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Acta Cardiol Sin 2014;30:16-21
CHA2DS2-VASc Score and Heart Rate Predict Ischemic Stroke Outcomes in Patients with Atrial Fibrillation Chih-Shan Huang,1 Chin-I Chen,1 Ya-Ting Liu,1 Jen-Hung Huang2 and Yi-Jen Chen2,3
Purpose: To evaluate the factors determining the severity and outcome of ischemic stroke in patients with atrial fibrillation (AF). Methods: Our study examined 210 patients with AF and acute ischemic stroke to investigate the relative risks of age, gender, comorbidities, CHADS2 and CHA2DS2-VASc scores, warfarin use, heart rate, and blood pressure on stroke severity, hospitalization duration, and mortality rate. Results: Patients with poor outcomes [n = 109, National Institutes of Health Stroke Scale (NIHSS) scores of ³ 8] had elevated CHA2DS2-VASc scores [5, interquartile range (IQR) 3-6 versus 4, IQR 2.5-5, p = 0.005] and were older with a female predominance, less prior warfarin use, and a higher heart rate (93 ± 24 versus 84 ± 20 beats/min, p = 0.004) in the emergency department, with a longer duration of hospitalization (24 ± 23 versus 11 ± 12 days, p < 0.001) and a higher mortality rate (11.0% versus 0.0%, p = 0.002) than those with better outcomes (n = 101, low NIHSS scores of £ 7). Patients who died (n = 12) were older and had a higher NIHSS, CHADS2 (3.5, IQR 2-4.75 versus 2, IQR 1-4, p = 0.040), or CHA2DS2-VASc (5.5, IQR 4-6 versus 4, IQR 3-5, p = 0.046) scores than patients who survived. The multivariate analysis showed that female gender, no prior warfarin use, and heart rate were independent predictors of stroke severity. Conclusions: Our results showed that CHADS2 and CHA2DS2-VASc scores, and heart rate were useful parameters for predicting outcomes in AF patients with stroke.
Key Words:
Atrial fibrillation · CHA2DS2-VASc score · Heart rate · Ischemic stroke
(congestive heart failure, hypertension, age ³ 75 years, diabetes mellitus, stroke) score, and the recently developed CHA2DS2-VASc (congestive heart failure, hypertension, age ³ 75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex category) score, were proposed to predict stroke risk, and thus are used to select high-risk AF patients who should take anticoagulant agents to reduce their risk of stroke.3-5 However, prognostic factors for AF patients with stroke are not fully elucidated. AF in older stroke patients (³ 75 years) is known to impact mortality and recurrence after an initial ischemic stroke.6 Moreover, females are associated with an elevated frequency of AF more than males,7 and AF is only an independent predictor of poor stroke out-
INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia which can induce stroke with a higher mortality rate and more-disabling outcomes.1,2 The CHADS2
Received: October 11, 2013 Accepted: November 13, 2013 1 Department of Neurology; 2Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University; 3Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Yi-Jen Chen, Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No. 111, Hsing-Lung Road, Sec. 3, Taipei 116, Taiwan. Tel: 886-2-2873-5656; Fax: 886-22933-9378; E-mail: [email protected]
Acta Cardiol Sin 2014;30:16-21
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Factors Affecting Stroke Outcome with Atrial Fibrillation
comes for woman.8 Therefore, aging and female gender might affect the prognosis of AF patients. 9-11 Recently, CHADS 2 and CHA 2 DS 2 -VASc scores were also proposed to be useful parameters for assessing outcomes after AF-induced stroke.12 Adequate control of the international normalized ratio (INR) with an anticoagulant decreases the occurrence of ischemic stroke in AF patients,13-16 and also may reduce its severity and the risk of death from stroke. 17 AF with a rapid ventricular rate can produce heart failure and increases the risk of stroke. However, RACEII showed that strict and lenient rates of control have similar stroke risks in AF patients.18 Moreover, it is not clear whether the heart rate or other hemodynamic parameters can predict stroke outcomes. Therefore, the purpose of this study was to investigate factors affecting potential outcomes in AF patients with acute stroke.
tutes of Health Stroke Scale (NIHSS),19 which includes 11 items: level of consciousness, horizontal eye movement, visual field test, facial palsy, motor arm, motor leg, limb ataxia, sensory loss, language, dysarthria, and extinction and inattention. Individual scores from each item are summed in order to calculate a patient’s total NIHSS score.
Statistical analysis All continuous variables are expressed as the mean ± standard deviation (SD). Comparisons between groups were made using a t-test or the Mann-Whitney ranksum test depending on the outcome of the normality test. Nominal variables were compared by a chi-square test. A logistic regression analysis was used to analyze stroke severity, in terms of the initial NIHSS score. Variables that reached statistical significance (p < 0.05) in the univariate analysis were applied to the multivariate analysis to determine independent variables associated with the initial stroke severity, hospitalization period and mortality. Statistical significance was set at p < 0.05 from a two-tailed t-test. Statistical analyses were performed using the SigmaPlot 12.3 and SPSS 13.0 (SPSS, Chicago, IL, USA) software packages.
MATERIALS AND METHODS Study subjects This study was approved by the Taipei Medical University Joint Institutional Review Board. Informed consent was obtained from all participants. In total, 210 patients in a university hospital with acute ischemic stroke and AF from January 2006 to December 2011, who had been consecutively registered in the Taiwan Stroke Registry, were enrolled in this study. During admission, all patients received computed tomography (CT) and/or magnetic resonance imaging (MRI) to exclude hemorrhagic stroke and to evaluate the ischemic stroke area. All patients were managed according to stroke guidelines (from the American Stroke Association). We recorded the gender, age, systolic blood pressure (SBP), and heart rate upon arrival at the emergency department, anticoagulant treatment at the time of stroke onset, prothrombin time (reported as the INR) at presentation, and days of hospitalization. The CHADS2 and CHA2DS2-VASc scores were calculated for each patient according to the clinical status.
RESULTS Patient characteristics Of the 210 patients with AF and ischemic stroke, 103 (49.0%) were female with an average age of 77 ± 11 (range, 40-97) years. Only 29 patients (13.8%) had received oral anticoagulant (i.e., warfarin) therapy, with an average INR of 1.47 ± 0.76, and only 2 (6.9%) of them had INR levels that had reached therapeutic intensity (INR > 2) at the time of the stroke. Fifty-five patients (26.2%) with heart failure, 169 patients (80%) with hypertension, 51 patients (24.3%) with diabetes mellitus (DM), 70 (33.3%) with a history of stroke, and 53 (25.2%) with vascular disease (coronary artery disease, peripheral artery disease, etc) were found among these patients. CHADS2 scores were 0 in 10 (4.8%) patients, 1 in 44 (20.9%) patients, 2 in 50 (23.8%) patients, 3 in 47 (22.4%) patients, 4 in 35 (16.7%) patients, 5 in 17 (8.1%) patients, and 6 in seven (3.3%) patients. CHA2DS2-VASc scores were 0 in two (1%) patients, 1 in 10 (4.8%) patients, 2 in 28 (13.3%) patients, 3 in 30 (14.3%) patients,
Neurological assessment The neurological condition of each patient was evaluated on arrival. The initial stroke severity was assessed by a trained neurologist using the National Insti17
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stroke (NIHSS ³ 8) were associated with an older age, a female gender, a higher CHA2DS2-VASc score, no prior warfarin use, a higher heart rate measured in the emergency department, a longer hospitalization period, and a higher mortality rate. High-NIHSS patients receiving warfarin (n = 9) had a similar INR (1.70 ± 1.28 vs. 1.36 ± 0.35, p > 0.05) to low-NIHSS patients receiving warfarin (n = 20). Figure 1 shows the relationship between NIHSS scores and heart rates. Most notably, we also found a good linear correlation between heart rates and NIHSS scores. Moreover, patients with a faster heart rate (³ 90 BPM) had a higher NIHSS score than patients with a slower heart rate (< 90 BPM), as shown in Table 2. In addition, the NIHSS score was also well correlated with the CHADS 2 (Figure 2A) and CHA 2 DS 2 -VASc scores (Figure 2B).
4 in 49 (23.3%) patients, 5 in 37 (17.6%) patients, 6 in 34 (16.2%) patients, 7 in 11 (5.2%) patients, 8 in seven (3.3%) patients, and 9 in two (1%) patients. Ratios of patients with a CHADS2 score of = 2 and a CHA2DS2-VASc score of ³ 2 were 74.3% and 94.3%, respectively. The mean SBP in the emergency department was 152 ± 28 mmHg. The mean heart rate in the emergency department was 89 ± 22 BPM. The median value of the initial NIHSS was 8, with a 25% value of 3 and a 75% value of 18. The mean duration of hospitalization was 18 ± 19 days. Twelve (5.7%) patients died after the stroke.
Stroke severity and outcomes We compared patients with high and low NIHSS values (Table 1) and found that patients with more-severe Table 1. Differences between atrial fibrillation (AF) patients with different stroke severities NIHSS £ 7 NIHSS ³ 8 p value (n = 101) (n = 109) Mean age (years) Gender, female (%) Heart failure (%) Hypertension (%) Diabetes mellitus (%) History of stroke (%) Vascular disease (%) CHADS2 score CHA2DS2-VASc score Prior warfarin use (%) Systolic blood pressure (mmHg) Heart rate (BPM) Hospitalization days Mortality (%)
074 ± 11 33.7 22.8 78.2 22.8 36.6 21.8 2 (1-3.5) 4 (2.5-5) 19.8 150 ± 27 084 ± 20 011 ± 12 0
80 ± 11 < 0.001 63.3 < 0.001 29.4 0.354 81.7 0.654 25.7 0.740 30.3 0.406 28.4 0.342 3 (2-4) 0.342 5 (3-6) 0.005 8.3 0.026 154 ± 30 0.236 93 ± 24 0.004 24 ± 23 < 0.001 11 0.002
Figure 1. Correlations of the NIHSS score and heart rate in patients with atrial fibrillation and stroke.
Table 2. Difference between faster or slower heart rates in atrial fibrillation stroke patients
Initial NIHSS score Mean age (years) Gender, female (%) Heart failure (%) Hypertension (%) Diabetes mellitus (%) History of stroke (%) Vascular disease (%) CHADS2 score CHA2DS2-VASc score Warfarin use (%) Systolic blood pressure (mmHg) Hospitalization days Mortality (%)
Acta Cardiol Sin 2014;30:16-21
Heat rate of < 90 BPM (n = 120)
Heart rate of ³ 90 BPM (n = 90)
p value
9.6 ± 8.1 77 ± 11 51.7 25.8 80.8 26.7 31.7 25.0 2 (2-4) 4 (3-5) 16.7 155 ± 290 19 ± 22 3.3
13.1 ± 10.6 77 ± 12 45.6 26.7 78.9 21.1 35.6 25.6 3 (1-4) 4 (3-6) 10.0 148 ± 270 17 ± 17 8.9
0.026 0.569 0.461 0.982 0.862 0.443 0.657 0.945 0.796 0.875 0.237 0.096 0.485 0.157
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Factors Affecting Stroke Outcome with Atrial Fibrillation
Table 3. Differences between atrial fibrillation and stroke patients with different hospitalization periods £ 17 days ³ 18 days p value (n = 140) (n = 70) Initial NIHSS score Mean age (years) Gender, female (%) Heart failure (%) Hypertension (%) Diabetes mellitus (%) History of stroke (%) Vascular disease (%) CHADS2 score CHA2DS2-VASc score Warfarin use (%) Systolic blood pressure (mmHg) Heart rate (BPM) Mortality (%)
A
8.8 ± 8.9 75 ± 12 44.3 25.0 81.4 25 37.9 24.3 3 (1-4) 4 (3-5.75) 15.7 149 ± 27 087 ± 20 7.1
15.8 ± 8.7 < 0.001 080 ± 10 < 0.001 58.6 0.071 28.6 0.698 77.1 0.583 22.9 0.864 24.3 0.070 27.1 0.779 2 (2-4) 0.925 4 (3-6) 0.380 10.0 0.358 159 ± 30 0.011 092 ± 26 0.338 2.9 0.344
B Figure 2. Correlations of NIHSS scores with CHADS2 (A) and CHA2DS2VASc scores (B) in patients with atrial fibrillation and stroke.
Table 3 compares patients with longer (³ 18 days) and shorter (£ 17 days) hospitalization stays. The cut-off value was set at 18 days because it was the mean duration of hospitalization. We found that patients with a longer hospitalization were older and had more-severe stroke (higher NIHSS scores) and higher SBP. Moreover, NIHSS scores were also correlated with the duration of hospitalization (Figure 3). Table 4 compares patients who died with those who survived. We found that patients who died had higher NIHSS, CHADS2, and CHA2DS2VASc scores, and were older than surviving patients. We added gender, age, CHA2DS2-VASc score, prior warfarin use and heart rate into the multivariate analysis, which showed that female gender [OR = 3.35 (95% CI: 1.76-6.37), p < 0.001], no prior warfarin use [OR = 2.58 (95% CI: 1.00-6.64), p < 0.05], and heart rate [OR = 1.02 (95% CI: 1.01-1.04), p < 0.005] were independent
Figure 3. Correlations of NIHSS scores with hospitalization length of stay in patients with atrial fibrillation and stroke.
risk factors for predicting a higher stroke severity (NIHSS ³ 8) after a stroke in patients with AF. In addition, the NIHSS score was the independent risk factor for predicting a long hospitalization (³ 17 days) [OR = 1.08 (95% CI: 1.04-1.11), p < 0.001] and for predicting mortality [OR = 1.13 (95% CI: 1.05-1.21), p = 0.001] from stroke in patients with AF.
DISCUSSION AF is more frequently associated with severe or fatal stroke.1,2 An anticoagulant agent is indicated to prevent 19
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Chih-Shan Huang et al.
comes.20 However, the incidences of comorbidities of hypertension, heart failure, diabetes mellitus, and a history of stroke or vascular diseases were similar between AF patients with different stroke severities. Therefore, female and aging might be the main factors contributing to the predictive role of the CHA 2 DS 2 -VASc score in stroke severity in AF patients. To date, it is not yet known why female AF patients have poor stroke outcomes. It may be attributable to physiology, genetic factors or hormonal factors that differ between men and women. Further studies may be needed to further investigate and more comprehensively explain sex differences in stroke severity. Through a multivariate analysis, we found that female gender, no prior warfarin use, and heart rate were independent factors for stroke severity. High-NIHSS patients also had high mortality and longer hospitalization. No patient with an NIHSS score of £ 7 died in this study. Stroke severity (NIHSS score) was the independent risk factor for longer hospitalization and for mortality. Therefore, different parameters were related to the severity, hospitalization length, and mortality in stroke patients with AF. Use of an anticoagulant can reduce the occurrence of stroke in AF patients. In this study, we found a larger proportion of patients had been taking warfarin in the low-severity group. Therefore, anticoagulant therapy might reduce the stroke incidence in patients with AF, and also lower stroke severity.17 However, in patients with AF and a stroke receiving warfarin, there were similar INR values between the high- and low-severity groups. This may have resulted from the fact that most of our stroke patients had not reached therapeutic intensity at presentation. 15 Since new anticoagulation therapies (thrombin or Xa inhibitors) have similar or even better effects than warfarin, the underuse or poor control of INR in our study suggests that these patients should be considered to receive these new agents. However, it is not clear whether the new anticoagulation therapies would change the outcome prediction of stroke patients with AF, and additional studies are required. There are some limitations to our study. First, this study only evaluated the acute outcome of stroke in AF patients. It is not clear whether these predictive parameters can be applied to long-term outcomes. Second, this is a single center, retrospective, non-randomized study. In addition, ethnicity plays an important role in the
Table 4. Differences between surviving patients with atrial fibrillation and stroke and those who died Surviving (n = 198) Initial NIHSS score 10.3 ± 9.0 Mean age (years) 076 ± 12 Gender, female (%) 48.5 Heart failure (%) 25.8 Hypertension (%) 79.3 Diabetes mellitus (%) 24.4 History of stroke (%) 31.8 Vascular disease (%) 25.8 2 (1-4) CHADS2 score 4 (3-5) CHA2DS2-VASc score Warfarin use (%) 13.6 Systolic blood pressure (mmHg) 153 ± 28 Heart rate (BPM) 088 ± 22
Died (n = 12)
p value
24.0 ± 6.5 < 0.001 84 ± 6 0.005 58.3 0.715 33.3 0.809 91.7 0.504 16.7 0.774 58.3 0.115 16.7 0.718 3.5 (2-4.75) 0.040 5.5 (4-6) 0.046 16.7 0.892 146 ± 31 0.467 095 ± 21 0.176
thromboembolisms and a stroke.13-16 A higher CHADS2 or CHA2DS2-VASc score is related to an increased risk of stroke occurrence,3-5 and a patient with a score of ³ 2 on the CHADS2 or CHA2DS2-VASc is recommended to receive an anticoagulant. In this study, we found that more than 90% of AF patients with stroke had a CHA2DS2VASc score of ³ 2, but only 74% of AF patients with a stroke had a CHADS2 score of ³ 2. In contrast, 95% of AF patients with a stroke had a CHADS2 score of ³ 1. Consistent with these recommendations, our findings also suggest that patients with a CHADS2 score of 1 should receive a CHA 2 DS 2 -VASc evaluation to reduce the inadequate use of anticoagulants. In this study, for the first time, we found that a faster heart rate in the emergency room is an important predictive factor for assessing the severity of stroke. This simple parameter was also correlated with the NIHSS score. The multivariate analysis also indicated that the heart rate is an independent predictive factor for stroke severity. The heart rate in AF patients is regulated by the conduction properties of the atrioventricular node, which is controlled by the autonomic nervous system. A faster heart rate may imply an unstable autonomic nervous system or more stress during a severe stroke. Although unstable hemodynamics may also produce AF with rapid ventricular responses, the SBP was similar between high- and low-NIHSS patients. Consistent with previous studies, we found that older and female AF patients had poor stroke outActa Cardiol Sin 2014;30:16-21
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Factors Affecting Stroke Outcome with Atrial Fibrillation after first ischemic stroke. J Am Geriatr Soc 1997;45:1297-301. 7. Friberg J, Scharling H, Gadsboll N, et al. Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (the Copenhagen City Heart Study). Am J Cardiol 2004;94:889-94. 8. Roquer J, Rodríguez-Campello A, Gomis M, et al. Comparison of the impact of atrial fibrillation on the risk of early death after stroke in women versus men. J Neurol 2006;253:1484-9. 9. Di Carlo A, Lamassa M, Baldereschi M, et al. Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe: data from a multicenter multinational hospital-based registry. Stroke 2003;34:1114-9. 10. Kelly-Hayes M, Beiser A, Kase CS, et al. The influence of gender and age on disability following ischemic stroke: The Framingham Study. J Stroke Cerebrovasc Dis 2003;12:119-26. 11. Santalucia P, Pezzella FR, Sessa M, et al. Sex differences in clinical presentation, severity and outcome of stroke: results from a hospital-based registry. Eur J Intern Med 2013;24:167-71. 12. Hong HJ, Kim YD, Cha MJ, et al. Early neurological outcomes according to CHADS2 score in stroke patients with non-valvular atrial fibrillation. Eur J Neurol 2012;19:284-90. 13. Hert RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007;146:857-67. 14. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011;57:e101-98. 15. Ogilvie IM, Newton N, Welner SA, et al. Underuse of oral anticoagulants in atrial fibrillation: a systemic review. Am J Med 2010;123:638.e4-645.e4. 16. O’Dell KM, Igawa D, Hsin J. New oral anticoagulants for atrial fibrillation: a review of clinical trials. Clin Ther 2012;34:894-901. 17. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-26. 18. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363-73. 19. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864-70. 20. Avgil Tsadok M, Jackevicius CA, Rahme E, et al. Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation. JAMA 2012;307:1952-8.
occurrence of stroke in AF patients. Applying our data to the general population should be done with caution.
CONCLUSIONS We confirmed in our study that AF patients with severe stroke had distinctive clinical characteristics. Namely, AF patients who were older and female, and had a faster heart rate, higher CHA2DS2-VASc score, and no use of warfarin carried a high risk of poor stroke outcomes and require additional attention.
ACKNOWLEDGEMENT The present work was supported by grants from Taipei Medical University-Wan Fang Hospital (102-wf-eva15), and grants from the National Science Council, Taiwan (NSC 100-2325-B-010-005, NSC 101-2325-B-010-005).
Competing interests and funding None declared.
REFERENCES 1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-8. 2. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760-4. 3. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-70. 4. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72. 5. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 6. Kaarisalo MM, Immonen-Räihä P, Marttila RJ, et al. Atrial fibrillation in older stroke patients: association with recurrence and mortality
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Acta Cardiol Sin 2014;30:16-21
Acta Cardiol Sin 2014;30:16-21
CHA2DS2-VASc Score and Heart Rate Predict Ischemic Stroke Outcomes in Patients with Atrial Fibrillation Chih-Shan Huang,1 Chin-I Chen,1 Ya-Ting Liu,1 Jen-Hung Huang2 and Yi-Jen Chen2,3
Purpose: To evaluate the factors determining the severity and outcome of ischemic stroke in patients with atrial fibrillation (AF). Methods: Our study examined 210 patients with AF and acute ischemic stroke to investigate the relative risks of age, gender, comorbidities, CHADS2 and CHA2DS2-VASc scores, warfarin use, heart rate, and blood pressure on stroke severity, hospitalization duration, and mortality rate. Results: Patients with poor outcomes [n = 109, National Institutes of Health Stroke Scale (NIHSS) scores of ³ 8] had elevated CHA2DS2-VASc scores [5, interquartile range (IQR) 3-6 versus 4, IQR 2.5-5, p = 0.005] and were older with a female predominance, less prior warfarin use, and a higher heart rate (93 ± 24 versus 84 ± 20 beats/min, p = 0.004) in the emergency department, with a longer duration of hospitalization (24 ± 23 versus 11 ± 12 days, p < 0.001) and a higher mortality rate (11.0% versus 0.0%, p = 0.002) than those with better outcomes (n = 101, low NIHSS scores of £ 7). Patients who died (n = 12) were older and had a higher NIHSS, CHADS2 (3.5, IQR 2-4.75 versus 2, IQR 1-4, p = 0.040), or CHA2DS2-VASc (5.5, IQR 4-6 versus 4, IQR 3-5, p = 0.046) scores than patients who survived. The multivariate analysis showed that female gender, no prior warfarin use, and heart rate were independent predictors of stroke severity. Conclusions: Our results showed that CHADS2 and CHA2DS2-VASc scores, and heart rate were useful parameters for predicting outcomes in AF patients with stroke.
Key Words:
Atrial fibrillation · CHA2DS2-VASc score · Heart rate · Ischemic stroke
(congestive heart failure, hypertension, age ³ 75 years, diabetes mellitus, stroke) score, and the recently developed CHA2DS2-VASc (congestive heart failure, hypertension, age ³ 75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex category) score, were proposed to predict stroke risk, and thus are used to select high-risk AF patients who should take anticoagulant agents to reduce their risk of stroke.3-5 However, prognostic factors for AF patients with stroke are not fully elucidated. AF in older stroke patients (³ 75 years) is known to impact mortality and recurrence after an initial ischemic stroke.6 Moreover, females are associated with an elevated frequency of AF more than males,7 and AF is only an independent predictor of poor stroke out-
INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia which can induce stroke with a higher mortality rate and more-disabling outcomes.1,2 The CHADS2
Received: October 11, 2013 Accepted: November 13, 2013 1 Department of Neurology; 2Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University; 3Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Yi-Jen Chen, Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, No. 111, Hsing-Lung Road, Sec. 3, Taipei 116, Taiwan. Tel: 886-2-2873-5656; Fax: 886-22933-9378; E-mail: [email protected]
Acta Cardiol Sin 2014;30:16-21
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Factors Affecting Stroke Outcome with Atrial Fibrillation
comes for woman.8 Therefore, aging and female gender might affect the prognosis of AF patients. 9-11 Recently, CHADS 2 and CHA 2 DS 2 -VASc scores were also proposed to be useful parameters for assessing outcomes after AF-induced stroke.12 Adequate control of the international normalized ratio (INR) with an anticoagulant decreases the occurrence of ischemic stroke in AF patients,13-16 and also may reduce its severity and the risk of death from stroke. 17 AF with a rapid ventricular rate can produce heart failure and increases the risk of stroke. However, RACEII showed that strict and lenient rates of control have similar stroke risks in AF patients.18 Moreover, it is not clear whether the heart rate or other hemodynamic parameters can predict stroke outcomes. Therefore, the purpose of this study was to investigate factors affecting potential outcomes in AF patients with acute stroke.
tutes of Health Stroke Scale (NIHSS),19 which includes 11 items: level of consciousness, horizontal eye movement, visual field test, facial palsy, motor arm, motor leg, limb ataxia, sensory loss, language, dysarthria, and extinction and inattention. Individual scores from each item are summed in order to calculate a patient’s total NIHSS score.
Statistical analysis All continuous variables are expressed as the mean ± standard deviation (SD). Comparisons between groups were made using a t-test or the Mann-Whitney ranksum test depending on the outcome of the normality test. Nominal variables were compared by a chi-square test. A logistic regression analysis was used to analyze stroke severity, in terms of the initial NIHSS score. Variables that reached statistical significance (p < 0.05) in the univariate analysis were applied to the multivariate analysis to determine independent variables associated with the initial stroke severity, hospitalization period and mortality. Statistical significance was set at p < 0.05 from a two-tailed t-test. Statistical analyses were performed using the SigmaPlot 12.3 and SPSS 13.0 (SPSS, Chicago, IL, USA) software packages.
MATERIALS AND METHODS Study subjects This study was approved by the Taipei Medical University Joint Institutional Review Board. Informed consent was obtained from all participants. In total, 210 patients in a university hospital with acute ischemic stroke and AF from January 2006 to December 2011, who had been consecutively registered in the Taiwan Stroke Registry, were enrolled in this study. During admission, all patients received computed tomography (CT) and/or magnetic resonance imaging (MRI) to exclude hemorrhagic stroke and to evaluate the ischemic stroke area. All patients were managed according to stroke guidelines (from the American Stroke Association). We recorded the gender, age, systolic blood pressure (SBP), and heart rate upon arrival at the emergency department, anticoagulant treatment at the time of stroke onset, prothrombin time (reported as the INR) at presentation, and days of hospitalization. The CHADS2 and CHA2DS2-VASc scores were calculated for each patient according to the clinical status.
RESULTS Patient characteristics Of the 210 patients with AF and ischemic stroke, 103 (49.0%) were female with an average age of 77 ± 11 (range, 40-97) years. Only 29 patients (13.8%) had received oral anticoagulant (i.e., warfarin) therapy, with an average INR of 1.47 ± 0.76, and only 2 (6.9%) of them had INR levels that had reached therapeutic intensity (INR > 2) at the time of the stroke. Fifty-five patients (26.2%) with heart failure, 169 patients (80%) with hypertension, 51 patients (24.3%) with diabetes mellitus (DM), 70 (33.3%) with a history of stroke, and 53 (25.2%) with vascular disease (coronary artery disease, peripheral artery disease, etc) were found among these patients. CHADS2 scores were 0 in 10 (4.8%) patients, 1 in 44 (20.9%) patients, 2 in 50 (23.8%) patients, 3 in 47 (22.4%) patients, 4 in 35 (16.7%) patients, 5 in 17 (8.1%) patients, and 6 in seven (3.3%) patients. CHA2DS2-VASc scores were 0 in two (1%) patients, 1 in 10 (4.8%) patients, 2 in 28 (13.3%) patients, 3 in 30 (14.3%) patients,
Neurological assessment The neurological condition of each patient was evaluated on arrival. The initial stroke severity was assessed by a trained neurologist using the National Insti17
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stroke (NIHSS ³ 8) were associated with an older age, a female gender, a higher CHA2DS2-VASc score, no prior warfarin use, a higher heart rate measured in the emergency department, a longer hospitalization period, and a higher mortality rate. High-NIHSS patients receiving warfarin (n = 9) had a similar INR (1.70 ± 1.28 vs. 1.36 ± 0.35, p > 0.05) to low-NIHSS patients receiving warfarin (n = 20). Figure 1 shows the relationship between NIHSS scores and heart rates. Most notably, we also found a good linear correlation between heart rates and NIHSS scores. Moreover, patients with a faster heart rate (³ 90 BPM) had a higher NIHSS score than patients with a slower heart rate (< 90 BPM), as shown in Table 2. In addition, the NIHSS score was also well correlated with the CHADS 2 (Figure 2A) and CHA 2 DS 2 -VASc scores (Figure 2B).
4 in 49 (23.3%) patients, 5 in 37 (17.6%) patients, 6 in 34 (16.2%) patients, 7 in 11 (5.2%) patients, 8 in seven (3.3%) patients, and 9 in two (1%) patients. Ratios of patients with a CHADS2 score of = 2 and a CHA2DS2-VASc score of ³ 2 were 74.3% and 94.3%, respectively. The mean SBP in the emergency department was 152 ± 28 mmHg. The mean heart rate in the emergency department was 89 ± 22 BPM. The median value of the initial NIHSS was 8, with a 25% value of 3 and a 75% value of 18. The mean duration of hospitalization was 18 ± 19 days. Twelve (5.7%) patients died after the stroke.
Stroke severity and outcomes We compared patients with high and low NIHSS values (Table 1) and found that patients with more-severe Table 1. Differences between atrial fibrillation (AF) patients with different stroke severities NIHSS £ 7 NIHSS ³ 8 p value (n = 101) (n = 109) Mean age (years) Gender, female (%) Heart failure (%) Hypertension (%) Diabetes mellitus (%) History of stroke (%) Vascular disease (%) CHADS2 score CHA2DS2-VASc score Prior warfarin use (%) Systolic blood pressure (mmHg) Heart rate (BPM) Hospitalization days Mortality (%)
074 ± 11 33.7 22.8 78.2 22.8 36.6 21.8 2 (1-3.5) 4 (2.5-5) 19.8 150 ± 27 084 ± 20 011 ± 12 0
80 ± 11 < 0.001 63.3 < 0.001 29.4 0.354 81.7 0.654 25.7 0.740 30.3 0.406 28.4 0.342 3 (2-4) 0.342 5 (3-6) 0.005 8.3 0.026 154 ± 30 0.236 93 ± 24 0.004 24 ± 23 < 0.001 11 0.002
Figure 1. Correlations of the NIHSS score and heart rate in patients with atrial fibrillation and stroke.
Table 2. Difference between faster or slower heart rates in atrial fibrillation stroke patients
Initial NIHSS score Mean age (years) Gender, female (%) Heart failure (%) Hypertension (%) Diabetes mellitus (%) History of stroke (%) Vascular disease (%) CHADS2 score CHA2DS2-VASc score Warfarin use (%) Systolic blood pressure (mmHg) Hospitalization days Mortality (%)
Acta Cardiol Sin 2014;30:16-21
Heat rate of < 90 BPM (n = 120)
Heart rate of ³ 90 BPM (n = 90)
p value
9.6 ± 8.1 77 ± 11 51.7 25.8 80.8 26.7 31.7 25.0 2 (2-4) 4 (3-5) 16.7 155 ± 290 19 ± 22 3.3
13.1 ± 10.6 77 ± 12 45.6 26.7 78.9 21.1 35.6 25.6 3 (1-4) 4 (3-6) 10.0 148 ± 270 17 ± 17 8.9
0.026 0.569 0.461 0.982 0.862 0.443 0.657 0.945 0.796 0.875 0.237 0.096 0.485 0.157
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Factors Affecting Stroke Outcome with Atrial Fibrillation
Table 3. Differences between atrial fibrillation and stroke patients with different hospitalization periods £ 17 days ³ 18 days p value (n = 140) (n = 70) Initial NIHSS score Mean age (years) Gender, female (%) Heart failure (%) Hypertension (%) Diabetes mellitus (%) History of stroke (%) Vascular disease (%) CHADS2 score CHA2DS2-VASc score Warfarin use (%) Systolic blood pressure (mmHg) Heart rate (BPM) Mortality (%)
A
8.8 ± 8.9 75 ± 12 44.3 25.0 81.4 25 37.9 24.3 3 (1-4) 4 (3-5.75) 15.7 149 ± 27 087 ± 20 7.1
15.8 ± 8.7 < 0.001 080 ± 10 < 0.001 58.6 0.071 28.6 0.698 77.1 0.583 22.9 0.864 24.3 0.070 27.1 0.779 2 (2-4) 0.925 4 (3-6) 0.380 10.0 0.358 159 ± 30 0.011 092 ± 26 0.338 2.9 0.344
B Figure 2. Correlations of NIHSS scores with CHADS2 (A) and CHA2DS2VASc scores (B) in patients with atrial fibrillation and stroke.
Table 3 compares patients with longer (³ 18 days) and shorter (£ 17 days) hospitalization stays. The cut-off value was set at 18 days because it was the mean duration of hospitalization. We found that patients with a longer hospitalization were older and had more-severe stroke (higher NIHSS scores) and higher SBP. Moreover, NIHSS scores were also correlated with the duration of hospitalization (Figure 3). Table 4 compares patients who died with those who survived. We found that patients who died had higher NIHSS, CHADS2, and CHA2DS2VASc scores, and were older than surviving patients. We added gender, age, CHA2DS2-VASc score, prior warfarin use and heart rate into the multivariate analysis, which showed that female gender [OR = 3.35 (95% CI: 1.76-6.37), p < 0.001], no prior warfarin use [OR = 2.58 (95% CI: 1.00-6.64), p < 0.05], and heart rate [OR = 1.02 (95% CI: 1.01-1.04), p < 0.005] were independent
Figure 3. Correlations of NIHSS scores with hospitalization length of stay in patients with atrial fibrillation and stroke.
risk factors for predicting a higher stroke severity (NIHSS ³ 8) after a stroke in patients with AF. In addition, the NIHSS score was the independent risk factor for predicting a long hospitalization (³ 17 days) [OR = 1.08 (95% CI: 1.04-1.11), p < 0.001] and for predicting mortality [OR = 1.13 (95% CI: 1.05-1.21), p = 0.001] from stroke in patients with AF.
DISCUSSION AF is more frequently associated with severe or fatal stroke.1,2 An anticoagulant agent is indicated to prevent 19
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Chih-Shan Huang et al.
comes.20 However, the incidences of comorbidities of hypertension, heart failure, diabetes mellitus, and a history of stroke or vascular diseases were similar between AF patients with different stroke severities. Therefore, female and aging might be the main factors contributing to the predictive role of the CHA 2 DS 2 -VASc score in stroke severity in AF patients. To date, it is not yet known why female AF patients have poor stroke outcomes. It may be attributable to physiology, genetic factors or hormonal factors that differ between men and women. Further studies may be needed to further investigate and more comprehensively explain sex differences in stroke severity. Through a multivariate analysis, we found that female gender, no prior warfarin use, and heart rate were independent factors for stroke severity. High-NIHSS patients also had high mortality and longer hospitalization. No patient with an NIHSS score of £ 7 died in this study. Stroke severity (NIHSS score) was the independent risk factor for longer hospitalization and for mortality. Therefore, different parameters were related to the severity, hospitalization length, and mortality in stroke patients with AF. Use of an anticoagulant can reduce the occurrence of stroke in AF patients. In this study, we found a larger proportion of patients had been taking warfarin in the low-severity group. Therefore, anticoagulant therapy might reduce the stroke incidence in patients with AF, and also lower stroke severity.17 However, in patients with AF and a stroke receiving warfarin, there were similar INR values between the high- and low-severity groups. This may have resulted from the fact that most of our stroke patients had not reached therapeutic intensity at presentation. 15 Since new anticoagulation therapies (thrombin or Xa inhibitors) have similar or even better effects than warfarin, the underuse or poor control of INR in our study suggests that these patients should be considered to receive these new agents. However, it is not clear whether the new anticoagulation therapies would change the outcome prediction of stroke patients with AF, and additional studies are required. There are some limitations to our study. First, this study only evaluated the acute outcome of stroke in AF patients. It is not clear whether these predictive parameters can be applied to long-term outcomes. Second, this is a single center, retrospective, non-randomized study. In addition, ethnicity plays an important role in the
Table 4. Differences between surviving patients with atrial fibrillation and stroke and those who died Surviving (n = 198) Initial NIHSS score 10.3 ± 9.0 Mean age (years) 076 ± 12 Gender, female (%) 48.5 Heart failure (%) 25.8 Hypertension (%) 79.3 Diabetes mellitus (%) 24.4 History of stroke (%) 31.8 Vascular disease (%) 25.8 2 (1-4) CHADS2 score 4 (3-5) CHA2DS2-VASc score Warfarin use (%) 13.6 Systolic blood pressure (mmHg) 153 ± 28 Heart rate (BPM) 088 ± 22
Died (n = 12)
p value
24.0 ± 6.5 < 0.001 84 ± 6 0.005 58.3 0.715 33.3 0.809 91.7 0.504 16.7 0.774 58.3 0.115 16.7 0.718 3.5 (2-4.75) 0.040 5.5 (4-6) 0.046 16.7 0.892 146 ± 31 0.467 095 ± 21 0.176
thromboembolisms and a stroke.13-16 A higher CHADS2 or CHA2DS2-VASc score is related to an increased risk of stroke occurrence,3-5 and a patient with a score of ³ 2 on the CHADS2 or CHA2DS2-VASc is recommended to receive an anticoagulant. In this study, we found that more than 90% of AF patients with stroke had a CHA2DS2VASc score of ³ 2, but only 74% of AF patients with a stroke had a CHADS2 score of ³ 2. In contrast, 95% of AF patients with a stroke had a CHADS2 score of ³ 1. Consistent with these recommendations, our findings also suggest that patients with a CHADS2 score of 1 should receive a CHA 2 DS 2 -VASc evaluation to reduce the inadequate use of anticoagulants. In this study, for the first time, we found that a faster heart rate in the emergency room is an important predictive factor for assessing the severity of stroke. This simple parameter was also correlated with the NIHSS score. The multivariate analysis also indicated that the heart rate is an independent predictive factor for stroke severity. The heart rate in AF patients is regulated by the conduction properties of the atrioventricular node, which is controlled by the autonomic nervous system. A faster heart rate may imply an unstable autonomic nervous system or more stress during a severe stroke. Although unstable hemodynamics may also produce AF with rapid ventricular responses, the SBP was similar between high- and low-NIHSS patients. Consistent with previous studies, we found that older and female AF patients had poor stroke outActa Cardiol Sin 2014;30:16-21
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Factors Affecting Stroke Outcome with Atrial Fibrillation after first ischemic stroke. J Am Geriatr Soc 1997;45:1297-301. 7. Friberg J, Scharling H, Gadsboll N, et al. Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (the Copenhagen City Heart Study). Am J Cardiol 2004;94:889-94. 8. Roquer J, Rodríguez-Campello A, Gomis M, et al. Comparison of the impact of atrial fibrillation on the risk of early death after stroke in women versus men. J Neurol 2006;253:1484-9. 9. Di Carlo A, Lamassa M, Baldereschi M, et al. Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe: data from a multicenter multinational hospital-based registry. Stroke 2003;34:1114-9. 10. Kelly-Hayes M, Beiser A, Kase CS, et al. The influence of gender and age on disability following ischemic stroke: The Framingham Study. J Stroke Cerebrovasc Dis 2003;12:119-26. 11. Santalucia P, Pezzella FR, Sessa M, et al. Sex differences in clinical presentation, severity and outcome of stroke: results from a hospital-based registry. Eur J Intern Med 2013;24:167-71. 12. Hong HJ, Kim YD, Cha MJ, et al. Early neurological outcomes according to CHADS2 score in stroke patients with non-valvular atrial fibrillation. Eur J Neurol 2012;19:284-90. 13. Hert RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007;146:857-67. 14. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011;57:e101-98. 15. Ogilvie IM, Newton N, Welner SA, et al. Underuse of oral anticoagulants in atrial fibrillation: a systemic review. Am J Med 2010;123:638.e4-645.e4. 16. O’Dell KM, Igawa D, Hsin J. New oral anticoagulants for atrial fibrillation: a review of clinical trials. Clin Ther 2012;34:894-901. 17. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-26. 18. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363-73. 19. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864-70. 20. Avgil Tsadok M, Jackevicius CA, Rahme E, et al. Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation. JAMA 2012;307:1952-8.
occurrence of stroke in AF patients. Applying our data to the general population should be done with caution.
CONCLUSIONS We confirmed in our study that AF patients with severe stroke had distinctive clinical characteristics. Namely, AF patients who were older and female, and had a faster heart rate, higher CHA2DS2-VASc score, and no use of warfarin carried a high risk of poor stroke outcomes and require additional attention.
ACKNOWLEDGEMENT The present work was supported by grants from Taipei Medical University-Wan Fang Hospital (102-wf-eva15), and grants from the National Science Council, Taiwan (NSC 100-2325-B-010-005, NSC 101-2325-B-010-005).
Competing interests and funding None declared.
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