Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 https://doi.org/10.1186/s12966-021-01144-5 RESEARCH Open Access Cost-effectiveness analysis of a multiple health behaviour change intervention in people aged between 45 and 75 years: a cluster randomized controlled trial in primary care (EIRA study) Ignacio Aznar-Lou1,2* , Edurne Zabaleta-Del-Olmo3,4,5,6, Marc Casajuana-Closas3,7, Alba Sánchez-Viñas1,2, Elizabeth Parody-Rúa1, Bonaventura Bolíbar3,7, Montserrat Iracheta-Todó1,7, Oana Bulilete8,9, Tomàs López-Jiménez3, Haizea Pombo-Ramos10,11, María Victoria Martín Miguel12,13, Rosa Magallón-Botaya14,15, Jose Ángel Maderuelo-Fernández16, Emma Motrico7,17, Juan Bellón7,18,19,20, Ruth Martí-Lluch3,21,22, Maria Rubio-Valera1,2† and Antoni Serrano-Blanco1,2† Abstract Background: Multiple health behaviour change (MHBC) interventions that promote healthy lifestyles may be an efficient approach in the prevention or treatment of chronic diseases in primary care. This study aims to evaluate the cost-utility and cost-effectiveness of the health promotion EIRA intervention in terms of MHBC and cardiovascular reduction. Methods: An economic evaluation alongside a 12-month cluster-randomised (1:1) controlled trial conducted between 2017 and 2018 in 25 primary healthcare centres from seven Spanish regions. The study took societal and healthcare provider perspectives. Patients included were between 45 and 75 years old and had any two of these three behaviours: smoking, insufficient physical activity or low adherence to Mediterranean dietary pattern. Intervention duration was 12 months and combined three action levels (individual, group and community). MHBC, defined as a change in at least two health risk behaviours, and cardiovascular risk (expressed in % points) were the outcomes used to calculate incremental cost-effectiveness ratios (ICER). Quality-adjusted life-years (QALYs) were estimated and used to calculate incremental cost-utility ratios (ICUR). Missing data was imputed and bootstrapping with 1000 replications was used to handle uncertainty in the modelling results. * Correspondence: i.aznar@pssjd.org † Maria Rubio-Valera and Antoni Serrano-Blanco are joint senior authors. 1 Research and development Unit, Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Dr. Antoni Pujades 42, 08830, Sant Boi de Llobregat, Barcelona, Catalonia, Spain 2 Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública - CIBERESP), Madrid, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 2 of 15 Results: The study included 3062 participants. Intervention costs were €295 higher than usual care costs. Five per- cent additional patients in the intervention group did a MHBC compared to usual care patients. Differences in QALYS or cardiovascular risk between-group were close to 0 (− 0.01 and 0.04 respectively). The ICER was €5598 per extra health behaviour change in one patient and €6926 per one-point reduction in cardiovascular risk from a societal perspective. The cost-utility analysis showed that the intervention increased costs and has no effect, in terms of QALYs, compared to usual care from a societal perspective. Cost-utility planes showed high uncertainty surrounding the ICUR. Sensitivity analysis showed results in line with the main analysis. Conclusion: The efficiency of EIRA intervention cannot be fully established and its recommendation should be conditioned by results on medium-long term effects. Trial registration: Clinicaltrials.gov NCT03136211. Registered 02 May 2017 – Retrospectively registered Keywords: Economic evaluation, Health promotion, Primary care, Hybrid trial Introduction adherence to the Mediterranean dietary pattern in PHC Chronic diseases are one of the main challenges for patients [11]. This study aimed to evaluate the cost- health systems. These diseases account for a high pro- utility and cost-effectiveness, in terms of MHBC and portion of morbidity and mortality worldwide [1]. The CVR reduction, of the EIRA intervention through a cost of these diseases, when they are considered alone, cluster-randomized controlled trial. has a relevant impact but it is even higher when comor- bidities are present [2]. It is estimated that 10 million Methods deaths attributed to chronic diseases can be prevented This was an economic evaluation alongside a 12-month by adopting healthy behaviours while not adopting them cluster-randomized control trial conducted between has a significant economic impact [3, 4]. Against this 2017 and 2018 in 25 PHC centres from seven Spanish background, the primary health care (PHC) system offers regions. The cost perspectives taken were societal and comprehensive, continuous care as the optimal context healthcare providers. The study protocol (NCT03136211.R), for the promotion of healthy lifestyles [5]. Health pro- with details on the study design and intervention, was motion does not have to be focused on specific health published elsewhere [11]. risk, but it can address several of them together. In this context, multiple health behaviour changes (MHBC) in- Setting terventions approach several risk factors within the same The Spanish public healthcare system provides universal intervention [6], which might increase their efficiency coverage for citizens and foreign nationals. It is funded and effectiveness. through taxes and free of charge at the point of use, with However, as far as we know, few economic evaluations some exceptions such as medication. Although it is a have assessed the impact of MHBC interventions [7]. decentralised system, where each of the 17 Spanish re- McRobbie et al showed that a diet and physical activity gions controls health planning, public health and the intervention addressing weight management in obese pa- management of health services (including tariffs publica- tients had an incremental cost-utility ratio (ICUR) of £7400 tion), PHC is the most accessible point of contact within per quality-adjusted life-year (QALY) gained using a health the public system [12]. system perspective [7], while van Keulen et al showed that a tailored print intervention aiming to improve physical activ- Participants ity and/or diet in adults between 45 and 70 years cost PHC centres €2867 per QALY gained and €160 per improved behaviour The following inclusion criteria were used for selection: [8]. Similar evidence is available on the assessment of single 1) internet access; 2) possibility of developing commu- behaviour interventions. Systematic reviews focused on nity activities; 3) not being located in areas with high cardiovascular risk (CVR) or physical activity did not find a cultural or linguistic diversity or tourist areas and; 4) great number of economic evaluations based on random- having a signed commitment document from the man- ized clinical trials [9, 10]. Indeed, some authors have agement team. Healthcare professionals and administra- pointed out that more robust, real-world evidence focused tive staff were involved in the study and signed a on MHBC intervention is needed, especially in light of the collaboration commitment form. resource requirements to implement them [9]. Participants were people aged between 45 and 75 years The EIRA study contained an MHBC intervention old who engaged in at least two of these behaviours: focused on smoking cessation, physical activity and smoking, insufficient physical activity or low adherence Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 3 of 15 to Mediterranean dietary pattern. Participants had to be Use of resources, loss of productivity and other costs registered in the health system and have an assigned Resources included healthcare utilisation in PHC (gen- healthcare professional. They needed to provide signed eral practitioner (GP) and nurse home or centre visits, informed consent. The exclusion criteria set were: laboratory test, social worker visits, emergency visits) advanced serious illnesses, dependence in daily life and hospital (admissions and length of admission, emer- activities, being included in long-term home health gency visits, diagnostic tests), medication use, sick leave programme and planning to move to another area in the and intervention-related costs such as tobacco use and current year. cost of activities (group activities were managed by a nurse but they varied in attendees and/or duration; cost Randomisation assumed was one nurse visit at the centre per patient). Twenty-six PHC centres were computer randomized 1:1 As described in Supplementary Table, information on based on each region at a central location (IDIAP Jordi healthcare utilisation and sick leave were collected from Gol, Barcelona, Spain). After randomisation, one inter- electronic health records, individual clinical record re- vention centre dropped out due to administrative view and/or a Case Report Form (CRF) depending on reasons, leaving 12 centres in the intervention group. the region. Intervention-related cost (tobacco use and Participants were assigned to the intervention or control cost of activities) were obtained from CRF. The informa- group based on their PHC centre. tion recorded at baseline referred to the previous year while information recorded at 12-month follow-up re- Interventions ferred to the year of the intervention. EIRA was a health promotion intervention designed following Medical Research Council methodology [13] Unit costs (including systematic reviews [14–22], citizen and Healthcare services unit costs were based on public professional participation through qualitative research health service tariffs published in Regional Government [23–25] and a previous pilot study, among other tech- Official Bulletins, which were updated to 2019 using the niques) and was based on the Transtheoretical Model specific regional healthcare Consumer Price Index. Sub- [26]. Physicians and nurses applied the intervention in sequently, the mean tariff was calculated for each health their routine practice in the PHC centre. It consisted of service. A social worker visit tariff was not found, and it a first screening visit where the PHC professionals was assumed to be the same as that of the Nurse centre assessed the potential risk behaviours. Subsequently, the visit. Medication cost was obtained from administrative PHC professionals advised the participant, reached an databases. The cost of productivity loss was calculated agreement with them on achievable goals, developed a based on the human capital approach using the mini- specific plan taking the three potential risks and stage of mum daily wage in Spain. All costs were expressed in change into account, assisted with anticipation of bar- euros 2019. Table 1 shows unit costs used in the study. riers and arranged follow-up support (i.e., 2–3 visits). The time horizon was one year and no discount rate was The duration of the intervention was 12 months and it applied. combined three action levels (i.e., individual, group and community). The individual intervention consisted of a Clinical outcomes face-to-face intervention to increase awareness of the The European Quality of Life instrument (EuroQol-5D- need for a behaviour change or making a plan for this 3L; EQ5D) was used to measure health-related quality of change. The group intervention consisted of two health life [32, 33]. QALYs were calculated by linearly interpol- education workshops about healthy diet and physical ac- ating baseline and one-year follow-up utility score based tivity while the community intervention consisted of so- on EQ5D Spanish tariffs. CVR (expressed in %) was cal- cial prescribing of resources available in the catchment culated using the REGICOR function chart based on area. sex, age, total cholesterol, HDL, diagnosis of diabetes, Participants in the control PHC centres received usual smoker status and blood pressure [34–36]. MHBC, care, which integrates Spanish preventive protocols which was the primary outcome of the intervention was involving lifestyle recommendations and preventive defined as a change in at least two unhealthy behaviours. activities based on screening and brief advice. These rec- This variable was recorded by the research team in the ommendations are focused on lifestyles, cardiovascular CRF and, lately, it was dichotomized between change in and mental diseases, cancer and vaccination [27–31]. at least two unhealthy behaviours and no change or change in only one unhealthy behaviour. Outcomes and data collection Other sociodemographic and clinical variables includ- Information was recorded at baseline and 12-month ing participant age, gender, civil status, education level, follow-up. diagnosis of hypertension, the presence of comorbidities Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 4 of 15 Table 1 Unit cost (€ in 2019) (mean cost and maximum and minimum regional official tariffs) Unit cost Mean Maximum unit cost Minimum unit cost Healthcare perspective GP visit in PHCC 55.81 74.80 41.33 GP home visit 77.76 99.47 64.34 Nurse visit in PHCC 25.51 34.51 15.06 Nurse home visit 48.18 80.30 32.06 GP emergency visit 115.42 266.50 62.00 Nurse emergency visit 88.85 278.40 42.92 Social work visit 25.51 34.51 15.06 Other specialist visit 139.15 242.21 54.56 Emergency hospital visit 214.09 375.15 88.77 Hospitalisation (one day of stay)a 652.90 925.23 501.62 Laboratory testb 49.81 73.66 29.26 Diagnostic testb 75.17 180.47 23.38 Medication Depending on the medication Goverment perspective Sick leavec 34.52 64.78 34.52 Societal perspective Tobacco Detailed by patients Community activities GP General Practitioner; PHCC Primary Health Care Centre. aBased on mean tariffs of all hospital complexity types published. bDiagnostic and laboratory test were classified by the research team based on clinical criteria. cMean and minimum cost in sick leave refer to minimum daily wage while maximum cost refers to mean daily wage and Body Mass Index (BMI) was also recorded on the reduction in CVR or per MHBC in one extra participant CRF. was estimated by obtaining incremental cost-utility (ICUR) and incremental cost-effectiveness ratios (ICER), Statistical analysis respectively. ICUR and ICER were calculated as the We assumed that the variables with missing values are difference in the cost between the intervention and the Missing At Random (MAR). MAR assumption can be control group, divided by the difference in QALYs, the made more plausible by collecting more explanatory var- difference in % CVR points and the probability of iables and including them in the analysis, and we have modifying behaviours. The base-case analysis was an included almost all the possible explanatory variables intention-to-treat analysis. Differences in cost and effects (excluding duplicate variables, very similar variables and were estimated using adjusted generalised linear models highly correlated variables to avoid collinearity). Imput- with gamma (for QALYs and cost) or Gaussian (CVR) ation was used to deal with missing data. Missing values distributions and estimating marginal means using mar- varied from 0 to 13% at baseline and from 1 to 44% at gins STATA command and adjusted logistic regression follow-up. Multiple imputation by chained equations for behaviour change. These adjustments consisted of (MICE) using 50 imputed databases was applied to all baseline cost or effects and those variables that showed variables. This number of the database was based on the statistically significant differences at baseline (i.e., BMI) fraction of missing information. To perform MICE, we as was indicated in the study protocol [37]. All analyses used predictive mean matching in continuous variables, clustered participants in PHC centres using the “vce” logistic regression in dichotomous variables and polyto- STATA option. We used bootstrapping with 1000 mous regression in categorical variables (more than two replications (20 replications in each of the 50 imputed categories). Societal perspective included all costs databases) to assess uncertainty and to construct the recorded while healthcare perspective included all costs cost-utility planes and acceptability curves. except productivity losses and tobacco costs. Cost-utility We performed six sensitivity analyses: 1) a complete- in terms of extra cost per QALY gain and cost- case analysis (only considering those participants who effectiveness in terms of extra cost per a one-point attended the follow-up visit); 2) an analysis considering Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 5 of 15 mean wage for productivity losses; 3) an analysis baseline in the BMI, with a higher proportion of the considering the maximum regional tariff for each of the control group in the overweight category and a higher healthcare services and 4) the minimum; 5) an analysis proportion of the intervention group in the obese adjusted only by baseline costs and effects (not adjusted category. by BMI) and 6) an analysis using seemingly unrelated regressions. The first four sensitivity analyses were pre- specified [11]. Cost-utility and cost-effectiveness of EIRA intervention Imputation analyses were performed with R and all The intervention mean cost, including individual visits, other analyses were performed with Stata MP 13.1. workshops and community activities, was €49.33 per person (minimum €0 and maximum €1188). Table 3 Results shows each mean cost by group at baseline and follow- Overall, 3062 participants (1481 in the intervention up and the unadjusted difference between groups at each group) were included in the study. Figure 1 shows the point. Table 4 shows unadjusted costs for both groups at study flowchart and intervention adherence rates. Lost baseline and follow-up. The intervention effectively participants in the follow-up assessment were around promoted MHBC. There were no statistically significant 22%. Some 41% of intervention participants were adher- differences between groups in costs, QALYs or cardiovas- ent to all MHBC interventions (79% to at least one). cular risk in the main analyses. Tables 5 and 6 shows the Table 2 presents the sample characteristics. There were results of the cost-utility and cost-effectiveness analyses. statistically significant differences between groups at Unadjusted effects for both groups are detailed in Table 4. Fig. 1 Flow diagram of clusters and participants through study. PHC, Primary Health Care Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 6 of 15 Table 2 Sociodemographic and clinical characteristics of the sample N (%) Control Group Intervention Group TOTAL % of missing (N = 1581) (N = 1481) (N = 3062) values Women 872 (55.15) 809 (54.63) 1681 (54.90) 0 Age, mean; SD 58.29; 8.31 57.74; 7.88 58.03; 8.11 0 Birth place 0.91 Spain 1479 (93.55) 1369 (92.44) 2848 (93.01) Other countries 97 (6.14) 89 (6.01) 186 (6.07) Civil Status 0.85 Married/co-habiting 1055 (66.73) 1024 (69.14) 2079 (67.90) Other civil status 520 (32.89) 437 (29.51) 957 (31.25) Education level 0.95 Secondary or university studies 888 (56.17) 820 (55.37) 1708 (55.78) Primary or lower studies 684 (43.26) 641 (43.28) 1325 (43.27) Diabetes 323 (20.43) 277 (18.70) 600 (19.60) 0.46 Smoker 697 (44.09) 641 (43.28) 1338 (43.70) 0 Hypertension 646 (40.86) 627 (42.34) 1273 (41.57) 1.27 Systolic arterial pressure (mmHg), mean; SD 131.74; 18.30 133.10; 16.33 132.39; 17.40 3.56 Diastolic arterial pressure (mmHg), mean SD 80.41; 10.68 82.37; 10.26 81.35; 10.53 3.59 Total Cholesterol (mg/dL), mean; SD 205.67; 38.79 205.97; 42.49 205.82; 40.63 8.20 High-density lipoprotein (mg/dL), mean; SD 53.48; 14.24 52.79; 14.41 53.15; 14.33 13.29 Body Mass Index, mean; SD 29.27; 5.64 30.62; 5.85 29.92; 5.78 1.11 Adherence to Mediterranean diet 6.79; 1.99 6.74; 1.97 6.77; 1.98 0.20 (PREDIMED range 0 -- 13), mean; SD Presence of comorbidities 935 (59.14) 8760 (58.07) 1795 (58.62) 7.32 Cardiovascular risk (REGICOR range 0.41–20.78), mean; SD 9.06; 6.42 8.99; 6.26 9.03; 6.34 13.32 Health-related quality of life (EQ5D range − 0.07 – 1), mean; SD 0.82; 0.19 0.81; 0.20 0.82; 0.19 1.5 Specific risks Tobacco 697 (44.09) 638 (43.08) 1335 (43.60) 0 Diet 1482 (93.74) 1384 (93.45) 2866 (93.60) 0 Physical activity 1448 (91.59) 1345 (90.82) 2793 (91.21) 0 Bold figures indicate statistical differences between intervention and control patients Usual care dominated (decreased cost and is more reduction and MHBC, the intervention fell in the north- effective) the intervention in the cost-utility analysis. east (intervention increased costs and is more effective When MHBC is considered in the cost-effectivity ana- than usual care) and south-east (intervention decreased lysis, ICERs from the societal and healthcare perspec- costs and is more effective than usual care) quadrants of tives were €5598 and €3932 per additional change in one the cost-utility place, although, in the healthcare per- patient, respectively. Considering the cardiovascular risk, spective, most pairs are distributed over the cost axis ICERs from the societal and healthcare perspectives (€0). The intervention was cost-saving in 32 and 49% of were €6926 and €4864 per one-point reduction in car- the pairs from the societal and healthcare perspectives diovascular risk, respectively. Figure 2 shows cost-utility while it was more effective in 9% of the pairs in terms of and cost-effectiveness planes. Cost-utility planes showed QALYS; 81% of the pairs in terms of CVR and all pairs high uncertainty surrounding the ICUR. Most boot- in terms of MHBC. Acceptability curves are shown in strapped incremental cost-utility pairs fell in the north- Supplementary Files. west (intervention increased costs and is less effective than usual care) or south-west quadrants (intervention Sensitivity analysis decreased costs and is less effective than usual care) of Table 5 shows the results of sensitivity analysis. All sen- the cost-utility plane. In terms of cardiovascular risk sitivity analyses showed similar results to those of the Table 3 Mean group cost at baseline and follow-up and difference between groups at both points Total costs at baseline Total costs at follow-up (95% CI) (95% CI) Control Intervention Diffa Control Intervention Diff a Healthcare perspective GP visit in PHCC 380.44 (361.74; 399.15) 330.20 (313.98; 346.42) −50.24 (−74.38; −26.11) 292.28 (277.21; 307.36) 305.48 (285.75; 325.22) 13.20 (−10.01; 36.41) GP home visit 37.42 (−32.78; 107.63) 41.48 (−35.06; 118.01) 4.05 (−11.79; 19.90) 31.72 (− 27.61; 91.07) 35.43 (−35.86; 106.71) 3.70 (−11.42; 18.83) Nurse visit in PHCC 77.12 (69.67; 84.56) 62.48 (56.54; 68.42) −14.63 (−24.01; −5.26) 80.89 (70.28; 91.49) 78.15 (66.95; 89.36) −2.73 (−16.10; 10.63) Nurse home visit 14.95 (−16.52; 46.43) 19.70 (−15.98; 55.39) 4.75 (−4.27; 13.78) 17.21 (−16.34; 50.76) 22.94 (−16.09; 61.96) 5.73 (−3.36; 14.81) GP emergency visit 76.82 (−34.69; 188.34) 87.42 (−37.48; 212.32) 10.60 (−18.58; 39.78) 125.57 (− 43.92; 295.07) 141.38 (−29.57; 312.32) 15.80 (−26.37; 27.97) Nurse emergency visit 101.29 (− 177.93; 380.51) 102.03 (− 209.28; 413.35) 0.75 (−59.45; 60.94) 155.61 (− 161.78; 473.00) 129.96 (− 159.40; 419.33) −25.64 (− 105.60; 54.31) Social work visit 7.32 (−12.08; 26.73) 5.04 (− 5.42; 15.51) −2.28 (−12.69; 8.12) 7.72 (− 10.12; 25.55) 5.05 (− 5.22; 15.32) −2.67 (− 11.09; 5.75) Other specialist visit 277.49 (248.90; 306.08) 286.29 (192.31; 380.26) 8.80 (−81.89; 99.48) 217.55 (187.69; 247.40) 196.26 (56.54; 335.99) −21.29 (− 149.80; 107.23) Emergency hospital visit 95.44 (84.17; 106.71) 109.10 (70.49; 147.71) 13.66 (−22.94; 50.26) 66.37 (55.73; 77.01) 89.59 (30.24; 148.93) 23.22 (−31.28; 77.71) Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity Hospitalisation 181.21 (118.15; 244.27) 280.87 (−86.03; 647.76) 99.66 (− 243.36; 433.68) 368.23 (174.78; 561.69) 516.06 (− 564.99; 1597.11) 147.83 (− 836.51; 1132.16) Laboratory test 138.58 (125.82; 151.34) 112.16 (103.75; 120.57) −26.43 (−41.91; −10.94) 86.98 (76.20; 97.76) 78.86 (70.84; 86.89) −8.12 (− 21.68; 5.45) Diagnostic test 113.02 (101.68; 124.35) 99.84 (89.78; 109.90) −13.18 (−28.39; 2.03) 73.17 (61.16; 85.19) 63.19 (56.16; 70.22) −9.98 (−24.12; 4.16) Medication 592.34 (−51.55; 1236.23) 626.45 (−345.15; 1598.23) 34.20 (− 231.60; 299.99) 682.08 (− 90.79; 1454.95) 768.14 (− 379.34; 1915.62) 86.06 (− 239.10; 411.21) (2021) 18:88 Goverment perspective Sick leave 425.23 (341.00); 509.45) 368.96 (287.50; 450.41) −56.27 (− 166.91; 54.37) 356.51 (280.57; 432.45) 404.07 (292.65; 515.48) 47.56 (−72.83; 167.94) Societal perspective Tobacco 556.41 (134.76; 978.06) 594.57 (187.79; 1001.34) 38.15 (−62.61; 138.92) 689.04 (−490.48; 1868.57) 698.39 (−598.83; 1995.61) 9.35 (− 122.35; 141.04) Community activities 251.69 (− 679.02; 1182.40) 255.70 (− 514.40; 1025.81) 4.01 (− 57.54; 65.57) 260.26 (− 595.66; 1116.17) 221.12 (− 304.42; 746.65) −39.14 (− 129.38; 51.10) GP General Practitioner; PHCC Primary Health Care Centre. Bold letters refer to statistically significant differences between groups. a Differences were obtained based on unadjusted linear regression where the independent variable was the intervention/control group and the dependent variable was the cost of each service/sick leave Page 7 of 15 Table 4 Unadjusted cost at baseline and follow-up and effects for intervention and control patients for the main and sensitivity analysis Baseline Baseline Follow-up Follow-up QALY QALY % in change in % in change in two REGICOR REGICOR costs costs costs costs control intervention two or three or three behaviours control intervention control intervention control intervention (95% CI) (95%CI) behaviours intervention (95% CI) (95%CI) (95% CI) (95%CI) (95% CI) (95%CI) control (95% CI) (95% CI) Main analysis - Societal 3317.81 (2472.88; 3371.50 (2184.26; 3509.14 (2097.21; 3719.10 (1701.58 0.82 (0.78; 0.80 (0.75; 8.95 (5.89; 12.01) 14.50 (10.53; 18.46) 9.04 (8.49; 8.83 (8.27; perspective (ITT and 4162.74) 4558.75) 4921.07) 5736.63) 0.86) 0.85) 9.59) 9.38) minimum wage) Main analysis – Healthcare 2264.69 (1554.81; 2321.81 (1240.24; 2342.46 (1382.32; 2480.86 (735.35; 0.82 (0.78; 0.80 (0.75; 8.95 (5.89; 12.01) 14.50 (10.53; 18.46) 9.04 (8.49; 8.83 (8.27; system perspective (ITT 2974.58) 3403.37) 3302.62) 4226.37) 0.86) 0.85) 9.59) 9.38) and minimum wage) Mean wage 3699.53 (2843.41; 3705.86 (4892.79) 3823.72 (2407.10; 4119.24 (2026.52; 0.82 (0.78; 0.80 (0.75; 8.95 (5.89; 12.01) 14.50 (10.53; 18.46) 9.04 (8.49; 8.83 (8.27; 4555.64) 5240.34) 6211.97) 0.86) 0.85) 9.59) 9.38) Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity Maximum regional tariffsa 4215.72 (3169.72; 4267.83 (5814.35; 4382.76 4543.97 (2099.43; 0.82 (0.78; 0.80 (0.75; 8.95 (5.89; 12.01) 14.50 (10.53; 18.46) 9.04 (8.49; 8.83 (8.27; 5261.71) 5721.32) (2717.33; 6048.20) 6988.51) 0.86) 0.85) 9.59) 9.38) Minimum regional tariffs 2650.33 (1836.93; 2693.01 (1578,15; 2840.45 (1536.42; 3031.95 (1243.45 0.82 (0.78; 0.80 (0.75; 8.95 (5.89; 12.01) 14.50 (10.53; 18.46) 9.04 (8.49; 8.83 (8.27; 3463.73) 3807.87) 4144.47) 4820.46) 0.86) 0.85) 9.59) 9.38) Complete-case 3285.49 (2480.49; 3438,17 (2275.87; 3396.87 (2246.36; 3556.06 (1827.95; 0.83 (0.82; 0.81 (0.80; 5.70 (4.38; 7.02) 11.56 (9.62; 13.51) 8.88 (8.44; 8.87 (8.43; 4090.49) 4600.47) 4547.365) 5284.16) 0.84) 0.82) 9.32) 9.32) (2021) 18:88 SUR 3317.81 (2472.88; 3371.50 (2184.26; 3509.14 (2097.21; 3719.10 (1701.58 0.82 (0.78; 0.80 (0.75; 8.95 (5.89; 12.01) 14.50 (10.53; 18.46) 9.04 (8.49; 8.83 (8.27; 4162.74) 4558.75) 4921.07) 5736.63) 0.86) 0.85) 9.59) 9.38) a Minimum daily wage is maintained as unit cost for sick leave in this sensitivity analysis Page 8 of 15 Table 5 Difference in cost and effects; ICUR and ICER between intervention and control patients for the main and sensitivity analyses based on adjusted models Cost QALY ICUR Difference in change in ICER (€/extra REGICOR reduction ICER difference difference (€/QALY) two or three behaviours change in two difference (95% CI) (€/REGICOR (95% CI) in € (95% CI) in one patient (95% CI)d or three reduction) behaviours in one patient) Main analysis - Societal perspective 295.02 (− 1402.75; 1992.78) − 0.009 (− 0.03; 0.01) Dominated 5.27 (2.59; 7.78) 5598 0.04 (− 0.12; 0.21) 6926 (ITT and minimum wage) Main analysis – Healthcare system 207.20 (− 1901.24; 2315.63) − 0.009 (− 0.03; 0.01) Dominated 5.27 (2.59; 7.78) 3932 0.04 (− 0.12; 0.21) 4864 perspective (ITT and minimum wage) Mean wage (Societal perspective) 433.19 (− 1487.19; 2354.10) − 0.009 (− 0.03; 0.01) Dominated 5.27 (2.59; 7.78) 8220 0.04 (− 0.12; 0.21) 10,169 Maximum regional tariffsa 266.19 (− 2405.15 2507.52) − 0.009 (− 0.03; 0.01) Dominated 5.27 (2.59; 7.78) 5051 0.04 (− 0.12; 0.21) 6285 Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity Minimum regional tariffs 271,64 (− 1137.75; 1681.02) −0.009 (− 0.03; 0.01) Dominated 5.27 (2.59; 7.78) 6377 0.04 (− 0.12; 0.21) 5154 Complete-case 126.76 (−1.535.45; 1788.98) −0.009 (− 0.024; 0.006) Dominated 5.68 (3.41;7.99) 2224 0.06 (− 0.10; 0.21) 2174 Unadjusted analysisb 343.60 (− 1406.84; 2094.05) −0.011 (− 0.032; 0.011) Dominated 4.47 (2.82; 8.09) 7690 0.05 (− 0.12; 0.21) 7288 SUR 129.82 (− 16.79; 276.43)c −0.008 (− 0.016; − 0.001) Dominated NA NA 0.04 (− 0.002; 0.087) 3048 (2021) 18:88 All sensitivity analyses considered societal perspective. SUR: Seemingly unrelated regressions. Dominated: Intervention was more costly and less effective. Bold letters refer to statistically significant differences between groups. a Minimum daily wage is maintained as unit cost for sick leave in this sensitivity analysis. b Only adjusted by baseline costs or effects. cConfidence interval in cost when CVR is consider as effect is (− 16.21; 275.85). dConfidence interval calculated based on bootstrapping. NA: Not applicable due to the outcome not being a continuous variable Page 9 of 15 Table 6 Difference in cost and effects (change in two or three behaviours and cardiovascular risk); ICER between intervention and control patients and Relative Value Index (RVI) for the main and sensitivity analyses based on adjusted models Usual Care Cost Usual Care % Change in ICER (€/extra change RVI Usual care REGICOR ICER (€/REGICOR RVI (95% CI) in € two or three behaviours in two or three (95% CI) reduction) in one patient (95% CI)d behaviours in one patient) Main analysis - Societal perspective 295.02 (− 1402.75; 1992.78) 5.27 (2.59; 7.78) 5598 5598 0.04 (− 0.12; 0.21) 6926 6926 (ITT and minimum wage) Main analysis – Healthcare system 207.20 (− 1901.24; 2315.63) 5.27 (2.59; 7.78) 3932 3932 0.04 (− 0.12; 0.21) 4864 4864 perspective (ITT and minimum wage) Mean wage (Societal perspective) 433.19 (− 1487.19; 2354.10) 5.27 (2.59; 7.78) 8220 8220 0.04 (− 0.12; 0.21) 10,169 10,169 Maximum regional tariffsa 266.19 (−2405.15 2507.52) 5.27 (2.59; 7.78) 5051 5051 0.04 (− 0.12; 0.21) 6285 6285 Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity Minimum regional tariffs 271,64 (− 1137.75; 1681.02) 5.27 (2.59; 7.78) 6377 6377 0.04 (− 0.12; 0.21) 5154 5154 Complete-case 126.76 (−1.535.45; 1788.98) 5.68 (3.41;7.99) 2224 2224 0.06 (− 0.10; 0.21) 2174 2174 Unadjusted analysisb 343.60 (−1406.84; 2094.05) 4.47 (2.82; 8.09) 7690 7690 0.05 (− 0.12; 0.21) 7288 7288 SUR 129.82 (− 16.79; 276.43)c NA NA NA 0.04 (− 0.002; 0.087) 3048 3048 (2021) 18:88 a All sensitivity analyses considered societal perspective. SUR: Seemingly unrelated regressions. Bold letters refer to statistically significant differences between groups. Minimum daily wage is maintained as unit cost for sick leave in this sensitivity analysis. b Only adjusted by baseline costs or effects. cConfidence interval in cost when CVR is consider as effect is (− 16.21; 275.85). dConfidence interval calculated based on bootstrapping. NA: Not applicable due to the outcome not being a continuous variable Page 10 of 15 Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 11 of 15 Fig. 2 Cost–utility and cost-effectiveness of EIRA intervention vs usual care main analyses. The scenarios where the differences in such as PHC. Participants from 25 PHC centres in 7 cost were smaller were the complete case and that using Spanish regions were included and this represents one seemingly unrelated regressions. The scenario with the of the first economic evaluations that has been devel- largest differences in cost was that considering the mean oped under these circumstances. The pragmatism of this wage as unit cost for sick leave. In terms of cost- trial is one of the key points of its design as it was devel- effectiveness, the best scenario for both outcomes was oped with the aim of an immediate implementation in the complete case (both ICER were around €2200 per the PHC system throughout the modification and elim- extra MHBC in one participant or REGICOR reduction), ination of potential barriers. We intended to develop a while the worse scenario was that considering the mean flexible intervention that could be adapted to different wage as unit cost for sick leave. PHC settings, and the intervention’s design was based Table 4 also shows the unadjusted mean cost and on the results of previous phases of the study. These fea- effects of the sensitivity analysis. tures led to adherence being measured in a permissive way and the content of the intervention itself in each of Discussion the centres was not fully documented. This fact together Summary with a low fidelity of the intervention could have limited The cost-effectiveness of the EIRA intervention mea- our capacity to detect differences between groups [38]. sured in terms of MHBC remains unclear. However, al- Similarly, not all cost information was gathered using though the intervention was shown to be no more costly the same protocols (each region has combined electronic than usual care and it promoted MHBC, the probabilis- health record download, individual clinical record review tic analysis showed high uncertainty surrounding cost and/or CRF based on availability) and this may introduce differences and intervention did not affect quality of life some bias. However, it increased the external validity of or cardiovascular risk reduction. Based on the results of the results of the study. The follow-up period may have this economic evaluation, the EIRA intervention should limited the impact of the intervention in outcomes such be reformulated before being translated to clinical prac- as QALYs and CVR reduction considering that interven- tice or it should be assessed with a longer follow-up tion is focused on health promotion. period. Comparison with existing literature Strengths and limitations There were no differences in costs between groups. As The large, representative sample is the main strength of suggested previously, health promotion interventions this study. This was a multisite study evaluating an have a very low cost or, at least, a similar cost compared MHBC intervention implemented in a complex context to usual care [7, 8, 39–41]. Similarly, the intervention Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 12 of 15 had no effect on QALYs at one-year follow-up. Although preventive protocols, it is very difficult to observe sub- QALYs are the standard effect measure in cost-utility stantial changes in these outcomes, and consequently, analysis, health promotion interventions are not ex- CVR in the short-medium term. Furthermore, changes pected to produce improvements in QALYs in the short in the medium-long term can be preceded by promotion term. Similar results have been observed in economic interventions on healthy lifestyles which have an impact evaluations of health promotion interventions in PHC on CVR [46]. [7, 8, 39–42]. However, some of these studies showed The largest effect in CVR and MHBC was observed in positive ICURs with a clear dominance of the interven- the complete-case analysis; this might suggest that tion [7, 40]. Although the effect of these interventions higher levels of intervention fidelity would have pro- was small (0.01 for QALYS and 80£ for costs [7] or 0.02 duced better results. However, this effect is still clearly for QALYS and €-16 for cost [40]), the uncertainty re- lower than previous preventive PHC interventions aim- garding the cost-effectiveness of the intervention was ing to reduce CVR [47], other related outcomes such as also small. The ICUR dominance in some of these pre- weight [7], or behaviour change [8, 10]. ventive interventions could be related to the targeted A technical but crucial issue is the model and assump- population (obese) [7] or the risk approached (major de- tion choice. In this paper, we considered generalized lin- pression) [40] while the EIRA intervention is focused on ear models as the main choice due to previous health behaviours in a general population sample where recommendations related to checking non-normality differences in QALYs after 1 year is hardly seen. distribution in cost and effects after a visual inspection MHBC was more sensitive to the intervention in the [37]. However, it is important to emphasise that seem- short term. The EIRA intervention presented statistical ingly unrelated regression, a choice that led to correlate differences in this outcome and showed a societal ICER the error terms across regression models in cost and ef- of €5600 per one extra patient changing two or three fects but assuming normality, was the second most unhealthy behaviours. This ICER was reduced to €3900 favourable scenario to the intervention in terms of cost- when the healthcare perspective was considered. Previ- utility. ous studies showed lower ICERs, up to £986 (€1098 at November 2020), per one extra patient behaviour change Implication for research and practice [8, 10]. However, most of these interventions only focus In a globalized world, it is increasingly important to de- on one behaviour. Although previous authors have sug- velop complex healthcare actions that can be adapted to gested proposals of transforming unit changes of differ- each patient and implemented in a large number of set- ent outcomes into comparable metrics, currently, there tings. At this point, developing hybrid trials is a very is no national or international threshold in terms of be- good option. This is particularly important in the con- haviour change to consider an intervention efficient. In text of PHC where systemic interventions predominate any case, the EIRA intervention would seem to exceed and professionals approach more than one health or risk this virtual threshold; especially when the national behaviour. However, researchers should not overlook threshold to consider an intervention efficient in terms the importance of monitoring the specific actions in of QALYs is €20,000 per QALYs [43] and given the diffi- each setting. This would ensure that clear information is culty in translating healthy behaviours into gains in available to determine whether these actions are genu- QALYs [44]. A suggested alternative to thresholds is the inely (cost)effective or not. Relative Value Index, being the formula for this index: Developing cost-effective interventions that promote RVI = (usual care mean costs/usual care mean effects)/ healthy lifestyles are crucial to support the healthcare ICER)) [45]. A Relative Value Index greater than 1 system. A healthy population should be an optimal tar- means that a new intervention would provide better out- get for these interventions although, due to patient comes at a lower incremental cost per outcome than the health status, intervention assessment needs to be comparator. However, values below 1 and close to 0, as extended into the medium-long term. Conducting EIRA intervention shows (taking into account mean cost economic models which assess the long-term cost- and effects, in terms of MHBC, in the usual care group) effectiveness using mortality and QALYS as outcomes would mean that the additional outcome associated with would give relevant information for health decision- the new intervention would cost more than the previously makers. Similarly, standardizing the use of other “accepted value” of a cost per outcome. generalizable outcomes that could be sensitive to health Partially similar results were observed when CVR was promotion interventions would help decision making in considered as the outcome. The EIRA intervention this field. A healthy population is usually located in very showed a societal ICER of €6900 per one-point reduc- heterogeneous and complex contexts, a fact that compli- tion in CVR and a healthcare ICER of 4900. In this situ- cated the registry and cost definition, key factors for ation, and considering that usual care already involves economic evaluations. In this line, efforts should be Aznar-Lou et al. International Journal of Behavioral Nutrition and Physical Activity (2021) 18:88 Page 13 of 15 taken in standardization without leaving the complexity Declarations of the context out of consideration [48]. Ethics approval and consent to participate The study was approved by the Clinical Research Ethics Committee at the Conclusions Jordi Gol i Gurina Foundation (P18/70). Patients needed to provide signed A health promotion PHC intervention such as EIRA informed consent to participate in the study. effectively impact MHBC in the Spanish context but its Consent for publication efficiency cannot be fully established under current cir- Not applicable. cumstances. The recommendation of this intervention should be conditioned by positive results in the medium- Competing interests long term clinical assessment or by modification of the Authors declare no conflict of interest. The funding bodies did not play any intervention. role in the design of the study and collection, analysis, or interpretation of data and writing. Abbreviations MHBC: Multiple health behaviour changes; QALY: Quality-adjusted life years; Author details 1 ICUR: Cost-utility ratio; ICER: Incremental cost-effectiveness ratio; PHC: Primary Research and development Unit, Parc Sanitari Sant Joan de Déu, Institut de health care; CVR: Cardiovascular risk; GP: General practitioner; CRF: Case Recerca Sant Joan de Déu, Dr. Antoni Pujades 42, 08830, Sant Boi de report form; EQ5D: EuroQol-5D-3L; BMI: Body mass index Llobregat, Barcelona, Catalonia, Spain. 2Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública - CIBERESP), Madrid, Spain. 3Fundació Institut Universitari per a la recerca a Supplementary Information l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. 4 The online version contains supplementary material available at https://doi. Gerència Territorial de Barcelona, Institut Català de la Salut, Barcelona, Spain. 5 org/10.1186/s12966-021-01144-5. Departament d’Infermeria, Facultat d’Infermeria, Universitat de Girona, Girona, Spain. 6Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain. 7Primary Care Prevention and Health Promotion Network Additional file 1: Supplementary Figure. Acceptability curves for (redIAPP), Palma de Mallorca, Spain. 8Primary Care Research Unit, Mallorca, cost-utility analysis. Balearic Public Health Service, Palma de Mallorca, Spain. 9Health Research Additional file 2: Supplementary Table. Source of information of cost Institute of the Balearic Islands (IdISBa), Palma de Mallorca, Spain. 10Primary and effects. Care Research Unit of Bizkaia, Basque Health Service-Osakidetza, Bilbao, Spain. 11Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain. 12 Vigo Primary Health Care, Vigo, Spain. 13I-Saúde Research Group (IISGS), Acknowledgements Vigo, Spain. 14IIS-Aragón Grupo b21-17R, Universidad de Zaragoza, Zaragoza, We are grateful to Stephen Kelly for his contribution to English language Spain. 15CS Arrabal.Servicio Aragonés de Salud, Zaragoza, Spain. 16Primary editing. Health Care Research Unit of Salamanca (APISAL), Health Service of Castilla y León (SACyL), Institute of Biomedical Research of Salamanca (IBSAL), Authors’ contributions Salamanca, Spain. 17Universidad Loyola Andalucía, Sevilla, Spain. 18Centro de ASB, BB and EZDO obtained the finances for this study. BB, EZDO, MCC, HPR, Salud El Palo, Málaga, Spain. 19Department of Preventive Medicine, University MVMM, RMB, JAMF, EM, RML, and JB developed and executed the study. IAL, of Málaga, Málaga, Spain. 20Biomedical Research Institute of Malaga (IBIMA), MRV and ASB advised on the conceptions of data collection, analyses and Málaga, Spain. 21ISV Research Group, Research Unit in Primary Care, Primary execution. TL contributed statistical expertise. IAL and MRV performed the Care Services, Girona, Catalan Institute of Health (ICS), Girona, Catalonia, analyses. IAL significantly contributed to the writing of the manuscript, while Spain. 22Biomedical Research Institute, Girona (IdIBGi), ICS, Girona, Catalonia, EPR, ASV, EZDO, MCC, MRV and ASB were involved in revising it. All authors Spain. have seen and approved of the version to be published. Received: 27 January 2021 Accepted: 27 May 2021 Funding This study was supported by a grant from the “Instituto de Salud Carlos III, Ministerio de Economía y Competitividad” (Institute of Health Carlos III, Ministry of Economy and competitiveness), Spain (FIS PI15–00114 & FIS PI15– References 00519); a grant from the Department of Health of the government of 1. James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, Catalonia, Spain (SLT002/16/00112); and a grant awarded by the “Pla regional, and national incidence, prevalence, and years lived with disability Estratègic de Recerca i Innovació en Salut” (PERIS) (Strategic Plan for Health for 354 diseases and injuries for 195 countries and territories, 1990-2017: a Research and Innovation) at the Ministry of Health (Government of systematic analysis for the global burden of disease study 2017. Lancet. Catalonia) (SLT002/16/00190). We thank the CIBERESP (CIBER in Epidemiology 2018;392(10159):1789–858. https://doi.org/10.1016/S0140-6736(18)32279-7. and Public Health, CB16/02/00322) the redIAPP “Red de Investigación en 2. Cortaredona S, Ventelou B. The extra cost of comorbidity: multiple illnesses Actividades Preventivas y Promoción de la Salud” Research Network and the economic burden of non-communicable diseases. BMC Med. 2017; Prevention and Health Promotion in Primary Care (RD12/0005/0006 & RD12/ 15:1–11. 0005/0008) and the European Union ERDF funds for support in the 3. Scarborough P, Bhatnagar P, Wickramasinghe KK, Allender S, Foster C, development of this study. MRV has a “Miguel Servet” research contract from Rayner M. The economic burden of ill health due to diet, physical inactivity, the Instituto de Salud Carlos III (ISCIII) at the Ministry of Economy and smoking, alcohol and obesity in the UK: an update to 2006-07 NHS costs. J Competitiveness (Spain) (CP19/00029). ASB has a personal grant funded by Public Health (Bangkok). 2011;33(4):527–35. https://doi.org/10.1093/ the PERIS programme (SLT006/17/68), Generalitat de Catalunya (Spain), to pubmed/fdr033. partially dedicate his time to research during the time the study was 4. Violán C, Foguet-Boreu Q, Roso-Llorach A, Rodríguez-Blanco T, Pons-Vigués conducted. M, Pujol-Ribera E, et al. Burden of multimorbidity, socioeconomic status and use of health services across stages of life in urban areas: a cross-sectional Availability of data and materials study. BMC Public Health. 2014;14(1):530. https://doi.org/10.1186/1471-24 The data that support the findings of this study are available from IDIAP 58-14-530. Jordi Gol but restrictions apply to the availability of these data, which were 5. World Health Organization. Noncommunicable diseases: country profiles used under license for the current study, and so are not publicly available. 2018. 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