Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts

Abstract

Background
Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk.

Methods
In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. In 2013, we reported the results for the primary end point in the Journal. We subsequently identified protocol deviations, including enrollment of household members without randomization, assignment to a study group without randomization of some participants at 1 of 11 study sites, and apparent inconsistent use of randomization tables at another site. We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned.

Results
A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol.

Conclusions
In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet. (Funded by Instituto de Salud Carlos III, Spanish Ministry of Health, and others; Current Controlled Trials number, ISRCTN35739639.)

Full text

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new england journal
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n engl j med 378;25 nejm.org June 21, 2018
e34(1)
The authors’ full names, academic de-
grees, and af filiations are listed in the
Appendix. Address reprint requests to Dr.
Martínez-González at the Depar tment of
Preventive Medicine and Public Health,
Facultad de Medicina–Clínica Universidad
de Navarra, Ir unlarrea 1, 31008 Pamplona,
Spain, or at mamartinez@ unav . es.
* The PREDIMED study investigators are
listed in the Supplementary Appendix,
available at NEJM.org.
Drs. Estruch and Martínez-González con-
tributed equally to this article.
This arti cle was published on June 13, 2 018,
at NEJM.org.
N Engl J Me d 2018;378:e3 4.
DOI: 10.1056/NEJMoa1800389
Copyright © 2018 Massachusetts Medical Society.
BACKGROUND
Observational cohort studies and a secondary prevention trial have shown inverse asso-
ciations between adherence to the Mediterranean diet and cardiovascular risk.
METHODS
In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57%
women) who were at high cardiovascular risk, but with no cardiovascular disease at enroll-
ment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil,
a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce
dietary fat). Participants received quarterly educational sessions and, depending on group
assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts.
The primary end point was a major cardiovascular event (myocardial infarction, stroke, or
death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was
stopped on the basis of a prespecified interim analysis. In 2013, we reported the results
for the primary end point in the Journal. We subsequently identified protocol deviations,
including enrollment of household members without randomization, assignment to a
study group without randomization of some participants at 1 of 11 study sites, and appar-
ent inconsistent use of randomization tables at another site. We have withdrawn our
previously published report and now report revised effect estimates based on analyses that
do not rely exclusively on the assumption that all the participants were randomly assigned.
RE SULT S
A primary end-point event occurred in 288 participants; there were 96 events in the group
assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group as-
signed to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%).
In the intention-to-treat analysis including all the participants and adjusting for baseline
characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval
[CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI,
0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results
were similar after the omission of 1588 participants whose study-group assignments were
known or suspected to have departed from the protocol.
CONCLUSIONS
In this study involving persons at high cardiovascular risk, the incidence of major cardio-
vascular events was lower among those assigned to a Mediterranean diet supplemented
with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet.
(Funded by Instituto de Salud Carlos III, Spanish Ministry of Health, and others; Current
Controlled Trials number, ISRCTN35739639.)
ABS TR AC T
Primary Prevention of Cardiovascular Disease
with a Mediterranean Diet Supplemented
with Extra-Virgin Olive Oil or Nuts
R. Estruch, E. Ros, J. Salas-Salvadó, M.-I. Covas, D. Corella, F. Arós,
E. Gómez-Gracia, V. Ruiz-Gutiérrez, M. Fiol, J. Lapetra, R.M. Lamuela-Raventos,
L. Serra-Majem, X. Pintó, J. Basora, M.A. Muñoz, J.V. Sorlí, J.A. Martínez, M. Fitó,
A. Gea, M.A. Hernán, and M.A. Martínez-González,
for the PREDIMED Study Investigators*
Origina l A rt icl e
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T
he traditional Mediterranean diet
is characterized by a high intake of olive
oil, fruit, nuts, vegetables, and cereals; a
moderate intake of fish and poultry; a low intake
of dairy products, red meat, processed meats,
and sweets; and wine in moderation, consumed
with meals.
1
In observational cohort studies
2,3
and a secondary prevention trial (the Lyon Diet
Hear t Study),
4
increasing adherence to the Medi-
terranean diet has been consistently associated
with lower cardiovascular risk.
2-4
A systematic
review ranked the Mediterranean diet as the
most likely dietary model to provide protection
against coronary heart disease.
5
Small clinical
trials have uncovered plausible biologic mecha-
nisms to explain the salutary effects of this
food pattern.
6-9
We designed a randomized trial,
PREDIMED (Prevención con Dieta Mediterránea),
to test the efficacy of two Mediterranean diets
(one supplemented with extra-virgin olive oil and
another with nuts), as compared with a control
diet (advice on a low-fat diet), on primary cardio-
vascular prevention. Our original report was pub-
lished in the Journal in 2013.
10
A 2017 analysis
11
of the distributions of baseline variables in ran-
domized trials identified the PREDIMED trial as
having distributions that were significantly dif-
ferent from what would have been expected to
result from randomization. This report led to our
conducting a review of how participants were
assigned to various intervention groups; that
review revealed irregularities in our randomiza-
tion procedures. Therefore, we have withdrawn
our original report
12
and now publish a new report.
We describe the protocol deviations and re-
port revised intention-to-treat and per-protocol
effect estimates that do not rely exclusively on
the assumption that all the participants had
been randomly assigned to the intervention
groups. A detailed description of the changes
that have been introduced and departures from
the protocol is provided in the Supplementary
Appendix, available with the full text of this ar-
ticle at NEJM.org.
Methods
Study Design
The PREDIMED study was designed as a parallel-
group, multicenter, randomized trial. Details of
the study design have been reported previous-
ly.
13,14
The protocol, available at NEJM.org, was
approved by the institutional review boards at all
study locations. The authors vouch for the accu-
racy and completeness of the data and all analy-
ses and attest that this report accurately de-
scribes the conduct of the study as we know it.
Funding was provided by grants from Insti-
tuto de Salud Carlos III, Spanish Ministry of
Health. Supplemental foods were donated, in-
cluding extra-virgin olive oil (by Hojiblanca and
Patrimonio Comunal Olivarero, both in Spain),
walnuts (by the California Walnut Commission),
almonds (by Borges, in Spain), and hazelnuts (by
Morella Nuts, in Spain). None of the sponsors
had any role in the study design, data analysis,
or reporting of the results.
Participant Selection and Randomization
Eligible participants were men (55 to 80 years of
age) or women (60 to 80 years of age) with no
cardiovascular disease at enrollment, who had
either type 2 diabetes mellitus or at least three
of the following major risk factors: smoking,
hypertension, elevated low-density lipoprotein
cholesterol levels, low high-density lipoprotein
cholesterol levels, overweight or obesity, or a
family history of premature coronary heart dis-
ease. Detailed enrollment criteria are provided on
pages 18 and 19 in the Supplementary Appendix.
All the participants provided written informed
consent.
The protocol specified that participants were
to be randomly assigned, in a 1:1:1 ratio, to one
of three dietary intervention groups: a Mediter-
ranean diet supplemented with extra-virgin olive
oil, a Mediterranean diet supplemented with nuts,
or a control diet. Enrollment began on June 25,
2003, and the last participant was recruited on
June 30, 2009. The analyses in this report were
based on a database locked as of September 2011
and included primary end-point events occurring
through December 1, 2010. Randomization was
concealed with the use of closed envelopes
8
dur-
ing part of the pilot phase of the study, but en-
velopes were not used for the remainder of the
study. A computer-generated random-number
sequence provided randomization tables for the
11 participating sites, which encompassed 169
clinics. These tables included four strata (men
<70 years of age, men ≥70 years of age, women
<70 years of age, and women ≥70 years of age)
and were initially generated for 1000 partici-
pants (250 per stratum) for each site. We did not
use blocks for randomization. Further details on
the use of these tables at each of the 11 sites can
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Cardiovascular Disease and Mediterra nean Diet
be found on pages 8 and 9 and 78 through 82 in
the Supplementary Appendix. All the sites were
given the same randomization sequence.
There were departures from the randomiza-
tion procedures that had been specif ied in the
protocol that were not described in our original
report. We included 425 participants who shared
a household with a previously enrolled partici-
pant. These 425 participants were not randomly
assigned but were assigned to the same interven-
tion as the member of the household who was
already enrolled (Tables S2 and S3 in the Supple-
mentary Appendix). This was done to allow the
recruitment of eligible household members and
to avoid members of the same household being
assigned to different diets. After the study had
begun, the steering committee approved this
protocol change. The protocol was not amended,
and this protocol change was not described in
the original report published in the Journal. In
July 2017, we learned that at 1 of the 11 study
sites (Site D), 467 participants were not randomly
assigned as individual participants but instead
were assigned according to clinic — that is, all
the participants in each clinic received the same
intervention (2 clinics assigned a Mediterranean
diet with extra-virgin olive oil, 5 assigned a
Mediterranean diet with nuts, and 4 assigned
a control diet) (see pages 9 and 10 in the Supple-
mentary Appendix for additional details). In addi-
tion, review of the documentation about random-
ization procedures and of the actual assignments
to the three groups suggested that the random-
ization tables were inconsistently used in another
study site (Site B, 593 participants) (see pages 10
and 11 in the Supplementary Appendix for details).
Interventions and Me asurements
The dietary intervention
8,1 3-1 5
is detailed on pages
20 through 24 in the Supplementary Appendix.
The specific recommended diets are summarized
in Table 1. Participants in the group assigned to
a Mediterranean diet with extra-virgin olive oil
received 1 liter of the oil per week per house-
hold, with the recommendation to consume at
least 4 tablespoons per day of extra-virgin olive
oil per person. Participants in the group assigned
to a Mediterranean diet with nuts received 30 g
of mixed nuts per day per person (15 g of wal-
nuts, 7.5 g of hazelnuts, and 7.5 g of almonds) at
no cost, and those in the control group received
small nonfood gifts. No total calorie restriction
was advised, nor was physical activity promoted.
Food Goal
Mediterranean diet
Recommended
Olive oil* ≥4 tbsp/day
Tree nuts and peanuts† ≥3 servings/wk
Fresh fruits ≥3 servings/day
Vegetables ≥2 servings/day
Fish (especially fatty fish), seafood ≥3 servings/wk
Legumes ≥3 servings/wk
Sofrito‡ ≥2 servings/wk
White meat Instead of red meat
Wine with meals (optionally, only for habitual drinkers) ≥7 glasses/wk
Discouraged
Soda drinks <1 drink/day
Commercial bakery goods, sweets, and pastries§ <2 servings/wk
Spread fats <1 serving/day
Red and processed meats <1 serving/day
Low-fat diet (control)¶
Recommended
Low-fat dairy products ≥3 servings/day
Bread, potatoes, pasta, rice ≥3 servings/day
Fresh fruits ≥3 servings/day
Vegetables ≥2 servings/day
Lean fish and seafood ≥3 servings/wk
Discouraged
Vegetable oils (including olive oil) ≤2 tbsp/day
Commercial bakery goods, sweets, and pastries§ ≤1 serving/wk
Nuts and fried snacks ≤1 serving/wk
Red and processed fatty meats ≤1 serving/wk
Visible fat in meats and soups‖ Always remove
Fatty fish, seafood canned in oil ≤1 serving/wk
Spread fats ≤1 serving/wk
Sofrito‡ ≤2 servings/wk
* The amount of olive oil includes oil used for cooking and salads and oil con-
sumed in meals eaten outside the home. In the group assigned to the Mediter-
ranean diet with extra-virgin olive oil, the goal was to consume 50 g (approxi-
mately 4 tbsp) or more per day of the polyphenol-rich olive oil supplied, instead
of the ordinary refined variety, which is poor in polyphenols. The participants
received a free supply (15 liters every 3 months) to include the oil used for
cooking and family needs.
† For participants assigned to the Mediterranean diet with nuts, the recommend-
ed consumption was one daily serving (30 g, composed of 15 g of walnuts,
7.5 g of almonds, and 7.5 g of hazelnuts). Participants received for free the
needed allotments of tree nuts in packages of 2 kg of walnuts, 1 kg of almonds,
and 1 kg of hazelnuts every 3 months, with the extra amounts to be shared
with family members.
‡ Sofrito is a sauce made with tomato and onion, often including garlic and aro-
matic herbs, and slowly simmered with olive oil.
§ Commercial bakery goods, sweets, and pastries (not homemade) included cakes,
cookies, biscuits, and custard.
¶ Up to September 2006, a brief personal recommendation and a leaflet with
written guidelines to attain these goals (see page 53 in the Supplementary
Appendix) were given to participants on a yearly basis. Starting in October 2006,
the intensity of these recommendations was increased, including also group
sessions and personal advice repeated every 3 months (i.e., with the same
intensity and frequency of contacts as in the two Mediterranean-diet groups).
The composition of the recommended diet, however, was not changed.
‖ Participants were advised to remove the visible fat (or the skin) of chicken,
duck, pork, lamb, or veal before cooking and the fat of soups, broths, and
cooked meat dishes before consumption.
Table 1. Summary of Dietary Recommendations to Participants
in the Mediterranean-Diet Groups and the Control-Diet Group.
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For participants in the two Mediterranean-
diet groups, dietitians held individual and group
dietary-training sessions at the baseline visit and
quarterly thereafter. In each session, participants
completed a 14-item dietary questionnaire to
assess adherence to the Mediterranean diet
8,16
(Table S4 in the Supplementary Appendix) so
that personalized advice could be provided to
the study participants in these groups. Question-
naire scores ranged from 0 to 14, with scores
lower than 10 defined as low adherence to the
Mediterranean diet.
Participants in the control group also received
dietary training at the baseline visit and com-
pleted the 14-item questionnaire at baseline to
assess their adherence to the Mediterranean diet.
During the first 3 years of the study, they re-
ceived a leaf let explaining the low-fat diet (see
page 53 in the Supplementary Appendix) on a
yearly basis. However, the realization that the
more infrequent visit schedule and less intense
support for the control group might be limita-
tions of the study prompted us to amend the
protocol in October 2006. Thereafter, participants
who were assigned to the control diet received
personalized advice and were invited to group
sessions with the same frequency and intensity
as those in the Mediterranean-diet groups, with
the use of a separate 9-item dietary questionnaire
(Table S5 in the Supplementary Appendix). Scores
ranged from 0 to 9, with higher scores indicat-
ing greater adherence to a low-fat diet. Except for
the Site D clinics discussed above and 11 clinics
at Site I, all clinics of sufficient size delivered all
three of the interventions (see page 11 in the
Supplementary Appendix).
A general medical questionnaire, a 137-item
validated food-frequency questionnaire,
17
and the
Minnesota Leisure-Time Physical Activity Ques-
tionnaire were administered on a yearly basis.
13
Information from the food-frequency questionnaire
was used to estimate intake of energy and nutri-
ents. Weight, height, and waist circumference were
directly measured annually.
18
Biomarkers of ad-
herence, including urinary hydroxytyrosol levels
(to confirm adherence in the group receiving extra-
virgin olive oil) and plasma alpha-linolenic acid
levels (to confirm adherence in the group receiv-
ing mixed nuts), were measured in random sub-
samples of participants at 1, 3, and 5 years (Figs.
S9 and S10 in the Supplementary Appendix).
End Po ints
The primary end point was a composite of myo-
cardial infarction, stroke, and death from car-
diovascular causes. Secondary end points were
stroke, myocardial infarction, death from car-
diovascular causes, and death from any cause.
We used four sources of information to identify
end points: repeated contacts with participants,
contacts with family physicians, a yearly review
of medical records, and consultation of the Na-
tional Death Index. All medical records that
were related to end points were examined by the
end-point adjudication committee, whose mem-
bers were unaware of the intervention-group
assignments. Only end points that were con-
firmed by the adjudication committee and that
occurred between June 25, 2003, and December 1,
2010, were included in the analyses. The criteria
for adjudicating primary and secondary end
points are detailed on pages 26 and 27 in the
Supplementary Appendix.
Statistical Analysis
We initially estimated that a sample of 9000
participants would be required to provide a sta-
tistical power of 80% to detect a 20% lower risk
of the primary end point in each Mediterranean-
diet group than in the control-diet group during
a 4-year follow-up period, assuming an absolute
cumulative risk of 12% in the control group.
13,19
In April 2008, on the advice of the data and
safety monitoring board and on the basis of
lower-than-expected rates of end-point events,
the sample size was recalculated as 7400 partici-
pants, with the assumption of a 6-year follow-up
period because of slower-than-expected recruit-
ment and an underlying absolute cumulative risk
of the primary end point of 8.8% in the control
group and 6.6% in the Mediterranean-diet groups.
The relationships bet ween enrollment size and
statistical power, under several assumptions,
are shown in Figure S6 in the Supplementary
Appendix.
Yearly interim analyses began on March 2008
after a median of 2 years of follow-up. With the
use of O’Brien–Fleming stopping boundaries, the
P values for stopping the study at each yearly
interim analysis were 5×10
−6
, 0.001, 0.009, and
0.02 for benefit and 9×10
−5
, 0.005, 0.02, and 0.05
for adverse effects.
20
The stopping boundary for
the benefit of the Mediterranean diets with re-
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Cardiovascular Disease and Mediterra nean Diet
spect to the primary end point was crossed at
the fourth interim evaluation; on July 22, 2011,
the data and safet y monitoring board recom-
mended stopping the study on the basis of end
points documented through December 1, 2010.
After the study was stopped, we advised all the
participants, including those in the control group,
to follow the Mediterranean diet.
The interim and original primary analyses es-
timated differences between the groups assigned
to different interventions (intention-to-treat analy-
ses). The information on protocol deviations was
not considered in these analyses. Participants
were followed from the baseline visit until the
occurrence of a primary end-point event, death,
or the last contact date from either medical rec-
ords or study visits. We did not record the date of
randomization and thus do not report the time
between randomization and the baseline visit;
for all the participants, we used the date of the
baseline visit as time 0 in our analyses. No par-
ticipant had a primary or secondary end-point
event between randomization and baseline ac-
cording to our review of the medical records.
We constructed Kaplan–Meier cumulative-inci-
dence curves according to intervention group and
calculated hazard ratios on an intention-to-treat
basis, with the control group as the reference,
using a Cox model with indicators for the Medi-
terranean diet with extra-virgin olive oil and the
Mediterranean diet with nuts. We used robust
variance estimators to account for intracluster
correlations in all Cox models, considering as
clusters the members of the same household and
the participants in the same clinic of Site D. We
compared baseline characteristics across the three
groups and conducted analyses that did not rely
on the assumption that all the participants were
randomly assigned and that randomization would
distribute baseline characteristics of the partici-
pants equally across intervention groups. Our
main analysis was a multivariable model strati-
fied according to site, sex, and educational level
(five categories); to account for potential imbal-
ances in baseline risk factors among the inter-
vention groups, the model included nine other
baseline variables as covariates (see page 12 in
the Supplementary Appendix). This model was
also adjusted for propensity scores that used 30
baseline variables to estimate the probability of
assignment to each of the intervention groups
(detailed on pages 12 through 17 in the Supple-
mentary Appendix).
Prespecif ied subgroup analyses were conduct-
ed according to sex, age, body-mass index (BMI),
status with respect to cardiovascular risk fac-
tors, and baseline adherence to the Mediterra-
nean diet. In sensitivity analyses, we excluded
the 1588 participants whose randomization pro-
cedures were known or suspected to have devi-
ated from the protocol: all 652 participants from
Site D (35 were second members of a household),
593 participants from Site B (47 were second
members of a household), and another 343 sec-
ond household members from other sites. In
addition, we performed sensitivity analyses to
assess how strong and prevalent an unmeasured
confounder would have to be to explain the ob-
served results (Table S25 in the Supplementary
Appendix). We also adjusted for missing data
and loss to follow-up, implemented other exclu-
sions, and used alternative analytic approaches
(see pages 30 through 35 and Figs. S2 and S4 in
the Supplementary Appendix).
A secondary analysis estimated the per-proto-
col effect
21
of the Mediterranean diet as compared
with the control diet that would have been ob-
served if all the participants had adhered to their
assigned interventions throughout the follow-up
period. For participants assigned to the Mediter-
ranean-diet groups, adherence was def ined as a
score of 10 or higher on the 14-item question-
naire. For those assigned to the low-fat diet,
adherence was defined as a fat intake of 30% or
less of total energy intake according to the food-
frequency questionnaires that were administered
annually to the three groups or a score or 6 or
higher on the 9-item questionnaire. We censored
data for participants when they first stopped ad-
hering to their assigned intervention, estimated
inverse-probability weights to adjust for postran-
domization prognostic factors, and estimated
the hazard ratio for an end-point event in the
Mediterranean-diet groups as compared with the
low-fat diet group.
22,23
The validity of the per-protocol effect estimate
relies on several assumptions. It assumes that
loss to follow-up, data collection, and adherence
can be treated as sequentially randomized at
each time point, given the measured prognostic
factors before and after randomization.
22
Both
Mediterranean-diet groups were combined for
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precision because only 39% of the events re-
mained uncensored after the application of our
strict def inition of adherence. We used the pre-
dicted values from this model after adding a
product term between intervention and time to
estimate cumulative-incidence curves (see pages
36 through 38 in the Supplementary Appendix
for details).
Resu lts
Baseline Characteristics
From June 25, 2003, through June 30, 2009, a
total of 8713 candidates were screened for eligi-
bility, and 7447 were assigned to one of the three
intervention groups (Fig. S7 in the Supplemen-
tary Appendix). Their baseline characteristics
according to intervention group are shown in
Table 2, and in Table S23 in the Supplementary
Appendix. The exclusion of participants whose
randomization procedures were known to have
deviated from the protocol did not materially
change these results. Drug-treatment regimens
at baseline were similar for participants in the
three groups, and they continued to be balanced
during the follow-up period (Table S6 in the
Supplementary Appendix).
Participants were followed for a median of
4.8 years (interquartile range, 2.8 to 5.8). After
the baseline visit, 210 participants (2.8%) chose
not to attend subsequent visits (1.2% of the par-
ticipants assigned to a Mediterranean diet with
extra-virgin olive oil, 2.7% of those assigned to
a Mediterranean diet with nuts, and 4.7% of
those in the control group). The rate of study
discontinuation (>2 years since last contact) was
11.3% in the control group and 4.9% in the
Mediterranean-diet groups; subsequent follow-up
was based on reviews of medical records (Fig. S7
and Table S24 in the Supplementary Appendix).
Participants who dropped out of the study were,
on average, 1.4 years younger than those who
remained in the study and had a higher BMI (the
weight in kilograms divided by the square of
height in meters) by 0.4, a higher waist-to-height
ratio (by 0.01), and a lower score for adherence
to the Mediterranean diet (by 1.0 points on the
14-item questionnaire) at baseline.
Adherence to the Dietary Intervention
The scores on the 14-item Mediterranean-diet
questionnaire increased over the follow-up period
for the participants in the two Mediterranean-
diet groups (Table S7 and Fig. S8 in the Supple-
mentary Appendix). There were substantial dif-
ferences between the Mediterranean-diet groups
and the control group in 12 of the 14 items (Table
S7 in the Supplementary Appendix). Changes in
biomarkers also indicated good adherence to the
dietary assignments (Figs. S9 and S10 in the Sup-
plementary Appendix).
Participants in the two Mediterranean-diet
groups increased weekly servings of fish (by 0.3
servings) and legumes (by 0.4 servings) in com-
parison with those in the control group (Table
S8 in the Supplementary Appendix). In addition,
participants assigned to a Mediterranean diet
with extra-virgin olive oil and those assigned to
a Mediterranean diet with nuts increased their
consumption of extra-virgin olive oil (to 50 and
32 g per day, respectively) and nuts (to 0.9 and
6 servings per week, respectively). The main nu-
trient changes in the Mediterranean-diet groups
reflected the fat content and composition of the
supplemental foods (Tables S9 and S10 in the
Supplementary Appendix). No relevant diet-related
adverse effects were reported (see page 38 in the
Supplementary Appendix). We found little differ-
ence in changes in physical activity among the
three groups.
End Po ints
In the intention-to-treat analysis, there were 96
primary end-point events in the group assigned
to a Mediterranean diet with extra-virgin olive
oil (3.8%), 83 in the group assigned to a Medi-
terranean diet with nuts (3.4%), and 109 in the
control group (4.4%). The respective incidence
rates were 8.1, 8.0, and 11.2 per 1000 person-
years, and the 5-year absolute risks were 3.6%,
4.0%, and 5.7%, respectively (Table 3). The un-
adjusted hazard ratios that used robust variance
estimators to account for intracluster correlations
were 0.70 (95% confidence interval [CI], 0.53 to
0.92) for a Mediterranean diet with extra-virgin
olive oil and 0.70 (95% CI, 0.53 to 0.94) for a
Mediterranean diet with nuts as compared with
the control diet.
Results of our primary analyses that included
adjustment for propensity scores and 12 baseline
participant characteristics were similar to those
of the unadjusted analyses, with hazard ratios of
0.69 (95% CI, 0.53 to 0.91) for a Mediterranean
diet with extra-virgin olive oil and 0.72 (95% CI,
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Cardiovascular Disease and Mediterra nean Diet
Characteristic
Mediterranean
Diet with EVOO
(N = 2543)
Mediterranean
Diet with Nuts
(N = 2454)
Control Diet
(N = 2450)
Female sex — no. (%)† 1493 (58.7) 1326 (54.0) 1463 (59.7)
Age — yr† 67.0±6.2 66.7±6.1 67.3±6.3
Race or ethnic group — no. (%)‡
White, from Europe 2470 (97.1) 2390 (97.4) 2375 (96.9)
Hispanic, from Central or South America 35 (1.4) 29 (1.2) 38 (1.6)
Other 38 (1.5) 35 (1.4) 37 (1.5)
Smoking status — no. (%)
Never smoked 1572 (61.8) 1465 (59.7) 1527 (62.3)
Former smoker 618 (24.3) 634 (25.8) 584 (23.8)
Current smoker 353 (13.9) 355 (14.5) 339 (13.8)
Body-mass index†§ 29.9±3.7 29.7±3.8 30.2±4.0
Waist circumference — cm 100±10 100±10 101±11
Waist-to-height ratio†¶ 0.63±0.06 0.63±0.06 0.63±0.07
Hypertension — no. (%)‖ 2088 (82.1) 2024 (82.5) 2050 (83.7)
Type 2 diabetes — no. (%)†** 1282 (50.4) 1143 (46.6) 1189 (48.5)
Dyslipidemia — no. (%)†† 1821 (71.6) 1799 (73.3) 1763 (72.0)
Family history of premature CHD — no. (%)‡‡ 576 (22.7) 532 (21.7) 560 (22.9)
Medication use — no. (%)
ACE inhibitors 1236 (48.6) 1223 (49.8) 1216 (49.6)
Diuretics† 534 (21.0) 477 (19.4) 562 (22.9)
Other antihypertensive agents 725 (28.5) 710 (28.9) 758 (30.9)
Statins 1039 (40.9) 964 (39.3) 983 (40.1)
Other lipid-lowering agents 121 (4.8) 145 (5.9) 126 (5.1)
Insulin 124 (4.9) 126 (5.1) 134 (5.5)
Oral hypoglycemic agents† 768 (30.2) 680 (27.7) 757 (30.9)
Antiplatelet therapy 475 (18.7) 490 (20.0) 513 (20.9)
Hormone-replacement therapy§§ 42 (2.8) 35 (2.6) 39 (2.7)
* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. ACE denotes angiotensin-
converting enzyme, and EVOO extra-virgin olive oil.
† P<0.05 for comparisons between groups.
‡ Race and ethnic group were determined by the staff of the trial (nurses or dietitians).
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ The waist-to-height ratio (an index of central obesity) is the waist circumference divided by height.
‖ Hypertension was defined as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg
or higher, or the use of antihypertensive therapy.
** Diabetes was defined as a fasting blood glucose level of 126 mg per deciliter (7.0 mmol per liter) or higher on two
occasions, a 2-hour plasma glucose level of 200 mg per deciliter (11.1 mmol per liter) or higher during a 75-g oral
glucose-tolerance test, or the use of antidiabetic medication.
†† Dyslipidemia was defined as a low-density lipoprotein cholesterol level higher than 160 mg per deciliter (4.1 mmol per
liter), a high-density lipoprotein cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or lower in men or 50 mg
per deciliter (1.3 mmol per liter) or lower in women, or the use of lipid-lowering therapy.
‡‡ A family history of premature coronary heart disease (CHD) was defined as a diagnosis of the disease in a male first-
degree relative younger than 55 years of age or in a female first-degree relative younger than 65 years of age.
§§ The values for hormone-replacement therapy are for women only.
Table 2. Baseline Characteristics of the Participants, According to Intervention Group.*
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End Point
Mediterranean
Diet with EVOO
(N = 2543)
Mediterranean
Diet with Nuts
(N = 2454)
Control Diet
(N = 2450)
No. of person-yr of follow-up 11852 10365 9763
Primary end point†
No. of events 96 83 109
Incidence rate per 1000 person-yr (95% CI) 8.1 (6.6–9.9) 8.0 (6.4–9.9) 11.2 (9.2–13.5)
5-yr absolute risk — % (95% CI)‡ 3.6 (2.8–4.5) 4.0 (3.1–5.0) 5.7 (4.6–6.9)
Secondary end points
Stroke
No. of events 49 32 58
Incidence rate per 1000 person-yr (95% CI) 4.1 (3.1–5.5) 3.1 (2.1–4.4) 5.9 (4.5–7.7)
5-yr absolute risk — % (95% CI) 1.7 (1.3–2.4) 1.5 (1.1–2.3) 3.0 (2.3–3.9)
Myocardial infarction
No. of events 37 31 38
Incidence rate per 1000 person-yr (95% CI) 3.1 (2.2–4.3) 3.0 (2.0–4.2) 3.9 (2.8–5.3)
5-yr absolute risk — % (95% CI) 1.4 (1.0–2.1) 1.6 (1.1–2.3) 2.1 (1.5–2.9)
Death from cardiovascular causes
No. of events 26 31 30
Incidence rate per 1000 person-yr (95% CI) 2.2 (1.4–3.2) 3.0 (2.0–4.2) 3.1 (2.1–4.4)
5-yr absolute risk — % (95% CI) 1.0 (0.6–1.5) 1.4 (0.9–2.1) 1.6 (1.1–2.3)
Death from any cause
No. of events 118 116 114
Incidence rate per 1000 person-yr (95% CI) 10.0 (8.2–11.9) 11.2 (9.3–13.4) 11.7 (9.6–14.0)
5-yr absolute risk — % (95% CI) 4.4 (3.6–5.4) 5.4 (4.4–6.6) 5.4 (4.4–6.7)
ITT analysis: hazard ratio for each Mediterranean
diet vs. control (95% CI)§
Primary end point
Unadjusted 0.70 (0.53–0.92) 0.70 (0.53–0.94) 1.00 (ref)
Adjusted¶ 0.69 (0.53–0.91) 0.72 (0.54–0.95) 1.00 (ref)
Secondary end points¶
Stroke 0.65 (0.44–0.95) 0.54 (0.35–0.82) 1.00 (ref)
Myocardial infarction 0.82 (0.52–1.30) 0.76 (0.47–1.25) 1.00 (ref)
Death from cardiovascular causes 0.62 (0.36–1.06) 1.02 (0.63–1.67) 1.00 (ref)
Death from any cause 0.90 (0.69–1.18) 1.12 (0.86–1.47) 1.00 (ref)
ITT analysis: hazard ratio for Mediterranean diets
combined vs. control (95% CI)§
Primary end point
Unadjusted 0.70 (0.55–0.89) 1.00 (ref)
Adjusted¶ 0.70 (0.55–0.89) 1.00 (ref)
Secondary end points¶
Stroke 0.58 (0.42–0.82) 1.00 (ref)
Myocardial infarction 0.80 (0.53–1.21) 1.00 (ref)
Death from cardiovascular causes 0.80 (0.51–1.24) 1.00 (ref)
Death from any cause 0.98 (0.77–1.24) 1.00 (ref)
Table 3. Estimates of Cardiovascular Events, According to Intervention Group.*
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e34(9)
Cardiovascular Disease and Mediterra nean Diet
0.54 to 0.95) for a Mediterranean diet with nuts
(Fig. 1A and Table 3). There were similar results
on three alternative analyses: one that was ad-
justed with inverse-probability weighting (mod-
els 3A through 3C in Fig. S2 in the Supplemen-
tary Appendix), one that included adjustments
for the Framingham risk score
24
(models 6A
through 6C in Fig. S2 in the Supplementary Ap-
pendix), and one that omitted participants
known or suspected to have been assigned to an
intervention group without individual random-
ization (Table 3 and Figs. 2 and 3, and Figs. S2
and S4 in the Supplementary Appendix). The
results for secondary end points are shown in
Table 3 and Figure 1B.
To provide an alternative, noncausal explana-
tion of the observed association (i.e., to change
the point estimate of the hazard ratio to ≥1.0),
an unmeasured binary confounder would need
to be present in at least 40% of the control group
but in less than 25% of each Mediterranean-diet
group and be associated with a relative risk of
more than 4 for the primary end point. For fur-
ther details, see Table S25 in the Supplementary
Appendix.
To explore the effect of the October 2006
protocol change that was implemented for the
control group to intensify nutritional counsel-
ing, we conducted separate analyses of the par-
ticipants recruited before the protocol change
and those recruited after the protocol change.
The hazard ratios for the Mediterranean diet
(both groups merged) as compared with the
control diet were 0.77 (95% CI, 0.59 to 1.00) for
the participants recruited before October 2006
and 0.49 (95% CI, 0.26 to 0.92) for those re-
cruited in October 2006 or later (P = 0.21 for
heterogeneity).
The per-protocol (adherence-adjusted) hazard
ratio for the primary end point was 0.42 (95%
CI, 0.24 to 0.63) for the Mediterranean diet as
compared with the control diet (Fig. 3); the esti-
mated absolute differences in incidence between
the combined Mediterranean-diet groups and
End Point
Mediterranean
Diet with EVOO
(N = 2543)
Mediterranean
Diet with Nuts
(N = 2454)
Control Diet
(N = 2450)
Primary end point, excluding Site D and second
household members‖
Each Mediterranean diet and control
No. of participants 2158 2109 2138
5-year absolute risk — % (95% CI) 3.4 (2.6–4.3) 3.9 (3.0–5.0) 5.9 (4.8–7.2)
Hazard ratio (95% CI)¶ 0.66 (0.49–0.89) 0.64 (0.47–0.88) 1.00 (ref)
Mediterranean diets combined and control
5-year absolute risk — % (95% CI) 3.6 (3.0–4.3) 5.9 (4.8–7.2)
Hazard ratio (95% CI)¶ 0.65 (0.50–0.85) 1.00 (ref)
* CI denotes confidence interval, and ref reference.
† The primary end point was a composite of myocardial infarction, stroke, and death from cardiovascular causes.
‡ In the combined Mediterranean-diet groups, the 5-year absolute risk of the primary end point was 3.8% (95% CI, 3.2
to 4.4).
§ The intention-to-treat (ITT) analysis included all 7447 participants.
¶ The Cox model was stratified according to sex, recruiting site, and educational level (five categories) and adjusted for
age (continuous variable), smoking status (never smoked, former smoker, or current smoker), hypertension at baseline
(yes or no), dyslipidemia at baseline (yes or no), diabetes at baseline (yes or no), family history of premature coronary
heart disease (yes or no), body-mass index (continuous variable), waist-to-height ratio (continuous variable), physical
activity (in quintiles), and propensity scores that used 30 baseline variables to estimate the probability of assignment
to each of the intervention groups (see pages 12 through 17 in the Supplementary Appendix). Robust standard errors to
account for intracluster correlations were used.
‖ The analysis included 6405 participants. Excluded were second members of the same household (425 participants) and
participants from Site D (617 participants). When participants from Site B were also excluded, the sample size was
5859 and the adjusted hazard ratios were 0.71 (95% CI, 0.52 to 0.97) for the group assigned to a Mediterranean diet
with extra-virgin olive oil, 0.68 (95% CI, 0.49 to 0.95) for the group assigned to a Mediterranean diet with nuts, and
0.69 (95% CI, 0.53 to 0.92) for the combined Mediterranean-diet groups, with the group assigned to a control diet as
the reference.
Table 3. (Continued.)
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The
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the control group were 0.67, 1.38, and 2.00 per-
centage points at 12, 24, and 36 months after
enrollment, respectively (see pages 36 through
38 in the Supplementary Appendix). The results
of additional sensitivity and subgroup analyses
were also consistent with the results of our pri-
mary analyses (Figs. 2 and 3, and Figs. S2, S4,
and S12 in the Supplementary Appendix).
Disc ussion
In this study involving high-risk persons without
cardiovascular disease, assignment to an energy-
unrestricted Mediterranean diet supplemented
with either extra-virgin olive oil or nuts was asso-
ciated with a lower risk of major cardiovascular
events over a period of 5 years than assignment
to a control (low-fat) diet, with a relative differ-
ence of 30% and an absolute difference of 1.7 to
2.1 percentage points. Our analysis, which in-
corporated information about adherence to the
diets, suggests that the difference in rates of
cardiovascular events between those assigned to
the Mediterranean diets and those assigned the
control diet was greater among participants with
better adherence. These results support previously
reported benef its of the Mediterranean diet for
cardiovascular risk reduction from a randomized
trial.
4,25,26
Our findings are also consistent with
those of previous observational studies.
2,5,23,25-33
Table S11 in the Supplementary Appendix sum-
marizes the f indings from systematic reviews on
this issue.
In response to a 2017 report
11
suggesting
that distributions of baseline variables in the
PREDIMED trial were signif icantly different from
what would have been expected to result from
randomization, we conducted an extensive review
Cumulative Incidence
0.8
0.9
1.0
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 1 2 3 4 5
0.07
0.06
0.04
0.03
0.01
0.05
0.02
0.00
0 1 2 3 4 5
Years
BTotal Mortality
APrimary End Point (acute myocardial infarction, stroke, or death from
cardiovascular causes)
Med diet, EVOO: hazard ratio, 0.69 (95% CI, 0.53–0.91)
Med diet, nuts: hazard ratio, 0.72 (95% CI, 0.54–0.95)
Med diet, EVOO: hazard ratio, 0.90 (95% CI, 0.69–1.18)
Med diet, nuts: hazard ratio, 1.12 (95% CI, 0.86–1.47)
No. at Risk
Control diet
Med diet, EVOO
Med diet, nuts
2450
2543
2454
2268
2486
2343
2020
2320
2093
1583
1987
1657
1268
1687
1389
946
1310
1031
Med diet,
EVOO
Med diet,
nuts
Control diet
Total Mortality
1.0
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 1 2 3 4 5
0.07
0.06
0.04
0.03
0.01
0.05
0.02
0.00
0 1 2 3 4 5
Years
No. at Risk
Control diet
Med diet, EVOO
Med diet, nuts
2450
2543
2454
2270
2486
2345
2027
2324
2097
1586
1991
1662
1272
1691
1395
949
1310
1037
Med diet,
EVOO
Med diet,
nuts
Control diet
Figure 1. Kaplan–Meier Estimates of the Cumulative
Incidence of End-Point Events in the Total Study
Population.
Panel A shows the incidence of the primary end point
(a composite of acute myocardial infarction, stroke,
and death from cardiovascular causes), and Panel B
shows total mor tality. The insets show the same data
on an expanded y axis. Hazard ratios were stratified
according to sex, recruiting site, and educational level
(five categories) and adjusted for age (continuous vari-
able), smoking (never smoked, former smoker, or cur-
rent smoker), hypertension (yes or no), dyslipidemia
(yes or no), diabetes (yes or no), family histor y of pre-
mature coronary heart disease, body-mass index (con-
tinuous variable), waist-to-height ratio (continuous
variable), physical activity (in quintiles), and propensity
scores that estimated the probability of assignment to
each intervention group on the basis of 30 baseline
variables (see pages 12 through 17 in the Supplemen-
tary Appendix). Robust standard errors to account for
intracluster correlations were used. CI denotes confi-
dence interval, EVOO extra-virgin olive oil, and Med
Mediterranean.
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e34(11)
Cardiovascular Disease and Mediterra nean Diet
of the documentation and data at the 11 recruit-
ment sites. After sharing this information with
the editors of the Journal, we withdrew our
original report of this trial and now publish this
new report. Despite some departures from the
randomization protocol, most of the baseline
covariates were balanced across groups, and
there was no meaningful difference in the pre-
dicted risks of future cardiovascular events
across the three groups (Fig. S13 in the Supple-
mentary Appendix).
We reanalyzed the data using methods that
do not rely exclusively on the assumption that all
the participants had been randomly assigned to
intervention groups and that adjusted for base-
line characteristics and propensity scores estimat-
ing probabilities of assignment to each interven-
tion on the basis of 30 baseline covariates. The
results of our reanalyses (Figs. 2 and 3 and Ta-
ble 3, and Figs. S2 and S4 in the Supplementary
Appendix) were similar to the results that we
originally reported. In addition, reanalyses of
our data did not reveal any evidence that certain
lifestyle or treatment factors that are potentially
related to the risk of cardiovascular disease either
biased the results or might provide an alternative
explanation for the observed benefits of the
Mediterranean-diet interventions on cardiovascu-
lar disease. Analyses that excluded participants
whose assignment to an intervention group was
known or suspected not to have followed the
randomization protocol (participants from Sites D
and B and second household members) yielded
results consistent with the results of our pri-
mary analysis.
The retention rate was higher in the group
Figure 2. Sensitivity Analyses of Each Mediterranean-Diet Group and the Control Group.
Shown are hazard ratios for the primary end point in each Mediterranean-diet group as compared with the control
group, with estimates based on different analytic approaches or exclusions. Hazard ratios were stratified according
to sex, recruiting site, and educational level (five categories) and (with the exception of the unadjusted intention-to-
treat [ITT] analysis) were adjusted for age, smoking (never smoked, former smoker, or current smoker), hyperten-
sion (yes or no), dyslipidemia (yes or no), diabetes (yes or no), family history of premature coronary heart disease,
body-mass index (continuous variable), waist-to-height ratio (continuous variable), and physical activity (in quintiles).
In addition, all multivariable models were adjusted for propensit y scores that estimated the probability of assign-
ment to each intervention group on the basis of 30 baseline variables. We used robust standard errors to account
for intracluster correlations. One analysis excluded all the par ticipants from Site D (652 participants) and all second
members of the same household (425 participants, including 35 from Site D); in total, 1042 participants were ex-
cluded from this analysis. Another analysis excluded all the participants from Site D (652 participants), all the par-
ticipants from Site B (593 participants), and all second members of the same household (425 participants, includ-
ing 35 from Site D and 47 from Site B); in total, 1588 participants were excluded from this analysis. The results of
additional sensitivity analyses are shown in Figures S2 and S4 in the Supplementary Appendix.
0.50 0.75 1.00 1.50
Control Diet
Better
Mediterranean Diet
Better
Unadjusted ITT analysis
Mediterranean diet with EVOO
Mediterranean diet with nuts
Adjusted ITT analysis
Mediterranean diet with EVOO
Mediterranean diet with nuts
Excluding Site D and second
household members (adjusted)
Mediterranean diet with EVOO
Mediterranean diet with nuts
Excluding Sites D and B and second
household members (adjusted)
Mediterranean diet with EVOO
Mediterranean diet with nuts
Hazard Ratio (95% CI)Subgroup
0.70 (0.53−0.92)
0.70 (0.53−0.94)
0.69 (0.53−0.91)
0.72 (0.54−0.95)
0.66 (0.49−0.89)
0.64 (0.47−0.88)
0.71 (0.52−0.97)
0.68 (0.49−0.95)
0.25
Mediterranean
Diet
Control
Diet
96/2543
83/2454
96/2543
83/2454
77/2158
67/2109
73/1976
62/1977
109/2450
109/2450
109/2450
109/2450
98/2138
98/2138
83/1906
83/1906
no. of events/total no. of participants
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The
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assigned to a Mediterranean diet with extra-virgin
olive oil than in the other two groups (the group
assigned to a Mediterranean diet with nuts and
the control group). These two groups were also
slightly smaller in size, which resulted in a larger
number of person-years of follow-up in the group
assigned to a Mediterranean diet with extra-virgin
olive oil. The different follow-up had the poten-
tial to bias the incidence rates toward lower rates
in the group assigned to a Mediterranean diet
with extra-virgin olive oil. However, analyses
that used multiple imputation and inverse-prob-
ability weighting to adjust for a potential selec-
tion bias due to differential losses to follow-up
yielded estimates consistent with the main analy-
sis (see pages 30 through 35 and Fig. S4 in the
Supplementary Appendix). An additional limita-
tion of our study is that participants were at high
cardiovascular risk; whether the results can be
generalized to persons at lower risk requires
further research.
As with many clinical trials, the observed rates
of cardiovascular events were lower than antici-
pated, with reduced statistical power to separately
assess components of the primary end point.
However, favorable trends were seen for both
stroke and myocardial infarction. It is possible,
but not likely, that some cardiovascular events
were not detected (see pages 28 and 29 in the
Supplementary Appendix).
Even though participants in the control group
received advice to reduce fat intake, changes in
total fat on the food-frequency questionnaire
were small and the largest differences at the end
of the study were in the distribution of fat sub-
types. The interventions were intended to im-
prove the overall dietary pattern, but the major
between-group differences involved the supple-
mental items, extra-virgin olive oil and nuts.
Differences were also observed in the consump-
tion of fish and legumes but not in the consump-
tion of other food groups. (It is worth noting
that on the 14-item Mediterranean-diet question-
naire, there were substantial between-group differ-
ences in 12 of the 14 items.) The modest between-
group differences according to the food-frequency
questionnaire can be explained by the facts that
most study participants had been consuming a
baseline diet similar to the study Mediterranean
diet and that the control group was given recom-
mendations for a healthy diet, factors that raise
the question of how applicable our results may be
to high-risk persons in other countries. Answer-
ing this question will require further research.
3
In conclusion, in this primary prevention study
involving persons at high risk for cardiovascular
events, those assigned to an energy-unrestricted
Mediterranean diet, supplemented with extra-
virgin olive oil or nuts, had a lower rate of major
cardiovascular events than those assigned to a
Figure 3. Sensitivity Analyses of the Combined Mediterranean-Diet Groups and the Control Group.
Shown are hazard ratios for the primary end point in the combined Mediterranean-diet groups as compared with
the control group, with estimates based on different analytic approaches or exclusions. Hazard ratios were stratified
according to sex, recruiting site, and educational level (five categories) and (with the exception of the unadjusted
ITT analysis) were adjusted for age, smoking (never smoked, former smoker, or current smoker), hypertension (yes
or no), dyslipidemia (yes or no), diabetes (yes or no), family history of premature coronar y heart disease, body-mass
index (continuous variable), waist-to-height ratio (continuous variable), and physical activity (in quintiles). In addi-
tion, all multivariable models were adjusted for propensity scores, and we used robust standard errors to account
for intracluster correlations.
0.50 0.75 1.00 1.25
Unadjusted ITT analysis
Adjusted ITT analysis
Excluding Sites D and B and second
household members (adjusted)
Per-protocol (adherence-adjusted)
analysis
Hazard Ratio (95% CI)Subgroup
0.70 (0.55−0.89)
0.70 (0.55−0.89)
0.69 (0.53−0.92)
0.42 (0.24−0.63)
0.25
288/7447
288/7447
218/5859
111/7356
No. of Events/
Total No. of Participants
Control Diet
Better
Mediterranean Diet
Better
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Cardiovascular Disease and Mediterra nean Diet
reduced-fat diet. Our f indings support a benefi-
cial effect of the Mediterranean diet for the pri-
mary prevention of cardiovascular disease.
Supported by Instituto de Salud Carlos III, Spanish Ministr y of
Health, through grants provided to research networks specif ica lly
develope d for the study (RTIC G03/140, to Dr. Est ruch, and RTIC RD
06/0045, to Dr. Martínez-González); Centro de Investigación Bio-
médica en Red de Fisiopatología de la Obesidad y Nutrición; a nd
grant s from Centro Nacional de Investigaciones Cardiovascu lares
(CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Euro-
peo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100,
PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658,
PI11/01647, and P11/02505), Ministerio de Ciencia e Innovación
(AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación
Mapfre 2010, Consejería de Salud de la Junt a de Andalucía
(PI0105/2007), Public Healt h Division of the Depart ment of Health
of the Autonomous Government of Catalonia, Generalitat Valen-
ciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151,
CS2010-AP-111, and CS2011-AP-042), and Regional Government
of Navarra (P27/2011). Dr. Hernán was supported by a grant
(ME-1503-28119) from the Patient-Centered Outcomes Research
Institute.
Disclosure forms provided by t he authors are available with
the fu ll text of this art icle at NEJM.org.
We thank t he participa nts for t heir involvement in t he study;
and Joan Vila from Instit ut Hospital del Mar d’Investigacions
Mèdiques, Barcelona, and Estefanía Toledo from the Universit y
of Navarra, Pamplona, for their assist ance with statist ical
analyses.
Appendix
The authors’ full names and academic degrees are as follows: Ramón Estruch, M.D., Ph.D., Emilio Ros, M.D., Ph.D., Jordi Salas-Sal-
vadó, M.D., Ph.D., Maria-Isabel Covas, D.Pharm., Ph.D., Dolores Corella, D.Pharm., Ph.D., Fernando Arós, M.D., Ph.D., Enrique Gó-
mez-Gracia, M.D., Ph.D., Valentina Ruiz-Gutiérrez, Ph.D., Miquel Fiol, M.D., Ph.D., José Lapetra, M.D., Ph.D., Rosa M. Lamuela-
Raventos, D.Pharm., Ph.D., Lluís Serra-Majem, M.D., Ph.D., Xavier Pintó, M.D., Ph.D., Josep Basora, M.D., Ph.D., Miguel A. Muñoz,
M.D., Ph.D., José V. Sorlí, M.D., Ph.D., J. Alfredo Martínez, D.Pharm., M.D., Ph.D., Montserrat Fitó, M.D., Ph.D., Alfredo Gea, D.Pharm.,
Ph.D., Miguel A. Hernán, M.D., Dr.P.H., and Miguel A. Martínez-González, M.D., Ph.D.
The authors’ affiliations are as follows: the PREDIMED (Prevención con Dieta Mediterránea) Network (RD 06/0045) (R.E., J.S.-S.,
F.A., E.G.-G., V.R.-G., R.M.L.-R., L.S.-M., X.P., J.B., J.V.S., J.A.M., M.A.M.-G.) and Centro de Investigación Biomédica en Red de Fisio-
patología de la Obesidad y Nutrición (R.E., E.R., J.S.-S., M.-I.C., D.C., F.A., M. Fiol, J.L., R.M.L.-R., L.S.-M., X.P., J.B., J.V.S., J.A.M.,
M. Fitó, A.G., M.A.M.-G.), Instituto de Salud Carlos III, Madrid, the Department of Internal Medicine, Hospital Clinic (R.E.), the Lipid
Clinic, Department of Endocrinology and Nutrition, Institut d’Investigacions Biomèdiques August Pi i Sunyer (E.R.), and the Depart-
ment of Nutrition, Food Sciences, and Gastronomy, Faculty of Pharmacy and Food Sciences, Xarxa de Referència en Tecnologia dels
Aliments, Instituto de Investigación en Nutrición y Seguridad Alimentaria (R.M.L.-R.), University of Barcelona, Institut Hospital del Mar
d’Investigacions Mèdiques (M.-I.C., M. Fitó), the Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge,
Hospitalet de Llobregat (X.P.), and the Primary Care Division, Catalan Institute of Health, Institut Universitari d’Investigació en Atenció
Primària (IDIAP)–Jordi Gol (M.A.M.), Barcelona, the Human Nutrition Department, Hospital Universitari Sant Joan, Institut
d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus (J.S.-S.), the Department of Preventive Medicine, University of
Valencia (D.C., J.V.S.), and the Primary Care Division, Valencia Institute of Health (J.V.S.), Valencia, the Department of Cardiology,
University Hospital of Álava, Vitoria (F.A.), the Department of Preventive Medicine, University of Malaga, Malaga (E.G.-G.), Instituto de
la Grasa, Consejo Superior de Investigaciones Científicas (V.R.-G.), and the Department of Family Medicine, Primary Care Division of
Sevilla, San Pablo Health Center (J.L.), Seville, the Institute of Health Sciences, University of the Balearic Islands, and Hospital Son
Espases, Palma de Mallorca (M. Fiol), the Research Institute of Biomedical and Health Sciences, Instituto Universitario de Investiga-
ciones Biomédicas y Sanitarias, University of Las Palmas de Gran Canaria, Las Palmas (L.S.-M.), the Primary Care Division, Catalan
Institute of Health, IDIAP–Jordi Gol, Tarragona-Reus (J.B.), and the Departments of Nutrition and Food Sciences and Physiology
(J.A.M.) and Preventive Medicine and Public Health (A.G., M.A.M.-G.), University of Navarra, Pamplona — all in Spain; and the Depart-
ments of Epidemiology and Biostatistics (M.A.H.) and Nutrition (M.A.M.-G.), Harvard T.H. Chan School of Public Health, and the
Harvard–MIT Division of Health Sciences and Technology (M.A.H.), Boston.
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The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.