(M)ultifactorial (I)ntervention in Patients with (P)eripheral (A)rterial (D)isease - A Randomised Controlled Trial

INTERVENTION: The aim of this study is to investigate the effects of a multifactorial intervention compared with standard treatment in patients with peripheral arterial disease. Patients with peripheral arterial disease are also at risk of coronary artery disease and cerebrovascular disease. Studies have shown that patients with peripheral arterial disease have suboptimal control of many cardiovascular risk factors. This study is a prospective, local multi‐centre randomised controlled trial. A total of 150 participants will be randomised in a 1:1 ratio to an intervention arm (group A) and a control arm (group B). The total followup is 12 months. Group A (Intervention arm) Group A will undergo a multifactorial intervention with comprehensive lifestyle and medical program designed to manage cardiovascular risk factors. Intervention in group A is intended to complement standard practice. Multifactorial intervention will occur in the medical clinic setting and can include: Frequent review in a medical clinic Review of blood pressure, cholesterol and diabetes with introduction of medications to treat these conditions Smoking cessation program Structured exercise program Weight loss program Obstructive sleep apnoea screening and treatment Procedure Specifics: Medical history and medication review Review by medical physician. Details include: symptoms, past medical history, social history, medication history, and drug allergies and intolerances. If any clinically significant adverse event occurs, in the judgement of the investigator, it will be reported on the adverse event form. It is intended that group A participants are seen mainly by a single medical physician during the study period, to provide continuity of care. Blood pressure management Blood pressure will be measured during clinic review or using a home‐based automated monitor. Group A participants with home‐based monitoring will record values in a journal. Hypertension will be treated with target resting BP less than 130/80 mmHg at least 80% of the time. Participants with hypertension will be monitored with echocardiography to assess for left ventricular hypertrophy progression/ regression. An echocardiogram will be performed at baseline and upon study completion. Lifestyle modification for treatment of hypertension will include dietary salt restriction and/or weight loss program. Pharmacotherapy will be initiated in a stepwise fashion with a preference for angiotensin‐converting enzyme inhibitors or angiotensin 2 receptor antagonists as first line treatment of choice. Lipid Management Serum lipid testing will be performed throughout the study. All participants will be commenced on statin medication, where tolerated. Lipid targets include: LDL less than 1.8 mmol/L and Non‐HDL cholesterol less than 2.6 mmol/L. Treatment of dyslipidaemia will include dietary guidance and escalation of statin therapy to maximum tolerated dose. Additional therapy such as ezetimibe or fibrates may be introduced, where targets are not being met. Weight Management Exercise Therapy CONDITION: Peripheral arterial disease PRIMARY OUTCOME: The maximum walking distance (MWD) at 12‐months, as defined as the distance the patient can walk on a treadmill (fixed at 2.4km/hour with a 6‐degree incline; up to 15 mins) before they have to stop due to any reason. ; SECONDARY OUTCOME: Berlin Questionnaire score snoring and sleep quality ; Blood pressure measured using sphygmomanometer. ; (1) Use of angiotensin‐converting enzyme inhibitor or angiotensin 2 receptor antagonist. Participant is taking medication, ascertained from history. ; ; (2) Use of statin. ; Participant is taking medication, ascertained from history. Where a group A participant has a BMI greater than or equal to 27kg/m2, they will be offered a weight management program. The goal will be for a BMI less than 27kg/m2 or at least 10% weight loss. The weight management program will emulate methodology executed in a previous cardiovascular risk factor modification study. Participants will have a structured motivational and goal‐directed program with physician‐led counselling. Meal plans will consist of a calorie‐restricted diet with foods high in protein and a low glycaemic index. In addition, participants will commence a structured exercise program as described below. These participants will be encouraged to maintain a lifestyle journal with documentation of a nutritional intake and physical activities during the week. Weight management will be a priority throughout the duration of the study. Investigators will provide regular feedback and advice to participants via clinic follow‐up and/or email contact. Frequency of contact at discretion of the treating physician. Group A participants will be offered an optional structured exercise program that is developed in consultation with an exercise physiologist. This plan is personalised and will consider the motivation and physical limitations of the individual. The program will begin with directly‐supervised exercise therapy, and then a structured home‐based exercise program thereafter. For example: An initial supervised exercise program occurs in an outpatient facility. Subsequently, the participant is counselled and given instructions for home‐based exercise therapy, such as walking, cycling and/or lower limb training. The participant is encouraged to exercise until moderate‐maximum claudication, alternating with periods of rest. The goal is to gradually increase the duration and/or intensity of prescribed activities. The participant logs an activity diary and keeps in regular contact ; The outcome will be continuous (specific blood pressure measure) and dichotomous (target met: yes/no). Target systolic blood pressure less than 130mmHg and diastolic blood pressure less than 80 mmHg. ; ; (3) Smoking abstinence for previous 3 months ; Participant has abstained from smoking, as ascertained from medical history. ; ; (4) Use of antithrombotic medication ; Participant is taking medication, ascertained from history. ; ; (5) Participation in a structured exercise program. ; Participation and review of exercise regimen within the last 3 months. Ascertained from history. The exercise program includes review in hospital or outpatient setting (within the last 3 months). There is guidance from a qualified healthcare provider specifically regarding exercise rehabilitation. Composite secondary outcome of number of risk factors under "control" (total of 7). ; The outcome will be continuous (specific glycated haemoglobin measurement) and dichotomous (target met: yes/no). Target glycated haemoglobin less than 7.0%. High sensitivity C‐reactive protein measured by serum assay. The outcome will be continuous (specific high sensitivity measure) and dichotomous (target met: yes/no). Target high sensitivity C‐reactive protein of less than 2mg/L. Initial claudication distance (ICD), which is defined as the distance the patient can walk on the treadmill before onset of claudication INCLUSION CRITERIA: 1. Established symptomatic peripheral arterial disease with diagnosis confirmed by either: ‐ Ankle brachial index (ABI) less than or equal to 0.9 OR ‐ Specialist review OR ‐ Documented history of a previous lower limb revascularisation procedure 2. Aged between 18 and 80 at the time of enrolment ; Body mass index calculated from height and weight. The outcome will be continuous (specific BMI measurement) and dichotomous (target met: yes/no). Target body mass index (BMI) less than 27kg/m2 or at least 10% weight loss (where baseline BMI greater than or equal to 27kg/m2). Change in markers of inflammation and endothelial function (including hsCRP, TNF, IL‐6, IL‐1B, s‐VCAM, MPO, neutrophil counts, lymphocyte/neutrophil ratio, Endothelin‐1 and other exploratory biomarkers). These markers will be measured using serum assay. Composite outcome of MACE, MALE, cardiovascular mortality, revascularisations, and hospitalisations. This will be identified from study‐specific questionnaire and/or consultation with medical records. Composite secondary endpoint of major adverse cardiovascular events (MACE) during study period. This includes non‐fatal myocardial infarction, non‐fatal stroke and cardiovascular‐mortality. This will be identified from study‐specific questionnaire and/or consultation with medical records. Composite secondary endpoint of major adverse limb events (MALE) during study period. This includes acute limb ischemia and/or limb amputation. This will be identified from study‐specific questionnaire and/or consultation with medical records. Composite secondary outcome of "adherence" (total of 5) to guideline‐based therapy: ; Assessment of each risk factor is dichotomous and will be categorised as under “control” if they are meeting specified targets: (1) Systolic BP less than 130mmHg and diastolic BP less than 80mmHg. Blood pressure measured using sphygmomanometer (2) Glycated haemoglobin less than 7.0%. Glycated haemoglobin measured using plasma assay. (3) LDL less than 1.8mmol/L. Low density lipoprotein measured using serum assay (4) Non‐HDL cholesterol less than 2.6 mmol/L. Non high density lipoprotein cholesterol measured using serum assay (5) hsCRP less than 2 mg/L. High sensitivity C‐reactive protein measured by serum assay. (6) Smoking abstinence for previous 3 months. Smoking abstinence will be assessed via participant self‐reporting. (7) Body mass index (BMI) less than 27kg/m2 or at least 10% weight loss. Body mass index calculated from height and weight. Glycated haemoglobin measured using a plasma assay. ; Low density lipoprotein measured using serum assay. The outcome will be continuous (specific LDL measurement) and dichotomous (target met: yes/no). Target LDL less than 1.8mmol/L. Mortality during study period ; Non high density lipoprotein cholesterol measured using serum assay. The outcome will be continuous (specific non‐HDL cholesterol measurement) and dichotomous (target met: yes/no). Target non‐HDL cholesterol less than 2.6 mmol/L. Number of hospitalisations during the study period. This will be identified from study‐specific questionnaire and/or consultation with medical records. Number of revascularisation procedures during the study period. This will be identified from study‐specific questionnaire and/or consultation with medical records. Quality of life score (as measured by the Peripheral Artery Questionnaire) Smoking abstinence for previous 3 months. The outcome will be dichotomous (target met: yes/no). Smoking abstinence will be assessed via participant self‐reporting.