Trial of Nonsurgical Treatment of Intermittent Claudication Due to Femoro-popliteal Disease

Study Overview
=================
Brief Summary
-----------------
Intermittent Claudication (IC)is a common condition characterised by pain in the muscles of the legs on exertion caused by hardening of the arteries and a reduced blood supply. The investigators know that the vast majority of people suffering from this condition remain stable and do not deteriorate, and thus in general the viability of legs is not at risk. The main aim of treatment, therefore, is to try and improve walking thus reducing the impact this problem has on patients life style. There are many methods of management of intermittent claudication, but the investigators do not know which produces the best results. This study aims to compare the short and medium term outcomes of exercise programmes, percutaneous transluminal angioplasty and a combination of the two treatments for patients with intermittent claudication.

Detailed Description
-----------------
Intermittent claudication (IC) is a common problem in the UK's elderly population with a prevalence of 5 -10%. Intermittent claudication infers significant quality of life limitations, however, it is a disease which generally runs a benign course with >80% of patients remaining stable. Yet the annual mortality rate in claudicants approaches 5%, three times that of age and sex matched population, due to the high prevalence of co-morbidity. IC is under-recognised as a risk factor for coronary and cerebrovascular events. Sixty percent of claudicants die from coronary heart disease and 10% of them die from stroke. Treating the patient with claudication, therefore, is likely to pay high dividends in terms of reducing deaths from myocardial infarction and stroke. The most appropriate management of IC, therefore remains a topic for debate but potentially beneficial therapies include: supervised exercise programmes (SEP); & percutaneous transluminal angioplasty (PTA). A recent Cochrane review of PTA versus non-surgical management for intermittent claudication highlighted only two appropriate studies. More recently the results of a randomized control trial from Sweden have been published. This emphasizes the dearth of reliable scientific data in this area. It is believed that aorta-iliac atherosclerosis is often a solitary disease as opposed to femoro-popliteal disease which is often a manifestation of more generalized atherosclerosis. Further, the 5-year PTA patency rates for aorta-iliac disease are much better than those for femoro-popliteal PTA. Therefore, PTA is a well-established treatment modality for aorta-iliac disease but its role in femoro-popliteal disease is debatable11. This trial aims to prove the most effective treatment modality for claudication due to femoro-popliteal disease. The two treatment modalities in question work by different mechanisms. PTA increases the blood flow to the limb. Whereas, exercise works by a combination of factors including optimized structural and metabolic performance of skeletal muscle, improvement in rheological parameters, development of collaterals, improved walking technique and marked psychological benefit. Still the efficacy of any treatment modality in claudication is judged by improvements in the standard measures of lower limb ischaemia as suggested by the International Society of Cardiovascular Surgery (ISCVS). These are essentially segmental pressure measurements and walking distances. The primary aim of any treatment for patients with peripheral vascular disease is to improve the quality of life (QoL) rather than prolong survival. Several studies have shown that the traditional measures of lower limb ischaemia bear little correlation to the patient's QoL and these therefore need to be assessed independently. Further, generic QoL measures on their own are not sensitive enough to detect minor changes in QoL and so disease-specific measures need to be included in the outcomes. Evidence is accumulating that each episode of exercise to the onset of claudication pain followed by rest may be considered as a low-grade ischaemia-reperfusion injury (IRI). Repeated episodes of IRI may have a cumulative effect leading to vascular endothelial damage and progression of atherosclerosis. This may explain the excess cardiovascular mortality seen in these patients16. Most experimental work measuring the biochemical markers of IRI is done following an episode of acute exercise. Few studies have shown the effect of an exercise -training programme on the biochemical markers of IRI. We intend to investigate this as a secondary component to the trial. Heat shock proteins (hsp) are ubiquitous proteins found in the cells of all organisms. They are mainly classified according to their molecular weight. In addition to being constitutively expressed heat shock proteins can be induced by a number of stressors including heat, ischaemia and oxidative stress. Members of the hsp70 family are the most extensively studied group of stress proteins and they have been implicated in the prevention of ischaemia-reperfusion induced apoptosis, necrosis and oxidative injury in a variety of cell types including the cardiac myocyte18. Studies have shown hsp and their antibodies in the serum of normal individuals. Anti-hsp70 antibody levels in serum have been shown to be higher in vascular patients (IC, critical ischaemia and aortic aneurysms). Heat shock proteins have been detected in atherosclerotic lesions in higher concentrations. It is postulated that hsp play a key role in the autoimmune pathogenesis of atherosclerosis. Levels of anti-hsp antibodies are elevated in patients with carotid and coronary atherosclerosis and this correlates with the degree of atherosclerosis. Measuring anti-hsp antibodies in patients with IC undergoing exercise over a period of time may provide further valuable evidence on the role of heat shock proteins in atherosclerosis. The secondary outcome measures of cost effectiveness analysis will interest health planners and clinicians as the health service has limited resources and 'value for money' has become increasingly important.

Official Title
-----------------
Randomised Controlled Trial of Percutaneous Transluminal Angioplasty (PTA) Versus a Supervised Exercise Programme (SEP) in the Management of Intermittent Claudication (IC) Due to Femoro-popliteal Disease

Conditions
-----------------
Femoropopliteal Disease, Intermittent Claudication

Intervention / Treatment
-----------------
* Procedure: Percutaneous Transluminal Angioplasty (PTA)
* Procedure: Supervised Exercise Programme (SEP)
* Procedure: Combined Treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Symptomatic unilateral Intermittent Claudication Femoro-popliteal lesion Angioplastiable lesion on duplex > 3 months on BMT Exclusion Criteria: Critical ischaemia Incapacitating systemic disease Inability to tolerate treadmill testing Ischaemic changes on ECG during treadmill testing Ipsilateral surgery / PTA in previous 6 months
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PTA<br> | Procedure: Percutaneous Transluminal Angioplasty (PTA)<br>* PTA will be performed by a consultant interventional radiologist with no deviation from the standard protocol at Hull & East Yorshire Yospitals NHS Trust.<br>|
| Active Comparator: SEP<br> | Procedure: Supervised Exercise Programme (SEP)<br>* SEP: Conducted 3 times per week for 12 weeks.The session will be supervised by a physiotherapist and conducted in the cardiac gym. Each session begins with gentle warming up exercises followed by an exercise circuit of 6 stations(2 minutes each). Station 1-Step-ups(20-cm high step,alternating leg after 10 step-ups) Station 2-Exercise bicycles Station 3-Knee extensions with weights(2kg beanbag) Station 4-Heel raises Station 5-Knee bends(Alternating legs after 10 bends) Station 6-Rest station(2Kg Biceps curls) Gentle walk for 2minutes in between the stations to recover.For first 6weeks patients complete one full circuit, followed by on extra station/week, thus by 12weeks patients will complete 2 full circuits.Finally patients perform a series of gentle stretching and cooling down exercises. This exercise programme was designed to comply with suggested guidelines based on a meta-analysis assessing the effectiveness of SEP for claudicants.<br>|
| Active Comparator: PTA+SEP<br> | Procedure: Combined Treatment<br>* PTA will be performed according to routine protocol followed by enrollment of patient in SEP. SEP will commence in the week following PTA.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treadmill walking distances - Intermittent claudication distance(ICD),maximum walking distance(MWD) |  | Pretreatment, 1, 3, 6, 12, 36, & 60 months post treatment | 
| Ankle brachial pressure indices(ABPI) measured at rest and post exercise |  | Pretreatment, 1, 3, 6, 12, 36, & 60 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Reported Walking Distances (PRWD) |  | Pre-treatment, 1, 3, 6, 12, 36, & 60 months post treatment | 
| Clinical outcomes(PTA patency,re-intervention rates, fatal&non-fatal events,amputation,mortality and ISCVS outcome) |  | Pre-treatment, 1, 3, 6, 12, 36, & 60 months post treatment | 
| Health economic analyses |  | Pre-treatment, 1, 3, 6, 12, 36, & 60 months post treatment | 
| Markers of ischaemia reperfusion |  | Pre-treatment, 1, 3, 6, 12, 36, & 60 months post treatment | 
| Heat-shock proteins |  | Pre-treatment, 1, 3, 6, 12, 36, & 60 months post treatment. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Claudication, Vascular claudication, Peripheral Vascular Disease, Peripheral arterial disease, Peripheral arterial occlusive disease, Angioplasty, Femoral angioplasty, Superficial femoral artery, Femoral arterial disease, Exercise, Supervised exercise, Exercise therapy, Exercise programme, Infrainuginal, Quality of life, SF36, Questionnaire, VascuQol, Randomised, Randomised trial, Combination therapy, Intermittent Claudication due to Femoropopliteal Disease