Vitamin D deficiency is associated with risk for a first cardiovascular event in the general population, possibly because of inflammation, insulin resistance, and neurohumoral activation. However, its relation with outcomes in acute coronary syndromes has not been reported. To test the hypothesis that severe deficiency of vitamin D is independently associated with cardiovascular mortality during ACS, 206 patients admitted for unstable angina, non–ST-segment elevation myocardial infarction, or ST-segment elevation acute myocardial infarction had 25-hydroxyvitamin D serum levels measured at admission. Severe vitamin D deficiency was defined a priori as a value ≤10 ng/ml. The average concentration of vitamin D was 20 ± 8.2 ng/ml, and 10% of patients were severely deficient (95% confidence interval 6.6% to 15%). Cardiovascular mortality during hospitalization took place in 14 patients, an incidence of 6.8%. Patients with severe vitamin D deficiency had in-hospital cardiovascular mortality of 24%, significantly higher than the 4.9% observed in the remaining patients (relative risk 4.3, 95% confidence interval 1.8 to 10, p = 0.001). After adjustment for Global Registry of Acute Coronary Events (GRACE) score, Gensini angiographic score, and potential confounding variables, severe deficiency of vitamin D remained an independent predictor of in-hospital cardiovascular mortality (odds ratio 14, 95% confidence interval 1.2 to 158, p = 0.03). In conclusion, severe vitamin D deficiency is independently associated with in-hospital cardiovascular mortality in patients with acute coronary syndromes.
Vitamin D deficiency was recently reported to be common in patients with acute coronary syndromes (ACS). Theoretically, the metabolic implications of vitamin D deficiency could delay plaque stabilization, predisposing to recurrent events. In addition, activation of the renin-angiotensin-aldosterone system might increase the risk for ventricular failure during ACS. However, the association between vitamin D deficiency and prognosis in patients with ACS has never been evaluated. In the first attempt to test the hypothesis that severe vitamin D deficiency is associated with prognosis in patients with ACS, we measured serum 25-hydroxyvitamin D levels at admission and prospectively followed these patients for cardiovascular mortality. The cut-off value for severe vitamin D deficiency according to previous publications (≤10 ng/ml) was tested as a predictor of mortality after multivariate adjustment for potential confounding variables that were related to predictor and outcome.
Methods
Consecutive patients with rest onset of typical chest discomfort within the previous 48 hours admitted to the coronary care units of 2 tertiary hospitals in Salvador, Brazil, from August 2007 to December 2011 were evaluated for inclusion in the Registry of Acute Coronary Syndromes (REACS). To include patients with non–ST-segment elevation ACS, ≥1 of the 3 objective criteria had to be present: electrocardiographic changes consisting of transient ST-segment depression (≥0.05 mV) or T-wave inversion (≥ 0.1 mV); troponin change to a level beyond the threshold of the 99th percentile of a healthy reference population, with 10% coefficient of variability ; or previous documentation of coronary artery disease, defined as a definitive history of myocardial infarction or coronary obstruction ≥50% on angiography. For inclusion of ST-segment elevation acute myocardial infarction, a persistent ST-segment elevation ≥0.1 mV in ≥2 contiguous leads or third-degree left bundle branch block with subsequent elevation of a serum marker of myocardial necrosis was required. Patient’s decision not to participate in the registry was an exclusion criterion. All participants provided written informed consent.
The study protocol conformed with the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research ethics committee. As previously defined, blood samples were obtained on arrival in the emergency room, and plasma was frozen at −70°C for subsequent analysis. From a total of 406 patients admitted to the REACS, 206 had samples stored at the time of the present analysis. Patients with missing samples were excluded from this particular study. All samples had 25-hydroxyvitamin D levels quantified in a central laboratory, on a same day, by the immunoassay method of ADVIA Centaur (Siemens Healthcare Diagnostics Inc., Tarrytown, New York), with a limit of detection of 3.5 ng/ml and a coefficient of variability ranging from 4.8% to 11.1%. Patients were followed during hospitalization and after discharge to identify clinical end points.
According to standard definition, severe vitamin D deficiency was classified as a serum concentration ≤10 ng/ml. The primary end point was cardiovascular death during hospitalization. It was defined when death was mediated by 1 of the following 5 mechanisms: acute ventricular failure, arrhythmias, complications of urgent revascularization, and bleeding or renal dysfunction, both due to percutaneous coronary intervention. Otherwise, death was defined as noncardiovascular. In addition, follow-up after discharge was performed by telephone contact at 30 days, 6 months, and every year subsequently to determine cardiovascular survival in the long term. As a secondary end point, cardiovascular death during long-term follow-up was defined by a clear relation with new episodes of ACS or sudden death. As measures of disease severity, the Global Registry of Acute Coronary Events (GRACE) score and the Gensini angiographic score were calculated, as previously defined.
Cardiovascular mortality during hospitalization was compared between patients with severe deficiencies (≤10 ng/ml) and the remaining patients using Pearson’s chi-square test. Baseline characteristics and treatment during hospitalization were compared between the 2 groups to search for confounding variables. Student’s t test for numeric variables and Pearson’s chi-square test for categorical variables were used. Variables associated with severe vitamin D deficiency with p values <0.10 were included in a logistic regression analysis to determine whether severe deficiency was independently associated with death. Regardless of their significance levels, the GRACE score and the Gensini score were included in the logistic regression model, on the basis of their clinical relevance. Long-term mortality since study admission was compared between the 2 groups using Kaplan-Meier analysis and the log-rank test, while hazard ratios were calculated using a Cox proportional model. In this analysis, noncardiac death was censored as loss to follow-up at the point it took place. SPSS version 9.0 (SPSS, Inc., Chicago, Illinois) was used for data analysis, and final statistical significance was defined as a p value <0.05.
Results
Two hundred six patients were included in the study (mean age 70 ± 13 years, 52% men, 52% African Brazilians), 93% of whom were admitted with non–ST-segment elevation ACS and the remaining with ST-segment elevation myocardial infarctions. Vitamin D concentration had a fairly normal distribution, with a mean of 19.5 ± 8.2 ng/ml, a median of 18.5 ng/ml, and an interquartile range of 13.9 to 23.3 ng/ml ( Figure 1 ). Severe deficiency of vitamin D was present in 10% of the sample (95% confidence interval [CI] 6.6% to 15%). Cardiovascular death during hospitalization occurred in 14 patients, an incidence of 6.8%. The specific causes of death were ventricular failure in 8 patients, sudden cardiac arrest in 3 patients, complications after bypass surgery in 2 patients, and severe bleeding after percutaneous coronary intervention in 1 patient. There was no death of a noncardiovascular nature.
In-hospital cardiovascular death in patients with severe deficiency was 24%, compared with 4.9% in the remaining patients (relative risk 4.3, 95% CI 1.8 to 10, p = 0.001). To search for confounding factors in the relation between severe deficiency of vitamin D and mortality, we compared baseline characteristics and treatment between patients dichotomized according to the presence or absence of severe deficiency ( Table 1 ). There was a trend toward more women and a higher prevalence of Killip class >I in those with severe deficiency. Numerically, there were more deaths in women than men (9.2% vs 4.6%) and in patients with Killip class >I than those with Killip class I (27% vs 3.5%). Thus, these variables were included in the logistic regression analysis as potential confounding factors. Despite their similarity between the 2 groups, measures of clinical risk (GRACE score) and angiographic severity of coronary disease (Gensini score) were also covariates in this multivariate analysis, because of their clinical relevance. After adjustment for these 4 covariates, severe vitamin D deficiency remained an independent predictor of in-hospital cardiovascular death, with an odds ratio of 14 (95% CI 1.2 to 158, p = 0.03). Female gender and Killip class >I lost statistical significance, while GRACE score (odds ratio 1.03, 95% CI 1.01 to 1.05, p = 0.004), and Gensini score (odds ratio 1.01, 95% CI 1.001 to 1.03, p = 0.04) remained predictors ( Table 2 ).
| Variable | Vitamin D Deficiency | p Value | |
|---|---|---|---|
| Severe (≤10 ng/ml) (n = 21) | Not Severe (>10 ng/ml) (n = 183) | ||
| Age (yrs) | 70 ± 12 | 68 ± 13 | 0.46 |
| Women | 14 (68%) | 84 (45%) | 0.06 |
| African Brazilians | 7 (33%) | 84 (45%) | 0.29 |
| Body mass index (kg/m 2 ) | 25.6 ± 4.5 | 26.9 ± 5.0 | 0.33 |
| Diabetes mellitus | 10 (48%) | 66 (36%) | 0.28 |
| Hypertension | 18 (86%) | 154 (83%) | 0.77 |
| Smokers | 2 (9.5%) | 20 (11%) | 0.86 |
| Troponin >99th percentile | 13 (62%) | 111 (60%) | 0.87 |
| ST-segment deviation | 5 (24%) | 47 (25%) | 0.87 |
| Killip class >I | 6 (29%) | 24 (13%) | 0.06 |
| Left ventricular systolic dysfunction ∗ | 4 (20%) | 27 (17%) | 0.72 |
| Creatinine clearance (ml/min) † | 47 ± 29 | 56 ± 25 | 0.11 |
| C-reactive protein (mg/L) | 7.9 (1.6–34) | 3.2 (1.0–10) | 0.20 |
| Blood glucose (mg/dl) | 142 ± 69 | 150 ± 82 | 0.67 |
| GRACE score | 134 ± 54 | 122 ± 36 | 0.14 |
| Gensini score ‡ | 105 (61–179) | 109 (68–169) | 0.80 |
| Hospital treatment | |||
| Aspirin | 20 (95%) | 182 (99%) | 0.20 |
| Clopidogrel | 17 (81%) | 168 (92%) | 0.11 |
| Full dose of any heparin | 18 (86%) | 167 (91%) | 0.41 |
| β blocker | 15 (71%) | 128 (70%) | 0.92 |
| Statin therapy | 20 (95%) | 174 (95%) | 0.98 |
| Percutaneous coronary intervention | 5 (24%) | 62 (34%) | 0.37 |
| Coronary bypass | 2 (10%) | 17 (9.5%) | 0.94 |
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