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NARRATIVE REVIEW
Peripheral arterial disease (PAD) in diabetics: diagnosis and management- a
narrative review
Zia Ur Rehman,1 Nanik Ram2
Abstract diabetes diagnosis; the number approaching 50% after 20
Peripheral arterial disease (PAD) in diabetic patients is years. ischaemic/neuroischaemic ulcers have a much
often overlooked due to associated neuropathy. The very higher probability of amputation and mortality than
first presentation of these patients is with an Ischaemic patients with neuropathic ulcers.6 ischaemic DFUs are due
ulcer or toe gangrene. Diabetics have a very high to macrovascular disease (atherosclerosis) or associated
amputation rate compared to non-diabetic patients due microvascular diseases.7
to diffuse multi-segmental disease in the calcified tibial
The infra-popliteal vessels are mostly involved with
arteries. Early detection of the condition is a challenge in
diffuse, multi-segmental, calcified atherosclerotic
these patients. Even ankle-brachial pressure index may
disease.8 In more than 90% cases, more than one tibial
not be reliable. Both surgical and endovascular options
artery is involved. Arteries at the ankle and the foot are
are effective in wound healing. Endovascular techniques
mostly spared.
include percutaneous transluminal angioplasty with and
without stenting, sub-intimal angioplasty, percutaneous Typical presentation of diabetic patients with PAD
transluminal angioplasty with drug-coated balloons, Neuropathy masks the symptoms of Ischaemia. Most of
covered stents, and use of atherectomy devices. The these do not have classic presentations of intermittent
current narrative review was planned to discuss the claudication and rest pain despite having severe PAD. The
essentials of diagnosing PAD in diabetic patients and its very first presentation can be with an Ischaemia ulcer or
various treatment options. toe gangrene. It is important to evaluate these patients
for improving blood supply to the foot before performing
Key Words: Diabetic foot, Foot ulcer, PAD, Peripheral
any minor or major amputation. In an intact foot without
vascular disease.
ulcer or gangrene, the diseased axial artery and collaterals
DOI: 10.47391/JPMA.4590 are adequate to provide blood, but they become
inadequate in case of an active foot ulcer. In the region of
Submission completion date: 31-08-2021 ankle and the foot, there are six angiosomes that emerge
Acceptance date: 01-09-2022 from the three below-the-knee (BTK) arteries. Angiosome-
Introduction oriented revascularisation has gained attention and its
Diabetic foot ulcers (DFUs) and its complications application has resulted in higher rates of limb salvage
represent the leading cause of hospitalisation among and wound healing.9
diabetic patients.1 Diabetics have 5-10 times more risk of Investigations to diagnose PAD and their limitations
amputation compared to non-diabetics.2 Also, 15% In examining any limb for chronic limb ischaemia, one
diabetics develop a foot ulcer over the life span. In about must look specifically for any hair loss, atrophy of skin and
85% patients with major amputations, there is a subcutaneous tissues, muscle atrophy, dry fissured skin,
preceding history of non-healing foot ulcer.3 DFUs can be discolouration, dependent hyperaemia, and the presence
either neuropathic (35%), ischaemic (15%), or of any ulcer or gangrene. Also, the presence and quality of
neuroischaemic (50%).4,5 pulses must be checked carefully10.
The incidence of peripheral arterial disease (PAD) a. Ankle brachial pressure index (ABPI)
increases with duration of diabetes. Approximately 15% ABPI is a useful bedside tool to diagnose and assess the
patients with diabetes develop PAD 10 years after severity of PAD in diabetics. Value <0.9 indicates that the
ulcer is ischaemia and is least likely to heal until the
1Department of Surgery, 2Department of Medicine, Aga Khan University vascularity is improved. Due to calcified, non-
Hospital, Karachi, Pakistan. compressible arteries in most diabetics, ABPI may be
Correspondence: Zia Ur Rehman. Email: [email protected] falsely high.11 In those patients, toe-brachial index (TBI)
ORCID ID. 0000-0002-4147-8962 and other non-invasive tests can help to detect PAD.

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 Z Rehman, N Ram
622
b. Toe-brachial index (TBI) In conventional angiography, images are not hindered by
This is simple, inexpensive, quick method for detecting calcifications. It can better define disease pattern. This can
small vessel artery disease. It can predict healing and limb be used as therapeutic purpose with some limitations.
survival. It is useful to monitor efficacy of therapeutic Although catheter angiography is the gold standard and
intervention. Patients with PAD have toe pressure gives the best imaging modality, it requires imaging in
<55mmHg or TBI <0.7. Foot wounds have lower chance of two planes. It also uses contrast that can be nephrotoxic.
healing at toe pressure <30mmHg. Pre-procedure hydration can protect the kidneys. Carbon
dioxide (CO2) angiography is an alternative in patients
c. Duplex ultrasound (DUS) who are at high risk for contrast-induced nephropathy, as
DUS is usually the initial investigation in patients with CO2 does not affect kidney functions.15 CO2 angiography
PAD to see the extent of the disease. It is very useful non- can show reasonable quality images of large vessels up to
invasive investigation with certain limitations (Table 1). knee, but the images may not be great in infra-popliteal
An arterial duplex scan in often sufficient to give a fair arterial segments.
idea of the site and extent of the disease without having
to resort to the use of radiation or contrast exposure12. WIfI classification system
This system stratifies limb risk by grading three critical
d. Computed tomography angiography (CTA) factors; wound, ischaemia and foot infection (WIfI). This is
Table-1: Limitations of various investigations in diabetic patients. like the Tumour, Nodes, Metastasis (TNM) system for
malignancy (Table 2). WIfI stage 1 is associated with very
US (Ultrasound) low amputation risk. Whereas stages 3 and 4 are more
! Operator dependent likely to require revascularisation and are at increased risk
! Difficult to visualize heavily calcified tibial vessels
for limb loss. WIfI stage may also predict wound healing
! Oedema, skin ulceration and vessel calcifications may limit vision
time and has been correlated with costs of care16.
CTA (Computed tomography angiography)
!Uses contrast
! Radiation exposure
Table-2: WIfI classifications for threatened lower limbs for the assessment of
! Calcium causes a ‘blooming’ artifact
amputation risk
! Metal implants can cause artifact
MRA (Magnetic resonance angiography) Component Grade Description
! As calcium does not make any artifact, plaque is visualized with difficulty Wound (W) 0 No wound
! Nephrogenic Systemic Fibrosis (NSF) occurs in patients with an eGFR < 30 with an 1 Small, shallow ulcer No exposed bone, unless limited to
incidence of 1 in 10000. distal phalynxNo gangrene
! Contraindicated in patients with pacemakers, defibrillators cochlear implants and
2 Deeper ulcer with exposed bone joint, or tendon, not
spinal cord stimulators
! MRI is not tolerated by approximately 10 to 15% of patients.
involving tissue heel.Shallow heel ulcer without calcaneal
! Venous contamination
involvementGangrene limited to digits
! Higher cost 3 Extensive, deep ulcer involving forefoot/midfoot.Deep,
! Long imaging time full thickness heel ulcer and/or calcaneal
! Invasive involvement.Extensive gangrene involving
Catheter Angiography forefoot/midfoot, Full thickness heel necrosis and
! Access related complications for transfemoral angiography in 1 in 1000 patients calcaneal involvement
(0.1%) Ischaemia (I) 0 TP >60 mm Hg; ABI >0.8; ASP >100 mm Hg
! Contrast induced renal damage
1 TP 40–59 mm Hg; ABI 0.6–0.79; ASP 70–100 mm Hg
CTA is a non-invasive and rapid method for evaluating 2 TP 30–39 mm Hg; ABI 0.4–0.59; ASP 50–70 mm Hg
PAD. It provides objective evidence of occlusive lesion 3 TP <30 mm Hg; ABI <0.39; ASP <50 mm Hg
and help in planning for any intervention. It can help in Foot Infection 0 No symptoms or signs of infection
detecting lesion in the inflow arteries (iliac arteries)13. (FI)
1 Local infection involving only skin, subcutaneous tissue
e. Magnetic resonance angiography (MRA)
The advantages of using MRA is that it is a non-invasive 2 Local infection with erythema >2 cm, or involving
investigation with no radiation exposure. It does not structures deeper than skin, subcutaneous (eg, abscess,
cause any calcium artifact, thus visualising the lumen of osteomyelitis)
even small, calcified vessels, like tibial, is easier14. 3 Local infection with signs of SIRS
WIfI: Wound, Ischaemia and foot Infection, TP: Toe pressure, ABI: Ankle -brachial index, ASP:
f. Catheter angiography Ankle systolic pressure, SIRS: Systemic inflammatory response syndrome.

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Peripheral arterial disease (PAD) in diabetics...
623
In 2019, Global Limb Anatomic Staging System (GLASS) patients as they are already maximally vasodilated.
classification was presented.17 In 2021, Liang P et al. Naftridrofuryl is another drug used in claudication.
evaluated this scoring system18 and showed that a higher All these drugs have been shown to improve walking
GLASS stage correlated well with disease recurrence and distance among the claudicants.
need for re-intervention.
d. Anticoagulation: The Cardiovascular Outcomes for
PAD in diabetics is complex, involving multiple organs. A People Using Anticoagulation Strategies (COMPASS)
team approach can significantly improve patient trial gives clear guidance that all patients with
outcomes with decreased amputation rate.19 symptomatic peripheral vascular disease had a
reduction in cardiovascular events (stroke,
Best medical treatment for these patients myocardial infarction [MI], death) and not reducing
Patients with diabetes, PAD and ulceration have overall major limb events.24 A subgroup analysis in a recent
5-year mortality of around 50% because of markedly trial of antiplatelets and anticoagulants suggested
increased risk of cardiovascular events.20 This survival rate that combination of aspirin and the direct oral
is less than patients with heart failure, stroke and most anticoagulant rivaroxaban was more effective at
cancers.21 reducing major limb events when compared with
Conservative measures are often the first-line treatment aspirin alone in patients with PAD, but this strategy
for patients with PAD. These include risk factor was at the expense of an increase in non-fatal
modification and exercise programme. Target is to stop events.25
smoking, treat hypertension with target BP 130/80 or less, Where surgical bypasses stand in this endovascular
treat hyperlipidaemia with target low-density lipoprotein era ?
(LDL) <70 mg/dl, and treat diabetes with target glycated Critical limb ischaemia patients present with either tissue
haemoglobin (HbA1c) <7%. loss or rest pain. Both surgical and endovascular methods
are effective in improving blood supply of the ischaemic
Smoking is one of the most important modifiable risk
ulcers.26 Infra-inguinal bypasses using veins have
factors for PAD. It is well known that smoking increases
excellent limb salvage rate with minimal perioperative
risk of PAD by three-fold. It does not only affect the
morbidity and mortality.27 These are best served for
development of PAD, but also clinical outcomes in
patients with good life expectancy and who are fit for
patients who continue to smoke. Smokers are also more
anaesthesia. The bypass inflow sites may be femoral,
likely to progress to critical limb ischaemic amputation or
above or below-knee popliteal, tibial, or peroneal artery.
vascular intervention. It also increases the mortality rate
Any infra-popliteal artery can be used for outflow.
among the claudicant by a factor of 1.5-3. The United
Although most ischaemic limbs can be re-vascularised.
Kingdom (UK) prospective diabetes (UK-PD) study
Peroneal artery is the least disease vessel. Idea is to
identified a strong association between HBA1c and PAD
maintain an inline flow to the ankle or foot with one of the
risk.22 Each 1% increase in HBA1c was associated with a pedal arteries to improve wound healing. Non-impeded
28% increased risk of PAD. inflow and low resistance outflow is a major factor in the
a. Supervised exercise therapy: This is an integral part success of a bypass conduit. A vein with adequate size
of this treatment. With risk factor modification and (>3mm) and of reasonable quality (without fibrosis and
supervised exercise, 33-65% of patients improve stenosis) is also a pre-requisite for these procedures. This
their claudicant distance. can be mapped pre-operatively. Calcified and sclerotic
veins are rejected. Veins can be used in reversed, non-
b. Anti-platelets: Either aspirin or clopidigrol is reversed or in-situ fashion.28 Vein harvesting can be done
prescribed.23 Antiplatelets do not improve through long continuous incisions, through skip incisions,
claudication symptoms, but are the mainstay of or endoscopically. Adequate inflow is ensured before
secondary prevention. commencing with these bypasses. Selective inflow
lesions can be treated either percutaneously in advance
c. Cilostazol/Pentoxifylline: Pentoxifylline acts as
or at the same operative sitting if needed. It is challenging
increasing the adenosine triphosphate (ATP) level,
to anastomose calcified arteries. Possible options to deal
reducing red blood cell aggregation and fibrinogen.
with calcified vessels are use of tourniquets, intraluminal
Cilostazol acts as a phosphodiesterase inhibitor and
balloons, glues or feeding tubes29.
has an antiplatelet effect as well as increasing ATP
levels in the red blood cell. There is minimal The indications for surgical bypasses or endovascular
vasodilatory properties of these drugs in these options are lifestyle limiting claudication, rest pain and

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624 Z Rehman, N Ram

non-healing ulcers. Surgical bypasses are the most associated with broadly similar outcomes in terms of
durable option for infra-inguinal revascularization of amputation-free survival, and in the short-term, surgery
chronic atherosclerotic occlusive disease. The key to their was more expensive than angioplasty.39 The Best
success is the calibre and quality of the venous conduit Endovascular versus Surgical Therapy in Patients with
and meticulous postoperative surveillance. They have Critical Limb Ischaemia (BEST-CLI) trial is a promising
better outcomes than complex endovascular therapy in current multicentre, randomised trial that will add
low-to-moderate risk patient with good quality evidence and further help guide treatment options for
autologous conduit. Open surgery versus endovascular critical limb Ischaemia (CLI) patients.40 The same is true of
therapy is a subject of debate.30 There is lack of the BASIL 2 trial.41
prospective, randomised data to support one treatment
Innovations in the endovascular treatment options
over the other. Bypasses are durable. Patency rate for
There is a myriad of endovascular techniques. They
femoropopliteal bypass have been reported 83% and
include percutaneous transluminal angioplasty (PTA) with
63% at 5-year and 10-year, respectively, with limb salvage
and without stenting, subintimal angioplasty, PTA with
rate of 89%. Same is true for pedal bypasses who have
drug-coated balloons, covered stents, cryotherapy,
median salvage rate of 78% at 5 years. Bypass to the tibial
brachytherapy and use of atherectomy devices (Table 3).
or pedal vessels with autogenous vein is the most
predictable method of improving blood flow to the Drug-eluting balloons and stents reduce the risk
threatened limb.31 neointimal hyperplasia and re-occlusion in these vessels.
Sirolimus-eluting stents have been shown to inhibit
Endovascular interventions neointimal hyperplasia in the coronary vasculature.
Infra-inguinal bypasses are major procedures and need
appropriate anaesthesia evaluation. Most patients with
Table-3: Recent advances in endovascular therapy (ET).
long-standing diabetes are high-risk cases for
anaesthesia. There may also be issues with the availability ! Drug-coated balloons
of the quality vein. In those cases, endovascular therapy is ! Drug-coated stents

a practical option which is minimal invasive and can be ! Re-entry devices

! Debulking devices
performed under local anaesthesia. Endovascular
! Low profile systems
interventions achieved better ulcer healing in Ishchaemic
! Use of novel access points
diabetic foot ulcer compared with the conservative ! Bio-resorbable stents and scaffolds
approach.33-34 “Endovascular first approach” is the ! Bifurcated stents
preferred approach to many interventionists.35 ! Tacking
Endovascular revascularisation has increased in ! Robotic ET
popularity in recent years; data from the United States ! Paclitaxil infusion

reveals a more than five-fold increase in endovascular ! Angioscopic assisted ET

! Endovascular venous arterialization
interventions from 1980 to 2000.36 In general,
endovascular revascularisation is more appropriate in
patients with relatively focal disease in arteries above the Subintimal angioplasty helps in improving blood flow
knee, but short-term success rates for opening long, even in occluded arteries in which conventional intra
totally occluded vessels and below-the-knee arteries are luminal angioplasty is not effective. It helps to achieve
improving. Low-profile coronary devices are commonly luminal patency in totally occluded arterial segments.
used for these lesions with improved outcomes. Imaging The atherosclerotic segments in diabetics may be stiff and
is key in the success of these procedures. Mostly 0.018/ calcified and simple angioplasty may not dilate them.
0.014 guidewires are used. Both hydrophilic/non- Atherectomy devices can debulk these lesions to facilitate
hydrophilic guidewires are used to cross these lesions.37 angioplasty. This spares the arteries from stents and later
Several trials, including the interm results of CRITISCH from in-stent stenosis which is much more difficult to
registry found no differences in long-term mortality or treat. The techniques to cross the difficult lesions have
major amputation when comparing both strategies.38 In also improved. As discussed in case of failure of
Bypass versus Angioplasty in Severe Ischaemia of the Leg ‘antegrade’ intraluminal approach, subintimal approach is
(BASIL 1) trial, patients presenting with severe limb the option. Even if it fails, ‘retrograde’ trans-pedal arteries
ischaemia due to infra-inguinal disease and who were approach can be used to cross these lesions. Limb salvage
suitable for surgery and angioplasty, a bypass-surgery- of 80-85% have been reported using either surgical,
first and a balloon-angioplasty-first strategy were endovascular or hybrid (combination of the two)

Open Access J Pak Med Assoc

Peripheral arterial disease (PAD) in diabetics... 625
revascularisation techniques in these patients. peripheral arterial disease: a systematic review and meta-analysis.
JAMA. 2009; 301:415-24.
Recent advances in atherectomy and drug-coated 14. Cavallo AU, Koktzoglou I, Edelman RR, Gilkeson R, Mihai G, Shin T,
balloon angioplasty have shown promising results. et al. Noncontrast Magnetic Resonance Angiography for the
Diagnosis of Peripheral Vascular Disease. Circ Cardiovasc Imaging.
Recent advances in retrograde tibiopedal access have 2019; 12:e008844. doi: 10.1161/CIRCIMAGING.118.008844.
dramatically increased the technical success of the distal 15. Gupta A, Dosekun AK, Kumar V. Carbon dioxide-angiography for
and long-segment occlusive disease, and more below- patients with peripheral arterial disease at risk of contrast-
knee and pedal-loop revascularisations are providing induced nephropathy. World J Cardiol. 2020; 12:76-90. doi:
10.4330/wjc.v12.i2.76.
increasing perfusion to distal tissues previously deemed 16. Darling JD, McCallum JC, Soden PA, Guzman RJ, Wyers MC,
non-salvageable.42,43 Hamdan AD, et al. Predictive ability of the Society for Vascular
Surgery Wound, Ischemia, and foot Infection (WIfI) classification
Conclusion system after first-time lower extremity revascularizations. J Vasc
PAD is very common in diabetic patients and need to be Surg. 2017; 65:695-704. doi: 10.1016/j.jvs.2016.09.055.
17. Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitrdge R, et al.
detected earlier. Patients with ulceration or tissue loss Global vascular guidelines on the management of chronic limb-
should be assessed earlier to improve foot perfusion threatening ischemia. J Vasc Surg. 2019; 58:S1-S109. DOI:
using either endovascular or surgical interventions. 10.1016/j.jvs.2019.02.016.
18. Liang P, Marcaccio CL, Darling JD, Kong D, Rao V, St John E, et al.
Disclaimer: We are grateful to Dr Shiraz Hashmi for Validation of the Global Limb Anatomic Staging System in first-
editorial assistance. time lower extremity revascularization. J Vasc Surg. 2021; 73:1683-
91. DOI: 10.1016/j.jvs.2020.08.151.
Conflict of Interest: None. 19. Dhand S. Multidisciplinary Approach to PAD: Who's on Your
Team? Semin Intervent Radiol. 2018; 35:378-83. DOI: 10.1055/s-
Source of Funding: None. 0038-1676094
20. Hinchliffe RJ, Brownrigg JR, Andros G, Apelqvist J, Boyko EJ,
Fitridge R, et al. Effectiveness of revascularization of the ulcerated
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