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.
Phase: NA
Conditions: Cardiovascular Diseases
Sponsor: Umeå University

Studie ID  
VIPVIZA 
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Visualization of Asymptomatic Atherosclerotic Disease for Optimum 
Cardiovascular Prevention: VIPVIZA – a Population-based RCT 
nested in Routine Care in Sweden  
 
NCT01849575 
 
Study Protocol Version 6.0 

Studie ID  
VIPVIZA 
Dokument version 
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Visualization of Asymptomatic Atherosclerotic Disease for Optimum 
Cardiovascular Prevention: VIPVIZA – a Population-based RCT 
nested in Routine Care in Sweden 
 
Study ID: VIPVIZA 
Protocol version: Version 4.0 
Principal Investigator, PI: Ulf Näslund, Department of Public Health and clinical medicine, 
Umeå University. 
Co-PI: Margareta Norberg, Department of Public Health and clinical medicine, Umeå 
University. 
 
 
 
 
Start of the study: 
2012-08-01    
End of study: 
2026-12-31   

Studie ID  
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Visualization of Asymptomatic Atherosclerotic Disease for Optimum 
Cardiovascular Prevention: VIPVIZA – a Population-based RCT 
nested in Routine Care in Sweden 
 
Study ID: VIPVIZA 
Protokollversion: Version 4.0 
Principal Investigator, PI: Ulf Näslund, Department of Public Health and clinical medicine, 
Umeå University. 
Co-PI: Margareta Norberg, Department of Public Health and clinical medicine, Umeå 
University. 
 
 
 
 
Start of the study: 
2012-08-01    
End of study: 
2026-12-31   
 

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PROTOCOL AGREEMENT 
PI and co-PI undertake to complete the study in accordance with protocols, and, referring to national and local 
regulations, in accordance with the Helsinki Declaration: Ethical Principles for Medical Research that Include 
People. 
PI and co-PI agree, through written consent, to this Protocol and to fully participate and allow direct access to 
all documentation, including source data, for the relevant authorities. 
 
 
The agreement above is signed 
 
 
 
 
 
Signature: 
 
 
 
Date: 
 
November 10 2017 
 
Ulf Näslund, Professor  
 
 
 
Signature: 
 
 
 
Date: 
 
November 10 2017 
 
 Margareta Norberg, Associate professor  
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1 
Abbreviations and definitions.……………………………………………………………………………………..7 
2 
Supplementary files……………………………………………………………………………………………………..8 
3 
Research team, contact information…………………………………………………………………………….8 
4      Summary…………………………………………………………………………………………………………….……… 10 
5 
Background .……………………………………………………………………………………….…..………………….12 
 
5.1 Survey of the field and  rationale .................................................................................... 12 
 
5.2 Hypotheses .................................................................................................................... 13 
 
5.3 Theoretical model ........................................................................................................... 13 
6 
Objective and aims ........................................................................................................... 14 
 
6.1 Objective ........................................................................................................................ 14 
 
6.2 Specific aims ................................................................................................................... 14 
7 
Endpoints .......................................................................................................................... 15 
 
7.1 Primary endpoints (or effect variable?) ........................................................................... 15 
 
7.2 Secondary endpoints ...................................................................................................... 15 
8 
Project description ........................................................................................................... 15 
 
8.1 Study design ................................................................................................................... 15 
 
8.2  Time plan…………………………………………………………………………………………………………………………..15 
 
8.3  Setting and research environment……………………………………………………………………………………16 
 
8.4 Risk-benefit evaluation ................................................................................................... 16 
 
8.5 Discontinuation of the study ........................................................................................... 17 
 
8.6 Pilot study ...................................................................................................................... 17 
9 
Study plan, the main study….............................................................................................17 
 
9.1 Flowchart………………………………………………………………………………………………………………………..17 
                 9.2 Visits……………………………………………………………………………………………………………………………18 
9.2.1  Baseline visit, participation in VIP…………………………………….………………………………18 
9.2.2 Baseline visit, ultrasound examination……………………………………………………………..18 
9.2.3 Follow-up after one year…………………………………………………………………..………………18 
9.2.4 Follow-up after three years………………………………………………………………………………18 
                9.3 Activity scheme…………………………………………………………………………………………………………….19 
10      Study population…………………………………………………………………………………………………………………20 
 
10.1 Target group and invitation ........................................................................................... 20 
 
10.2 Selection  criteria …………………………………………………………………………………………….…………...20 
 
         10.2.1 Inklusion criteria ......................................................................................................... 20 
 
         10.2.2 Exklusion criteria ........................................................................................................ 20 
11 Examinations and measurements ................................................................................... 21 
 
11.1 Demography, socio-economic and psychosocial data…………………………………………………….21 
 
11.2 Life style anad health status………………………………………………………………………………………….21 
 
11.3 Clinical risk factors for CVD ........................................................................................... 21 
 
11.4 Psychometric data…………………………………………………………………………………………….…………..21 
 
11.5 Ultrasound data…………………………………………………………………………………………………………….22 
 
11.6 Qualitative data ……………………………………………………………………………………………………………22 
 
11.7 Biomarkers ................................................................................................................... 22 

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11.8 Registry data ................................................................................................................ 22 
 
         11.8.1 Pharmacological treatment…………………………………………………………………………………….22 
              11.8.2 Socio-economic status……………………………………………………………………………………….………23 
              11.8.3 Cognitive characteristics……………………………………………………………………………………………23 
 
      11.8.4 Clinical events ................................................................................................................ 23 
12   Intervention and control……………………………………………………………………………………………………....23 
12.1 Randomization and invitation to visits…………………………………………………………………………….23 
12.2 Intervention group…………………………………………………………………….………………………………….…23 
12.2.1      Procedures………………………………………………………………………………….................23 
12.2.2      Image based pictorial information…………………………………………………………26 
12.3 Control group, procedures ………………………………………………………………………………………………27 
13    Statistical analyses and considerations..................................................................................27 
 
13.1 Power and number of participants ................................................................................ 27 
 
13.2 Statistical analyses ………………………………………………………………………………………………............28 
13.2.1      Dataset and study population ……………………………………………………………………28 
13.2.2      Interim analyses ………………………………………………………………………………………..28 
13.2.3     Summary of planned analyses …………………………………….……………………………..28 
 
13.3 Planned drop-ut analysis………………………………………………………………………………………………….30  
13.3.1     Non participants to participation…………………………………………………………….….30 
13.32      Drop outs at one year follow-up………………………………………………………………...30 
13.3.3     Drop outs at three year follow-up……………………………………………………………...30 
14 Study administration…………………………………………………………………………………………………………….31 
 
14.1 Procedures for collection of Informed Consent……………………………………………………..........31 
 
14.2 Definition of sorce data ................................................................................................. 31 
 
14.3 Quality control .............................................................................................................. 32 
 
14.4 Quality assessment……………………………………………………………………………………………………….32 
 
14.5 End of the study ............................................................................................................ 32 
 
14.6 The VIPVIZA research data base and its management .................................................... 32 
14.7 Import of data to the database…………………………………………………………………………………………33 
 
14.8 Proposal application system and data handling ............................................................. 33 
15 Ethical and legal aspects .................................................................................................. 34 
 
15.1 Ethical considerations ................................................................................................... 34 
 
15.2 Approval of the study……………………………………………………………………………………………………35 
15.3 Major amendments………………………………………………………………………………………...........36 
16 Funding of the study and insurances...................................................................................... 36 
17 References ................................................................................................................................... 37 
 
 
 
 
 
 
 

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1. Abbreviations and definitions 
VIPIVZA 
VIsualiZation of asymptomatic Atherosclerotic disease for optimum 
cardiovascular prevention ─ a pragmatic randomized controlled trial nested in 
the Västerbotten Intervention Program. The setting is highlighted by VIP 
positioned first in the acronym. 
 
 
BMI 
Body Mass Index 
BMQ 
Beliefs about Medicines Questionnaire 
CIMT 
Carotid artery Intima-Media Thickness 
CVD 
Cardiovascular disease 
GCP 
Good Clinical Practice  
HDL 
High density Lipoprotein 
HbA1c 
Hemoglobin A1c 
LDL 
Low Density Lipoprotein 
KFC 
The clinical research center at Umeå University Hospital [Swedish: Kliniskt 
Forsknings Center] 
PCI 
Percutaneous Coronary Intervention.  
PTCA 
Percutaneous transluminal coronary angioplasty 
RCT 
Randomized Controlled Trial 
SCORE 
Systematic Coronary Risk Evaluation 
SP 
Study participant in VIPVIZA 
VIP 
Västerbotten Intervention PRogramme 
 
 
 
 
 
 

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2. Supplementary files 
Appendix 1 The Informed Consent form translated from Swedish to English. 
Appendix 2 VIPVIZA diagnoses clinical events and causes of death  
Appendix 3 VIPIVZA Database Description 
Appendix 4 Statistical analyses plan, primary outcomes at one-year evaluation  
Appendix 5 Monitoring plan 
All documents in Swedish are available from co-PI Margareta Norberg. This include all 
applications to the Regional Ethical Board and the respective decisions, written information 
about the study  to VIP-participants, information about VIPVIZA to district nurses and family 
physicians, written information to VIPVIZA-participants, questionnaires used in the study, 
the written report on ultrasound results and forms for postal information about results on 
CVD risk factors.  
3. Research team, contact information  
Role 
Name, title, Tel  
Institution/department/ 
address 
Function in the study 
Principal  
Investigator  
(PI) / sponsor  
Ulf Näslund, MD, PhD 
Prof 
+46 70 514 6322  
Umeå University, Department of public health 
and clinical medicine, Heart center, SE-90187 
Umeå, Sweden  
Principal 
Investigator/Sponsor 
Steering group 
Co-PI/study 
director 
Margareta Norberg, MD, PhD 
Associate prof 
+46 70 187 1335 
Umeå University, Department of public health 
and clinical medicine, Epidemiology and 
global health, SE-90187 Umeå, Sweden  
Co-PI/Study director 
Steering group 
Co-
Investigators 
Per Wester, MD, PhD 
Prof 
Tel +46 70 328 0001 
Umeå University, Department of public health 
and clinical medicine, Stroke Center, SE-90187 
Umeå, Sweden  
Researcher 
Steering group 
Christer Grönlund, PhD 
title 
tel +46  70 330 4544 
Umeå University, Department of Radiation 
sciences, SE-90187 Umeå, Sweden  
Researcher 
Steering group 
Bernt Lindahl, MD, PhD 
Associate prof 
Tel +46 70 2737 805 
Ume Umeå University, Department of public 
health and clinical medicine, Behavioral 
Medicine, SE-90187 Umeå, Sweden å 
Researcher 
Steering group 
Joakim Rocklöv 
Associate prof 
Tel +46 70 636 1635 
Umeå University, Department of public health 
and clinical medicine, Epidemiology and 
global health, SE-90187 Umeå, Sweden 
Statistician, researcher 
Steering group 
Patrik Wennberg, MD, PhD 
Associate prof 
Tel +46 73 832 8819 
Ume Umeå University, Department of public 
health and clinical medicine, Family Medicine, 
SE-90187 Umeå, Sweden å 
Researcher 
Steering group 
Stefan K Nilsson, PhD 
Tel +46 70 578 1768 
Umeå University, , Department of Medical 
Biosciences, Unit of Physiological chemistry , 
SE-90 187 Umeå, Sweden 
Researcher 
Steering group 
Bertil Lindahl 
Prof 
+46 701429580 
Uppsala university, UCR-Uppsala Clinical 
Research Center, SE-75183 Uppsala 
Researcher 
Steering group 

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Role 
Name, title, Tel  
Institution/department/ 
address 
Function in the study 
Bo Carlberg, MD, PhD 
Ass prof 
+46 70 577 5883 
Umeå University, Department of public health 
and clinical medicine, Medicine, SE-90187 
Umeå, Sweden 
Researcher 
Steven Nordin, PhD 
Prof  
Tel +46 70 609 6006 
Umeå University, Department of psychology, 
SE-90187 Umeå, Sweden 
Researcher 
Maria Nordin, PhD 
Associate prof 
+46 90 7869924 
Umeå University, Department of psychology, 
SE-90187 Umeå, Sweden 
Researcher 
Maria Sjölander, PhD 
Post doc 
Tel +46 73 736 4804 
Umeå University, Department of public health 
and clinical medicine, SE-90 187 Umeå 
Researcher 
Gunilla Olivecrona MD, PhD 
Prof 
+46 70 5480262 
Umeå University,  Department of Medical 
Biosciences, Unit of Physiological chemistry, 
SE-90 187 Umeå 
Researcher 
Per Lindqvist 
Associate prof 
+46 707601502 
Umeå University, Department of Surgery and 
perioperative sciences, Clinical physiology, 
Heart Centre, SE-90 187 Umeå, Sweden 
Researcher 
Helene Johansson,PhD, 
Physioteraphist 
+46 73 025 5173 
Umeå University, Department of public health 
and clinical medicine, Epidemiology and 
global health, SE-90187 Umeå, Sweden 
Researcher 
Eva Fhärm, 
MD, PhD 
+46 70 351 5166 
Umeå University, Department of public health 
and clinical medicine, Family Medicine, SE-
90187 Umeå, Sweden å 
Researcher 
Kristina Lindvall, PhD, 
Dietician 
Tel +47 70 584 5952 
Umeå University, Department of public health 
and clinical medicine, Epidemiology and 
global health, SE-90187 Umeå, Sweden 
Researcher 
Nawi Ng, Md, PhD 
Prof 
Tel +46 72 540 3851 
Umeå University, Department of public health 
and clinical medicine, Epidemiology and 
global health, SE-90187 Umeå, Sweden 
Researcher 
Davide Vanoli MD, PhD 
MD, PhD 
+46 070 396 1161 
Umeå University, Department of public health 
and clinical medicine, Heart center, SE-90187 
Umeå, Sweden 
Researcher 
Publication 
manager 
Rachel Nicoll, PhD 
Research assistant 
Tel +44 7917 787350 
Umeå University, Department of public health 
and clinical medicine, SE-90187 Umeå, 
Sweden 
Publication manager, 
researcher 
Data base 
manager 
Wolfgang Lohr 
+46 90 7865205 
Umeå University, Department of public health 
and clinical medicine, Epidemioogy and global 
health, SE-90187 Umeå, Sweden 
Data base manager 
Doctoral 
Students 
Anna Lundgren  MD 
Emma Nyman 
Fredrik Landfors 
Oleg Kovrov 
Ka Chung Tsan  
Monitor 
Clinical Trial Unit 
Unit for clinical research, Västerbotten county 
council, SE-908   Umeå 

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4. Summary   
Scientific title:  
Visualization of Asymptomatic Atherosclerotic Disease for Optimum 
Cardiovascular Prevention: VIPVIZA – a Population-based RCT nested 
in Routine Care in Sweden 
Principal Investigator 
Study director  
Ulf Näslund 
Margareta Norberg 
Study   period 
2012-08-01─2026-12-31 
Hypotheses and aims 
 
VIPVIZA has three distinct, but complementary hypotheses: 
Pictorial representation of asymptomatic atherosclerotic 
disease, assessed with carotid ultrasound, has the potential to 
identify individuals at high risk of CVD with higher precision 
than conventional risk factor-based statistical models. 
The clear understanding of an image of arterial disease during 
an early asymptomatic phase is of superior value in optimizing 
adherence to clinical preventive management for both 
physicians and patients, Literally, the English quotation is ‘A 
picture speaks a thousand words’.  
The resulting preventive management will improve control of 
premature CVD. 
Specific aims 
To assess the prevalence of asymptomatic atherosclerotic 
disease in men and women through identification of carotid 
plaques and measurement of CIMT, and to relate plaques and 
CIMT to clinically estimated CVD risk factors.  
To assess the impact of visualization of atherosclerosis on 
quality of life, preventive measures, risk factor control and 
progress of atherosclerotic disease over the course of three 
years. 
To explore the impact of visualization of atherosclerosis, as a 
low-intensive preventive intervention, on physicians´ and 
patients´ risk perception, communication and attitudes to CVD 
prevention. 
To evaluate how individuals’ health literacy and coping 
strategies relate to CVD risk at baseline, attitudes to screening, 
risk perception and preventive measures. 
To investigate novel biomarkers in relation to CIMT and 
plaques at baseline, changes in conventional CVD risk markers 
and lifestyle, and progression of atherosclerosis.  
To assess the impact of visualization of atherosclerosis by 
carotid ultrasound on premature CVD morbidity and mortality 
over the course of 5 and 10 years. 
Primary outcome 
SCORE and Framingham risk scores 

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Secondary outcomes 
CVD risk factors, lifestyle, ultrasound results (CIMT, presence of 
plaque, quantitative and qualitative plaque parameters, presence and 
degree of significant stenosis), prescriptions and purchases of 
medications (for the treatment of hypertension, dyslipidemia and 
diabetes), biochemical markers, and the clinical endpoints myocardial 
infarction, stroke, revascularization procedures and mortality (all-
cause and CVD-specific).  
Study design 
A pragmatic randomized controlled trial nested within routine clinical 
care  
Study population  
Subjects aged 40, 50 or 60 years, invited as part of their VIP participation 
within Västerbotten primary healthcare. 
No:3700 
Follow-up period 
10 years from first ultrasound examination 
Inclusion criteria 
 
• 
age=40 years and first-degree relative with history of CVD at 
age <60 years  
• 
age=50 years and at least one of the following: first-degree 
relative with history of CVD at age <60 years, smoking, 
diabetes, hypertension, S-LDL cholesterol ≥4.5 mmol/L, 
abdominal obesity 
• 
age=60 years 
Individuals are included in the study only once, at whichever qualifying 
age point is achieved first. 
 
Statistical methods 
The differences in primary outcomes (SCORE risk and Framingham Risk 
Score) at one year between the treatment groups will be measured and 
analyzed using t-test. Differences in changes of SCORE and FRS from 
baseline to 1-year follow-up will be analyzed with regression methods 
to identify predictors of the changes in the scores. 
Survival curves will be established using Kaplan-Meier curves for CVD 
mortality and morbidity at 5 and 10 years of follow up comparing the 
intervention to the control group. Predictive Cox Proportional Hazard 
models will be developed to estimate the overall predictive ability of 
CIMT, plaque and risk factors on CVD morbidity and mortality at 5 and 
10 years. 
Health economic modelling studies will be performed for evaluation of 
cost-effectiveness. Interviews with participants and physicians will be 
analyzed using qualitative content analysis. 
Evaluation criteria  
Primary and secondary outcomes will be evaluated according to 
Intention-to-treat methodology 

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5. Background 
5.1Survey of the field and rationale for the trial 
Primary prevention of cardiovascular disease (CVD) often fails due to the low precision of the 
conventional risk scores, and poor adherence among practitioners and patients to evidence-based 
prevention guidelines. Moreover, these risk scores focus on high-risk individuals only, despite 60-70% 
of all CVD events occurring among individuals at low or intermediate risk for CVD (1).  VIPVIZA takes a 
different approach from current practice for the prevention of CVD. Instead of being based solely on 
indirect risk factors, this project evaluates the atherosclerotic disease itself while it still is silent, 
providing improved assessment, communication and perception of the CVD risk and higher 
motivation for prevention. 
  
The evidence for effective modification of risk factors by lifestyle change and pharmacological 
treatment is well established. Despite this, suboptimal adherence to CVD prevention guidelines 
among practitioners and patients leads to poor risk factor control in both primary and secondary 
prevention (2-4). Contributory factors include poor communication about the CVD risk by the 
physician, inaccurate risk perception and lack of awareness of the weak association between the 
actual estimated and perceived CVD risk among patients(5, 6). The risk message is usually 
communicated verbally or numerically (7), while potentially more effective visual tools are seldom 
used. In addition to the format and framing of the message, the perceived risk also depends on social 
and cultural factors (8).  
Moreover, for the success of risk management, the extent of the patient’s behavioral change is 
crucially dependent on their psychological characteristics. The individual’s ability to cope with 
stressful situations (coping strategy) (9), trust in their own capability to change behaviour (self-
efficacy) (10), level of positive expectations in life (dispositional optimism) (11), and health literacy 
(capacity to understand health information and make appropriate related health decisions) (12) are 
important. Rational choices due to increased risk awareness often fail, and knowledge about a risk, 
on its own is rarely enough for sustainable behavioural change. These aspects are usually ignored in 
the field of primary prevention (13). For CVD prevention programs to be effective, a more person-
centred approach towards the individual’s clinical and behavioural change may need to be 
implemented (14), and in order to make use of existing evidence-based methods to the fullest 
extent, both the physicians’ and individuals’ adherence to existing CVD prevention guidelines should 
be targeted.  
An alternative strategy to evaluate and improve CVD risk communication would be to directly view in 
pictorial form the degree of atherosclerotic disease before symptoms develop, rather than to 
indirectly evaluate risk factors of atherosclerosis (15-17). This is achieved with ultrasonography of 
medium sized arteries with assessment of carotid artery intima-media thickness (CIMT) and existing 
atherosclerotic plaques, which have a clearly higher predictive power for plaques. Pharmacological 

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and lifestyle interventions have the potential to slow down or even reverse the progress of 
ultrasound-assessed atherosclerosis (18, 19), but results on the contributory impact from image-
based information on adherence to prevention are inconsistent (20, 21). 
Therefore, large-scale randomized controlled trials (RCTs) targeting low and intermediate-risk adults 
with a focus on assessing the impact of viewing an image of existing silent disease on the 
stratification and communication of CVD risk to physicians and patients, as well as on major clinical 
outcomes, should be prioritized (1, 2, 21).  
5.2 Hypotheses 
VIPVIZA has three distinct, but complementary hypotheses: 
 
- 
Direct viewing of a pictorial representation of asymptomatic atherosclerotic disease, 
assessed with carotid ultrasound, has the potential to identify individuals at high risk of CVD 
with higher precision than conventional risk factor-based statistical models. 
- 
The clear understanding of an image of arterial disease during an early asymptomatic phase 
is of superior value in optimizing adherence to clinical preventive management for both 
physicians and patients: ”A picture speaks a thousand words”.  
-     The resulting preventive management will improve the control of premature CVD. 
5.3 Theoretical model 
Social, genetic, psychological and behavioral mechanisms impact the subclinical molecular processes 
that manifestas clinical risk factors and the subclinical morphologic atherosclerotic process, and 
eventually in clinical cardiovascular disease events or death. 
Athero-
sclerosis
Clinical
Risk factors
Biomarkers
Inflammation
Insulin resistance
Lipid changes
Endothelial dysfunction
Oxadative stress
Brown adipose tissue activation
Ect.
Behavioural 
change
Medication
Lifestyle
Health
Literacy 
CVD risk
information
CVD
Death
Genes
Stress
Anxiety
Coping
Moti-
vation
Self-
efficacy
Opti-
mism
Demographics
Socioeconomy
 

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6. Objective and aims 
6.1 Objective 
To assess the impact of a visual image and pictorial report, seen and discussed by both physician and 
patient, for improving guideline adherence and patient perception and understanding of the CVD risk 
and consequent motivation for prevention. The extent of the impact is assessed by differences 
between randomization groups in Framingham Risk Score and SCORE as well as changes in these 
scores after one and three years. Differences between groups will also be evaluated by risk factor 
assessment and a further scan after three years to determine disease progression, and a comparison 
of the prevalence of acute events and mortality at five and 10 years. 
6.2  Specific aims 
1.  To assess the prevalence of asymptomatic atherosclerotic disease in men and women 
through identification of carotid plaques and measurement of CIMT, and to relate plaques 
and CIMT to clinically estimated CVD risk factors.  
2.  To assess the impact of pictorial representations of atherosclerosis on quality of life, 
preventive measures, risk factor control and progress of atherosclerotic disease over the 
course of three years. 
3. To explore the impact of pictorial representations of atherosclerosis, as a low-intensive 
preventive intervention, on physicians´ and patients´ risk perception, communication and 
attitudes to CVD prevention. 
4. To evaluate how individuals’ health literacy and coping strategies relate to CVD risk at 
baseline, attitudes to screening, risk perception and preventive measures. 
5. To investigate biomarkers in relation to CIMT and plaques at baseline, changes in 
conventional CVD risk markers and lifestyle, and progression of atherosclerosis.  
6. To assess the impact of the pictorial representation of atherosclerosis by carotid ultrasound 
on premature CVD morbidity and mortality over the course of 5 and 10 years. 

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7. Endpoints 
7.1 Primary endpoints:  
7.1.1 
SCORE (22) 
7.1.2 
Framingham risk score (23)   
7.2 Secondary endpoints  
7.2.1 
CVD risk factors (blood pressure, serum cholesterol, LDL, HDL, triglycerides, 
fasting glucose, HbA1c) 
7.2.2 
Lifestyle (physical activity, tobacco use, alcohol use, eating habits) 
7.2.3 
Ultrasound results (CIMT, presence of plaque, quantitative and qualitative 
plaque parameters, presence and degree of significant stenosis)  
7.2.4 
Pharmacological treatments of hypertension, dyslipidemia and diabetes, 
prescriptions and purchases  
7.2.5 
Biochemical biomarkers 
7.2.6 
Clinical endpoints: Hospitalizations due to CVD, diagnostic and therapeutic 
revascularization procedures (PTCA, PCI, stent) regarding atherosclerotic disease 
and deaths (all-cause and CVD-specific), as specified in Appendix 2:  VIPVIZA 
diagnoses clinical events and causes of deaths 
7.2.7 
Quality of life. 
 
8 
Project description  
8.1 Study design The design is a pragmatic randomized controlled trial (24, 25). 
8.2 Time plan A summary of the time plan for participants’ visits in the study as well as for 
interviews and acquisition of register data from the National Board of Health and Welfare is 
shown in the figure below. 
 

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8.3 Setting and research environment 
VIPVIZA is integrated in the Västerbotten Intervention Program (VIP) (26), which is a population-
based CVD screening and prevention program in the County of Västerbotten, Sweden (population 
265,000). Since the 1990s, VIP has provided health surveys for all county inhabitants during the year 
in which they turn 40, 50 and 60 years (n=6500-7000/year), comprising CVD risk factor screening and 
individual promotion of healthy lifestyle and pharmacological CVD prevention.  
 
To date, over 170,000 health surveys have been performed. Participation rates during recent years 
were around 60-70% with only small social selection bias (27). VIP is one of the largest long-term CVD 
prevention programs in the world. It provides a unique arena for pragmatic studies of population-
based CVD risk intervention 
 
The ultrasound examinations in VIPVIZA are performed at the hospitals in three cities/towns (Umeå, 
Skellefteå, Lycksele), and in remote rural areas at primary health care centres.  Risk factor 
measurements and questionnaires at follow-up are carried out for participants in Umeå at the 
Clinical Research Centre at Umeå University Hospital, and for participants in the rest of the county at 
their local primary health care center.  
8.4 Risk-benefit evaluation for the individual  
The intervention in VIPVIZA is the provision of pictorial information about the presence and extent of 
the individual’s atherosclerosis from their ultrasound results. This is considered to be a low-intensity 
intervention in comparison to interventions with pharmacological drugs or surgical procedures. The 
ultrasound examination cannot cause any harm, physical discomfort or risk.  
As with all screening which targets a healthy population, it is a dilemma whether or not to inform 
asymptomatic individuals of silent disease, in this case an ongoing atherosclerotic process with 
increased risk of future CVD. The presence of atherosclerosis can be perceived by the subject as 
more serious than just an increased level of risk markers, and may therefore result in anxiety. In 
order to avoid unjustified concerns, all persons in the intervention group receive a telephone call 
from a research nurse and, if necessary, a doctor in charge, to give in-depth and balanced 
information about the ultrasound results. This conversation is conducted according to the 
methodology of motivational interviewing and also aims to increase awareness of the possibility of 
reducing the individual’s risk by means of their own preventive measures. This is expected to 
alleviate anxiety and increase motivation to follow the recommendations for preventive treatment. 
According to the study hypotheses, this is expected to benefit the individual due to risk reduction 
and a more healthy lifestyle is also expected to bring benefits through increased well-being and 
quality of life. Similarly, subjects without ongoing atherosclerotic disease will be able to avoid 
unjustified concerns that their risk factors, if any, may be contributing to an active disease process.  
All individuals with severe carotid stenosis will be excluded from the study and are referred directly 
to the Stroke Center for assessment and treatment. This may potentially be life-saving for these 
people, and may, to some extent, mitigate the fact that no information is provided to half the group 
until 3 years after they enter the study, even if small/moderate changes are detected.  
 

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8.5 Discontinuation of the study 
Individuals at high risk of stroke, defined as severe carotid stenosis, i.e. stenosis >50% of the lumen, 
are excluded from the study, informed of the results and referred to the Stroke Center, University 
Hospital, Umeå, with treatment in accordance with current guidelines for this group.  
8.6 Pilot study  
A pilot study with 95 participants was performed September-October 2012. The study organisation 
worked well and protocols and procedures were further developed and showed good feasibility, 
although randomization to intervention and control groups was not carried out. In order to optimize 
understanding of atherosclerosis as a process and the accurate perception of the ultrasound result, 
the information was calibrated according to participants’ experiences and suggestions, collected 
through questionnaires and interviews. After 3 years, complete data on risk factors from 81 pilot 
participants was collected, and favorable changes regarding LDL-cholesterol, triglycerides and fasting 
glucose were observed, with the addition of favorable weight changes among women only.  
 
9. Study plan, the main study 
9.1 Flow chart 
Eligible, Informed consent
N ~3700
Stenosis >50%
Specialized care
n <1%
Intervention group: Information 
about ultrasound results
Control group: No information
Visit 2 after one year: Cardiovascular risk factors and questionnaires
Visit 3 after 3 years: Carotid ultrasound 2, cardiovascular risk factors and questionnaires
Clinical events at 5 and 10 years
Visit 1: Randomization, inclusion.
Carotid ultrasound 1, 
Psychometric questionnaires
Västerbotten Intervention Programme
Health survey in routine primary health care
Measurements of cardiovascular risk factors
and questionnaire
 

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9.2 Visits 
9.2.1 Baseline visit, participation in VIP. Data collection: demographic, socio-economic, 
clinical risk factors for CVD, and lifestyle. This data is used in an individual health dialogue with a 
trained district nurse at the primary health care center. Applying the methodology of Motivational 
Interviewing, this session aims at health promotion and CVD prevention. A pictorial tool, the “Star 
profile” (Figure below), is used to facilitate the individual’s understanding of how his/her lifestyle is 
linked to CVD risk factors.  
 
Tobacco
Self reported 
health
Physical 
Activity
Sitting
time
Lipids
BMI
waist
Blood
pressure
Oral glucose
tolerance
Eating 
habits
Alcohol
© Dr Claes Lundgren, Skellefteå Sjukvård
Tobacco
Self reported 
health
Physical 
Activity
Sitting
time
Lipids
BMI
waist
Blood
pressure
Oral glucose
tolerance
Eating 
habits
Alcohol
© Dr Claes Lundgren, Skellefteå Sjukvård
 
When requested, VIP-participants are also recommended follow-up visits or referrals to the 
family physician for pharmacological treatment according to guidelines. Samples of blood are frozen 
andstored at the Biobank, Umeå University Hospital. 
VIP participants who are eligible for participation in VIPVIZA are given written and verbal information 
about the VIPVIZA study and are invited to the study at the occasion of their participation in VIP at 
their primary health care centre. The district nurses who conduct the health dialogues also sign that 
the study information is given and collect the informed consent forms and send them to research 
nurses at KFC. The research nurses register all forms. Appendix 1: The Informed Consent form 
translated from Swedish to English 
9.2.2 Baseline visit with ultrasound examination. Study participants are randomized into 
two equal groups, intervention and control, following a computer-generated randomization list. They 
then complete psychometric questionnaires, questions about self-rated risk of CVD and health-
specific self-efficacy, and undergo the first ultrasound examination of both carotids. Written 
information about results are sent to those in the intervention group and their respective family 
physician in primary care.  
9.2.3 Follow-up one year after the ultrasound examination. Measurement of clinical risk 
factors for CVD, lifestyle, self-reported pharmacological treatment, self-rated health, risk of CVD and 
health-specific self-efficacy. Framingham Risk Score and Score are estimated. 
9.2.4 Follow-up three years after the ultrasound examination Data collection: clinical risk 
factors for CVD, completion of lifestyle questionnaire, psychometric questionnaires, questions about 
self-rated risk of CVD and health-specific self-efficacy. Participants also undergo the second 
ultrasound examination of both carotids. Samples of blood are drawn, frozen and stored at the 

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Medical Biobank, Umeå University Hospital. Written information about ultrasound results are sent to 
all SPs and their respective family physicians in primary care.  
 
9.3 Activity scheme    
 
Base line 
Follow-up 
Action defined 
 
Visit 1 
VIP 
exam 
Visit 2 
Ultrasound 
Visit 3 
1 year 
 
Visit 4 
3 years 
5 
and 
10 
years 
 
Informed consent 
X 
 
 
 
 
9.2.1, 11.1, 12.1, 
14.1 
Clinical risk markers 
X 
 
X 
X 
 
9.2.1, 9.2.3, 9.2.4, 
11.3, 12.2, 12.3 
Lifestyle habits 
X 
 
X 
X 
 
9.2.1, 9.2.3, 9.2.4, 
11.2, 12.2.1, 12.3 
Demographic 
socioeconomyic and 
psychosocial factors 
 
 
 
 
 
9.2.1, 11.1, 11.8.2 
Ultrasound 
examination 
 
X 
 
X 
 
9.2.2, 9.2.4, 11.5, 
12.2.1, 12.2.2, 12.3 
Psychometric 
questionnaires 
 
X 
 
X 
 
9.2.2, 9.2.4, 11.4, 
11.8.3 
Self-rated health, 
risk of CVD and 
health-specific self-
efficacy 
 
X 
X 
X 
 
9.2.1, 9.2.2, 9.2.3, 
9.2.4, 11.4, 12.2.1 
Interviews with GPs 
 
X 
 
 
 
11.6, 12.2.1 
Interviews with 
study participants 
 
X 
 
X 
 
11.6, 12.2.1 
Pharmacological 
treatment 
X 
 
X 
X 
 
9.2.1, 9.2.3, 9.2.4, 
11.2, 11.8.1 
Biomarkers 
X 
 
 
X 
 
9.2.1, 9.2.4, 11.7 
Hospitalizations 
registry data 
 
 
 
 
X 
11.8.2, 11.8.4 
Deaths 
registry data 
 
 
 
 
X 
11.8.2, 11.8.4 
 
 

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10 Study population 
10.1 Target group and invitation 
The study focuses on subjects at intermediate risk of CVD. Based on VIP data from 2012, around 60% 
of all VIP participants of 40, 50 and 60 years of age, i.e. n= 4000/year, was estimated to be at 
moderate risk of CVD due to having at least one conventional CVD risk factor (see below for inclusion 
criteria). Since VIP is on-going continuously in primary care, inclusion can continue until the desired 
number of SPs is reached. 
VIP participants who are eligible for participation in VIPVIZA are given written and verbal information 
about the VIPVIZA study and are invited to the study at the occasion of their participation in VIP at 
their primary health care centre. The district nurses who conduct the health dialogues also sign that 
the study information is given and collect the informed consent forms and send them to research 
nurses at KFC. The research nurses register all forms (baseline visit performed in the VIP). 
10.2 Selection criteria 
10.2.1 Inclusion criteria were based on 1/ the aim of targeting subjects at 
intermediate risk of CVD, and 2/established clinical criteria (smoking, 
diabetes, hypertension, abdominal obesity) or evaluation of levels and 
distribution of clinical CVD risk markers (S-LDL) in the 2011 VIP population. 
In this population, the cut-off for the 4th quartile among 50 years old men 
and women was 4.4 mmol/L and 4.0 mmol/L, respectively, while 9% and 12% 
respectively had S-LDL concentrations ≤2.5 mmol/L, and 81% and 88% 
respectively had S-LDL concentrations ≤4.5 mmol/L.  
• 
age=40 and a history of CVD at age <60 years among first-degree 
relative(s)  
• 
age=50 years and at least one of the following: a history of CVD at age 
<60 years among first-degree relative(s), smoking, diabetes, 
hypertension, S-LDL-cholesterol ≥4.5 mmol/L, abdominal obesity defined 
by waist >88cm for women and >102 cm for men  
• 
age=60 years 
Individuals are included in the study only once, at whichever qualifying age 
point is achieved first. 
 
10.2.2 Exclusion criteria 
Significant stenosis as defined as >50% luminal narrowing of the investigated carotid arteries according 
to vascular ultrasound. These individuals are informed about results irrespective of randomization 

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status, are excluded from the study and referred to the Stroke Center, Umeå University Hospital, for 
further evaluations and treatment. 
11 
Examinations and measurements 
 
                  11.1    Demography, socio-economic and psychosocial data 
From the baseline VIP questionnaire:  Age, sex,  civil status, education, family history of premature 
CVD and diabetes, social  network and support according to the International schedule on social 
interaction (Swedish version) (28) and work stress (according to the Karasek-Theorell 
demand/control  model) (29). 
 
 
11.2    Lifestyle and health status 
From VIP data at base line and at 1- and 3-year follow-up visits: Questionnaire data including self-
reported physical activity, sitting time, tobacco habits, alcohol (AUDIT questionnaire), diet (food-
frequency questionnaire, except at the 1-year visit), self-rated health, self-reported (known) diabetes 
as well as blood pressure and lipid-lowering pharmacological treatment. At 3-year follow-up, the 
Swedish version of the Beliefs about Medicines Questionnaire (BMQ) (30, 31)was also added from 
March 2017. 
 
 
11.3    Clinical risk factors 
At baseline, 1- and 3-years. Measurements:  
• 
Anthropometrics: Waist is measured on the skin at the point mid-way between the 
last palpable rib and the iliac crest, using a non-elastic measuring tape; height and weight are 
measured in light clothing without shoes using calibrated scales and stadiometers.  
• 
Systolic and diastolic blood pressure is measured twice with a calibrated digital blood 
pressure gauge at the precision of 2 mm after 5 minutes rest with the subject in a sitting position. 
The mean value of the two systolic and diastolic measurements are recorded. 
• 
Lipids: Blood samples for serum-cholesterol, serum-LDL, serum-HDL, serum-
triglycerides are drawn after an overnight fast and sent to the department of Clinical Chemistry at 
the nearest local hospital and analyzed with standard clinical biochemical methods. The three 
hospital labs in the county are all quality assured. 
• 
Glucose status: Within the VIP (26), at baseline after an overnight fast, an oral glucose 
tolerance test is carried out according to WHO standards, with measurements of capillary fasting 
plasma glucose and 2-hour plasma glucose (32). At 1- and 3-year follow-up, capillary fasting plasma 
glucose is measured using HemoCue® Glucose  analyzer (HemoCue AB, Ängelholm, Sweden). 
 
 
11.4    Psychometric data 
Psychometric data will be utilized as moderators and/or mediators of the intervention effect on 
primary and secondary outcomes, and also as outcomes at 3-year examination. At baseline and 3-
year examination: Health literacy (33), Coping strategies (Brief Cope) (34), General Self-Efficacy (35) , 
Anxiety and Depression  (HAD) (36), Optimism/Pessimism (LOT-R) (37). At base-line, 1- and 3-year 
follow-up there are also questions about self-rated health (5 alternatives) (38), self-rated risk of CVD 
and health-specific self-efficacy (ability to reduce the CVD risk through preventive actions) using a 

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VAS scale 0-10. In a subset of the study population, the Newest Vital Sign test on health literacy (39) 
was added to the questionnaire at 1-year follow-up from January 2017 until completion of 1-year 
visits in August 2017. 
 
 
11.5    Ultrasound data 
IMT variables measured at specific positions and angles on both sides of the arteria carotis. Since 
there is no international consensus on which specific IMT measurement to use optimally, in 
particular in early stage atherosclerosis, a separate explorative analyses will be performed on this 
issue. Vascular age is calculated based on IMT and related to IMT values among subjects matched for 
sex and age in the Atherosclerosis Risk In Communities study population (ARIC) (40). This reference 
study was selected due to similarity with risk factor patterns in the VIP population. Plaque is defined 
according to the Mannheim Consensus (41). The presence of plaque on both sides of the carotid 
artery, plaque area and plaque texture are recorded. 
 
 
11.6    Qualitative data  
 
Telephone interviews with around 25 purposively sampled participants from the intervention group 
(based on age, sex, ultrasonography results) are conducted within four weeks of receiving the 
baseline ultrasound information, as well as at 3-year follow-up. Interviews will also be performed 
with practitioners, who have received at least five different patients’ ultrasound results, to explore 
how viewing the ultrasound results affects physicians´ perceptions of their patients’ risk, the 
communication with patients and attitudes to treatment of CVD risk factors. 
 
 
11.7    Biomarkers 
Plasma samples are collected at baseline for the entire study population and in a subsample of SPs 
living in Umeå and surrounding municipalities. These samples are centrifuged and stored at -80º C at 
the Medical Biobank, Umeå University Hospital, to be analyzed at the 3-year follow-up for 
hypothesized CVD biomarker. Examples ares: 
• 
The end product of oxidized LDL detected via autoantibodies against distinct apoB peptides 
and its prospective correlation to current atherosclerotic burden (42, 43).  
• 
Bile acid receptors: the farsenoid xenobiotic receptor (FXR) and the G-protein coupled 
receptor TGR5 (44) and their longitudinal role related to CVD.  
• 
Lipoprotein lipase (LPL) activity (45) to assess whether substrate differences for LPL 
translates into predictive risk changes (Lookene et al. in preparation). 
• 
Metabolomics, particularly lipidomics: (Umeå Plant Science Centre, SciLifeLab, and Uppsala 
Clinical Research Centre, Sweden) 
 
11.8    Registry data 
 
11.8.1 Pharmacological treatment: At baseline, 1 and 3 years: Prescriptions  retrieved 
from medical records in the Västerbotten County Council digital system registries. At 1 and 3 years: 
purchases of pharmacological products from the Statistics on Pharmaceuticals at the National Board 
of Health and Welfare. 

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11.8.2 Socio-economic status: Income and highest attained educational level from 
Statistics Sweden. 
 
11.8.3 Cognitive characteristics at age 18 (males only): The Conscripts register at the 
National Archives Database. 
 
11.8.4 Clinical events: From data retrieved from registers at the National Board of 
Health and Welfare at 5 and 10 years after the last ultrasound examination: Hospitalizations due to 
cardiovascular morbidity and diagnostic and therapeutic procedures and mortality (all-cause and 
CVD-specific), according to the International Classification of Diagnoses ICD10, as specified in  
Appendix 2 VIPVIZA diagnoses clinical events.  
  
12 
Intervention and control 
12.1 Randomization and invitations to visit.  
VIP participants who are eligible for participation in VIPVIZA are given written and verbal information 
about the VIPVIZA study and are invited to the study at the occasion of their participation in VIP at 
their primary health care centre. The district nurses who conduct the health dialogues also sign that 
the study information is given and collect the informed consent forms and send them to research 
nurses at KFC. The research nurses register all forms.  
SPs are then randomized to two equal groups (intervention and control group) before the first 
ultrasound examination. The randomization list is generated prior to the study through simulation 
from a uniform probability distribution. At this stage a unique identification code is assigned to each 
SP. Invitation with appointment times for the baseline visit is sent by mail to both groups by the 
research nurses who manage the study at KFC.  
12.2 
Intervention group 
12.2.1 Procedures 
• Baseline: Research nurses send invitation letters with an appointment time for the baseline 
ultrasound examination by mail to those who gave informed consent to participation in 
VIPVIZA. One reminder letter with a new appointment time is sent to non-attenders. At this 
visit, participants answer the psychometric questionnaires and undergo the baseline 
ultrasound examination. 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 
undertaken in hospitals in three towns in Västerbotten county (Umeå, Skellefteå and 
Lycksele), and at the local primary healthcare centres in rural areas. A portable automatic 
carotid ultrasound equipment (CardioHealth Station®, Panasonic Healthcare Corporation of 
North America, Newark, NJ, USA ) is used. A standardized protocol according to current 
guidelines is applied for the examinations (46, 47). The angle of insonation is automatically 
provided by the system and is recorded. Measurements of CIMT (max, min and mean values) 

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are automatically obtained (41).  The same ultrasound machine is used during the entire 
study period. 
 
Within two weeks of the ultrasound examination, information about the carotid ultrasound 
results are sent by post to the participant, see 12.2.2. At the same time, exactly the same 
information is sent to their respective primary care physician. After an additional 2-4 weeks 
participants receive a follow-up phone call by a research nurse in order to ascertain whether 
the information was accurately understood and to reassure the participant and give 
additional information if needed.  
• Qualitative interviews with a subgroup of around 20 SPs within the intervention group 
concerning their experiences and reactions to the information about the ultrasound results. 
• Qualitative interviews with General Practitioners who have received at least five written 
reports from VIPVIZA regarding their patients. 
• At 6 months, participants receive a reminder in the form of a letter with the identical 
information about the ultrasound results and very brief reminder about possible preventive 
measures. 
• At 9 months, participants receive a letter with information about proceedings in the study 
and reminder about the 1-year follow-up. 
• At 1 year, participants receive an invitation to the follow-up visit, with an appointment time 
at KFC. This is sent by research nurses to participants living in Umeå and surrounding 
municipalities. The information is also sent to the health care centers outside the Umeå area, 
where VIPIVIZA participants are eligible for the 1-year follow-up. Nurses at these health care 
centers conduct the 1-year visits for their VIPIVZA participants. This visit includes 
measurement of risk factors and a questionnaire including self-rated health, health-related 
quality of life (RAND 36), prescribed medication for hypertension and dyslipidemia, tobacco 
and alcohol use, physical activity, usual portion sizes as an indicator of possible changes of 
eating habits, and self-rated risk of CVD as well as possibilities to reduce this risk, i.e. health-
specific self-efficacy.  
  
   The results regarding risk factor measurements are provided on a form that has been  
approved by the Steering Group and also includes recommendations for preventive 
measures depending on the levels of risk factors. This form is sent by post by the research 
nurses at KFC and district nurses at health care centers.  
   In the intervention group, the questionnaire which was sent during the spring semester 2017 
to the last 500 participants before completion of the 1-year visits, includes questions 
concerning how participants perceived and recalled the pictorial ultrasound information and 
the phone call received at baseline  
• At 2 years, a letter is sent with information about proceedings in the study and a reminder 
about the 3-year follow-up. 
• At 2.5 years, a letter is sent with repeated information about the atherosclerotic process, as 
well as general information regarding healthy eating. 

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• At the 3-year follow-up: Invitations and appointment time for the  ultrasound examination, 
risk factor measurement and questionnaire completion is sent by post to participants living in 
Umea and surrounding municipalities by research nurses at KFC; all examinations are 
conducted at KFC. Participants outside this area are also invited for ultrasound examinations 
undertaken in hospitals in the three towns in Västerbotten County (Umeå, Skellefteå and 
Lycksele), and at the local primary health care centres in rural areas. Invitations are sent only 
once, with no reminder following non-attendance.  .  Research nurses also inform the health 
care centers outside the Umeå area when it is time to invite participants to the 3-year visit, 
although this visit is managed by the health care centers, including risk factor measurements 
and questionnaire completion. At this time point, the intervention group also answer 
questions about how they perceived the pictorial information and phone call received at 
baseline concerning the ultrasound results. 
 
Results of clinical risk factor measurements and the completed questionnaires are sent to KFC 
and the research nurses give feedback to participants using a predefined form similar to the 
form used at the 1-year follow-up. 
 
Within two weeks of the carotid ultrasound examination, information about the results are 
sent by post to the participant, see 12.2.2. At the same time, exactly the same information is 
sent to their respective primary care physician. After an additional 2-6 weeks, participants 
whose ultrasound results indicated CIMT values higher than expected according to age and 
sex (red gauge) or with plaques (red), receive a follow-up phone call by a research nurse in 
order to ascertain whether the information is accurately understood and to reassure the 
participant and give additional information if needed. Participants without plaques (green) or 
vascular age similar or lower than expected (green or yellow/orange gauge) are informed by 
a standard letter  including the contact information for research nurses, in case of questions 
or concerns.  
Qualitative interviews are conducted with a few SPs, regarding their experience of receiving 
the second ultrasound report and how they interpreted this in relation to any life style 
modification carried out, including taking prescribed medications, following the first 
ultrasound examination. 
12.2.2 Image-based pictorial information  
This information was developed during the pilot phase. The original report from the 
CardioHealth station was tested and refined in communication with VIPVIZA pilot participants, 
with patients at the clinic of Behavioral Medicine, who had a different educational status and 
who had lifestyle related metabolic diseases. The research nurses’ experiences from 
discussions of the results with participants were also considered. The team of researchers 
compiled the collected impressions and developed the written information, aiming to provide 
easy and accurate understanding of the scanning result and concerning atherosclerosis as a 
dynamic process that can be modified by lifestyle changes and pharmacological treatment. A 

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technician adjusted the print scripts accordingly, so that the approved  information is 
automatically generated by the CardioHealth station, including both graphics and text.  
The information includes the following:                    
• 
The carotid intima media thickness is presented as vascular agee with graphic presentations 
of atherosclerosis highlighted in color against normal vascular age patterns as a gauge, 
proceeding from a green sector, through yellow and orange to a red sector to illustrate the 
percentiles 1-25, 26─50, 51─75 and 76─100, respectively. Since no data are available from 
VIPVIZA’s source population, the Atherosclerosis Risk In Communities study population (ARIC) 
(40) was selected as the reference population for calculation of vascular age by sex and age 
due to the similarity with the VIP population of  risk factor patterns. 
• 
Plaque formation shown as a traffic light for each side of the carotid artery, with a green circle 
for ‘no plaque detected’ and a red circle for ‘plaque detected’.  
• 
A stylized picture of the participant’s own ultrasound image showing vascular age as a colored 
line and plaques as a red mark.  
• 
Brief written information about atherosclerosis as a dynamic process, which is modifiable by a 
healthy lifestyle and pharmacological treatments for hypertension, dyslipidemia and diabetes. 
 
 

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12.3 Control group procedures  
• 
Baseline: Identical to procedures for the intervention group, except that no information about 
ultrasound results are sent to SPs and their respective GPs, and there are no qualitative 
interviews. 
• 
At 1-year: Identical to follow-up procedure for the intervention group, except that there is no 
sub-study regarding perceptions about the baseline ultrasound report. 
• 
At 3-years: Identical to follow-up procedures for the intervention group, except that there 
are no questions regarding perceptions about the baseline ultrasound report and the phone  
call and no qualitative interviews. 
 
 
13 
Statistical analyses and considerations 
13.1 Power and number of study participants 
Calculations were performed to estimate the sample size needed to detect a clinically significant 
difference between the control group and the intervention group with sufficient power regarding 
change from baseline to 1-year follow-up in the primary clinical outcome variables, Framingham Risk 
Score and  SCORE, as well as for S-LDL and total cholesterol, systolic blood pressure. Regarding 
possible detectable change of CIMT from baseline to 3-year follow-up, the available literature 
reported a mean change  of 0.010±05 mm/year from the MESA study (48) and in a meta-analysis the 
progression was 0.000-0.023/year for mean maximal IMT of the common carotid artery (49).  For 
evaluating the effects of the various CIMT variables on the sample-size calculation for a trial, we used 
a pooled common CIMT progression rate of 0.0147 mm/y (0.044 mm/3 y) with the corresponding SD. 
For the mean maximum progression rates, we used an estimate of 0.0176 mm/y (50). 
 Since no data was available from the current population, we hypothesized that a change of CIMT of 
0.02 mm would be theoretically possible to detect having standardized protocols for IMT assessment  
including multiple angles of insonation, anatomic landmarks  and automated edge detection 
software technology as was also recommended in a state of the art paper (15). As the design utilizes 
randomization, the groups were assumed comparable at baseline, thus no further adjustment for 
background factors was considered. As a lower limit for power we used a threshold of 0.8, and for 
significance level we used 0.05. These calculations were based on standard deviations on 
conventional risk factors derived from VIP 2012 and on CIMT from the Tromsö study (51).  The power 
calculations revealed that an initial total number of 3500 participants with a drop-out rate of 15 % 
during the study would be sufficient. The limiting factor demanding the largest group size to show a 
hypothesized detectable effect was CIMT. Thus, the sample size was decided based on that. 
 

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Variabel 
Precision 
Power 
SD 
Relevant change  
Population level 
Sample 
size 
per group 
 
Minimum 
detectable 
change if 
n=1500/group 
SBP (mmHg) 
0.05 
0.8 
16 
2 
1500 
1.7 
Serum Cholesterol 
(mmol/L) 
0.05 
0.8 
0.5 
0.5 
1500 
0.05 
LDL (mmol/L) 
0.05 
0.8 
0.5 
0.5 
1500 
0.05 
CIMT (mm) 
0.05 
0.8 
0.2 
0.02 
1500 
0.02  
SCORE 
0.05 
0.8 
1.40 
0.5  
1500 
0.143  
Framingham Risk 
Score 
0.05 
0.8 
6.60 
1 
1500 
0.7 
 
13.2 Statistical analyses 
13.2.1 Dataset and study population  
All subjects participating in the study will be included in the analyses. For the drop-out analyses, non-
participants (those who did not consent to participation or failed to attend the first ultrasound 
examination) will be included in the analyses of selection bias for participation, but this evaluation will 
be based on only a restricted number of variables (sex, age, education, clinical CVD risk factors and 
lifestyle). 
 
13.2.2 Interim analyses 
No interim analysis is planned. Any eventual differences in deaths and clinical events such as 
myocardial infarction, stroke and revascularisation procedures cannot be expected to be identified 
and analyzed statistically before three years of follow-up in this middle-aged, low/intermediate risk 
population. Furthermore, since they participate in the VIP, the control population (not informed) 
receives primary prevention actions according to guidelines and to a relatively high extent in 
comparison with most other counties in Sweden and most other countries globally. 
13.2.3 Summary of planned analyses 
The differences in primary outcomes (SCORE risk and Framingham Risk Score) at one year between 
the treatment groups will be measured and analysed using t-test, for a detailed statistical analyses 
plan see Appendix 4. As the group sizes are large (more than thousand), it is valid to assume normal 
distribution of the error around the mean value estimates in both the intervention and the control 
group. A two-sided p-value <0.05 will be regarded as statistically significant. Complementary to the 
absolute difference in the Score and the statistical testing of hypotheses, Cohen´s effect size will be 
derived for the difference in mean outcome values divided by a pooled standard deviation of the 
Score between the 2 groups.  
 
In sensitivity analyses, we will conduct a linear regression covariate-adjusted analysis. We will use the 
continuous form of the primary outcomes (SCORE risk and Framingham Risk Score) as outcome in the 

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regression analysis. We will assess the effects of the intervention independently for each of the 
outcome measures. As many of the baseline co-variates (including sex and age) are related to the 
prognosis of outcomes, adjustment of pre-defined covariates in the regression analysis might yield in 
adjusted coefficients which are slightly further from 1.  
 
We will also analyze the changes of SCORE and FRS from baseline to 1-year follow-up and use 
regression methods to identify predictors of the changes in the scores.  
 
Since patients are recruited into the study during three years from mid-2013 to mid-2016, any 
change in physicians’ prescribing behaviour over the course of the study will be evaluated by 
comparing prescriptions issued for lipid-lowering and anti-hypertensive medication to participants 
recruited during the first, second and third years. 
 
Similar statistical methods will be applied for evaluation of the three-year results. At that time point 
also changes in plaque distributions and IMT variables including differences between intervention 
and control group will be evaluated. 
 
In long-term, adding risk communication using visualisation of carotid ultrasound results will be 
compared to routine CVD risk assessment and control within the primary health care setting in 
hospitalisation due to stroke, myocardial infarctions and revascularisations (at 5-year and 10-year) 
and  reducing overall mortality and cause-specific mortality due to myocardial infarctions and stroke 
(at 5-year and 10-year) compared to.  
 
Simple survival curves will be established using Kaplan-Meier curves for CVD mortality and morbidity 
at 5 and 10 years of follow up comparing the intervention to the control group. Thereafter, predictive 
Cox Proportional Hazard models will be developed to estimate the overall predictive ability of CIMT, 
plaque and risk factors on CVD morbidity and mortality at 5 and 10 years in the control group and in 
the intervention group, taking into account time at risk for disease and deaths. Receiver Operating 
Characteristic Curves (ROC) will be calculated by estimating the Area Under the Curve (AUC) to 
ensure the highest possible sensitivity and specificity of the predictions. Confirmatory and 
exploratory statistical modelling will establish relationships between the intervention 
and intermediate and mediating factors and variables’ relative contribution to explain changes in the 
outcome variables. 
 
Since participants are recruited into the study during the three years from mid-2013 to mid-2016, 
any change in physicians’ prescribing behaviour over the course of the study will be evaluated by 
comparing prescriptions issued for lipid-lowering and anti-hypertensive medications among 
participants recruited during the first, second and third years. 
 
As a basis for how to build regression models Causal diagrams (directed acyclic graphs - DAGs) will be 
established and causal mediation analysis will be undertaken to illustrate the impact of social, 
gender, psychological and environmental factors by biomedical risk indices on CVD morbidity and 
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Health economic modelling studies will be performed for evaluation of cost-effectiveness. 
Interviews with participants and physicians will be transcribed verbatim and analyzed using 
Qualitative Content Analysis (52). 
 
13.3 Planned drop-out analyses 
13.3.1 Non-participants vs participants 
This category includes all individuals who were informed about VIPVIZA at the occasion of participation 
in the VIP and who did not consent (ticked ‘NO’ on the form) to participation in VIPVIZA, as well as 
subjects who initially consented to participate but withdrew their consent, either actively by phone or 
mail to the research nurses, or passively, through failing to attend the baseline ultrasound 
examination. One reminder to those who fail to attend is sent with a new appointment time for the 
baseline ultrasound examination but if they still fail to attend, they are categorized as  a non-
participant. Aggregated data on the group of non-participants will be compared with the included 
study participants regarding CVD risk markers and lifestyle as well as educational level and civil status. 
In this analysis, published data on participation and selection to the VIP will also be considered (27). 
 
13.3.2 Drop-outs at the 1-year evaluation   
At one year, the study population will be further reduced as a result of exclusions due to significant 
carotid stenosis (10.2.2), deaths and migration out from the county. Drop-outs will be defined as 
active withdrawal of consent to participation or failure to attend the 1-year follow-up evaluation 
after postal invitation and one reminder.  Drop-outs will be compared to the other participants 
regarding risk factors, lifestyle, level of education, and intervention group status at baseline. 
13.3.3 Drop-outs at the 3-year evaluation:  
SPs will be invited to the 3-year examination irrespective of participation status at the 1-year follow-
up, provided they were not excluded according to 10.2.2 or have withdrawn their consent). 
Therefore, drop-outs at Year 3 will be defined as active withdrawal following the 1 year examination 
or failure to attend the 3-year follow-up after postal invitation and one reminder. Drop-outs will be 
compared to the other participants regarding risk factors, lifestyle and educational level as well as 
intervention group status at baseline. 
 
 
 
 
 

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14 Study administration 
14.1 Procedures for collection of informed consent 
At the occasion of participation in the VIP, subjects are given written information about VIPVIZA, 
including the form for informed consent. Those who fulfill the inclusion criteria are informed verbally 
by the VIP nurse, who also collects the forms, both from those who consent to and those who decline 
to participate in the study. These forms are sent to the research nurses at KFC, who insert the data 
from those who consent into the electronic CRF document. Subjects who do not consent to 
participation in the study are listed separately for analysis of selection bias using aggregated data and 
a restricted number of variables. 
14.2 Definition of source data 
There are several different sources of data in VIPVIZA. See also below section Data Management.  
 
Sources for VIPVIZA data comprise: 
• 
VIP data: The VIP questionnaires are sent from healthcare centers to the Medical Biobank, 
Umeå University Hospital, where they are registered and optically read by ITS, Umeå 
University. The electronic data are sent to the VIP database at the Unit of Epidemiology 
and Global Health, Umeå University. The questionnaires are stored at the Medical Biobank, 
Umeå University Hospital.   
• 
The Case Report Form (CRF) contains information about randomization, as well as 
administrative information about visits, exclusions and drop-outs. The CRF is electronic and 
managed by the research nurses and located within the Västerbotten County Council’s 
computer system. 
• 
All questionnaires answered by participants at base line, 1-year and 3-year visits are kept 
in files  at the Clinical Research Center under a code for each participant. After completion 
of all visits in the study (June 2019) they will be stored at the Unit of Epidemiology and 
Global Health during the entire study period in a safe archive. 
• 
Clinical risk markers at 1- and 3-year visits are written on the front page of the lifestyle 
questionnaire.  
• 
Ultrasound data are registered and stored in the CardioHealth Station. 
• 
Pharmacological prescriptions:  Stored in the electronic medical records at the participants’ 
respective primary health care centers within the Västerbotten County Council.  
• 
Interviews: Audiotapes taken at the occasion for interviews [should we say something 
about secure storage?] 
• 
Register data: The pharmaceutical register, the Statistics on inpatient diseases in Sweden, 
and the Statistics on causes of death are stored at the National Board of Health and 
Welfare. The Conscripts register is stored at the National Archives Database. Statistics 
Sweden (Educational attainment and income) [are we missing something here?] 

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14.3 Quality control  
The study is quality-controlled based on protocols and data collection on site to verify that: 
• 
That data is reliable, accurate and complete 
• 
That the safety and rights of all involved in the study are protected 
• 
That the study has been conducted in accordance with current protocols and study 
agreements as well as GCP and all applicable government requirements.  
 
An external monitor is selected at the Clinical Trial Unit at Västerbotten County Council. The monitor 
is not involved in the study. 
 
The monitor has the necessary education, and the scientific and/or clinical knowledge necessary to 
monitor the trial adequately. 
 
The Principal Investigator approves that the monitor has direct access to all relevant documentation. 
 
Monitoring takes place in accordance with current GCP during and after the study. If any violation or 
negligence is discovered, the Principal Investigator shall be notified of corrective and/or preventive 
measures. See Appendix 5 Monitoring plan. 
 
14.4 Quality assessment 
It is the responsibility of the principal Investigator to ensure that a) collected data is checked, 
complete, signed and dated, b) that the study is conducted according to the protocol, to study 
agreements, to GCP and obligations from authorities, bearing in mind and that regulatory 
control/audits/inspections could be made at any time during or after closure of the study c) ensure 
that co-investigators and departments participating in the study approve and assist in any kind of 
inspection.  
 
14.5 End of the study 
The study will be formally closed on Dec 31 2026. Study visits and data collection from participants will 
be finalized in June 2019 or when all 3-year visits are completed. From that time point, SPs will be 
followed through registers for an additional 10 years. Since there is no intervention other than 
providing information about silent atherosclerosis to all participants at baseline and at 3-year follow-
up, which qualifies as clinical prevention according to guidelines for CVD preventions, any premature 
termination before Dec 31 2026 will not be applicable.  
14.6 The VIPVIZA research database and its management  
All data will be entered into the VIPVIZA research database, which is managed by a trained database 
manager. The database and the database management is described in detail in Appendix 3:  VIPVIZA 
Database Description. This document describes the original data, source files and the structured data 
and their content, purpose and physical storage including hardware encryption and back-up. It also 

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describes the variable catalogue and proposal application system. The pass word is only known by 
the data manager and the data can only be accessed by the data manager. The pass word is kept in a 
sealed envelope in a safe at the Department of Public health and clinical medicine. In order to link 
data from external sources to the VIPVIZA database repeatedly and during the whole study period, 
personal identification numbers are retained in the data base.   
 
The key code will be retained for 10 years until register data on clinical events are retrieved and then 
destroyed, or if the follow-up is terminated earlier, the key code will be destroyed in the same way. 
All personal data will be processed in accordance with the Personal Data Act (1998: 204) and the 
study participants are entitled to receive information on the data recorded in the study annually free 
of charge and to have any errors corrected. The exception to this is base-line ultrasound results for 
individuals in the control group. 
The files containing consent forms, questionnaires, as well as copies of the ultrasound report for the 
intervention group, will be archived at the Department of Public Health and Clinical Medicine. 
14.7 Import of questionnaire data, risk factor data, CRF and ultrasound data to the database 
Questionnaire data and risk factor data are entered into an access file on two laptops that are used 
for this sole purpose. The database manager creates the access file and also imports the data from 
the access files, as well as data from the CRFs  and the ultrasound data on IMT and plaque to the 
VIPVIZA database.  
14.8 Proposal application system and data handling 
Researchers do not have access to the database. Researchers who are affiliated to VIPVIZA have 
access to an internal webpage for VIPVIZA. On this page, available data sets and variables are listed, 
including aggregated information, but no individual data. The web page also offers functionality for 
developing and sharing research proposals. Every authorized researcher can create and upload a 
proposal using a standardized form. External researchers may also apply for data if they collaborate 
with at least one member of the steering group. In such cases, external researchers will get access to 
the internal web page to follow the proposal routines regarding applications and approvals. Data 
without personal identification numbers will be exported to the researcher by the data manager 
after approval from the VIPVIZA steering group. and results  will be reported only at an aggregated 
level. No researcher will be able to identify any participant, and therefore publications based on the 
study do not cause any ethical dilemma.  
 
 
 
 
 
 
 

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15 Ethical and legal aspects of the study 
15.1 Ethical considerations 
The study will be conducted according to the ethical principles based on the Helsinki Declaration, 
GCP, national regulatory mandatory instructions and this study protocol.  
Both written and oral information to all participants in the study declares that participation in the 
study is voluntary and can be withdrawn at any time without any consequences for their ordinary 
health care.  
 
Study participants will be carefully informed in a standardized way to ensure full and adequate 
communication, including information about randomization to an intervention or control group and 
treatments within primary care, prescribed according to guidelines about cardiovascular risk factors 
and preventive treatments, irrespective of whether information about the vascular ultrasound is 
provided or not. The signed consent from participants also includes information about the 
monitoring of the study and access to their confidential medical records at the County Council of 
Västerbotten, as well as, when appropriate, medical records from private primary health care 
centers, and register data from national registers. Specific written consent applies to storage of data 
and blood samples at the Biobank. The participants can at any time communicate questions to 
research nurses and can, without any payment, obtain information about their individual data in the 
study and to revise any incorrect data. 
 
The issue of not providing information about silent atherosclerosis to half of the study population 
was thoroughly discussed with the Regional Ethical Board. It was judged to be acceptable, because 1/ 
individuals with severe carotid stenosis (<1% in the pilot study) are excluded and promptly referred 
for expert care (through potentially life- or function-saving measures), and 2/ there are no specific 
treatments for mild-moderate atherosclerotic disease other than risk factor control, according to 
guidelines. Risk factor control will be given irrespective  of whether or not the ultrasound results are 
disclosed to participants.  
The ultrasound message was extensively tested during the pilot study 2012 to ensure that easily 
understandable information is reported, that is accurately interpreted. This was carried out among 
out-patients with intermediate risk of CVD at the clinic of Behavioural Medicine, among patients with 
history of a CVD event at Heart Centre, as well as among the pilot participants.  
 
During the study, any negative reaction, such as anxiety due to image results, is balanced through the 
provision of additional information and supportive counselling by research nurses in a phone call to 
each participant. This issue is also specifically in focus in the qualitative sub-studies and its 
investigation is included in the objectives of the study.  
 
It is possible and hypothesized that the compliance to guidelines for prevention of CVD among 
physicians at health care centers will increase as a result of the information about ultrasound results 
in the intervention group. This is not considered an ethical problem, since there are no studies 

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demonstrating improved prognosis by using imaging techniques among subjects without signs of 
high-degree flow-limiting stenosis of the carotid arteries, and no study participants are excluded 
from prevention measures according to the current CVD prevention guidelines for health care. 
Previous studies of imaging techniques in health screening for cardiovascular disease suggest 
improved risk stratification. Therefore, from an ethical perspective it is important to investigate new 
pathways towards improved prevention and to discard old inefficient methods. 
 
The study is integrated into an environment with direct links to ordinary health care, with its routines 
for follow up and prevention, including rapid direct referrals if pathological conditions (requiring 
further diagnostic or therapeutic interventions) are detected. The study is performed with stable 
research conditions for all study participants  
 
There is no selection of participants in the VIP. All citizens in the county have the same opportunity 
to be invited the year they are 40, 50 and 60 years old. The study has no negative effects for the 
health care of any citizen or group of citizens. Once invited to VIP, clear information is given that the 
health screening is combined with advice, motivational information and measures to improve long-
term health. VIPVIZA adheres fully to all the intentions of VIP.  
Altogether, the eventual improved risk stratification and risk communication to physicians and study 
participants outweighs any potential negative effect of the study. There is no risk for harm with the 
direct procedure for vascular ultrasound.  
 
15.2  Approval of the study 
The application was submitted to the Regional Ethics Examination Board in Umeå, December 13 2011 
and was approved February 7 2012. Documented approval to participate in study activities according 
to the study protocol and informed consent forms was obtained from authorities of the County 
Council of Västerbotten, representing the participating primary health care centers and hospital 
clinics, as well as from managers of private primary health care centers. These documents were 
attached to the application to the Regional Ethical Board (Appendix 1). Applications for amendment 
concerning all significant changes to the protocol thereafter have been approved by the Regional 
Ethics Committee.  The significant amendments are: 
 
 
 
 
 
 
 

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15.3 Major amendments  
• 
Repeated risk factor measurements and questionnaires about lifestyle at a one-year follow-
up (added visit) as well as at the 3-year follow-up. 
• 
A questionnaire to all SPs concerning important determinants of perceived risk of CVD and 
performance of preventive lifestyle modifications. 
• 
Interviews with primary care physicians concerning their perceptions and reactions to the 
baseline ultrasound information. 
• 
Repeated ultrasound information to the intervention group 6 months after the baseline 
examination. 
• 
The psychometric questionnaires added to the 3-year follow-up. 
• 
Qualitative interviews at 3 years among SPs in the intervention group. 
• 
Collection of samples of blood to be frozen and stored in the Medical Biobank, Umeå 
University Hospital at the 3-year visit. 
• 
To keep the personal identification number in the database to allow for linkage with register 
data from different sources at different time points during the whole study period until 
collection of data on clinical events and deaths after 10 years. The personal ID is not available 
to researchers, only to the database manager. 
• 
The Beliefs about Medicines Questionnaire added to the 3-year questionnaire. 
• 
Extended ultrasound examinations, that are necessary in cases where the CardioHealth 
station does not provide sufficient technological quality to allow a definite evaluation of 
potential significant stenosis information. This includes contrast enhancement and advanced 
ultrasound imaging to evaluate plaque texture. 
• 
Psychometric data from the Conscripts register and income and education from Statistics 
Sweden as well as data on air-borne pollutants.  
 
16 Funding of the study and insurances  
 
VIPIVZA is supported by the Swedish Research Council Dnr 521-2013-2708 and Dnr 2016-02891, 
Västerbottens County council ALFVLL-2988001, VLL-583721 and  ALFVLL-643391, the Swedish 
Medical Society SLS-405351 and -503111, the Northern county councils VISARENORR 465621,561592 
and 741711, the Heart and Lung Foundation Dnr 20150369 and 20170481, SKANDIA insurance 
company Risk Hälsa, the Heart Foundation of Northern Sweden, Riksförbundet Hjärt-Lung, , STROKE- 
the national association, the Foundation for Stroke Research in Northern Sweden, AFA Insurance and 
an unconditional donation from Carl Bennet Ltd, Sweden. The funders have no role in the design, 
methods, subject recruitment, data collections, analysis or preparation of manuscripts in the project. 
The views expressed in this study protcol are those of theresearchers and not those of the funders. 
 
The Patient Injury Act applies to all patients and subjects participating in research treated in Swedish 
health care. The Patient Insurance as well as the Pharmaceutical Insurance also applies to the study 
participants in this study. 

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Visualization of Asymptomatic Atherosclerotic Disease for Optimum 
Cardiovascular Prevention: VIPVIZA – a Population-based RCT 
nested in Routine Care in Sweden  
 
NCT01849575 
 
Amendment to Study Protocol version 4.0 
 
Additional  major amendments  
 
A Discrepancy between first date registered on clinicaltrials.gov and first ultrasound 
examination in VIPVIZA                                                                                                            Page 42 
B Data on health and physical testing from the Conscripts registry and data for the baseline 
drop-out analyses from Västerbotten Intervention Programme regarding eligible non-
responders and drop-outs.                                                                                                       Page 42 
C Follow-up six years after Baseline 
 
       Page 43 
D Follow-up ten years after Baseline 
 
       Page 45 
 
 
Version 1. 
26/11/2019 

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A Discrepancy between first date registered on clinicaltrials.gov and first 
ultrasound examination in VIPVIZA 
The VIPVIZA trial was approved by the Regional Ethical Review Board at Umeå University  February 
7th 2012, Dnr 2011-445-31M. A pilot study was performed September-October 2012, Study Protocol . 
page17 section 8.6.  
 
The first date regarding VIPVIZA in clinicaltrials.gov was May 8th 2013, while the first baseline 
ultrasound examination in the main study was performed April 29th 2013. This delay is completely 
explained by the administrative issues that occurred during registration of the VIPVIZA record at 
clinicaltrials.gov. Thus, it is documented in mail conversations that the record holder (Margareta 
Norberg) at April 29th 2013 filled in the form for registration of VIPVIZA at clinicaltrials.gov, but it was 
not possible for the record holder to determine how to register members of the Steering Committee 
and the International Advisory Board. This had nothing to do with study procedures, inclusion of 
study subjects or the conducted examinations. This issue regarding registration of  VIPVIZA's 
administrative and leadership structure was solved on May 2nd 2013, but on the same day the 
response message by mail from clinicaltrials.gov was that "PRS Administrator for Umeå University 
must Approve and Release this record". (Moreover April 30th and May 1st are normally out-of-office-
days in Sweden). Furthermore, the central administrator for clinicaltrials.gov for Umeå University had 
only recently been appointed. This delayed the actual registration date further until May 8th 2013. 
 
We therefore claim that the discrepancy of nine days between the date registered at clinicaltrials.gov 
and the first day for any baseline examination is entirely due to administrative reasons and should 
not prohibit publication of manuscripts based on the VIPVIZA trial in journals requiring registration 
before the first examination.  
Through documentation in our encrypted database, which is available only to a database manager, it 
can be demonstrated that the very few subjects, out of the total of 3532 participants included up 
until June 2016,  who were examined during this 9-day period were informed about the trial 
according to regulations, and had given their written informed consent before being included, 
thereby ensuring the safety of participants in advance of any treatment or intervention commencing. 
 
B Data from the Swedish Conscripts registry regarding health information and 
physical testing and data from the Västerbotten Intervention Programme on 
eligible non-responders and drop-outs at the baseline examination in VIPVIZA 
 
This was approved by the Regional Ethical Review Board Umeå University at December 27th 
2018, Dnr 2018-482-32M 
 
 
 
 

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C Follow-up six years after baseline 
This amendement to the VIPVIZA Study protocol Version 4.0, regards continued follow-up with data 
collection and examination six years after inclusion in the study using the same research questions as 
originally and the supplementary changes that have already been made (See Study protocol version 
4.0, Major amendments section 15.3 page 36).   
 
Study progress: The three-year follow-up: data collection was completed on June 16 2016. VIPIVZA 
has followed the study plan. The evaluation of the primary endpoint was completed published in 
Lancet (Publication 4). Additional publicatins up to November 30 2019 are listed in the Publications 
list. The two publications by Vanoli et al concern the preparatory evaluations of the ultrasound 
examination methodology; these evaluations were performed before the study start and did not use 
data from any VIPIVZA participants. All other publications are based on data collected within the 
main trial. To date, several substudies are ongoing. The project includes one completed PhD 
projectand three on-going PhD projects, and a two-year post-doctoral study period that was finalised 
in June 2019. 
 
The 6-year follow-up includes the following additions, removals or changes. 
 
1. Added measuement or clinical data 
a. Objective measurement of physical activity with accelerometer 
b. Dental health: Two questions in the questionnaire to participants regarding dental 
health and retrieval of clinical data on dental health and dental radiological 
examinations from Dental Care. 
2. Changes in the questionnaire to participants regarding psychological and social determinants 
of health behaviours in particular with respect to cardiovascular disease (CVD). Overall, the 
questionnaires were reduced in scope. 
a. Deleted: the Three-item Brief Health Literacy Screen (BHLS), Questions on anxiety 
deleted from HADS (Hospital Anxiety and Depression Scale), Brief Cope on coping 
strategies, LOT-R on optimistic/pessimistic disposition, the 66 item Food Frequency 
questionnaire that is used in the Västerbotten Intervention Programme (VIP), BMSQ 
Beliefs about Medicines Questionnaire, 
b. Additions: International Schedule of Social Interaction (ISSI), the Karasek Demand 
/Control model questionnaire (ISSI and Karasek D/C were included in the baseline VIP 
questionnaire), questions regarding reactions to the 3-year ultrasound information 
based on qualitative interviews with participants, SOM/Hp5i a validated 
questionnaire about personality. Questions to women about pregnancy 
complications and menopause and reproductive hormonal 
therapy. 
3. New data from registries 
a. Blood group 
b. Data from VIPVIZA participants’ previous VIP-examinations before entry to VIPIVZA 
10, 20 or even 30 years earlier. Example: A person who was included in VPVIZA in 

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relation to participating in VIP at the age of 60 years, could have participated in VIP 
also at ages 50 years, 40 years and even 30 years.  
4. Electronic questionnaire: A possibility to answer the questionnaires electronically. The Umeå 
University data collection platform is used to guarantee confidentiality and secure data 
handling according to GDPR. 
 
Motivation for the extension of the trial with a 6-year follow-up: The three measurement points of 
ultrasound data on subclinical atherosclerosis provide a much greater statistical certainty in assessing 
trends, notably the effect of the intervention, as compared to only two measuring points. The 
problem of mis-classification ”towards the null” decreases. Moreover, the atherosclerotic process is 
so slow that a long follow-up period is necessasry and also, for CVD prevention measures to be 
effective with regard to affect hard endpoints, they have to be sustainable over long periods. 
 
Ethical considerations regarding risk vs benefit: As previously during the VIPIVZA trial, there is a risk 
of potentially strong emotional reactions in connection with obtaing ultrasound results. However, 
this risk is considered to be small as the entire study population was informed about  about their 
personal ultrasound result at the 3-year follow-up and very large individual changes to the 6-year 
follow-up  cannot be expected. This risk is also balanced by the possibility of feedback regarding 
implemented prevention efforts, both by the individual and provided by health professionals in 
terms of pharmacological treatment. As before, subjects with severe ultrasound results will also be  
followed up by research nurses. If strong emotional reactions nevertheless occur, the study team is 
prepared to take care of these cases. 
There is a risk that some parts of the questionnaires, as well as collection of health data from Dental 
Care, may be perceived as violating privacy. This is balanced by the fact that all data is handled with 
complete confidentiality and that only aggregated data will be reported, and also that the results 
may be the basis for development of  personalized CVD prevention methods.  
As in previous follow-up, as well as at baseline, sampling of blood to the local Medical Biobank for 
future analyses of novel biomarkers  carries only a minor risk of transient tenderness and bruising. 
The study projects do not have any direct benefit from these changes of the project. However, even 
if the usage of an Accelerometer does not entail any direct risk or benefit to participants, the 
research group’s experience from previous projects is that this measurement is appreciated by 
participants when they get a brief feedback on their own results. 
 
This amendment was approved by the Swedish Ethical Review Authority at September 24th 2019, Dnr 
2019-04691. 

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Visualization of Asymptomatic Atherosclerotic Disease for Optimum 
Cardiovascular Prevention: VIPVIZA – a Population-based RCT 
nested in Routine Care in Sweden  
 
NCT01849575 
 
Amendment to Study Protocol version 5.0 
 
Additional  major amendments  
Version 1. 
12/12/2023 
Follow-up ten years after baseline 
This amendement to the VIPVIZA Study protocol Version 5.0, regards continued follow-up with data 
collection and examination ten years after inclusion in the study using the same research questions 
as originally and the supplementary changes that have already been made (See Study protocol 
version 5.0).   
 
Study progress: The six-year follow-up: data collection was completed in April, 2023. VIPIVZA has 
followed the study plan. Publications up to December 13, 2023, are listed in the Publications list. 
Several substudies are ongoing. 
 
The 10-year follow-up is conducted in a very similar way compared with that at six-year follow-up 
with clinical sampling (height, weight, waist, blood glucose and lipid status, blood pressure, including 
pulse wave velocity, medication for blood pressure, for angina pectoris/heart, for lipid lowering, for 
diabetes); carotid ultrasound; blood samples for biobank; dental health; grip strength; physical 
activity measurement (accelerometer) and cognition (MoCA test).  
1. Added measurements of clinical data include measurements of ancle-brachial index.  
2. The questionnaires at 10-year will be answered electronically (REDCap) as default with option 
of answering on paper. Overall, the extent of questionnaires is unchanged compared with 
that at 6-year follow-up. The changes in the questionnaires at 10-year include:  
a. Food habits (decreased, the current shorter food habit form in VIP is used)  
b. Oral health and swallowing (new questions)  
c. Sleeping habits (new questions) 
 

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Motivation for the extension of the trial with a 10-year follow-up: The longitudinal long-term follow-
up in VIPVIZA with repeated measurements offers a unique opportunity to study progression, 
regression or steady state of early arteriosclerosis in middle-aged low to middle risk asymptomatic 
individuals related to anthropometric, clinical, medical, biochemical, behavioral and psychological 
aspects.  
 
Ethical considerations regarding risk vs benefit: As previously during the VIPIVZA there is a risk of 
potentially strong emotional reactions in connection with obtaining ultrasound results. However, this 
risk is considered to be small as the entire study population was informed about their personal 
ultrasound result at the 3- and 6-year follow-up. This risk is balanced by the possibility of feedback 
regarding implemented prevention efforts, both by the individual and provided by health 
professionals in terms of pharmacological treatment. As before, subjects with severely altered 
findings will be followed up by the research nurses and others in the study team.  
 
This amendment was approved by the Swedish Ethical Review Authority at April 3rd 2023, Dnr 2023-
01781-02.