High Blood Pressure on Admission in Relation to Poor Outcome in Acute Ischemic Stroke with Intracranial Atherosclerotic Stenosis or Occlusion Zilong Hao, MD, PhD, Ming Liu, MD, PhD, Deren Wang, MD, PhD, Bo Wu, MD, PhD, Wendan Tao, MD, PhD, and Xueli Chang, MD
Background: Intracranial atherosclerotic stenosis is common in Asian, black, and Hispanic individuals. However, the management of blood pressure (BP) in the setting of acute stage in these patients is controversial. The present study aims to explore the relationship between BP on admission and outcomes in acute ischemic stroke patients with intracranial atherosclerotic stenosis or occlusion. Methods: We prospectively registered consecutive cases of acute ischemic stroke from September 01, 2009, to August 31, 2011. Patients with severe intracranial stenosis or occlusion were included. Death or disability was followed up at the end of the third month. The multivariate logistic regression model was used to analyze the relationship between BP on admission and clinical outcomes. Results: We included 215 cases, which accounted for 22.7% (215 of 946) of the total registered cases. The mean age was 60.44 6 13.23 years. The median time of symptoms onset to admission was 72 hours (2-270 hours). Patients with systolic blood pressure (SBP) of 120-159 mm Hg or diastolic BP of 70-89 mm Hg had the lowest death or disability. After adjustment of confounders, SBP of 160 mm Hg or more on admission was the independent predictor of death or disability at the third month (relative risk [RR], 2.89; 95% confidence interval [CI], 1.20-6.91). SBP less than 120 mm Hg on admission had a trend of increasing death or disability (RR, 1.96; 95% CI, .60-6.33). Conclusions: Higher BP on admission was associated with an increased risk of death or disability in patients with symptomatic intracranial artery stenosis or occlusion. It is reasonable that further studies on the effects of BP lowering in acute stroke include these patients. Key Words: Acute ischemic stroke—intracranial stenosis or occlusion—blood pressure—death or disability. Ó 2013 by National Stroke Association
From the Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. Received October 16, 2013; revision received November 18, 2013; accepted November 27, 2013. This research was supported by the Science and Technology Infrastructure Projects of Sichuan Province (No. 2012JCPT008) and the Science and Technology Program of Science and Technology Department of Sichuan Province (No. 2011SZ0202). Address correspondence to Ming Liu, MD, PhD, Stroke Clinical Research Unit, Department of Neurology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, China. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.11.025
Introduction The optimal management of blood pressure (BP) in acute ischemic stroke is inconclusive, and current published guidelines are based on few studies and expert opinions.1-5 Intracranial atherosclerotic stenosis is common in Asian, black, and Hispanic individuals.6 It is estimated to account for 33%-50% of strokes and 50% of transient ischemic attacks in the Chinese population.7,8 So it is important to determine the best BP management in these patients. As we know, epidemiology suggests that high BP could result in worsening cerebral edema and hemorrhagic transformation, whereas pathophysiology argues that lower systemic BP could put brain tissue at
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a risk of underperfusion and worsening infarction. This argument is further compounded by the fear that patients with intracranial atherosclerotic stenosis or occlusion may be even more at a risk of hemodynamic compromise. The analysis of data from the Warfarin–Aspirin Symptomatic Intracranial Disease study provides the most information to date on the relationship between the BP level and risk of stroke in these patients.11 It indicates that higher BP is associated with an increased (not decreased) risk of ischemic stroke and stroke in the territory of the stenotic vessels. However, these data examined long-term BP treatment rather than in the acute or subacute phase of stroke. Recently, the results of the Scandinavian Candesartan Acute Stroke Trial, which aimed to explore whether lowering of BP would be beneficial in patients with acute stroke, showed that treatment with candesartan was associated with a nonsignificant worse functional outcome and no reduction in vascular events.12 Although the results were adjusted for age, cause of stroke (ischemic versus hemorrhagic), stroke severity, and systolic blood pressure (SBP) levels, the trial did not consider effects of treatment in other relevant clinical subgroups, such as patients with atherosclerotic stenosis or occlusion. In the absence of definitive data from clinical trials, the best clinical practice for the management of BP in the setting of acute ischemic stroke with intracranial atherosclerotic stenosis or occlusion is unclear. This study aims to describe the characteristics of BP and explore the relationship between BP on admission and outcomes in these common subgroup patients.
age data were recorded at the time of assessment using a standardized structured form. Risk factors included hypertension, diabetes, dyslipidemia, coronary heart disease, history of stroke, and status of smoking and alcohol. Severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS). NIHSS score was graded as follows: mild (0-6), medium (7-15), and severe ($16).14 Laboratory data included levels of triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein on admission. We also recorded the using of antiplatelet therapy, antihypertensive treatment, and statins therapy during the hospitalization. Details of the Chengdu Stroke Registry have been described previously.15 In this analysis, severe intracranial atherosclerotic stenosis (70%-99%) or occlusion was defined using the criteria of Samuels for MR angiography16 or the North American Symptomatic Carotid Endarterectomy Trial for digital subtraction angiography (DSA).17 Patients with cardiac embolism, other causes of intracranial stenosis or occlusion, or a lack of vascular investigation were excluded.
BP Measurement and Group BP measurements were taken at 9 AM daily since admission when patients were in the supine position using a wrist BP meter for 7 days or when patients die or are discharged. BP readings were grouped as follows: SBP less than 120, 120-139, 140-159, 160-179, 180-199, 200-219, and of 220 mm Hg or more; diastolic blood pressure (DBP) less than 60, 60-69, 70-79, 80-89, 90-99, 100-109, 110-119, and of 120 mm Hg or more.
Assessment of Outcome
Subjects and Methods Subjects We included acute ischemic stroke admitted consecutively to neurologic wards of the West China Hospital, Sichuan University, within 30 days of symptom onset between September 01, 2009, and August 31, 2011. All patients had a clinical diagnosis of stroke according to the World Health Organization criteria,13 and intracranial hemorrhage was further excluded by computed tomography or magnetic resonance (MR) imaging scan in the hospital. Because this is an observational study that will only assess outcomes in participants, all participants or their designated relatives provided verbal informed consent for obtaining relative prognostic information. This research project was approved by the Scientific Research Department of West China Hospital, which conformed to the local ethic criteria for human researches.
Data Collection Details of patient demography, risk factors, stroke severity, BP on admission, laboratory test, and brain im-
The main outcomes were death and disability at 3 months after stroke. Death was all-cause case fatality. Disability was defined as the modified Rankin Scale score greater than 2.18 Patients were followed up by telephone call, clinic interview, or letter inquiry. To ensure the quality of information collection, all staff members received training in the beginning according to our standard operational manual. All data were recorded in a structured data sheet. The outcome assessors were blinded to the information of patients.
Statistical Analysis Differences between 2 groups were tested using t test, Mann–Whitney U test, or chi-square test whichever was appropriate. Variables that were identified as significant in the univariate analyses (P , .05) and clinical significant variables were entered into multivariate logistic regression analyses. The multivariate logistic regression model was used to determine the association between BP on admission and patient outcomes. All statistical analyses were performed with SPSS for Windows, Version 16.0 (IBM, Chicago, IL).
BLOOD PRESSURE AND INTRACRANIAL ATHEROSCLEROTIC STENOSIS
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Table 1. Blood pressure–lowering agents during hospitalization Drugs
N, %
Drugs
N, %
Drugs
N, %
CCB 1 ARB CCB 1 ACE-I CCB 1 B ARB 1 B ARB 1 D ACE-I 1 D
23, 26.4% 5, 5.7% 2, 2.3% 2, 2.3% 2, 2.3% 1, 1.2%
ARB CCB B
30, 34.5% 19, 21.8% 1, 1.2%
CCB 1 ARB 1 B
2, 2.3%
Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blockers; B, beta-blockers; CCB, calcium channel blockers; D, diuretic agents.
Results Baseline Characteristics We included 1655 patients with acute ischemic stroke within 30 days of symptom onset from onset. Of them, patients with severe intracranial stenosis or occlusion accounted for 13% (215 of 1655). When excluded cardiac embolism or other causes of intracranial stenosis or occlusion or a lack of vascular investigation, patients with severe intracranial stenosis or occlusion accounted for 22.7% (215 of 946). The mean age was 60.44 6 13.23 years (25-90 years). Men accounted for 60.5% (130 of 215). The median time of symptoms onset to admission was 72 hours (2-270 hours). A total of 90.2% (194 of 215) of cases were admitted within 2 weeks. The proportions of vascular investigations were 88.4% MR angiography and 25.6% DSA, respectively. During hospitalization, 97.2% patients received antiplatelet therapy, 40.5% patients received antihypertensive treatment, and 70.7% patients received statins. Seventy-eight patients had death or disability at 3 months after stroke. The antihypertensive treatments were oral drugs, and the details are reported in Table 1. Compared with patients without severe intracranial stenosis or occlusion, patients with intracranial severe stenosis or occlusion were younger, had admission delay, had slight lower BP on admission, had higher proportion of severe patients, and case fatality or disability at the end of 3 months. There were no significant differences between 2 groups on vascular risk factors, antiplatelet therapy, antihypertensive treatment, and statins therapy (data not shown). Compared with patients without BP lowering, patients receiving antihypertensive treatment during hospitalization were older, had higher SBP or DBP on admission, had higher proportion of patients with hypertension, diabetes mellitus, statins therapy and case fatality, or disability at the end of 3 months (Table 2).
Relationship between BP on Admission and Outcomes There were no significant differences as to the proportion of SBP of 220 or more, 200 or more, and 180 mm Hg or more and DBP greater than 120, greater than 110, and greater than 100 mm Hg between patients
with severe intracranial stenosis or occlusion and overall patients (Table 3). The trends of BP were downward, especially in the first day. The relationship between BP on admission and death or disability was U-shaped curve. Patients with SBP of 120-159 mm Hg or DBP of 70-89 mm Hg had the lowest rate of death or disability (Fig 1).
The Influence of BP on Outcomes at the End of Follow-up After adjustment of potential confounders, such as age, sex, NIHSS score on admission, and vascular risk factors, etc., SBP of 160 mm Hg or more on admission was the independent predictor of death or disability at the third month, and the patients had a significant higher risk for death or disability (relative risk [RR], 2.89; 95% confidence interval, 1.20-6.91). SBP less than 120 mm Hg on admission was not the independent predictor of death or disability but had a trend of increasing death or disability (RR, 1.96; 95% confidence interval, .60-6.33) (Table 4).
Discussion Intracranial atherosclerotic stenosis or occlusion is common in Asian, black, and Hispanic individuals; however, the best clinical practice for the management of BP in these patients is unclear. In the present study, we investigated the relationship between BP on admission and outcomes in acute ischemic stroke with severe intracranial atherosclerotic stenosis or occlusion in a hospitalized Chinese population. We found that SBP of 160 mm Hg or more on admission was associated with z3.0-fold increased risk of death or disability in these patients after adjustment for age, sex, NIHSS scores, and vascular risk factors. We found that there were no significant differences as to the proportion of SBP of 220 or more, 200 or more, and 180 mm Hg or more and DBP greater than 120, greater than 110, and greater than 100 mm Hg between patients with severe intracranial stenosis or occlusion and overall patients. The proportion of patients with very high BP, such as SBP of 220 or more, 200 or more, and 180 mm Hg or more, was also very low. Current
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Table 2. Comparison of patients with intracranial severe stenosis/occlusion with BP lowering and without BP lowering Variates
BP lowering (N 5 87)
Non-BP lowering (N 5 128)
P
Age (y) Male (%) Time from onset (h) SBP on admission (mm Hg) DBP on admission (mm Hg) Hypertension (%) Diabetes mellitus (%) Dyslipidemia (%) Coronary heart disease (%) History of ischemic stroke (%) Alcohol (%) Smoking (%) NIHSS score on admission Triglyceride Cholesterol Low-density lipoprotein High-density lipoprotein Antiplatelet therapy (%) Statins therapy (%) Death or disability at 3 mo (%)
63.87 (12.15) 56 (64.4%) 72 (24-144) 153.72 (21.75) 89.11 (14.24) 68 (78.2%) 20 (23.0%) 8 (9.2%) 5 (5.7%) 6 (6.9%) 15 (17.2%) 27 (31.0%) 6 (3-12) 1.84 (1.30) 4.59 (1.02) 2.89 (1.30) 1.20 (.33) 84 (96.6%) 68 (78.2%) 40 (46.0%)
57.90 (13.95) 74 (57.8%) 72 (24-168) 133.69 (18.57) 80.13 (12.84) 47 (36.7) 14 (10.9%) 10 (7.8%) 5 (3.9%) 9 (7.0%) 22 (17.2%) 37 (28.9%) 5 (2-10) 1.62 (.92) 4.60 (.98) 2.75 (.89) 1.27 (.33) 126 (98.4%) 83 (64.8%) 38 (29.7%)
.001 .335 .979 .000 .000 .000 .017 .719 .530 .970 .992 .738 .520 .155 .959 .360 .116 .396 .036 .021
Abbreviations: DBP, diastolic blood pressure; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.
guidelines generally recommend control of high SBP (.180, .200, and .220 mm Hg). These findings emphasized that the value of BP lowering in these patients should be re-evaluated in light of very low proportion. In contrast to the clinical practice that many clinicians allow BP to keep high in patients with intracranial stenosis to protect against hypoperfusion, we found that higher BP on admission was associated with the increased risk of death or disability, which is similar to the findings from the Warfarin-Aspirin Symptomatic Intracranial Disease study.11 It indicates that higher BP is associated with the increased (not decreased) risk of ischemic stroke and stroke in the territory of the stenotic vessel. However, these data examined long-term BP treatment (within 90 days). Our study reinforces the results in the setting of the acute or subacute stage; 90.2% of cases were
admitted within 2 weeks. Recently, the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which was the first randomized controlled trials to evaluate stenting for symptomatic intracranial artery stenosis ($70%), was terminated owing to safety concerns, and it concluded that aggressive medical management was superior to percutaneous transluminal angioplasty and stenting. In this study, patients were targeted an SBP of less than 140 mm Hg (,130 mm Hg in the case of patients with diabetes).19 It hints that lowering BP in patients with symptomatic intracranial artery stenosis is safety and even can be beneficial. Paciaroni et al20 reported that high BP was associated with a lower mortality at 3 months in patients with carotid stenosis of 50% or more or occlusion. The study of
Table 3. BP characteristics between patients with severe intracranial stenosis or occlusion and overall patients
BP on admission
All patients (N 5 1655)
Severe stenosis/occlusion (N 5 215)
P value
Mean SBP (mm Hg) Mean DBP (mm Hg) SBP $ 220 (mm Hg) DBP . 120 (mm Hg) SBP $ 200 (mm Hg) DBP . 110 (mm Hg) SBP $ 180 (mm Hg) DBP . 100 (mm Hg) SBP , 120 (mm Hg)
142.42 6 23.41 83.45 6 14.53 6 (.4%) 24 (1.5%) 23 (1.4%) 68 (4.1%) 108 (6.5%) 193 (11.7%) 249 (15.0%)
141.84 6 22.19 83.79 6 14.10 0 (0%) 4 (1.9%) 1 (.50%) 10 (4.7%) 10 (4.7%) 24 (11.2%) 22 (10.2%)
.730 .752 1.000 .554 .513 .708 .288 .830 .059
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
BLOOD PRESSURE AND INTRACRANIAL ATHEROSCLEROTIC STENOSIS
Figure 1. Relationship between blood pressure on admission and rate of death or disability.
Rothwell et al21 had shown that the risk of stroke increases with BP in most patients with symptomatic carotid artery disease, but it is inverted in patients with bilateral carotid stenosis of 70% or more. Recently, interim data analysis from the Efficacy of Nitric Oxide in Stroke trial showed that patients with ipsilateral carotid stenosis of 50% or more were no more likely to suffer from stroke recurrence or neurologic deterioration by day 7 than those without.22 It is reasonable to include patients with carotid stenosis into trials of acute BP lowering. On the other hand, the systematic review from Sare et al23 showed there was little existing evidence that antiTable 4. Multivariate logistic analysis of the influence of BP on death or disability Variables
RR
95% CI
P value
Age Gender Hypertension Diabetes mellitus Dyslipidemia NIHSS score on admission Antiplatelet therapy Statins therapy SBP (120-159) (mm Hg) SBP , 120 (mm Hg) SBP $ 160 (mm Hg)
1.02 .84 1.35 .69 .63 1.27 .09 .93
.99-1.05 .40-1.79 .60-3.06 .23-2.03 .16-2.53 1.17-1.38 .01-1.34 .41-2.14
.241 .655 .472 .498 .518 .000 .081 .868
1.96 2.89
.60-6.33 1.20-6.91
.263 .017
Abbreviations: CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; RR, relative risk; SBP, systolic blood pressure.
5
hypertensive agents reduce cerebral blood flow in spite of their effects on lowering BP. In addition, the mechanisms proposed for patients with intracranial atherosclerotic disease include artery-to-artery embolism, local branch occlusion, hemodynamic compromise resulting from progressive arterial narrowing, or a combination of these factors.24 It is thus safe to treat hypertension in most patients with symptomatic intracranial artery stenosis or occlusion. More data are required on the effects of BP lowering on cerebral perfusion in these patients. Our study has several limitations. We analyzed only the effect of BP on admission. Thus, the effect of long-term BP treatment after hospitalization on outcome was not explored. Furthermore, arterial stenosis was not verified by DSA; however, it is impractical in a large consecutive registry study to verify stenosis by DSA. In addition, we did not analyze the effect of BP on recurrence because only 1.8% recurrences were verified in hospital. However, we speculated that the higher dependency or death in these patients may be attributed to the impairment resulting from recurrence. Despite these limitations, our study explored the relationship between BP on admission and outcomes in the setting of the acute or subacute stage by inclusion of consecutive patients and the blind evaluation of the study outcome.
Conclusions We found that higher BP on admission was associated with an increased risk of death or disability in patients with symptomatic intracranial atherosclerotic stenosis. It is reasonable that further studies on the effects of BP lowering in acute stroke include patients with intracranial atherosclerotic stenosis or occlusion.
References 1. Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension 2004;43:18-24. 2. Ntaios G, Bath P, Michel P. Blood pressure treatment in acute ischemic stroke: a review of studies and recommendations. Curr Opin Neurol 2010;23:46-52. 3. The European Stroke Organisation (ESO) Executive Committee and the ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507. 4. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870-947. 5. Geeganage CM, Bath PM. Relationship between therapeutic changes in blood pressure and outcomes in acute stroke: a metaregression. Hypertension 2009;54:775-781. 6. Gorelick PB, Wong KS, Bae HJ, et al. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke 2008;39:2396-2399. 7. Wong LK. Global burden of intracranial atherosclerosis. Int J Stroke 2006;1:158-159.
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6 8. Huang YN, Gao S, Li SW, et al. Vascular lesions in Chinese patients with transient ischemic attacks. Neurology 1997;48:524-525. 9. Qureshi AI. Acute hypertensive response in patients with stroke: pathophysiology and management. Circulation 2008;118:176-187. 10. Tikhonoff V, Zhang H, Richart T, et al. Blood pressure as a prognostic factor after acute stroke. Lancet Neurol 2009; 8:938-948. 11. Turan TN, Cotsonis G, Lynn MJ, et al. Relationship between blood pressure and stroke recurrence in patients with intracranial arterial stenosis. Circulation 2007;115:2969-2975. 12. Sandset EC, Bath PM, Boysen G, et al. The angiotensinreceptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, doubleblind trial. Lancet 2011;377:741-750. 13. Stroke–1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. Stroke 1989;20:1407-1431. 14. Wilterdink JL, Bendixen B, Adams HP Jr, et al. Effect of prior aspirin use on stroke severity in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Stroke 2001; 32:2836-2840. 15. Hao Z, Wu B, Lin S, et al. Association between renal function and clinical outcome in patients with acute stroke. Eur Neurol 2010;63:237-242. 16. Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000;21:643-646. 17. Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic mod-
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erate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998;339:1415-1425. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604-607. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011;365:993-1003. Paciaroni M, Agnelli G, Caso V, et al. Effect of carotid stenosis on the prognostic value of admission blood pressure in patients with acute ischemic stroke. Atherosclerosis 2009;206:469-473. Rothwell PM, Howard SC, Spence JD. Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease. Stroke 2003; 34:2583-2590. Sare GM, Gray LJ, Wardlaw J, et al. Is lowering blood pressure hazardous in patients with significant ipsilateral carotid stenosis and acute ischaemic stroke? Interim assessment in the ‘‘Efficacy of Nitric Oxide in Stroke’’ trial. Blood Press Monit 2009;14:20-25. Sare GM, Gray LJ, Bath PM. Effect of antihypertensive agents on cerebral blood flow and flow velocity in acute ischaemic stroke: systematic review of controlled studies. J Hypertens 2008;26:1058-1064. Wong KS, Gao S, Chan YL, et al. Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study. Ann Neurol 2002; 52:74-81.
Background: Intracranial atherosclerotic stenosis is common in Asian, black, and Hispanic individuals. However, the management of blood pressure (BP) in the setting of acute stage in these patients is controversial. The present study aims to explore the relationship between BP on admission and outcomes in acute ischemic stroke patients with intracranial atherosclerotic stenosis or occlusion. Methods: We prospectively registered consecutive cases of acute ischemic stroke from September 01, 2009, to August 31, 2011. Patients with severe intracranial stenosis or occlusion were included. Death or disability was followed up at the end of the third month. The multivariate logistic regression model was used to analyze the relationship between BP on admission and clinical outcomes. Results: We included 215 cases, which accounted for 22.7% (215 of 946) of the total registered cases. The mean age was 60.44 6 13.23 years. The median time of symptoms onset to admission was 72 hours (2-270 hours). Patients with systolic blood pressure (SBP) of 120-159 mm Hg or diastolic BP of 70-89 mm Hg had the lowest death or disability. After adjustment of confounders, SBP of 160 mm Hg or more on admission was the independent predictor of death or disability at the third month (relative risk [RR], 2.89; 95% confidence interval [CI], 1.20-6.91). SBP less than 120 mm Hg on admission had a trend of increasing death or disability (RR, 1.96; 95% CI, .60-6.33). Conclusions: Higher BP on admission was associated with an increased risk of death or disability in patients with symptomatic intracranial artery stenosis or occlusion. It is reasonable that further studies on the effects of BP lowering in acute stroke include these patients. Key Words: Acute ischemic stroke—intracranial stenosis or occlusion—blood pressure—death or disability. Ó 2013 by National Stroke Association
From the Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. Received October 16, 2013; revision received November 18, 2013; accepted November 27, 2013. This research was supported by the Science and Technology Infrastructure Projects of Sichuan Province (No. 2012JCPT008) and the Science and Technology Program of Science and Technology Department of Sichuan Province (No. 2011SZ0202). Address correspondence to Ming Liu, MD, PhD, Stroke Clinical Research Unit, Department of Neurology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, China. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.11.025
Introduction The optimal management of blood pressure (BP) in acute ischemic stroke is inconclusive, and current published guidelines are based on few studies and expert opinions.1-5 Intracranial atherosclerotic stenosis is common in Asian, black, and Hispanic individuals.6 It is estimated to account for 33%-50% of strokes and 50% of transient ischemic attacks in the Chinese population.7,8 So it is important to determine the best BP management in these patients. As we know, epidemiology suggests that high BP could result in worsening cerebral edema and hemorrhagic transformation, whereas pathophysiology argues that lower systemic BP could put brain tissue at
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2013: pp 1-6
1
Z. HAO ET AL.
2 9,10
a risk of underperfusion and worsening infarction. This argument is further compounded by the fear that patients with intracranial atherosclerotic stenosis or occlusion may be even more at a risk of hemodynamic compromise. The analysis of data from the Warfarin–Aspirin Symptomatic Intracranial Disease study provides the most information to date on the relationship between the BP level and risk of stroke in these patients.11 It indicates that higher BP is associated with an increased (not decreased) risk of ischemic stroke and stroke in the territory of the stenotic vessels. However, these data examined long-term BP treatment rather than in the acute or subacute phase of stroke. Recently, the results of the Scandinavian Candesartan Acute Stroke Trial, which aimed to explore whether lowering of BP would be beneficial in patients with acute stroke, showed that treatment with candesartan was associated with a nonsignificant worse functional outcome and no reduction in vascular events.12 Although the results were adjusted for age, cause of stroke (ischemic versus hemorrhagic), stroke severity, and systolic blood pressure (SBP) levels, the trial did not consider effects of treatment in other relevant clinical subgroups, such as patients with atherosclerotic stenosis or occlusion. In the absence of definitive data from clinical trials, the best clinical practice for the management of BP in the setting of acute ischemic stroke with intracranial atherosclerotic stenosis or occlusion is unclear. This study aims to describe the characteristics of BP and explore the relationship between BP on admission and outcomes in these common subgroup patients.
age data were recorded at the time of assessment using a standardized structured form. Risk factors included hypertension, diabetes, dyslipidemia, coronary heart disease, history of stroke, and status of smoking and alcohol. Severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS). NIHSS score was graded as follows: mild (0-6), medium (7-15), and severe ($16).14 Laboratory data included levels of triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein on admission. We also recorded the using of antiplatelet therapy, antihypertensive treatment, and statins therapy during the hospitalization. Details of the Chengdu Stroke Registry have been described previously.15 In this analysis, severe intracranial atherosclerotic stenosis (70%-99%) or occlusion was defined using the criteria of Samuels for MR angiography16 or the North American Symptomatic Carotid Endarterectomy Trial for digital subtraction angiography (DSA).17 Patients with cardiac embolism, other causes of intracranial stenosis or occlusion, or a lack of vascular investigation were excluded.
BP Measurement and Group BP measurements were taken at 9 AM daily since admission when patients were in the supine position using a wrist BP meter for 7 days or when patients die or are discharged. BP readings were grouped as follows: SBP less than 120, 120-139, 140-159, 160-179, 180-199, 200-219, and of 220 mm Hg or more; diastolic blood pressure (DBP) less than 60, 60-69, 70-79, 80-89, 90-99, 100-109, 110-119, and of 120 mm Hg or more.
Assessment of Outcome
Subjects and Methods Subjects We included acute ischemic stroke admitted consecutively to neurologic wards of the West China Hospital, Sichuan University, within 30 days of symptom onset between September 01, 2009, and August 31, 2011. All patients had a clinical diagnosis of stroke according to the World Health Organization criteria,13 and intracranial hemorrhage was further excluded by computed tomography or magnetic resonance (MR) imaging scan in the hospital. Because this is an observational study that will only assess outcomes in participants, all participants or their designated relatives provided verbal informed consent for obtaining relative prognostic information. This research project was approved by the Scientific Research Department of West China Hospital, which conformed to the local ethic criteria for human researches.
Data Collection Details of patient demography, risk factors, stroke severity, BP on admission, laboratory test, and brain im-
The main outcomes were death and disability at 3 months after stroke. Death was all-cause case fatality. Disability was defined as the modified Rankin Scale score greater than 2.18 Patients were followed up by telephone call, clinic interview, or letter inquiry. To ensure the quality of information collection, all staff members received training in the beginning according to our standard operational manual. All data were recorded in a structured data sheet. The outcome assessors were blinded to the information of patients.
Statistical Analysis Differences between 2 groups were tested using t test, Mann–Whitney U test, or chi-square test whichever was appropriate. Variables that were identified as significant in the univariate analyses (P , .05) and clinical significant variables were entered into multivariate logistic regression analyses. The multivariate logistic regression model was used to determine the association between BP on admission and patient outcomes. All statistical analyses were performed with SPSS for Windows, Version 16.0 (IBM, Chicago, IL).
BLOOD PRESSURE AND INTRACRANIAL ATHEROSCLEROTIC STENOSIS
3
Table 1. Blood pressure–lowering agents during hospitalization Drugs
N, %
Drugs
N, %
Drugs
N, %
CCB 1 ARB CCB 1 ACE-I CCB 1 B ARB 1 B ARB 1 D ACE-I 1 D
23, 26.4% 5, 5.7% 2, 2.3% 2, 2.3% 2, 2.3% 1, 1.2%
ARB CCB B
30, 34.5% 19, 21.8% 1, 1.2%
CCB 1 ARB 1 B
2, 2.3%
Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blockers; B, beta-blockers; CCB, calcium channel blockers; D, diuretic agents.
Results Baseline Characteristics We included 1655 patients with acute ischemic stroke within 30 days of symptom onset from onset. Of them, patients with severe intracranial stenosis or occlusion accounted for 13% (215 of 1655). When excluded cardiac embolism or other causes of intracranial stenosis or occlusion or a lack of vascular investigation, patients with severe intracranial stenosis or occlusion accounted for 22.7% (215 of 946). The mean age was 60.44 6 13.23 years (25-90 years). Men accounted for 60.5% (130 of 215). The median time of symptoms onset to admission was 72 hours (2-270 hours). A total of 90.2% (194 of 215) of cases were admitted within 2 weeks. The proportions of vascular investigations were 88.4% MR angiography and 25.6% DSA, respectively. During hospitalization, 97.2% patients received antiplatelet therapy, 40.5% patients received antihypertensive treatment, and 70.7% patients received statins. Seventy-eight patients had death or disability at 3 months after stroke. The antihypertensive treatments were oral drugs, and the details are reported in Table 1. Compared with patients without severe intracranial stenosis or occlusion, patients with intracranial severe stenosis or occlusion were younger, had admission delay, had slight lower BP on admission, had higher proportion of severe patients, and case fatality or disability at the end of 3 months. There were no significant differences between 2 groups on vascular risk factors, antiplatelet therapy, antihypertensive treatment, and statins therapy (data not shown). Compared with patients without BP lowering, patients receiving antihypertensive treatment during hospitalization were older, had higher SBP or DBP on admission, had higher proportion of patients with hypertension, diabetes mellitus, statins therapy and case fatality, or disability at the end of 3 months (Table 2).
Relationship between BP on Admission and Outcomes There were no significant differences as to the proportion of SBP of 220 or more, 200 or more, and 180 mm Hg or more and DBP greater than 120, greater than 110, and greater than 100 mm Hg between patients
with severe intracranial stenosis or occlusion and overall patients (Table 3). The trends of BP were downward, especially in the first day. The relationship between BP on admission and death or disability was U-shaped curve. Patients with SBP of 120-159 mm Hg or DBP of 70-89 mm Hg had the lowest rate of death or disability (Fig 1).
The Influence of BP on Outcomes at the End of Follow-up After adjustment of potential confounders, such as age, sex, NIHSS score on admission, and vascular risk factors, etc., SBP of 160 mm Hg or more on admission was the independent predictor of death or disability at the third month, and the patients had a significant higher risk for death or disability (relative risk [RR], 2.89; 95% confidence interval, 1.20-6.91). SBP less than 120 mm Hg on admission was not the independent predictor of death or disability but had a trend of increasing death or disability (RR, 1.96; 95% confidence interval, .60-6.33) (Table 4).
Discussion Intracranial atherosclerotic stenosis or occlusion is common in Asian, black, and Hispanic individuals; however, the best clinical practice for the management of BP in these patients is unclear. In the present study, we investigated the relationship between BP on admission and outcomes in acute ischemic stroke with severe intracranial atherosclerotic stenosis or occlusion in a hospitalized Chinese population. We found that SBP of 160 mm Hg or more on admission was associated with z3.0-fold increased risk of death or disability in these patients after adjustment for age, sex, NIHSS scores, and vascular risk factors. We found that there were no significant differences as to the proportion of SBP of 220 or more, 200 or more, and 180 mm Hg or more and DBP greater than 120, greater than 110, and greater than 100 mm Hg between patients with severe intracranial stenosis or occlusion and overall patients. The proportion of patients with very high BP, such as SBP of 220 or more, 200 or more, and 180 mm Hg or more, was also very low. Current
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Table 2. Comparison of patients with intracranial severe stenosis/occlusion with BP lowering and without BP lowering Variates
BP lowering (N 5 87)
Non-BP lowering (N 5 128)
P
Age (y) Male (%) Time from onset (h) SBP on admission (mm Hg) DBP on admission (mm Hg) Hypertension (%) Diabetes mellitus (%) Dyslipidemia (%) Coronary heart disease (%) History of ischemic stroke (%) Alcohol (%) Smoking (%) NIHSS score on admission Triglyceride Cholesterol Low-density lipoprotein High-density lipoprotein Antiplatelet therapy (%) Statins therapy (%) Death or disability at 3 mo (%)
63.87 (12.15) 56 (64.4%) 72 (24-144) 153.72 (21.75) 89.11 (14.24) 68 (78.2%) 20 (23.0%) 8 (9.2%) 5 (5.7%) 6 (6.9%) 15 (17.2%) 27 (31.0%) 6 (3-12) 1.84 (1.30) 4.59 (1.02) 2.89 (1.30) 1.20 (.33) 84 (96.6%) 68 (78.2%) 40 (46.0%)
57.90 (13.95) 74 (57.8%) 72 (24-168) 133.69 (18.57) 80.13 (12.84) 47 (36.7) 14 (10.9%) 10 (7.8%) 5 (3.9%) 9 (7.0%) 22 (17.2%) 37 (28.9%) 5 (2-10) 1.62 (.92) 4.60 (.98) 2.75 (.89) 1.27 (.33) 126 (98.4%) 83 (64.8%) 38 (29.7%)
.001 .335 .979 .000 .000 .000 .017 .719 .530 .970 .992 .738 .520 .155 .959 .360 .116 .396 .036 .021
Abbreviations: DBP, diastolic blood pressure; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.
guidelines generally recommend control of high SBP (.180, .200, and .220 mm Hg). These findings emphasized that the value of BP lowering in these patients should be re-evaluated in light of very low proportion. In contrast to the clinical practice that many clinicians allow BP to keep high in patients with intracranial stenosis to protect against hypoperfusion, we found that higher BP on admission was associated with the increased risk of death or disability, which is similar to the findings from the Warfarin-Aspirin Symptomatic Intracranial Disease study.11 It indicates that higher BP is associated with the increased (not decreased) risk of ischemic stroke and stroke in the territory of the stenotic vessel. However, these data examined long-term BP treatment (within 90 days). Our study reinforces the results in the setting of the acute or subacute stage; 90.2% of cases were
admitted within 2 weeks. Recently, the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which was the first randomized controlled trials to evaluate stenting for symptomatic intracranial artery stenosis ($70%), was terminated owing to safety concerns, and it concluded that aggressive medical management was superior to percutaneous transluminal angioplasty and stenting. In this study, patients were targeted an SBP of less than 140 mm Hg (,130 mm Hg in the case of patients with diabetes).19 It hints that lowering BP in patients with symptomatic intracranial artery stenosis is safety and even can be beneficial. Paciaroni et al20 reported that high BP was associated with a lower mortality at 3 months in patients with carotid stenosis of 50% or more or occlusion. The study of
Table 3. BP characteristics between patients with severe intracranial stenosis or occlusion and overall patients
BP on admission
All patients (N 5 1655)
Severe stenosis/occlusion (N 5 215)
P value
Mean SBP (mm Hg) Mean DBP (mm Hg) SBP $ 220 (mm Hg) DBP . 120 (mm Hg) SBP $ 200 (mm Hg) DBP . 110 (mm Hg) SBP $ 180 (mm Hg) DBP . 100 (mm Hg) SBP , 120 (mm Hg)
142.42 6 23.41 83.45 6 14.53 6 (.4%) 24 (1.5%) 23 (1.4%) 68 (4.1%) 108 (6.5%) 193 (11.7%) 249 (15.0%)
141.84 6 22.19 83.79 6 14.10 0 (0%) 4 (1.9%) 1 (.50%) 10 (4.7%) 10 (4.7%) 24 (11.2%) 22 (10.2%)
.730 .752 1.000 .554 .513 .708 .288 .830 .059
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
BLOOD PRESSURE AND INTRACRANIAL ATHEROSCLEROTIC STENOSIS
Figure 1. Relationship between blood pressure on admission and rate of death or disability.
Rothwell et al21 had shown that the risk of stroke increases with BP in most patients with symptomatic carotid artery disease, but it is inverted in patients with bilateral carotid stenosis of 70% or more. Recently, interim data analysis from the Efficacy of Nitric Oxide in Stroke trial showed that patients with ipsilateral carotid stenosis of 50% or more were no more likely to suffer from stroke recurrence or neurologic deterioration by day 7 than those without.22 It is reasonable to include patients with carotid stenosis into trials of acute BP lowering. On the other hand, the systematic review from Sare et al23 showed there was little existing evidence that antiTable 4. Multivariate logistic analysis of the influence of BP on death or disability Variables
RR
95% CI
P value
Age Gender Hypertension Diabetes mellitus Dyslipidemia NIHSS score on admission Antiplatelet therapy Statins therapy SBP (120-159) (mm Hg) SBP , 120 (mm Hg) SBP $ 160 (mm Hg)
1.02 .84 1.35 .69 .63 1.27 .09 .93
.99-1.05 .40-1.79 .60-3.06 .23-2.03 .16-2.53 1.17-1.38 .01-1.34 .41-2.14
.241 .655 .472 .498 .518 .000 .081 .868
1.96 2.89
.60-6.33 1.20-6.91
.263 .017
Abbreviations: CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; RR, relative risk; SBP, systolic blood pressure.
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hypertensive agents reduce cerebral blood flow in spite of their effects on lowering BP. In addition, the mechanisms proposed for patients with intracranial atherosclerotic disease include artery-to-artery embolism, local branch occlusion, hemodynamic compromise resulting from progressive arterial narrowing, or a combination of these factors.24 It is thus safe to treat hypertension in most patients with symptomatic intracranial artery stenosis or occlusion. More data are required on the effects of BP lowering on cerebral perfusion in these patients. Our study has several limitations. We analyzed only the effect of BP on admission. Thus, the effect of long-term BP treatment after hospitalization on outcome was not explored. Furthermore, arterial stenosis was not verified by DSA; however, it is impractical in a large consecutive registry study to verify stenosis by DSA. In addition, we did not analyze the effect of BP on recurrence because only 1.8% recurrences were verified in hospital. However, we speculated that the higher dependency or death in these patients may be attributed to the impairment resulting from recurrence. Despite these limitations, our study explored the relationship between BP on admission and outcomes in the setting of the acute or subacute stage by inclusion of consecutive patients and the blind evaluation of the study outcome.
Conclusions We found that higher BP on admission was associated with an increased risk of death or disability in patients with symptomatic intracranial atherosclerotic stenosis. It is reasonable that further studies on the effects of BP lowering in acute stroke include patients with intracranial atherosclerotic stenosis or occlusion.
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