European Heart Journal (2022) 43, 3732–3745 https://doi.org/10.1093/eurheartj/ehac378 CLINICAL RESEARCH Clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects of a comprehensive lifestyle intervention on cardiovascular health: the TANSNIP-PESA trial Ines Garcia-Lunar 1,2,3, Hidde P. van der Ploeg4, Juan Miguel Fernández Alvira1, Femke van Nassau4, Jose Maria Castellano Vázquez1,5, Allard J. van der Beek4, Xavier Rossello1,2,6, Antonio Fernández-Ortiz1,2,7, Jennifer Coffeng8, Johanna M. van Dongen9, Jose Maria Mendiguren10, Borja Ibáñez1,2,11, Willem van Mechelen4, and Valentin Fuster 1,12* 1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 2CIBER Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; 3Cardiology Department, University Hospital La Moraleja, Madrid, Spain; 4Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands; 5Centro Integral de Enfermedades Cardiovasculares (CIEC), Hospital Universitario Monteprincipe, Grupo HM Hospitales, Madrid, Spain; 6Cardiology Department, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, Palma, Spain; 7Instituto Cardiovascular, Hospital Clínico San Carlos, IdISSC, Madrid, Spain; 8Dutch Institute of Employee Benefits Schemes (UWV), Amsterdam, The Netherlands; 9Department of Health Sciences, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; 10Banco de Santander, Madrid, Spain; 11Cardiology Department, IIS-Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; and 12Cardiovascular Institute, Mount Sinai Heart at Icahn School of Medicine, New York, NY, USA Received 29 January 2022; revised 29 April 2022; accepted 30 June 2022; online publish-ahead-of-print 23 July 2022 See the editorial comment for this article ‘Primary lifestyle intervention: the challenge of making a difference’, by Christian Torp- Pedersen et al., https://doi.org/10.1093/eurheartj/ehac376. Abstract Aims To investigate the effectiveness of a 3-year worksite lifestyle intervention on cardiovascular metrics and to study whether outcomes are influenced by baseline subclinical atherosclerosis (SA) by non-invasive imaging. Methods and results A randomized controlled trial was performed to compare a lifestyle intervention with standard of care in asymptomatic middle-aged subjects, stratified by SA. The intervention consisted of nine motivational interviews during the first year, followed by three further sessions between Years 1 and 3. The primary outcome was the change in a pre-specified adap- tation of the Fuster-BEWAT score (Blood pressure, Exercise, Weight, Alimentation, and Tobacco) between baseline and follow-up Years 1–3. A total of 1020 participants (mean age 50 ± 4 years) were enrolled, of whom 510 were randomly assigned to the intervention and 510 to the control group. The baseline adapted Fuster-BEWAT score was 16.2 ± 3.7 points in the intervention group and 16.5 ± 3.5 points in the control group. At Year 1, the score improved significantly in intervention participants compared with controls [estimate 0.83 (95% CI 0.52–1.15) points]. However, intervention ef- fectiveness decreased to non-significant levels at Year 3 [0.24 (95% CI –0.10 to 0.59) points]. Over the 3-year period, the intervention was effective in participants having low baseline SA [0.61 (95% CI 0.30–0.93) points] but not in those with high baseline SA [0.19 (95% CI –0.26 to 0.64) points]. Conclusion In middle-aged asymptomatic adults, a lifestyle intervention was associated with a significant improvement in cardiovas- cular health and behavioural metrics. The effect attenuated after 1 year as the intensity of the intervention was reduced. Trial registration ClinicalTrials.gov (NCT02561065). * Corresponding author. Tel: +34 91 4531200, Fax: +34 91 4531240, Email: vfuster@cnic.es © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 The TANSNIP-PESA trial 3733 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structured Graphical Abstract Left pannel: Summary of the design and primary outcome of the TANSNIP-PESA trial. Right upper pannel: Worksite lifestyle intervention com- ponents. Right lower pannel: Primary outcome results. BEWAT, Blood pressure, Exercise, Weight, Alimentation, and Tobacco; CVD, cardiovascular disease; PESA, Progression of Early Subclinical Atherosclerosis; TANSNIP, Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention; SA, subclinical atherosclerosis. Keywords Lifestyle intervention • Subclinical atherosclerosis • Cardiovascular • Randomized controlled trial D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 3734 I. Garcia-Lunar et al. Introduction Cardiovascular disease (CVD) is the leading healthcare burden in the world and is a major contributor to reduced quality of life.1 In add- ition to causing premature deaths and morbidity, CVD also presents an overwhelming economic burden for society and healthcare sys- tems.2 There is therefore an urgent need for preventive strategies to tackle this worrisome and growing public health problem.3 A large part of the CVD burden is attributable to modifiable, lifestyle-related risk factors, such as smoking, low physical activity (PA), high seden- tary time, and poor dietary pattern.1,4–6 Lifestyle interventions, whether individual or population-based, are among the recom- mended strategies for cardiovascular (CV) health promotion and risk factor control.3,7,8 However, evidence supporting the benefit of such interventions, particularly in the context of primary preven- tion, is limited.9–12 The workplace is a promising setting for the im- plementation of CVD prevention programmes, and several worksite health promotion strategies have been tested, focusing on improving PA, dietary pattern, sedentary behaviour, or smoking status.13–18 Nevertheless, most of these studies are relatively small trials with short-term intervention programmes and follow-ups and their effectiveness has been mixed. Opinion in the field has thus recognized the need for evidence from larger high-quality ran- domized controlled trials (RCTs).12–14 The Progression of Early Subclinical Atherosclerosis (PESA) is an ongoing prospective cohort study examining imaging, biological, and behavioural parameters associated with the presence and progression of early subclinical atherosclerosis (SA) in mid-life.19,20 Working with a PESA sub-cohort, here, we conducted an RCT to assess whether a 3-year worksite lifestyle intervention was able to improve CV health metrics. The primary objective was to assess the effectiveness of the lifestyle intervention on a CVD risk and lifestyle score over 3 years. Additionally, we hypothesized that awareness of the SA burden would lead to more favourable changes in those participants having a high baseline SA burden by creating a greater sense of urgence about chan- ging their behaviour, in order to slow down the progression of their already existing SA disease (awareness of the disease as the motiv- ational factor). Our secondary objective was to evaluate whether the effectiveness of the lifestyle intervention differed between partici- pants with either a high or a low baseline SA burden (evaluated with multi-territorial non-invasive imaging modalities). Methods Study design The design and rationale of the TANSNIP (Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention)-PESA study have been published previously.21 Briefly, the study is an RCT including middle-aged asymptomatic subjects from the PESA cohort in Spain in whom SA was assessed by non-invasive imaging of the carotid, iliofemoral, and aortic arteries using vascular ultrasound as well as by coronary artery calcification with computed tomography (CT)19,20 (Figure 1). The study was approved by the Instituto de Salud Carlos III (ISCIII) ethics committee, and all eligible participants gave writ- ten informed consent. An overview of the PESA design, together with the Consolidated Standards of Reporting Trials (CONSORT) checklist can be found in the Supplementary material online, Appendix. Participant selection All PESA participants (N = 4184, aged 40–54 years at inclusion) were screened to participate in this RCT, and those showing interest in joining were scheduled for a first visit with the study nurse to give written in- formed consent and to undergo baseline assessments. Participants were included in the study if they had completed all baseline TANSNIP-PESA assessments (wearing an activPAL PA monitor for 7 consecutive days, providing a blood sample, and completing the study questionnaires) and had valid imaging results from PESA for stratification into the low or high SA study subgroups.21 It was a requirement to have undergone all baseline evaluations before randomization in order to avoid the baseline questionnaire responses to be influenced by treatment allocation. High SA was defined as being in the highest plaque thickness tertile on vascular ultrasound and/or having any coronary artery calcifica- tion on cardiac CT.19 Low SA was defined as being in the two lowest pla- que thickness tertiles on vascular ultrasound and having no calcified coronary atherosclerosis [coronary artery calcium score (CACS) = 0]. All study participants were informed of their atherosclerosis burden on written reports. Additionally to the general exclusion criteria for the PESA study (pre- vious CVD, cancer, or any other disease expected to shorten life span or influence protocol adherence),19 subjects with no plaque burden, a nor- mal body mass index (BMI, 18.5–25 kg/m2),22 and a healthy lifestyle were also excluded from this RCT. This criterion was set in order to include participants who had at least one non-ideal CV behaviour to ensure cer- tain room for improvement. Randomization After completing baseline measurements, participants were randomized 1:1 to receive the lifestyle intervention at their workplace or standard care (usual care at the discretion of their occupational physician and other primary care providers). Randomization was performed using stratified computerized fixed blocks with SA burden as the stratification variable and a block size of 10. Group allocation was performed by the study nurse. Procedures The lifestyle intervention was systematically designed using a socioeco- logical approach and has been described in detail elsewhere.21 In sum- mary, the intervention had three objectives: to increase daily PA, reduce sedentary time, and promote a healthier (i.e. Mediterranean) dietary pattern. The intervention consisted of 12 individual motivational interview sessions delivered over a 3-year period (nine motivational interview sessions during the first year, followed by three sessions in Years 1–3). Also, participants allocated to the intervention arm received a wrist-worn PA tracker and were offered to have a sit–stand worksta- tion installed at their workplace. Motivational interviewing is an individual-centred counselling style aimed at eliciting behavioural change that has shown to improve adher- ence to lifestyle intervention programmes in different contexts.23–25 In TANSNIP-PESA, the participant and interviewing psychologist agreed on a plan of action that was developed thereafter. The first seven motiv- ational interview sessions (each lasting 1 h) were structured around per- sonalized lifestyle and behavioural change modules (PA, sedentary behaviour, dietary pattern, and smoking) and took place every second week during the first 3 months after inclusion [see detailed timing and content of the lifestyle intervention as well as the TIDieR (Template for Intervention Description and Replication) guidelines in the Supplementary material online, Appendix]. Sessions 8–12 (30-min dur- ation) focused on the maintenance of healthy behaviours acquired through the programme and took place at 5, 10, 16, 22, and 30 months. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 The TANSNIP-PESA trial 3735 Sessions were delivered by three psychologists trained in motivational in- terviewing and who received expert feedback on their adherence to mo- tivational interviewing techniques every 6 months. During Session 2, participants received a Fitbit Flex PA tracker to fa- cilitate PA self-monitoring and goal setting. Around the time of Session 3, participants in the intervention arm were also offered an Ergotron sit–stand workstation. This device was on request installed in partici- pants’ workspaces, allowing them to alternate between sitting and stand- ing while working at their desk (further information in the Supplementary material online, Appendix). Outcomes The primary outcome measure was the change in a pre-specified adapted version of the Fuster-BEWAT score between baseline and Years 1–3. The Fuster-BEWAT score is a composite measurement consisting of Blood pressure (BP), Exercise, Weight, Alimentation, and Tobacco. This score is a simple, non-invasive tool for monitoring lifestyle behaviours and CVD risk,26 and has been internally validated against the ideal CV health score in the PESA cohort, and externally validated in the Northeast China Rural Cardiovascular Health study population.27,28 Moreover, this tool has been used to assess outcomes after lifestyle in- terventions across diverse populations such as parents or caregivers of children from a socioeconomically disadvantaged community in the New York City, or low–middle-income individuals from the island of Grenada.26,29,30 For the current TANSNIP-PESA study, an adapted ver- sion of the original Fuster-BEWAT score was pre-established as the pri- mary outcome.21 The reasons to adapt the original score were to enable the detection of relevant changes in the PESA cohort (a homogeneous physically active population with overall low–intermediate CVD risk20) and to incorporate sedentary time, which is one of the three target beha- viours of the TANSNIP-PESA intervention. The adapted Fuster-BEWAT score consists of BP, Exercise (objectively measured PA and seden- tary time), Weight (BMI), Alimentation (fruit and vegetable consump- tion), and Tobacco. Scoring of each of the components is shown in Supplementary material online, Table S1. The score ranges from 0 (poor CV health) to 24 (ideal CV health) and is the sum of the scores for the individual components (0–4 points each). Secondary outcomes included the original Fuster-BEWAT score, indi- vidual components of the adapted score, anthropometric measure- ments, blood biomarkers, psychosocial measures, and work-related outcomes. Separate analyses will assess the cost-effectiveness and feasibility of the programme, as well as the degree of compliance with the intervention by process evaluation at the following three levels: the participant, the psychologist, and other involved stakeholders. Each participant received four worksite medical follow-up visits: at baseline, and at 1–3 years. Each visit included anthropometric assess- ments (i.e. body height, body weight, and waist circumference), BP meas- urement, placement of an activPAL PA monitor, drawing a fasting blood sample, and completion of the study questionnaires. These visits took place at the Banco Santander Headquarters or at the CNIC facilities in Madrid. Outcomes were assessed by PESA technicians or nurses, who were not blinded to participant allocation arm. Nevertheless, all assess- ments were performed according to previously described standardized protocols (details on data collection are provided in the Supplementary material online, Appendix).19,21 Blinding to allocation arm was likewise not possible for participants, the TANSNIP-PESA coordinator, or the intervention psychologists. Study statisticians were blinded to the alloca- tion arm until the data were analysed [see Statistical Analysis Plan (SAP) in the Supplementary material online, Appendix]. PA and sedentary time were objectively measured with an activPAL activity monitor (PAL Technologies Limited, Glasgow, UK), which was attached during the visit to the participant’s thigh, worn for at least 7 con- secutive full days, and then returned to the TANSNIP staff via the Bank’s internal mail system. ActivPAL data were post-processed to calculate ob- jective PA (number of steps/day) and sedentary time [defined as any wak- ing behaviour characterized by an energy expenditure ≤1.5 metabolic equivalents of task (METs) while in a sitting, reclining, or lying posture]. Dietary pattern, including fruit and vegetable consumption, was mea- sured using the Mediterranean Diet Adherence Screener (MEDAS) score from the PREDIMED trial.31 Tobacco consumption was assessed with a self-report questionnaire. Other self-reported behavioural and psychosocial parameters were collected through online questionnaires completed after each check-up. Cardiometabolic biomarkers were mea- sured in fasting blood samples. A more detailed description of the pro- cedures is included in the Supplementary material online, Appendix. Statistical analysis Using a stratified analysis and assuming a different treatment effect be- tween low and high SA participants, the study was powered to detect between-group relative changes in the adapted Fuster-BEWAT score of 6.1% in the low SA subgroup and 10.9% in the high SA subgroup (low SA participants were expected to have a smaller treatment effect, Figure 1 Schematic representation and timeline of the PESA and PESA-HEALTH studies and the present TANSNIP-PESA RCT nested within the PESA cohort. PESA, Progression of Early Subclinical Atherosclerosis; RCT, randomized controlled trial; SA, subclinical atherosclerosis; TANSNIP, Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 3736 I. Garcia-Lunar et al. whereas high SA participants were expected to have a larger treatment effect). This required 590 and 260 participants in the low and high SA subgroups, respectively (with 80% power and two-sided α=0.05), and within these subgroups in a 1:1 ratio for the intervention and control groups.21 All effectiveness analyses were performed according to the intention-to-treat principle. Data are expressed as mean (standard devi- ation) of non-missing values for continuous variables and as frequencies and percentages for categorical variables. For the primary outcome ana- lysis, measurements at each follow-up time point were analysed longitu- dinally by repeated linear mixed model analysis. The regression model included the outcome variable measured at the different follow-up mea- surements adjusted for the baseline value of the outcome. A random intercept at the individual level was added to deal with correlated obser- vations within the individual.32 Interaction tests in the primary outcome model were performed to determine whether the intervention effective- ness was not homogeneous by age or gender. Furthermore, we carried out an intention-to-treat analysis of the pri- mary outcome (adapted Fuster-BEWAT score) after multiple imputation for missing data by the monotone imputation method including all rando- mized participants with valid data at baseline, as pre-established in the SAP. The adapted Fuster-BEWAT score values at follow-ups were set as imputed dependent variables. The following covariates were used for the imputation approach: age (continuous variable), sex (binary vari- able), risk group (binary variable), intervention group (binary variable), and baseline adapted Fuster-BEWAT score (continuous variable). Missing data were assumed to be missing at random. Complete covari- ates information was available for all randomized enrolled participants. The number of iterations was set at 50. Secondary outcomes were analysed with linear mixed effect regres- sion models (or logistic models where applicable), where the outcome was the intention-to-treat dependent variable, and where the group (intervention vs. standard care) was modelled as an independent variable, and values were adjusted to the baseline outcome value. The 3-year follow-up was prioritized to ensure a high retention rate. Due to logistic- al reasons (extension of the inclusion period that resulted in overlapping yearly follow-up visits and lack of capacity to perform these visits simul- taneously), the percentage of participants with missing data at the second-year follow-up was higher than expected. For this reason, the SAP pre-established that it would be inadequate to evaluate Year-2 mea- surements separately, as an independent outcome. However, informa- tion about outcomes at Year 2 was included in the repeated measures analysis. All analyses included the total study population, stratified by SA as pre-specified. Between-group comparisons were reported as esti- mated mean differences with a 95% confidence interval (CI) and P-value. For all analyses, a two-tailed significance level of P < 0.05 was considered statistically significant. To control Type I error, and to correct for mul- tiple testing in reporting the effect on individual components of the pri- mary outcome,33 the level of statistical significance was adjusted for the number of comparisons (Bonferroni correction). All analyses were per- formed with SPSS version 23.0 (for multiple imputation) or 24.0. The signed SAP is included on the Supplementary material online, Appendix. The trial is registered at ClinicalTrials.gov (NCT02561065). Results A total of 1034 participants from the PESA cohort were assessed for eligibility for the TANSNIP-PESA RCT between May 2015 and February 2017. Of them, 1020 fulfilled all inclusion criteria and had no exclusion criteria, and 720 were in the low and 300 in the high SA subgroup. After signing the informed consent and completing all baseline assessments, participants were randomized to the intervention or control arm. In total, 959 participants (94.0%) completed the Year-1 follow-up assessment, 692 (67.8%) the Year-2 assessment, and 896 (87.8%) the Year-3 assessment. For the re- peated measure analysis of the primary outcome, 942 participants (92.4%) were included. A summarized CONSORT flowchart is shown in Figure 2 (see the extended version in Supplementary material online, Figure S1). Compliance with the three elements of the intervention was evaluated in each of the 12 motivational inter- view sessions, and the results are shown in Supplementary material online, Figure S2. In brief, attendance to motivational interviews was high (91% of the intervention group over the 12 sessions), as was Fitbit use (81%). In contrast, on average only 37% of participants used the sit–stand workstation over the 3-year period. Baseline demographic characteristics are presented in Table 1 for the total population and for the low and high SA subgroups. Mean age at inclusion was 49.9 ± 3.9 years, and 30.9% of the participants were women. Compared with low SA participants, the high SA sub- group had a worse CV risk profile at baseline, i.e. they were signifi- cantly older, higher percentage were male, they had lower educational level, and higher values for BP, BMI, glucose and lipid pro- file as well as poorer baseline adapted Fuster-BEWAT score than their low SA counterparts (see Supplementary material online, Table S2). In the high SA subgroup, the mean CACS was 40.8 ± 135.7 Agatston Units, and 2D-vascular ultrasound revealed athero- sclerotic plaques in the abdominal aorta, carotid arteries, and iliofe- moral arteries of 51.0%, 56.0%, and 80.0% of participants, respectively. Low SA participants were free of calcified coronary ar- tery disease at baseline by definition,19,20 but atherosclerotic plaques were present by ultrasound imaging in 16.3%, 21.5%, and 30.1% for the abdominal aorta, carotid arteries, and iliofemoral arteries, re- spectively. At baseline, the study population had a low-intermediate prevalence of classical CV risk factors (approximately 10% of partici- pants had hypertension, 15% were obese, and nearly 20% were smo- kers). Participants were physically active (40% exceeded 10 000 steps/day), but sedentary time was high (nearly 70% above 9.5 h/ day) (see Supplementary material online, Figure S3). Compared with the control group, the intervention group showed a significant improvement in the primary outcome measure (adapted Fuster BEWAT score) over the 3-year period, indicating a healthier CV status. The overall repeated measures effect over the 3-year period was 0.49 (95% CI 0.23–0.75) points in favour of the intervention group (Table 2). The effect of the intervention on the adapted Fuster-BEWAT score was maximal and statistically sig- nificant at Year 1 [estimate 0.83 (95% CI 0.52–1.15) points] and decreased to non-significant levels at Year 3 [estimate 0.24 (95% CI –0.10 to 0.59) points] (Table 2 and Figure 3). To better illustrate the within-group temporal changes in adapted Fuster-BEWAT score, Figure 4 presents change categories in adapted Fuster-BEWAT score for the intervention and control groups at Years 1 and 3. Over the 3-year period, the intervention was effective in partici- pants with a low baseline SA [overall effect 0.61 (95% CI 0.30– 0.93) points] but not in those with a high baseline SA [overall effect 0.19 (95% CI –0.26 to 0.64) points] (Table 2). As in the total popu- lation, the intervention effect in the low SA subgroup was highest at the first-year follow-up and attenuated at Year 3. No significant intervention effect was observed at either time point in the high SA subgroup (Table 2). Since there was no interaction for the D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 The TANSNIP-PESA trial 3737 Figure 2 Summarized CONSORT flowchart. CONSORT, Consolidated Standards of Reporting Trials; FU, follow-up; int, intervention; SA, subclinical atherosclerosis. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 3738 I. Garcia-Lunar et al. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 1 Baseline characteristics of the TANSNIP-PESA study population Total sample (n= 1020) Low SA (n=720) High SA (n= 300) Total sample (n=1020) Intervention (n=510) Control (n= 510) Intervention (n= 360) Control (n=360) Intervention (n=150) Control (n=150) Age (years) 49.9 (3.9) 50.0 (3.9) 49.9 (3.9) 49.4 (3.7) 49.2 (3.7) 51.3 (3.9) 51.7 (3.8) Female sex 315 (30.9%) 154 (30.2%) 161 (31.6%) 122 (33.9%) 130 (36.1%) 32 (21.3%) 31 (20.7%) Marital status Married/Defacto 771 (75.8%) 379 (74.3%) 392 (77.3%) 265 (73.6%) 278 (77.4%) 114 (76.0%) 114 (77.0%) Other 246 (24.2%) 131 (25.7%) 115 (22.7%) 95 (26.4%) 81 (22.6%) 36 (24.0%) 34 (23.0%) Working hours per week 39.7 (1.2) 39.7 (1.0) 39.6 (1.3) 39.7 (1.0) 39.5 (1.5) 39.7 (1.0) 39.8 (0.9) Education level Without University degree 161 (15.8%) 94 (18.4%) 67 (13.1%) 58 (16.1%) 42 (11.7%) 36 (24.0%) 25 (16.9%) With University degree 856 (84.2%) 416 (81.6%) 440 (86.9%) 302 (83.9%) 317 (88.3%) 114 (76.0%) 123 (83.1%) Data are mean (SD) or N (%). PESA, Progression of Early Subclinical Atherosclerosis; SA, subclinical atherosclerosis; TANSNIP, Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 2 Changes and between-group comparisons in the adapted Fuster-BEWAT score for all TANSNIP-PESA participants and the low and high SA subgroups Intervention Control Intervention effect N mean (SD) N mean (SD) Estimate (95% CI) P-value Adapted Fuster-BEWAT score (all participants) (0–24) Baseline 425 16.2 (3.7) 445 16.5 (3.5) – – Year 1 425 17.1 (3.6) 445 16.5 (3.5) 0.83 (0.52–1.15)a <0.001 Year 3 408 16.6 (3.7) 395 16.5 (3.6) 0.24 (−0.10 to 0.59)a 0.161 Overall time trend 468 – 474 – 0.49 (0.23–0.75)b <0.001 Adapted Fuster-BEWAT score (low SA participants) (0–24) Baseline 307 16.5 (3.7) 320 16.7 (3.4) – – Year 1 307 17.4 (3.6) 320 16.7 (3.4) 1.01 (0.63–1.39)a <0.001 Year 3 289 17.0 (3.5) 272 16.7 (3.5) 0.34 (−0.07 to 0.76)a 0.105 Overall time trend 333 – 337 – 0.61 (0.30–0.93)b <0.001 Adapted Fuster-BEWAT score (high SA participants) (0–24) Baseline 118 15.4 (3.7) 125 16.0 (3.6) – – Year 1 118 16.2 (3.6) 125 16.2 (3.6) 0.38 (−0.20 to 0.95)a 0.195 Year 3 119 15.7 (3.8) 123 16.0 (4.0) 0.03 (−0.57 to 0.63)a 0.927 Overall time trend 135 – 137 – 0.19 (−0.26 to 0.64)b 0.405 Fuster-BEWAT score and estimate mean difference are expressed in points. aFor the outcome analysis at Years 1 and 3, estimates were calculated using linear mixed effect regression models. bFor the overall time trend, estimates were calculated with repeated measures regression models. BEWAT, Blood pressure, Exercise (objectively measured PA and sedentary time), Weight (BMI), Alimentation (fruit and vegetable consumption), and Tobacco; PESA, Progression of Early Subclinical Atherosclerosis; SA, subclinical atherosclerosis; TANSNIP, Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 The TANSNIP-PESA trial 3739 primary outcome between the intervention arm and age or gender (P = 0.596 and P = 0.592, respectively), further stratified analyses by these factors were not performed. After using a multiple imputation technique for missing data, the intention-to-treat analysis of the primary outcome showed consist- ent findings with the non-imputed dataset. The overall intervention effect was in favour of the intervention group with a borderline stat- istical significance [overall effect 0.40 (95% CI–0.02 to 0.82) points, P = 0.064]. Similar to the non-imputed results, the intervention was ef- fective over the 3-year period in those participants with a low base- line SA [overall effect 0.54 (95% CI 0.07–1.01) points, P = 0.024] but not in those with high baseline SA [overall effect 0.07 (95% CI –0.70 to 0.49) points, P = 0.855]. Results of individual adapted Fuster-BEWAT score components are shown in Table 3. There were significant between-group differ- ences in favour of the intervention group in PA, sedentary time, and fruit and vegetable consumption. All these effects were attenu- ated and were no longer different at the 3-year follow-up assessment. These between-group treatment effect differences in the adapted Fuster-BEWAT score behavioural components were also present (and were of higher magnitude) in the low SA subgroup (Table 4). The high SA group showed no statistically significant effect for these outcomes at either Year 1 or Year 3 follow-up. No significant changes were found in BMI or the number of cigarettes smoked/day. Additionally, we found a borderline-significant between-group ef- fect on total cholesterol levels at Year 3 in favour of the intervention [–4.05 (95% CI –8.00 to –0.10) mg/dL] (Table 5). In the low SA sub- group, between-group differences in favour of the intervention were significant in total and low-density lipoprotein (LDL) cholesterol le- vels at Year 3 and borderline-significant in triglyceride levels at Years 1 and 3 (see Supplementary material online, Table S3). High SA participants showed no significant between-group differences in blood biomarkers (see Supplementary material online, Table S4). The results presented above were generally supported by behav- ioural results from the activPAL PA monitor and questionnaires, showing improvements in the first year and attenuation at Year 3 (see Supplementary material online, Table S5). No significant changes were seen in the anthropometric variables. Psychosocial and work- related results showed a few non-significant effects at Year 1 in the expected direction, most notably a reduction in work absentee- ism in favour of the intervention group (see Supplementary material online, Table S6). The findings presented above were further sup- ported by the results for the other secondary outcomes in low and high SA participants (see Supplementary material online, Tables S7–S10). Supplementary material online, Table S11 shows the num- ber of missing data for the primary endpoint at each follow-up visit. Discussion In this RCT, conducted in an asymptomatic middle-aged population at low–intermediate CV risk, the most important result was that a Figure 3 Change in the primary outcome at baseline, 1-year follow-up, and 3-year follow-up in all TANSNIP-PESA participants. The line-plot re- presents mean change (dots) for the adapted Fuster-BEWAT score at different follow-up times relative to values at the initial screening for intervened participants (orange) and controls (blue). P-values as derived from between-group differences of Fuster-BEWAT score change at each follow-up assessment from baseline using linear mixed effect regression models. The score ranges from 0 (poor cardiovascular health) to 24 (ideal cardiovas- cular health) and is derived from the sum of the individual components (0–4 points each). Adapted Fuster-BEWAT score, Blood pressure, Exercise (PA and sedentary time), Weight (BMI), Alimentation (fruit and vegetable consumption), and Tobacco (smoking habit); PESA, Progression of Early Subclinical Atherosclerosis; TANSNIP, Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 3740 I. Garcia-Lunar et al. 3-year intensive worksite intervention was able to produce a modest improvement in lifestyle behaviour and overall CV health. However, intervention effectiveness peaked 1 year after baseline and attenu- ated at the Year-3 evaluation (Structured Graphical Abstract). In light of the motivational interview scheme used (one session every second week for the first 3 months followed by booster sessions spaced every 5–8 months), one possible explanation for the observed at- tenuation of intervention effectiveness is that maintenance of lifestyle improvements beyond the first year requires sustained and more in- tensive behavioural support over time, similar to preventive pharma- cological approaches that are maintained chronically. Second, the intervention was effective in participants having low baseline SA, but counterintuitively not in those with high SA. From a health pro- motion perspective, one may argue that prevention efforts should be increased for those subjects with high SA. Comparison with other studies The pattern of transient favourable changes after a lifestyle interven- tion that tend to dilute over time is consistent with the existing litera- ture. For instance, the Fifty–Fifty trial was a multicentre RCT conducted in Spain testing the effect of a peer-group intervention in adults with at least one CV risk factor.26 In this trial, the interven- tion produced a significant improvement in the Fuster-BEWAT score at the first-year follow-up compared with the control group. However, the residual beneficial effect in the intervention group vs. the control group was negligible at 4-year follow-up.34 FAMILIA, the Grenada Heart Project and the Look AHEAD trial,29,30,35 among others, are recent large-sized lifestyle intervention trials that have failed to demonstrate a benefit of different lifestyle interventions in either participants, or patients with Type 2 diabetes, thus illustrating the difficulty to obtain significant and sustained life- style changes through coaching in adulthood. Different intervention effect between subclinical atherosclerosis groups Our stratified analysis shows a stronger treatment effect in the low SA subgroup and a smaller, non-significant effect in the high SA sub- group. This counterintuitive finding conflicts with our initial hypoth- esis that the high SA group would be more receptive to the intervention, based on our expectation that the higher atherosclerot- ic plaque burden in this group would foster a greater sense of urgency about lifestyle changes. We do not have a clear explanation for this finding. Analysis of the baseline differences among our two study sub- groups showed that high SA participants had a less favourable CV risk profile than the low SA subgroup (see Supplementary material online, Table S2). One possibility is that the high SA group had been struggling with a healthy lifestyle for a longer period and the intervention was not intensive enough to resolve those struggles. From this perspec- tive, the chances to improve would be higher in the low SA subgroup (since the baseline motivation towards CV health was probably higher to begin with). Another possibility is that differences on the imple- mentation process and/or adherence to individual intervention com- ponents between the low and high SA subgroups may have influenced the intervention effect. Our ongoing (pre-specified) process evalu- ation21 will provide further insight into the level of implementation and barriers for adoption of the TANSNIP-PESA intervention and will explore the association between the degree of implementation and changes in participants’ outcomes, especially with regard to the high and low SA subgroups. In line with our results, one previous RCT found a limited value of motivational interviewing for CVD Figure 4 Distribution of participants according to their degree of absolute change in the adapted Fuster-BEWAT score at Year 1 (left panel) and Year-3 follow-up (right panel) in both study treatment arms. The adapted Fuster-BEWAT score ranges from 0 (poor cardiovascular health) to 24 (ideal cardiovascular health) and is derived from the sum of the individual components (0–4 points each). Participants were classified into five cat- egories according to their change in the adapted Fuster-BEWAT score from baseline: Markedly improved (dark green: a >3 point change); moderately improved (light green: a 2–3 point change); stable (yellow: a –1 to 1 point change); moderately worse (orange: a –2 to –3 point change) and markedly worse (red: a >–3 point change). BEWAT, Blood pressure, Exercise (objectively measured PA and sedentary time), Weight (BMI), Alimentation (fruit and vegetable consumption), and Tobacco. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 The TANSNIP-PESA trial 3741 risk reduction and PA increase in individuals at high baseline CVD risk.36 What remains to be elucidated and should be tested in future trials is whether high SA participants would benefit from more aggressive interventional strategies, including a higher frequency life- style intervention or eventually direct early initiation of pharmaco- logical approaches. TANSNIP-PESA process evaluation will analyse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 3 Changes and between-group comparisons in the individual components of the adapted Fuster-BEWAT score for all TANSNIP-PESA participants Intervention Control Intervention effect N mean (SD) N mean (SD) Estimate (95% CI) P-value Systolic Blood Pressure (mmHg) Baseline 477 115.6 (13.6) 481 113.6 (12.2) – – Year 1 477 116.6 (12.9) 481 116.6 (12.3) −1.36 (−2.47 to −0.25) 0.017 Year 3 451 119.3 (14.8) 434 118.2 (13.8) −0.85 (−2.15 to 0.44) 0.197 Diastolic Blood Pressure (mmHg) Baseline 477 77.6 (9.5) 481 76.0 (8.4) – – Year 1 477 72.3 (8.9) 481 72.0 (8.4) −0.83 (−1.59 to −0.08) 0.031 Year 3 451 75.4 (10.2) 434 74.8 (9.8) −0.92 (−1.85 to 0.02) 0.055 Physical activity (activPAL) (steps/day) Baseline 459 9480 (2743) 465 9452 (2874) – – Year 1 459 10241 (3319) 465 9712 (3139) 508 (182 to 833) 0.002 Year 3 424 10079 (3166) 408 9806 (3249) 222 (−137 to 580) 0.226 Sedentary time (activPAL) (h/day) Baseline 459 10.6 (1.3) 465 10.5 (1.3) – – Year 1 459 10.5 (1.3) 465 10.4 (1.3) −0.21 (−0.34 to −0.07) 0.003 Year 3 424 10.1 (1.3) 408 10.1 (1.5) −0.05 (−0.22 to 0.12) 0.563 BMI (kg/m2) Baseline 476 26.3 (3.6) 482 26.3 (3.9) – – Year 1 476 26.2 (3.7) 482 26.2 (3.9) −0.06 (−0.21 to 0.09) 0.435 Year 3 450 26.6 (3.8) 436 26.4 (4.0) 0.07 (−0.11 to 0.25) 0.451 Fruit and vegetable consumption (servings/day) Baseline 462 3.3 (1.6) 467 3.2 (1.6) – – Year 1 462 3.4 (1.6) 467 3.1 (1.6) 0.23 (0.08–0.38) 0.003 Year 3 456 3.3 (1.6) 438 3.2 (1.5) 0.05 (−0.11 to 0.20) 0.558 Smoking (units/day) Baseline 474 1.7 (5.1) 474 1.3 (4.3) – – Year 1 474 1.5 (4.7) 474 1.4 (4.1) −0.13 (−0.50 to 0.24) 0.498 Year 3 457 1.2 (4.3) 438 1.3 (4.2) −0.31 (−0.64 to 0.03) 0.074 Original BEWAT Score (0–15) Baseline 429 10.4 (2.5) 450 10.7 (2.4) – – Year 1 429 10.9 (2.4) 450 10.7 (2.4) 0.39 (0.18–0.60) <0.001 Year 3 410 10.6 (2.6) 402 10.4 (2.5) 0.19 (−0.04 to 0.42) 0.11 For the outcome analysis at Years 1 and 3, estimates were calculated using linear mixed effect regression models. BEWAT, Blood pressure, Exercise (objectively measured PA and sedentary time), Weight (BMI), Alimentation (fruit and vegetable consumption), and Tobacco; BMI, body mass index; PESA, Progression of Early Subclinical Atherosclerosis; SA, subclinical atherosclerosis; TANSNIP, Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 3742 I. Garcia-Lunar et al. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 4 Changes and between-group comparisons in the individual components of the adapted Fuster-BEWAT score in the low and high SA subgroups Intervention Control Intervention effect N mean (SD) N mean (SD) Estimate (95% CI) P-value Low SA subgroup Systolic Blood Pressure (mmHg) Baseline 339 114.8 (14.0) 344 112.4 (12.1) – – Year 1 339 115.8 (12.6) 344 115.3 (11.7) −1.06 (−2.35 to 0.23) 0.105 Year 3 316 118.6 (15.0) 305 116.8 (13.6) −0.32 (−1.88 to 1.25) 0.692 Diastolic Blood Pressure (mmHg) Baseline 339 76.9 (9.8) 344 75.2 (8.4) – – Year 1 339 71.7 (9.0) 344 71.4 (8.2) −0.91 (−1.78 to −0.05) 0.039 Year 3 316 74.7 (10.4) 305 73.8 (9.7) −0.65 (−1.77 to 0.47) 0.255 Physical activity (activPAL) (steps/day) Baseline 326 9354 (2674) 334 9456 (2803) – – Year 1 326 10083 (2907) 334 9623 (3077) 530 (170 to 890) 0.004 Year 3 301 10038 (3179) 284 9575 (2988) 472 (63 to 881) 0.024 Sedentary time (activPAL) (h/day) Baseline 326 10.6 (1.3) 334 10.4 (1.3) – – Year 1 326 10.3 (1.3) 334 10.4 (1.3) −0.229 (−0.39 to −0.07) 0.004 Year 3 301 10.1 (1.3) 301 10.1 (1.5) −0.07 (−0.27 to 0.13) 0.489 BMI (kg/m2) Baseline 338 25.8 (3.4) 345 26.1 (4.0) – – Year 1 338 25.7 (3.5) 345 26.1 (4.1) −0.09 (−0.26 to 0.09) 0.333 Year 3 314 26.0 (3.6) 307 26.3 (4.1) 0.00 (−0.22 to 0.22) 0.988 Fruit and Vegetable consumption (servings/day) Baseline 330 3.3 (1.6) 334 3.3 (1.5) – – Year 1 330 3.4 (1.6) 334 3.1 (1.6) 0.28 (0.09–0.46) 0.003 Year 3 320 3.3 (1.6) 308 3.2 (1.5) 0.08 (−0.106 to 0.265) 0.400 Smoking (units/day) Baseline 337 1.4 (4.4) 351 1.3 (3.9) – – Year 1 337 1.2 (4.5) 351 1.4 (4.1) −0.28 (−0.69 to 0.14) 0.192 Year 3 321 0.9 (3.9) 308 1.2 (3.7) −0.31 (−0.70 to 0.08) 0.113 Original BEWAT Score (0–15) Baseline 309 10.7 (2.5) 324 10.8 (2.4) – – Year 1 309 11.2 (2.4) 324 10.8 (2.3) 0.45 (0.20–0.71) 0.001 Year 3 290 10.9 (2.5) 279 10.5 (2.5) 0.30 (0.02–0.58) 0.038 High SA subgroup Systolic Blood Pressure (mmHg) Baseline 138 117.7 (12.3) 137 116.6 (11.9) – – Year 1 138 118.6 (13.3) 137 119.7 (13.0) −1.98 (−4.15 to 0.18) 0.072 Continued D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 The TANSNIP-PESA trial 3743 in depth the lessons learned from the participants who made the greatest (and smallest) improvement that may be useful to design these future interventions. Other intervention approaches such as group-based dynamics, use of behavioural psychology game theory or population-based approaches with a focus on changing workplace culture and behavioural norms might be alternative intervention strategies to be considered. Overall, our results reinforce the concept that the CVD-prevention programmes need to start early, at ages when subclinical disease is presumably less advanced, and that this support needs to be sustained throughout life. Clinical implications of this study and future research The TANSNIP-PESA intervention was able to modestly improve PA, sedentary, and dietary behaviours after 1 year, and these lifestyle im- provements had a small and transitory effect on CV risk factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 4 Continued Intervention Control Intervention effect N mean (SD) N mean (SD) Estimate (95% CI) P-value Year 3 135 120.9 (14.2) 129 120.9 (14.2) −2.09 (−4.42 to 0.24) 0.079 Diastolic Blood Pressure (mmHg) Baseline 138 79.4 (8.4) 137 78.1 (8.0) – – Year 1 138 73.8 (8.7) 137 73.5 (8.8) −0.63 (−2.15 to 0.90) 0.421 Year 3 135 77.1 (9.6) 129 77.4 (9.5) −1.52 (−3.23 to 0.19) 0.080 Physical activity (activPAL) (steps/day) Baseline 133 9790 (2890) 131 9438 (3059) – – Year 1 133 10627 (4148) 131 9942 (3294) 400 (−298 to 1097) 0.260 Year 3 123 10179 (3144) 124 10337 (3738) −355 (−1076 to 367) 0.334 Sedentary time (activPAL) (h/day) Baseline 133 10.7 (1.3) 131 10.8 (1.1) – – Year 1 133 10.4 (1.4) 131 10.5 (1.3) −0.14 (−0.41 to 0.13) 0.307 Year 3 123 10.2 (1.4) 124 10.2 (1.5) 0.00 (−0.32 to 0.32) 0.994 BMI (kg/m2) Baseline 138 27.6 (3.9) 137 26.5 (3.5) – – Year 1 138 27.5 (4.0) 137 26.5 (3.3) 0.04 (−0.28 to 0.379) 0.800 Year 3 136 27.9 (3.9) 129 26.8 (3.6) 0.27 (−0.06 to 0.60) 0.114 Fruit and Vegetable consumption (servings/day) Baseline 132 3.2 (1.5) 133 3.2 (1.6) – – Year 1 132 3.2 (1.7) 133 3.1 (1.5) 0.12 (−0.16 to 0.40) 0.402 Year 3 136 3.1 (1.5) 130 3.1 (1.5) −0.03 (−0.33 to 0.26) 0.840 Smoking (units/day) Baseline 137 2.7 (6.5) 139 1.4 (5.1) – – Year 1 137 2.3 (5.2) 139 1.2 (4.2) 0.35 (−0.40 to 1.09) 0.359 Year 3 136 2.0 (4.9) 130 1.5 (5.0) −0.28 (−0.94 to 0.38) 0.405 Original BEWAT Score (0–15) Baseline 120 9.8 (2.5) 126 10.5 (2.5) – – Year 1 120 10.3 (2.3) 126 10.6 (2.4) 0.23 (−0.17 to 0.63) 0.264 Year 3 120 9.8 (2.4) 123 10.2 (2.5) −0.08 (−0.49 to 0.32) 0.689 For the outcome analysis at Years 1 and 3, estimates were calculated using linear mixed effect regression models. BEWAT, Blood pressure, Exercise (objectively measured PA and sedentary time), Weight (BMI), Alimentation (fruit and vegetable consumption), and Tobacco; BMI, body mass index; PESA, Progression of Early Subclinical Atherosclerosis; SA, subclinical atherosclerosis; TANSNIP, Trans-Atlantic Network to study Stepwise Non-invasive Imaging as a tool for CVD Prognosis and prevention. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 3744 I. Garcia-Lunar et al. reduction. In our low SA subgroup, blood cholesterol changes did not appear immediately after lifestyle improvements but appeared later, and the effect was sustained in the Year-3 evaluation (see Supplementary material online, Table S3). Our results suggest that sustainability may depend on the maintenance of the coaching sup- port although this issue should be further investigated. Given that atherosclerosis (the underlying cause of most CVD) is a chronic dis- order with a very long asymptomatic period, it is also logical to think that behavioural strategies aiming to reduce this problem should be applied recurrently, otherwise their beneficial effect on individuals will disappear once the support is withdrawn, as happened in TANSNIP-PESA and other lifestyle intervention RCTs.34 Although the absolute reduction in the primary outcome observed in our study may seem small, it is known that prevention strategies aimed at a population level often offer little benefit to each participating individual, but much to the population as a whole; ‘where a little means a lot’.37 We plan to further assess the effect of the TANSNIP-PESA intervention on SA initiation and/or progression using the extensive phenotyping available from the ongoing PESA imaging studies.20 Strengths and limitations of this study Strengths of the current trial include the large sample, the prolonged intervention and follow-up periods for the study of lifestyle-change maintenance, the high retention rates at Years 1 and 3 and the ob- jective measurement of outcomes such as PA and sitting time with accelerometry. Nesting of TANSNIP-PESA within the PESA cohort provides a perfect opportunity for further comprehensive assess- ments of the relationship between lifestyle behavioural changes and SA. Similarly, cost-effectiveness analyses will be undertaken using data from subsequent PESA follow-ups. The PESA cohort is a homogeneous, highly educated, and quite physically active population, with overall low–intermediate CVD risk. This limits the generalizability of the results to the general popu- lation. Although this RCT was conducted in Spain, the baseline ad- herence to a Mediterranean dietary pattern was only moderate, giving plenty of room for dietary improvement. Due to logistical is- sues, almost one-third of the study population did not undergo follow-up measurements at Year 2. Therefore, Year 2 data were only included in the repeated measures analysis and were not ana- lysed separately, as indicated in the SAP (see Supplementary material online, Appendix). However, the Year-3 retention rate was 87.8%. There were no significant differences between baseline Fuster-BEWAT score values of those participants with and without missing value on the outcome at Year 2 (data not shown). Due to the study design, neither participants, intervention providers, nor data collection staff could be blinded to the allocation arm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 5 Laboratory measurements for all participants Intervention Control Intervention effect (between-group differences) N mean (SD) N mean (SD) Estimate (95% CI) P-value Baseline Glucose, mg/dL 464 92.4 (11.1) 469 92.0 (14.8) – – Total cholesterol, mg/dL 464 188.9 (31.0) 469 189.5 (30.3) – – LDL, mg/dL 461 115.4 (27.1) 466 115.5 (26.8) – – HDL, mg/dL 464 55.7 (12.8) 469 55.9 (13.2) – – Triglycerides, mg/dL 464 91.6 (53.1) 469 96.3 (71.7) – – Year 1 Glucose, mg/dL 464 90.7 (13.4) 469 90.1 (13.3) 0.45 (−0.97 to 1.86) 0.535 Total cholesterol, mg/dL 464 188.0 (31.2) 469 189.5 (33.5) −1.24 (−4.88 to 2.40) 0.504 LDL, mg/dL 461 117.2 (26.4) 466 118.0 (28.4) −0.80 (−3.80 to 2.20) 0.602 HDL, mg/dL 464 53.3 (13.0) 469 52.7 (12.4) 0.74 (−0.57 to 2.04) 0.267 Triglycerides, mg/dL 464 89.5 (51.7) 469 96.9 (63.4) −5.22 (−11.64 to 1.19) 0.111 Year 3 Glucose, mg/dL 437 88.8 (17.1) 423 87.4 (11.6) 0.98 (−0.80 to 2.76) 0.281 Total cholesterol, mg/dL 437 196.6 (32.3) 423 200.8 (33.4) −4.05 (−8.00 to −0.10) 0.044 LDL, mg/dL 434 122.0 (29.1) 414 125.2 (29.7) −3.31 (−6.84 to 0.24) 0.067 HDL, mg/dL 437 54.8 (14.2) 423 54.9 (13.7) −0.11 (−1.56 to 1.34) 0.882 Triglycerides, mg/dL 437 100.0 (63.3) 423 107.6 (88.7) −5.14 (−14.39 to 4.11) 0.276 For the outcome analysis at Years 1 and 3, estimates were calculated using linear mixed effect regression models. HDL, high-density lipoprotein; LDL, low-density lipoprotein. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 The TANSNIP-PESA trial 3745 Nevertheless, all study measurements followed standardized proce- dures, and many outcomes relied on objective parameters not sub- ject to self-report bias (such as laboratory tests or accelerometer assessments). An interaction test was not conducted to fully confirm differences between SA subgroups (adhering to our SAP, see Supplementary material online, Appendix). Finally, the laboratory ana- lyses were performed on frozen samples at baseline and Year 1, whereas fresh samples were analysed at Years 2 and 3. This may have generated some intra-individual longitudinal variation. However, any systematic bias would be the same for the control and intervention groups. Conclusion This RCT provides evidence of beneficial effects of a lifestyle inter- vention on lifestyle behaviours and CV health in asymptomatic low–intermediate risk middle-aged adults. Intervention effects on lifestyle attenuated over time, suggesting that sustained effects need a more intense intervention beyond the first year. The inter- vention was especially effective in participants with low SA burden whereas subjects with high SA might need extra support or alterna- tive approaches for behaviour change. Authors’ contributions I.G.-L was involved in investigation, methodology, project administra- tion, writing of the original draft. H.P.v.d.P. was involved in conceptual- ization, methodology, supervision, writing, reviewing, and editing of the article. J.M.F.A. and F.v.N were involved in data curation, formal analysis, investigation, methodology, writing, reviewing, and editing of the article. J.M.C.V. was involved in conceptualization, methodology, project ad- ministration, supervision, writing, reviewing, and editing of the article. A.J.v.d.B. was involved in conceptualization, methodology, supervision, writing, reviewing, and editing. X.R. was involved in formal analysis, methodology, supervision, writing, reviewing, and editing. A.F.-O. was involved in project administration, resources, supervision, writing, re- viewing, and editing. J.C. was involved in conceptualization, investigation, methodology, writing, reviewing, and editing. J.M.v.D. was involved in conceptualization, methodology, data curation, formal analysis, writing, reviewing, and editing. J.M.M. was involved in project administration, re- sources, supervision, writing, reviewing, and editing. B.I. was involved in conceptualization, methodology, project administration, resources, supervision, writing, reviewing, and editing. W.v.M. was involved in con- ceptualization, methodology, supervision, writing, reviewing, and editing.V.F. was involved in conceptualization, funding acquisition, meth- odology, supervision, writing, reviewing, and editing. Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgements The authors thank all TANSNIP-PESA participants for their invaluable participation in this trial. Evelyn Cárdenas Marín and Antonio Quesada Navidad were outstanding in the coordination of the RCT and the overall development of the project. The authors also acknowledge the work of Carolina Rojas Murcia and Maria Isabel Martínez Castro, who provided top quality motivational interview sessions; Sergio Cárdenas and Jesús Molina for their continuous IT support; Magdalena López for logistics within Santander Bank; Marta Cortés-Canteli for helpful discussions and all the PESA nutrition, bio- bank, and imaging technicians and CNIC nurses for their enthusiastic contributions. Simon Bartlett provided English editing. The authors also thank Ergotron Inc. for providing partial support for the acquisi- tion of the sit-stand workstations used in the intervention programme. Funding TANSNIP-PESA is funded by Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III through an Investigator-initiated Study grant to Icahn School of Medicine from AstraZeneca. The PESA study is co- funded by the CNIC and Banco Santander. The study also received funding from the Instituto de Salud Carlos III (PI15/02019) and the European Regional Development Fund (ERDF) ‘A way to make Europe’. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033. The study funders were not in- volved in the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the paper for publication. Conflict of interest: W.v.M. wishes to declare for the avoidance of doubt that he is the director of the former VU University Medical Center spin-off company Evalua Nederland B.V. (www.evalua.nl) and non- executive director of Arbo Unie B.V. (www.arbounie.nl; ‘B.V.’ stands for Ltd; both companies are active in the Dutch occupational health care market). In addition, W.v.M consults with the Dutch Ministry of Social Affairs and Welfare and to the Executive Board of the Groningen Academic Medical Centre, Groningen, NL on Public Health matters. A.J.v.d.B. works as a con- sultant for Evalua Nederland B.V. for <4 h per week. Ergotron, Inc. provided partial support for the acquisition of the sit–stand workstations. Ergotron was not involved in the study design; the collection, analysis, or interpret- ation of data; the writing of the report; or the decision to submit the paper for publication. There are no other financial or personal relationships to de- clare. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf Data availability • Will individual participant data be available (including data dictionar- ies)? Yes. • What data in particular will be shared? Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices). • What other documents will be available? Study protocol, statistical analysis plan, informed consent form. • When will data be available? Immediately following publication; no end date. • With whom? Investigators whose proposed use of the data has been approved by the TANSNIP-PESA scientific and publications commit- tee and by the PESA scientific committee. • For what types of analyses? To achieve the aims of the approved proposal. • By what mechanism will data be made available? Proposals should be directed to pesa-h@cnic.es. To gain access, data requestors will need to sign a data access agreement. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023 3745a I. Garcia-Lunar et al. References 1. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020;76:2982–3021. 2. Timmis A, Townsend N, Gale CP, Torbica A, Lettino M, Petersen SE, et al. European society of cardiology: cardiovascular disease statistics 2019. Eur Heart J 2020;41: 12–85. 3. Gupta R, Wood DA. Primary prevention of ischaemic heart disease: populations, in- dividuals, and health professionals. Lancet 2019;394:685–696. 4. Zhang YB, Chen C, Pan XF, Guo J, Li Y, Franco OH, et al. Associations of healthy lifestyle and socioeconomic status with mortality and incident cardiovascular disease: two prospective cohort studies. BMJ 2021;373:n604. 5. Lear SA, Hu W, Rangarajan S, Gasevic D, Leong D, Iqbal R, et al. The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high- income, middle-income, and low-income countries: the PURE study. Lancet 2017; 390:2643–2654. 6. Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 2016;375: 2349–2358. 7. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by represen- tatives of 10 societies and by invited experts). Developed with the special contribu- tion of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–2381. 8. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, et al. ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42:3227–337. 9. Sisti LG, Dajko M, Campanella P, Shkurti E, Ricciardi W, de Waure C. The effect of multifactorial lifestyle interventions on cardiovascular risk factors: a systematic re- view and meta-analysis of trials conducted in the general population and high risk groups. Prev Med 2018;109:82–97. 10. Alageel S, Gulliford MC, McDermott L, Wright AJ. Multiple health behaviour change interventions for primary prevention of cardiovascular disease in primary care: sys- tematic review and meta-analysis. BMJ Open 2017;7:e015375. 11. Jorgensen T, Jacobsen RK, Toft U, Aadahl M, Glumer C, Pisinger C. Effect of screen- ing and lifestyle counselling on incidence of ischaemic heart disease in general popu- lation: Inter99 randomised trial. BMJ 2014;348:g3617. 12. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple risk fac- tor interventions for primary prevention of coronary heart disease. Cochrane Database Syst Rev 2011;1:CD001561. 13. Shrestha N, Grgic J, Wiesner G, Parker A, Podnar H, Bennie JA, et al. Effectiveness of interventions for reducing non-occupational sedentary behaviour in adults and older adults: a systematic review and meta-analysis. Br J Sports Med 2019;53:1206–1213. 14. Shrestha N, Kukkonen-Harjula KT, Verbeek JH, Ijaz S, Hermans V, Pedisic Z. Workplace interventions for reducing sitting at work. Cochrane Database Syst Rev 2018;6:CD010912. 15. Gysan DB, Millentrup S, Albus C, Bjarnason-Wehrens B, Latsch J, Gohlke H, et al. Substantial improvement of primary cardiovascular prevention by a systematic score-based multimodal approach: A randomized trial: The PreFord-Study. Eur J Prev Cardiol 2017;24:1544–1554. 16. Cahill K, Lancaster T. Workplace interventions for smoking cessation. Cochrane Database Syst Rev 2014;2:CD003440. 17. Rongen A, Robroek SJW, van Lenthe FJ, Burdorf A. Workplace health promotion: a meta-analysis of effectiveness. Am J Prev Med 2013;44:406–415. 18. Hutchinson AD, Wilson C. Improving nutrition and physical activity in the work- place: a meta-analysis of intervention studies. Health Promot Int 2012;27:238–249. 19. Fernandez-Ortiz A, Jimenez-Borreguero LJ, Penalvo JL, Ordovas JM, Mocoroa A, Fernandez-Friera L, et al. The Progression and Early detection of Subclinical Atherosclerosis (PESA) study: rationale and design. Am Heart J 2013;166:990–998. 20. Ibanez B, Fernandez-Ortiz A, Fernandez-Friera L, Garcia-Lunar I, Andres V, Fuster V. Progression of early subclinical atherosclerosis (PESA) study: JACC focus seminar 7/ 8. J Am Coll Cardiol 2021;78:156–179. 21. Coffeng JK, van der Ploeg HP, Castellano JM, Fernandez-Alvira JM, Ibanez B, Garcia-Lunar I, et al. A 30-month worksite-based lifestyle program to promote car- diovascular health in middle-aged bank employees: Design of the TANSNIP-PESA randomized controlled trial. Am Heart J 2017;184:121–132. 22. Rossello X, Fuster V, Oliva B, Sanz J, Fernandez Friera LA, Lopez-Melgar B, et al. Association between body size phenotypes and subclinical atherosclerosis. J Clin Endocrinol Metab 2020;105:3734–3744. 23. Lundahl B, Moleni T, Burke BL, Butters R, Tollefson D, Butler C, et al. Motivational interviewing in medical care settings: a systematic review and meta-analysis of ran- domized controlled trials. Patient Educ Couns 2013;93:157–168. 24. Stonerock GL, Blumenthal JA. Role of counseling to promote adherence in healthy lifestyle medicine: strategies to improve exercise adherence and enhance physical ac- tivity. Prog Cardiovasc Dis 2017;59:455–462. 25. Burgess E, Hassmen P, Welvaert M, Pumpa KL. Behavioural treatment strategies im- prove adherence to lifestyle intervention programmes in adults with obesity: a sys- tematic review and meta-analysis. Clin Obes 2017;7:105–114. 26. Gomez-Pardo E, Fernandez-Alvira JM, Vilanova M, Haro D, Martinez R, Carvajal I, et al. A comprehensive lifestyle peer group-based intervention on cardiovascular risk factors: the randomized controlled fifty-fifty program. J Am Coll Cardiol 2016; 67:476–485. 27. Fernandez-Alvira JM, Fuster V, Pocock S, Sanz J, Fernandez-Friera L, Laclaustra M, et al. Predicting subclinical atherosclerosis in low-risk individuals: ideal cardiovascular health score and Fuster-BEWAT score. J Am Coll Cardiol 2017;70:2463–2473. 28. Wang HY, Dou KF, Sun YX. Fuster-BEWAT score versus cardiovascular health score to predict subclinical target organ damage: Insights from a large-scale Asian population. Eur J Prev Cardiol 2020;27:2292–2295. 29. Latina J, Fernandez-Jimenez R, Bansilal S, Sartori S, Vedanthan R, Lewis M, et al. Grenada Heart Project-Community Health ActioN to EncouraGe healthy BEhaviors (GHP-CHANGE): A randomized control peer group-based lifestyle inter- vention. Am Heart J 2020;220:20–28. 30. Fernandez-Jimenez R, Jaslow R, Bansilal S, Diaz-Munoz R, Fatterpekar M, Santana M, et al. Different lifestyle interventions in adults from underserved communities: the FAMILIA trial. J Am Coll Cardiol 2020;75:42–56. 31. Martinez-Gonzalez MA, Garcia-Arellano A, Toledo E, Salas-Salvado J, Buil-Cosiales P, Corella D, et al. A 14-item Mediterranean diet assessment tool and obesity indexes among high-risk subjects: the PREDIMED trial. PLoS One 2012;7:e43134. 32. Twisk J, Bosman L, Hoekstra T, Rijnhart J, Welten M, Heymans M. Different ways to estimate treatment effects in randomised controlled trials. Contemp Clin Trials Commun 2018;10:80–85. 33. Pocock SJ, Rossello X, Owen R, Collier TJ, Stone GW, Rockhold FW. Primary and secondary outcome reporting in randomized trials: JACC State-of-the-Art Review. J Am Coll Cardiol 2021;78:827–839. 34. Fernandez-Alvira JM, Fernandez-Jimenez R, de Miguel M, Santos-Beneit G, Bodega P, Hill CA, et al. The challenge of sustainability: long-term results from the Fifty-Fifty peer group-based intervention in cardiovascular risk factors. Am Heart J 2021;240: 81–88. 35. Look ARG, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369: 145–154. 36. Ismail K, Bayley A, Twist K, Stewart K, Ridge K, Britneff E, et al. Reducing weight and increasing physical activity in people at high risk of cardiovascular disease: a rando- mised controlled trial comparing the effectiveness of enhanced motivational inter- viewing intervention with usual care. Heart 2020;106:447–454. 37. Rose G. Sick individuals and sick populations. Int J Epidemiol 2001;30:427–432. dis- cussion 33-4. D ow nloaded from https://academ ic.oup.com /eurheartj/article/43/38/3732/6649085 by Fundacion C entro N acional user on 16 M arch 2023