What does the future hold for the patient with peripheral arterial disease?
Department of Vascular Surgery, KAS Gentofte University of Copenhagen, N. Andersensuej, 2900 Hellerup, Denmark
* Correspondence: Dr. H. Sillesen, Department of Vascular Surgery, KAS Gentofte University of Copenhagen, N. Andersensuej, 2900 Hellerup, Denmark. Tel. +45-39-77-3402; fax: +45-39-77-7614
hens{at}gentoftehosp.kbhamt.dk
Abstract
Individuals with peripheral arterial disease (PAD) have a significantly elevated risk of developing major cardiovascular complications, but, until recently, the atherosclerotic manifestation of PAD has largely been regarded as a local problem of limited blood supply in the lower limbs, and treatment has reflected this. The association between PAD and cardiovascular mortality suggests that treatment strategies should, however, take into account the systemic nature of atherosclerosis and focus on the management of recognized atherosclerotic risk factors. This is reflected in national and international treatment guidelines, which recommend that patients with PAD should be targeted for aggressive atherosclerotic risk factor therapy. Although interventional and medical therapies are available, and are continuing to be developed, PAD patients are currently being undertreated, and there is, therefore, a need for unbiased and comprehensive reporting of treatment results and quality assurance, so that awareness is raised and the management of PAD is improved.
Key Words: Cardiovascular risk factor management • Intermittent claudication • Interventional therapy • Lipid-lowering therapy • Peripheral arterial disease
Introduction
Peripheral arterial disease (PAD), a disorder characterized by obstruction of arteries supplying the lower limbs, is an important manifestation of atherosclerosis, with a prevalence ranging from 3% for people under the age of 60, to 20% at age 75 and over.1 There is a higher incidence in men than in women up to the age of 70, after which the prevalence rates equalize.2 The most common symptom of PAD is intermittent claudication (IC), painful cramping in the leg or hip, particularly when walking, which eases when the muscles are rested.
Depending on the severity of symptoms (if any), mortality rates among patients with PAD have been shown to be 2–4 times greater than that of a sex- and age-matched control group without any atherosclerotic manifestations (Fig. 1).3 This increased mortality may be attributed to the strong correlation between PAD and coronary heart disease (CHD), an association that is evident even in individuals without a history of CHD and without symptoms of claudication. Indeed, mortality rates among patients with PAD and patients with CHD are similar.4,5
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Until recently, atherosclerotic manifestations in the lower limbs have been regarded as a local problem of limited blood supply. Thus, treatment has been directed towards improving blood supply, or towards lifestyle changes, such as smoking cessation and initiation of exercise programmes. In a few patients, these measures are supplemented with medicines that are intended to relieve symptoms – some proving more effective than others. However, the association between PAD and cardiovascular mortality suggests that treatment strategies should take into account the systemic nature of atherosclerosis and focus on the management of recognized atherosclerotic risk factors.
This paper will focus on the treatment possibilities that are available today for the patient with PAD; whether the available treatment strategies are being adequately implemented and monitored; and how the quality of treatment for the patient with PAD can be improved in the future.
Treatment options for PAD
Interventional techniques
Improving blood supply to the lower limbs may involve vascular surgical treatment by endarterectomy and/or bypass surgery, or interventional treatment with percutaneous transluminal angioplasty (PTA), which today accounts for approximately 30% of re-vascularization procedures.
In contrast to coronary arteries, the vessels that are affected in PAD tend to be bent in some situations and straight in others. For example, the popliteal artery in the knee has to be able to bend more than 90°. Consequently, in order to treat a lesion that is located in such a vessel using endovascular techniques, one must use a stent that is also flexible. New, spiral-formed stents have the necessary ability to bend, and have the additional benefit of allowing side vessels to be kept open.
Other interventional techniques that have recently been developed include the abdominal aortic aneurysm (AAA) stent graft, which is introduced via the femoral artery and opened up inside the body, thereby excluding the aneurysm sac, reducing the pressure, and preventing rupture of the aneurysm. The main limitation of such a technique is the durability of the stent material, since a patient receiving an operation for an aneurysm may survive for 10 years or more.
The use of radiological techniques to visualize the vascular system, such as X-rays, ultrasound and magnetic resonance, has also greatly facilitated the practice of interventional therapies, and their use is likely to increase as methodologies become more refined.
The success of an interventional therapy is often expressed in terms of its patency, but this takes no account of the patient's experience of the procedure and their pre- and post-operative quality of life. This was illustrated in a prospective, randomized trial in which PTA was compared with exercise training for the treatment of stable claudication.6 Fifty-six patients were randomized to one of the two treatments, and assessed for ankle/brachial pressure index (ABPI), treadmill claudication and maximum walking distance at 3-monthly intervals for 15 months, and at approximately 6 years follow-up (37 patients were available for long-term review). Although significant increases in ABPI were seen in the patients treated with PTA at all assessments up to 15 months, the most significant changes in claudication and maximum walking distance were seen in the exercise training group (Fig. 2). At long-term follow-up, there was no significant difference between the groups.6
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New interventional techniques, mostly endovascular based, will continue to be developed and used in addition to adjunctive procedures and medications. However, the long-term effects of interventional treatment, such as balloon angioplasty and surgery, should be evaluated not only technically but also in terms of improvement in the patient's symptoms (walking ability or quality of life). It is also important to remember that although interventional treatment may relieve the symptoms caused by atherosclerotic obstructive disease, it cannot cure the disease itself.
Drug therapies
Statins, angiotensin-converting enzyme (ACE) inhibitors and antiplatelet drugs have all been shown to reduce the risk of coronary events in patients with CHD.7–11 Due to the strong and independent association between PAD and cardiovascular mortality, guidelines of various national and international bodies recommend that patients with PAD should be targeted for aggressive atherosclerotic risk factor therapy.12,13
Although data for the effects of lipid lowering in PAD patients are limited, what evidence there is from previous studies is encouraging. In the Cholesterol Lowering Atherosclerosis Study (CLAS), angiographic assessment demonstrated that patients treated with colestipol and niacin experienced more atherosclerotic regression and less atherosclerotic progression in the femoral arteries than those receiving placebo.14 Other studies have shown cholesterol lowering to be associated with a reduction in risk of IC.15,16 Retrospective analysis of data from the Scandinavian Simvastatin Survival Study (4S) supports these findings: in the subgroup of patients with PAD, over the median follow-up period of 5.4 years, the risk of new or worsening IC was reduced by 38% in the simvastatin group compared with the placebo group.17
In the MRC/BRF Heart Protection Study, results of which have recently been published, more than 20,000 UK adults with CHD, or other occlusive arterial disease, were randomized to receive either simvastatin 40 mg/day or placebo over a 5-year treatment period.18 All-cause mortality was significantly (
) reduced in patients who received simvastatin (n=10,269). Subgroup analysis showed that statin treatment benefited patients with PAD who had no prior CHD (n=1325) to a similar extent as it did the overall population (Fig. 3).18
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The ongoing TREatment of peripheral Arterial Disease with Moderate or Intensive Lipid Lowering (TREADMILL) study has been designed to prospectively assess whether statin therapy, compared with placebo, has a beneficial effect on walking distance in patients with PAD, and whether aggressive cholesterol lowering can provide additional clinical benefits. It is also intended that the study should raise awareness for claudication as a marker of more generalized atherosclerotic disease, and for the necessity to look more broadly at a patient's overall vascular risk and act accordingly. A total of 364 patients with chronic to severe IC, from 25 sites in North America, have been randomized to receive either atorvastatin 10 mg/day, atorvastatin 80 mg/day or placebo. The study reported a significant improvement in pain-free walking after 12 months of treatment, although the primary efficacy parameter, maximal walking time, did not improve significantly.24
The most recent drug to have been introduced as a treatment for IC is cilostazol, a phosphodiesterase inhibitor with antiplatelet and vasodilator effects. Although the drug's exact mechanism of action is unknown, four randomized trials, involving over 1500 patients in total, have shown positive results, with an average increase in mean walking distance of approximately 50%.19 Cilostazol therapy is associated with a higher incidence of headache than placebo, and although the Federal Drug Administration approved its use for the treatment of claudication in 1999, it is not available in parts of Europe. It is also salient to remember that exercise therapy alone will more than double the walking distance in patients with IC.
Although the use of ACE inhibitors for the treatment of PAD has not been prospectively evaluated, the Heart Outcomes Prevention Evaluation (HOPE) study showed that ramipril had the greatest effect in reducing cardiovascular events in those patients with reduced ABPI.20
Quality assurance
The problem of publication bias can lead to a misleading representation of the quality of treatment strategies, since `poor' results are not published as readily as `good' results. A clearer picture is obtained by using clinical databases. In Sweden, for example, 90% of data relating to vascular treatments is entered into a national clinical database and, for the past 5 years in Denmark, all such data have been registered in this way. The variables that are entered into these databases include information on patient demographics, risk factors, status, previous interventional treatment, complications and follow-up. Clinical databases provide an effective means of quality control at the local and national level.
The management of PAD
The problem of undertreatment
Since the practising of evidence-based medicine is deemed increasingly important, there is concern that current knowledge on the prevention of cardiovascular events may only benefit a minority of PAD patients. This notion is supported by the observed low level of CHD preventive measures adopted by physicians treating their PAD patients. In a retrospective review of all patients operated on for critical lower extremity ischaemia in 1998, Bismuth et al.21 showed that only 5% of patients were treated with lipid-lowering therapy, and only 39% were using acetylsalicylic acid. The mortality of these patients over 2 years was 35%, compared with only 10% in the sex- and age-matched control group (Fig. 4).21 In a similar study, designed to assess the implementation of secondary prevention guidelines for CHD in patients undergoing peripheral re-vascularization surgery, Nass et al.22 demonstrated that patients with lower extremity disease were significantly less likely than patients with carotid disease to be on aspirin (45% versus 62%; 
), a lipid-lowering agent (30% versus 45%; ), or a ß-blocker (26% versus 39%; ).
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In the primary care setting, the PAD Awareness, Risk, and Treatment: NEw Resources for Survival (PARTNERS) programme found that patients with PAD, compared with patients with CHD, were receiving significantly less lipid-lowering therapy (50% versus 73%;
), antihypertensive therapy (86% versus 95%; ), and antiplatelet agents (44% versus 71%; ).23 It is therefore clear that patients with PAD are not being treated adequately. Since multiple studies have confirmed that PAD patients are at high risk of cardiovascular events, it is surprising that the level of implementation of CHD prevention strategies in this patient population remains low. Perhaps it is because, in most countries, symptoms of PAD are dealt with by vascular surgeons who are not educated in risk-factor modification; or because specialists within internal medicine are less interested in patients with PAD. Regardless of the reasons for undertreatment, responsibility for the management of PAD must be better defined.
Despite the problem of undertreatment, the ankle-brachial index (ABI) is a strong predictor of CHD morbidity and mortality in PAD patients, and should be included in general health examinations – at the very least to provide at-risk individuals with the impetus to adopt lifestyle changes (e.g. smoking cessation, initiation of an exercise regime and dietary modification).
The `one-stop clinic'
The patient with PAD has many requirements in order for their condition to be effectively managed: dietary advice; advice on smoking cessation; supervised exercise from a physiotherapist; treatment/monitoring by an endocrinologist; treatment/monitoring by a cardiologist; clinical physiological examination; radiological examination (X-ray, ultrasound, magnetic resonance). To overcome the logistical complexity of effective management, the concept of a `one-stop clinic' was developed, firstly in the UK, and has now been taken up by other countries. The idea is that the activities listed above are centralized around the patient. The patient is seen by a consultant and a treatment plan is drawn up for them, based on the clinical investigations, laboratory tests and physiological measurements that are carried out the same day. The patient also sees a vascular nurse, who gives advice on exercise, diet and smoking cessation. Since most PAD patients should be managed medically (at least to begin with), the patient is prescribed platelet inhibitors and statins, according to guidelines. The patient returns to the clinic for follow-up after 1, 3, 6 and 12 months and, at each visit, is given a report to take home, outlining his/her medications and diet, which also includes a record of weight, blood pressure, lipid parameters, ABPI, walking ability, etc., so the patient can monitor how they are progressing. Interventional treatment should only be considered if medical treatment fails, or if the patient is at risk of losing a limb, and should always be carried out in conjunction with medical treatment.
Conclusion
It is likely that, in addition to reducing cardiovascular events and increasing survival rates in PAD patients, medical therapy for CHD prevention will be found to improve the results of peripheral arterial interventions such as PTA and surgery. New interventional technologies will become available, and it is likely that new drug therapies will also be developed. However, greater effort should be made to improve the reporting of treatment results and the quality assurance of treatment, in order that the overall service that is provided to the patient with PAD is as good and as comprehensive as possible. Of greatest importance is that effective treatment is provided for the PAD patient as a whole, and not just for their lower limb symptoms.
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