See corresponding editorial on page 1409.

Fiber intake and all-cause mortality in the Prevencion con DietaMediterranea (PREDIMED) study1–3

Pilar Buil-Cosiales, Itziar Zazpe, Estefanıa Toledo, Dolores Corella, Jordi Salas-Salvado, Javier Diez-Espino, Emilio Ros,Joaquin Fernandez-Creuet Navajas, Jose Manuel Santos-Lozano, Fernando Aros, Miquel Fiol, Olga Casta~ner,Lluis Serra-Majem, Xavier Pinto, Rosa M Lamuela-Raventos, Amelia Marti, F Javier Basterra-Gortari, Jose V Sorlı,Jose Ma Verdu-Rotellar, Josep Basora, Valentina Ruiz-Gutierrez, Ramon Estruch, and Miguel A Martınez-Gonzalez

ABSTRACTBackground: Few observational studies have examined the effectof dietary fiber intake and fruit and vegetable consumption on totalmortality and have reported inconsistent results. All of the studieshave been conducted in the general population and typically usedonly a single assessment of diet.Objective: We investigated the association of fiber intake andwhole-grain, fruit, and vegetable consumption with all-cause mortalityin a Mediterranean cohort of elderly adults at high cardiovasculardisease (CVD) risk by using repeated measurements of dietary infor-mation and taking into account the effect of a dietary intervention.Design: We followed up 7216 men (55–75 y old) and women (60–75 yold) at high CVD risk in the Prevencion con Dieta Mediterranea(PREDIMED) trial for a mean of 5.9 y. Data were analyzed as anobservational cohort. Participants were initially free of CVD. A137-item validated food-frequency questionnaire administered bydietitians was repeated annually to assess dietary exposures (fiber,fruit, vegetable, and whole-grain intakes). Deaths were identifiedthrough the continuing medical care of participants and the NationalDeath Index. An independent, blinded Event Adjudication Commit-tee adjudicated causes of death. Cox regression models were used toestimate HRs of death during follow-up according to baseline di-etary exposures and their yearly updated changes.Results: In up to 8.7 y of follow-up, 425 participants died. Baselinefiber intake and fruit consumption were significantly associated withlower risk of death [HRs for the fifth compared with the first quintile:0.63 (95% CI: 0.46, 0.86; P = 0.015) and 0.59 (95% CI: 0.42, 0.82; P =0.004), respectively]. When the updated dietary information was con-sidered, participants with fruit consumption .210 g/d had 41% lowerrisk of all-cause mortality (HR: 0.59; 95% CI: 0.44, 0.78). Associationswere strongest for CVD mortality than other causes of death.Conclusion: Fiber and fruit intakes are associated with a reduction intotal mortality. PREDIMED was registered at controlled-trials.com asISRCTN35739639. Am J Clin Nutr 2014;100:1498–507.

Keywords dietary fiber intake, fruit consumption, mortality, Mediter-ranean diet, olive oil, monounsaturated fat, tree nuts, feeding trial, cohort

INTRODUCTION

Prospective cohort studies have consistently shown that highconsumption of dietary fiber (DF)4, fruit, and vegetables lowersrisk of stroke (1, 2) and heart disease (3, 4). In epidemiologic

studies, dietary fiber has been associated with lower cardiovas-cular disease (CVD) mortality (5) and lower incidences of type 2diabetes (6), some cancers (7) and inflammatory diseases (8–10).

Fruit, vegetables, legumes, and grains are the main sources ofDF, but some investigators have argued that the fiber content is

1From the Prevencion con Dieta Mediterranea Research Network (Red 06/

0045) (PB-C, IZ, ET, JS-S, JD-E, FA, LS-M, XP, RML-R, AM, FJB-G, JB,

VR-G, RE, and MAM-G) and the Centro de Investigacion Biomedica en Red

Fisiopatologıa de la Obesidad y Nutricion (PB-C, IZ, ET, DC, JS-S, JD-E,

ER, JF-CN, JMS-L, FA, MF, OC, LS-M, XP, RML-R, AM, FJB-G, JVS,

JMV-R, JB, VR-G, RE, and MAM-G), Instituto de Salud Carlos III, Madrid,

Spain; the Servicio Navarro de Salud-Osasunbidea (PB-C, JD-E, and FJB-G),

Pamplona, Spain; the Departments of Preventive Medicine and Public Health

(IZ, ET, and MAM-G) and Nutrition (AM), University of Navarra, Pamplona,

Spain; the Department of Preventive Medicine, University of Valencia, Valencia,

Spain (DC and JVS); the Human Nutrition Department, Hospital Universitari

Sant Joan, Institut d’Investigacio Sanitaria Pere Virgili, Universitat Rovira i

Virgili, Reus, Spain (JS-S and JB); the Lipid Clinic, Department of Endocri-

nology and Nutrition (ER), the Department of Internal Medicine (RE), Institut

d’Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, and the

Department of Nutrition and Food Science, School of Pharmacy, Xarxa de

Referencia en Tecnologia dels Aliments, Instituto de Investigacion en Nutricion

y Seguridad Alimentaria (RML-R), University of Barcelona, Barcelona, Spain

(ER); the Department of Preventive Medicine, University of Malaga, Malaga,

Spain (JF-CN); the Department of Family Medicine, Primary Care Division

of Seville, San Pablo Health Center, Seville, Spain (JMS); the Department of

Cardiology, University Hospital of Alava, Vitoria, Spain (FA); the Institute of

Health Sciences, University of Balearic Islands, and Hospital Son Espases,

Palma de Mallorca, Spain (MF); the Cardiovascular and Nutrition Research

Group, Institut de Recerca Hospital del Mar, Barcelona, Spain (OC); the De-

partment of Clinical Sciences, University of Las Palmas de Gran Canaria, Las

Palmas, Spain (LS-M); the Lipids and Vascular Risk Unit, Internal Medicine,

Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain

(XP); the Instituto de la Grasa, Consejo Superior de Investigaciones Cientıficas,

Sevilla, Spain (VR-G); and the Primary Care Division, Catalan Institute of

Health, Barcelona, Spain (JMV-R).2Supported by the official funding agency for biomedical research of the

Spanish government, Instituto de Salud Carlos III, through grants provided to

research networks specifically developed for the trial [Red Tematica de

Investigacion Cooperativa en Salud (RTIC) G03/140 to RE; RTIC RD

06/0045 to MAM-G] and the Centro de Investigacion Biomedica en Red de

Fisiopatologıa de la Obesidad y Nutricion and grants from Centro Nacional

de Investigaciones Cardiovasculares (06/2007), the Fondo de Investigacion

Sanitaria–Fondo Europeo de Desarrollo Regional [Proyecto de Investigacion

1498 Am J Clin Nutr 2014;100:1498–507. Printed in USA. � 2014 American Society for Nutrition

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

not the sole reason for the preventive effects of these foods.Different components present in their natural matrix may berelevant and even more important than their fiber contents. Thispossibility raises the interest of simultaneously assessing the roleof fiber-rich foods and not only total DF intake. In addition, onlya limited number of observational studies have examined theeffect of DF intake on total mortality and have reported in-consistent results (7, 9, 11).

Few prospective studies have shown an inverse associationbetween fruit and vegetable consumption and all-cause mortality.In some of these studies, fruit and vegetable intakes were ana-lyzed together (12–15), and fruit and vegetable consumption wasinversely associated with total mortality. Contrarily, in studies inwhich the association between fruit and vegetable intakes wereanalyzed separately, results were inconsistent. In some of thesestudies, a high vegetable consumption or high vegetable fiberintake were inversely associated with total mortality, whereas nosignificant association between fruit consumption and mortalitywas observed (7, 16). In other studies, fruit consumption but notvegetable consumption was inversely associated with totalmortality (17–19). These available prospective studies have beenconducted in cohorts from the general population with low CVDrisk, and some of them explicitly excluded participants withbaseline diabetes or dyslipidemia (3). To the best of ourknowledge, no prospective study has assessed this association ina cohort entirely composed of subjects at high CVD risk. Fur-thermore, the usual approach in large cohorts has been limited toa single baseline assessment of diet. The need for updating theinformation on dietary habits by using repeated questionnaireshas been advocated because the use of a single measurement ofdietary habits at baseline may lead to an increased measurementerror, unrealistic assumptions about the induction period, and,consequently, a potential attenuation of the true association (20,21). In this context, it is likely that the use of cumulative av-erages of intake, which reflect long-term diet, is more relevantetiologically than the use of either the most-remote (baseline) ormost-recent diet. We used yearly repeated measurements ofdietary information to investigate the association of fiber intakeand whole grain, fruit, and vegetable consumption with all-cause

mortality in a Mediterranean cohort of elderly adults at highCVD risk.

SUBJECTS AND METHODS

The current cohort study was conducted within the frameworkof the Prevencion con Dieta Mediterranea (PREDIMED) trial,the design of which has been described in detail elsewhere (22,23). Briefly, the PREDIMED study was a large, parallel-group,multicenter, randomized, controlled field trial that aimed toassess the effects of the Mediterranean diet on the primaryprevention of CVD (www.predimed.es) (controlled-trials.com;ISRCTN35739639). The PREDIMED study was conducted inSpain. Recruitment took place between October 2003 and January2009 in Primary Health Clinics by their family practitioners. Werandomly assigned 7447 participants to 1 of 3 interventions(2 Mediterranean diets enriched with extra-virgin olive oil ormixed nuts and a control low-fat diet). Participants were menaged 55–80 y and women aged 60–80 y who were free of CVDat baseline but who had either type 2 diabetes or met $3 of thefollowing criteria for CVD risk factors: current smoking,hypertension (blood pressure $140/90 mm Hg or treatmentwith an antihypertensive medication), a high plasma LDL-cholesterol concentration ($160 mg/dL or lipid-loweringtherapy), a low plasma HDL-cholesterol concentration (#40in men and #50 mg/dL in women), overweight or obesity[BMI (in kg/m2) $25], and family history of premature CVD(aged #55 y in men and #60 y in women). Exclusion criteriafor the PREDIMED study were the presence of any severechronic illness, previous history of CVD, alcohol or drugabuse, BMI $40, and history of allergy or intolerance to oliveoil or nuts. The intervention took place in 11 different centers.At baseline and in yearly follow-up visits, trained personnelperformed anthropometric and blood pressure measurementsand obtained samples of fasting blood.

Dietary assessment

Dietary intake was measured with the use of a validated food-frequency questionnaire (FFQ) repeatedly administered every year.The validation study indicated a correlation between intakes offiber, fruit, and vegetables on the dietary questionnaire and intakeassessed on four 3-d dietary records of 0.66, 0.72, and 0.81, re-spectively (24). The reproducibility was also validated (25). TheFFQ included 137 food items, and frequencies of consumption offood items were reported on an incremental scale with 9 levels(never or almost never; 1–3 times/mo; 1, 2–4, and 5–6 times/wk;and 1, 2–3, 4–6, and.6 times/d). Nutrient intakes were computedby using Spanish food-composition tables (26).

Primary endpoint

The primary endpoint was death from any cause. We used thefollowing 4 sources of information to identify deaths: contacts withfamilies of participants, contacts with general practitioners whowere responsible for the routine clinical care of participants, yearlyconsultation of the National Death Index, and a comprehensiveyearly review of medical records of all participants by medicaldoctors who were blinded with respect to the group allocation andall nutritional information. All medical records related to endpointswere examined by the Event Adjudication Committee, whose

(PI) 04-2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI

07/0473, PI10/01407, PI10/02658, PI10/01407, PI11/01647, PI11/02505,

and PI13/00462], the Ministerio de Ciencia e Innovacion [Recursos y Tec-

nologıas Agroalimentairas (AGL)-2009-13906-C02, AGL2010-22319-C03,

and AGL2013-49083-C3-1-R], the Fundacion Mapfre 2010, the Consejerıa

de Salud de la Junta de Andalucıa (PI0105/2007), the Public Health Division

of the Department of Health of the Autonomous Government of Catalonia,

the Generalitat Valenciana [Generalitat Valenciana AyudaComplementaria

(GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151, Consel-

leria de Sanidad y AP, AtencionPrimaria (CS) 2010-AP-111, and CS2011-

AP-042], and the Regional Government of Navarra (P27/2011). ET is

supported by a Rio Hortega postresidency fellow of the Instituto de Salud

Carlos III, Ministry of Economy and Competitiveness, Spanish Government.3Address correspondence to MA Martınez-Gonzalez, Department of Preven-

tive Medicine & Public Health, School of Medicine, University of Navarra,

Irunlarrea 1, 31008-Pamplona, Navarra, Spain. E-mail: mamartinez@unav.es.4Abbreviations used: CVD, cardiovascular disease; DF, dietary fiber;

FFQ, food-frequency questionnaire; PREDIMED, Prevencion con Dieta

Mediterranea.

ReceivedJune 23, 2014. Accepted for publication August 21, 2014.

First published online September 10, 2014; doi: 10.3945/ajcn.114.093757.

FIBER AND MORTALITY 1499

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

members were unaware of the dietary information. Only endpointsthat were confirmed by the Event Adjudication Committee andoccurred between 1 October 2003 and 30 June 2012 (maximum:8.7 y; mean: 5.9 y) were included in this analysis.

Statistical analysis

Participants were categorized into fifths of consumption foreach food group. The sample size was estimated by assuminga 2-tailed a error = 0.05, RR = 0.60, absolute risk (cumulativeincidence) = 6%, and statistical power = 0.80. Under these as-sumptions, the required sample size in each compared group was1327 subjects, which was covered with the number of partici-pants in each of the extreme fifths. Tests for trend included alldata and had higher statistical power. We used the residualsmethod to adjust DF, fruit, vegetable, and whole-grain consumptionfor total energy intake (27). We excluded participants with totalenergy intake out of predefined limits (800 and 4000 kcal/d formen and 500 and 3500 kcal/d for women)

Baseline characteristics are presented according to fifths ofbaseline intake of DF as the mean (6SD) for quantitative traitsand n (%) for categorical variables.

Cox regression models were used to assess the relation be-tween categories of baseline fiber, fruit, vegetable, and whole-grain intakes and death during follow-up. We also analyzedseparately the consumption of high– and low–glycemic indexfruit (28) and, in addition, considered different causes of death.HRs and their 95% CIs were calculated by using the group withthe lowest consumption (,20th percentile) as the referencecategory. The entry time was defined as the date at recruitment.The exit time was defined as the date at death or the date whencompleting the last interview was completed or 30 June 2012,whichever came first.

To minimize any effects of a variation in diet, we also cal-culated the average of food consumption by using yearly updatedinformation for each participant from repeated FFQs collected atbaseline and during follow-up after 1, 2, 3, 4, 5, or 6 y.

Multivariable models were adjusted for known or suspectedpredictors of death. First we adjusted only for age and sex andstratified by recruitment center. In model 2, additional adjust-ments for smoking status (nonsmokers, former smokers, andcurrent smokers), diabetes (yes or no), BMI, and systolic anddiastolic arterial blood pressures (mm Hg) were done. Model 3was the same as model 2 with additional adjustments for the useof statins (yes or no), alcohol consumption (g/d), educationallevel (up to primary school, university graduate, or others),physical activity (metabolic equivalent tasks per day), and totalenergy intake (kcal/d). In a final model, we also adjusted forvegetable (g/d) and whole-grain (g/d) consumption in the fruit-consumption analysis, fruit (g/d) and whole-grain (g/d) con-sumption in analyses that assessed vegetable consumption, andvegetable (g/d) and fruit (g/d) consumption in analyses of whole-grain intake.

To test for the linear trend across successive categories, wecreated a continuous variable with the median value within eachcategory and regressed risk of death on this variable.

Finally, we estimated the average of all repeated measurementsof intake during follow-up (i.e., by excluding the baselinequestionnaire and using only questionnaires that assessed dietaryhabits after the intervention) and created 4 joint categories as

follows: participants whose intakes was low (lowest fifth) in thebaseline questionnaire and did not increase their intakes (low/low), those whose intakes were adequate (4 upper categories) atbaseline but whose intakes during follow-up went down below thelowest baseline quintile (20 g for fiber intake and 210 g for fruitconsumption) (adequate/low), those with low consumption atbaseline but who increased their consumption beyond the rankof these same limits (fiber .20 g/d; fruit .210 g/d) duringfollow-up (low/adequate), and participants with an appropriateconsumption in both baseline and follow-up measurements(adequate/adequate). Cox regression models were used to assessthe relation between these categories and all-cause mortality afteradjustment for the same variables mentioned previously.

Statistical tests were 2-sided, and P , 0.05 was considered toindicate statistical significance. Statistical analyses were performedwith STATA software (version SE 11, 2009; StataCorp LP).

RESULTS

From October 2003 through June 2009, a total of 8713 can-didates were screened for eligibility, and 7447 subjects wererandomly assigned to 1 of 3 study groups. Of these subjects, 153participants who were outside the limits for total energy intake atbaseline were excluded. We also excluded 78 participants withmissing baseline dietary information. Thus, analyses were carriedout in 7216 participants.

Over 5.9 y of mean follow-up, 425 participants died. Ananalysis of causes of death showed that 169 participants died ofcancer (40%); 153 subjects died from no-cancer, no-CVD death(36%); and 103 subjects died of CVD (24%).

The comparison of participants’ characteristics according to theirbaseline DF intakes is shown in Table 1. No differences wereobserved across categories of DF intake in the distribution ofclassical confounding factors. As expected, participants with higherDF intake consumed more fruit, vegetables, and whole grains andless refined grains. They also consumed more omega-3 fatty acidsand less MUFAs. They were also more likely to use statins.

In our population, the most-frequently consumed vegetableswere in this order: tomatoes; the group of lettuce, endive, andcurly endive; and the group zucchini, eggplant, and cucumber.The most-frequently consumed fruit was as follows: the group ofapples and pears, the citrus fruit group (oranges, tangerines, andgrapefruit), and watermelon. Finally, main sources of cereal fiberwere whole-grain bread, white bread, and pasta. When fiberintake was considered as a whole, main sources of fiber werewhole-grain bread, apples and pears, and the citrus fruit group.

Age and sex-adjusted and multivariable-adjusted analysesshowed a significant inverse association between baseline fiberconsumption and all-cause mortality (Table 2). Compared withthe lowest group of DF intake, participants in the highest fifth ofDF intake had 37% lower RR of death. In separate analyses forthe consumption of fruit, vegetables and whole grains, the in-verse association was similar for the consumption of fruit, butresults neither for vegetables nor whole grains were significant.

After follow-up, we showed higher fiber intake because ofincreased consumption of fruit, vegetables, and whole grains thatwas reflected in higher values for medians of the first quartile for4 nutritional variables. In the cumulative analysis that usedrepeated measurements of diet, we showed significant inverseassociations of DF intake and fruit consumption with all-cause

1500 BUIL-COSIALES ET AL.

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

mortality in age- and sex-adjusted models (Table 3). The asso-ciation became nonsignificant in the fully adjusted multivariablemodel for total DF intake, but it was still significant for fruit.When we compared participants with updated fruit consumption.210 g/d and those with consumption #210 g/d (below the firstquintile at baseline), we showed an HR of all-cause death of 0.59(95% CI: 0.44, 0.78) in the multivariable-adjusted model.

We also compared participants who were below the firstquintile at baseline and exhibited no increase in their consumptionof fruit (or further decreased it) during the intervention comparedwith subjects who had an appropriate consumption at baseline andmaintained it during the intervention (Figure 1). Participantswho had low baseline fruit consumption and also low con-sumption of fruit during the trial had an HR of death of 2.64(95% CI: 1.67, 4.17) compared with participants with adequate

consumption both at baseline and during follow-up. HRs for othercombinations of baseline fruit consumption and changes duringthe trial are also shown in Figure 1. Participants with low fruitconsumption at baseline but adequate consumption during follow-up had significantly lower risk of mortality than did participantswith steady low fruit consumption (HR: 0.62; 95% CI: 0.38, 1.00;P = 0.049). Regarding dietary fiber intake, compared with thereference category of adequate intake both at baseline and fol-low-up, participants who had low baseline intake but increased itduring follow-up showed significantly higher mortality risk (HR:1.42; 95% CI: 1.03, 1.95), as did participants with steady lowdietary fiber intake (HR: 2.18; 95% CI: 1.45, 3.29).

In additional analyses by the specific cause of death (Table 4),the significant protection provided by fiber intake and fruit con-sumption was apparent only for CVD mortality. Participants in

TABLE 1

Demographic and lifestyle characteristics and daily nutrient intakes according to baseline quintiles of dietary fiber intake

among participants in the PREDIMED study1

Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5

Dietary fiber intake,2 g/d 17 21 24 28 35

n 1444 1443 1443 1443 1443

Age, y 67 6 6.33 67 6 6.4 67 6 6.1 67 6 6.2 67 6 6.0

Male sex, % 43 43 43 43 43

BMI,4 kg/m2 30 6 3.9 30 6 3.8 30 6 3.8 30 6 4.0 30 6 3.8

Waist circumference, cm 101 6 11 101 6 10 100 6 10 100 6 11 100 6 9.9

Serum total cholesterol,5 mg/dL 213 6 39 210 6 37 208 6 38 210 6 39 209 6 38

Serum triglycerides,5 mg/dL 140 6 81 137 6 72 135 6 75 137 6 73 134 6 73

Serum HDL cholesterol,5 mg/dL 54 6 14 53 6 15 54 6 15 54 6 14 54 6 14

Serum LDL cholesterol,5 mg/dL 132 6 34 130 6 33 127 6 34 129 6 36 129 6 35

Systolic blood pressure, mm Hg 150 6 21 151 6 21 150 6 20 149 6 20 147 6 21

Diastolic blood pressure, mm Hg 84 6 11 84 6 11 83 6 11 83 6 10 82 6 11

Use of statin medication, % 36 39 40 44 43

Hypercholesterolemia, % 69 70 72 75 75

Olive oil intervention group, % 35 34 33 34 36

Nuts intervention group, % 30 33 34 33 33

Current smokers, % 19 16 13 11 11

Former smokers, % 24 24 25 25 25

Educational level, %

University 5 3 3 5 4

High school 21 19 17 18 18

Physical activity, METs-min/d 194 6 210 218 6 215 236 6 241 250 6 247 258 6 271

Energy intake, kcal/d 2392 6 539 2184 6 534 2152 6 526 2154 6 523 2299 6 557

Carbohydrate, % of energy 39 6 7 40 6 6 41 6 7 43 6 7 45 6 7

Protein, % of energy 16 6 3 16 6 3 17 6 3 17 6 3 17 6 3

Fat, % of energy 42 6 7 40 6 6 40 6 7 38 6 7 36 6 6

SFAs, % of energy 11 6 2 10 6 2 10 6 2 10 6 2 9 6 2

MUFAs, % of energy 21 6 4 20 6 4 20 6 5 19 6 4 17 6 4

PUFAs, % of energy 6 6 2 6 6 2 6 6 2 6 6 2 6 6 2

Long-chain omega-3 fatty acids, g/d 0.77 6 0.47 0.78 6 0.45 0.78 6 0.55 0.81 6 0.49 0.85 6 0.51

Short-chain omega-3 fatty acids, g/d 1.40 6 0.60 1.31 6 0.65 1.33 6 0.64 1.38 6 0.76 1.46 6 0.77

Phytosterols, mg/d 327 6 101 320 6 99 332 6 989 350 6 101 399 6 113

Alcohol, g/d 13 6 20 9 6 14 7 6 12 7 6 11 6 6 10

Refined grains, g/d 141 6 88 132 6 90 119 6 91 103 6 87 71 6 78

Whole grains, g/d 4 6 14 7 6 21 17 6 32 31 6 45 89 6 93

Vegetables, g/d 244 6 99 285 6 99 331 6 112 366 6 126 445 6 191

Fruit, g/d 234 6 129 304 6 135 357 6 156 430 6 179 518 6 252

1METs-min, metabolic equivalent task-minutes; PREDIMED, Prevencion con Dieta Mediterranea.2All values are medians.3Mean 6 SD (all such values).4BMI is weight divided by the square of height.5Data were available for only 4260 participants (quintile 1: 927 subjects; quintile 2: 827 subjects; quintile 3: 813

subjects; quintile 4: 792 subjects; and quintile 5: 901 subjects).

FIBER AND MORTALITY 1501

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

the highest category of fiber intake showed 54% lower risk ofCVD mortality than that of participants in the lowest fifth of fiberintake (P-trend = 0.059). Also, participants in the highest fruit-consumption category showed significantly lower cardiovasculardeath risk (HR: 0.44; 95% CI: 0.22, 0.89).

DISCUSSION

In our study, that included elderly adults at high risk of CVD,higher baseline intakes of fiber or fruit were inversely associatedwith all-cause mortality. The observed dose-response pattern wascompatible with a threshold effect. Thus, a person who consumed$210 g fruit/d or had fiber intakes of $20 g/d exhibited sig-nificantly lower risk of death. In our models, we adjusted for themore-important risk factors, and estimates did not substantiallychange. We observed reduced risk of death for participants whohad low baseline fruit consumption and increased their con-sumption during the trial compared with for participants with

steady low fruit consumption. When we analyzed separatelylow– and high–glycemic index fruit, we observed no substantialdifferences between both types of fruit. The observed reductionin all-cause mortality was mainly driven by reduced CVDmortality. We did not show any significant association betweenvegetable or whole-grain consumption and total mortality. Thisresult might be explained by the already high consumption ofvegetables in our population at baseline (the lowest quintile ofvegetable consumption was 224 and 220 g/d for women andmen, respectively) and low between-subject variability in wholegrains in this population who consumed almost exclusively re-fined cereals (mainly white bread) (28).

Our results for fiber intake were consistent in direction andmagnitude with those from other cohort studies (7, 10, 11, 30, 31)(ORs between 0.57 and 0.96) and in the same direction but witha greater magnitude for fruit consumption (ORs between 0.79 and0.92) (14, 16, 18, 19, 32, 33). The results also were consistentwith results for vegetable consumption in these studies; only

TABLE 2

HRs (95% CIs) of all-cause mortality according to baseline quintiles of fiber, fruit, vegetable, and whole-grain intakes

Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P-trend

Dietary fiber intake (g/d)1 17 21 24 28 35

n 1444 1443 1443 1443 1443 —

No. of deaths 116 80 88 74 67 —

Person-years 8618 8659 8563 8358 8267 —

Age, sex, and center adjusted 1 (reference)2 0.63 (0.48, 0.84) 0.71 (0.54, 0.94) 0.63 (0.47, 0.85) 0.60 (0.44, 0.82) 0.004

Adjusted for risk factors3 1 (reference) 0.63 (0.47, 0.83) 0.71 (0.54, 0.95) 0.64 (0.47, 0.87) 0.62 (0.45, 0.85) 0.010

Multivariable adjusted4 1 (reference) 0.63 (0.47, 0.84) 0.72 (0.54, 0.96) 0.65 (0.48, 0.89) 0.63 (0.46, 0.86) 0.015

Fruit consumption (g/d)1 153 256 339 439 613 —

n 1444 1443 1443 1443 1443 —

No. of cases (death) 121 77 90 73 64 —

Person-years 8794 8742 8411 8302 8215 —

Age, sex, and center adjusted 1 (reference) 0.61 (0.46, 0.81) 0.73 (0.55, 0.96) 0.58 (0.43, 0.79) 0.55 (0.40, 0.75) ,0.001

Adjusted for risk factors3 1 (reference) 0.61 (0.46, 0.81) 0.73 (0.55, 0.96) 0.60 (0.44, 0.80) 0.56 (0.41, 0.76) 0.001

Multivariable adjusted4 1 (reference) 0.61 (0.46, 0.81) 0.72 (0.54, 0.96) 0.60 (0.44, 0.82) 0.58 (0.42, 0.79) 0.002

Further adjusted5 1 (reference) 0.61 (0.46, 0.82) 0.73 (0.55, 0.97) 0.61 (0.44, 0.84) 0.59 (0.42, 0.82) 0.004

Vegetable consumption (g/d)1 178 255 316 386 503 —

n 1444 1443 1443 1443 1443 —

No. of cases (death) 104 82 96 82 61 —

Person-years 8669 8705 8443 8356 8291 —

Age, sex, and center adjusted 1 (reference) 0.82 (0.62, 1.10) 1.00 (0.76, 1.32) 0.87 (0.65, 1.16) 0.69 (0.50, 0.96) 0.052

Adjusted for risk factors3 1 (reference) 0.84 (0.63, 1.12) 1.00 (0.76, 1.33) 0.86 (0.64, 1.16) 0.70 (0.50, 0.97) 0.051

Multivariable adjusted4 1 (reference) 0.85 (0.63, 1.13) 1.01 (0.77, 1.34) 0.89 (0.66, 1.19) 0.72 (0.52, 1.00) 0.083

Further adjusted6 1 (reference) 0.87 (0.65, 1.16) 1.04 (0.79, 1.38) 0.92 (0.68, 1.25) 0.77 (0.55, 1.08) 0.203

Whole-grain consumption (g/d)1,7 0 5 19 84 —

n 2887 1443 1443 1443 —

No. of cases (death) 168 96 90 71 —

Person-years 17,146 8446 8293 8580 —

Age, sex, and center adjusted 1 (reference) 0.73 (0.49, 1.10) 0.66 (0.42, 1.02) 0.90 (0.62, 1.30) 0.139

Adjusted for risk factors3 1 (reference) 0.75 (0.50, 1.12) 0.68 (0.44, 1.05) 0.89 (0.62, 1.29) 0.141

Multivariable adjusted4 1 (reference) 0.76 (0.51, 1.14) 0.65 (3.42, 1.01) 0.92 (0.64, 1.32) 0.102

Further adjusted8 1 (reference) 0.78 (0.52, 1.17) 0.67 (0.43, 1.04) 0.92 (0.64, 1.33) 0.124

1All values are medians.2HR; 95% CI in parentheses (all such values). HRs were obtained from Cox models.3Adjusted for age, sex, smoking status, diabetes, BMI, baseline systolic and diastolic arterial blood pressures, and intervention group and stratified by

recruitment center.4Further adjusted for use of statins, alcohol intake, educational level, physical activity, and total energy intake.5Further adjusted for vegetable and whole-grain consumption.6Further adjusted for fruit and whole-grain consumption.7Quintiles 1 and 2 were merged because of the large number of participants who did not consume whole grains.8Further adjusted for fruit and vegetable consumption.

1502 BUIL-COSIALES ET AL.

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

Sayoun et al. (16) and Lenders et al. (34) showed an inversesignificant association between vegetable consumption and all-cause mortality.

Large cohort studies conducted in the United States andEurope (7, 9) showed a strong linear trend for the inverse as-sociation between fiber and mortality. In our study, we showeda threshold effect between the first and the second quintiles. Theconsumption observed in the PREDIMED trial was higher thanthat observed in these surveys. Concretely, participants in thePREDIMED trial in the second fifth of fiber intake consumedalready .20 g/d, whereas in other studies this amount of fiber

intake was reached only by participants between the second andthird fifths (7) or between the third and fourth categories (9).

It is known that a steady state plasma concentration of vitaminC is achieved at a dose of 200 mg acid ascorbic/d, but between100 and 200 mg acid ascorbic/d, there is little increase in theplasma concentration (35). The fruit consumption in our studywas higher than those observed in other previous studies (16, 17,34) but similar to the reported amounts from studies conducted inGreece (18), Italy (15), and Spain (36). Agudo et al. (19), in theSpanish cohort of the European Prospective Investigation intoCancer and Nutrition study with fruit consumption similar to that

TABLE 3

HRs (95% CIs) of death according to cumulative quintiles of fiber, fruit, vegetable, and whole-grain intakes

Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P-trend

Fiber consumption (g/d)1 19 22 25 28 33

Age, sex, and center adjusted 1 (reference)2 0.71 (0.54, 0.94) 0.65 (0.48, 0.87) 0.62 (0.45, 0.84) 0.67 (0.49, 0.91) 0.014

Adjusted for risk factors3 1 (reference) 0.70 (0.53, 0.93) 0.67 (0.50, 0.90) 0.64 (0.47, 0.87) 0.71 (0.52, 0.97) 0.045

Multivariable adjusted4 1 (reference) 0.72 (0.54, 0.96) 0.70 (0.51, 0.95) 0.66 (0.48, 0.92) 0.74 (0.54, 1.02) 0.095

Fruit consumption (g/d)1 203 299 365 443 585

Age, sex, and center adjusted 1 (reference) 0.64 (0.48, 0.85) 0.51 (0.37, 0.68) 0.63 (0.47, 0.85) 0.56 (0.41, 0.77) 0.001

Adjusted for risk factors3 1 (reference) 0.65 (0.49, 0.86) 0.52 (0.38, 0.70) 0.66 (0.49, 0.88) 0.58 (0.43, 0.80) 0.004

Multivariable adjusted4 1 (reference) 0.66 (0.49, 0.88) 0.52 (0.38, 0.71) 0.68 (0.50, 0.93) 0.59 (0.43, 0.82) 0.007

Further adjusted5 1 (reference) 0.66 (0.50, 0.89) 0.53 (0.39, 0.73) 0.70 (0.51, 0.96) 0.61 (0.43, 0.85) 0.016

Vegetable consumption (g/d)1 206 276 328 381 477

Age, sex, and center adjusted 1 (reference) 0.72 (0.54, 0.96) 0.71 (0.53, 0.95) 0.70 (0.52, 0.94) 0.74 (0.54, 1.02) 0.057

Adjusted for risk factors3 1 (reference) 0.74 (0.56, 0.98) 0.72 (0.53, 0.96) 0.72 (0.53, 0.97) 0.76 (0.55, 1.05) 0.083

Multivariable adjusted4 1 (reference) 0.74 (0.56, 0.99) 0.74 (0.55, 0.99) 0.73 (0.54, 0.98) 0.75 (0.54, 1.05) 0.092

Further adjusted6 1 (reference) 0.76 (0.57, 1.01) 0.77 (0.57, 1.03) 0.77 (0.56, 1.05) 0.81 (0.57, 1.15) 0.240

Whole-grain consumption (g/d)1 0 1 7 33 89

Age, sex, and center adjusted 1 (reference) 0.99 (0.74, 1.33) 0.90 (0.67, 1.21) 0.93 (0.69, 1.25) 0.91 (0.67, 1.24) 0.389

Adjusted for risk factors3 1 (reference) 0.96 (0.72, 1.29) 0.86 (0.63, 1.16) 0.93 (0.68, 1.26) 0.90 (0.66, 1.23) 0.437

Multivariable adjusted4 1 (reference) 0.89 (0.64, 1.24) 0.79 (0.54, 1.15) 0.86 (0.60, 1.24) 0.88 (0.62, 1.24) 0.651

Further adjusted7 1 (reference) 0.90 (0.65, 1.26) 0.81 (0.55, 1.19) 0.90 (0.63, 1.30) 0.93 (0.65, 1.31) 0.882

1All values are medians. Medians for each group were calculated by using the food residual (energy-adjusted) model as proposed by Willett et al. (27, 29). We

computed residuals of food intake by removing the variation caused by each individual’s total energy intake; thus the food intakes of the individuals were regressed

on their total energy intakes. We added a constant (the predicted nutrient intake at the mean total energy intake) to the residuals from this regression (differences

between each individual’s actual intake and the intake predicted by their total energy intake, with mean ¼ 0) to obtain energy-adjusted intakes.2HR; 95% CI in parentheses (all such values). HRs were obtained from Cox models.3Adjusted for age, sex, smoking status, diabetes, BMI, baseline systolic and diastolic arterial blood pressures, and intervention group and stratified by

recruitment center.4Further adjusted for use of statins, alcohol intake, educational level, physical activity, and total energy intake.5Further adjusted for vegetable and whole-grain consumption.6Further adjusted for fruit and whole-grain consumption.7Further adjusted for fruit and vegetable consumption.

FIGURE 1 HRs (95% CIs) for all-cause mortality according to fruit consumption in the Prevencion con Dieta Mediterranea trial, 2003–2012. HRs wereobtained from Cox models. Ref., reference.

FIBER AND MORTALITY 1503

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

in our study, showed an inverse linear trend, but after the secondfifth (median: 225 g/d), a threshold effect was suggested.

Some investigators (20, 21, 37) have postulated that the cu-mulative average of nutrient intake represents better the long-term integration of dietary exposures and helps to minimize anyeffects of within-person variations. Unlike other authors, we didnot stop updating the dietary information after an intermediateoutcome occurred because our participants had risk factors beforestudy entry (e.g., dyslipidemia and diabetes). Also, we assumedthat nutrient intakes before and after cardiovascular outcomeswere equally important regarding death risk. Nevertheless, we areaware that this model likely underestimated the magnitude of the

inverse association between nutrient intake and death (20). Weshowed an inverse association between fruit consumption andtotal mortality in the cumulative analyses. However, the inverseassociation in multiple-adjusted analyses was not statisticallysignificant for fiber intake, although the magnitude of this as-sociation was similar to that shown in previous studies.

Our participants received an intervention that encouraged theconsumption of fiber, fruit, and vegetables, and we did enhance theconsumption of these 3 elements, and thus, the contrast betweenthe lowest and highest categories in the cumulative analysis wasnarrower than when we used only baseline dietary information.Thus, the narrower between-group contrast after follow-up may not

TABLE 4

HRs (95% CIs) for specific causes of death according to baseline quintiles of fiber, fruit, vegetable, and whole-grain intake

CVD deaths (n = 103) Cancer deaths (n = 169) Other-cause deaths (n = 153)

Fiber intake1

Quintile 1 (17 g/d)2 1 (reference)3 1 (reference) 1 (reference)

Quintile 2 (21 g/d) 0.55 (0.31, 0.95) 0.67 (0.42, 1.06) 0.66 (0.41, 1.09)

Quintile 3 (24 g/d) 0.57 (0.32, 1.02) 0.78 (0.50, 1.23) 0.79 (0.49, 1.29)

Quintile 4 (28 g/d) 0.65 (0.35, 1.19) 0.59 (0.35, 0.98) 0.77 (0.46, 1.29)

Quintile 5 (35 g/d) 0.46 (0.23, 0.93) 0.69 (0.42, 1.14) 0.72 (0.44, 1.19)

P-trend 0.059 0.177 0.379

Fruit consumption4

Quintile 1 (153 g/d) 1 (reference) 1 (reference) 1 (reference)

Quintile 2 (257 g/d) 0.51 (0.28, 0.93) 0.66 (0.43, 1.03) 0.68 (0.41, 1.12)

Quintile 3 (339 g/d) 0.64 (0.36, 1.12) 0.61 (0.38, 0.99) 0.98 (0.61, 1.58)

Quintile 4 (439 g/d) 0.33 (0.17, 0.66) 0.83 (0.52, 1.34) 0.66 (0.38, 1.14)

Quintile 5 (613 g/d) 0.44 (0.22, 0.89) 0.63 (0.37, 1.07) 0.71 (0.42, 1.21)

P-trend 0.015 0.219 0.250

Vegetable consumption5

Quintile 1 (178 g/d) 1 (reference) 1 (reference) 1 (reference)

Quintile 2 (255 g/d) 0.88 (0.50, 1.57) 0.79 (0.50, 1.25) 0.97 (0.58, 1.63)

Quintile 3 (316 g/d) 1.02 (0.58, 1.80) 1.11 (0.72, 1.71) 0.96 (0.57, 1.61)

Quintile 4 (386 g/d) 0.81 (0.43, 1.51) 0.66 (0.40, 1.10) 1.42 (0.87, 2.32)

Quintile 5 (503 g/d) 0.83 (0.40, 1.72) 0.60 (0.34, 1.03) 0.98 (0.57, 1.69)

P-trend 0.568 0.051 0.630

Whole-grain consumption6

Quintile 1 (0 g/d) 1 (reference) 1 (reference) 1 (reference)

Quintile 2 (1 g/d) 0.79 (0.39, 1.59) 0.94 (0.55, 1.62) 0.89 (0.49, 1.63)

Quintile 3 (5 g/d) 0.76 (0.33, 1.76) 0.91 (0.48, 1.73) 1.03 (0.52, 2.02)

Quintile 4 (19 g/d) 0.81 (0.35, 1.90) 0.83 (0.40, 1.69) 1.03 (0.51, 2.10)

Quintile 5 (84 g/d) 0.73 (0.34, 1.58) 0.75 (0.40, 1.41) 0.76 (0.38, 1.53)

P-trend 0.608 0.318 0.291

1Adjusted for age, sex, smoking status, diabetes, BMI, baseline systolic and diastolic arterial blood pressure, and

intervention group use of statins, alcohol intake, educational level, physical activity, and total energy intake and stratified by

recruitment center.2Median (all such values). Medians for each group were calculated by using the food residual (energy-adjusted) model

as proposed by Willett et al. (27, 29). We computed residuals of food intake by removing the variation caused by each

individual’s total energy intake; thus the food intakes of the individuals were regressed on their total energy intakes. We

added a constant (the predicted nutrient intake at the mean total energy intake) to the residuals from this regression

(differences between each individual’s actual intake and the intake predicted by their total energy intake, with mean ¼ 0)

to obtain energy-adjusted intakes.3HR for cause specific mortality; 95% CI in parentheses (all such values).4Adjusted for age, sex, smoking status, diabetes, BMI, baseline systolic and diastolic arterial blood pressures, and

intervention group use of statins, alcohol intake, educational level, physical activity, total energy intake, and vegetable and

whole-grain consumption and stratified by recruitment center.5Adjusted for age, sex, smoking status, diabetes, BMI, baseline systolic and diastolic arterial blood pressures, and

intervention group use of statins, alcohol intake, educational level, physical activity, total energy intake, and fruit and

whole-grain consumption and stratified by recruitment center.6Adjusted for age, sex, smoking status, diabetes, BMI, baseline systolic and diastolic arterial blood pressures, and

intervention group use of statins, alcohol intake, educational level, physical activity, total energy intake, and fruit and

vegetable consumption and stratified by recruitment center.

1504 BUIL-COSIALES ET AL.

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

have been sufficient to detect a significant association. Moreover,the median in the lowest fifth with updated information was higherthan the threshold shown in the analysis with baseline information.In contrast, in our cumulative analysis, participants who consumedhighest amounts of fiber at baseline (probably reflecting that theywere high-fruit consumers during most of their previous lives) wereconsidered together with participants who increased only recentlytheir fiber intake, and this merging of both types of participantscould have brought on some degree of misclassification bias. Thispossibility could explain the nonsignificant results observed inmultiple-adjusted cumulative average analyses.

Neither the baseline nor cumulative consumption of vegetablesor whole grains was significantly associated with mortality. Veryfew studies (16, 34) had shown a significant association betweenvegetable consumption and total mortality.

Wang et al. (38) recently assessed, in a meta-analysis of pro-spective studies, the association between fruit and vegetableconsumption and all-cause mortality. They reported significantreductions in total mortality and CVD mortality for fruit or vege-tables, but they did not observe any significant association withcancer mortality. Some investigators (39) think that only somevegetables or some specific fruit are associated with risk of cancer.

Our data were consistent with a wealth of existing studies insupporting the health benefits of fiber and fruit consumption;indeed, clinical trials have shown that both elements have ben-eficial effects on some intermediate markers of chronic diseases.In a subsample of the PREDIMED study, DF intake after a 3-mobehavioral intervention to enhance the Mediterranean diet (40)was associated with significant reductions in body weight, waistcircumference, systolic and diastolic blood pressures, and fastingglucose as well as a greater increase in HDL cholesterol. Inaddition, when changes in the consumption of soluble DF werespecifically assessed, participants in the highest category (.80thpercentile) also showed a significantly greater reduction in serumLDL-cholesterol concentrations than did those ,20th percentile.

Fruit and vegetables contain a wide array of nutrients andphytochemicals that may act together to produce a benefit; vitamins,fiber, and minerals may confer cardioprotective, anticarcinogenic,anti-inflammatory and antioxidant properties. Rissanen et al. (14)showed that intakes of energy-adjusted folate, lycopene, andvitamins C and E explained 28% of the protective effect of fruit,berries, and vegetables against all-cause mortality. However, othernutrients besides them may be driving the association of fruit andvegetables with mortality.

The current study had also some limitations. First, the methodused for dietary assessment was an FFQ with the potential formisclassification bias. However, the FFQ was extensively vali-dated, and the cumulative average estimate of consumptions mayhave been more robust than with a one-time assessment. Second,residual confounding might be a possible explanation of ourfindings. However, we have adjusted for many possible con-founders. And third, the generalizability of our study results islimited because all participants lived in a Mediterranean countryand were at high CVD risk. Our study had the following im-portant strengths: a large sample size, the relative homogeneity ofparticipants, the prospective design, the use of repeated dietarymeasurements during follow-up, and adjustment for a wide arrayof potential confounders.

In conclusion, fiber and fruit intakes are associatedwith a reducedrate of total mortality. To the best of our knowledge, this study is the

first to provide epidemiologic evidence with yearly repeatedmeasurements of intake that increasing fruit and fiber consumptionis associated with decreasing risk of all-cause mortality.

The PREDIMED Study Investigators are as follows—the University of

Navarra, Primary Care Centers, Pamplona, Spain: B Sanjulian, JA Martınez

M Serrano-Martinez, A Sanchez-Tainta, A Garcia-Arellano, JV Extremera-

Urabayen, M Ruiz-Canela, Garcia-Perez L, Arroyo-Azpa C, Sola-Larraza

A, Barcena F, Oreja-Arrayago C, Lasanta-Saez MJ, Amezqueta–Go~ni C,

Cia-Lecumberri P, Elcarte-Lopez T, Artal-Moneva F, Esparza-Lopez JM,

Figuerido-Garmendia E, Tabar-Sarrias JA, Fernandez-Urzainqui L, Ariz-

Arnedo MJ, Cabeza-Beunza JA, Pascual-Pascual P, Martinez-Mazo MD,

Arina-Vergara E, Macua-Martınez T, and Parra-Oses A; the Hospital Clinic,

Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain:

M Serra, A Perez-Heras, C Vinas, R Casas, L de Santamaria, S Romero,

JM Baena, M Garcia, M Oller, J Amat, I Duaso, Y Garcia, C Iglesias,

C Simon, Ll Quinzavos, Ll Parra, M Liroz, J Benavent, J Clos, I Pla,

M Amoros, MT Bonet, MT Martin, MS Sanchez, J Altirruba, E Manzano,

A Altes, M Cofan, C Valls-Pedret, A Sala-Vila, and M Domenech; the Uni-

versity Rovira i Virgili, Reus, Spain: M Bullo, R Gonzalez, C Molina,

F Marquez, N Babio, M Sorli, J Garcıa Rosello, M Guasch-Ferre, A Diaz-

Lopez , P Martınez, R Balanza, BF Martin, R Tort, A Isach, B Costa, JJ Cabre,

J Fernandez-Ballart, N Ibarrola-Jurado, C Alegret, P Martınez, S Millan, JL Pi~nol,

T Basora, and JM Hernandez; the Institute de Recerca Hospital del Mar,

Barcelona, Spain: M Fito, S Tello, J Vila, R de la Torre, D Munoz-Aguayo,

R Elosua, J Marrugat, and M Ferrer; the University of Valencia, Valencia,

Spain: P Carrasco, R Osma, M Guillen, P Guillem-Saiz, O Portoles,

V Pascual, C Riera, J Valderrama, A Serrano, E Lazaro, A Sanmartin,

A Girbes, V Santamaria, C Sanchez, Z Pla, EM Asensio, and JI Gonzalez;

the University Hospital of Alava, Vitoria, Spain: I Salaverria, T del Hierro,

J Algorta, S Francisco, A Alonso, J San Vicente, A Casi, E Sanz, I Felipe,

J Rekondo, and A Loma-Osorio; the University of Malaga, Malaga, Spain:

E Gomez-Gracia, J Warnberg, R Benitez Pont, M Bianchi Alba, Navajas,

R Gomez-Huelgas, J Martinez-Gonzalez, V Velasco Garcia, J de Diego

Salas, A Baca Osorio, J Gil Zarzosa, JJ Sanchez Luque, and E Vargas

Lopez; the Instituto de la Grasa, Consejo Superior de Investigaciones

Cientificas, Sevilla, Spain: J Sanchez Perona, E Montero Romero,

M Garcia-Garcia, and E Jurado-Ruiz; Instituto de Investigacion Sanitaria de

Palma (IdISPa), University of Balearic Islands, and Hospital Son Espases,

Palma de Mallorca, Spain: M Garcia-Valdueza, M Monino, A Proenza,

R Prieto, G Frontera, M Ginard, A Jover, D Romaguera, and J Garcia; the

Department of Family Medicine, Primary Care Division of Sevilla, Sevilla,

Spain: J Lapetra M Leal, E Martinez, M Ortega-Calvo, P Roman, P Iglesias,

Y Corchado, E Mayoral, L Mellado, L Miro, JM Lozano, and C Lama; the

School of Pharmacy, University of Barcelona, Barcelona, Spain: AI Castellote-

Bargallo, A Medina-Remon, and A Tresserra-Rimbau; the University of Las

Palmas de Gran Canaria, Las Palmas, Spain: J Alvarez-Perez, E dıaz Benitez,

I Bautista Casta~no, I Maldonado Diaz, A Sanchez-Villegas, MJ Fernandez-

Rodrıguez, F Sarmiento de la Fe, C Simon Garcia, I Falcon Sanabria,

B Macias Gutierrez, AJ Santana Santana, MJ Rodrıguez-Fernandez, and

J Garcıa-Pastor; the Hospital Universitario de Bellvitge, Hospitalet de

Llobregat, Barcelona, Spain: E de la Cruz, A Galera, Y Soler, F Trias,

I Sarasa, E Padres, and E Corbella; the Primary Care Division, Catalan

Institute of Health, Barcelona, Spain: MA Mu~noz, C Cabezas, E Vinyoles,

MA Rovira, L Garcia, G Flores, P Baby, A Ramos, L Mengual, P Roura,

MC Yuste, A Guarner, A Rovira, MI Santamaria, M Mata, C de Juan, and

A Brau; and other investigators of the PREDIMED network: JATur (University

of Balearic Islands), MP Portillo (University of Basque Country), and G Saez

(University of Valencia).

The authors’ responsibilities were as follows—PB-C, DC, JS-S, JD-E,

ER, RE, and MAM-G: conceived the project; PB-C, IZ, ET, DC, JS-S,

JD-E, JF-CN, JMS, OC, FA, MF, LS-M, XP, RE, and MAM-G: conducted

the research; PB-C, IZ, ET, and MAM-G: analyzed the data; PB-C, IZ, ET,

and MAM-G: wrote the manuscript and had primary responsibility for the

final content of the manuscript; and all authors: read and approved the final

manuscript. ER reported serving on the board of and receiving travel sup-

port, as well as grant support through his institution, from the California

FIBER AND MORTALITY 1505

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

Walnut Commission; serving on the board of the Flora Foundation (Uni-

lever); receiving lecture fees from Danone; and receiving grant support

through his institution from Nutrexpa, Feiraco, Unilever, and Karo Bio.

JS-S reported serving on the board of and receiving grant support through

his institution from the International Nut and Dried Fruit Council, receiving

consulting fees from Danone, and receiving grant support through his in-

stitution from Eroski and Nestle. LS-M reported serving on the boards of the

Mediterranean Diet Foundation and the Beer and Health Foundation. XP

reported serving on the board of and receiving grant support through his

institution from the Residual Risk Reduction Initiative Foundation, serving

on the board of Omegafort, serving on the board of and receiving payment

for the development of educational presentations, receiving lecture fees from

Danone, and receiving grant support through his institution from Unilever

and Karo Bio. RE reported serving on the board of and receiving lecture fees

from the Research Foundation on Wine and Nutrition, serving on the boards

of the Beer and Health Foundation and the European Foundation for Alcohol

Research, and receiving lecture fees from Cerveceros de Espana. PB-C, IZ,

ET, DC, JD-E, JF-CN, JMS-L, FA, MF, OC, RML-R, AM, FJB-G, JVS,

JMV-R, JB, VR-G, and MAM-G had no conflicts of interest. Funding sources

had no role in the design and conduct of the study; collection, management,

analysis, and interpretation of data; or preparation, review, or approval of the

manuscript.

REFERENCES1. Dauchet L, Amouyel P, Dallongeville J. Fruit and vegetable con-

sumption and risk of stroke: a meta-analysis of cohort studies. Neu-rology 2005;65:1193–7.

2. He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumptionand stroke: meta-analysis of cohort studies. Lancet 2006;367:320–6.

3. Pereira MA, O’Reilly E, Augustsson K, Fraser GE, Goldbourt U,Heitmann BL, Hallmans G, Knekt P, Liu S, Pietinen P, et al. Dietaryfiber and risk of coronary heart disease: a pooled analysis of cohortstudies. Arch Intern Med 2004;164:370–6.

4. Dauchet L, Amouyel P, Hercberg S, Dallongeville J. Fruit and vege-table consumption and risk of coronary heart disease: a meta-analysisof cohort studies. J Nutr 2006;136:2588–93.

5. Streppel MT, Ocke MC, Boshuizen HC, Kok FJ, Kromhout D. Dietaryfiber intake in relation to coronary heart disease and all-cause mortalityover 40 y: the Zutphen Study. Am J Clin Nutr 2008;88:1119–25.

6. de Munter JS, Hu FB, Spiegelman D, Franz M, van Dam RM. Wholegrain, bran, and germ intake and risk of type 2 diabetes: a prospectivecohort study and systematic review. PLoS Med 2007;4:e261.

7. Chuang SC, Norat T, Murphy N, Olsen A, Tjønneland A, Overvad K,Boutron-Ruault MC, Perquier F, Dartois L, Kaaks L, et al. Fiber intake andtotal and cause-specific mortality in the European Prospective Investigationinto Cancer and Nutrition cohort. Am J Clin Nutr 2012;96:164–74.

8. Jacobs DR Jr, Andersen LF, Blomhoff R. Whole-grain consumption isassociated with a reduced risk of noncardiovascular, noncancer deathattributed to inflammatory diseases in the Iowa Women’s Health Study.Am J Clin Nutr 2007;85:1606–14.

9. Park Y, Subar A, Hollenbeck A, Schatzkin A. Dietary fiber intake andmortality in the NIH-AARP Diet and Health Study. Arch Intern Med2011;171:1061–8.

10. Martınez-Gonzalez MA, de la Fuente-Arrillaga C, Lopez-del-Burgo C,Vazquez-Ruiz C, Benito S, Ruiz-Canela M. Low consumption of fruitsand vegetables and risk of chronic disease: a review of the epidemiol-ogical evidence and temporal trends among Spanish graduates. PublicHealth Nutr 2011;14:2309–15.

11. Bazzano LA, He J, Ogden LG, Loria CM, Whelton PK. Dietary fiberintake and reduced risk of coronary heart disease in us men andwomen: the National Health and Nutrition Examination Survey I Ep-idemiologic Follow-up Study. Arch Intern Med 2003;163:1897–904.

12. Bazzano LA, He J, Ogden L, Loria CM, Vupputuri S, Myers L,Whelton PK. Fruit and vegetable intake and risk of cardiovascular diseasein US adults: the first National Health and Nutrition Examination SurveyEpidemiologic Follow-up Study. Am J Clin Nutr 2002;76:93–9.

13. Genkinger JM, Platz EA, Hoffman SC, Comstock JW, He KJ. Fruit,vegetable, and antioxidant intake and all-cause, cancer, and cardio-vascular disease mortality in a community-dwelling population inWashington County, Maryland. Am J Epidemiol 2004;160:1223–33.

14. Rissanen TH, Voutilainen S, Virtanen JK, Venho B, Vanharanta M,Mursu J, Salonen JT. Low intake of fruits, berries and vegetables isassociated with excess mortality in Men: the Kuopio Ischaemic HeartDisease Risk Factor (KIHD) Study. J Nutr 2003;133:199–204.

15. Bamia C, Trichopoulos D, Ferrari P, Overvad K, Bjerregaard L,Tjønneland A, Halkjær J, Clavel-Chapelon F, Kesse E, Boutron-RuaultMC, et al. Dietary patterns and survival of older Europeans: the EPIC-Elderly Study (European Prospective Investigation into Cancer andNutrition). Public Health Nutr 2007;10:590–8.

16. Sahyoun NR, Jacques PF, Russell RM. Carotenoids, vitamins C and E,and mortality in an elderly population. Am J Epidemiol 1996;144:501–11.

17. Strandhagen E, Hansson PO, Bosaeus I, Isaksson B, Eriksson E. Highfruit intake may reduce mortality among middle-aged and elderly men.The Study of Men Born in 1913. Eur J Clin Nutr 2000;54:337–41.

18. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence toa Mediterranean diet and survival in a Greek population. N Engl J Med2003;348:2599–608.

19. Agudo A, Slimani N, Ocke MC, Naska A, Miller AB, Kroke A, BamiaC, Karalis D, Vineis P, Palli D, et al. Consumption of vegetables, fruitsand other plant foods in the European Prospective Investigation intoCancer and Nutrition (EPIC) cohorts from 10 European countries.Public Health Nutr 2002;5:1179–96.

20. Bernstein AM, Rosner B, Willet W. Cereal fiber and coronary heartdisease: a comparison of modeling approaches for repeated dietarymeasurements, intermediate outcomes and long follow-up. Eur J Epi-demiol 2011;26:877–86.

21. Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman D,Willett W. dietary fat and coronary heart disease: a comparison ofapproaches for adjusting for total energy intake and modeling repeateddietary measurements. Am J Epidemiol 1999;149:531–40.

22. Martınez-Gonzalez MA, Corella D, Salas-Salvado J, Ros E, Covas MI,Fiol M, Warnberg J, Aros F, Ruız-Gutierrez V, Lamuela-Raventos RM,et al. Cohort profile: design and methods of the PREDIMED study. IntJ Epidemiol 2012;41:377–85.

23. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F,Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, et al. Primaryprevention of cardiovascular disease with a Mediterranean diet. N EnglJ Med 2013;368:1279–90.

24. Fernandez-Ballart JD, Pi~nol JL, Zazpe I, Corella D, Carrasco P, ToledoE, Perez-Bauer M, Martınez-Gonzalez MA, Salas-Salvado J, Martın-Moreno JM. Relative validity of a semi-quantitative food-frequencyquestionnaire in an elderly Mediterranean population of Spain. BrJ Nutr 2010;103:1808–16.

25. de la Fuente-Arrillaga C, Vazquez Ruiz Z, Bes-Rastrollo M, SampsonL, Martinez-Gonzalez MA. Reproducibility of an FFQ validated inSpain. Public Health Nutr 2010;13:1364–72.

26. Moreiras O, Carbajal A, Cabrera L. Tablas de composicion de ali-mentos. [Food composition tables.] 9th ed. Madrid, Spain: EditorialPiramide, 2005 (in Spanish).

27. Willet W, Stampfer MJ. Implications of total energy intake for epi-demiologic analisys. In: Willet W, ed. Nutritional epidemiology, 2nded. New York: Oxford University Press, 1998:273–301.

28. Jenkins DJ, Srichaikul K, Kendall CW, Sievenpiper JL, Abdulnour S,Mirrahimi A, Meneses C, Nishi S, He X, Lee S, et al. The relation oflow glycaemic index fruit consumption to glycaemic control and riskfactors for coronary heart disease in type 2 diabetes. Diabetologia2011;54:271–9.

29. Willett WC, Howe GR, Kushi LH. Adjustment for total energy intakein epidemiologic studies. Am J Clin Nutr l997;65(suppl):1220S–8S.

30. Lubin F, Lusky A, Chetrit A, Dankner R. Lifestyle and ethnicity playa role in all-cause mortality. J Nutr 2003;133:1180–5.

31. Todd S, Woddward M, Tunstall-Pedoe H, Bolton-Smith C. Dietaryantioxidant vitamins and fiber in the etiology of cardiovascular diseaseand all-cause mortality: results from the Scottish heart health study.Am J Epidemiol 1999;150:1073–80.

32. Key TJ, Thorogood M, Appleby PN, Burr ML. Dietary habits andmortality in 11000 vegetarians and health conscious people: results ofa 17 year follow up. BMJ 1996;313:775–9.

33. Nagura J, Iso H, Watanabe Y, Maruyama K, Date CH, Toyoshima H. Fruit,vegetable and bean intake and mortality from cardiovascular disease amongJapanese men and women: the JACC Study. Br J Nutr 2009;102:285–92.

34. Leenders M, Sluijs I, Ros M, Boshuizen HC, Slersema PD, Ferrari P,Tjønneland A, Olsen A, Boutron-Ruault MC, Clavel-Chapelon F, et al.

1506 BUIL-COSIALES ET AL.

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from

Fruit and vegetable consumption and mortality. European Prospective In-vestigation Into Cancer and Nutrition. Am J Epidemiol 2013;178:590–602.

35. Padayatty SJ, Levine M. New insights into the phsysiology and phar-macology of vitamin C. CMAJ 2001;164:353–5.

36. Varela-Moreiras G, Ruiz E, Valero T, Avila JM, del Pozo S. TheSpanish diet: an update. Nutr Hosp 2013;28(Suppl 5):13–20.

37. Bao Y, Han J, Hu F, Giovannucci EL, Stampfer MJ, Willet WC, FuchsCS. Association of nut consumption with total and cause-specificmortality. N Engl J Med 2013;369:2001–11.

38. Wang X, Ouyang Y, Liu J, Zhu M, Zhao G, Bao W, Hu FB. Fruit andvegetable consumption and mortality from all causes, cardiovascular

disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ 2014;349:g4490.

39. Martınez-Gonzalez MA, de la Fuente-Arrillaga C, Lopez del Burgo C,Vazquez-Ruiz Z, Benito S, Ruiz-Canela M. Low consumption of fruitand vegetables and risk of chronic disease: a review of the epidemiol-ogical evidence and temporal trends among Spanish postgraduates.Public Health Nutr 2011;14:2309–15.

40. Estruch R, Martınez-Gonzalez MA, Corella D, Basora-Gallisa J, Ruiz-Gutierrez V, CovasMI, Fiol M, Gomez-Gracia E, Lopez-Sabater MC, EscodaR, et al. Effects of dietary fibre intake on risk factors for cardiovascular diseasein subjects at high risk. J Epidemiol Community Health 2009;63:582–8.

FIBER AND MORTALITY 1507

at UN

IVE

RS

IDA

D D

E N

AV

AR

RA

BIB

LIOT

EC

A H

UM

AN

IDA

DE

S on D

ecember 3, 2014

ajcn.nutrition.orgD

ownloaded from