Mediterranean Diet and Survival Among Patients With Coronary Heart Disease in Greece FREE

The Mediterranean diet was first considered by Keys¹ as a diet low in saturated lipids that conveyed protection against coronary heart disease by lowering plasma cholesterol levels. Over the years, however, the emphasis shifted away from the low content of saturated lipids in this diet toward its high content of olive oil and, somewhat vaguely, toward its overall constellation of characteristics.^2- 6 Moreover, the study of the Mediterranean diet expanded beyond its effects on coronary heart disease to include possible effects on total mortality.^6- 9 Given the continuous nature of the pathobiological processes in coronary heart disease, the Mediterranean diet has been hypothesized to affect its clinical prognosis, as well as its incidence. Indeed, 2 major randomized controlled trials have provided evidence that versions of the Mediterranean diet can significantly reduce fatality among patients who had suffered myocardial infarction,¹⁰ or among patients who were diagnosed as having angina pectoris, myocardial infarction, or surrogate risk factors for coronary heart disease.¹¹ These 2 studies had the methodological strength of the randomized design, but both used designer diets with emphasis on α-linolenic acids and both included selected patients under intense clinical observation. We have been able to evaluate the effects of the traditional Mediterranean diet on survival among individuals previously diagnosed as having coronary heart disease who volunteered for participation in a large, general population–based cohort study in Greece.

Between 1994 and 1997, 28 572 volunteers, 20 to 86 years old, were recruited from all regions of Greece to participate in the Greek component of the European Prospective Investigation Into Cancer and Nutrition (EPIC). The EPIC is conducted in 23 research centers across10 European countries under the coordination of the International Agency for Research on Cancer. The aims of the EPIC are the elucidation of the role that biological, dietary, lifestyle, and environmental factors play in the etiology of chronic diseases.¹² Each country, however, has the right to undertake different, independent studies that do not focus on cancer. All procedures were in line with the Helsinki declaration for human rights, all volunteers signed informed consent forms, and the study protocol was approved by ethical committees at the International Agency for Research on Cancer and at the University of Athens Medical School.

The study was an observational epidemiologic investigation. Dietary intake during the year preceding enrollment was assessed with the use of a formally validated, interviewer-administered food frequency questionnaire that includes approximately 150 foods and beverages commonly consumed in Greece.^13- 14 Nutrient intakes were calculated with the use of a food composition database that has been modified to accommodate the particularities of the Greek diet.¹⁵ For the analysis, 15 all-inclusive food groups or nutrients were considered: vegetables, legumes, fruit and nuts, dairy products, cereals, meat and products, fish and seafood, olive oil, potatoes, eggs, sugar and confectionary, nonalcoholic beverages and juices, monounsaturated lipids (mainly olive oil), saturated lipids, and polyunsaturated lipids. There is no overlap among the 15 different food groups except with respect to type of lipids. For each participant, grams per day of intake of each of the indicated categories and total energy intake (in kilojoules per day) were calculated.¹⁶

The Mediterranean diet has been operationalized by Willett et al,⁵ and a scale indicating the degree of adherence to the traditional Greek variant of it was constructed by Trichopoulou et al⁶ and later revised to include fish intake.⁷ Values of 0 or 1 were assigned to each of 9 indicated components, using as cutoff the sex-specific median among the study participants who did not report at enrollment that they had been diagnosed as having coronary heart disease, diabetes mellitus, or any form of cancer (“healthy” individuals). Specifically, persons whose consumption of presumed beneficial components (vegetables, legumes, fruits, cereal, fish) was below the median consumption were assigned a value of 0, whereas for individuals with consumptions above the median, a value of 1 was given. In contrast, persons with below-the-median consumption of presumed detrimental components (meat and dairy products, which, until recently, were rarely nonfat or low-fat in Greece) were assigned a value of 1, whereas individuals whose consumption of these 2 components was above the corresponding median were given a value of 0. For ethanol, a value of 1 was given to men consuming quantities of ethanol from 10 g/d to less than 50 g/d, whereas for women the corresponding cutoffs were 5 and 25 g/d. These choices were dictated by the reported U-shaped association of alcohol intake with coronary mortality and the apparent higher susceptibility of women to alcohol intake.^17- 18 Finally, for lipid intake, the ratio of monounsaturated fats to saturated fats was constructed, in line with the customary ratio use, but with monounsaturated fats instead of polyunsaturated fats in the numerator because the former are used in much higher quantities in Greece. Thus, the total Mediterranean diet score can take a value from 0 (minimal adherence to the traditional Mediterranean diet) to 9 (maximal adherence to the traditional Mediterranean diet).

The frequency and duration of participation in occupational and leisure-time physical activities were recorded for each participant¹⁹ and a metabolic equivalent index was computed by assigning a multiple of resting metabolic rate²⁰ to each activity (MET value). Time spent on each of these activities was multiplied by the MET value of the activity, and all MET-hour products were summed to produce an estimate of daily physical activity, indicating the amount of energy per kilogram of body weight expended during an average day. Anthropometric measurements were made by trained study personnel, and demographic and lifestyle characteristics and medical data were recorded by standardized procedures. In particular, participants were asked whether they had been medically diagnosed as having diabetes mellitus, myocardial infarction (with or without angina pectoris), or angina pectoris (without myocardial infarction). All individuals were also asked whether they were taking drugs for hypertension and/or hypercholesterolemia. No attempt was made to classify individuals according to prevalence of metabolic syndrome at enrollment.

Greek EPIC participants were followed up by teams led by qualified physicians until December 31, 2003. Follow-up was active in all instances. From the initial 28 572 participants, 1384 reported, at enrollment, a previous diagnosis of coronary heart disease, with or without diabetes mellitus but no cancer. However, for 56 of the 1384 participants who lived in remote areas of Greece, vital status had not been ascertained as of this date. In addition, for 26 of the 1384 study participants, information was missing for 1 or more of the sociodemographic, medical, dietary, somatometric, lifestyle, or medication variables used in the present investigation. Thus, the remaining 1302 participants who reported at enrollment a previous diagnosis of coronary heart disease, with or without diabetes mellitus but no cancer, for whom vital status had been ascertained and for whom all the required information was available were considered in this study. Deaths were categorized as cardiac and noncardiac on the basis of information contained in death certificates, which were available in all instances.

All analyses were performed with STATA statistical software (Stata Corp, College Station, Tex).²¹ Descriptive statistical analysis was performed through cross-tabulations. Dietary variables, as well as energy intake, were presented as means and standard deviations. Survival data were modeled through proportional hazards (Cox) regression. Regarding power considerations, previous observational studies documenting an apparent effect of the Mediterranean diet on overall survival, and randomized trials documenting the effect of the Mediterranean diet on survival of patients with coronary heart disease, have generally relied on smaller study samples, so that our study was considered to be more powerful for documentation of an association of comparable strength between Mediterranean diet score and fatality.

Among the study participants with a diagnosis of coronary heart disease at enrollment, the association between the studied food groups or nutrients and mortality, as well as between the Mediterranean diet score and mortality (fatality), was assessed through proportional hazards models, always adjusting for sex and age (<45, 45-54, 55-64, or ≥65 years, categorically). In addition, adjustment was made for treatment of hypertension (yes or no), treatment of hypercholesterolemia(yes or no), diabetes mellitus at enrollment (yes or no), years of schooling (<6, 6-11, 12, or ≥13, categorically), smoking status (never or former, and 1-10, 11-20, 21-30, 31-40, or ≥41 cigarettes/d, ordered), waist-to-hip ratio (quintiles, ordered), MET score (quintiles, ordered), body mass index (quintiles, ordered), and total energy intake (quintiles, ordered). Eggs and potatoes are not part of the Mediterranean diet score, but in analyses that investigated the impact of Mediterranean diet score on mortality, they were controlled for as continuous variables to accommodate possible confounding by these nutritional variables.

Separate Cox analyses were performed for total mortality, mortality from cardiac death, and mortality from all other causes (apart from cardiac death), with the focal outcome events being death from any cause, cardiac death, and death from all causes except for cardiac death, respectively. In all survival analyses, subjects who were alive as of the date of last follow-up or who were lost to follow-up were considered censored. In an analysis of mortality from cardiac death, subjects who died of any other cause were considered censored as to the date of their death, and vice versa. The proportionality assumption was checked with the log-log plots. No time-dependent variables were included in the Cox models.

Survival status at the end of a median follow-up period of 3.78 years (range, 0.04 years [a study participant who died 14 days after enrollment] to 10.2 years) was ascertained for the 1302 study participants who, at enrollment, reported prevalent coronary heart disease. Of those, 492 (37.8%) reported that they had had a myocardial infarction with or without angina pectoris, whereas the remaining 810 (62.2%) reported that they had had medically diagnosed angina pectoris but no myocardial infarction. Table 1 shows the distribution of the 1302 study participants by sex and baseline sociodemographic, somatometric, lifestyle, and medical characteristics, as well as their mean Mediterranean diet score and its standard deviation. The distributions shown in this table integrate the risk profile of coronary heart disease and the prevalence of the indicated risk factors in the study population. Notable are the high prevalence of obesity among both men and women, and of ever smoking among men. This table also shows that the Mediterranean diet score varied considerably by age and several sociodemographic and lifestyle variables, making it necessary to adjust for them in multivariate analysis focusing on the association between Mediterranean diet score and mortality (fatality) among persons with prevalent coronary heart disease.

Table 2 shows the distribution of 1302 study participants with a diagnosis of coronary heart disease at enrollment, by sex and by single units of the Mediterranean diet score. Of these, 22.0% showed poor adherence to the Mediterranean diet (score of 0-2), 40.9% average adherence to this diet (score of 3 or 4), 29.3% better than average adherence to this diet (score of 5 or 6), and 7.9% very good adherence to the Mediterranean diet (score of 7-9).

Table 3 shows the mean daily intake and standard deviation of 12 food groups, as well as the mean daily intake of lipids by type and the mean total energy intake among the study participants with prevalent coronary heart disease at enrollment. Table 3 also shows mortality ratios per changes in the intakes of the indicated dietary variables approximately equal to 1 SD. The mortality ratios are not mutually adjusted but are adjusted for sex, age, previous treatment for hypertension or hypercholesterolemia, diabetes mellitus at enrollment, years of schooling, smoking status, waist-to-hip ratio, MET score, body mass index, and total energy intake. The hazard ratio associated with energy intake was adjusted for all these variables except for energy intake itself. Several associations in Table 3 are in expected directions, but only 3 of them are statistically significant: the one between mortality ratio and intake of dairy products (detrimental), the one between mortality ratio and the ratio of monounsaturated to saturated lipids (beneficial), and the one between mortality ratio and total energy intake (beneficial).

Table 4 shows adjusted mortality ratios associated with a 2-unit increment in the Mediterranean diet score, overall and among major subgroups. Increased adherence to the Mediterranean diet by 2 units was associated with a 27% lower mortality rate among persons with prevalent coronary heart disease at enrollment. Exclusion of deaths that occurred during the first 3 months of follow-up had little effect on the point estimate of the mortality ratio, which changed from 0.73 to 0.77 (95% confidence interval, 0.60-0.98). The reduced mortality was more evident and amounted to 31% when only cardiac deaths were considered as the relevant outcome. There are indications that the protective effect of the Mediterranean diet may be more evident among men, among older individuals, among current or past smokers, among those with a lower body mass index, among those with a higher waist-to-hip ratio, among the less educated, and among those with lower levels of physical activity, but in no instance were the respective interaction terms statistically significant (Table 4).

We evaluated whether there was an exposure response pattern in the apparent effect of the Mediterranean diet on mortality among participants with prevalent coronary heart disease by dividing study subjects into those with poor adherence to the Mediterranean diet (score of 0-2), average adherence (score of 3-4), better than average adherence (score of 5-6), and very good adherence (score of ≥7). Mortality ratios followed a smooth pattern. In comparison with those with poor adherence (referent), those with average adherence had a mortality ratio of 0.79 (95% confidence interval, 0.51-1.22); those with better than average adherence, a mortality ratio of 0.57 (95% confidence interval, 0.33-0.97); and those with very good adherence, a mortality ratio of 0.25 (95% confidence interval, 0.08-0.73).

In an analysis of a fairly large sample of individuals participating in a general population cohort study who, at enrollment, had already been diagnosed as having coronary heart disease but no cancer, we found that adherence to the traditional Mediterranean diet was significantly associated with a reduced mortality rate. Clearly, dietary intakes among participants with prevalent coronary heart disease are not representative of those in the Greek population because diet affects the incidence of this disease and individuals are known to change their diet after they are diagnosed with the disease. Nevertheless, among study participants with prevalent coronary heart disease, a 2-unit increment in the 10-unit Mediterranean diet score was associated with a 27% lower overall mortality and a 31% lower cardiac mortality. The association of the Mediterranean diet score with a reduced mortality rate was remarkable even though no striking associations were evident for the components of the score. The Mediterranean diet score may be more discriminatory than each of its components, because it captures the extremes of the nutritional exposures of interest (adherence to the Mediterranean diet), preempts nutritional confounding by incorporating possible confounders in the score, overcomes collinearity, and captures possible effect modification among the nutritional variables.^22- 24 It should be noted that the 9 criteria used to assess adherence to the Mediterranean diet are conceptually independent, and the almost normal distribution of individuals by Mediterranean diet score (Table 2) indicates that no individuals tended to cluster with respect to most of the 9 components. Creating a 9-dimensional exposure matrix by combining distributions of 9 distinct components, instead of the unidimensional one that we have used, might have generated a more informative complex exposure, but it would be difficult to analyze and interpret.

The beneficial effects of the Mediterranean diet in the prognosis of coronary heart disease have been demonstrated in 2 large, randomized secondary prevention trials.^10- 11 de Lorgeril and colleagues¹⁰ randomized 605 patients into 2 groups and, after a mean follow-up of 27 months, found a reduction of overall mortality by 70% and of cardiac mortality by 81% in the intervention group. They concluded that a Mediterranean diet rich in α-linolenic acid is more efficient in the secondary prevention of cardiac deaths than diets routinely recommended by hospital dietitians or attending physicians. Singh and colleagues¹¹ randomized 1000 patients with coronary artery disease into 2 groups, one receiving a diet rich in whole grains, fruits, vegetables, and nuts (Indo-Mediterranean diet) and the other receiving a diet similar to the step I National Cholesterol Education Program²⁵ prudent diet. After 2 years of follow-up, the intervention Indo-Mediterranean diet was associated with a 37% reduction in total mortality and a 49% reduction in cardiovascular mortality. In a recent randomized trial exploring the possible mechanisms of the effect of the Mediterranean diet, Esposito and colleagues²⁶ reported that this diet is likely to reduce endothelial dysfunction and markers of vascular inflammation. No observational study, to our knowledge, has previously addressed the role of the Mediterranean diet on survival of coronary patients. The results of our study do not challenge the findings of these randomized investigations, but they complement them by showing that α-linolenic acid may not be the central beneficial component in the Mediterranean diet and by indicating that the benefits of the Mediterranean diet also apply to people with coronary heart disease in the general population whose diets approach the Mediterranean optimal diet in variable ways chosen at will. This is an important point for the generalizability of the results concerning the role of the Mediterranean diet in the survival of patients with coronary heart disease. It should be noted that the apparent effectiveness of the Mediterranean diet was not lower in our data than in those of the 2 randomized studies, because our estimates are anchored to an increment of 2 units whereas the contrasted diets in the 2 trials are likely to differ by more than 2 units of the scale used in the present investigation. Indeed, at the extremes of the Mediterranean scores in our study, a mortality ratio of 0.25 was evident, as well as a smooth exposure-response curve.

Advantages of this population-based investigation are its fairly large sample size and minimal losses to follow-up, and its reliance on a naturally consumed diet assessed through a validated food frequency questionnaire. Disadvantages are the lack of medical documentation and timing of the self-reported coronary heart disease, as well as lack of information on laboratory data at follow-up. However, misclassification in diagnosis (possible inclusion in the study group of some participants without coronary heart disease, who have a lower death hazard and may pay less attention to their diet) is likely to have attenuated the observed difference, whereas controlling for laboratory variables may not have been wholly appropriate because of their likely intervening role in the pathway linking diet to coronary outcome. We do not have information on α-linolenic acid intake with increasing Mediterranean diet score, but the apparent, although not statistically significant, beneficial effect of vegetables and olive oil, both of which contain α-linolenic acid, indicate that this compound may play an important role in the beneficial effect of the Mediterranean diet on the prognosis of coronary heart disease. Finally, our observational study does not have the ability that randomized studies have to control for unidentified or poorly measured confounders but, instead, it provides data reflecting realistic and widely consumed diets (at least in Mediterranean countries) by free-living individuals in the general population.

In conclusion, we found evidence that the Mediterranean diet in the general population, a substantial fraction of whom have coronary heart disease,²⁷ appears to improve survival of patients with coronary heart disease to a degree comparable with that found in randomized studies that have used strict medical regimens designed to resemble the characteristics and properties of the Mediterranean diet.

Correspondence: Antonia Trichopoulou, MD, Department of Hygiene and Epidemiology, University of Athens Medical School, 75 Mikras Asias St, 115 27 Athens, Greece (antonia@nut.uoa.gr).

Accepted for Publication: December 11, 2004.

Financial Disclosure: None.

Funding/Support: The EPIC is coordinated by the International Agency for Research on Cancer, Lyon, France (part of the World Health Organization, Geneva, Switzerland), and supported by the Europe Against Cancer programme of the European Commission, Luxembourg, Luxembourg, Belgium. The Greek segment of the EPIC is also supported by the Greek Ministry of Health, Athens, and the Greek Ministry of Education, Athens, as well as by a fellowship honoring Vasilios Trichas and Nafsika Tricha, Athens.

Role of the Sponsors: None of the indicated funding sources was involved in any way in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, or approval of the manuscript. Dr Bamia was the chief biostatistician for the project.