Visualization of Asymptomatic Atherosclerotic Disease for Optimum Cardiovascular Prevention (VIPVIZA)
This population based pragmatic randomized controlled trial (RCT) aims at optimizing cardiovascular disease (CVD) prevention through accurate identification of individuals at high risk of CVD and accurate perception of the risk, and better compliance to preventive treatments and reduced premature CV morbidity and mortality Increased carotid artery intima-media thickness (CIMT) and carotid plaques, assessed by ultrasonography, are early signs of atherosclerosis and associated with myocardial infarction and stroke. Few studies have systematically evaluated image-based risk stratification and its effect on clinical outcomes and results are conflicting.
The Västerbotten Intervention Programme (VIP), Northern Sweden, is integrated in primary care services with assessment of traditional CV risk factors and individual health promoting counseling for all 40-, 50- and 60-year olds (n=6500/yr). Those with diabetes, hypertension, family history of premature CVD and/or hypercholesterolemia are referred to treatment.
VIP participants with at least one conventional CV risk factor (60% of participants) are eligible for inclusion in VIPVIZA. During 2013-2015, 3200 participants will be enrolled. Portable carotid ultrasound machines will be used for ultrasound examinations, whereby CIMT and plaque formation will be visualized and measured.
Subjects will be randomly assigned to one of two groups; 1/ Intervention: Written information to patient and physician, including graphic presentation in color of CIMT and of plaque, vascular age, an ultrasound image, general information about atherosclerosis as a dynamic process, and recommendation to follow clinical guidelines for risk factor control. 2/ Control: No information from the baseline ultrasonography.
We will explore determinants of behavioral change using psychometric questionnaires and level of health literacy. Deep interviews at the time point for the ultrasound examinations will explore how the screening relates to risk perception, quality of life, coping strategies, attitudes to and skills of self-care.
Both groups will be managed according to clinical guidelines within the usual health care. After three years (2015-2017), the ultrasonography is repeated and information given to all participants and their physicians.
CV risk factors, life style and pharmacological treatments will be assessed after one and three years. CV morbidity and mortality and all-cause mortality will be followed during five years, i.e. until 2020.
Behavioral: Information vs no information about carotid ultrasound results on asymptomatic atherosclerosis
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||Direct VIsualiZAtion of Asymptomatic Atherosclerotic Disease for Optimum Cardiovascular Prevention. A Population Based Pragmatic Randomised Controlled Trial Within Västerbotten Intervention Programme (VIP) and Ordinary Care.|
- Framingham score evaluation [ Time Frame: 12 and 36 months ] [ Designated as safety issue: No ]Composite gender-specific algorithm used to estimate the 10-year cardiovascular risk of an individual, based on levels of blood pressure, total cholesterol, LDL-cholesterol, systolic bloodpressure, treatment for high blood pressure, diabetes, smoking and age
- SCORE evaluation [ Time Frame: 12 and 36 months ] [ Designated as safety issue: No ]Risk of death in myocardial infarction within 10 years expressed as statistical assessment based on smoking, systolic blood-pressure, blood cholesterol, age and sex.
- Life style [ Time Frame: 12 month and three years ] [ Designated as safety issue: No ]Patient questionnaire. Composite measure
- Hospitalizations due to stroke [ Time Frame: Five years ] [ Designated as safety issue: No ]Data will be collected from computerized medical records from hospital care in the county, regional quality registry on stroke and from the In-patient registry at the National Board of Health and Welfare.
- Hospitalizations due to revascularizations [ Time Frame: Five years ] [ Designated as safety issue: No ]Data will be collected from computerized medical records from hospital care in the county and from the In-patient registry at the National Board of Health and Welfare.
- Cause-specific mortality due to myocardial infarctions and stroke [ Time Frame: Five years ] [ Designated as safety issue: No ]Data will be collected from the Causes of Deaths registry at the National Board of Health and Welfare.
- Total mortality [ Time Frame: Five years ] [ Designated as safety issue: No ]Data will be collected the Causes of Deaths registry at the National Board of Health and Welfare.
- Hospitalizations due to myocardial infarctions [ Time Frame: Five years ] [ Designated as safety issue: No ]Data will be collected from computerized medical records from hospital care in the county, regional quality registry on myocardial infarctions and from the In-patient registry at the National Board of Health and Welfare.
- Carotid ultrasonography results [ Time Frame: 3 years ] [ Designated as safety issue: No ]Compound measure. Carotid Intima Media Thickness Carotid plaques: Total plaque area, Grey scale median (GSM)
- Pharmacological treatment, composite outcome [ Time Frame: 1, 3 and 5 years after baseline ] [ Designated as safety issue: No ]
Prescriptions of medications for hypertension, diabetes and dyslipidemia. Data collected from computerized medical records in primary and hospital care in the county.
Purchases of medications for hypertension, diabetes and dyslipidemia followed through data from the Pharmaceutical registry, National Board of Health and Wellfare
|Study Start Date:||April 2013|
|Estimated Study Completion Date:||April 2020|
|Estimated Primary Completion Date:||April 2016 (Final data collection date for primary outcome measure)|
Experimental: Info about carotid ultrasound results
Information about carotid ultrasound results to patient and physician
|Behavioral: Information vs no information about carotid ultrasound results on asymptomatic atherosclerosis|
No Intervention: No info about carotid ultrasound results
No information about carotid ultrasound results to patient and physician.
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Visualization of asymptomatic atherosclerotic disease to improve cardiovascular prevention. Design of a randomized controlled intervention within ordinary health care - VIPVIZA.
VIPVIZA is the acronym for VIsualiZation of asymptomatic Atherosclerotic disease for optimum cardiovascular prevention - a randomized controlled trial within the Västerbotten Intervention Programme. The setting is highlighted by VIP positioned first in VIPVIZA.
Three thousand two hundred people who are 40, 50 or 60 years old and have at least one risk factor for cardiovascular disease (CVD) will be recruited. Participants undergo extensive enquiries, blood sampling and carotid ultrasound assessing atherosclerosis as carotid intima-media wall thickness and plaque formation at baseline. They are randomized 1:1 to be informed (Group I) or not (Group NI) about the ultrasound result with graphics, images and text.
VIPVIZA encompasses the whole process from screening and risk assessment, over information about the results for accurate risk perception to optimization of the CVD prevention through intervention with pharmacotherapy and lifestyle modification. The field of risk communication and determinants of risk perception will be explored with quantitative and qualitative methods and. The goal is to sort out what are the facilitators and barriers for effective efficient individual CVD prevention. The study is expected to contribute to the evidence on the contributory role of CIMT and plaques to risk stratification for CVD, as well as to reduction of premature CVD morbidity and mortality. To benefit study participants and to be valid for clinical practice in general, the study is performed using the existing set-up of population-based screening and risk factor intervention program within the ordinary health care in Västerbotten County, Sweden. The study is driven by the researchers and is performed as an independent trial with support from Västerbotten County Council, Umeå University and the Swedish Research Council.
INTRODUCTION Atherosclerotic cardiovascular disease (CVD) is the number one cause of premature death and approximately 90% of myocardial infarctions (MI) and strokes, are caused by factors that are modifiable by pharmacological intervention and lifestyle change. Screening models to identify individuals at high risk for CVD, based on conventional risk factors and using statistical risk calculation, are widely used in clinical practice as a foundation for risk management. However, their accuracy in differentiating between high and intermediate risk is only modest , they do not predict those events that occur at only intermediate risk , i.e. the large proportion of acute CVD events (60-70%), and no randomized trials have shown improved results of prevention when it is based on these risk stratification models . Furthermore, those models are able only to predict the 10-year CVD risk, which from a clinical perspective and also the screened individuals' point of view might be less pertinent at younger ages. For example, 40 years old men and woman still have a long expected remaining life time and low risk of suffering a myocardial infarction within 10 years, even at high risk factor burden. Thus - improved methods for high precision CVD risk assessment are needed.
Suboptimal compliance with guidelines for prevention among practitioners and poor adherence to CVD prevention with life style change and medications among patients, lead to poor risk factor control. The association between perceived and actual CVD risk among patients is generally weak, with inappropriate optimism among high-risk patients, particularly men. Health care providers might not be aware of this, or the risk message is only verbal or numerical despite other formats, e.g. visual tools, being more effective . Risk communication is increasingly recognized as important within the medical community including for CVD . It is not self-evident for apparently healthy individuals to recognize their risk as high, particularly if there is a long delay between having risk factors, e.g. high cholesterol, and the outcome that might occur, a heart attack (13). Poor communication and inaccurate perception of risk are two major barriers for adherence to preventive measures. The perceived risk depends on the format and framing of the message, and also on psychological, social and cultural factors.
Whether information about a health threat leads to behavioural change depends on many factors. The individual's repertoire to cope with stressful situations and trust in own capability to manage demands are crucial for the response to health threats. Health literacy, the degree to which individuals have the capacity to understand health information to make appropriate health decisions, is also an important determinant of risk perception and health related behaviours. An increased risk of a disease will direct the individual's behaviour towards health-promotion . However, according to Social Cognitive Theory solely information about a risk due to a specific behaviour is not enough for long-term behaviour change, more important is the individual's belief in its own ability to change behaviour (self-efficacy expectancy) . An optimistic vs. a pessimistic style will more often boost self-efficacy and be more persistent in achieving goals. Thus - there is a need to develop new models for communication of CVD risk and to investigate determinants of risk perception and adherence to CVD prevention.
An alternative strategy to evaluate and inform about risk for CVD would be to measure and visualize the degree of actual atherosclerotic disease, i.e. by ultrasonography of medium sized arteries. Increased carotid artery intima-media thickness (CIMT) is an early sign of atherosclerosis, can be accurately assessed by ultrasound, and is associated with both myocardial infarction and stroke . The demonstration of atherosclerotic plaques in an individual are absolute proof that this individual has an actual atherosclerotic process and this sign has probably higher predictive power for major clinical events like cardiovascular death, myocardial infarction, stroke or the need for revascularisation procedures. Controversies exist regarding the contributory role of CIMT and plaque formation for risk stratification. In addition, some studies demonstrate that imaging-based identification of at-risk subjects may improve their adherence to prevention, while other studies do not. Thus - there is a need of studies of appropriate sample size that evaluate the possible benefits and challenges of using image based stratification of risk and risk communication.
Importantly, pharmacological treatment and life style modification have the potential of slowing down the progress of atherosclerosis and even reducing CIMT and plaque. However, if prevention strategies shall have any major impact on CVD prevalence, they need to be more widely used in populations. Today only few studies have systematically evaluated the effects of image-based risk stratification and image-based risk communication on risk factor burden and major clinical outcomes. The results are conflicting and recent reviews conclude that large-scale randomized controlled studies (RCTs) targeting low- and intermediate-risk adults with focus on the impact of imaging are needed. Moreover, to benefit study participants and to be valid for clinical practice in general, a pragmatic randomized controlled intervention study is best tested using the existing set-up of population-based screening and risk factor intervention already existing within the ordinary health care.
AIMS AND HYPOTHESES
In view of the above background three distinguished but complementary hypotheses were formed as the starting point for planning of the VIPVIZA study. These hypothesis are:
- Direct visualization of asymptomatic atherosclerotic disease, assessed by carotid ultrasonography, has the potential of identifying individuals at high risk of CVD with higher precision than conventional risk factor based statistical models.
- Clear understanding of an image of arterial disease, particularly during an early asymptomatic phase, is expected to be of superior value compared to statistical risk models, in optimizing adherence to clinical preventive management of both doctors and patients
- The enhanced clinical preventive management results in improved long-term survival and better control of premature CVD morbidity.
The overall aim is to optimize CVD prevention through accurate identification of individuals at high risk and assist in better adherence to preventive treatments by improved clinical risk communication about the risk of CVD.
- To assess the impact of visualization of asymptomatic atherosclerosis, compared to traditional statistical risk factor based risk evaluation, on doctor´s and patient´s adherence to clinical guidelines for CVD prevention, assessed by traditional risk factor control, life style modification and pharmacological treatment at one year of follow-up, and also any measurable changes in CIMT or carotid plaques at three years of follow-up.
- To evaluate how individuals' health literacy, way of coping, degree of optimism and self-efficacy influence on attitudes to screening, risk assessment and preventive measures when subjected to different ways of communication of CVD risk.
- To assess the prevalence of asymptomatic atherosclerotic disease in men and women through measurement of intima-media thickness (CIMT) and identification of carotid plaques, and to relate CIMT and plaques to clinically estimated CVD risk factors, traditional risk stratification, and to CV morbidity and mortality over the course of 5 years.
- To evaluate (in a sub-study) the effect of adding intensive pharmacological treatment or intensive life style modification that target subjects at high risk during three years of follow-up.
- To develop advanced ultrasound techniques for characterisation of atherosclerotic plaque.
POPULATION AND SETTING Setting: VIPVIZA is integrated in the Västerbotten Intervention Programme (VIP) , i.e. the existing set-up for population based CVD screening and prevention within regular health care in the County of Västerbotten, Sweden. This programme has been continuously running for 25 years and has so far included 105,000 individuals. In total 153,000 health surveys have been performed and 50,000 subjects have participated at least once VIP provides health surveys for all 40-, 50- and 60-year olds at their primary health care centre (PHC), N=6500-7000/year. Conventional CVD risk factor screening is conducted, followed by individual counselling and promotion of healthy lifestyle and, pharmacological CVD prevention according to clinical guidelines. Participation rates are around 70% with only small social selection bias. This is the largest long-term CV screening and prevention program in the world. The VIP therefore provides a unique arena for pragmatic studies of innovative models for CVD risk stratification and intervention.
Recruitment to VIPVIZA: VIP participants are informed about VIPVIZA at the occasion of health examination at the respective PHC and invited to sign an informed consent. Recruitment started in the spring 2013 at six PHCs, together covering 23% of the county population and the first ultrasound-examinations were performed in April 2013. The project has then gradually beendisseminated to the rest of 39 PHCs in the County. A total of 3200 participants will be recruited.
Inclusion criteria; (i) age=60 years, (ii) age=50 years and at least one of the following: smoking, diabetes, hypertension, S-LDL-cholesterol ≥4.5 mmol/L, abdominal obesity, a history of CVD at age < 60 years among first-degree relative, (iii) age=40 years and a history of CVD at age < 60 years among first-degree relative.
Based on VIP data from 2012, around 60% of all participants of 40, 50 and 60 years of age, i.e. n= 4000, are estimated to be eligible for the study annually.
Exclusion criteria; (i) significant flow-limiting stenosis of the investigated carotid arteries according to vascular ultrasound and Doppler measurements.
THE VIPVIZA INTERVENTION AND CONTROL Intervention and randomization: Participants are randomly assigned to the intervention group (I) or the control group (NI) before the ultrasound examination using a randomization list generated by the study statistician before start of the study. The intervention and the control groups are equally sized. The randomization list was generated by simulating from a uniform probability distribution and by dichotomizing the outcome into the two groups (I and NI) with equal probability..
Group I (Information about carotid ultrasound): Written and visual information to the patient and his/her primary care physician. This includes graphic presentations in colour of CIMT and plaque, information about vascular age and a stylized ultrasound image. Furthermore, information is given about atherosclerosis as a dynamic process modifiable by pharmacological treatments and healthy lifestyle, and recommendation to follow clinical guidelines for risk factor control. A few weeks after receiving this information, participants will be followed-up by phone-call by a research nurse, to guarantee that the information is understood and the risk perception proper. Exactly the same written and graphic information will be posted to the study participant at 6 months after inclusion in the study.
Group NI (No information): No information about the carotid ultrasound from the baseline examination will be given.
Both groups will be followed and managed according to clinical guidelines within the ordinary health care during the entire study period.
DESIGN OF VIPVIZA The design is a pragmatic randomized controlled trial .
BASELINE MEASUREMENTS Risk factors for cardiovascular disease are measured at the baseline VIP health survey in usual care; blood-pressure, S-Cholesterol, S-HDL-Cholesterol, S-LDL-cholesterol, S-triglycerides, BMI and waist. An oral glucose tolerance test is performed according to WHO-standards providing fasting- and 2-hour capillary plasma glucose. A comprehensive questionnaire covering health, socioeconomic situation, quality of life (SF 36), life style habits (physical activity, tobacco and alcohol consumption, diet and stress). The VIP procedures are previously described in detail.
Carotid ultrasound examinations are performed by sonographers specifically trained in carotid ultrasound techniques (Biomedical Scientists) from the department of Clinical Physiology, Heart Centre, Umeå University Hospital. Examinations are done in hospitals in the three towns in the County of Västerbotten (Umeå, Skellefteå and Lycksele), and at the local PHC centres in rural areas. A portable, automatic, carotid ultrasound equipment (CardioHealth Station®, Panasonic Healthcare Co., Ltd, Tokyo, Japan) is used. The examinations are performed according to a standardized protocol according to the current guidelines. The angle of insonation is automatically provided by the system and recorded. Measurement of CIMT (max, min and mean values) is automatic. Luminal plaques are defined according to the current consensus statement (Mannheim Consensus). Plaques are characterised off-line according to an internal protocol. Individuals with a stenosis ≥50 % of the carotid lumen will be excluded and referred to the Stroke Centre, Umeå. The remaining participants will be classified as "high risk" of future CVD events based on CIMT >75th percentile for age and sex, or "very high risk" based on the presence of plaque .
Vascular age: The ARIC study population is used for estimation of vascular age due to similarity with the VIP population regarding age and risk factor profiles. Information about vascular age with regards to CIMT is included in the written information about carotid ultrasound results presented for the individuals in the Intervention group (I).
Evaluation of communication and perception of risk Both quantitative and qualitative methods will be applied to explore determinants of behavioural change including adherence to risk stratification (or no change).
Baseline questionnaire questionnaire is answered at the same occasion as the baseline carotid ultrasound examination. It contains several validated psychometric instruments including:
- Brief COPE to explore the coping pattern an individual has in a stressful situation;
- Life Orientation Test-Revised to assess where the individual is on an optimism-pessimism scale;
- The General Self-efficacy Scale that measures trust in own ability to change behavior; * Health literacy, the ability to understand a health message and make appropriate decisions,
- HADS a brief questionnaire on anxiety and depression,
- PSS on perceived stress are used to explore risk communication and risk perception
- Self rated risk of CVD and Self rated possibility to reduce this risk is plotted on VAS scales 1-10, where 1 is "very low" and 10 "very high".
Interviews: Qualitative deep interviews with study participants will be conducted with a purposive sampling (by age, sex, risk factor pattern) in order to gain deeper knowledge and understanding of the concept risk communication, and how this impacts on quality of life, perception of risk, coping strategies and motivation for life style modification. An interview guide has been developed based on results from interviews during the pilot study. The focus is on perception of "risk of CVD" and how this relates to the way risk of CVD is communicated (i.e. based on risk factor evaluation only or with the added visualized information about early disease).
Interviews will also be performed with practitioners in order to gain knowledge on how information on ultrasound affects physicians´ perception of risk, communication with patients and attitudes to treatments of CVD risk factors.
The interviews with study participants and practitioners will be recorded and transcribed verbatim. Data will be analysed using Qualitative Content Analysis.
DATA COLLECTION DURING FOLLOW-UP One year after the baseline ultrasound, measurements of CVD risk factors (blood pressure, lipids, glucose, HbA1c, BMI, waist) and a questionnaire on lifestyle (a short-form of the VIP-questionnaire) will be performed (primary outcome).
Postal questionnaire: Based on important concepts/themes generated in the qualitative analysis and in order to evaluate their distribution in the population, a postal questionnaire will be developed and sent to the whole study population before the 3-year follow-up.
Three years after inclusion a follow-up carotid ultrasound (secondary outcome ultrasound), risk factor measurements, a VIP questionnaire (life style, quality of life) as well as qualitative deep interviews with study participants will be done. The results of the carotid ultrasound will be presented to all participants and their general practitioners.
Follow-up at five and ten years: CVD morbidity and mortality (secondary outcome clinical events, see below) will be recorded by linking the subject's data to national diagnostic and death registries.
OUTCOME DEFINITIONS Primary outcome The primary outcome is change of Framingham risk score after one and three years.
- Changes of blood pressure, S-cholesterol, S-LDL-cholesterol, diabetes including P-glucose, BMI, waist and lifestyle (smoking, physical activity, food habits, alcohol consumption), as well as change in SCORE risk assessment .
- Ultrasound results: change in CIMT, presence of plaque, quantitative and qualitative plaque parameters, GSM, presence and degree of significant stenosis between baseline and follow-up ultrasound at three years.
- Change of Health related quality of life, self rated risk of CVD and participant's own possibility to reduce this risk.
- Prescriptions and purchases of medications for the treatment of hypertension, dyslipidemia and diabetes.
- Clinical endpoints: Myocardial infarctions (MI), stroke, revascularization procedures (percutaneous coronary interventions (PCI), coronary artery by-pass grafting (CABG) and vascular surgery of atherosclerotic lesions in the carotid, aortic and peripheral vascular territories), and deaths (all-cause and CVD specific).
Clinical Events Committee adjudication An independent, blinded, clinical events committee (CEC) adjudicates all recorded events of myocardial infarction, stroke, revascularization procedures caused by atherosclerotic complications in the aorta, carotid, coronary and peripheral artery vascular territories, and cardiovascular and all-cause death.
Prespecified event definitions are used for myocardial infarction and stroke. Only myocardial infarctions type I and II according to the ACC/ESC universal definition of myocardial infarction (excluding myocardial injury occurring during or caused by revascularisation procedures) are adjudicated to avoid double events during revascularization. Stroke is defined according to the WHO definition as a neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours. The stroke diagnosis encompasses both ischemic and hemorrhagic events. Cerebrovascular diseases include stroke as well as transitory ischemic attack (TIA), which is defined as stroke but with symptoms persisting less than 24 hours.
The adjudication is performed in two phases. In phase I all endpoints are adjudicated by two independent physician reviewers. All stroke events are evaluated by at least one stroke physician or neurologist. Disagreements between the phase I reviewers are brought in phase II to the committee for final result being a judgement to consensus of the committee members present.
SPECIFIC DATA COLLECTION AND SUBSTUDIES
Intensive multimodal intervention sub-study - a phase 2 randomized controlled trial -VIPVIZA-I This is a proof-of-concept phase II 1:1:1 randomized controlled study where we test the hypothesis that the established process of atherosclerosis can be retarded, alleviated or even eliminated by intensive treatment.
Inclusion criteria in the VIP-VIZA intensive sub-group study are the same as in the large VIP-VIZA study with the addition that the individuals are living in or close to the city of Umeå, have a visible carotid plaque and give informed consent to participate also in this sub-study. Exclusion criteria (include previous known cardiovascular disease, short life expectancy due to other comorbidity, contraindication for or otherwise) not compliant with repeated carotid ultrasound or other investigations, already receiving high-dose statin therapy, documented allergy or intolerance to any of the study drugs without possibility to change to an alternative, severe psychiatric condition or other reason that jeopardize compliance with repeated follow up.
The primary endpoint is the progression/regression/no-change over time in plaque characteristics and composition as assessed at 0 (baseline) and at 6, 12 and 36 months by advanced ultrasound techniques. Secondary endpoints include changes in risk factor burden, blood chemistry parameters, blood pressure and heart variability and life style changes.
Among VIP-VIZA participants in group I with carotid plaques, eligible individuals will be randomized to :
Group 1 (N=30) Intensive multi-modal pharmacological treatment which includes a) visualization of the carotid ultrasound investigation showing the plaque progression/regression/no-change over time to the individual/patient and communication of this information in order to motivate the treatment; b) potent lipid-lowering treatment; c) antihypertensive treatment; d) oral antidiabetics in case of impaired glucose tolerance (IGT); e antiplatelets and f) general life style information.
Group 2 (N=30) Intensive lifestyle program will be given at the Department of Behavioural Medicine (BM) in the county of Västerbotten which includes a) visualization of the carotid ultrasound investigation showing the plaque progression/regression/no-change over time to the individual/patient and communication of this information in order to motivate the intensive lifestyle treatment; b) a one-week basic course followed by a half-day group session weekly during six months and at 9 and 12 months (BM in Umeå), alternatively a 15-day basic course of in-patient training followed by a four-day booster session at 6 and 12 months at the clinical facility in the village of Sorsele in the northwest corner of the county of Västerbotten (BM Sorsele). The program focuses on sustainable behaviour modification, empowerment, stress management and health promotion through lifestyle change.
Group 3 (N=30) ordinary care but more frequent follow-up as groups 1 and 2.
Development of ultrasound technology and interpretation - VIPVIZA US A scientific program is running during the course of VIPVIZA in order to develop improved methods to quantify plaque properties, to describe atherosclerotic plaque texture, characteristics of vulnerable plaque and identify dynamic aspects of progression and regression of atherosclerosis identifiable by carotid ultrasound. 3D and contrast-enhanced ultrasound (CEUS) will also be used. A series of ultrasound methods and parameters will be explored in the intensive multimodal intervention sub-study - a phase 2 randomized controlled trial -VIPVIZA-I outlined above.
STATISTICAL ANALYSES Aim 1: Hypotheses driven analytical tests will be used to estimate the effect of the intervention on the primary and secondary outcome variables comparing the intervention group/s to the control group/s at 1 and 3 year of follow up according to the primary and secondary outcome variables. A two-sided students t-test will be used to compare mean values in the I and NI groups. A significance level of 0.05 will be employed. A two sided Chi square test will be used to compare how categorical outcome variables differ between the I and NI groups. The effect of the intervention will be estimated according to the differences between groups in changes of CVD risk score after 1 year and 3 years primarily. Analyses will also be run per each risk indicator and risk factor after 1 and 3 years in subsequent analyses adjusting for multiple testing using the Bonferroni method. Sample size calculations have been carried out to assure that the groups' sizes are sufficiently large to have sufficient power to detect effects of clinical importance. The primary outcome variable show sufficient power with at least a probability of 0.8 to avoid false negative conclusions with a limit value of detecting a difference in the I and the NI groups of 0.7% in the Framingham risk score at a sample size of approximately 3000 participants. To account for an assumed drop-out rate of 5% we will invite 200 participants more The mean of the Framingham risk score was estimated to 11.8% in average with a standard deviation of 6.6 according to the VIP register in year 2011.
Similar analysis using t-tests and Chi square tests will be conducted for the secondary outcome measures.
The results of the primary outcome at one year will be used as an interimistic analysis for the decision to interrupt or continue the study. The steering group of VIPVIZA will be advised by the international advisory board.
Aim 2 Modelling using more advanced statistical methods will be employed. The primary aim of the second stage of analyses is to contribute to the understanding to what underlying sub-groups and mechanisms are involved in the potential change of risk factors. Here confirmatory (structural equation modelling) and exploratory (partial least squares analysis) statistical modelling will be done. The primary objective of the structural equation modelling will be to establish a cause and effect structural relationship between the intervention and the intermediate and mediating factors involved in the behaviour change leading to the potential risk factor impact. This type of modelling will be applied for subgroups to explore determinants of changes in smaller groups (for example a group with a specific coping strategy). Explorative modelling, e.g. multivariate partial least squares, will be used for the evaluation of variables relative contribution to explain changes in the outcome variables when all variables interacting i.e. are tested in the same model.
Aim 3: The CIMT measurements will be related to the risk factors and risk indicators using a simple correlation analysis. Predictive models will be developed to explore the predictive ability of CIMT , plaque and risk factors on morbidity and mortality in CVD at 5 years (and 10 years) And this will be compared with CVD risk scores. A new score will be developed including these measurements to assess individual's risk for CVD morbidity and mortality. Cox proportional hazard models will be employed to assess risk over time, and predictive models will be evaluated using Receiver Operating Characteristic Curves (ROC) to minimize prediction errors and assure high sensitivity and specificity of the new score. The influential variables will be analysed as independent and synergistic factors.
ETHICAL APPROVAL All individuals participating in the study has to provide written informed consent. The Regional Ethical Review Board, Umeå University, has approved the VIPVIZA study including the above described substudies (Dnr 2011-445-31M,2012-463-32M, 2013-373-32M) .
Please refer to this study by its ClinicalTrials.gov identifier: NCT01849575
|Clinical Reseach Center Umeå University Hospital||Recruiting|
|Umeå, Sweden, Se-90185|
|Contact: Margareta Norberg, MD,PhD +46 90 785 ext 3343 firstname.lastname@example.org|
|Contact: Ulf Näslund, Professor,MD +46 90 785 ext 3600 email@example.com|
|Principal Investigator: Margareta Norberg, MD, PhD|
|Principal Investigator:||Margareta Norberg, MD, PhD||Umeå University|
|Principal Investigator:||Ulf Näslund, Professor,MD||Umeå University Hospital|