Homocysteine as a Predictor of Early Neurological Deterioration in Acute Ischemic Stroke
Background and Purpose—Hyperhomocysteinemia is a well-known risk factor for vascular disease. However, its action, mechanism, and role in the acute phase of stroke have not been determined. We tried to determine whether an association existed between elevated serum homocysteine levels and early neurological deterioration (END) in patients with acute ischemic stroke.
Methods—We performed a secondary analysis from the Cilostazol in Acute Ischemic Stroke Treatment (CAIST) trial, which was a double-blinded, randomized, multicenter trial, assessing the noninferiority of cilostazol over aspirin within 48 hours of an acute ischemic stroke. END was defined as an increase of ≥1 point in motor power or an increase of ≥2 points in the total National Institute of Health Stroke Scale score within 7 days.
Results—The mean (±SD) serum homocysteine level was 11.4±4.7 μmol/L. Of the 396 patients studied, 57 (14.4%) patients worsened during the 7 days after inclusion. Most (68%) of the END cases occurred within the first 24 hours after treatment. High levels (>10.3 μmol/L) of serum homocysteine were independent predictors for END (third quartile odds ratio, 3.45; 95% confidence intervals, 1.25–9.50; P=0.016; fourth quartile odds ratio, 3.36; 95% confidence intervals 1.18–9.52; P=0.023) in multivariate analysis.
Conclusions—Patients with acute stroke with elevated serum homocysteine levels are at an increased risk for END.
Elevated serum homocysteine has been associated with an increased risk for vascular disease.1 Increased levels of homocysteine may cause neurotoxicity and be associated with other prothrombotic factors.2 Experimental evidence suggests that elevated plasma homocysteine levels may cause toxicity by a variety of mechanisms, which include direct toxicity and vascular endothelial injury.3
Some reports have also suggested that an elevated homocysteine is an independent predictor of poor outcome in patients with stable and acute coronary disease.4,5 There are also a few studies reporting a relationship between homocysteine and functional disability in the acute phase of stroke.6,7 However, whether high homocysteine levels are a risk factor for acute stroke complications, such as early neurological deterioration (END), has not been well addressed. Therefore, the purpose of this study was to investigate the possible relationship between homocysteine levels and END in a large prospective multicentered study.
Patients and Variables
We performed a secondary analysis of the Cilostazol in Acute Ischemic Stroke Treatment (CAIST) trial,8 which was a double-blinded, randomized, multicenter trial assessing the noninferiority of cilostazol over aspirin in patients who developed an acute ischemic stroke within 48 hours. Detailed background information of the patients was described in the previous article.8 The institutional review boards of the participating hospitals provided ethics approval, and all patients provided a written informed consent.
Baseline demographic data, stroke risk factors, premorbid modified Rankin scale, and National Institute of Health Stroke Scale (NIHSS) scores were recorded. All patients underwent a baseline MRI. We performed laboratory tests on the day of hospital arrival for initial fasting blood glucose, hemoglobin A1c (HbA1c), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, serum homocysteine, and high-sensitivity C-reactive protein levels. For measuring serum homocysteine, venous samples were immediately separated by centrifugation at 3500 rpm for 15 minutes. The separated sera were stored in a refrigerator within 48 hours before being tested. Homocysteine was measured on serum using chemiluminescent microparticle immunoassay.
END was assessed as the secondary end points. We defined END as an incremental increase in the NIHSS score by ≥1 point in motor power, or ≥2 points in the total score within the first week after admission. The neurological status of the patients was assessed by trained neurologists on a daily basis.
We examined total homocysteine by quartiles of increasing levels to evaluate for possible threshold effects. Baseline and clinical characteristics were compared using χ2 test or Fisher exact test (categorical variables) and the Student t test (continuous variables). A multiple logistic regression analysis was performed for the evaluation of possible contributing factors for END using variables with P values < 0.1 in univariate analysis. All statistical analyses were performed using SPSS version 20.0 for Windows (SPSS IBM Inc, Chicago, IL).
A total of 396 patients (240 men; mean age, 63.5 years) were recruited for the secondary analysis. END was determined in 57 patients (14.4%) within 7 days after admission. About two thirds (68%) of the END cases occurred within the first 24 hours after admission. The mean homocysteine level was 11.4±4.7 μmol/L, with quartile levels as follows: 4.67 to 8.38 μmol/L (first quartile); 8.39 to 10.30 μmol/L (second quartile); 10.31 to 13.09 μmol/L (third quartile); and 13.10 to 42.76 μmol/L (fourth quartile).
Baseline epidemiological and clinical characteristics between 2 groups according to the presence or absence of END were shown in Table I in the online-only Data Supplement. The mean homocysteine level was 13.16±5.25 μmol/L in the END(+) and 11.11±4.54 μmol/L in the END(−). Detailed demographic data are summarized in Table 1. As expected, increased age and male sex significantly correlated with increased homocysteine levels (P<0.05). Hypertension, current smoking status, HbA1c, and high-sensitivity C-reactive protein showed borderline significance. Homocysteine levels were not associated with diabetes mellitus, coronary artery disease, hyperlipidemia, or stroke subtype.
Diabetes mellitus, initial NIHSS score, HbA1c, and homocysteine level were associated with END by univariate analysis. After multiple logistic regression analysis, 3 factors (initial NIHSS, HbA1c, and homocysteine) remained as independent predictors of END. The odds ratio for END increased with increasing quartile levels of homocysteine with the lowest quartile used as the reference value (Table 2). The third and fourth highest quartiles of homocysteine levels were identified as independent predictors of END. As shown in the Figure, there was an increase in the risk of END with higher level of homocysteine.
Spearman rank-order correlation showed that there was significant association between homocysteine levels and NIHSS at 7 days and modified Rankin scale scores at 3 months (P<0.001).
There are few reports describing the predictive value of homocysteine levels for early deterioration during the acute phase of an ischemic stroke. This study found that elevated homocysteine levels are associated with END in acute ischemic stroke, and that the risk of END tended to increase because the levels of homocysteine increased. END is a common and prognostically important problem in acute ischemic stroke because it portends a more severe functional disability.9 This study is the first to report a positive relationship between homocysteine levels and END in a large-scaled prospective design.
During the past few years, increased plasma homocysteine levels have been linked to an increased risk of ischemic stroke.10 However, the relationship between high plasma homocysteine levels and stroke outcomes remains controversial because some studies have found an association, whereas others have not.6,7,11 The mechanisms underlying these associations are incompletely understood; however, some hypothetical causes might lead to functional disability.12
Our study has several limitations. First, the time interval from onset to admission was variable. Therefore, the patients who already had deteriorated within that time before enrollment may not have been recognized as END. Second, the time interval from stroke onset to sampling for homocysteine was variable. Nevertheless, homocysteine levels may be a useful parameter for predicting END in acute stroke because all patients took blood test within 8 hours of admission and homocysteine levels are not affected by acute stroke itself.13
The present study reveals that elevated homocysteine levels are significantly associated with END. Therefore, homocysteine levels may be valuable as a predictor of prognosis in patients with acute stroke.
Korea Otsuka Pharmaceutical and Otsuka Pharmaceutical sponsored and funded the CAIST trial, which is the source of this analysis. The sponsors were not involved in this study design, analysis of the data, and decision to submit the paper for publication.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.004099/-/DC1.
- Received November 20, 2013.
- Accepted December 10, 2013.
- © 2014 American Heart Association, Inc.
- Steinke W,
- Ley SC
- Meiklejohn DJ,
- Vickers MA,
- Dijkhuisen R,
- Greaves M