risk factors; however, it can also favorably affect limb-related
outcomes by achieving pain relief, ulcer care or infection control, and achieving
ambulation. Hence, our prime focus should be on the use of optimal medical therapy
as it has been shown that optimal medical therapy is not always used. A study evaluating
patients requiring infra-inguinal bypass for limb salvage had shown that nearly two-third
of patients (aspirin in 50%; thienopyridine in 17%) were taking an antiplatelet drug,
whereas only nearly less than half were taking lipid-lowering therapy (46%) or beta-blocker
(49%).[[28]] In another trial, 80% of CLI patients received an antiplatelet agent with only
46% received statin and 77% received beta-blocker.[[29]] Regardless of the treatment strategy employed for these patients, treating physicians
must increase their efforts to place them on appropriate cardio-protective medications.
Smoking cessation, control of hypertension, and hypercholesterolemia with strict glycemic
control must be ensured in these patients to achieve optimal cardio-protection. Smoking
cessation has been given a high level of recommendation in various guidelines for
PAD management as it has been shown to considerably decrease the progression to CLI,
amputation, and mortality in these patients.[[30]] Moreover, active smoking is associated with devastating cardiovascular complications
including death. Adequate control of blood pressure (less than 130/80 mmHg) should
be maintained in these patients, as 10 mmHg reduction in systolic blood pressure has
been shown to be associated with 16% reduction in limb amputation and PAD-related
deaths. Angiotensin-converting enzyme inhibitors or β-blocker therapy has been used
with encouraging results (ramipril use associated with 27% decrease in the rate of
combined cardiovascular events) in such patients.[[31]]
Hypercholesterolemia has also been shown to be an independent predictor for the development
of PAD, and lipid lowering drugs, particularly statins, have been used with a favorable
reduction in cardiovascular events, mortality, and limb events following revascularization.
Moreover, recent recommendations now stress the use of moderate- to high-intensity
statin therapy in these patients.[[32]] Moreover, patients with symptomatic PAD should also be prescribed antiplatelet
monotherapy (aspirin or clopidogrel associated with a reduction in cardiovascular
events in nearly a quarter of patients) as dual therapy has shown only a marginal
benefit in these patients as compared to the increased risk of bleeding.[[33]] Use of vasodilators such as iloprost (prostanoids) or naftidrofuryl has also been
tried but with variable results.[[34]] Cilastazol (phosphodiesterase III inhibitor having antiplatelet, vasodilator, and
antimitogenic properties) has been shown to favorably increase skin perfusion pressure
and wound healing in patients with CLI.[[35]] Use of oral cilostazol (dosage of 100 mg twice daily), in addition to best medical
therapy has resulted in improvement in nearly a quarter of patients with nonreconstructable
CLI; however, further studies are required to adequately evaluate its role in these
patients.
Revascularization
Revascularization aiming at re-establishing continuous, in-line pulsatile flow to
the pedal arch remains the preferred treatment option for CLI patients, which can
be achieved by surgery (lower extremity bypass or endarterectomy) or endovascular
therapy. Goal of revascularization includes wound healing or treatment of at least
one level of obstructive disease in case of tissue loss or ischemic pain, respectively,
thereby preserving a functional limb, achieving ambulation, and preventing major limb
amputation. The choice of treatment between surgical versus endovascular treatment
will largely depend on various patient and procedure-specific factors such as age
and co-morbidity, severity of limb ischemia, vascular anatomy/extent of involvement
and presence of useable vein graft, and it should be individualized. However, in the
recent years, a trend in favor of initial endovascular treatment has been seen. Although
there is still a considerable amount of skepticism about the need for angiosome-related
revascularization, the concept provides a framework for the interventionalist to plan
the procedure. As CLI patients are very sick and have limited options for limb salvage,
modified access techniques such as subintimal antegrade flossing using antegrade and
retrograde intervention (SAFARI), tibio-pedal arterial minimally invasive retrograde
revascularization (TAMI), or pedal loop techniques may improve chances of recanalization
in cases where even conventional methods fail to cross the lesion. Moreover, multiple
technical advancements such as atherectomy devices, cryoplasty, drug-eluting balloons,
and stents have been made with advanced delivery systems, which make endovascular
treatment an attractive option.
However, reintervention rate is higher in the endovascular group to the tune of over
3 interventions for 1 surgical procedure declined, which fades the early benefit of
this treatment option.[[36],[37],[38]] The Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial, the
only randomized controlled trial directly comparing open bypass surgery with balloon
angioplasty in CLI patients, has not shown any significant difference in terms of
amputation-free survival at 1 and 3 year follow-up.[[39]] Further, BEST-CLI, BASIL-2, and BASIL-3 trials are still underway, which may provide
further direct comparisons between these treatment options. Among endovascular option,
different drug-eluting stents were tried in PAD patients. Studies with sirolimus or
everolimus drug-eluting stents have not shown any significant difference as compared
to PTA or BMS; however, paclitaxel have shown promising results (improved event-free
survival with superior primary patency, results being sustained at 2 years follow-up)
in femoropopliteal lesions, as in ZILVER PTX trial, which allowed its FDA approval
for use in PAD in 2012.[[40],[41]] However, its use in infrapopliteal disease is still limited to focal disease (mean
lesion length 26.8 mm) and needs further validation in more common diffuse lesions.[[42]] Paclitaxel has proved to be a better agent than limus-class drugs, owing to its
superior lipophilicity, which allows rapid uptake across cell membranes, thus reducing
the risk of systemic absorption. Moreover, it can be applied directly to the metal,
which obviates the risk of bio-incompatibilty of delivery polymers.
Amputation
Primary amputation rates have declined to nearly half in the previous decade with
the increase in surgical or endovascular revascularization rates. Primary amputation
is now reserved to patients with extensive tissue loss or infection, unreconstructable
arterial disease, terminal illness, and nonambulatory status with flexion contractures.
Efforts should be made to preserve knee joint, as below knee amputation is associated
with reduced 30-day mortality (5% versus 16%) and increased long-term survival (74.5%
versus 50.6%) as compared to above knee amputation.[[43],[44]]
Gene and Cell-Based Therapies
Gene and cell-based therapies are emerging treatment modalities, which showed evidence
for favorable outcome in CLI patients, particularly in initial trials. Various gene
(fibroblast growth factor, vascular endothelial growth factor, hypoxia inducible factor
1, and hepatocyte growth factor) and cell-based (bone marrow mononuclear cells, mesenchymal
stem cells, and endothelial progenitor cells) therapies have been tried, with the
majority of studies using intramuscular injection and intra-arterial delivery in minority
of the protocols.[[45],[46],[47],[48],[49],[50]] Hepatocyte growth factor and mesenchymal stem cells currently seem most promising,
however, needs further validation. Moreover, we should keep in mind that the large
and especially randomized placebo-controlled trials failed to replicate these initial
promising results, and future larger trials are needed to establish the efficacy of
these therapies.
Platelet Rich Plasma
Use of platelet-rich plasma has also been shown beneficial for limb salvage with improvement
in ulcer healing rates in CLI patients.[[51],[52]] Concentration and sequestration of platelets within the plasma fraction of autologous
blood provide a milieu of various growth factors such as chemokines and cytokines.
They may play a major role in initiation and promotion of the process of bone and
soft tissue healing by enhancing in vivo angiogenesis, improving microcirculation, tissue remodeling, and enhanced wound healing.
The notion that platelet-rich plasma could be a source of various essential growth
factors, thereby directly benefiting these patients show promise, however, needs further
supportive evidence by future studies.
Arterialization of Deep Veins
Arterialization of Deep Veins
Deep venous arterialization (DVA) has also been shown to be a safe and feasible novel
alternative to prevent major amputation in no-option CLI patients.[[53],[54]] It acts by providing arterialized blood at significant pressure and volumes to
the ischemic tissue, thereby enabling wound healing. The LimFlow device (LimFlow SA)
is currently the only registered device for total percutaneous DVA, which allows for
disruption of the veins with a dedicated valvulotome, in addition to percutaneous
creation of an arteriovenous fistula. Although early experience with DVA shows promising
results, additional research is necessary for a better understanding of the involved
physiologic mechanisms in tissue perfusion, thereby improving clinical outcomes in
this subset of patients.
Future Directions
Technical advancements and ongoing research hold promise for further improvements
in the management strategies of CLI patients. Combined gene and stem cell therapy
may improve outcomes by selectively promoting particular cellular processes to induce
a desired biological response. Moreover, it may overcome many limitations by controlling
cell behavior at the intracellular signaling level. Further, ongoing research for
the feasibility and efficacy of stem cell or growth factor eluting stents, bilayered
stents (paclitaxel on inner layer and growth factor plasmid on outer layer), and advancements
in angioplasty balloons (cryoplasty, laser, or vibrational angioplasty) may help in
improving the outcome in these patients.
Conclusion
CLI poses considerable effect on the quality of patient life with huge economical
impact. Moreover, the management of these patients is quite variable and not yet standardized.
Revascularization remains the cornerstone of management; however, optimal revascularization
strategy remains elusive. Use of optimal medical therapy should be stressed in all
such patients as it is associated with improved outcome with reduction in mortality
and morbidity. Recent therapeutic advances with evolving endovascular techniques and
gene or cell-based therapies have the potential to dramatically change the therapeutic
outlook in these patients.
