Lower limb peripheral arterial diseases: diagnosis, management and the effect of pedal arch reconstruction on the overall outcomes

INTRODUCTION

Peripheral arterial disease (PAD) is a chronic progressive atherosclerotic disease leading to incomplete or total vascular occlusion. The abdominal aorta, iliac and lower limb arteries are typically affected. Involvement of the upper extremities is relatively infrequent.¹ PAD is estimated to affect 237 million people worldwide, with an annual prevalence of 10.7% among hospital admissions.^2,3 PAD remains asymptomatic or unrecognised in a sizable portion of the population.⁴ The disease presentation is variable and can manifest as intermittent claudication, resting limb pain, ulceration, gangrene or limb loss.⁵ PAD is associated with other cardiovascular diseases. 90% of PAD patients show coronary artery disease on angiography. Carotid artery stenosis of >70% can be demonstrated in 25% of PAD patients.⁶ The crude five-year all-cause mortality rate of PAD is 33.2%.⁷ A multidisciplinary team approach is essential for improving patient outcomes.

ETIOLOGY

Atherosclerosis accounts for 95% of the cases of PAD.⁸ Progression of atherosclerosis causes gradual narrowing of the vascular lumen and leads to end-organ ischemia.⁹

Several modifiable and non-modifiable risk factors are implicated in the progression of atherosclerosis.^5,10-12 They are smoking, diabetes, family history of cardiovascular diseases, hypertension, dyslipidemia, age >50 years, obesity (BMI>30 kg/m²), and increased homocysteine levels.

EPIDEMIOLOGY

PAD affects 237 million people worldwide. It is infrequent in the younger age groups. However, the incidence increases to 20% in individuals over 70 years.^13,14 The role of gender in PAD is confounding. In the Framingham and Rotterdam studies, men were more likely to have intermittent claudication than women.^15,16 However, there were no statistically significant gender discrepancies in the Rotterdam Study, and Cardiovascular Health Study on an Ankle-brachial index (ABI) based diagnosis.^9,14 PAD may be significantly underdiagnosed at the primary care level, as most patients do not present with the characteristic claudication symptoms.¹⁴ Smoking is the most significant risk factor for PAD.¹⁷ Smokers have shorter lifespans than non-smokers and are more prone to progress to critical limb ischemia.¹⁸

PATHOPHYSIOLOGY

The progression of atherosclerosis affects both macro-and microvascular circulation. Lower extremity vasculature is typically affected. However, the larger iliac arteries and abdominal aorta are also frequently involved. In severe disease, the affliction can be multi-level or diffuse.

Reactive oxygen species or free radicals (ROS) escalate the expression of Cell adhesion molecules (CAM). Monocyte adherence to the endothelial cells is mediated through CAM. Low-density lipoprotein cholesterol (LDL-C) is oxidised to minimally modified LDL (MM-LDL), which stimulates the endothelial cells and smooth Muscle cells to produce chemoattractant protein-1 (MCP-1).¹⁹ MM-LDL is further oxidised to fully oxidised LDL (OX-LDL).²⁰ OX-DL and MCP-1 accelerate the migration of monocytes to the subendothelial area.^21-23

OX-LDL is a ligand for the scavenger receptor expressed in monocyte differentiated into tissue macrophage.^24,25 This monocyte/macrophage differentiation is facilitated by releasing Monocyte colony-stimulating factor (MCSF) from the endothelial cells under the influence of MM-LDL.¹⁹

The differentiated macrophage develops receptors for OX-LDL, which receptors take up to produce foam cells. Foam cells also generate ROS.²⁶

Macrophages generate a host of growth-regulating molecules and cytokines that affect neighbouring cells. Gene expression and transcription in the smooth muscle cells could result in smooth muscle cell proliferation and migration, synthesis of connective tissue and its matrix, migration of monocytes and formation of foam cells that results in the development and progression of atherosclerosis.²⁷

Atherosclerotic plaque gradually builds up within the vessel wall. This results in vascular stenosis and reactive dilation to maximise end-organ perfusion. Once the vessel dilation capacity is exceeded, the continuous plaque accumulation leads to critical narrowing of the artery. Collateral circulation develops to preserve distal perfusion and tissue viability; however, these collaterals cannot match the blood supply of a typical healthy vessel. When the oxygen requirement of the tissue exceeds this fixed oxygen supply, intermittent claudication, resting limb pain or tissue loss ensues as the tissues crave oxygen.^28,29

Sudden vascular occlusion occurs with the development of in-situ vascular thrombosis or an embolism from a cardiac source.³⁰ In-situ thrombosis secondary to progressive atherosclerosis represents 40% of Acute limb ischemia (ALI) cases. In comparison, embolic causes account for 30% of ALI cases.³¹ Atherosclerotic plaque rupture leads to the exposure of subendothelial collagen and other inflammatory cells, causing platelet adhesion, aggregation with the development of in-situ thrombosis within the vessel lumen.

Patients with in-situ thrombosis tend to have better outcomes than embolic causes due to extensive collateral circulation.³¹ ALI is a vascular emergency that requires immediate intervention to prevent limb loss.⁹

CLINICAL FEATURES

Diagnosis of PAD requires a high index of suspicion. Many patients are asymptomatic (over 50%).³² Some mild to moderate PAD patients rarely exert themselves to a level that requires increased blood flow to the lower extremity muscles.

Other patients attribute the symptoms of discomfort to the natural consequences of ageing and do not report them. Comorbidities such as advanced diabetes mellitus, spinal disease, or lumbosacral disease may alter the pain perception and lead to atypical presentations.⁸

Claudication is the most classic symptom. It is initiated by walking and relieved with rest. It is often described as cramping, aching, pressure, weakness or leg fatigue. On exertion, symptoms occur in the muscle groups distal to the narrowed artery.¹⁴ In severe PAD, patients can develop ischemic rest pain, which worsens at night. The symptoms are exacerbated by limb elevation and relieved by placing the limb in a dependent position. In some cases, oedema may develop from keeping the leg in a dependent position which may be mistakenly attributed to venous thrombosis. Non-healing wounds are also complained about by some patients.³³

The physical exam may reveal the following: (a) reduced or absent pulses; (b) tenderness; (c) pallor with limb elevation, dependent rubor; (c) cool and cyanotic skin; (d) muscle atrophy; (e) loss of hair; (f) audible bruits; (g) non-healing ulcers; (h) delayed capillary refill time; and (i) lower limb gangrene.^14,33 Critical limb ischemia (CLI) is a severe form of PAD characterised by clinical findings of (1) ischemic rest pain; and/or (2) ischemic tissue loss (ulceration or gangrene).³⁴

DIAGNOSIS

PAD diagnosis depends on the patient risk profile, history, clinical presentation and objective tests.³⁵

ABI is a non-invasive, cost-effective, objective measure for PAD diagnosis. It is the ratio of systolic ankle pressure to the highest systolic brachial pressure. A healthy ABI ratio ranges from 0.9 to 1.2. Values lower than 0.9 are diagnostic of PAD. Noncompressible vessels (as seen in advanced renal diseases or diabetes) have falsely elevated ratios. These patients tend to have higher all-cause mortality.³⁶ Further evaluation of a toe-brachial index (the ratio of the systolic toe pressure to the highest brachial systolic pressure) is warranted in these patients.²⁸

Duplex ultrasonography (DUS) is a non-invasive, safe and relatively cost-effective imaging modality. It can determine the length, location, plaque characteristics and hemodynamic severity of the stenosis. DUS is helpful in the initial diagnosis, decision-making when planning for other diagnostics or interventions, or post-procedure follow-up.³⁷ Contrast-enhanced ultrasound (CEUS) imaging using microbubble contrast agents is another emerging concept with considerable potential for diagnostic and therapeutic applications. There is enhanced overall contrast and quality, and accuracy of ultrasound images. However, proper technician training and widespread adoption are needed to reap the full benefits.³⁸ Digital subtraction angiography (DSA) is considered the gold standard for PAD decision-making.

It has both diagnostic and therapeutic implications.³⁹ MRA has 90% sensitivity and 97% specificity compared to DSA. However, MRA can delineate small runoff vessels, missed on DSA. The diagnostic accuracy of CTA is comparable to MRA.³⁷

TREATMENT/MANAGEMENT

Management is aimed at improving symptoms and decreasing cardiovascular events. PAD patients are at an increased risk of coronary artery disease mortality (CAD) (RR=6.6), cardiovascular mortality (RR=5.9), and all-cause mortality (RR=3.1).⁴⁰

Lifestyle/risk factor modification

Smoking cessation

It is achieved by patient education, behavioural therapy, nicotine replacement, or pharmacological therapy (varenicline and bupropion).^9,41 Failure to quit might limit the improvement obtained from exercise and pharmacological treatment.⁴²

Exercise therapy

Exercise improves pain-free walking distance and total walking distance. However, there is no effect on overall mortality. Exercise programs typically consist of 30 to 45-minute sessions conducted 4 to 5 times a week over three months.⁴³

Glycemic control

A multidisciplinary team approach is preferable for the optimal management of diabetes in PAD patients.⁴¹ A combination of a well-balanced diet, weight control, and pharmacotherapy are prerequisites for optimal glycemic control and is associated with reduced amputation rates and improved post-revascularisation patency.^44,45

Antihypertensive therapy

It is indicated for all hypertensive patients with PAD. The choice of therapeutic agent required depends on the patient comorbidities.⁴¹ Angiotensin-converting enzyme inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs) are considered first-line therapy because they significantly reduce adverse cardiovascular events in patients with PAD.^46-48 Calcium channel blockers, beta-blockers and diuretics are reliable alternatives.³³

Statin therapy

Early statin initiation is associated with a reduction of adverse cardiovascular events and mortality. Hence it is indicated for all PAD patients.^41,48-51

Antiplatelet therapy

Single-antiplatelet therapy with aspirin alone (75-325 mg/day) or clopidogrel alone (75 mg/day) is associated with a reduction in adverse cardiovascular events, non-fatal strokes and vascular deaths among patients with symptomatic PAD on antiplatelet therapy. Clopidogrel is superior to aspirin for monotherapy in PAD patients.^52,53

Dual-antiplatelet therapy demonstrated a reduction in adverse limb-related events and the need for repeat revascularisation procedures in patients with PAD who underwent endovascular intervention or below-knee bypass prosthetic grafting.^54-56

Cilostazol, naftidrofuryl and pentoxifylline

Cilostazol (phosphodiesterase type 3 inhibitor) significantly improves pain-free and total walking distances.⁵⁷ In addition, it also demonstrates antiplatelet, vasodilatory, and anti-smooth muscle cell proliferation properties.⁵⁷ Naftidrofuryl (5-hydroxytryptamine-2-receptor antagonist) has lesser adverse effects than cilostazol and is more likely to be cost-effective than cilostazol or pentoxifylline.^58,59 Due to the lack of high-quality evidence, the role of pentoxifylline (competitive nonselective phosphodiesterase inhibitor) in managing intermittent claudication is uncertain.⁶⁰

Revascularisation

Revascularisation is typically employed in patients with burdening symptoms unresponsive to conventional approaches like lifestyle modification, exercise therapy and pharmacotherapy. Indications include severe claudication causing marked limitation of activities of daily living, to prevent tissue loss in CLI. Depending on the patient profile and the decision of the healthcare team, the modalities of recanalisation include endovascular, surgical or a combined approach.⁶¹

The goal of revascularisation is to restore perfusion of the extremity with CLI.⁴¹ In CLI without revascularisation, amputation rates reach 20% to 40%, and 6-month mortality exceeds 20%.^58,62-65 The four-year amputation and mortality rates approach two-thirds.^66,67

Open surgical techniques for CLI primarily consist of endarterectomy and bypass. Bypass is favoured over endarterectomy for the management of aortoiliac segment disease.⁶⁸ Endarterectomy is favoured for the treatment of disease in the femoral arteries. The five-year patency rates as high as 91% have recently been reported.⁶⁹ Distal stenoses are generally treated via bypass.⁷⁰

Endovascular techniques used for the management of CLI include percutaneous balloon angioplasty (using conventional plain, drug-coated or cutting balloons), laser or mechanical atherectomy and stenting with bare metal or drug-eluting stents.^71,72 In the past 20 years, the rate of lower limb endovascular interventions has more than quadrupled.^73-77 Recent advancements in technologies have resulted in the ever-expanding utilisation of these interventions in patients with disease characteristics once thought to preclude endovascular interventions. Albeit with limited data, these newer applications have met some success in CLI.^78-82 Treatment biases among the various provider specialities impact the decision-making as to which modality is offered to patients with CLI.^71,83-85

In the Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial, the amputation free survival at 1 and 3 years for the bypass surgery cohort was 68% and 57%, and 71% and 52% for the angioplasty first group, which was not statistically significant.⁸⁶ Surgery had lower re-intervention rates (18% vs 26%). Bypass surgery was associated with higher early morbidity than angioplasty.

However, there were no differences in overall mortality. Health-related quality of life was similar in both cohorts. Hospital expenses were higher during the first year for the surgery-first group.⁸⁶ The limitations of the study were the small sample size, non-randomisation, retrospective design, failure to distinguish intermittent claudication from CLI, poorly defined interventions, failure to restrict to infrainguinal anatomic disease pattern, and/or inadequate follow-up.^71,87,88

The ongoing Best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI) trial attempts to address many of the limitations of the BASIL trial and may provide further data about issues previously unexplored in randomised studies (e.g., angiosome-directed outcomes vs conventional in-line revascularisation strategies, as well as anatomic predictors of outcome).^41,87,89,90 Two additional randomized controlled trials in the United Kingdom promise to complement the findings of BEST-CLI.⁷¹ The BASIL-2 trial aims to compare primary vein bypass versus primary best endovascular treatment focused on infrageniculate disease.⁹¹ The BASIL-3 trial seeks to compare the efficacy of endovascular options with three randomisation arms: 1) plain angioplasty, 2) drug-coated balloon angioplasty, and 3) drug-eluting stents.⁹²

ROLE OF PEDAL ARCH RECONSTRUCTION (INFRAMALLEOLAR ANGIOPLASTY)

The development of endovascular techniques and advances in guidewire and stent design have facilitated Below-the-ankle (BTA) revascularisation strategies.⁹³ Jung et al reported a higher freedom major amputation significant (96.3% vs 84.2%; p=009) in the Pedal arch revascularisation (PAR) at one-year follow-up. Wound healing rate was higher in the successful PAR group compared to the non-PAR subgroup (p=0.031). PAR was an independent factor related to improved wound healing rate (p=0.015).

Pre-procedural absence of pedal arch was associated with impaired wound healing.⁹⁴ Teymen et al reported a decrease in major and minor lower limb amputation in the BTA angioplasty arm in comparison to the Above the ankle (ATAn) angioplasty alone arm (0.0% vs 8.0%, and 15.0% vs 24.0%, respectively) at 12-month follow-up; however, this failed to reach statistical significance.⁹⁵ Nakama et al reported a significant increase in the rate of wound healing at 12-month follow-up in the BTA angioplasty arm in comparison to the ATAn angioplasty alone arm (59.3% vs 38.1%, p<0.05). Time to wound healing was also significantly shorter in the BTA angioplasty arm (211 days vs 365 days, p=0.008).⁹⁶ Kawarada et al reported that 83% of participants achieved the composite outcome of improvement in rest pain or wound healing at follow-up.⁹⁷

Kawarada et al reported a composite outcome of improvement of rest pain and wound healing.⁹⁷ Wei et al used improvement in rest pain as an outcome but did not report symptomatology at follow-up.⁹⁸

Dua et al saw an overall increase in QoL scores (1.3 pre-study to 0.7 at six months follow-up) and significant increases in activity ('fairly' to 'well', p=0.014) and mood parameters (0 to 0.1, p=0.033).⁹⁹ Lower restenosis rates were observed in the BTA angioplasty arm in comparison to the ATAn angioplasty alone arm, which approached significance at one year (15.8% vs 47.8%, p.0.059).⁹⁵ The post-BTA angioplasty arm represented an 80.3% overall freedom from re-intervention at follow-up.¹³ Complications between the BTA and ATAn cohorts do not vary significantly. The pooled complication rate is 12.5%. Some commonly encountered complications include puncture site hematoma, vessel rupture, distal embolisation, dissection, balloon rupture, bleeding, or vasospasm.^13,94

OUR INSTITUTION APPROACH

The procedure is performed under local anaesthesia following strict aseptic protocol. The patient is placed in the supine position on the angiographic table. An ipsilateral transfemoral arterial access is taken. A 7F sheath [Cook Medical, USA] is placed into the Common femoral artery (CFA) anterogradely towards the Popliteal artery (PA). An angiogram is done to assess the vascularity of the foot. The Superficial femoral artery (SFA), PA and Below-knee arteries (BKA), including the Anterior tibial artery (ATA), Posterior tibial artery (PTA) and the common peroneal arteries are examined. The pedal arch is studied (Figure 1).

Once the pedal arch disease is confirmed, pedal arch angioplasty is planned. It could be associated with the disease of the BKA, PA, SFA, or it could be an isolated problem in itself. The pedal arch is accessed with a distal access catheter (DAC- Stryker Neurovascular, USA) placed from the groin into the PA or selectively into the ATA or PTA when feasible. A 2×100 mm balloon, Whisper wire was navigated into the ATA, and the pedal arch was accessed at the base of the first metatarsal. Then the wire was slowly navigated through the arch, and a path was created into the PTA through the foot.

The 2×100 mm balloon was navigated across the arch, and angioplasty was commenced (Figure 2). The balloon was inflated for 90 seconds. A Post-angioplasty angiogram was done to assess the result of the angioplasty (Figure 3).

In case of focal stenosis or slow flow, the angioplasty was repeated at the particular segment. After achieving adequate pedal arch flow, the procedure was completed by removing the catheter, wire and the balloon, and hemostasis was achieved for the groin puncture site after removing the sheath.

CONCLUSION

PAD are a significant cause of morbidity and limb loss. A significant majority are atherosclerosis related. Physicians should have a high index of suspicion to diagnose PAD. Various modalities of radiological investigations can be employed to establish the diagnosis. Treatment is centered around lifestyle modification, pharmacotherapy and revascularisation. The use of endovascular therapy is gaining significant traction in the recent years to technological advances and product development. Timely interventions and pedal arch reconstructions are vital in achieving the best possible outcomes.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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