The Impact of Educational Status on 10-Year (2004-2014) Cardiovascular Disease Prognosis and All-cause Mortality Among Acute Coronary Syndrome Patients in the Greek Acute Coronary Syndrome (GREECS) Longitudinal Study

Sampling Procedure and 10-Year Follow-up

From October 2003 to September 2004, almost all consecutive patients (n = 2172) with a discharge diagnosis of ACS (i.e., acute myocardial infarction [AMI] or unstable angina) who had been hospitalized in the cardiology clinics or the emergency units of six major general hospitals in Greece (Hippokration Hospital in Athens and the general prefectural hospitals in Lamia, Karditsa, Halkida, Kalamata, and the island of Zakynthos) were enrolled in the study, with participation rates ranging from 80% to 95%. Of the enrolled patients, 1649 (76%) were males (mean age, 65±13 years) and 523 (24%) were females (mean age, 62±11 years). With the exception of Athens, where there are several other hospitals, all the other hospitals cover the entire populations of the relevant regions, including urban and rural areas. The hospitals were selected in order to represent populations with diverse socioeconomic, cultural and regional characteristics. In 2014, a 10-year follow-up (2004 -2014) of the patients was performed through face-to-face interviews by the investigators. Of the initially enrolled participants, 1918 participated in the follow-up (participation rate, 88%). The remaining 254 patients (11.7%) who were lost to the 10-year follow-up were considered to be censored.

Baseline Diagnosis of Acute Coronary Syndrome and Measurements

At the time of admission, as well as during the course of hospitalization (at 6 to 9 hours, and again at 12 to 24 hours if earlier samples were negative but the clinical index of suspicion was high) biomarkers suggesting cardiac injury and AMI were measured in each patient, including troponin I, creatine phosphokinase (CK), and the MB fraction of total CK (CK-MB). Moreover, a 12-lead electrocardiogram (ECG) was performed and clinical symptoms were evaluated in all patients by a cardiologist involved in the study. AMI was defined by the typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis accompanied by at least one of the following: (1) ischemic symptoms, (2) development of pathologic S-T segment elevations on the ECG, (3) ECG changes indicative of ischemia (S-T segment elevation or depression) or (4) a coronary artery intervention (e.g., coronary angioplasty) [11]. Unstable angina was defined as the occurrence of one or more episodes of angina at rest within the preceding 48 hours, corresponding to class III of the Braunwald classification [12].

We evaluated the following sociodemographic and lifestyle characteristics: age, sex, physical activity, dietary and smoking habits, years of education, and financial status. In particular, educational status, which was the main exposure factor analyzed in the present work, was classified as low (<9 years of school), intermediate (9 to 14 years or technical/vocational school) and high (>14 years). These cut-off values were used because a cut-off of 9 years corresponds to the obligatory level of education, a cut-off of 14 years represents subjects who completed technical/vocational education, and subjects who completed >14 years entered college. Patients’ self-reported mean household annual income over the last three years was recorded. Their usual dietary intake over the year preceding enrollment was assessed by a semi-quantitative food frequency questionnaire, and level of adherence to the Mediterranean dietary pattern was calculated using the MedDietScore (range, 0 to 55) [13]. A modified version of the self-reported questionnaire provided by the American College of Sports Medicine was used to evaluate patients’ physical activity during the previous year [14]. Current smokers were defined as those who smoked at least one cigarette per day at the time of enrollment or had stopped smoking cigarettes during the previous 12 months. The medical history assessment included each patients’ history of hypertension, hypercholesterolemia, diabetes mellitus, and CVD, as well as the techniques used to manage these conditions. All patients were also asked about adherence to medication prescribed for hypertension, diabetes, dyslipidemia, nephropathy, and pre-existing CVD. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m²).

Further details about the procedures and measurements of the GREECS study may be found elsewhere [10].

Endpoints at 10-Year Follow-up

The endpoints studied in the 10-year follow-up of the study were: (1) all-cause mortality and (2) recurrent fatal or non-fatal ACS events. In particular, we recorded the occurrence of new AMIs, angina pectoris, other forms of ischemia (International Classification of Diseases, 9th edition [ICD-9] codes 410.0-414.9, 427.2, and 427.6), heart failure of different types, and chronic arrhythmias (ICD-9 codes 400.0-404.9, 427.0-427.5, and 427.9). Information regarding each patient’s baseline medical history and 10-year endpoints was retrieved through their medical records or hospital registries.

Statistical Analysis

Continuous variables are presented as mean values±standard deviation, while categorical variables are presented as absolute (n) and relative (%) frequencies. Associations between normally distributed continuous variables and education status were evaluated through analysis of variance, after controlling for equality of variances (homoscedasticity). Due to multiple comparisons, the Bonferroni rule was applied to correct for the inflation of type I errors. Associations between categorical variables were tested by the use of the chi-square test. Correlations between continuous variables were evaluated by the use of Pearson’s correlation coefficient for normally distributed variables and by the use of Spearman’s rho coefficient for ordinal or skewed variables. Associations between patients’ education status and 10-year outcomes were evaluated by the use of nested Cox proportional hazard models; the nested models were used to evaluate the potential moderating or mediating effects of various patient characteristics on the research hypothesis. The proportionality of the hazards was graphically tested by plotting the logarithm [−log(survival)] vs. the logarithm of elapsed time. Appropriate tests for goodness-of-fit (i.e., deviance and Pearson’s residuals) were applied. For the 254 censored cases, information was taken from their 1-year follow-ups. The results are presented as hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). The p-values <0.05 were considered to indicate statistical significance. All statistical calculations were performed using SPSS version 21.0 (IBM SPSS Inc., Athens, Greece).

Bioethics

The study was approved by the medical research ethics committee of the participating institutions and was carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association. Participants were informed about the aims and procedures of the study and provided written informed consent.

All-cause Mortality and 10-Year Acute Coronary Syndrome Events

The crude overall all-cause mortality was 32.4 per 100 population (n=703) (31.6% in males, 34.8% in females, p=0.17); 52.8% of deaths were due to AMI, 8.3% were due to stroke, 8.3% were due to other CVD events, 8.7% were due to cancer, and the remaining 21.9% were due to other causes. The incidence of fatal or non-fatal 10-year recurrent ACS events were 37.3 per 100 population (n=811) (38.8% in males and 32.9% in females, p=0.02). Moreover, the median survival time was 8.08 years for males and 7.78 years for females (p=0.07); thus, the all-cause mortality rate was 404 deaths per 10 000 population and the recurrent ACS events rate (fatal or non-fatal) was 466 per 10 000 population.

Distribution of Baseline Demographic, Lifestyle, and Clinical Characteristics By Educational Status

Patients in the low-education group were older than those in the intermediate-education and high-education groups, reported more years of active smoking, and were less likely to follow a healthy diet or to have a comfortable financial status (p<0.001 for all variables). In contrast, patients with higher educational levels were more likely to be physically active, had diets that were more similar to the traditional Mediterranean diet, and were less likely to have a history of hypertension or diabetes or a family history of CVD in comparison to patients with lower educational levels (p<0.001); however, they were more likely to be obese (p=0.05). Patients from the low-education group were less likely to have a history of hypercholesterolemia than patients from the high-education group (p<0.001). Furthermore, it was observed that patients in the low-education and intermediate-education groups were less likely to comply with their prescribed medication for various comorbidities in comparison with the high-education group (p<0.001) (Table 1).

Table 1.

Baseline demographic, lifestyle, and clinical characteristics of participants in the GREECS study by education status (n=2172)

All-cause Mortality By Education Level During the 10-Year (2004-2014) Follow-up of Acute Coronary Syndrome Patients

Univariate analysis showed that overall all-cause mortality was almost twofold higher in the low-education group than in the intermediate-education and high-education groups (p<0.001). This difference was lower among females than among males (p<0.001) (Table 2).

Table 2.

Results of the unadjusted analysis of 10-year recurrent ACS events (fatal or non-fatal) according to the education status of the GREECS study participants (n=2172)

Moreover, the median follow-up time for the low-education group was much lower than for the intermediate-education and high-education groups (7.4 vs. 8.8 and 8.9 years, respectively (data not presented in Table 2).

In order to account for the potential confounding of patient characteristics on associations between education status and all-cause mortality, multivariate analysis was applied. Intermediate and low education levels were positively associated with all-cause mortality after adjusting for various potential confounders (Table 3). In particular, ACS patients with a low level of education had a 53% higher risk for all-cause mortality during the follow-up period than those with a high educational level (Table 3, model 1). After adjusting for age; sex; BMI; smoking; a history of hypertension, hypercholesterolemia, or diabetes; a family history of CVD (in order to account for the overall burden of CVD risk); and physical activity status, the impact of educational level on all-cause mortality remained significant only among those in the intermediate-education group (Table 3, model 2). When the MedDietScore, which was used to measure the overall dietary habits of the patients (Table 3, model 3) and alcohol consumption, which has been suggested to be a confounder when studying relationships between socioeconomic status and health (Table 3, model 4), were added to model 2, the relationship between low levels of education and all-cause mortality remained significant (HR, 1.47; 95% CI, 1.00 to 2.17). Alcohol consumption was adjusted for separately from the MedDietScore to avoid co-linearity of these factors in the same model. The inclusion of financial status (Table 3, model 5) did not alter the above relationships, in particular the associations of high/low education status with all-cause mortality in ACS patients (HR, 1.31; 95% CI, 0.89 to 2.00). Finally, when adherence to medication was added to the final model, an aggravating effect of low and intermediate educational levels was observed (HR, 2.08; 95% CI, 1.14 to 3.84 and HR, 3.13; 95% CI, 2.12 to 4.54, respectively) (Table 3, model 6). In all models, only the intermediate-education group remained significantly associated with all-cause mortality.

Table 3.

Results from nested, multi-adjusted Cox proportional hazard models regarding associations between education status and all-cause mortality in ACS patients at10 years of follow-up among participants in the GREECS study (n=2172)

Recurrent Acute Coronary Syndrome Events By Education Level During the 10-Year (2004-2014) Follow-up of Acute Coronary Syndrome Patients

The risk for a short-term fatal or non-fatal ACS event (i.e., within 30 days after hospital discharge) was substantially higher among the high-education group than in the intermediate-education and low-education groups (p<0.001), whereas at one year after hospital discharge no differences were observed among the education groups (Table 2). The highest 10-year incidence of recurrent ACS events (fatal or non-fatal) was observed in the low-education group, whereas no significant differences were observed between the intermediate-education and high-education groups. Patients with an intermediate level of education (9 to 14 years of formal education) had a better long-term prognosis than the other two groups (Figure 1, Table 2).

Figure. 1.

Survival curves for fatal or non-fatal acute coronary syndrome events by educational level (<9 years, 9-14 years, >14 years) over 10 years of follow-up of the Greek acute coronary syndrome study patients (A: male, B: female).

In order to further explore associations between education status and the 10-year incidence of ACS, a multi-adjusted analysis was performed (Table 4). Similarly to all-cause mortality, the intermediate-education group showed a significantly higher unprotected effect than the high-education group. Patients in the low-education group did not seem to be protected in comparison with the high-education group. Similarly, after adjusting for patients’ adherence to medication for various comorbidities, no significant effect of educational level on ACS events was observed (HR, 0.82; 95% CI, 0.34 to 2.00) (Table 4, model 6).

Table 4.

Results from nested, multi-adjusted Cox-proportional hazard models regarding associations between education status and the incidence of fatal or non-fatal ACS events over 10 years of follow-up among participants in the GREECS study (n=2172)

Limitations

The present study, despite its strong findings with specific public health implications, has some limitations that should be acknowledged in order to better interpret the results. In studies that use self-reported data, social desirability reporting bias is possible in subjects with both higher and lower educational levels; the former tend to be more aware of the characteristics of a healthy diet and have more knowledge about which food items are healthier, while the latter tend to present a more desirable profile. Additionally, educational level was used as the only indicator of socioeconomic status, although our data also included other social determinants, such as the patients’ financial status. All patient characteristics were measured once, at the baseline examination, and therefore may have been prone to life-course changes during the decade of follow-up. This consideration may influence the robustness of our findings.

In summary, the present 10-year follow-up study revealed that ACS patients with a low level of education were at a higher risk for fatal or non-fatal ACS events as well as for all-cause mortality, irrespective of their lifestyle and clinical characteristics. Low educational status had an adverse effect on longterm ACS incidence as well as on all-cause mortality among cardiac patients. Moreover, high educational levels did not appear to be as protective as has been argued, particularly regarding cardiac outcomes. In light of the recent financial crisis, emphasis should be placed on the pursuit of cost-effective healthcare services, especially among poorly educated and chronically ill patients, in order to close the gap in health disparities. The issues of inequalities in treatment, non-adherence to medical recommendations, and health literacy still remain a great public health challenge. The present analysis implies that less educated patients may be regarded as an emerging high-risk social group in the context of public health intervention strategies.