Hypertensive Patients Using Thiazide Diuretics as Primary Stroke Prevention Make Better Functional Outcome after Ischemic Stroke Hong-Mo Shih, MD, Wei Chun Lin, MD, Cheng-Hsien Wang, MD, and Leng-Chieh Lin, MD
Background: Thiazides have been used for the control of blood pressure and primary prevention of ischemic stroke. No previous studies have assessed the influence of thiazides on functional prognosis after ischemic stroke. Methods: Demographics, prestroke conditions, poststroke National Institutes of Health Stroke Scale score, and clinical and laboratory parameters were prospectively registered in 216 Taiwanese patients. One hundred forty patients who completed follow-up 3 months after experiencing ischemic stroke were assessed with the modified Rankin scale as functional prognoses. Results: Twenty-one patients used thiazide to control hypertension before experiencing ischemic stroke. No differences of stroke subtypes and comorbidities before stroke were observed between the 2 groups. The emergency department National Institutes of Health Stroke Scale was lesser among thiazide users (4 [2-7] versus 6 [4-16], P 5 .02). Among 140 patients who completed follow-up in 90 days, thiazide users had more favorable functional status (modified Rankin scale #2: 42.4% versus 26.9%, P 5 .02, odds ratio 3.34, 95%, confidence interval .130-.862). Conclusion: Hypertensive patients treated with thiazides long term had a lesser severity of stroke and better functional outcomes after ischemic stroke. Key Words: Thiazide-diuretics—ischemic stroke—hypertension— functional prognosis—stroke in evolution—stroke primary prevention. Ó 2014 by National Stroke Association
Introduction Ischemic stroke is one of the major causes of death worldwide. Epidemiologic studies have revealed that arterial hypertension is the most likely risk factor for From the Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi and Chang Gung University College of Medicine, Puzi City, Chiayi County, Taiwan (R.O.C.). Received March 28, 2014; revision received May 15, 2014; accepted May 20, 2014. Supported by grants CMRPG690441, CMRPG690442, CMRPG 690443, CMRPG 690431, CMRPG 690432, and CMRPG 690433 from the Chang Gung Medical Research Council. Address correspondence to Leng-Chieh Lin, MD, Attending Physician of Emergency Medicine, Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi and Chang Gung University College of Medicine, Chiayi No. 6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 613, Taiwan (R.O.C.). E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.05.021
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stroke.1,2 Approximately 54% of stroke and 47% of ischemic heart disease cases worldwide are attributable to high blood pressure.1 The risk of hypertension in ischemic stroke patients, however, can be reversed with antihypertensive drug treatment, especially in elderly patients who have isolated systolic hypertension.3,4 Thiazide diuretics have been a mainstay of essential hypertension therapy. A recent Cochrane review of 19 randomized controlled trials demonstrated that thiazide diuretics reduced overall mortality and risk of stroke.5 In the Systolic Hypertension in the Elderly Program, chlorthalidone caused a 36% reduction in the incidence of stroke.3 Without contraindication, thiazide diuretics may serve as a first-line antihypertensive medication for primary stroke prevention.6 Only a small amount of medical literature has been published about the prognosis of long-term thiazide users after acute ischemic stroke. We performed this prospective observational study to evaluate the severity and
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 9 (October), 2014: pp 2414-2418
STROKE IN THIAZIDE USERS
functional outcome after ischemic stroke in patients who used thiazides to control hypertension.
Methods and Materials Study Design This was a prospective observational study of consecutive patients admitted to the Chia-Yi Chang Gung Memorial Hospital, a stroke referral center, in the period from between October 2007 and June 2010. All patients with a measurable National Institutes of Health Stroke Scale (NIHSS) score were recruited to participate. In addition, patients transferred from other hospitals also were eligible for enrollment. Patients were excluded if they had a previous acute ischemic stroke, unknown drug history, recorded time .12 hours between the onset of neurologic symptoms and presentation to the emergency department (ED), evidence of hemorrhagic stroke assessed by brain computed tomography (CT), fibrinolytic therapy requirement, diagnosed transient ischemic attack, or lack of ischemic stroke diagnosis on discharge. The study protocol was approved by the Chang Gung Memorial Hospital institutional review board. Written informed consent was obtained from all approached patients.
Diagnostic Studies Data were collected from the ED participants via a standardized data collection form, including age, sex, arterial blood pressure on ED admission and every 8 hours for the first 3 days, admission blood glucose, complete blood count, blood urea nitrogen, creatine, blood urea nitrogen/creatine ratio, triglycerides, and total cholesterol. All patients received brain CT scans within 6 hours of ED admission. A radiologist from the stroke team interpreted the CT findings. Previous medication histories also were reviewed.
Clinical Assessment Stroke severity was assessed via the NIHSS and performed by physicians trained in NIHSS assessment. This assessment was carried out immediately after a patient’s ED admission and every 24 hours within the first 3 days during hospitalization. NIHSS of ED and 24 hours after admission were compared to see whether there was early improvement clinically. Stroke in evolution (SIE) was diagnosed in those patients who experienced worsening neurologic condition as indicated by an increase of 4 or more points on the NIHSS within 72 hours after stroke onset. Stroke subtype using TOAST classification was made before discharge after surveyed possible cause of stroke. Neurologists evaluated patient functional independent status with modified Rankin scale (mRS) 3 months after stroke. A good functional outcome was defined as mRS #2.7
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Statistical Analysis Patients were divided into 2 groups according to use or nonuse of thiazides. The differences between the 2 groups were analyzed using the chi-square (c2) test for categorical variables; they were expressed as frequencies and percentages. Continuous data were analyzed with independent two sample t tests for continuous variables expressed as a mean 6 SD. NIHSS was analyzed with the Mann-Whitney U test and presented via median (interquartile range). Variables that were associated with a prognosis of stroke, including age, sex, stroke subtype (lacunar or nonlacunar), risk of cardiac embolism (atrial fibrillation or congestive heart failure), use or nonuse of thiazide, SIE, and glucose level on admission, were used in multivariate analysis.8 All statistical assessments were 2-sided, and differences with P-values , .05 were considered statistically significant. Statistical analyses were performed using SPSS 17.0 statistical software (SPSS Institute, Chicago, IL).
Results There were 216 patients who met the enrolled criteria and agreed to join this study. Only 140 patient completed followup in 90 days. Patients were divided into 2 groups according to their thiazide use for controlling blood pressure. Twentyone patients used thiazides. The mean age of 140 patients was 70.1 6 10.3 years of age with a range between 46 and 96 years of age. Table 1 summarizes both the demographic and clinical characteristics of 21 thiazide users and 119 thiazide nonusers. There were no differences found between the 2 groups in multiple variables, including associated underlying disease, age, and sex, as well as clinical features, including blood pressure measurements, heart rate, blood glucose levels, and triglyceride levels. Table 2 compares initial NIHSS at ED, better NIHSS when followed 24 hours after admission, SIE within 72 hours, favorable outcome as mRS #2 90 days after stroke, and stroke subtypes using the TOAST (ie, Trial of Org 10172 in Acute Stroke Treatment) classification. There was no difference in stroke subtypes between the 2 groups. The ED NIHSS was lower among thiazide users (4 [2-7] versus 6 [4-16], P 5 .02). There also was more neurologic improvement at 24 hours after admission and less SIE within 72 hours in thiazide users, although not statistically significant. There was a statistically significant increase in favorable function outcome among thiazide users as seen by the mRS followed at 90 days later (mRS #2: 42.4% versus 26.9%, P 5.02, odds ratio [OR] 3.34, 95%, confidence interval [95% CI] .130-.862). Table 3 shows the result of multivariate logistic regression of variables that may influence functional outcome of stroke patients, including age, sex, use or nonuse of thiazides, glucose levels on admission, SIE $4, the presence
H.-M. SHIH ET AL.
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Table 1. Demographic data, clinical feature and comorbidities
Demographic Age* Maley Diabetes mellitusy Hyperlipidemiay Coronary artery diseasey Atrial fibrillationy Systolic blood pressure, * mmHg Diastolic blood pressure, * mmHg Heart rate, * beats/min Hemoglobin, * g/dL Glucose,* mg/dL Triglycerides,* mg/dL Cholesterol, * mg/dL Uric acid, * mg/dL BUN/Cr . 15y
Thiazide nonusers, n 5 119
Thiazides users, n 5 21
P -value
70.6 6 10.5 71 (59.7%) 54 (45.4%)
67.4 6 9.6 15 (71.4%) 13 (61.9%)
.199 .307 .162
7 (5.9%) 8 (6.7%)
2 (9.5%) 1 (4.8%)
.530 .736
30 (25.2%)
6 (28.6%)
.745
169.7 6 35.1 178.5 6 33.5 91.1 6 21.3
93.5 6 17.5
.289
Table 2. Comparison of stroke subtypes and stroke severity, functional outcomes Stroke subtypes, severity and outcomes ED NIHSS* NIHSS 24 hours , ED SIE $4 mRS #2* Large-artery atherosclerosis Cardioembolism Lacunar stroke Stroke of undetermined etiology
Thiazide nonusers, n 5 119
Thiazide users, n 5 21
6 (4-16) 25 (21%)
P OR -value
4 (2-7) 7 (33.3%)
.02 .26
17 (14.3%) 1 (4.8%) 3.33 32 (26.9%) 11 (42.4) 26 (21.8%) 4 (19.0%) 1.19
.310 .02 .773
16 (13.4%) 33 (27.7%) 44 (37%)
.621 .607 .922
2 (9.5%) 1.47 7 (33.3%) .77 8 (38.1%) .95
.623
82.2 6 16.8
80.0 6 17.2
.589
13.4 6 2.1
13.8 6 1.9
.274
161.7 6 95.1 191.2 6 91.1 118.7 6 66.8 117.6 6 69.8
.190 .948
178.3 6 44.4 168.2 6 5.36
.384
5.4 6 1.8
6.0 6 1.4
.207
51 (42.9%)
5 (23.8%)
.100
Abbreviations: BUN, blood urea nitrogen; Cr, creatine. *Continuous data expressed as mean 6 SD. yCategorical data expressed as number (%).
of lacunar stroke, and the risk of cardioembolic stroke.8 After multivariate adjusted analyses, age (OR 1.084, 95% CI 1.037-1.134, P , .001), cardioembolic stroke (OR .539, 95% CI .296-.984, P 5 .044), and use of thiazides (OR .326, 95% CI .111-.956, P 5 .041) remained independent predictors.
Abbreviations: ED, emergency department; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; OR, odds ratio; SIE, stroke in evolution. Categorical data are expressed as number (%); NIHSS presented with median (interquartile range). *P , .05.
and lead to lesser stroke severity and favorable functional outcomes. Long-term thiazide therapy lowers blood pressure through a vasodilation effect,9,10 and this vasodilation effect persists for weeks after stopping thiazide therapy.11 As Fujii et al12 discussed in their study, treating hypertension with hydrochlorothiazide can lead to smaller infarct volumes. Thiazides may restore the dilatory capacity of cerebral arterioles, consequently improving the cerebral blood flow reserve and the collateral vascular capacity after acute ischemic stroke.12 This collateral cerebral blood supply may attenuate arterial occlusion effects associated with infarct growth.13-16 As a result, patients with long-term thiazide use might have better collateral circulation and relative smaller infarct Table 3. Multivariate logistic regression analysis of favorable functional outcome in 90 days (mRS # 2) Multivariate (adjusted)
Discussion We found that long-term thiazide uses who experienced their first acute ischemic stroke experienced it less severely, with lower initial NIHSS and better 3-month mRS score results. No previous studies have assessed the severity of stroke and functional outcomes after ischemic stroke in long-term thiazide users. The exact mechanism to achieve this benefit remains unclear; we have discussed possible contributing mechanisms subsequently. Several factors may contribute. First, long-term thiazide users may have a better collateral cerebral blood supply after ischemic stroke that can reduce infarct volumes
Variables Age* Sex Thiazide user* Glucose SIE $4 Lacunar stroke Cardioembolic stroke*
OR
95% CI
1.084 1.037-1.134 1.165 .487-2.785 .326 .111-.956 1.004 .999-1.009 6.762 .815-56.119 .872 .640-1.189 .539 .296-.984
P-value ,.001 .732 .041 .164 .077 .386 .044
Abbreviations: CI, confidence interval; mRS, modified Rankin Scale; OR, odds ratio; SIE, stroke in evolution. *P , .05.
STROKE IN THIAZIDE USERS
volume, which accounted for less stroke severity and better functional outcome, as seen in our study. Although no statistically significant, the greater ratio of decreased 24 hours NIHSS among thiazides users also may support our hypothesis about better collateral circulation. On the other hand, the effect of fluid retention from thiazide withdrawal may help provide adequate postischemic stroke cerebral circulation. Increased blood pressure during the acute stage of ischemic stroke is necessary to maintain brain perfusion in borderline ischemic areas.17 Thus, we often discontinued antihypertensive agents during the early stage of ischemic strokes. As Tarazi et al11 have discussed, patients who withdrew from long-term thiazide diuretics increased their body weight and plasma volume during the first week. The fluid retentive effect avoided dehydration status that increases blood viscosity and elevates hematocrit, which have been shown to be associated with a larger infarct volume in patients with cerebral infarction.18 In addition, the relative hemodilutory effect on such fluid retention status also may play a neuroprotective role postischemic stroke.19 Stroke patients who withdraw from thiazides may achieve adequate plasma volume through this fluid retention effect, which leads to better cerebral circulation and better functional outcomes. In our study, the finding that long-term thiazide users experienced lesser amounts of SIE may support the concept of more adequate fluid status from thiazides withdrawal. There were a total of 18 patients (12.86%) who had early neurologic deterioration, similar to previous studies.20-22 As a previous study discussed, dehydration status increased an early stroke-in-evolution.23,24 Although long-term thiazide use caused depletion of plasma volumes, volumes returned to nearly normal levels after long-term use.9-11,25 In our observational study, the slight degree of dehydration did not cause greater amounts of SIE. On the contrary, there was decreased risk of SIE among thiazide users, which may support the hypothesis of fluid retention effect after thiazide withdrawal. The expanded plasma volume protected stroke patients from dehydration, resulting in a decreased risk of SIE and better functional outcomes.
Limitations Our results are limited by sample size and thus statistical power. The use of a single institution also may limit the results, because there is no comparison with other geographic locations. The hypothesis of collateral circulation and fluid retention could not be proven directly. In addition, we did not compare thiazides with other antihypertensive drugs, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and even combination therapy for primary stroke prevention. Further randomized control studies may be needed to verify functional progress results of
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different antihypertensive treatments for primary stroke prevention.
Conclusion Our findings suggest that hypertensive patients treated long term with thiazides had lesser stroke severity, better functional outcomes after ischemic stroke, and showed no difference in SIE risk. Hence, it is safe to use thiazides as a first-line antihypertensive treatment. There may be additional benefits from thiazides along with lowering blood pressure and stroke prevention.
References 1. Lawes CM, Vander Hoorn S, Rodgers A, International Society of Hypertension. Global burden of bloodpressure-related disease, 2001. Lancet 2008;371:1513-1518. 2. D’Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: adjustment for antihypertensive medication. The Framingham Study. Stroke 1994;25:40-43. 3. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-3264. 4. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000;355:865-872. 5. Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database Syst Rev 2009;(3):CD001841. 6. Ravenni R, Jabre JF, Casiglia E, Mazza A. Primary stroke prevention and hypertension treatment: which is the first-line strategy? Neurol Int 2011;3:e12. 7. Leifer D, Bravata DM, Connors JJ 3rd, et al. Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2011;42:849-877. 8. Saposnik G, Raptis S, Kapral MK, et al. Investigators of the Registry of the Canadian Stroke Network and the Stroke Outcome Research Canada Working Group The iScore predicts poor functional outcomes early after hospitalization for an acute ischemic stroke. Stroke 2011; 42:3421-3428. 9. Shah S, Khatri I, Freis ED. Mechanism of antihypertensive effect of thiazide diuretics. Am Heart J 1978; 95:611-618. 10. van Brummelen P, Man in’t Veld AJ, Schalekamp MA. Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders. Clin Pharmacol Ther 1980;27:328-336. 11. Tarazi RC, Dustan HP, Frohlich ED. Long-term thiazide therapy in essential hypertension. Evidence for persistent alteration in plasma volume and renin activity. Circulation 1970;41:709-717. 12. Fujii K, Weno BL, Baumbach GL, et al. Effect of antihypertensive treatment on focal cerebral infarction. Hypertension 1992;19:713-716. 13. Shuaib A, Butcher K, Mohammad AA, et al. Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. Lancet Neurol 2011;10:909-921.
2418 14. Campbell BC, Christensen S, Tress BM, et al, EPITHET Investigators. Failure of collateral blood flow is associated with infarct growth in ischemic stroke. J Cereb Blood Flow Metab 2013;33:1168-1172. 15. Kucinski T, Koch C, Eckert B, et al. Collateral circulation is an independent radiological predictor of outcome after thrombolysis in acute ischaemic stroke. Neuroradiology 2003;45:11-18. 16. Lima FO, Furie KL, Silva GS, et al. The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. Stroke 2010;41:2316-2322. 17. Aiyagari V, Gorelick PB. Management of blood pressure for acute and recurrent stroke. Stroke 2009;40:2251-2256. 18. Harrison MJ, Pollock S, Kendall BE, et al. Effect of haematocrit on carotid stenosis and cerebral infarction. Lancet 1981;2:114-115. 19. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008;55:363-389.
H.-M. SHIH ET AL. 20. Tei H, Uchiyama S, Ohara K, et al. Deteriorating ischemic stroke in 4 clinical categories classified by the Oxfordshire Community Stroke Project. Stroke 2000;31:2049-2054. 21. Arenillas JF, Rovira A, Molina CA, et al. Prediction of early neurological deterioration using diffusion- and perfusion-weighted imaging in hyperacute middle cerebral artery ischemic stroke. Stroke 2002;33:2197-2203. 22. Yamamoto H, Bogousslavsky J, van Melle G. Different predictors of neurological worsening in different causes of stroke. Arch Neurol 1998;55:481-486. 23. Lin LC, Lee TH, Chang CH, et al. Predictors of clinical deterioration during hospitalization following acute ischemic stroke. Eur Neurol 2012;67:186-192. 24. Schrock JW, Glasenapp M, Drogell K. Elevated blood urea nitrogen/creatinine ratio is associated with poor outcome in patients with ischemic stroke. Clin Neurol Neurosurg 2012;114:881-884. 25. Freis ED, Reda DJ, Materson BJ. Volume (weight) loss and blood pressure response following thiazide diuretics. Hypertension 1988;12:244-250.
Background: Thiazides have been used for the control of blood pressure and primary prevention of ischemic stroke. No previous studies have assessed the influence of thiazides on functional prognosis after ischemic stroke. Methods: Demographics, prestroke conditions, poststroke National Institutes of Health Stroke Scale score, and clinical and laboratory parameters were prospectively registered in 216 Taiwanese patients. One hundred forty patients who completed follow-up 3 months after experiencing ischemic stroke were assessed with the modified Rankin scale as functional prognoses. Results: Twenty-one patients used thiazide to control hypertension before experiencing ischemic stroke. No differences of stroke subtypes and comorbidities before stroke were observed between the 2 groups. The emergency department National Institutes of Health Stroke Scale was lesser among thiazide users (4 [2-7] versus 6 [4-16], P 5 .02). Among 140 patients who completed follow-up in 90 days, thiazide users had more favorable functional status (modified Rankin scale #2: 42.4% versus 26.9%, P 5 .02, odds ratio 3.34, 95%, confidence interval .130-.862). Conclusion: Hypertensive patients treated with thiazides long term had a lesser severity of stroke and better functional outcomes after ischemic stroke. Key Words: Thiazide-diuretics—ischemic stroke—hypertension— functional prognosis—stroke in evolution—stroke primary prevention. Ó 2014 by National Stroke Association
Introduction Ischemic stroke is one of the major causes of death worldwide. Epidemiologic studies have revealed that arterial hypertension is the most likely risk factor for From the Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi and Chang Gung University College of Medicine, Puzi City, Chiayi County, Taiwan (R.O.C.). Received March 28, 2014; revision received May 15, 2014; accepted May 20, 2014. Supported by grants CMRPG690441, CMRPG690442, CMRPG 690443, CMRPG 690431, CMRPG 690432, and CMRPG 690433 from the Chang Gung Medical Research Council. Address correspondence to Leng-Chieh Lin, MD, Attending Physician of Emergency Medicine, Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi and Chang Gung University College of Medicine, Chiayi No. 6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 613, Taiwan (R.O.C.). E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.05.021
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stroke.1,2 Approximately 54% of stroke and 47% of ischemic heart disease cases worldwide are attributable to high blood pressure.1 The risk of hypertension in ischemic stroke patients, however, can be reversed with antihypertensive drug treatment, especially in elderly patients who have isolated systolic hypertension.3,4 Thiazide diuretics have been a mainstay of essential hypertension therapy. A recent Cochrane review of 19 randomized controlled trials demonstrated that thiazide diuretics reduced overall mortality and risk of stroke.5 In the Systolic Hypertension in the Elderly Program, chlorthalidone caused a 36% reduction in the incidence of stroke.3 Without contraindication, thiazide diuretics may serve as a first-line antihypertensive medication for primary stroke prevention.6 Only a small amount of medical literature has been published about the prognosis of long-term thiazide users after acute ischemic stroke. We performed this prospective observational study to evaluate the severity and
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 9 (October), 2014: pp 2414-2418
STROKE IN THIAZIDE USERS
functional outcome after ischemic stroke in patients who used thiazides to control hypertension.
Methods and Materials Study Design This was a prospective observational study of consecutive patients admitted to the Chia-Yi Chang Gung Memorial Hospital, a stroke referral center, in the period from between October 2007 and June 2010. All patients with a measurable National Institutes of Health Stroke Scale (NIHSS) score were recruited to participate. In addition, patients transferred from other hospitals also were eligible for enrollment. Patients were excluded if they had a previous acute ischemic stroke, unknown drug history, recorded time .12 hours between the onset of neurologic symptoms and presentation to the emergency department (ED), evidence of hemorrhagic stroke assessed by brain computed tomography (CT), fibrinolytic therapy requirement, diagnosed transient ischemic attack, or lack of ischemic stroke diagnosis on discharge. The study protocol was approved by the Chang Gung Memorial Hospital institutional review board. Written informed consent was obtained from all approached patients.
Diagnostic Studies Data were collected from the ED participants via a standardized data collection form, including age, sex, arterial blood pressure on ED admission and every 8 hours for the first 3 days, admission blood glucose, complete blood count, blood urea nitrogen, creatine, blood urea nitrogen/creatine ratio, triglycerides, and total cholesterol. All patients received brain CT scans within 6 hours of ED admission. A radiologist from the stroke team interpreted the CT findings. Previous medication histories also were reviewed.
Clinical Assessment Stroke severity was assessed via the NIHSS and performed by physicians trained in NIHSS assessment. This assessment was carried out immediately after a patient’s ED admission and every 24 hours within the first 3 days during hospitalization. NIHSS of ED and 24 hours after admission were compared to see whether there was early improvement clinically. Stroke in evolution (SIE) was diagnosed in those patients who experienced worsening neurologic condition as indicated by an increase of 4 or more points on the NIHSS within 72 hours after stroke onset. Stroke subtype using TOAST classification was made before discharge after surveyed possible cause of stroke. Neurologists evaluated patient functional independent status with modified Rankin scale (mRS) 3 months after stroke. A good functional outcome was defined as mRS #2.7
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Statistical Analysis Patients were divided into 2 groups according to use or nonuse of thiazides. The differences between the 2 groups were analyzed using the chi-square (c2) test for categorical variables; they were expressed as frequencies and percentages. Continuous data were analyzed with independent two sample t tests for continuous variables expressed as a mean 6 SD. NIHSS was analyzed with the Mann-Whitney U test and presented via median (interquartile range). Variables that were associated with a prognosis of stroke, including age, sex, stroke subtype (lacunar or nonlacunar), risk of cardiac embolism (atrial fibrillation or congestive heart failure), use or nonuse of thiazide, SIE, and glucose level on admission, were used in multivariate analysis.8 All statistical assessments were 2-sided, and differences with P-values , .05 were considered statistically significant. Statistical analyses were performed using SPSS 17.0 statistical software (SPSS Institute, Chicago, IL).
Results There were 216 patients who met the enrolled criteria and agreed to join this study. Only 140 patient completed followup in 90 days. Patients were divided into 2 groups according to their thiazide use for controlling blood pressure. Twentyone patients used thiazides. The mean age of 140 patients was 70.1 6 10.3 years of age with a range between 46 and 96 years of age. Table 1 summarizes both the demographic and clinical characteristics of 21 thiazide users and 119 thiazide nonusers. There were no differences found between the 2 groups in multiple variables, including associated underlying disease, age, and sex, as well as clinical features, including blood pressure measurements, heart rate, blood glucose levels, and triglyceride levels. Table 2 compares initial NIHSS at ED, better NIHSS when followed 24 hours after admission, SIE within 72 hours, favorable outcome as mRS #2 90 days after stroke, and stroke subtypes using the TOAST (ie, Trial of Org 10172 in Acute Stroke Treatment) classification. There was no difference in stroke subtypes between the 2 groups. The ED NIHSS was lower among thiazide users (4 [2-7] versus 6 [4-16], P 5 .02). There also was more neurologic improvement at 24 hours after admission and less SIE within 72 hours in thiazide users, although not statistically significant. There was a statistically significant increase in favorable function outcome among thiazide users as seen by the mRS followed at 90 days later (mRS #2: 42.4% versus 26.9%, P 5.02, odds ratio [OR] 3.34, 95%, confidence interval [95% CI] .130-.862). Table 3 shows the result of multivariate logistic regression of variables that may influence functional outcome of stroke patients, including age, sex, use or nonuse of thiazides, glucose levels on admission, SIE $4, the presence
H.-M. SHIH ET AL.
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Table 1. Demographic data, clinical feature and comorbidities
Demographic Age* Maley Diabetes mellitusy Hyperlipidemiay Coronary artery diseasey Atrial fibrillationy Systolic blood pressure, * mmHg Diastolic blood pressure, * mmHg Heart rate, * beats/min Hemoglobin, * g/dL Glucose,* mg/dL Triglycerides,* mg/dL Cholesterol, * mg/dL Uric acid, * mg/dL BUN/Cr . 15y
Thiazide nonusers, n 5 119
Thiazides users, n 5 21
P -value
70.6 6 10.5 71 (59.7%) 54 (45.4%)
67.4 6 9.6 15 (71.4%) 13 (61.9%)
.199 .307 .162
7 (5.9%) 8 (6.7%)
2 (9.5%) 1 (4.8%)
.530 .736
30 (25.2%)
6 (28.6%)
.745
169.7 6 35.1 178.5 6 33.5 91.1 6 21.3
93.5 6 17.5
.289
Table 2. Comparison of stroke subtypes and stroke severity, functional outcomes Stroke subtypes, severity and outcomes ED NIHSS* NIHSS 24 hours , ED SIE $4 mRS #2* Large-artery atherosclerosis Cardioembolism Lacunar stroke Stroke of undetermined etiology
Thiazide nonusers, n 5 119
Thiazide users, n 5 21
6 (4-16) 25 (21%)
P OR -value
4 (2-7) 7 (33.3%)
.02 .26
17 (14.3%) 1 (4.8%) 3.33 32 (26.9%) 11 (42.4) 26 (21.8%) 4 (19.0%) 1.19
.310 .02 .773
16 (13.4%) 33 (27.7%) 44 (37%)
.621 .607 .922
2 (9.5%) 1.47 7 (33.3%) .77 8 (38.1%) .95
.623
82.2 6 16.8
80.0 6 17.2
.589
13.4 6 2.1
13.8 6 1.9
.274
161.7 6 95.1 191.2 6 91.1 118.7 6 66.8 117.6 6 69.8
.190 .948
178.3 6 44.4 168.2 6 5.36
.384
5.4 6 1.8
6.0 6 1.4
.207
51 (42.9%)
5 (23.8%)
.100
Abbreviations: BUN, blood urea nitrogen; Cr, creatine. *Continuous data expressed as mean 6 SD. yCategorical data expressed as number (%).
of lacunar stroke, and the risk of cardioembolic stroke.8 After multivariate adjusted analyses, age (OR 1.084, 95% CI 1.037-1.134, P , .001), cardioembolic stroke (OR .539, 95% CI .296-.984, P 5 .044), and use of thiazides (OR .326, 95% CI .111-.956, P 5 .041) remained independent predictors.
Abbreviations: ED, emergency department; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; OR, odds ratio; SIE, stroke in evolution. Categorical data are expressed as number (%); NIHSS presented with median (interquartile range). *P , .05.
and lead to lesser stroke severity and favorable functional outcomes. Long-term thiazide therapy lowers blood pressure through a vasodilation effect,9,10 and this vasodilation effect persists for weeks after stopping thiazide therapy.11 As Fujii et al12 discussed in their study, treating hypertension with hydrochlorothiazide can lead to smaller infarct volumes. Thiazides may restore the dilatory capacity of cerebral arterioles, consequently improving the cerebral blood flow reserve and the collateral vascular capacity after acute ischemic stroke.12 This collateral cerebral blood supply may attenuate arterial occlusion effects associated with infarct growth.13-16 As a result, patients with long-term thiazide use might have better collateral circulation and relative smaller infarct Table 3. Multivariate logistic regression analysis of favorable functional outcome in 90 days (mRS # 2) Multivariate (adjusted)
Discussion We found that long-term thiazide uses who experienced their first acute ischemic stroke experienced it less severely, with lower initial NIHSS and better 3-month mRS score results. No previous studies have assessed the severity of stroke and functional outcomes after ischemic stroke in long-term thiazide users. The exact mechanism to achieve this benefit remains unclear; we have discussed possible contributing mechanisms subsequently. Several factors may contribute. First, long-term thiazide users may have a better collateral cerebral blood supply after ischemic stroke that can reduce infarct volumes
Variables Age* Sex Thiazide user* Glucose SIE $4 Lacunar stroke Cardioembolic stroke*
OR
95% CI
1.084 1.037-1.134 1.165 .487-2.785 .326 .111-.956 1.004 .999-1.009 6.762 .815-56.119 .872 .640-1.189 .539 .296-.984
P-value ,.001 .732 .041 .164 .077 .386 .044
Abbreviations: CI, confidence interval; mRS, modified Rankin Scale; OR, odds ratio; SIE, stroke in evolution. *P , .05.
STROKE IN THIAZIDE USERS
volume, which accounted for less stroke severity and better functional outcome, as seen in our study. Although no statistically significant, the greater ratio of decreased 24 hours NIHSS among thiazides users also may support our hypothesis about better collateral circulation. On the other hand, the effect of fluid retention from thiazide withdrawal may help provide adequate postischemic stroke cerebral circulation. Increased blood pressure during the acute stage of ischemic stroke is necessary to maintain brain perfusion in borderline ischemic areas.17 Thus, we often discontinued antihypertensive agents during the early stage of ischemic strokes. As Tarazi et al11 have discussed, patients who withdrew from long-term thiazide diuretics increased their body weight and plasma volume during the first week. The fluid retentive effect avoided dehydration status that increases blood viscosity and elevates hematocrit, which have been shown to be associated with a larger infarct volume in patients with cerebral infarction.18 In addition, the relative hemodilutory effect on such fluid retention status also may play a neuroprotective role postischemic stroke.19 Stroke patients who withdraw from thiazides may achieve adequate plasma volume through this fluid retention effect, which leads to better cerebral circulation and better functional outcomes. In our study, the finding that long-term thiazide users experienced lesser amounts of SIE may support the concept of more adequate fluid status from thiazides withdrawal. There were a total of 18 patients (12.86%) who had early neurologic deterioration, similar to previous studies.20-22 As a previous study discussed, dehydration status increased an early stroke-in-evolution.23,24 Although long-term thiazide use caused depletion of plasma volumes, volumes returned to nearly normal levels after long-term use.9-11,25 In our observational study, the slight degree of dehydration did not cause greater amounts of SIE. On the contrary, there was decreased risk of SIE among thiazide users, which may support the hypothesis of fluid retention effect after thiazide withdrawal. The expanded plasma volume protected stroke patients from dehydration, resulting in a decreased risk of SIE and better functional outcomes.
Limitations Our results are limited by sample size and thus statistical power. The use of a single institution also may limit the results, because there is no comparison with other geographic locations. The hypothesis of collateral circulation and fluid retention could not be proven directly. In addition, we did not compare thiazides with other antihypertensive drugs, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and even combination therapy for primary stroke prevention. Further randomized control studies may be needed to verify functional progress results of
2417
different antihypertensive treatments for primary stroke prevention.
Conclusion Our findings suggest that hypertensive patients treated long term with thiazides had lesser stroke severity, better functional outcomes after ischemic stroke, and showed no difference in SIE risk. Hence, it is safe to use thiazides as a first-line antihypertensive treatment. There may be additional benefits from thiazides along with lowering blood pressure and stroke prevention.
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