Milionis Et Al - Anemia on Admission Predicts Short and Long Term Outcomes in Patients With Acute...

8/9/2019 Milionis Et Al - Anemia on Admission Predicts Short and Long Term Outcomes in Patients With Acute Ischemic Stroke

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Anemia on admission predicts short- and long-term outcomes in patients withacute ischemic stroke

Haralampos Milionis 1,2 , Vasileios Papavasileiou1,3 , Ashraf Eskandari 1,Suzette DAmbrogio-Remillard 1, George Ntaios 1,3 , and Patrik Michel 1*

Background It is still debatable whether anemia predictsstroke outcome. Aim To describe the characteristics of patients with acute isch-emic stroke (AIS) and anemia and identify whether hemoglo-bin status on admission is a prognostic factor of AIS outcome.Methods All 2439 patients of the Acute Stroke Registry andAnalysis of Lausanne (ASTRAL) between January 2003 andJune 2011 were selected. Demographics, risk factors, prestroketreatment, clinical, radiological and metabolic variables inpatients with and without anemia according to the denitionof the World Health Organization were compared. Functionaldisability and mortality were recorded up to 12 months fromadmission.Results Anemic patients (175%) were older, had lower body

mass index, higher rates of coronary artery disease (CAD),atrial brillation, diabetes mellitus and peripheral arterydisease. Anemia was associated with more severe stroke mani-festations, lower systolic and diastolic blood pressure mea-surements, worse estimated glomerular ltration rate andelevated C-reactive protein concentrations upon admissionand with increased modied Rankin scores during the follow-up. Anemic patients had higher 7-day, 3-month and 12-monthmortality, which was associated with hemoglobin status andother factors, including age, CAD, stroke severity, and baselineC-reactive levels. Hemoglobin levels were inversely associatedwith recurrent stroke and mortality throughout the 12-monthfollow-up.Conclusion Anemia is common among AIS patients and isassociated with cardiovascular comorbidities. Low hemoglobin

status independently predicts short and long-term mortality.Key words: anemia, disability, hemoglobin, ischemic stroke, mortality,outcome

Introduction

Anemia is associated with increased mortality, decreased physicalperformance and disability regardless of the underlying cause(1,2). It is associated with adverse outcomes in patients with acutemyocardial infarction,congestive heart failure and chronic kidney disease (36).

Anemia represents a risk factor for ischemic stroke, and isassociated with a higher mortality following hospitalization (7,8).Low hemoglobin levels are associated with decreased oxygen-carrying, inammatory response, alterations in blood viscosity and impairment of cerebral autoregulation (9,10). Nonetheless,data with regard to the relationship between anemia status uponadmission and short- and long-term outcome post-stroke arescarce (1113). There are no specic recommendations as to themanagement of acute stroke patients with anemia other thansickle cell disease (14). It would be therefore useful to know therange of hemoglobin or the severity of anemia on presentation toidentify patients at higher risk of adverse outcomes and to further

design potential intervention.

Aim

In this study, we examined the characteristics of patients withanemia in a consecutive series of patients with acute ischemicstroke and assessed the relationship between anemia and strokeoutcome.

Methods

We used data derived between January 2003 and June 2011 fromthe Acute STroke Registry and Analysis of Lausanne (ASTRAL).Design, methods of data collection and denitions of recordedvariables have been described elsewhere (15). All patients receivea basic blood chemistry prole on admission that includes fullblood count, INR, apTT, glucose, creatinine, sodium, potassium,total cholesterol and mostly CRP. These values are oftenrepeated in the subacute phase but were not used for thisanalysis.

Acute stroke management and secondary prevention of ASTRAL patients followed current European Stroke Organization(ESO) guidelines (16).

The World Health Organization guidelines that dene anemiaas a blood hemoglobin level on admission of


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Statistical analysis

Statistical analysis was performed to compare stroke patients withanemia vs. nonanemic patients in terms of demographics, preex-isting conditions (comorbidities), medications prior to strokeevent, clinical and laboratory characteristics on admission andsubacutely, treatment modalities, favorable outcome (dened asmRS = 02) at 3 and 12 months and mortality at seven-days,three-months and one-year after stroke onset.

After testing for statistical normality, dichotomous or categori-cal variables were compared with the 2-test and continuous vari-ables were compared with the unpaired t -test or MannWhitney U -test, as indicated. Furthermore, univariate and multivariatelogistic regression analyses were performed to identify factorsassociated with anemia in stroke patients. Associations are pre-sented as odds ratios (OR) with their corresponding 95% con-dence intervals (95%CI). The KaplanMeier product limitmethod was used to estimate the probability of survival at 12months after the index event according to the presence of anemia.

To evaluate the contribution of anemia (dichotomous variable)and the levels of hemoglobin (continuous variable) on outcomes,a univariate Coxs proportional hazards model was initially used.Multivariate analyses were performed including demographics,preexisting conditions, medications prior to stroke, clinical andlaboratory features on admission. Associations are presented ashazard ratios (HR) with their corresponding 95% condenceintervals (CIs). To conrm the robustness of the multivariablemodels, we performed all analyses using a forward selection pro-cedure. HosmerLemeshow statistic was used to evaluate modelsgoodness-of-t. Signicance levels were set at P < 005 in all cases.

Analyses were performed utilizing stata 111 (College Station,Texas) and spss version 150 (SPSS Inc., Chicago, IL).

Results

All 2439 patients registered during the observation period wereincluded in the analysis; 427 (175%) were diagnosed withanemia.

There was a strong correlation between hemoglobin levels andhematocrit (Spearmans rho, 096, P < 0001). Demographic data,comorbidities, treatment, medication prior and post stroke andmetabolic parameters between anemic and nonanemic patientsare summarized in Table 1. Anemic patients were older thannonanemic ones which could explain most of the differences

observed in other parameters in Table 1. In multivariate linearregression analysis, increasing age, decreasing BMI, CAD, hyper-tension and diabetes were independent predictors of anemia inpatients with stroke (Table 2). There was an inverse relationshipbetween anemia and the presence of dyslipidemia,diastolic bloodpressure measurements and serum glucose levels; on the contrary,there was a positive association with CRP levels on admission(Table 2).

Functional independence at 3 and 12 months was less frequentin anemic patients. Ordinal shift analysis showed an increase inmRS scores in anemic patients (Fig. 1). There was a tendency forhigher stroke recurrence rates in anemic patients (Table 3). Risk

of early (up to three-months) and late (up to 12 months) recur-

rent stroke was higher in patients presenting with anemia (logrank test, 4860, P = 0027 and 6391, P = 0011, respectively;Fig. 2a). However, in multivariate cox-regression analysis,anemia was not a signicant predictor of strokerecurrence duringfollow-up.

Mortality rates at 7 days, 3 months and 12 months were higheramong patients with low hemoglobin (Table 3). Survival wasbetter in patients with nonanemic patients (log rank test: 75487,P < 0001; Fig. 2b).

Anemia either as a dichotomous variable or as continuousvariable was found to be a signicant predictor of mortality throughout the follow-up period on univariate cox-regression

Fig. 1 Modied Rankin Scale (mRS) at 3 months (a) and 12 months (b)according to the presence of anemia. Unadjusted odds ratios for patientswith anemia vs. nonanemic patients have been calculated with mRS = 02(i.e. favorable outcome) as the reference category.

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Table 1 Demographic and clinical characteristics for patients with rst-ever ischemic stroke according to anemia status (as dened by WHO criteria)

CharacteristicAnemia No-anemiaN = 427 N = 2012

GenderWomen 189 (443) 876 (435)

Age (years) 7345 1477 * 6882 2568

SmokingActively smoking (or stopped


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analysis (Table 4). Decreasing levels of hemoglobin remained asignicant predictor of short- and long-term mortality in themultivariate analysis. Other signicant independent predictorswere increasing age, documented CAD, CRP levels on admission,the severity of stroke reected on NIHSS score. (Table 4).

Discussion

In this study of a large number of consecutive acute ischemicstrokes, patients with anemia had higher 7-day, 3-month and

12-month death rates and disability compared with nonanemicpatients.

The prevalence of anemia in acute stroke patients has beenreported to range between 17% and 29% (19,20). Accordingly,anemia dened according to an admission hemoglobin status waspresent in 27% of our study population. There is long-standingevidence that a high hematocrit may increase the risk of cerebralinfarction (21). The few studies investigating a low hematocrit orhemoglobin value as a risk factor for ischemic stroke have pro-duced conicting ndings and anemia is not considered a denite

Table 2 Logistic regression analysis for factors associated with anemia in patients with acute ischemic stroke

Multivariate analysis

Model A Model B

Odds ratio 95% CI Odds ratio 95% CI

Age (10 years) 119 102141Body mass index (kg/m 2) 093 088099Coronary artery disease 169 100297Hypertension 194 111337Diabetes mellitus 296 * 155566 296 140626Dyslipidemia 060 039091Diastolic blood pressure on admission (10 mmHg) 082 066090Serum glucose (mmol/l) 083 071097C-reactive protein (mg/l) 103 * 102104

Adjustment for all variables described in Table 1 concerning demographics, comorbid conditions and medications prior to admission (model A) and,in addition, clinical and laboratory characteristics as recorded on admission (model B).* P < 0001; P < 001; P < 005.

Table 3 Stroke severity and outcomes according to the admission hemoglobin status

Characteristic Anemia No-anemia Odds ratio (95% CI)

NIHSS at admission 8 (13) 6 (11) 103 * (102105)NIHSS 24 h after admission 5 (12) 4 (9) 103 * (101104)NIHSS at 7 days 3 (13) 3 (8) 102* (101103)Hemorrhagic transformation 07 days according to ECASS-II 8 (21) 33 (18) 119 (055260)Length of hospital stay (days) 10 (8) 9 (8) 101 (101102)Orientation at discharge

Home/short recovery 135 (379) 772 (417) 100 a

Any institution/hospital (including palliative care) 221 (621) 1078 (583) 135 * (108169)Recurrent cerebrovascular events (within rst 12 months):

None 288 (862) 1475 (893) 100 a

1 ischemic event (stroke, TIA, retinal event) 42 (126) 167 (101) 129 (090185)1 intracranial hemorrhage(s) 4 (12) 10 (06) 205 (064658)

Favorable outcome (mRS 02)3 months 181 (485) 1118 (640) 053 * (042066)12 months 160 (448) 1083 (640) 046 * (036057)

Mortality7 days 65 (152) 134 (67) 251 * (183345)3 months 103 (241) 216 (107) 264 * (203344)12 months 133 (311) 289 (144) 270 * (212343)

Cause of deathStroke-related 66 (537) 169 (612) 100 a

Nonstroke-related 52 (423) 85 (308) 157 (100245)Unknown 5 (40) 22 (80) 058 (021160)

* P < 0001; P < 001; P < 005.aReference group.Non-normally distributed variables, including NIHSS and length of stay are presented as median (interquartile range), and noncontinuous data as

numbers (percentages). ECASS, European Cooperative Acute Stroke Study.




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risk factor for stoke (22,23). It has been suggested that low hema-tocrit levels lead to low blood oxygen content, which may subse-quently cause cerebral ischemia (24). Anemia might also induce ahyperkinetic circulatory state and upregulate the endothelialadhesion molecule genes, which could lead to thrombus genera-tion (25). Furthermore, blood ow augmentation and turbulencemay result in the migration of an already existing thrombusleading to artery-to-artery embolism (25).

As yet, there is a paucity of studies that clarify the relationshipbetween anemia and stroke recurrence. In line with Huang et al .,we found that the rate of stroke recurrence was similar in anemia

and anemia-free groups, which may indicate that anemia does notinuence stroke recurrence (20).

Few studies have looked into the relationship between thehemoglobin or hematocrit level and stroke outcome. Indeed,some (4,8,12,13,2628) but not all (28,29) studies indicated low hemoglobin as a predictor of poor outcome after ischemic stroke.Moreover decreasing hemoglobin and hematocrit levels as well astheir nadir during the rst 5 days after admission have beenassociated with either three-month poor outcome or mortality (30). Also hemoglobin levels that decrease after admission inde-pendently predict infarct growth in thrombolyzed stroke patients

Fig. 2 KaplanMeier estimates of recurrent stroke risk and survival of patients with anemia and without anemia.

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(31). It has been reported that midrange hematocrit levels wereassociated with a better outcome after discharge (32). Our study shows that hemoglobin levels at admission constitute an indepen-dent predictor of short- and long-term mortality. A J-shapedrelationship between hematocrit level and adverse outcomes inpatients with severe stroke has also been described (13). Never-theless, in our cohort, survival in patients with hemoglobin values>16, 17 or 18 g/dl was similar to nonanemic patients (data notshown).

The results of our study must be interpreted in view of severallimitations. This is a retrospective observational single-centerstudy of prospectively collected, consecutive, acute ischemicstroke patients. Despite a potential selection bias in the analysis,ASTRAL is a solid hospital-based registry with well-characterizedvariables, meticulous monitoring and prospective follow-up for12 months for disability, mortality and recurrences. Additional

strengths of our study include analysis of hemoglobin status bothas a dichotomous and continuous variable, while the large data-base permitted additional multivariate modeling. However,unmeasured confounding variables or complex interactionsbetween covariates on the observed associations cannot be ruledout. Furthermore, we cannot comment on the etiology of anemia(acute blood loss anemia, anemia due to chronic disease, etc),and/or on the relationship between etiology of anemia and post-stroke outcomes. Moreover, subsequent measurements of hemo-globin are not systematically performed and therefore not usedfor analysis. Finally, we cannot comment on the role of directinterventions for anemic patients with stroke (e.g. blood transfu-

sions). Although patients with moderate to severe anemia had ahigher mortality rate, anemia was rarely in the range to requireblood transfusion.

Despite the study limitation our data suggest that patientswith moderate anemia on admission should be monitoredclosely. Our observational, retrospective study of prospectively collected data cannot answer the question whether anemia itself causes poor outcome after stroke or whether anemia is just asurrogate marker for general poor health of the patient; this canonly be addressed by well-designed, prospective studies. Wecannot generate a hypothesis about specic interventions likeblood transfusion or synthetic erythropoietin administration,since we could not identify a cutoff value toward the category of severe anemia and the benets of these measures have not beenproven in stroke patients, while potential harm should beavoided. For example, in the context of nonstroke diabetic

patients, anemia was found to be a risk factor for cardiovascularevents and death, but the use of darbepoetin alfa in patients withdiabetes, chronic kidney disease, and moderate anemia (hemo-globin < 110 g/dl) was associated with an increased risk of fatalor nonfatal stroke (hazard ratio, 192; 95% CI, 138268) (33).What seems to be a reasonable recommendation for strokepatients with anemia is to avoid excess blood sampling. Firstthings rst, anemia has to be recognized in stroke patients uponadmission and a diagnostic work-up toward reversible causesshould be implemented.

In conclusion, anemia is common among patients with acuteischemic stroke and is associated with cardiovascular comorbidi-

Table 4 Cox regression analyses determining the effect of hemoglobin status and various factors on mortality in patients with acute ischemic stroke

Univariate analysis Multivariate analysis

Hazard ratio 95% CI Hazard ratio 95% CI

Mortality at 7 daysAnemia 236 * 175317 145 087189

Age (10 years) 142*

122168Coronary arterydisease 172 111267Serum glucose (mmol/l) 112 104121C-reactive protein (10 mg/l) 106 102110NIHSS on admission 115 * 112117Hemoglobin (g/dl) 079 * 073085 089 080099

Mortality at 3 monthsAnemia 242 * 192306 149 089166Age (10 years) 152 * 134174Coronary artery disease 167 117238C-reactive protein (10 mg/l) 108 * 105117NIHSS on admission 114 * 112113Hemoglobin (g/dl) 077 * 073081 088 082097

Mortality at 12 monthsAnemia 241 * 196296 135 101183

Age (10 years) 155*

137174Coronary artery disease 183 * 134249C-reactive protein (mg/l) 108 * 105111NIHSS on admission 112 * 110114Hemoglobin (g/dl) 078 * 074082 089 083097

* P < 0001; P < 001; P < 005.Multivariate analysis included demographics, preexisting conditions, medications prior to stroke, clinical and laboratory features on admission. NIHSS,National Institutes of Health Stroke Scale.




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ties. Low hemoglobin status, especially in the range of moderate/severe anemia predicts short- and long-term mortality.

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