FCEB Journal Club 14 th March 2013 Presented by: A/Prof Richard Woodman

1. Primary Prevention of CardiovascularDisease with a Mediterranean DietRamón Estruch, M.D., Ph.D., …and 18 othersfor PREDIMED study investigatorsPublished: NEJM 25th Feb 2013 at NEJM.org FCEB Journal Club 14th March 2013 Presented by: A/Prof Richard Woodman

2. Background • MED diet works well for CV risk in • Observational studies (meta-analyses) • Secondary prevention • Possible biological mechanisms for the benefits • MED diet characterised by: • Olive oil, nuts, fruit, vegetables, cereals • Fish and poultry, wine consumed with meals • Dairy products, red and processed meats, sweets

3. Participants • All residing in Spain • Age range • Men (55-80) • Women (60-80) • No CVD at enrolment • Diabetes or at least 2 other CVD risk factors; smoking, hypertension, high LDL, low HDL, overweight or obese, family Hx

4. PREDIMED trial • Parallel group multi-centre RCT • Supplemental foods were provided (OO, walnuts, almonds, hazelnuts) or small gifts! • No calorie restriction • No promotion of physical activity • 3 groups: • 30g mixed nuts per day • 1 litre/week olive oil • Low fat diet • Diet in Table 1 • 7447 ramdomised 1:1:1 beginning October 2003.

8. Diet training and adherence • MED groups: • 14-item dietary questionnaire at quarterly diet training sessions. • Control group: • Same questionnaire at baseline only • Leaflet explaining the low fat diet • October 2006 started quarterly group sessions with personal dietary advice with sessions same as MED groups and 9-item questionnaire. • Urinary hydroxytyrosol measured in OO group at 1,3,5 years in a random sample. • Plasma alpha-linolenic acid measured for nut compliance.

9. Outcomes • Primary • Combined rate of major CV events (MI, stroke, CV death). • Secondary • Event rate for stroke • Event rate for MI • Event rate for death from CV causes • Event rate for death from any cause

10. Statistics • Yearly interim analysis after median 2 years FU • O’Brien Fleming stopping values: • 5x10-6, 0.001, 0.009, 0.02 for benefit • 9x10-5, 0.005, 0.02, 0.05 for adverse effects • Cox PH models • ITT analysis • Sensitivity analysis for missing data

11. Results • Stopping boundary crossed on 4th yearly analysis on 22nd July 2011 • Median FU 4.5 years (IQR 2.5-5.8 years) • 7% lost to follow-up

18. Results 2 • 14-point MED scores increased by 1.4 to 1.8 points in the combined MED groups. • Differences in MED diet to controls for the 14 point items mostly not that large. • Mean change in WEEKLY meals for MED diets • fish servings: 0.3 servings! • legume servings: 0.4 servings! • By 50g and 32g/day Olive Oil for OO and Nut groups • By 0.9 and 6 servings/week of nuts for OO and Nut groups • Did not report changes in weight.

19. 14-point MED diet score

22. Their discussion • Olive oil and nut diets reduced CV events by approximately 3 events per 1000 py • Findings are consistent with smaller trials, effects on CV risk factors (traditional and novel) • Results are plausible and may explain lower CV mortality in Mediterranean countries. • Results are better than the Women’s Health Initiative trial (low fat diet) • Individual components or synergistic effect? • Generalizability of the findings – Spanish population at high CV risk • Underpowered – too few events for stroke and MI • Most of the diet changes were the supplements – plus more fish and legumes • Baseline diets were close to Mediterranean already

23. Other discussion points Should they have stopped the trial early? Was the absolute risk reduction clinically significant? Saved strokes? Saved MI’s Saved deaths? Effects more pronounced in those overweight or obese, hypertensive and with dyslipidaemia. Was there a weight reduction? Reduced strokes Very early reduction in strokes Mechanism Adherence - olive oil versus nuts

24. Pocock SJ. Clinical Trials 2006; 3:513-521.

25. Pocock SJ. Clinical Trials 2006; 3:513-521.