Peripheral arterial disease: Scoping review of patient‐centred outcomes

Abstract

Peripheral arterial disease (PAD) impairs patients’ quality of life (QOL), walking and ulcer healing, increasing patient pain, costs, and risks of amputation or mortality. A literature appraisal described PAD treatment capacity to improve validated patient‐centred outcomes in controlled clinical studies. The PUBMED database was searched from 1 January 1970 to 21 June 2018, for original and derivative controlled clinical trial references addressing MeSH terms for ‘ischemia’ AND ‘leg ulcer’. Non‐ischemic ulcer treatment references were excluded. Frequencies of improved (P < .05) outcomes were reported. Eighty‐eight studies on 4153 patients were summarized. Walking, pain or QOL improved mainly for interventions administered before PAD became severe. Amputation incidence, pain and ulcer healing were more frequently reported in those with severe PAD. Independent of PAD severity, patients experienced more likely improved walking, QOL, or pain reduction in response to structured walking interventions or those increasing calf muscle activity. Those with more severe PAD were more likely to report amputation reduction, mainly in response to invasive interventions. Those with PAD experienced more consistently improved patient‐centred outcomes if they received multidisciplinary PAD management with supervised walking or calf muscle activity, with more likely amputation risk reduced for those with more severe PAD.

Key Messages.

• Peripheral arterial disease (PAD) progresses in severity from impaired walking and quality of life (QOL) through increasing likelihood of pain, ulceration, gangrene, amputation, or death and magnifies clinical, economic, and patient burdens of venous insufficiency or diabetes

• improving PAD‐related patient‐centred outcomes requires consistent early, effective PAD diagnosis and effective treatment to improve lower limb perfusion

• a literature appraisal of significantly improved patient‐centred outcomes in controlled clinical studies enrolling patients with PAD reported walking, QOL, and pain reduction as the most frequently improved outcomes, mainly for those with less severe PAD randomised to receive structured walking exercise or interventions that stimulated calf muscle activity

• for those with more severe PAD, reduced risk of amputation was also improved mainly in response to invasive interventions

• benefits of structured walking exercise were robust across levels of PAD severity and when used jointly with invasive interventions.

Abbreviations

ABI

ankle‐to‐brachial systolic blood pressure index (ratio), optimally performed using handheld Doppler ultrasound

ALU

arterial leg ulcers

CLI

critical limb ischaemia

DAPT

dual antiplatelet therapy, for example, aspirin plus low molecular weight heparin

DFU

diabetic foot ulcers

ER

endovascular revascularisation

HBO

hyperbaric oxygen

IC

intermittent claudication

IPC

intermittent pneumatic compression of the calf muscle

MLU

mixed aetiology leg ulcers complicated with peripheral arterial disease

NMES

neuromuscular electrical stimulation sufficient to cause contraction of the calf muscle

PAD

peripheral arterial disease

PPG

photoplethysmography a technique for measuring venous emptying

QOL

quality of life

RCT

randomised clinical trial

SET

structured exercise therapy supervised by a professional

SOC

standard of care

TcPO₂

transcutaneous partial pressure of oxygen

VLU

venous leg ulcer

1. INTRODUCTION

Peripheral arterial disease (PAD) increases cardiovascular morbidity and mortality1, 2 in 3% to 10% of the global population.3, 4 It is associated with an increased hypertensive response and decreased calf muscle oxygenation during calf muscle flexion exercise.5 Up to 18% of those over 50 years of age with PAD experience intermittent claudication (IC), that is, pain on walking that subsides at rest.6

Among those with PAD, 20% to 70% have chronic leg ulcers.7, 8, 9, 10, 11 Those with a chronic leg ulcer have a 37% to 70% likelihood of having PAD complication.6, 7, 8, 9, 12 Without timely, appropriate interventions, progressive PAD‐related ischaemia increases the 1‐year risk of lower limb wound deterioration by 35% and likelihood of major amputation by 22%.12 The 55% five‐year mortality rate after ischaemic ulcer diagnosis exceeds that of breast cancer and prostate cancer combined.13 These estimates may be conservative because PAD and ischaemic leg ulcers are often underdiagnosed and ineffectively treated.8, 14

1.1. Expected PAD outcomes

The increasing clinical, economic, and patient‐centred burdens of ischaemic leg ulcers remain to be fully charted. Patients with PAD are typically first diagnosed in outpatient settings,15 and are less likely to receive treatment for their conditions than those with cardiovascular disease.8 The resulting treatment gap allows PAD progression, inadequately treated, until the patient is hospitalised with critical limb ischaemia (CLI) or PAD so severe that revascularisation may pose unacceptable risk for many frail patients or their damaged arteries.16

Cool, pale, hairless lower leg(s) symptomatic of early PAD are often unnoticed or ignored.8 Walking pain may increase progressively with exercise, eventually occurring at rest or with brief exercise. In those with a palpable pedal pulse determining a ratio of ankle‐to‐brachial seated systolic blood pressure (ABI) less than 0.9 indicates arterial perfusion sufficiently compromised to delay tissue healing, causing a chronic arterial leg ulcer (ALU) or a mixed leg ulcer (MLU) if combined with other aetiologies such as venous insufficiency or diabetes. Those with ABI < 0.5 have a higher risk of experiencing chronic ALU or MLU, pain at rest, or a major limb amputation than those with ABI > 0.5.16

It has been widely recognised that PAD complicates diabetic foot ulcers.17 MLU with venous insufficiency and an ABI of 0.51 to 0.90 are an increasing proportion of the chronic leg ulcer population.7, 18 Ischaemia has been reported to precede up to 94% of lower limb amputations in elderly patients.19 These alarming trends have generated growing interest in patient‐focused approaches to managing PAD‐related leg ulcers20 and measuring content validated patient‐centred wound outcomes (21, 22, 23).

2. PURPOSE

A scoping review of published literature explored numbers of studies reporting significant beneficial patient‐centred outcomes in prospective controlled clinical trials enrolling patients with a chronic ALU or MLU, stratified by having (a) mild‐to‐moderate PAD, that is, ABI of 0.6 to 0.9 and/or reported as Fontaine stage I/II or (b) severe PAD, that is, ABI < 0.6 or Fontaine stage III/IV.

3. METHODS

The National Institutes of Health, National Library of Medicine PubMed reference database, was searched from 1 January 1970 to 21 June 2018 for original and derivative clinical trial references addressing the combined MeSH terms for ‘clinical trial’ or ‘review’ combined with ‘ischaemia’ and ‘leg ulcer’. Randomised or convenience controlled trials or case‐controlled registries or cohort studies were included if they reported a significant improvement in one or more of the following measured PAD patient‐centred outcomes: ALU or MLU healing time, infection, pain or odour or PAD‐related patient pain, analgesic use, amputation timing, incidence or level(s), physical function or walking, quality of life (QOL) including depression or social isolation, costs of care, or mortality.

Human clinical studies of at least 2 weeks duration evaluating the efficacy or safety of PAD or ischaemic leg ulcer treatment in any setting were included if they reported patient‐centred outcomes of treating individuals with documented (eg, by Fontaine score, invasive angiography, or ABI < 0.9) PAD with or at risk of developing a chronic ALU or MLU. Leg ulcers were considered chronic and non‐healing if they were present for at least 4 weeks before enrolment, without decreasing in area at least 40% while receiving the best standard of care with moisture‐retentive dressings, infection control, and appropriate compression.24 Preclinical studies or those investigating foot ulcer or non‐ischaemic ulcer treatment were excluded to avoid mixing PAD aetiologies with other aetiologies. Diabetic foot ulcer studies, reviewed elsewhere,25 were excluded as they typically require glycaemic management, off‐loading, or other interventions not always relevant for managing PAD.26

One author (LLB) screened abstracts for eligibility. The authors reviewed 221 abstracts and/or full‐text studies qualifying for inclusion and summarised evidence, supporting significant improvements reported for each patient‐centred outcome measured in response to one or more interventions studied. Study quality and risk of bias, graded elsewhere,27, 28, 29, 30 were not addressed in this work, which aimed to describe the frequency of studies improving patient‐centred outcomes, not evaluating evidence strength or quality. Probability of type I error of ≤.05 was the criterion for a statistically significant effect of an intervention on a patient‐centred outcome.

4. RESULTS

The literature searches returned 471 studies plus eight derivative references described in the PRISMA diagram31 in Figure 1. Patient‐centred outcome improvements were summarised for 88 unique studies on 4230 patients with PAD. Controlled study frequencies supporting at least one significantly (p < .05) favourable patient‐centred outcome of applying one intervention as compared to another were stratified by PAD severity for intervention categories in Figure 2. Patient numbers in parentheses were those receiving the described intervention. Settings were mainly in hospital‐based or free‐standing leg ulcer clinics. Outcomes of PAD‐related treatment were heterogeneous across studies,27, 29 resulting from variations in methods and timing of treatments or outcomes measurement and non‐stratified variability of PAD severity or patient PAD risk factors.

Figure 1.

PRISMA flow diagram for literature searches on patient‐centred outcomes from managing PAD in those with or at risk of developing an ALU or a mixed arteriovenous leg ulcer (MLU). ALU, arterial leg ulcer; MLU, mixed arteriovenous leg ulcer; PAD, peripheral arterial disease [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2.

Number of controlled clinical trials supporting improved patient‐centred outcomes for those treated using the indicated intervention(s) for a PAD‐related condition. Each intervention is followed by the number of studies supporting its beneficial effects on patients with PAD (number of subjects receiving the intervention) [Color figure can be viewed at wileyonlinelibrary.com]

4.1. Study frequencies by PAD severity

Patient‐centred outcome measure patterns differed with PAD severity. Most studies on those with more severe PAD reported amputation reduction, healing, pain reduction, improved walking, or QOL. The latter three outcomes were reported most frequently for patients with less severe PAD. Most studies were randomised clinical trials (RCTs) with non‐blind outcomes' evaluation and fewer than 50 patients treated with the described intervention. Comparing effects across interventions or to standard‐of‐care benchmarks was not feasible due to differences in outcomes measured and variability in baseline patient PAD severity and risk factors.

4.2. Improved walking distance (44 studies on 2109 patients)

PAD‐related IC was defined as ischaemic leg pain, increasing with walking and abating with rest. For those with less severe PAD, 19 studies on 1129 patients receiving structured exercise therapy supervised by a professional (SET),28, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 three studies on 84 patients receiving endovascular revascularisation (ER),33, 50, 51 two studies on neuromuscular electrical stimulation sufficient to activate calf muscles (NMES),52, 53 and one study each on intermittent pneumatic compression (IPC)54 or shock wave therapy55 improved walking for patients compared with control interventions. SET effects increased for those receiving combined ER and SET as reported in one RCT on 62 patients with moderate or less severe PAD.32

For those with severe PAD, significant walking improvements were reported for up to 7 years for those receiving SET (6 studies treating 364 patients46, 48, 56, 57, 58, 59) and/or invasive ER.32, 33, 34, 60 Three studies improved walking outcomes for 48 patients with severe PAD receiving autologous stem cells compared with controls61, 62, 63 High IPC improved peak walking time (P < .04) compared with 20 minutes of daily walking after patients with severe PAD received 16 weeks of treatment, with each intervention increasing peak walking time from 4 weeks onwards.55

Studies of combined therapies were common. A meta‐analysis of seven RCTs reported that a 6‐month course of SET following ER improved walking distance in individuals with PAD as compared to either SET or ER alone.64 Combining SET with NMES of the non‐operated leg gastrocnemius muscle of 25 amputees increased leg muscle activity between SET sessions, improving walking recovery in those with severe PAD after major amputations.65 Patients receiving 8‐hour daily infusions of the vasodilator iloprost alone or with NMES 1 hour in four for 2 weeks increased walking distance, more so when the therapies were combined (P < .03), with a greater increase in tibial artery blood velocity compared with 8‐hour daily infusions of iloprost alone.66

Maximum walking distance and maximum pain‐free (addressed under pain reduction outcomes) walking distance outcomes were the most commonly reported walking outcomes. Up to 12 weeks of three‐times weekly supervised treadmill aerobic exercise increased maximum walking distance after 6 weeks to 6 months of therapy as compared to home‐based walking advice.67 Clinical, patient‐centred, and economic benefits of SET were so consistent68 that in 2017, the United States Centers for Medicare and Medicaid Services issued a decision memorandum to support health insurance coverage for 12 weeks of supervised treadmill exercise for patients with walking impairment due to PAD.69

SET improved walking, haemodynamic, and metabolic outcomes in home or clinical settings using treadmills or other calf‐muscle flexing interventions,58, 70, 71 but not using stretching exercises.49 Structured exercise programmes generated more improvement in PAD‐related walking and QOL than non‐structured exercise or exercise advice alone,23 doubling pain‐free and maximum walking distance for both men and women in 3 months with men experiencing greater gains.59

4.3. Alleviating pain in ischaemic legs and/or leg ulcers (36 studies on 1302 patients with PAD)

Among patients (n = 432) with less severe PAD, treatment with SET reduced pain at rest and during walking compared with those receiving home‐based non‐structured walking or walking advice.35, 36, 41, 43, 44, 45, 72, 73, 74 For similar patients, three RCTs on 63 patients treated with ER,50, 51, 75 two RCTs on 28 patients treated with NMES,52, 53 and one RCT on 15 patients who received shock wave calf‐stimulation55 reported reduced walking pain. For those with severe PAD, ischaemic ulcer pain decreased in response to treatment with stem cells (6 RCTs; 133 patients),61, 62, 63, 76, 77, 78 ER + SET (3 RCTs; 196 patients),33, 48, 79 and one study each on ER80 or SET.56

For the 25% to 35% of individuals with PAD whose pain on walking prevented exercise, electrical spinal cord stimulation using an implanted epidural pulse generator improved ischaemia‐related leg pain and reduced analgesic use for 104 patients with severe PAD,81, 82, 83 while increasing inflammation mainly at the pulse generator implantation site.

Two studies on 81 patients with severe PAD treated with systemic prostanoid therapy84, 85 reduced PAD‐related pain, with notable side effects including headache, nausea, vomiting, diarrhoea, flushing, and hypotension.

Local interventions reducing wound pain included one study each on ibuprofen‐containing wound dressings,86 or a growth factor construct30 or two studies applying topical anaesthetic cream before ulcer debridement.87, 88

4.4. Chronic ischaemic leg ulcer healing (16 studies on 537 patients)

Most ALU or MLU healed in 1 year or less receiving conservative care with adequate protection from injury or pressure, debridement, infection control, and moist wound healing.16, 89 Evidence‐based guidelines90 encourage improved consistency of PAD management and outcomes reporting across specialties and settings, stratifying patient PAD severity and ischaemic leg ulcer risk of experiencing delayed healing.

Most (14 controlled studies on 389 patients) reported healing outcomes for those with severe PAD. Systematic reviews have reported that three RCTs each supported faster or earlier complete healing of ischaemic ulcers on patients with ABI > 0.5 managed with autologous stem cell therapy29 or angiogenic growth factors.30 Two studies each supported improved ulcer healing in patients with severe PAD receiving lower leg IPC56, 91 or spinal cord stimulation.83, 92 Endovascular reconstruction,81 walking therapy,56 hyperbaric oxygen,93 or low‐frequency non‐contact ultrasound94 interventions each supported improved healing of patients with severe PAD with one controlled study. Two studies supported improved healing of 148 patients with less severe PAD treated with systemic prostanoids with increased likelihood of headache, nausea, vomiting, flushing, diarrhoea, or hypotension.95, 96

4.5. Reducing likelihood of limb amputations (24 studies on 1539 patients)

Studies differed in outcomes reported amputation levels, duration of limb salvage, or amputation‐free days. Major limb amputations were defined as at or above the ankle, with minor amputations below the ankle. Durations of limb salvage reported ranged from 6 months to 5 years. Placebo effects cannot be ruled out for these interventions as patients, caregivers, and/or evaluators knew what treatments were applied.

Most studies (23 studies on 1433 patients) supported improved amputation incidence or levels for patients with severe PAD. A meta‐analysis of seven RCTs comparing the efficacy of SET alone to ER, with or without SET, reported lower risk of future revascularisation or amputation for ER with SET as compared to SET alone.97 Another meta‐analysis27 of three RCTs reported reduced amputations for patients with severe PAD treated with ER as compared to bypass surgery.98, 99, 100 In one of the three RCTs,101 patients who received bypass surgery before ER had increased long‐term survival if they survived the first 2 years after the bypass, suggesting that bypass surgery may reduce long‐term mortality, without significantly affecting overall mortality, amputation‐free survival, or health‐related QOL. This hypothesis merits a further study.

Reduced levels or incidence of amputations were also reported in seven studies on 164 patients treated with autologous stem cells63, 77, 101, 102, 103, 104, 105; seven studies on 294 patients receiving spinal cord electrical stimulation81, 82, 83, 106, 107, 108, 109; four studies on 764 patients receiving ER27, 60, 110, 111; two studies on 107 patients treated with systemic prostanoids84, 112; two studies on 80 patients treated with growth factors within a meta‐analysis30; and one study on 24 patients receiving IPC.91

One study reported improved amputation outcomes for 106 individuals with mild‐to‐moderate PAD who received ER with SET.33

Meta‐analyses of controlled and non‐controlled clinical studies27 of very low quality reported similar amputation outcomes for subjects with CLI undergoing surgery as compared to ER. Overall, the 1‐year major amputation rate following bypass surgery was 11%, that is, 89% major limb salvage with an autogenous graft or 84% with a non‐autogenous graft. One 14‐year cohort study of patients with PAD113 reported limb salvage rates of 87% for 5 years following surgical bypass grafting of the distal peroneal artery or other arteries near the malleolus. Preliminary studies reported less extensive amputations compared with initially planned or avoided amputations in 92% of patients at 30 days and 82% of patients at 6 months after ER.110, 111

4.6. Improved QOL (19 studies on 1043 patients with PAD)

Three RCTs on 196 patients with moderate‐to‐severe PAD supported better QOL for those treated with ER with SET compared with ER or SET alone.33, 48, 79 Two RCTs on 174 patients with severe PAD reported better QOL for those treated with ER compared with conventional medical care48 or bypass surgery.98 One study each supported improved QOL in 19 patients with severe PAD treated with spinal cord electrical stimulation83 or 43 patients with moderate‐to‐severe PAD who received stents (ER) compared with conventional medical care.48

For 438 patients with less severe PAD, nine studies supported improved QOL for those receiving SET as compared to various control treatments that did not engage patients in supervised calf muscle exercise.34, 39, 44, 114, 115, 116, 117, 118, 119 One study treating 20 patients with IPC54 improved QOL compared with conventional care, and one study treating 47 patients with ER34 improved QOL compared to SET.

Patients with severe PAD receiving standardised medical care plus a stent (N = 41) or SET (N = 34) reported 18‐month improved QOL compared with those randomised to receive standardised medical care only (N = 18). 48

4.7. Costs of care (1 study on 60 patients with severe PAD) and mortality legs (1 study on 131 patients with severe PAD)

One study each reported significantly reduced costs of care and mortality, only for those with severe PAD. Spinal cord stimulation treatment was associated with reduced care costs compared with usual care,82 and ER reduced mortality more than bypass surgery did.98 Both outcomes were reported to need higher quality evidence.120

5. DISCUSSION

All validated patient‐centred outcomes were addressed in at least one RCT and were significantly improved by at least one intervention. Figure 2 shows that most research addressed outcomes of those with more severe PAD. This suggests a need for earlier screening, diagnosis, and research focusing on patients earlier in the course of PAD progression, where improved QOL and walking function are more likely outcomes.

5.1. Implications for practice

This literature search revealed that the opportunities to combine conservative therapies such as SET, IPC, or NMES reported to improve lower leg arterial perfusion earlier in the course of PAD development, with more invasive ER, surgical, or other interventions. Recent research improved patient‐centred outcomes of conservative medical or exercise therapy33, 48 before or after invasive revascularisation procedures confirming this synergistic potential.

When discussing ER with patients, it should be emphasised that stenting is an invasive therapy involving major surgery with potential bleeding or intimal damage. Clinicians disagree on whether ER is the most beneficial therapy for IC. Many suggest that walking and smoking cessation is a better plan for these patients. Treated medically, patients with PAD can reduce adverse limb events with LDL‐lowering drugs or monoclonal antibodies or patient‐appropriate statins.121

Practice needs to be more harmonised in reporting PAD severity criteria, outcomes, and referral criteria across settings and specialties. PAD delayed healing of more VLUs than previously supposed when ABI < 0.7, the cut‐off point for coronary artery disease was the assumed cut‐off point for PAD‐related healing delay. Recent Task Force recommendations91 reset the PAD cut‐off point to ABI < 0.9. A limitation of this work was that studies reviewed lacked standardised criteria for reporting PAD severity, so ABI levels and Fontaine scores were used to differentiate less severe PAD from more severe PAD. Recent research suggests that toe pressures <30 mmHg or toe/brachial systolic blood pressure ratio <0.25 may predict 36‐month amputation or mortality,122 offering support to inform clinical decisions regarding conservative and/or invasive practice. Many clinicians believe that even with ABI < 0.9 and symptomatic IC, one should not operate on a patient who can walk at least two blocks. Standardised criteria for PAD severity reporting would improve clinical decision‐making and render future literature reviews to be more meaningful and clinically relevant.

Despite PAD patients' robust benefits of SET on walking, QOL, and amputation outcomes, practice lags behind evidence in many settings. Improved reimbursement and inclusion of adequately trained physiotherapists on clinical teams managing patients with PAD could help improve outcomes.123 Complete healing is not an expected outcome for many patients with PAD, so healing endpoints currently required for regulatory clearance in Europe and the United States may be inappropriate for ischaemic leg ulcers.21, 124

Strong evidence supported improved walking capacity, pain, and QOL parameters in patients with PAD managed with either SET or ER, especially so if combined or administered to those with less severe PAD. This pattern was paralleled by studies using NMES and IPC interventions, which may represent opportunities for calf muscle activity stimulation between scheduled SET interventions.

If patients are too frail for surgery or have a high likelihood of complications or vascular deterioration too great to correct, community‐based programmes offering SET and/or IPC or NMES offer accessible, low cost options to improve patient‐centred outcomes, alone, or in combination with ER therapy for avoiding amputation‐related disability and mortality.6, 125

5.2. Opportunities for research

The literature reviewed suggests that improving PAD patients' arterial blood flow below the knee, for example, with SET, IPC, or NMES may potentiate a patient's response to ER. Research is needed to explore synergy of such treatments with other interventions, such as bypass surgery, allograft, autograft, or hyperbaric oxygen, which work better in well‐perfused tissues. Preparatory (or follow‐up) treatment with SET, IPC, or NMES therapy sufficient to improve lower leg circulation, along with appropriate smoking cessation, cardiovascular medications, and nutrition, may improve PAD patients' outcomes from using a wide variety of interventions.

For PAD patients unable to engage in SET programmes due to limited coordination, range of joint motion, or lack of clinic access, these results suggest the merit of research exploring synergistic effects of interventions such as NMES or IPC that may serve as remote exercise surrogates between SET sessions. These are adjunct to, not a substitute for, early PAD diagnosis and referral for supervised exercise or other multidisciplinary interventions to improve ischaemic leg symptoms to stem the tide of ensuing pain, ulceration, amputation, disability, and death.

Patient‐centred outcomes measured differed with PAD severity. Further research is needed to optimise treatment parameters and minimise side effects of autologous stem cells or spinal cord stimulation, which improved ulcer healing, pain, walking, and amputation outcomes for those with severe PAD. More rigorous evaluator‐blind RCTs on patients with PAD are needed to confirm the effects on patient‐centred outcomes of systemic prostanoids, growth factors, hyperbaric oxygen, anaesthetic topical cream, ibuprofen foam dressings, or extracorporeal shock wave therapy. By the time, patients require surgical bypass or invasive revascularisation interventions, amputation, disability, and mortality are expected outcomes.126 Future rigorously controlled, blind evaluated studies stratifying outcome analyses by patient PAD severity are needed to clarify longer term effects on long‐term patient‐centred outcomes including costs, amputation risk, and mortality.100, 127, 128

For those with PAD, SET has improved 3‐ and 6‐month maximum or pain‐free walking distance compared with placebo, usual care, iloprost, or vitamin E, paralleled by a 3‐month increase in ABI mainly for patients with ABI levels >0.5.28 SET, smoking cessation, and antiplatelet therapy are important standard care interventions for those with PAD. All interventions may be more likely to result in significantly improved patient‐centred outcomes before PAD progresses to the point of inoperability or ulcer development.129 Testing this hypothesis requires rigorous attention to walking and smoking cessation components of therapy in RCTs consistently monitoring patient‐centred outcomes risk‐adjusted for ischaemia severity (eg, ABI or toe/brachial index, or pulse volume recordings) or PAD symptoms (eg, IC limits or CLI indicated by rest pain, ulceration, or gangrene).

5.3. Opportunities for education

Growing evidence suggests that PAD is an important circulatory system disorder as prevalent as stroke or coronary heart disease, but is generally underdiagnosed or neglected6, 8, 12 until it becomes critical—too late for effective management. It is a stealthy killer, accompanied by many risk factors that limit the quality of patient‐centred treatment outcomes. These include increasing patient age, nicotine use, hyperlipidaemia, cardiovascular comorbidities, race, gender, and diabetes mellitus.9, 129 Setting a higher priority on earlier, more consistent, PAD screening and diagnosis in community and primary care settings could reverse this trend. If PAD diagnosis had a similar high priority to monitoring hypertension during each physical examination, with appropriate early referral to multidisciplinary limb preservation clinics, PAD's relentless, painful progression to limb loss and death could be prevented for millions of patients.

Health care reimbursement services are recognising the value of early PAD diagnosis and SET treatment sufficient to improve functional walking outcomes and lower leg circulation. Along with early diagnosis and treatment, appropriate reimbursement of SET programmes could save enormous downstream costs of managing patients with an ALU, MLU, or PAD‐related disability, amputation, morbidity, and mortality.

Patients and care providers have been lulled into complacency by clinical findings of ‘early PAD’ in the same way they once were for early hypertension or ‘pre‐diabetes’. It is vital to address PAD early and effectively, recognising that an ischaemic ulcer diagnosis is just as deadly as that of dreaded cancers. Unlike cancer, ischaemic leg ulcers can be prevented with exercise and/or interventions that increase lower leg vascular perfusion.

5.4. Limitations

This appraisal of the literature evaluated the frequency of significantly improved patient‐centred outcomes in research characterised by non‐standardised varying outcome measures. Evidence quality, assessed elsewhere, was often very low due to heterogeneity of data, lack of blinding, and small study sample size.27, 29, 30, 33, 48 The extent of PAD involvement in ulcer development was unclear for MLU, so ulcer healing results stratified to moderate severity in Figure 2 may have included subjects with severe PAD. Also QOL measures often included pain reduction and walking capacity, so these patient‐centred outcomes were not independent.

Readers should interpret these results cautiously as only studies with significant positive effects on patient‐centred outcomes were reported. This approach can identify effective interventions with effects obscured when they were combined with dissimilar interventions or when used on heterogeneous samples in meta‐analyses.29 Most studies were randomised, but many lacked blinded treatment application or outcomes evaluation. The variety of different interventions and criteria for PAD severity in the literature described is the hallmark of a dynamic field actively seeking to improve screening, diagnosis, and outcomes for patients with PAD. As research accumulates, interventions supported by high‐quality evidence will ideally become part of evidence‐based algorithms for PAD management.

6. CONCLUSION

Abundant research showed that multidisciplinary teams improved patient‐centred outcomes for those with PAD, particularly if smoking cessation, nutritional interventions, appropriate medications, structured walking exercise, and calf muscle activity stimulation were administered before PAD became severe or if these interventions were combined with more invasive interventions.

Bolton L. Peripheral arterial disease: Scoping review of patient‐centred outcomes. Int Wound J. 2019;16:1521–1532. 10.1111/iwj.13232