Risk of first non-fatal myocardial infarction negatively associated with olive oil consumption: a case-control study in Spain

Abstract

Background Olive oil is the main source of dietary lipids in most Mediterranean countries where mortality and incidence rates for coronary heart disease (CHD) are the lowest in Europe. Although international comparisons and mechanistic reasons support the hypothesis that a high olive oil intake may prevent CHD, limited data from studies of individuals are available.

Methods A hospital-based case-control study was conducted in Pamplona (Spain) recruiting 171 patients (81% males, age <80 years) who suffered their first acute myocardial infarction and 171 age-, gender- and hospital-matched controls (admitted to minor surgery, trauma or urology wards). A validated semi-quantitative food frequency questionnaire (136 items) was used to appraise previous long-term dietary exposures. The same physician conducted the face-to-face interview for each case patient and his/her matched control. Conditional logistic regression modelling was used to take into account potential dietary and non-dietary confounders.

Results The exposure to the upper quintile of energy-adjusted olive oil (median intake: 54 g/day) was associated with a statistically significant 82% relative reduction in the risk of a first myocardial infarction (OR = 0.18; 95% CI : 0.06–0.63) after adjustment for dietary and non-dietary confounders.

Conclusions Our data suggest that olive oil may reduce the risk of coronary disease. These findings require confirmation in further observational studies and trials.

Diet, epidemiology, coronary disease, fatty acids

Dietary patterns found in olive-growing areas of the Mediterranean region have been postulated as protective against coronary heart disease (CHD).¹ Olive oil, rich in monounsaturated fatty acids (MUFA), is the main source of dietary lipids in most Mediterranean countries.

The very low CHD mortality rates found in Mediterranean countries, together with a wide array of mechanistic reasons, have led to the idea that instead of recommending a low-fat diet to prevent CHD, it would be worthwhile to give the population the message of augmenting the intake of olive oil, while avoiding animal and trans-fats.^2,3 A widespread recommendation promoting olive oil consumption to replace saturated and trans-unsaturated fat needs to be solidly based on epidemiological findings conducted in populations where consumption levels are high and heterogeneous.

Apart from international comparisons and ecological correlations, and the outstanding findings of the Seven Countries Study,⁴ there is little direct evidence from analytical epidemiological studies relating diet to CHD in Mediterranean countries. A small randomized trial of corn oil and olive oil carried out almost 40 years ago by GA Rose found no benefit for olive oil and even an adverse significant effect for corn oil in 80 coronary patients after 2 years of follow-up.⁵ A case-control study in Italian women (287 cases/649 controls) reported no significant benefit for oil consumption (odds ratio [OR] = 0.7 for the second tertile and 1.1 for the third).⁶ A case-control study in Greece did not find any significant protection from MUFA intake.⁷

The same group⁸ found that an a priori defined Mediterranean dietary pattern was associated with advantageous survival in a cohort of elderly people. Three other small studies have consistently reported similar results in Australia,⁹ Spain¹⁰ and Italy¹¹ using analogous methodologies. However, the outcome in all of these four studies included every cause of death and no information about the specific role of olive oil on CHD risk was reported.

A randomized secondary prevention trial conducted in France¹² showed an impressive protection provided by an experimental Mediterranean diet on the risk of death and re-infarction among survivors of a first acute myocardial infarction (AMI). Nevertheless, as the major element of the assigned diet was an experimental canola-oil based margarine and the diet simultaneously included a high intake of alpha-linolenic acid, fruit and vegetables, it was not possible to attribute its benefit to a single factor. In addition, the nutritional factors associated with primary and secondary prevention of CHD need not to be the same. The aim of our study was to assess the potential role of olive oil for the primary prevention of CHD and to quantify the reduction in the risk of a first AMI that can be provided by a high dietary olive oil intake.

Methods

Cases were defined as male or female subjects, aged under 80, survivors of a first AMI (ICD code 410) admitted to one of the three tertiary hospitals of Pamplona (Spain) within the periods October 1999–June 2000 or October 2000–February 2001. They had to fulfil the criteria¹³ for definite AMI of the MONICA project (two or more ECG showing specific changes; ECG showing probable changes plus abnormal cardiac enzymes; or typical symptoms plus abnormal enzymes). A previous history of angina pectoris, a previous diagnosis of CHD or other prior diagnosis of major cardiovascular disease were exclusion criteria. Informed consent was obtained from the patients and the project was approved by the Institutional Review Board of the Medical School. We identified 180 eligible cases. Nine of them refused to participate (participation = 95%).

A control subject of the same age (5-year bands), gender and hospital was matched to each case. Eligible controls were patients admitted to the surgical, trauma or urology wards of the same hospital during the same month that matched cases for diseases believed to be unrelated to diet. Eight eligible controls refused to participate (participation: 96%) and each of them was replaced by other patients of similar characteristics for matching variables.

Cases and controls were interviewed in a standard way with the same questionnaire. All interviews were conducted by four physicians belonging to the research team (EFJ, EML, MP, CB). The same physician who interviewed a case patient also interviewed the respective matched control. The physicians had to exclude cases with a previous history of angina or other cardiovascular symptoms. Therefore, they were not blinded to the participant's disease status. The physician approached the patients, invited them to participate and provided them with the self-administered questionnaire. It included a semi-quantitative food-frequency questionnaire (118 food items), previously validated in Spain,¹⁴ that was slightly expanded for this study (136 items plus vitamin supplements). For each food item, a commonly used portion size was specified, and participants were asked how often they had consumed that unit on average over the previous year. Emphasis was added to ensure that the answers were related to long-term dietary exposures and not to recent changes in diet. Nine options for frequency of consumption were possible. The type of fat used in frying was specifically assessed. A dietitian updated the nutrient data bank using the latest available information included in the food composition tables for Spain. Total energy-adjusted intakes were computed using the residuals method.¹⁵

The participants were asked to report their usual time spent practising the following activities: walking, jogging, running, athletics, cycling, swimming, racquet sports, soccer, team-sports other than soccer, dancing, aerobics, hill-walking, climbing, gardening, skiing, skating, fishing, martial arts, and watersports. To quantify the volume and intensity of leisure-time physical activity, we computed an activity metabolic equivalent (MET) index by assigning a multiple of resting metabolic rate (MET score) to each activity. It was multiplied by the weekly time spent in each activity obtaining a value of overall weekly MET-hours.¹⁶ This measurement represents both the amount and relative intensity of physical exercise during a week for each participant. Five cases did not personally answer the questionnaire, and we used the answers given by a relative. We used the same procedure for matched controls.

The physician clarified any questions the patient may have had in completing the questionnaire, and subsequently the physician conducted a face-to-face interview about his or her coronary risk factors (smoking, diabetes, high blood pressure, high blood cholesterol, recent weight changes) and family history of cardiovascular disease. The physician took systolic and fifth-phase diastolic blood pressure readings and measured weight and height according to a standardized protocol, with the subject barefoot and dressed in light clothing. For each participant we calculated the body mass index (BMI) as the weight in kilograms divided by the squared height in metres (kg/m²).

Most cases (166/171) were interviewed in the cardiology ward once they had been discharged from the coronary unit. Two of them were interviewed at their homes after being discharged from the hospital. All control subjects were interviewed in hospital wards, except one who was interviewed at home.

The association of olive oil consumption with myocardial infarction was calculated through conditional logistic regression using matched data of 171 case-control pairs. Quintiles of olive oil intake defined according to the distribution among controls were compared regarding several potential confounding variables. First, we fitted models using crude olive oil intake (unadjusted for total energy intake) as the independent variable. Then we used energy-adjusted values of olive oil.¹⁵ Potential confounders were introduced in two steps in both multivariable models. First, we introduced non-dietary confounders. In a second model we also added the dietary confounders. Quadratic terms for some confounders, including ethanol, were used to account for non-linear relationships. We selected confounders by taking into account previous published literature about coronary risk factors and avoided the reliance on P-values or stepwise approaches. Tests for trend were done using the median of each quintile as a continuous variable. Reported P-values are two-tailed; values <0.05 were considered significant.

Results

The average daily intake of olive oil was 22.8 g (SD: 19.9) in women and 25.3 g (SD: 18.0) in men. The total energy-adjusted mean was 24.9 for both genders. Thus, the slightly higher absolute intake among men was explained by their higher energy intake.

The distribution of socio-demographic variables was similar in cases and controls (Table 1). Nevertheless, a slightly higher proportion of cases than controls had a university degree, whereas a higher proportion of controls than cases were working in qualified non-manual jobs (i.e. ‘white collar‘). As expected, cases were more likely to be current smokers, have a higher BMI, prior history of hypertension, diabetes or high blood cholesterol. Also as expected, leisure-time physical activity was higher among controls. Most case-control differences in the crude mean intake of nutrients were not statistically significant, and in general, they were small.

The cut-off points for the quintiles of energy-adjusted olive oil intake were 10.4, 17.6, 21.2 and 37.9 g/day in the whole sample and 11.4, 18.2, 24.6 and 40.7 g/day among controls. The mean paired difference in the intake of energy-adjusted olive oil between cases and controls was –1.4 g/day (higher intake among controls).

Table 2 shows the distribution of potential confounding variables across quintiles of energy-adjusted olive oil intake among control subjects. A higher proportion of married subjects, of those with prior history of diabetes and of current smokers was found among those with a higher energy-adjusted olive oil intake. A higher mean ethanol intake was also associated with a higher olive oil intake. The intake of some nutrients previously reported to be inversely associated with CHD, such as total dietary fibre,¹⁷ folic acid,¹⁸ vitamin B6,¹⁸ and vitamin C,¹⁹ was significantly lower among those controls with greater energy-adjusted olive oil consumption. A lower glycaemic load²⁰ was found in the highest quintile of olive oil consumption, but the trend was not statistically significant.

When we used the quintiles of olive oil intake without energy-adjustment as the exposure variable (Table 3), the point-estimates for the OR were lower than 1 in the three upper quintiles of olive oil intake. Exposure to the upper quintile of olive oil was associated with a relative risk reduction of 64% (OR = 0.36, 95% CI : 0.12–1.08) with respect to the first quintile (median intake: 7.2 g/day). The linear trend test was in the limit of statistical significance when we adjusted for smoking (four categories), BMI (continuous variable, adding a quadratic term to account for non-linearity), high blood pressure, high blood cholesterol, diabetes, leisure-time physical activity (METS-h/week, continuous variable, adding a quadratic term), marital status, occupation and educational level (four categories). Further adjustment for other nutrients (saturated fat, trans fat and total fibre intake as continuous variables) led to statistically significant results with OR = 0.26 (95% CI : 0.08–0.85) for the upper quintile and P = 0.02 for the linear trend test.

We also fitted conditional logistic regression models using energy-adjusted intake of olive oil as the exposure variable (Table 4). The risk reduction was then more apparent. We found point-estimates lower than 1 for the OR in the four upper quintiles of energy-adjusted olive oil intake and a significant linear trend test either when we adjusted only for non-dietary confounders (P = 0.03) or also for relevant nutrients (P = 0.03). The relative reduction in the risk of a first myocardial infarction was greater than 75% for the upper quintile, OR = 0.22 (95% CI : 0.07–0.67) after adjusting for non-dietary confounders and OR = 0.18 (95% CI : 0.05–0.63) after adjustment for dietary and non-dietary confounders.

When we excluded diabetic subjects (28 cases and 13 controls) and fitted a multivariate unconditional logistic regression model (adjusting for age and gender in addition to the variables shown in the first footnote of Table 4) the odds ratio for the upper quintile of energy-adjusted olive oil intake was 0.45 (95% CI : 0.23–1.00, P < 0.05). When we excluded case and control subjects with previous history of high blood cholesterol (total cholesterol >240 mg/dl, 21 cases and 15 controls), the adjusted OR for the highest quintile of energy-adjusted olive oil intake was 0.12 (95% CI : 0.03–0.54).

Discussion

To our knowledge this is the first analytical epidemiological study finding direct evidence supporting an important protective effect of olive oil against a first AMI. The protective role for olive oil is firmly consistent with many international comparisons of CHD mortality and incidence rates. Very low rates of CHD have usually been found in countries where olive oil consumption is higher.²¹ Our results can be also explained according to several plausible biological mechanisms. In comparison with saturated fatty acids, olive oil reduces low-density lipoprotein (LDL) cholesterol,²² and compared with carbohydrates, it maintains or even increases the levels of high-density lipoprotein (HDL) cholesterol.²³ In addition, it is relatively resistant to oxidation and contains a large amount of antioxidants relative to its polyunsaturated fat content.²⁴ Some polyphenol constituents of olive oil (hydroxytirosol and oleuropein) are potent scavengers of superoxide radicals²⁵ and inhibit LDL oxidation.²⁶ Olive oil has induced a regression of atherosclerosis in animal models²⁷ and may slow the development of coronary atherosclerosis, being associated with a reduced DNA synthesis in human coronary smooth muscle cells.²⁸ A recent trial showed that olive oil significantly improved endothelial function in hypercholesterolaemic men.²⁹

Olive oil also favourably affects postprandial factor VII activity, avoiding a prolonged thrombotic response to a high-fat diet.^30,31 A beneficial effect of MUFA on the endothelium and von Willebrand factor,³² as well as other benefits of olive oil on the haemostatic system³³ have been recently suggested. In diabetic patients, olive oil improves the lipid profile³⁴ and glycaemic control.³⁵ The potential cardiovascular benefits purportedly attributed to olive oil in diabetics led us to include them as eligible either as cases or controls in our study.

A randomized trial showed that olive oil markedly lowered blood pressure and reduced daily antihypertensive dosage requirement among hypertensive subjects.³⁶ Therefore, many roads may lead from olive oil intake to a lower risk of a first AMI, increasing the likelihood of a causal association.

In addition to the contrast of our results with the negative findings reported from previous studies,^5–7 some other inconsistencies must also be acknowledged. For example, the decreasing CHD mortality and the decreasing average per capita consumption of olive oil in Spain (and other Mediterranean countries) during the last three decades show secular trends that are in sharp contrast with the protective hypothesis for olive oil that our data support.³⁷ However, mortality data depend not only on incidence rates, but also on medical care of CHD patients, which is very likely to have improved during these decades in Spain and other Mediterranean countries.

Several limitations of our study which might be alternative explanations to our findings must be acknowledged. Our sample size was not very large. At the design stage, the study size was calculated assuming an alpha error = 0.05, and 80% power to detect OR ≥2.0 with a 20% probability of exposure among controls and that the exposure correlation between case and control subjects would be less than 0.45.³⁸ If this correlation were 0.3 (as was the actual case in our study), the power would be 90%. Subsequently, we have used the comparison among extreme quintiles, thus reducing the statistical power. We chose to focus on this comparison between extreme quintiles because it is very unlikely that it would lead to misclassification due to measurement error.³⁹ Although the magnitude of the relative effect was large (relative risk reduction >75%), we were approaching the limits of statistical significance. However, after adjustment for total energy intake and several known confounders, the inverse association with olive oil intake was still apparent.

Our design is susceptible to being affected by recall bias. However, recall bias is more likely to happen when differential over-reporting exists in cases, because they may be more aware of the greater risk associated with publicly known determinants of disease. This is unlikely to occur when assessing the intake of protective factors (olive oil in our study). Moreover, when the assessment of exposure is done via different items in a comprehensive questionnaire, such as in this case, it would be more difficult for a patient to consistently underestimate his/her exposure to olive oil. Although the in-hospital selection of controls facilitates higher participation, it also imposes some caution in the interpretation of findings because the exposure may be related to the diseases causing the hospital admission of controls. Olive oil has not been found to induce any trauma or genitourinary disease or any common disease needing minor surgery. Thus, it is very unlikely that our findings could be alternatively explained by selection bias due to an association between olive oil exposure and a higher probability of being admitted to a hospital with these diagnoses.

Although the mean of energy expenditure was slightly higher among controls than cases, we found no statistically significant association of energy expenditure (METS-hours/weeks) with the risk of myocardial infarction (P = 0.21 for the linear trend test). In previous epidemiological studies a higher caloric intake was usually protective. One of the most consistent findings of prospective studies about diet and CHD is a strong inverse association between total energy intake and CHD.⁴⁰ However, as some of our control patients were bedridden and had limited physical activity, it is not surprising that we missed this association.

An inherent limitation of a case-control design is that some fatal cases may be lost for the case series if they are fatal early on. Thus, the observed results would be compatible with olive oil having no effect on risk of myocardial infarction but an effect on chance of survival. However, this potential bias would require impossible assumptions to explain our results. For example, an incredibly high adverse effect of olive oil on survival, in the range of an early mortality OR >100 (fifth versus first quintile) would be needed to explain the OR found for the fifth quintile. Therefore, the alternative explanation that the observed inverse association with non-fatal infarction was due to poorer survival caused by olive oil seems extremely unlikely.

The possibility that people with first myocardial infarction may have been aware of early symptoms and have made more recent changes to their diet was explicitly addressed in the design stage. To avoid it, we made the decision to exclude cases with previous symptoms (angina or other cardiovascular manifestations) and used physicians as interviewers to carefully screen case patients and exclude those with any previous symptom predating the infarction. We also interviewed patients as soon as possible after the acute event to prevent this bias. Moreover, this bias would tend to diminish the association if people with myocardial infarction had recently increased their consumption of olive oil. The precautions we took to prevent this bias might help to explain the divergence of our results with two previous case-control studies conducted in Mediterranean countries which found no association for MUFA intake⁵ or for oils consumption.⁷

Another potential concern is represented by the fact that the physicians who carried out the interviews were not blind to the case-control status of the patient. However, this fact is very unlikely to have caused a serious bias in our estimates of the effect of olive oil consumption on AMI risk because the food-frequency questionnaire was self-administered. The interviewing physician did not ask any questions of the patient regarding the consumption of olive oil, but simply provided him/her with the self-administered questionnaire, and the patient completed the questionnaire by himself/herself.

Food-frequency questionnaires have become the primary method for measuring dietary intake in epidemiological studies.⁴¹ Although the food-frequency questionnaire used in this study was specifically validated in Spain against dietary records,¹⁴ and dietary records are likely to have the least correlated errors,³⁹ we acknowledge that this instrument might have misclassified participants at some level regarding their olive oil consumption. Because olive oil is widely used in cooking and on foods, it may be difficult to quantify accurately. A trained dietitian (CF) with special expertise in nutritional epidemiology reviewed the major available sources of information about oil use in Spain in order to make the calculations and derive the total intake of olive oil from the answers to the food-frequency questionnaires. However, measurement error always exists in nutritional epidemiology and it usually introduces non-differential exposure misclassification.⁴² It is commonly believed that non-differential misclassification of a exposure predictably biases the OR towards the null value. Nevertheless, sometimes, when the exposure has more than two categories, this bias can be away from the null value.⁴³ This possibility might result in an alternative explanation to our results, but would be unusual. Moreover, it has been shown that measurement error is very unlike to misclassify individuals from one extreme quintile into the other extreme³⁹ because much of the measurement error probably concentrates in the middle categories.⁴² The strongest association we found was precisely for the comparison between extreme quintiles.

KEY MESSAGES

• A wide variety of physiological reasons support that olive oil may exert a beneficial effect on the risk of coronary disease.

• International comparisons, with the pioneering results of the Seven Countries Study, also support this hypothesis.

• In this hospital-based matched case-control study, conducted in Navarre (Spain), the relative risk reduction for myocardial infarction was greater than 75% for participants in the highest quintile of olive oil consumption (median = 54 g/day) versus the first quintile (median = 7 g/day), after multivariate adjustment for a wide array of dietary and non-dietary confounders.

• Some inconsistencies remain: previous case-control studies in Italy and Greece did not find any association, and a small randomized trial on coronary patients conducted by Rose almost 40 years ago was also negative for olive oil, and even harmful for corn oil.

• There is a need for large, prospective cohort studies conducted in Mediterranean countries where high and heterogeneous consumption of olive oil exists.

The degree of between-subject variability in the intake of a particular nutrient or food item in the population under study is a strong determinant of the ability of a study to detect an association between that nutrient and CHD. A higher level of consumption of a food item is usually associated with higher between-subject variability. This has been the case in our findings with a wide contrast of consumption between extreme quintiles (medians = 7 versus 54 g/day). Therefore, the very high levels and the heterogeneity of olive oil consumption found in Spain are advantages of our study and may explain why we have found such a strong association. However, because of the inconsistency with previous studies (and the inherent limitations of our design), further epidemiological studies, preferably following a cohort instead of a case-control design, and also trials are needed in Mediterranean countries to confirm our findings.

Table 1

Characteristics of case and control participants

	Cases (n= 171)	Controls (n = 171)	Pa
aMeans were compared using t-tests. Proportions were compared using χ2 tests (or a linear trend test for educational level).
bAge and gender were matching variables.
cMetabolic equivalents.
dMonounsaturated fatty acids/saturated fatty acids.
Age (years, mean)	61.7	61.4	b
Gender (% men)	81	81	b
Educational level (%)			0.37
<Primary	28	29
Primary	44	45
Secondary	12	16
University	16	10
Occupational level (%)			0.63
White collar	21	25
Blue collar	18	16
Retired	44	46
Housewife	12	10
Other	5	3
Marital status (% married)	79	76	0.52
Smoking (%)			0.001
Never	32	44
Currently	40	23
Ex-smoker (<3 years)	12	6
Ex-smoker (≥3 years)	17	26
Body mass index (kg/m2, mean)	27.7	27.3	0.37
History of hypertension (%)	42	30	0.02
History of diabetes (%)	16	8	0.01
High blood cholesterol in last 5 years (%)	19	11	0.04
Leisure-time physical activity(METSc-h/week, mean)	31.5	34.5	0.32
Total energy intake (kcal/day, mean)	2631	2578	0.55
% energy from fat (mean)	31.2	31.3	0.90
MUFA/SFAdintake (mean)	1.51	1.54	0.51
% energy from trans-fatty acids (mean)	0.17	0.19	0.97
Total ethanol intake (g/day, mean)	19.0	18.2	0.75
Glycaemic load (g/day, mean)	233	225	0.42
Vitamin B6 intake (mg/day, mean)	2.8	2.8	0.93
Vitamin C intake (mg/day, mean)	268	257	0.53
Vitamin E intake (mg/day, mean)	8.0	7.7	0.54
Folic acid intake (microg/day, mean)	419	428	0.67

Table 2

Distribution of potential confounding variables across quintiles of energy-adjusted olive oil intake among control subjects (n = 171)

	Quintiles of energy-adjusted olive oil intake
	1	2–4	5	P for trend
aMetabolic equivalents.
bMonounsaturated fatty acids/saturated fatty acids.
Energy-adjusted olive oil (g/day, mean)	6.3	22.5	54.1	–
% white collar	18	28	24	0.91
% educational level higher than primary	18	30	21	0.75
% married	56	80	85	0.03
% smokers	18	21	35	0.06
% high blood cholesterol	15	12	6	0.24
% high blood pressure	29	33	21	0.25
% diabetes	6	5	18	0.02
Body mass index (kg/m2, mean)	26.8	27.3	27.8	0.30
Ethanol intake (g/day, mean)	16.0	16.1	27.2	0.02
Leisure-time physical activity (METSa-h/week, mean)	30.5	36.3	33.8	0.90
Total energy intake (kcal/day, mean)	2882	2417	2778	0.49
% energy from fat (mean)	28.7	30.6	35.8	<0.001
% energy from saturated fat (mean)	10.8	10.3	10.3	0.58
% energy from monounsaturated fat (mean)	12.4	15.1	20.4	<0.001
MUFA/SFAb intake (mean)	1.18	1.50	2.02	<0.001
% energy from trans-fatty acids (mean)	0.23	0.19	0.14	0.11
Glycaemic load (g/day, mean)	235	231	207	0.34
Total fibre intake (g/day, mean)	37.6	30.2	29.0	0.04
Folic acid intake (microg/day, mean)	513	409	395	0.03
Vitamin B6 intake (mg/day, mean)	3.3	2.6	2.5	0.02
Vitamin C intake (mg/day, mean)	320	262	233	0.06
Vitamin E intake (mg/day, mean)	8.7	7.4	7.5	0.54

Table 3

Odds ratios (OR) (95% CI) of a first myocardial infarction according to olive oil intake (unadjusted for total energy intake)

Quintile	Controls/cases (n)	Median intake (g/day)	Multivariate adjusted ORa (95% CI)	Multivariate adjusted ORb (95% CI)
aConditional logistic regression (age-, hospital- and gender-matched pairs), adjusted for smoking, body mass index, high blood pressure, high blood cholesterol, diabetes, leisure-time physical activity (METS-hours/week), marital status, occupation and study level.
bAdditionally adjusted for saturated fat, trans fat and total fibre intake.
1	32/36	7.2	1 (ref.)	1 (ref.)
2	35/37	12.0	1.17 (0.46–3.02)	1.16 (0.46–2.95)
3	36/30	25.0	0.69 (0.28–1.67)	0.60 (0.24–1.49)
4	31/39	29.3	0.91 (0.38–2.18)	0.83 (0.34–2.01)
5	37/29	54.3	0.36 (0.12–1.08)	0.26 (0.08–0.85)
Trend test P-value			0.05	0.02

Table 4

Odds ratios (OR) (95% CI) of a first myocardial infarction according to energy-adjusted olive oil intake

Quintile	Controls/cases (n)	Median intake (g/day)	Multivariate adjusted ORa (95% CI)	Multivariate adjusted ORb (95% CI)
aConditional logistic regression (age-, hospital- and gender-matched pairs), adjusted for smoking, body mass index, high blood pressure, high blood cholesterol, diabetes, leisure-time physical activity (METS-hours/week), marital status, occupation and study level.
bAdditionally adjusted for % energy derived from saturated fat, % energy derived from trans fat, total fibre consumption, folic acid intake, vitamin C intake, glycaemic load and ethanol intake (adding a quadratic term to account for non-linearity).
1	28/40	6.1	1 (ref.)	1 (ref.)
2	38/31	13.6	0.39 (0.15–1.00)	0.45 (0.16–1.25)
3	38/30	21.0	0.40 (0.17–0.93)	0.44 (0.18–1.07)
4	29/40	30.9	0.59 (0.23–1.52)	0.70 (0.24–2.02)
5	38/30	52.2	0.22 (0.07–0.67)	0.18 (0.05–0.63)
Trend testP-value			0.03	0.03

Partially funded by the Department of Health (Navarre Regional Government Project 24/99) and by another grant from Banco Santander-Central-Hispano. We are specially indebted to Ms Carmen de la Fuente, our dietitian, who updated the food composition data-bank according to current Spanish food composition tables and worked in the calculation of nutrients taken into account as potential confounders in our analyses. We thank the following persons for technical assistance and support: Prof. Jokin De Irala-Estévez, Prof. J Alfredo Martínez, Dr Isabel Coma MD, Ms Almudena Sánchez-Villegas, Ms Jane Hoashi and Ms Estefanía Ruiz-Gaona. We thank the Cardiology Chairmen of the three hospitals that participated in this study: Hospital de Navarra (Dr Enrique de los Arcos, MD), Hospital Virgen del Camino (Dr Eugenio Torrano, MD), and University Clinic of Navarre (Dr Joaquín Barba, MD).