Atherosclerotic peripheral artery disease: the growing challenge to improve life and limb

Introduction

Currently, worldwide, there is an impending epidemic of symptomatic peripheral artery disease (PAD). This is largely due to the increasing prevalence of risk factors such as: smoking, diabetes, high blood pressure (BP), cholesterol, and end-stage renal disease (ESRD). In the developed world this is largely due to an epidemic of diabetes and obesity. There is a wide spectrum of PAD that ranges from asymptomatic disease through to chronic limb-threatening ischaemia (CLTI). Depending upon income and region, the number of sufferers with PAD has increased by 13–25% during the last decade, accounting for 202 million people worldwide in 2010.¹ The majority of those affected are represented by people older than 60 years, of whom 10–20% are thought to be affected by PAD.² PAD is believed to double the risk of cardiovascular morbidity and mortality, even without major limb ischaemia.³

Awareness of PAD is low among patients and the public, despite PAD having five-year mortality rates higher than common cancers and acute myocardial infarction (MI) in both symptomatic and asymptomatic groups (figure 1).^4–6 Despite this clear clinical need, the evidence underpinning treatment in PAD, and CLTI in particular, is poor. Heterogeneity in the literature and poor levels of evidence make any conclusions difficult to generalise to the PAD population. In 2012, the National Institute for Health and Care Excellence (NICE) suggested areas of focus for future research in patients with symptomatic PAD (table 1).⁷ These call for focus on: assessment, patients with PAD and diabetes, infra-geniculate disease and improving patient awareness. Below, we discuss the challenges of improving life and limb, including unmet needs for the whole spectrum of patients with PAD.

Asymptomatic PAD and primary prevention

Screening by measurement of the ankle-brachial pressure index (ABPI) is formally required to assess PAD, with an index of <0.9 being diagnostic. The prevalence of asymptomatic PAD is of interest due to its implications for cardiac and stroke risk.³ Studies have suggested that approximately 35% of women aged over 65 years have ABPI-detected PAD,⁸ compared with 29% in men over the age of 68.⁹

The randomised Aspirin for Asymptomatic Atherosclerosis trial failed to show any benefit of aspirin on reducing future vascular events,¹⁰ despite asymptomatic PAD being associated with functional decline, and a five-fold higher baseline mortality from cardiovascular events than a non-PAD population.¹¹ A recent systematic review into the effectiveness of screening using ABPI and its effect on outcome, proved inconclusive.¹² Fowkes et al. estimated the odds ratios for all-cause mortality in individuals with asymptomatic and symptomatic PAD (1.53 and 1.98, respectively) compared with matched, disease-free individuals in a pooled analysis of known population studies to date.¹³ This was supported by long-term findings from Sartipy et al., who demonstrated all-cause, 10-year mortality of 56% for patients with asymptomatic PAD (APAD) and a doubling of the age-adjusted hazard ratio for cardiovascular death.¹⁴ At present, the European Society of Cardiology (ESC) recommends screening for APAD only in patients with previously diagnosed heart failure or coronary artery disease, based on level IIb evidence.¹⁵

Due to a lack of evidence, it is difficult to estimate the proportion of patients with APAD that go on to develop symptoms; a meta-analysis estimated that those developing intermittent claudication having been previously diagnosed with APAD is somewhere between 4–11%.⁶ Without a large, worldwide public health effort, it is unlikely that the true incidence of APAD can be identified, as current data are available only from selected interventional studies. The outcomes from treating APAD with best medical therapy (BMT; antiplatelet and statin) or otherwise are largely unknown.

Best medical therapy – secondary prevention

In patients diagnosed with symptomatic PAD, a regime of BMT is recommended in national guidelines worldwide. This constitutes lifestyle modification and control of known risk factors. In the UK, NICE recommend an antiplatelet agent (clopidogrel 75 mg once daily) and lipid-lowering therapy (high-dose statin such as 80 mg atorvastatin daily as first line), as widely used in patients with coronary artery disease. Research into the use of direct oral anticoagulants (DOACs), dual antiplatelet agents and combinations of the two continue, with the ultimate goal of a tailor-made, individual approach to addressing individual risk factors. Ongoing genomic testing is investigating targeted alleles expressed in some patients who cannot metabolise antiplatelet therapies. This may have screening implications in the future. There are wider issues around compliance, adherence and patient and public education; even in large, prospective clinical trials the uptake of BMT is poor at around 70%.

Direct oral anticoagulants

The recent publication of the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial has raised hope that adjunctive, low-dose rivaroxaban (2.5 mg twice daily) with aspirin will improve long-term cardiovascular outcomes, particularly in patients with PAD¹⁶ (the COMPASS trial outcomes and results are discussed in detail elsewhere in this supplement).

Antiplatelet therapy

Encouraging results from the PLATO (Platelet Inhibition and Patient Outcomes) study demonstrated a reduction in secondary cardiac events when ticagrelor was given with aspirin (as opposed to clopidogrel and aspirin) in patients with acute coronary syndrome.¹⁷ There were no reductions in cardiovascular morbidity in patients with symptomatic PAD, however, when ticagrelor was given as a monotherapy, compared with clopidogrel alone.¹⁸ Some evidence from the American Vascular Quality Initiative suggests a survival benefit in those patients undergoing lower limb revascularisation when using dual antiplatelet therapy, particularly in high-risk patients.¹⁹ More evidence is required to define the dosage and combination of therapies of most benefit.

Lipid modification

The evidence underpinning the use of statins and other lipid-lowering therapies is primarily extrapolated from the coronary literature. Most guidelines in the US, UK and rest of Europe recommend the use of high-intensity statin treatment to reduce secondary cardiovascular events. There is limited evidence in the literature pertaining to the use of lipid-lowering therapy and its specific benefits for patients with PAD. One recent study reported that patients with CLTI, the most severe form of PAD, had reduced mortality and improved freedom from major adverse limb events when lipid therapy guidelines were followed in patients undergoing revascularisation.²⁰

Intermittent claudication

Adverse prognosis

Intermittent claudication, a clinical syndrome of exertional pain in the muscles of the lower limbs that terminates with rest, is the commonest manifestation of symptomatic PAD. The long-term risks of cardiovascular mortality in patients with intermittent claudication are well documented, and 20% of individuals will have a cardiovascular event in a 10-year period.^11,21,22 Symptomatic PAD, in general, is a stronger predictor of mortality than CAD or cerebrovascular disease alone.^23–25 Although intermittent claudication is generally considered as a ‘benign’ condition, one patient in five will progress to CLTI in a five-year period,⁶ and those with diabetes and persistent smokers are most at risk. The lifetime amputation risk for all patients with claudication is thought to be around 1%. Despite these clear risks, uptake and delivery of recommended, evidence-based treatment strategies remain problematic.

In the UK, intervention in patients with intermittent claudication is discouraged by NICE unless a patient is thought by local multidisciplinary teams to be symptomatic enough that health-related quality of life (HRQoL) is significantly impacted.⁷ They must also have made a concerted effort to control any identified risk factors such as smoking and attended a 12-week programme of supervised exercise therapy (if available, see below). Intervention for intermittent claudication is on the increase in other parts of the developed world, particularly as most countries are now practising an endovascular first revascularisation strategy.

Supervised exercise therapy

The aforementioned NICE guidance (Clinical Guideline 147) stipulates that all patients should have any risk factors for PAD addressed as part of secondary prevention (smoking, obesity, hypertension, dyslipidaemia, diabetes) and also be enrolled in a programme of supervised exercise therapy (SET).⁷ Despite good quality evidence that SET is beneficial²⁶ and cost effective at current willingness to pay thresholds in the UK,²⁷ provision and uptake is low. This may be due to a variety of issues, including lack of funding from healthcare providers, poor patient compliance and an upturning worldwide trend towards increasing use of endovascular treatment, such as angioplasty, drug-eluting technology, atherectomy and stenting.²⁸

The benefits of SET on overall health, even in those undergoing intervention, are clear; a recent systematic review and meta-analyses of seven randomised trials reported improved outcomes in terms of reduced numbers of amputation, increased walking distance and ABPI in patients receiving adjunctive SET with endovascular treatment versus those receiving endovascular treatment alone.²⁹ Despite high quality evidence, only around 30–40% of vascular centres in the UK currently offer SET.³⁰ Regardless of intervention, a regime that improves overall health and treats risk factors to reduce secondary events seems logical and the evidence to support this approach is growing.³¹

Drug-eluting endovascular technology

Many industry-funded studies have assessed anatomically-based outcomes of patients with intermittent claudication receiving drug-eluting endovascular technology with paclitaxel coated balloons and stents in small, selected groups of claudicants with primarily femoropopliteal disease initially demonstrating promising results.^32-35 However, the recent meta-analysis by Katsanos et al.³⁶ has resulted in considerable controversy, demonstrating an increase in mid-term mortality for patients undergoing drug-eluting endovascular treatment when compared with those undergoing plain balloon angioplasty. The impact of this on clinical practice and translation to patients with chronic limb-threatening ischaemia is currently a topic of debate.

Chronic limb-threatening ischaemia

CLTI represents the most severe form of PAD and also carries by far the worst outcomes. The average five-year survival is known to be around 50%. By definition, patients usually present with challenging, multilevel disease that is often above and below the inguinal ligament. Tibial involvement is increasingly common. Despite this, there is still, to date, only one randomised controlled trial comparing revascularisation outcomes in people with CLTI.

The BASIL (Bypass vs. Angioplasty in Severe Ischaemia of the Leg) trial demonstrated that those with a predicted survival of two years or greater fared better in terms of amputation-free survival with open surgical bypass, rather than best endovascular treatment.³⁷ About 75% of patients in BASIL had primarily femoro-popliteal disease. A recent post-hoc, subgroup analysis from the trial of patients with primarily infra-popliteal disease demonstrated a reduction in rest pain but similar clinical outcomes in other domains, when comparing the same two revascularisation options. The trial, however, was not powered to demonstrate significant differences in this subgroup.³⁸

The longstanding debate regarding which revascularisation modality should be used as a first treatment strategy remains – ‘endo-enthusiasts’ claim that if the BASIL trial were to be repeated using modern endovascular technology, the outcomes may be different. Ongoing trials in the US and UK aim to resolve this debate.^39–41 A recent, large meta-analysis of around 8,000 patients undergoing infra-inguinal revascularisation demonstrated higher patency rates for patients undergoing vein bypass. The authors commented, however, that a severe lack of high-quality data and heterogeneity made any comparisons difficult.⁴² There have been recent attempts to improve reporting, assessment and classification of CLTI, and recently, the Global Vascular Guidelines have been published which focus on a new ‘Global Limb Anatomical Staging System’ (GLASS) that aims to improve reporting standards in future trials as well as predicting endovascular treatment failure in patients with CLTI.^43–44

The future

The lack of patient and public awareness, high quality randomised data and disparity in treatment algorithms worldwide is concerning, given that PAD is common and has relatively poor outcomes. A significant effort is required on a worldwide scale from clinicians, researchers, health care providers and public health to address these highlighted shortcomings. In particular, more work is needed to clarify the role of therapies in APAD to prevent deterioration, defining best medical treatment for those with symptomatic disease and revascularisation options for those with end-stage PAD, with the hope of improving long-term outcomes both in terms of limb and life.

Key messages

• There is an impending global epidemic in peripheral artery disease (PAD) due to increasing levels of diabetes, hypertension, smoking and end-stage renal disease
• Such patients have poorer health outcomes than aged-matched populations with other cardiovascular disease
• There is a lack of robust evidence to guide treatment in all forms of PAD that urgently needs addressing
• A global, public health effort is required to boost patient and public awareness and improve health outcomes in patients with PAD

Conflicts of interest

AG has received honoraria from Bayer. MAP, RB and OF: none declared.

Matthew A Popplewell
Academic Clinical Lecturer in Vascular Surgery

Email: ([email protected])

Ruth A Benson
Academic Clinical Lecturer in Vascular Surgery

Institute of Translational Medicine,
University of Birmingham, Edgbaston, Birmingham, B15 2TH

Owain Fisher
ST5 in Vascular Surgery
University Hospital of Coventry and Warwick, Clifford Bridge Road, Coventry, CV2 2DX

Andrew Garnham
Consultant Surgeon
Black Country Vascular Service, New Cross Hospital, Wolverhampton, WV10 0QP

Articles in this supplement

Introduction
Atherosclerotic peripheral artery disease: the growing challenge to improve life and limb
Peripheral artery disease: current diagnosis and management
Combining rivaroxaban with aspirin in stable atherosclerotic vascular disease: clinical evidence from the COMPASS study

Once you have read all these articles, you can take the ‘Learning with reflection’ CPD activity on this supplement.

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