www.unav.es/preventiva the predimed trial

www.unav.es/preventiva

The PREDIMED trial

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• Rationale• Funding sources• Methods and intervention protocol• Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006)

• Cross-sectional assessments:o Diet & inflammatory markers (Eur J Clin Nutr 2007)

o MeDiet & risk factors (Eur J CV Prev 2008)

• 3-mo changes in oxLDL (Arch Intern Med 2008)

• 1-yr changes in diet (J Am Diet Assoc 2008)

• 1-yr changes in MetS (Arch Intern Med 2008)

• Other nested sub-studies

PREDIMED TRIAL

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Micronutrients: antioxidants, vitamins, etc.

Single macronutrient: CHO, Types of Fat, Protein

Food items: olive oil, tomato, garlic, etc.

Food grouping & indexes

Food patterns

Evolution of exposure in nutritional epidemiology

Ecological (cross-cultural, international comparisons)

Case-control

Nested case-control

Cohort

Randomized Trial

Evolution of designs

HighHigh

LowLow

Qu

alit

y o

f ev

iden

ceQ

ual

ity

of

evid

ence

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Mediterranean Food pattern Rapidly increasing evidence

Increased Longevity Prevention of

CV mortality Cancer mortality CVD incidence Metabolic syndrome Diabetes Dementia Depression

Highly palatable! Scarcity of large randomized trials

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de Lorgeril M, Salen P, Martin JL, et al. Final Report of de Lorgeril M, Salen P, Martin JL, et al. Final Report of the the LyonLyon Diet Heart Study. Diet Heart Study. Circulation 1999;99:779-785.Circulation 1999;99:779-785.

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www.unav.es/preventivaEur J Epidemiol 2004;19:9-13.

• What is the MeDiet?• Olive oil as the main added lipid• Unrestricted Total Fat• MUFA-rich diet in the intervention group• Low consumption of meat / meat products

• and what it is NOT the MeDiet• Margarine, soybean oil, mustard oil...

de Lorgeril et al. de Lorgeril et al. LyonLyon trial. Circulation 1999;99:779-785. trial. Circulation 1999;99:779-785.

Diet assessed in ~30% of control

~50% of experimental

No biochemical confirmation of

adherence.

Trial stopped after 27 months.

Low number of observed endpoints

(14 vs. 44).

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PREDIMED TRIAL

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Funding agency

Network RD 06/0045

Consortium (CIBER-OBN)

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Funding HistoryFunding History

2003 2004 2005 2006 2007 2008 2009

17 15 15 14 17 18 19adhoc grantInitial Network

Network RD 06/0045

Consortium ciberobn

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Centers

11 RECRUITMENT GROUPS

• Navarra- MA Martinez-Gonzalez

• Valencia- D Corella• Reus- J Salas-Salvado• Mallorca- M Fiol• Sevilla- J Lapetra• Málaga- E Gomez-Gracia• Barcelona-1- R Estruch• Vitoria- F Aros• Barcelona-2- MI Covas• Las Palmas- L Serra-Majem• Barcelona-3- X Pinto

8 ONLY-LAB GROUPS

• Barcelona-1- E Ros• Sevilla- V Ruiz-Gutierrez• Barcelona-2- RM Lamuela-Raventos

• Navarra- JA Martinez• Valencia- G Saez• Barcelona-3- MT Mitjavila• Mallorca- JA Tur• Vitoria- MP Portillo

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Funded by network (RD 06/0045)




7 LAB-ONLY GROUPS



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Funded by consortium (ciberobn)




1 LAB-ONLY GROUP



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Food industry: only food itemsFood industry: only food items

Provision of Olive oil~2 000 l/wk

Provision of nuts30 kg/wk walnuts

15 kg/wk almonds

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PREDIMED TRIAL

Men: 55-80 yr

Women: 60-80 yr

High CV risk without CVD

type 2 diabetics

3+ risk factors

PREDIMED TRIAL: DESIGN

RandomRandom

1. Smoking

2. Hypertension

3. LDL

4. HDL

5. Overweight/obes

6. Family history

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PREDIMED Participants

n ~P-YNavarra 1048 5470Valencia 1049 3830Reus 870 3680Mallorca 594 2460Málaga 540 2400Barcelona 1 667 2400Sevilla 659 2220Vitoria 641 2210Barcelona 2 570 2060Las Palmas 356 690Barcelona 3 238 490

Total 7232 27,910



• Valencia- D Corella

• Reus- J Salas-Salvado

• Mallorca- M Fiol

• Málaga- E Gomez-Gracia

• Barcelona-1- R Estruch

• Sevilla- J Lapetra

• Vitoria- F Aros

• Barcelona-2- MI Covas

• Las Palmas- L Serra-Majem

• Barcelona-3- X Pinto

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Project Leader: Dr. Ramón Estruch

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PREDIMED Participants

Mediet + VOO(n= 2487)

MeDiet + Nuts(n=2396)

Control(n=2349)

Age (SD) 67 (6) 67 (6) 67 (6)

Women (%) 57 54 58

Diabetes (%) 50 47 48

Hypertension (%) 82 82 84

Current smokers (%) 14 15 14

High cholest. (%) 72 73 72

BMI (SD) 30 (4) 30 (4) 30 (4)

Waist (SD) 100 (10) 100 (10) 101 (11)

MeDiet 0-14 p (SD) 8.7 (2) 8.7 (2) 8.3 (2)

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PREDIMED: primary end-point

Either: cardiovascular death myocardial infarction stroke

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PREDIMED: Secondary end-points

total mortality heart failure major cancers diabetes dementia

We will also ascertain intermediate outcomes:

•blood pressure (BP)

•fasting blood glucose

•lipid profile

•markers of inflammation

•other markers of CVD

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PREDIMED: intervention

Introduce changes in the overall food pattern Mediterranean diet: 2 groups

Total Fat: ad libitum High in

MUFA (virgin olive oil) Fish Fruits, vegetables, legumes

Low in meats & dairy alcohol permitted: wine

Low-fat diet - Control Reduce every fat Increase CHO

No Energy limitation

tocopherols polyphenols flavonoids

phytosterols

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14-point score1. Olive oil main culinary fat 8. Wine >=3 glasses/wk2. Olive oil >=4 tablespoons/d 9. Legumes >=3/wk3. Vegs>=2 serv./d 10. Fish & seafood >=3/wk4. Fruits>=3 serv./d 11. Cakes, sweets <3/wk5. Red meats<1/d 12. Nuts >=1/wk6. Butter, marg, cream<1/d 13. Poultry > red meats7. Soda drinks<1/d 14. Sofrito

Ann Intern Med 2006;145:1-11 Appendix, table 1 (on-line)

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Strategies for behavior change Repeated personal contacts: every 3-mo Group sessions: every 3-mo Holistic approach

Written information Self-monitoring Individualized goal-setting Quick feedback Individual motivational interviews (every 3-mo)

adapted to the patient’s features clinical condition preferences beliefs

expressed in servings/d to improve understanding

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Strategies for behavior change-2

Additional strategies Seasonal buying lists Menus and recipes

Only in the 2 MeDiet groups Provision of key food items for free

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Special emphasis

Negotiated goal setting Contracted agreement Understandable: units=servings

Options for the negotiation Serving size Frequency of consumption Way of cooking

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Group sessions

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2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013Recruitm.1 yr2 yr3 yr4 yr5 yr6 yr

Year % of recruitment

Cum. %

2003 9 92004 21 302005 28 582006 11 692007 13 822008 17 992009 1 100Total 100

Projected follow-up = 6 years (median)

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PREDIMED TRIAL

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3-mo changes

Ann Intern Med 2006;145:1-11

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•772 participants (55-80 yr)

•Randomization:•257 to a MeDiet + (free provision of olive oil)

•258 to a MeDiet + (free provision of nuts)

•257 to a LFD (control group)

•Follow-up: 3 months•Nutrient profile and food items consumption

•Mediterranean score (14-point score)

•Classical risk factors

•Novel risk factors (CRP, IL6, VCAM, ICAM)

3-mo changes in RF

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3-mo changes in RF

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3-mo changes in diet

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-7-6-5-4-3-2-10123

SBP change(mmHg)

DBP change(mm Hg)

LDL change(mg/dl)

HDL change(mg/dl)

MeDiet (+VOO) MeDiet (+Nuts) CONTROL

p<0.001

p<0.001

p=0.001

p=0.048

p=0.006

p<0.001

3-mo changes in Risk Factors

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-12-10-8-6-4-202468

TG change (mg/dl) Glucose change (mg/dl) Insulin change (pmol/L)


p=0.022 p=0.039

p=0.017

p<0.001

p<0.001


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-1

-0,8

-0,6

-0,4

-0,2

0

0,2

0,4

TC/HDL ratio (change) HOMA index (change) Waist change (cm)


p=0.002 p<0.001

p<0.001

p=0.84

p=0.37p<0.001


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PREDIMED TRIAL

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Salas-Salvado et al, Eur J Clin Nutr 2008;62:651-9

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•339 men and 433 women (55-80 yr)

•Exposure: •Food groups (137-item FFQ)

•MeDiet adherence (14-point score)

•Outcomes:•hs-C Reactive protein

•interleukin-6 (IL-6)

•intracellular adhesion molecule-1 (ICAM-1)

•vascular cell adhesion molecule-1 (VCAM-1)


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Change (p value*) CRP IL6 VCAM1 ICAM1

Cereals (0.005)

Fruits (0.008)

Nuts (0.003)

Virgin Olive Oil (0.02)

MeDiet** (0.14) (0.49) (0.09) (0.09)

*Adjusted for age, gender, diabetes, smoking, BMI, educational level, use of statins, NSAID, and aspirin.

**Test for linear trend (multivariate adjusted)


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0

200

400

600

800

1000

1200

1400

<7 7 to 10 >10MeDiet score (0-14)

ng

/m

l

VCAM-1I CAM-1

3.513.18

3.59

0

1

2

3

4

5

6

7

8

<7 7 to 10 >10MeDiet score (0-14)

IL-6 (pg/ml)CRP (mg/l)


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• Cross-sectional assessments:o MeDiet & inflammatory markers (Eur J Clin Nutr 2007) o MeDiet & risk factors (Eur J CV Prev 2008)





PREDIMED TRIAL

•3204 participants

•Exposure: MeDiet (14-point score)

•Adherence: Above Median (9) in the score

•Ordered categories (5) in the score

•Outcomes:•Diabetes

•Hypertension

•Obesity

•Hypercholesterolemia

All of them together

Sánchez-Tainta, et al. Eur J Cardiovasc Prev Rehabil. 2008;15:589-93.

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0

0,2

0,4

0,6

0,8

1

1,2

Hypertension Diabetes Obesity Hypercholesterolemia

Ad

j. P

reva

len

ce O

R (

95%

CI)

Adjusted for age, gender, leisure-time physical activity (tertiles), smoking (5 categories), marital status (4 categories), educational level (4 categories), and BMI (3 categories, except when using obesity as outcome).

MeDiet (>Median) and prevalence of Risk Factors


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Adjusted for age, gender, leisure-time physical activity (tertiles), smoking (5 categories), marital status (4 categories), educational level (4 categories), and BMI (3 categories).

0.670.69

1.000.991 (ref.)

0

0,2

0,4

0,6

0,8

1

1,2

1,4

<=7 (n=802) 8 (n=547) 9 (n=570) 10 (n=507) >=11 (n=778)

Mediterranean diet score (14 points)

adj.

OR

(95%

CI)

Adherence to MeDiet and prevalence of diabetes

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Adjusted for age, gender, leisure-time physical activity (tertiles), smoking (5 categories), marital status (4 categories), and educational level (4 categories).

p<0.001 for linear trend

0.38

0.680.78

1.031 (ref.)

0

0,2

0,4

0,6

0,8

1

1,2

1,4

<=7 (n=802) 8 (n=547) 9 (n=570) 10 (n=507) >=11 (n=778)

Mediterranean diet score (14 points)

adj.

OR

(95%

CI)

Adherence to MeDiet & prevalence of all 4 RF


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PREDIMED TRIAL

Fitó for the PREDIMED group. Arch Inter Med 2007;167:1195-1203.

n = 372 n = 372 Mediet+VOO=123 Mediet+nuts=128Mediet+VOO=123 Mediet+nuts=128 control=121control=121

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PREDIMED TRIAL

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Zazpe et al for the PREDIMED group,

J Am Diet Assoc 2008;108:1134-44

1-yr changes in diet

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1-yr changes in diet

n= 1551 in 3 groups:

• MeDiet +VOO: 533• MeDiet +Nuts: 533 • Control: 485

Assessment of changes from baseline

Baseline characteristics of the 3 randomized groups

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1-yr within-group changesin VIRGIN OLIVE OIL (VOO) consumption

0

0,5

1

1,5

2

2,5

3

3,5

VOO Nuts Control

Ser

vin

gs/

d

*

*

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1-yr within-group changesin REFINED OLIVE OIL consumption

-2,5

-2

-1,5

-1

-0,5

0

0,5

VOO Nuts Control

Ser

vin

gs/

d

*

*

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1-yr within-group changesTOTAL NUTS

-0,2

0

0,2

0,4

0,6

0,8

1

VOO Nuts Control

Ser

vin

gs/

d

*

*

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1-yr within-group changesVEGETABLES

0

0,1

0,2

0,3

0,4

0,5

VOO Nuts Control

Ser

vin

gs/

d

*

*

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1-yr within-group changesFRUITS

0

0,1

0,2

0,3

0,4

0,5

0,6

VOO Nuts Control

Ser

vin

gs/

d

**

*

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1-yr within-group changesCEREALS

-0,5

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0,3

0,4

0,5

VOO Nuts Control

Ser

vin

gs/

d

* *Between-group: non-significant

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1-yr within-group changesLEGUMES

-0,5

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0,3

0,4

0,5

VOO Nuts Control

Ser

vin

gs/

d * *

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1-yr within-group changesFISH / SEAFOOD

-0,5

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0,3

0,4

0,5

VOO Nuts Control

Ser

vin

gs/

d

Between-group: non-significant

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1-yr within-group changesMEAT / MEAT PRODUCTS

-0,5

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0,3

0,4

0,5

VOO Nuts Control

Ser

vin

gs/

d

* * *


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1-yr within-group changesDAIRY

-0,5

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0,3

0,4

0,5

VOO Nuts Control

Ser

vin

gs/

d


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1-yr within-group changesALCOHOL

-10

-8

-6

-4

-2

0

VOO Nuts Control

g/d

** *


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Baseline vs. 1-yr 14-unit Score

9,0 8,98,4

10,8 11,2

8,9

0

2

4

6

8

10

12

14

MeDiet+VOO MeDiet+Nuts Control

Un

its

Baseline1-y follow-up

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1-yr within-group changesNutrient profile

-3-2,5

-2-1,5

-1-0,5

00,5

11,5

22,5

3

VOO Nuts Control% E

ner

gy Fat

CHO

Prot.

*

*

*

**

*

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-15-12,5

-10-7,5

-5-2,5

02,5

57,510

12,515

Intervention Control% E

ne

rgy Fat

CHOProt.

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1-yr within-group changesTypes of Fat

-3-2,5

-2-1,5

-1-0,5

00,5

11,5

22,5

3

VOO Nuts Control% E

ne

rgy

SFA

MUFA

PUFA

**

** **

*

Between-group: non-significant for SFA

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Urine tyrosol (μg/L): baseline vs. 1-yr

41,7 40,3

55,4

0

10

20

30

40

50

60

70

VOO (n=127) Nuts (n=115) Control (n=102)


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Plasma alpha-linolenic acid (%): baseline vs. 1-yr

61

4241

0

10

20

30

40

50

60

70

VOO (n=112) Nuts (n=101) Control (n=101)


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Intervention vs. control Significant between-group changes in food groups

VOO & nuts (+) Vegetables (+) Fruits (+) Legumes (+) 14-unit MeDiet score (+)

Significant between-group changes in nutrient intake Energy (+) Carbohydrates (-) Fiber (+) Total fat (+) MUFA, MUFA/SFA (+) PUFA (+) alpha-Linolenic acid (+) Marine n-3 fatty acids (+)

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PREDIMED TRIAL

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1224 participants 409 VOO 411 Nuts 404 Control

Changes in the prevalence of MetS ATP-III: 3 out of five

Waist TG HDL Glucose BP

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PREDIMED TRIAL

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Main trial

1234567...n

Nested substudies

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www.predimed.es

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Thank you very much

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de reserva

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Effects of Mediterranean diet on the primary prevention of cardiovascular disease

http://www.controlled-trials.com/ISRCTN35739639

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Dietary changes at 1-yr & 2-yr follow-up

Nutrient MD+VOO MD+nuts Control

Prot 1yr2 yr

-0.1-0.6*

-0.3*-0.5*

+0.1+0.3

CHO 1yr2 yr

-1.3*-1.4*

-2.1*-0.7*

+1.0*+2.5*

Fat 1yr2 yr

+1.8*+2,6*

+2.7*+1,5*

-1.0*-2,5*

SFA 1yr2 yr

-0.6*-0,6*

-0.7*-0,8*

-0.4*-1,0*

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Dietary changes at 1-yr & 2-yr follow-up

Nutrient MD+VOO MD+nuts Control

MUFA 1yr 2 yr

+2.1*+2.5*

+1.6*+1.8*

-0.3-1.0*

PUFA 1yr 2 yr

+0.2+0.7*

+1.8+0.7*

-0.3*-0.4*

Fibre 1yr2 yr

+2.2*+2.9*

+3.1*+3.3*

-0.5-0.5

MD 1yr14p 2 yr

+1.9*+2.4*

+2.3*+2.2*

+0.5*+0.8*

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Power (asumming RR = 0,75)

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

600 580 560 540 520 500 480 460 440 420 400 380 360 340 320 300Total # of events

(3 groups together)

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The data from the PREDIMED trial will be analyzed at 5 intervals (4 interim analyses and the final analysis).

The 4 interim analyses to decide on the continuation of the PREDIMED trial will be conducted after 2, 3, 4 and 5 years of median follow-up.

The 2-sided p-values for stopping the trial at each interim analysis are

Yr Benefit Harm

2 5*10-6 9*10-5

3 0.001 0.005

4 0.009 0.02

5 0.02 0.05

Apr 08

Jun 09

Jul 10

Jun 11

www.unav.es/preventiva the predimed trial

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