In this large randomized controlled trial, participants in all three groups showed improvement in their BP levels, and, consequently, the percentage of participants with controlled BP also increased in all three groups. However, a greater reduction in diastolic BP was obtained with the MD interventions than with control intervention (advice to follow a low-fat diet). This could partly explain the recently reported benefit of the MD intervention on clinical disease end-points , especially the reduction in incidence of stroke, a cardiovascular event clearly related to high BP. However, other mechanisms apart from BP also need to be taken into account .
BP tends to increase with age. Thus, had our participants not experienced any intervention, they would be expected to show an increase in their BP levels during the follow-up period ; however, they actually had a decrease in their BP levels during the intervention. It could be argued that participants in clinical trials undergo more evaluations, and thus their doctors are more likely to prescribe a better adjustment of their anti-hypertensive medication. However, it should be noted that the intervention was based only on dietary changes, and no adjustments in the participants’ regular prescriptions were part of the intervention. In addition, participants in the PREDIMED trial were recruited from their primary healthcare centers, therefore, they were already attending medical consultations regularly prior to study entry. In fact, the number of outpatient contacts in 2004 in Spain was higher than the average in the European Union . In addition, our participants were already under medical treatment for their cardiovascular risk factors.
Current guidelines for the prevention and treatment of high BP recommend adhering to the DASH diet , which is a healthy eating plan low in saturated fat, cholesterol, and in total fat. This diet emphasizes the consumption of fruits, vegetables, and fat-free or low-fat milk and dairy products . The basic recommendations provided to our participants in the control group had many aspects in common with the DASH eating plan, and was not similar to a conventional placebo. Therefore, it was foreseeable that participants in the control group would also improve their BP levels if they followed this advice. In fact, a cohort study with healthy young participants also conducted in Spain previously reported an inverse association between adherence to the DASH diet and incident hypertension . Thus, had we had a ‘true’ control group (for example, with a typical Western dietary pattern, or with no intervention at all) the between-group differences both in stroke and BP would have been greater. Regarding the intervention groups, the traditional MD is also rich in fruits and vegetables, has low content of saturated fat and dietary cholesterol, and is rich in magnesium and potassium , thus, in spite of its high total fat content, the MD could enhance BP control. Even though greater adherence to the MD has shown no association with incident hypertension in some large cohorts , a meta-analysis of trials with the MD on the components of metabolic syndrome found beneficial effects on average systolic and diastolic BP levels . Similarly, we found a significant decrease in systolic and diastolic BP in both MD groups. Even though the intervention did not target sodium intake, participants in the PREDIMED trial on the whole did experience a significant reduction in their average sodium intake, as measured by the semi-quantitative food-frequency questionnaire. In addition, we found between-group significant differences (P<0.001) in sodium reductions favoring the two MD groups. Specifically, participants in both intervention (MD) groups experienced greater sodium reductions than did participants in the control group. However, these differences are unlikely to explain the observed results, as 1-year changes in sodium intake were not significantly associated with 1-year changes in BP after adjustment for major confounders, including the allocation group (data not shown). In addition, changes in potassium or calcium were also significantly associated with changes in BP in the multivariate analyses (data not shown). When we compared the two intervention groups with the control group, we found a significantly larger decrease in diastolic BP in both MD groups than in the control (low-fat) group. These results suggest that the MD may have a greater effect on diastolic BP control than a low-fat diet. Even though the between-group differences may seem small, it has been estimated that small differences in BP may have a large influence on cardiovascular and total mortality . This influence needs to be considered within the context of the population strategy for preventive medicine . Considering the strong association between diastolic BP and vascular mortality , these results have important clinical relevance but need to be taken in consideration when explaining the mechanisms of CVD risk reduction of the MD.
Our results may not seem in perfect agreement with our previously published results in a small subsample of PREDIMED participants (our pilot study) after only a 3-month follow-up. Greater reductions in systolic and diastolic BP were then seen in both MD groups compared with the control group . There may be several explanations for these differences. First, only the first participants recruited for the trial were included in the pilot study. Second, the current work is based on a longer follow-up than the pilot study, therefore, a different and longer induction period is assumed. Third, in 2006 the protocol was reviewed; prior to 2006, no active nutritional education was given to the control group to foster their adherence to the low-fat diet, and they received only an information brochure. After the protocol review, an educational intervention was also devised and implemented for participants in the control group to promote the adherence to a low-fat diet with similar methodology to that of the two MD groups. Fourth, a higher rate of loss to follow-up occurred in the control group than in the two MD groups. It is possible that the participants retained in the control group had a healthier profile, as suggested by their baseline information ; this would selectively bias the results in the control group towards better BP levels had all participants in this group been followed up.
The present study has several limitations. First, changes in BP were a secondary end-point, not the primary end-point of the PREDIMED trial. Nevertheless, changes in BP were included in the protocol as a secondary specific aim from the very beginning of the trial design. Second, at baseline, a initial fair level of adherence to the MD was present in all participants, regardless of their allocated group, and participants in the control group also maintained their relatively high scores of adherence to the traditional MD during the study . Therefore, the magnitude of attained between-group differences in adherence to the MD during follow-up was not large. These modest differences can be explained because for most participants their baseline diet was similar to the trial Mediterranean diet. In addition, even though participants in the control group received advice to reduce fat intake, changes in total fat were small, and the largest differences at the end of the trial were in the distribution of fat subtypes. The good quality of the diet in the control group may have impaired our ability to find large between-group differences in BP changes. Notwithstanding, a significantly better adherence to the prescribed diet was found in the two MD groups than in the control group, and after the first follow-up year, mean scores of adherence to the prescribed diet were significantly higher in the two MD groups than in the control diet group (P<0.001 for all yearly comparisons from years 1 to 4 of follow-up). After 3 years of follow-up we found significantly better scores in both MD groups than in the control group for 12 of the 14 items included in the MD adherence screening questionnaire. Therefore, a modest change in many aspects of the overall dietary pattern, and not only in the provided supplemental foods, was achieved with our intervention. Third, information on BP during follow-up was not available for a subset of participants, especially in the control group. As has been already published, participants for whom this information was not available during follow-up had a worse cardiovascular profile at study inception than participants who were retained, suggesting a bias toward a benefit in the control group . Fourth, our participants lived in a Mediterranean country, had a high cardiovascular risk, and were mainly hypertensive subjects; all these characteristics may limit the generalizability of our findings. Fifth, information on anti-hypertensive drugs dosage was not available, and this precluded a detailed analysis on anti-hypertensive drug usage. However, because all participants usually attend consultations with their primary healthcare providers, it is unlikely that participants in one or the other group would be differentially treated.
The strengths of the study include the randomized design, the long duration of the intervention, the high compliance of the participants allocated to the MD with the intended intervention, the large study size, and the uniformity of study implementation across the different study sites.