Study design
This is a randomised, parallel group, active-control trial to compare the effectiveness of the risk factor modification intervention programme to standard healthcare in a tertiary vascular care centre, in the reduction of modified risk factors in PAD patients.
This trial will involve 208 patients with PAD, to be randomised in an equal ratio to one of two treatment arms. One arm will be randomised to undergo a risk factor modification intervention programme at a community based centre. The other arm will be provided with standard healthcare advice, in the outpatient PAD clinic in a tertiary referral vascular centre. Patients randomised into the risk factor modification intervention programme will have the intervention administered for 12 weeks. Patients will then be followed for 12 months to determine further PAD outcomes. The participant flowchart through the study is shown in Figure 1. SPIRIT figure for this trial is given in Figure 2.
Study setting
Potential participants will be identified from the outpatient PAD clinic at the University Hospital Galway, Ireland (UHG). Patients will be screened and randomised at the outpatient PAD clinic in UHG.
The risk factor modification intervention programme will be administered in a nurse led community-based centre (Croí Heart and Stroke centre, Galway, Ireland), in the presence of a physiotherapist and dietitian. The control arm will be managed in the outpatient PAD clinic, UHG.The coordinating centre will be the Department of Vascular and Endovascular Surgery, UHG, and the School of Medicine at the National University of Ireland Galway (NUI Galway). Patients are directly supervised during the intervention.
Follow up at 1 year will be at the outpatient PAD clinic in UHG.
Eligibility criteria
Inclusion Criteria
- Aged 18 years or more
- Provide written informed consent
- PAD: diagnosed by at least one of the following:
- Ankle-brachial index of less than 0.90 in at least one lower extremity9
- Toe brachial index of less than 0.609
- Evidence of arterial occlusive disease in one lower extremity detected by duplex ultrasonography, computed tomographic angiography, or magnetic resonance angiography9
- Symptomatic PAD ( Rutherford category 2 and above20)
- Patients should have at least one of the following risk factors:
- Blood pressure > 140/80 mmHg
- Fasting blood sugar (FBS) >53 mmol/mol
- Glycosylated haemoglobin (HbA1c) >7%
- Total cholesterol >5 mmol/L
- Low density lipoprotein (LDL) cholesterol >2.6 mmol/L
- Triglycerides >1.7 mmol/L
- High density lipoprotein (HDL) <1.0 mmol/L in men and <1.2 mmol/L in women
- Physical activity less 30 minutes for 5 days per week
- Body mass index (BMI) 25>kg/m2
- Waist circumference >80 cm in women, and >94 cm in men.
- Current smoker or exposure to tobacco in any form
- Unhealthy diet, Mediterranean diet score less than 10 points
Exclusion Criteria
- Rutherford category zero or one20
- Involvement in another clinical trial in the previous six months
- Legal incapacity
- Inadequate English language ability to understand the content of the intervention programme
- Significant cognitive impairment or mental illness
- Refusal to participate in a certain part of the intervention
- Patient is immobile
- Contraindication to anticoagulation and antiplatelet medications or any of the risk factors treatment.
Study screening
Patients with Symptomatic PAD (Rutherford category 2 and above20) will be invited to join the study. Invited patients will be provided with a pre-designed information leaflet. This leaflet will be fully explained to the patient at the initial assessment. The study researchers will answer any questions about the study. Informed consent will be obtained from the patient on a formatted consent form. Patients will be given the freedom to give consent either on the same day or at a later date in accordance with a study within a trial (SWAT) that would run in conjunction with this trial.
- Researchers will screen the patient for inclusion and exclusion criteria and administer a series of the following:
- Record PAD risk factors such as smoking, hyperlipidaemia, diabetes, hypertension, increased body weight, as well as the patient’s current medication.
- Document the Rutherford category20, claudication distance and absolute walking distance for each patient, to assess the severity of PAD.
- Schedule appointments for baseline health assessments over the following month.
Randomisation
After meeting the inclusion criteria, screened patients will be randomised to one of two treatment arms. One arm will receive the 12-week intensive risk factor modification intervention programme. The control arm will be provided with standard care in the outpatient PAD clinic. This is an intention to treat designed study, where patients are analysed as randomised. Each screened patient will be given a unique screening number.
Screened patients will be randomised in a 1:1 ratio of study intervention: control according to a randomisation scheme. The randomisation scheme will be produced using the PROC PLAN® procedure of the SAS®software package (version 9.2.2). The scheme will be concealed from all patients and study personnel until after database lock.
Patients will be allocated to intervention via an automated telephone system, which will not deliver the randomised allocation except after registering the subject screening number. Each screened patient who is recruited to the trial will be given a unique patient trial number.
The statistician will remain blinded to the treatment allocation until all the data have been
analysed to minimise bias. Outcome assessors and data analysts will be blinded, however, in the event of an adverse event outcome assessors will be unblinded.
Baseline, prior to intervention
All randomised patients will undergo a full baseline assessment prior to their intervention:
- PAD assessment;
- Ankle brachial index (ABI)
- Digital pressure
- Rutherford category20
- Wound ischaemia and foot infection classification (WIfI)21
- Blood samples including:
- Fasting blood lipids,
- Fasting glucose
- HbA1c
- Blood pressure documentation
- Anthropometric measurements including:
- BMI
- Waist Circumference
- Sub –maximal functional capacity exercise testing including:
- Shuttle test 22
- Claudication distance23
- Absolute walking distance24
- Behavioural and psychological survey using the Hospital anxiety and depression scale (HADS)25.
- Health related quality of life assessment: Dartmouth Quality of Life score26.
- Smoking status assessment using the Fagerstrom Test for Nicotine Dependence 27.
- Physical activity assessment: Godin and Shepard Leisure Exercise Questionnaire28.
- Nutritional assessment through the Mediterranean Diet Questionnaire29.
Intervention
Risk Factor Modification Structured Programme
The risk factor modification intervention programme is a 12-week intensive lifestyle programme. The programme includes
- Phase 1: Initial individualised assessment by the multidisciplinary team (MDT), will include previously mentioned baseline assessment in addition to the following:
- Dietician will assess, current eating habits and food diary
- Exercise specialist will assess, seven-day activity recall, barriers to exercise, seven-day pedometer and Functional Capacity Test
- Phase 2: The intervention including:
- Weekly exercise class and educational workshops.
- Serial blood pressure, body mass index, waist circumference, glucose and lipid measurements with goal setting.
- Weekly MDT meetings.
- Targeted and protocol-based pharmacotherapy to support lifestyle changes.
Standard healthcare
The control group will receive the standard healthcare advice provided to PAD patients in the outpatient PAD clinic. In this study, standard care will be conducted by the researchers which includes:
- Advising patients to quit smoking, regular exercise and healthy eating, but neither structured intervention nor organised cessation plans will be addressed.
- Non-specific interventions, such as providing patients with educational material on general health problems.
12-week assessment
- On completion of the 12 weeks in both groups, patients are reassessed for risk factors, therapeutic management and lifestyle changes which will include:
- PAD assessment:
- ABI
- Digital pressure
- Rutherford category
- WIfI
- Blood samples including:
- Fasting blood lipids,
- Fasting glucose
- HbA1c
- Blood pressure documentation
- Anthropometric measurements including:
- BMI
- Waist Circumference
- Physical capacity including:
- Shuttle test
- Claudication distance
- Absolute walking distance
- Behavioural and psychological survey using HADS.
- Health related quality of life assessment: Dartmouth Quality of Life score.
- Smoking status assessment using the Fagerstrom Test for Nicotine Dependence
- Physical activity assessment: Godin and Shephard Leisure Exercise Questionnaire.
- Nutritional assessment through the Mediterranean Diet Questionnaire.
One year assessment
Similar to the baseline and 12-week assessment in addition to assessment and documentation of clinical outcomes which include:
- If the patient underwent a major amputation and level of amputation
- If required a revascularisation procedure or a re-intervention
- Any intervention or stenosis
- If developed a major adverse cardiovascular event (MACE) or major adverse limb event (MALE)
- Health related quality of life
- Cost-effectiveness of the programme
Endpoints
Primary endpoint
Achieving target Improvement in lifestyle risk factors. Target improvement will be considered if the patient achieves any one or more of the following:
- Smoking cessation
- BMI 20-25 (kg/m^2). BMI is calculated by dividing body weight in kilograms by the square of height in meters
- HbA1c less than 7%
- Total Cholesterol less than 5.0 mmol/L
Secondary endpoints
Secondary endpoints of PAD outcomes are based on the Society for Vascular Surgery (SVS) reporting standards30:
- Amputation free survival; if the patient underwent a major amputation and level of amputation
- Re-intervention or stenosis rate; any re-intervention or stenosis among patients who already underwent vascular surgery
- Freedom from major adverse cardiovascular events (MACE) and major adverse limb events (MALE); if the patient developed a major adverse cardiovascular event (MACE) or major adverse limb event (MALE)
- Revascularisation-free survival; if the patient underwent any revascularisation procedure.
- Health related quality of life; assessed using the Dartmouth Cooperative Information Project (COOP) charts at enrolment and after one year. The COOP charts measure six core aspects of functional status: physical fitness, feelings, daily activities, social activities, change in health, pain, and overall health. The instrument consists of six charts, referring to the above mentioned aspects of functioning. Each chart consists of a simple title, a question referring to the status of the patient and an ordinal five-point response scale illustrated with a simple drawing. Each item is rated on this five-point ordinal scale ranging from 1 (no limitation at all) to 5 (severely limited); for 'change in health' score 1 means 'much better' and score 5 'much worse'. The designers do not advocate summing the responses to gain a single index figure of health status.
Safety endpoints
- Incidence and severity of adverse events
- Incidence of side effects due to medication
Sample size calculation
For sample size calculation, the EUROACTION study14 was used to estimate the coefficient of variation for sample proportions.
Data from the EUROACTION14 study suggest that 12-week intervention response rates for the primary endpoint of 54.8% (Intervention programme) and 35.6% (Usual care). 80% statistical power and an alpha level of 5% were chosen.
With these parameters, the G*Power31 software yields a trial with a maximum sample size of 208 patients completing the intervention (104 per intervention group).
Statistical analysis
All data will be analysed according to the intention to treat principle. The primary outcome, the achievement of treatment goals for PAD risk factors between both groups at 12 weeks and 12 months will be compared using Chi square, Fisher’s Exact, t-test and Mann-Whitney U Tests where appropriate. An exact 95% confidence interval will be applied for the difference between intervention groups in terms of PAD risk factor reduction.