Cost-effectiveness and diet quality in a 3-year follow-up of a randomised controlled trial (The BALANCE trial)

Background: A healthy diet is essential to reduce cardiovascular disease (CVD) risk and mortality. However, recent studies lack conclusive evidence on the affordability of cardioprotective diets 62 worldwide. The Brazilian Cardioprotective Nutritional Program Trial (BALANCE Program) is a 63 randomized multicenter clinical trial that proposes regionally adapted cardioprotective diet that 64 achieves nutritional recommendations and incorporates accessible and affordable foods. The study 65 aim is to analyze cost-effectiveness of the BALANCE Program in comparison to generic dietary 66 advice for individuals, based on diet costs and nutritional quality among patients with high adherence 67 to the study protocol in both control and intervention groups. 68 Methods: We conducted a cost-effectiveness analysis of subsample from the BALANCE Program 69 (1,161 individuals with previous event of CVD and high adherence to study protocol enrolled in 35 70 research sites throughout Brazil) after a 3-year follow-up. Direct costs and nutritional quality of diets 71 reported by participants were estimated at the individual level. Diet costs were based on market prices 72 collected from five major supermarket chains. Effectiveness was measured in terms of diet quality, 73 according to adherence to the Brazilian Health Eating Index Revised (BHEI-R). Mean differences 74 were compared between groups using generalized estimating equation. Monte Carlo simulations were 75 performed to comprise probabilistic sensitivity analysis regarding trends in the comparison between 76 groups. 77 Results: At baseline, mean direct diet costs were equal (U$3.9/day), and there were small differences 78 in BHEI-R between groups (53.5 points in BALANCE Program, and 51.8 points in control group). 79 After the 3-year follow-up, the intervention was associated with a mean cost saving of U$0.31/day 80 (95%CI: -0.59; -0.04) and mean BHEI-R increase of 4.38 (95%CI: 2.81; 5.95). The intervention was 81 dominant strategy in terms of cost-effectiveness due to higher effectiveness at lower costs in 82 comparison with the control group.


5
Background 89 Cardiovascular disease (CVD) is a leading cause of death and disability worldwide, and also 90 in Brazil (1,2) . Secondary prevention programs with focus on management of cardiovascular risk 91 factors have been associated with substantially lower risk of recurrent cardiovascular events (3,4) . 92 Additionally, the adoption of healthy behaviors (e.g., diet, exercise, smoking cessation, etc.) is 93 recommended by international guidelines (5,6) . There are many studies indicating that specific 94 combinations of foods and dietary patterns contribute to prevent new events and to control CVD risk 95 factors (7,8) . 96 According to current epidemiologic evidence, food-based measures to reduce CVD risk and 97 mortality include an optimal intake of whole grains, fruits, vegetables, legumes, nuts, seeds, fish and 98 reduced consumption of red and processed meat (9,10) . Although this is considered the best nutritional 99 recommendation, health professionals must ponder that food availability is highly diverse worldwide, 100 so dietary advice might fail without personal tailoring. One potential explanation for that failure could 101 be the high food expenditures resulting from the intake of non-locally-produced foods (11) . 102 Furthermore, food prices directly influence food choice and are among the main barriers to dietary 103 changes (12) . 104 Overall, whether the cost of a cardioprotective diet is higher or lower compared with a 105 conventional diet remains unclear. Observational studies have shown that cardioprotective dietary 106 patterns (DASH or Mediterranean diet) are more expensive than usual local diets (13)(14)(15) . In addition, 107 the adherence to a Mediterranean dietary pattern in non-Mediterranean population could cost 24% 108 more (14) . Recently, there have been efforts to develop a regional adaptations of the Mediterranean diet 109 in studies with non-Mediterranean populations (16)(17)(18) . Once the diet is adapted, it is possible to increase 110 its affordability, reaching the same price as the conventional diet (16,17) . developing a Brazilian cardioprotective diet that achieves standard nutritional recommendations for 115 treatment of CVD and, concurrently, incorporates local food products to respect regional habits, 116 multi-cultural factors and affordability. The main results of the BALANCE Program were previously 117 published (19)(20)(21) showing diet quality improvement after a 48-months follow-up, but no differences in 118 mortality or cardiovascular events.

119
In this study, the objective was to analyze cost and diet quality and to perform a cost-120 effectiveness analysis of the BALANCE Program in comparison with generic dietary advice (control 121 group) in individuals with high adherence to study protocol.

124
Study design and participants 125 The study design is a retrospective analysis of 24-hour recalls from participants of the 126 BALANCE program study (https://www.clinicaltrials.gov/; NCT01620398). A description of the 127 original study has been published elsewhere (20) . cardioprotective role (i.e., 50% to 60% of energy from carbohydrate, 10% to 15% from protein, 25% 140 7 to 35% from total fat, 7% from saturated fatty acids, 10% polyunsaturated fatty acids, 20%    Cost-effectiveness analysis 156 The economic assessment for comparison of the two strategies (control and BALANCE 157 Program) was performed based on cost-effectiveness ratios (CER) and incremental cost-effectiveness 158 ratios (ICER). The analyses were conducted using the perspective of the patients. This perspective 159 was adopted because patients are directly affected by the intervention, and decide to follow or not the interviews. The direct costs to perform the intervention (e.g., researchers wages, transport of subjects 166 8 to study centers, biochemical analyses, etc.) were not included in the analysis, considering that the 167 program was designed to comprise a strategy for secondary prevention at primary health care level; 168 therefore, should be implemented in local settings near individuals' residence. referring to sales or bulk acquisition were discarded during consistency analysis. In the case of more 178 than one product available of the same food, data were collected from up to three items, and the 179 average price of the items was used as the final price.

180
The price of each raw food was converted into price per gram of food ready to eat by applying 181 correction and cooking factors. The recipes were obtained from the BALANCE Program recipes book 182 or a Brazilian standard book for recipes (21) , using the amount of main ingredients in the recipes, and 183 including standardized amounts of seasonings (e.g., 5% of sugar, 1% of salt and 2% of soy oil for 184 cooked or 10% for fried foods), in order to allow its inclusion in costs. Prices of food items were 185 deflated to the period of 24-hour recall interviews using official data on specific inflation rates for   Society of Cardiology (27) .

198
The BHEI-R score for each 24-hour recall was obtained by the sum of scores referring to 199 twelve components: nine based on the consumption of food groups (total cereals; whole grains; total in the case of the group "total fruit", dietary intake equal to or greater than the recommended per 207 1,000 kcal was given the maximum score of the item (five points).

208
Nutritional values of 24-hour recalls were calculated using the Nutriquanti software, and 209 BHEI-R score, ranging from 0 to 100 points, was considered the outcome variable in the economic  Differences in scores of BHEI-R components, total energy, total amount of food, amount of 221 food group, costs, energy density, and macronutrients between the intervention and control groups at 222 end point were analysed using ANCOVA, with baseline variables as covariates. Mean difference was 223 presented as difference between the BALANCE and the control group.

224
Analyses considered a 2-tailed statistical significance level of =0.05, and were performed 225 using R software, version 3.6.0 (R Foundation for Statistical Computing).

226
Economic analyses were conduct with data from baseline and 36 month 24-hour recall only.

227
The cost-effectiveness ratios (CER) were calculated with the following equations:    Table 3 shows that there were increases in diet quality scores for the BALANCE group  (Figures 1 and 2).   studies assessed the association between HEI scores and diet costs. A recent meta-analysis found no 304 significant differences in prices ($1.61 international per capita per day, 95% CI -0.61;3.84) between 305 diets considered healthy and unhealthy according to the HEI-2005 score (15) . Our study found opposite 306 results for the Brazilian diet quality indicator, showing that participants with higher BHEI-R score 307 spent less money during the follow-up.

308
On the other hand, the same meta-analysis found that food intake according to Mediterranean 309 dietary patterns became more expensive ($1.18 international per capita per day, 95% CI 0.01;2.36) (15) .

310
A Spanish study found that a greater adherence to a Mediterranean dietary pattern was associated 311 with higher spending on foods: daily cost was +$0.72 euros for the highest diet scores (28) . Individuals

322
BHEI-R index does not permit a detailed analysis that shows which specific food or food 323 group was able to contribute to the reduction in cost observed in BALANCE group. This is because 324 scores of BHEI-R components are not directly correspondent to food amounts (27) . Thus, we level. In the present study, the objective was to analyze data from participants who engaged in at least 346 80% of the study protocol for both groups (intervention and control).

347
The guidelines for economic evaluations of clinical trials recommend considering intention-348 to-treat analyses (datasets from the original trial) to perform cost-effectiveness analysis(32).

349
However, considering real world scenarios, neither costs nor benefits are incurred by non-350 participants (24) . In addition, the perspective adopted in the current study aimed to provide economic   Availability of data and materials 516 The datasets used and/or analysed during the current study are available from the corresponding 517 author on reasonable request.