Anemia is associated with the cardiovascular outcome in healthy subjects but its impact on outcome in patients with cardiovascular disease has not yet been fully understood. Therefore, we assessed the long-term influence of hemoglobin on all-cause and cardiovascular mortality in patients with atherosclerotic disease. We prospectively studied 1,065 of 1,286 consecutive patients with asymptomatic carotid narrowing. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Continuous measures of hemoglobin displayed a significant inverse effect on all-cause mortality and cardiovascular mortality (adjusted hazard ratio [HR] for increase of 1 SD of hemoglobin 0.73, 95% confidence interval [CI] 0.64 to 0.83; p <0.001) and adjusted HR 0.76, 95% CI 0.64 to 0.89; p = 0.001, respectively). The cumulative 6-year survival rate was 61%, 79%, 80%, and 81% in the first, second, third, and fourth quartile of hemoglobin (log-rank p <0.001). Patients within the first quartile (<12.9 g/dl) had a significantly increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.46 to 2.54, p <0.001) and cardiovascular mortality (adjusted HR 1.68, 95% CI 1.19 to 2.36, p = 0.003) compared to patients with greater levels. In conclusion, our study has demonstrated a significant association with hemoglobin levels and all-cause and cardiovascular mortality in patients with carotid narrowing. Nevertheless, additional research, in terms of randomized controlled trials, is needed to warrant these findings and to evaluate potential therapeutic interventions.
The aim of our study was to prospectively assess the long-term influence of hemoglobin on all-cause and cardiovascular mortality in patients with asymptomatic carotid arterial narrowing.
Methods
Between March 2002 and March 2003, we prospectively included 1,286 asymptomatic patients with ultrasound diagnosed carotid narrowing in the Inflammation and Carotid Artery-Risk for Atherosclerosis Study (ICARAS), as previously described. Patients with previous cardiovascular events within 6 months of study initiation were excluded. All study participants were recruited at the Vienna General Hospital, a university-affiliated tertiary care center. The study protocol was in line with the Declaration of Helsinki and was approved by the institutional review board of the Medical University of Vienna. Every enrolled patient had to finish a detailed study questionnaire that was reviewed by a physician assessing the patient’s medical history, medication use, biometric data, lifestyle factors, and family history. All recorded parameters were checked for completeness and accuracy by 2 independent observers. Duplex ultrasound examinations were performed on an Acuson 128 XP10 with a 7.5-MHz linear array probe (Acuson, Malvern, Pennsylvania). The degree of carotid stenosis was quantified as previously described. Antecubital venous blood samples were drawn and analyzed directly without freezing according to local laboratory standard procedure.
All-cause mortality was the primary study end point. The end point of interest was obtained by screening the national register of death, including screening for the cause of death (according to the “International Statistical Classification of Diseases and Related Health Problems, 10th Revision”). To prevent study participants being lost to follow-up owing to migration or other causes, telephone contact to the subject or their relatives was also used to check on the patients’ vital status. This was done if a patient had not been seen at our outpatient department within the preceding 12 months. No patient was lost to follow-up for the final analysis.
Continuous data are presented as the median and interquartile range (25th to 75th percentile), and discrete data are presented as counts and percentages. Analysis of variance and the chi-square test were used for comparisons between quartiles, as appropriate. Cox proportional hazard regression analysis was used to assess the effect of variables on survival. The results of the Cox regression analysis are presented as the hazard ratio (HR) for 1 SD increase of continuous variables and the respective 95% confidence intervals (CIs). The final multivariate model was adjusted for the following established cardiovascular risk factors: age, gender, active smoking, hypertension, previous myocardial infarction, previous stroke, statin treatment, hemoglobin A1c, and estimated glomerular filtration rate using Chronic Kidney Disease Epidemiology Collaboration. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. p Values <0.05 were used to indicate statistical significance. Stata, version 11, software package (StataCorp, College Station, Texas) and PASW, version 18.0 (IBM SPSS, Somers, New York) were used for all analysis.
Results
Between March 2002 and March 2003, 1,364 patients underwent initial screening for the study. Of these, 78 subjects did not meet the eligible criteria, because they had experienced a cardiovascular event within the preceding 6 months. A sensitivity analysis including these 78 patients with recent events revealed virtually identical effect sizes as with the final analysis of the study population (data not shown). The remaining 1,286 patients were eligible and were enrolled in the present study. For 221 patients, no data with respect to complete blood count or hemoglobin levels were available, leaving 1,065 patients for the final analysis. Detailed baseline characteristics are listed in Table 1 . During a median follow-up of 6.2 years (interquartile range 5.9 to 6.6), corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Of these, 182 patients (66.2%) died from cardiovascular causes, 76 patients (27.6%) from cancer, 5 (1.8%) from end-stage renal disease, and 12 (4.4%) from other causes.
| Characteristic | All (n = 1,065) | Quartile | p Value | |||
|---|---|---|---|---|---|---|
| First (n = 265) | Second (n = 267) | Third (n = 266) | Fourth (n = 267) | |||
| Age (years) | <0.001 ⁎ | |||||
| Median | 69 | 73 | 71 | 68 | 66 | |
| Interquartile range | 61–76 | 65–78 | 62–78 | 61–75 | 59–73 | |
| Men | 668 (63%) | 121 (46%) | 121 (45%) | 172 (65%) | 228 (85%) | <0.001 ⁎ |
| Body mass index (kg/m 2 ) | 0.47 | |||||
| Median | 26.1 | 26 | 26 | 27 | 26 | |
| Interquartile range | 24.0–28.7 | 24–28 | 24–29 | 24–29 | 24–29 | |
| Hypertension | 731 (68.6%) | 61 (23%) | 88 (33%) | 97 (36%) | 72 (27%) | 0.01 ⁎ |
| Current smokers | 287 (27%) | 46 (17%) | 55 (21%) | 78 (29%) | 96 (36%) | <0.001 ⁎ |
| Family history atherosclerosis | 590 (55.4%) | 137 (52%) | 139 (52%) | 145 (55%) | 141 (53%) | 0.93 |
| History of myocardial infarction | 257 (24.1%) | 68 (26%) | 70 (26%) | 50 (19%) | 56 (21%) | 0.04 ⁎ |
| History of stroke | 176 (16.5%) | 48 (18%) | 35 (13%) | 35 (13%) | 49 (18%) | 0.11 |
| Hematocrit (%) | ||||||
| Median | 41.1 | 36 | 40 | 42 | 45 | <0.001 ⁎ |
| Interquartile range | 38.3–43.7 | 34–37 | 39–41 | 41–43 | 44–47 | |
| Mean corpuscular volume (fL) | <0.001 ⁎ | |||||
| Median | 90 | 90 | 90 | 90 | 91 | |
| Interquartile range | 87–93 | 86–93 | 87–93 | 88–93 | 88–94 | |
| Mean corpuscular hemoglobin (pg) | 0.66 | |||||
| Median | 31 | 30 | 31 | 31 | 32 | |
| Interquartile range | 30–32 | 28–31 | 30–32 | 30–32 | 31–33 | |
| Mean corpuscular hemoglobin concentration (g/dl) | <0.001 ⁎ | |||||
| Median | 34 | 33 | 34 | 34 | 35 | |
| Interquartile range | 33–35 | 33–34 | 33–34 | 34–35 | 34–35 | |
| Diabetes mellitus | 242 (22.7%) | 68 (26%) | 63 (24%) | 55 (21%) | 43 (16%) | 0.01 ⁎ |
| Hemoglobin A1c (%) | 0.13 | |||||
| Median | 6.0 | 6.1 | 6.1 | 5.9 | 5.8 | |
| Interquartile range | 5.6–6.6 | 5.7–6.7 | 5.7–6.7 | 5.6–6.4 | 5.5–6.3 | |
| Total cholesterol (mg/dl) | 0.02 ⁎ | |||||
| Median | 205 | 201 | 203 | 207 | 209 | |
| Interquartile range | 175–236 | 168–228 | 175–232 | 180–244 | 181–240 | |
| Low-density lipoprotein cholesterol (mg/dl) | 0.01 ⁎ | |||||
| Median | 118 | 115 | 115 | 121 | 122 | |
| Interquartile range | 94–146 | 90–137 | 92–144 | 95–153 | 95–149 | |
| High-density lipoprotein cholesterol (mg/dl) | 0.88 ⁎ | |||||
| Median | 50 | 48 | 51 | 50 | 49 | |
| Interquartile range | 42–60 | 40–60 | 42–61 | 42–60 | 42–59 | |
| Serum creatinine (mg/dl) | <0.001 ⁎ | |||||
| Median | 1.06 | 1.14 | 1.03 | 1.07 | 1.05 | |
| Interquartile range | 0.93–1.23 | 0.93–1.49 | 0.92–1.19 | 0.92–1.2 | 0.96–1.19 | |
| Estimated glomerular filtration rate † (ml/min/1.73 m 2 ) | <0.001 ⁎ | |||||
| Median | 79 | 75 | 78 | 80 | 82 | |
| Interquartile range | 73–86 | 66–80 | 72–85 | 75–87 | 76–89 | |
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