Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03946410 |
| Other study ID # |
S201600164 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2017 |
| Est. completion date |
August 1, 2027 |
Study information
| Verified date |
May 2019 |
| Source |
Odense University Hospital |
| Contact |
Jes S Lindholt, PhD |
| Phone |
+45 24641214 |
| Email |
jes.sanddal.lindholt[@]rsyd.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This study attempts to reduce social inequality in cardiovascular health by performing an
interventional screening trial on how best to decrease cardiovascular disease (CVD) among
people with low social status.
Description:
Background
Although CVDs have decreased, they are still among the most predominant cause of morbidity
and mortality in the western world, incl. Denmark, where about 420,000 people have recognized
CVD symptoms. Due to an aging population, the decline has not reduced CVD admissions and
healthcare costs. In Denmark, the CVD related hospital admission costs are DKK 4.6 billion
and the pharmaceutical cost DKK 2.4 billion. The Danish National Board of Health has reported
that CVD carries the second largest socioeconomic difference in burden of disease.
Unfortunately, population-based health checks and screening for risk factors has proven not
efficient. Consequently, screening of asymptomatic CVD is discussed intensively. In the
investigators first unique CVD screening RCT (2008-11), the Viborg Vascular (VIVA) trial,
more than 50.000 65-74 year old men were randomised for population-based ultrasound screening
for abdominal aortic aneurysm (AAA), peripheral arterial disease (PAD) and hypertension. In
case of positive finding, preventive medical actions were initiated. A significant reduction
in overall mortality by 7% after 5 years was observed. Using a non-contrast computered
tomography (CT) scan, instead of the ultrasound based screening approach, has the opportunity
to identify aneurysms in the entire aortic, coronary artery calcification (CAC) and arterial
fibrillation, so individualized risk assessment and initiation of preventive actions on those
with sign of early asymptomatic CVD is possible. A second trial - The Danish Cardiovascular
Screening (DANCAVAS) trial initiated was initiated in 2014 randomizing 45.000 65-74 year old
men with the potential of a huge beneficial effect on health, quality of life (QoL) and
survival. However, screening is impaired by lower social class, and adherence to initiated
prevention could be impacted as well. Consequently, we want to conduct a third RCT (Fighting
Social Inequality in Cardiovascular Health (FISICH) to test a number of add-ons to screening
that potentially balance the benefits across socio economic groups. The perspective is to
establish a clear decision foundation for public health care policy incl. benefits, cost
effectiveness and impact on social inequality of alternative variants of population screening
for CVD.
Hypotheses
The primary hypothesis is that an extensive circulatory screening and intervention programme
reduces social inequality in cardiovascular health and fulfills the WHO criteria for
screening. However, this reduction can be even more pronounced, if factors reducing the
social selection to attend screening and adherence to preventive actions initiated are
identified.
Aims
The aims are to
1. Estimate benefits of using DANCAVAS screening methodology in men aged 60-64. This
evaluation will be overall, and subgroup-analyzed concerning educational level, income level,
and psychiatric disease.
Materials and methods 20.000 60-64 year old men are randomized to the control group, while
another 5.000 are randomized to the screening and intervention program for CAC, aortic and
iliac aneurysms, atrial fibrillation, PAD, hypertension, diabetes and hypercholesterolaemia.
There is no exclusion criteria. The screening setup is similar to DANCAVAS:
1. A small questionnaire on life style, medical history, and the QoL a.o. will be enclosed
with the invitation. Non-responders are re-invited once.
2. The participant will be informed at attendance to the screening visit, and their consent
will be obtained together with the questionnaire, weight, height, and waist
circumference.
3. The CT scan will cover the area from the mandibular bone distally to the proximal third
of the femur. Calcium scores for the common carotids, coronary arteries, aorta, and
common iliac, and femoral arteries will be calculated. The aorta are visualized, and the
diameter is measured in ascending, arcus, descending and abdominal, and if possible in
the iliac arteries. Further the heart rhythm during the CT scan is evaluated.
4. Bilateral blood pressure will be recorded three times after 5 minutes of supine rest,
and concurrently the ankle blood pressure are measured.
5. The HbA1c and lipid parameters will be measured. Biobank blood samples are then taken,
centrifuged, labelled, cooled, and stored at -80 degrees Celsius.
Follow-up visit after screening
If the CAC is above the median or if an aneurism of peripheral arterial disease are detected
the participant is informed of the finding and its implications at a follow-up visit. At this
visit, the patient will be recommended suitable prophylactic measures, including smoking
cessation, walking/exercise, a low-fat diet. Additionally to start treatment with aspirin 75
mg/day and atorvastatin 40 mg/day. If an aneurism is large the patient is referred vascular
surgical assessment for the repair. Otherwise, an annual check-up of the aneurism including a
CT scan will be offered.
If no positive findings (CAC above the median, aneurysm or PAD) are detected, the
participants will be informed of the findings by e-mail or ordinary post as preferred.
Independent of the above findings, the patients will be encouraged to see their GP for
further assessment if potential undiagnosed hypertension (systolic blood pressure >160 mmHg),
diabetes mellitus (HbA1c >48 mmol/mol), or significant isolated hypercholesterolemia
(total-cholesterol >8.0 mmol/l) are observed, as possible continuous medical treatments will
be better managed by the GPs.
The GPs will be informed by a letter of all negative and positive results and the initiated
actions.
Enrolment started mid 2017 with sites in Silkeborg, Svendborg, Odense, Vejle and Nykøbing
Sjælland.
Power calculations and Randomisations
A study with 4 controls per invited subject is planned based upon the mortality reduction in
the VIVA study, a hazard ratio of 0.93 in the screening group is expected. If so, with a 0.05
significance level, and 90% power, we´ll need 5245 experimental subjects and 20980 controls.
The randomisation procedure will be stratified by geographical area (municipalities), as
sociodemographics, attendance, and disease prevalence are expected to differ across areas.
Randomisation will be performed in SPSS by providing each individual a random number from
1-20. Those numbered +16 will be invited to participate in the screening program.
Baseline variables
Age, smoking, previous or current stroke, ischemic heart disease, PAD, chronic obstructive
pulmonary disease, diabetes, hypertension, use of statins, use of antithrombotics, body mass
index, systolic- and diastolic blood pressure, ankle brachial index, marital status, highest
educational level, personal- and in house income, psychiatric morbidity defined as any
diagnosis and/or use of medications for mental illness, and quality of life (QoL).
Baseline and outcome variables from national registries
The CPR number assigned to Danish citizens enables individual-level linkage to multiple
nation-wide healthcare and administrative registries which have proved valid. Registry-based
information on outpatient visits, hospitals admissions and procedures (The Danish National
Patient Registry), relevant prescribed drugs dispensed (The Danish National Prescription
Registry), socio economic status etc. (Registries at Statistics Denmark) and primary care
service use (National Health Insurance Service Registry) will be obtained.
Outcomes
The primary outcome is
1. All-cause mortality (time to event or censoring).
Secondary outcomes are:
1. Positive findings by screening, in all and by specific condition,
2. Mortality due to CVD (time to death),
3. Initiation of first redeement of prophylactic pharmaceutical therapy in participants not
in therapy at baseline - split on antithrombotic,- lipid lowering and antihypertensive
agents,
4. Initiation of prophylactic surgery and avoidance of acute surgery (time to first
procedure concerning AAA, PAD, and coronary revascularization,
5. Morbidity due to CVD (time to first hospital-based diagnosis and total number of
inpatient days) as a composite measure,
6. Adverse events (time to first hospital-based diagnosis) split on diabetes, intracerebral
haemorrhage, and cancer,
7. Safety (30d postoperative mortality) split on AAA, PAD and coronary revascularization,
8. QoL,
9. Health care costs and cost-effectiveness.
Statistical analysis
Baseline characteristics will be analysed using conventional summary statistics. Outcomes
representing a time to event are analysed and compared between randomisation groups including
subgroups defined by social status and mentally ill using Cox proportional hazards model. All
outcomes representing density of events are analysed and compared between randomisation
groups including corresponding subgroups using plain incidence rate ratios.
Health economic models
Multivariate regression analysis will be undertaken to analyse health care costs (one year
before and after screening) across socioeconomic groups due to pharmacological
over-/undertreatment. A cost-effectiveness analysis with 5 years of follow-up adopting a
health care perspective will be performed to investigate cost-effectiveness of screening
across socioeconomic groups (population heterogeneity). All cause mortality is the primary
outcome and costs include screening costs and primary- and secondary care costs. Finally, a
health economic decision model based on available evidence (literature review and meta
analysis) and original data from the three trials will be developed to inform decision makers
about the (distributional) consequences of implementing different variants of population
screening in Denmark. The specification of the model will be based on a Markov state model
allowing for the analysis of the total number of expected life years and the total health
care costs for a lifetime perspective in different scenarios with different variants of
screening. The modelling of social inequality (tagging who receives the benefit of screening)
is novel in this literature and a unique opportunity given the Danish trials and register
data.
Biobank
As in the DANCAVAS study, a biobank will be organised. 40 mL of blood form each of the
participants are centrifuged, labelled, and stored at -80 degrees Celsius. The purpose of the
biobank is to perform pathophysiological and translational studies, and to facilitate new
knowledge of development and treatment of atherosclerosis. Analyses of (1) atherosclerosis
and (2) inflammation in the vessel wall, (3) diseases in the myocardium, (4) calcium /
phosphate metabolism and (4) proteomics are intended.
Remaining blood samples are planned to be stored for a ten-year period for future research,
and subsequently data will be anonymous. This is to be approved by the Danish Data Protection
Agency. Prior to future analyses approval by the Region Committee on Biomedical Research
Ethics
