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 the prevalence of modifiable risk factors in PAD patients.
This trial will randomise patients with PAD 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.
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. The twelve-week and one-year assessments will take place at the outpatient PAD clinic in UHG.
- 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 above21)
- 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
- 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 suffering from a comorbidity that could affect either their physical participation in the intervention arm or influence outcomes (e.g. ischemic heart failure or severe chronic kidney disease with an estimated glomerular filtration rate of less than 30 mL/min22)
- Patient is immobile
- Contraindication to anticoagulation and antiplatelet medications or any of the risk factors treatment.
Patients with Symptomatic PAD (Rutherford category 2 and above21 ) 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), entitled “Same-day Consent vs Delayed Consent in a Randomised Trial: A Study within a Trial” 23. This SWAT aims to ensure the rigorousness of the consent process and will run in conjunction with this randomised controlled 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 category21, 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.
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) using a simple randomisation strategy. 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 category21
- Wound ischaemia and foot infection classification (WIfI)24
- Blood samples including:
- Fasting blood lipids,
- Fasting glucose
- Blood pressure documentation
- Anthropometric measurements including:
- Waist Circumference
- Sub-maximal functional capacity exercise testing including:
- Shuttle test 25
- Claudication distance26
- Absolute walking distance27
- Behavioural and psychological survey using the Hospital Anxiety and Depression Scale (HADS) 28.
- Health related quality of life assessment: Dartmouth Quality of Life score20.
- Smoking status assessment using the Fagerstrom Test for Nicotine Dependence 29.
- Physical activity assessment: Godin and Shepard Leisure Exercise Questionnaire30.
- Nutritional assessment through the Mediterranean Diet Questionnaire31.
Risk Factor Modification Structured Programme
The risk factor modification intervention programme is a 12-week intensive lifestyle programme. This is a nurse-led, community-based, lifestyle and risk factor modification intervention modelled on the European Society of Cardiology demonstration project, a large clinical trial called EuroAction14 .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.
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 include:
- 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.
On completion of the 12 weeks in both groups, patients are reassessed for risk factors, therapeutic management and lifestyle changes similar to baseline.
Similar to the baseline and twelve-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.
- Any residual stenosis of more than 30 %19
- If developed a major adverse cardiovascular event (MACE) or major adverse limb event (MALE)
- Health related quality of life
- Cost-effectiveness of the programme
Achieving target Improvement in lifestyle risk factors at twelve-week and at one-year. 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
Patients will be reassessed for the primary endpoint at one year. If they fail the criteria by which they were deemed at twelve weeks to have achieved the primary endpoint, they will then be considered to not have achieved the one-year primary endpoint.
We will report the primary endpoint for both time points.
Secondary endpoints of PAD outcomes are based on the Society for Vascular Surgery (SVS) reporting standards19:
1. Amputation free survival; defined as time spent free from any major above ankle amputation19
2. Hemodynamic improvement: defined as an increase in the ABI by at least 0.1019
3. Clinical improvement: which is defined as an upward shift by at least one Rutherford category. However, PAD patients suffering from actual tissue loss (Rutherford category 521) should move up two Rutherford categories to be considered improved32.
4. Re-intervention or stenosis rate; any re-intervention or stenosis among patients who already underwent vascular surgery19
5. Freedom from major adverse cardiovascular events (MACE). MACE is defined as any major cardiovascular event such as myocardial infarction, cerebrovascular accident or death19.
6. Major adverse limb events (MALE). MALE is defined as any major amputation or revascularization procedure19.
7. Revascularisation-free survival; defined as time free from any revascularisation procedure regardless of if it were an endovascular intervention or an open surgery19.
8. Change from baseline of the following risk factors:
a-BMI (measured in kg/m^2)
b-HbA1c (measured as a percentage)
c-Total Cholesterol (measured in mmol/L)
9. Health related quality of life20; 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
- Incidence and severity of adverse events
- Incidence of side effects due to medication commenced during the trial, for the modulation of any PAD risk factor. This includes any drug interaction of these medications with any previously assumed medication the patient was using regularly prior to commencing the trial.
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 twelve-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. A two-sample comparison of proportions sample size calculation was implemented.
With these parameters, the G*Power33 software yields a trial with a maximum sample size of 208 patients completing the intervention (104 per intervention group).
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 or Fisher’s Exact where appropriate. Secondary outcomes including time to event will be assessed using Kaplan Meier survival curves and Log rank test. An exact 95% confidence interval will be applied for the difference between intervention groups in terms of PAD risk factor reduction.