A Comparison of Acute Hemorrhagic Stroke Outcomes in 2 Populations The Crete Boston Study

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1 A Comparison of Acute Hemorrhagic Stroke Outcomes in 2 Populations The Crete Boston Study Ioannis Zaganas, MD, PhD; Amy P. Halpin, BS; Alexandra Oleinik, BA; Athanasios Alegakis, PhD; Dimitra Kotzamani, MD; Spiros Zafiris, MD; Chryssanthi Chlapoutaki, MD; Dimitris Tsimoulis, MD; Emmanouil Giannakoudakis, MD; Nikolaos Chochlidakis, MD; Aikaterini Ntailiani, MD; Christina Valatsou, MD; Efrosini Papadaki, MD, PhD; Antonios Vakis, MD, PhD; Karen L. Furie, MD; Steven M. Greenberg, MD, PhD; Andreas Plaitakis, MD, PhD Downloaded from by guest on May 8, 2018 Background and Purpose Although corticosteroid use in acute hemorrhagic stroke is not widely adopted, management with intravenous dexamethasone has been standard of care at the University Hospital of Heraklion, Crete with observed outcomes superior to those reported in the literature. To explore this further, we conducted a retrospective, multivariable-adjusted 2-center study. Methods We studied 391 acute hemorrhagic stroke cases admitted to the University Hospital of Heraklion, Crete between January 1997 and July 2010 and compared them with 510 acute hemorrhagic stroke cases admitted to Massachusetts General Hospital, Boston, from January 2003 to September Of the Cretan cases, 340 received a tapering scheme of intravenous dexamethasone, starting with 16 to 32 mg/day, whereas the Boston patients were managed without steroids. Results The 2 cohorts had comparable demographics and stroke severity on admission, although anticoagulation was more frequent in Boston. The in-hospital mortality was significantly lower on Crete (23.8%, n 340) than in Boston (38.0%, n 510; P 0.001) as was the 30-day mortality (Crete: 25.4%, n 307; Boston: 39.4%, n 510; P 0.001). Exclusion of patients on anticoagulants showed even greater differences (30-day mortality: Crete 20.8%; n 259; Boston 37.0%; n 359; P 0.001). The improved survival on Crete was observed 3 days after initiation of intravenous dexamethasone and was pronounced for deep-seated hemorrhages. After adjusting for acute hemorrhagic stroke volume/location, Glasgow Coma Scale, hypertension, diabetes mellitus, smoking, coronary artery disease and statin, antiplatelet, and anticoagulant use, intravenous dexamethasone treatment was associated with better functional outcomes and significantly lower risk of death at 30 days (OR, 0.357; 95% CI, ). Conclusions This study suggests that intravenous dexamethasone improves outcome in acute hemorrhagic stroke and supports a randomized clinical trial using this approach. (Stroke. 2011;42:00-00.) Acute hemorrhagic stroke (AHS) often carries a poor prognosis, because effective treatments are lacking. 1 Although the use of corticosteroids in intracerebral hemorrhage (ICH) is widely discouraged, 2 7 management with intravenous dexamethasone (IVDxM) has been the standard of care at the University Hospital of Heraklion, Crete. Because review of the data indicated better outcomes than historical nontreated controls, we conducted a retrospective, multivariable-adjusted 2-center study comparing outcomes in a Cretan cohort treated with corticosteroids to a US cohort in Boston managed without corticosteroids. Key Words: dexamethasone ICH stroke management Methods Of the 391 AHS cases admitted to the University Hospital of Heraklion, Crete between January 1997 and July 2010, 340 are known to have received IVDxM (Supplemental Figure I; These were compared with all patients with AHS admitted to the Stroke Service of Massachusetts General Hospital, Boston, from January 2003 to September This study was approved by the Institutional Review Boards of both centers. Brain imaging studies from Boston were sent to Crete in digital form and were compared with those from Crete regarding ICH location and volume (for details, see Supplementary Data). On Crete, patients with AHS were placed on a tapering IVDxM scheme within Received July 11, 2011; accepted July 28, Ralph L. Sacco, MD, was the Guest Editor for this paper. From the Neurology (I.Z., D.K., S.Z., C.C., D.T., E.G., A.P.), Toxicology (A.A.), Neurosurgery (N.C., A.V.), and Radiology (A.N., C.V., E.P.), Departments, University Hospital of Heraklion, Crete, Greece; and the Stroke Service (A.P.H., A.O., K.L.F., S.M.G.), Massachusetts General Hospital, Boston, MA. The online-only Data Supplement is available at Correspondence to Andreas Plaitakis, MD, PhD, Professor and Chairman, Department of Neurology, University Hospital of Heraklion, Voutes, 71021, Heraklion, Crete, Greece. plaitakis@yahoo.com 2011 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 2 Stroke December 2011 Table 1. Clinical Outcomes Boston (n 510) Crete (n 340) Crete (n 190) Death in the hospital, no. (%) 194 (38.0%) 81 (23.8%) (25.3%) Death at 30 d, no. (%) 201 (39.4%) 78 (25.4%) (26.0%) Death at 90 d, no. (%) 223 (43.7%) 92 (32.7%) (33.3%) Average hospital stay, d (mean SD) Modified Rankin Scale on discharge (mean SD) SD indicates standard deviation; d, days. Downloaded from by guest on May 8, hours from admission with the starting dose being 16 to 32 mg/day given in 4 divided doses. Every 2 days afterward, IVDxM was decreased to half and was discontinued within 10 to 12 days from the start. The decision to use 16 mg, 24 mg, or 32 mg IVDxM initially was made by the attending neurologist using the hemorrhage size and the patient clinical status as a guide (Supplemental Table I). To prevent hyperglycemia, patients were kept under an insulin-sliding scheme. Prophylaxis from an ulcer was provided with the use of an intravenous proton pump inhibitor and from deep venous thrombosis with low-molecular-weight heparin and/or elastic stockings. Neurological evaluations were performed on admission and at regular intervals afterward or as needed. Neurological status was assessed by the Glasgow Coma Scale and the modified Rankin Scale. For the Boston cohort, 1- and 3-month mortality was established by a follow-up phone call to the patient or next of kin or review of the US Social Security Death Index. For the Cretan patients, data were obtained from the records of the outpatient stroke clinic, by follow-up phone call between May 2009 and July 2010, and by search of computerized hospital records. Statistical analyses were performed with the PASW software, using Pearson 2 statistics and independent samples t test, or the corresponding Mann-Whitney test. Adjusted ORs were estimated using multiple logistic regression models including age; sex; anticoagulant, antiplatelet, and statin use; hematoma volume and location; admission Glasgow Coma Scale; hypertension; diabetes mellitus; coronary artery disease; and smoking in the last 5 years; and dexamethasone administration. Results The 2 cohorts were similar regarding patients demographics, smoking habits, history of diabetes mellitus, admission blood glucose levels, and previous ICH (Supplemental Table II). Also, the size and location of the ICH and the severity of stroke (as judged by the Glasgow Coma Scale) on admission were similar. Moreover, the time from symptom onset to the emergency department or to CT was comparable. However, hypertension, coronary artery disease, atrial fibrillation, and use of statins, antiplatelets, and anticoagulants were more frequent in the Boston cohort (Supplemental Table II). The in-hospital mortality was significantly lower on Crete (23.8%; n 340) than in Boston (38.0%; n 510; P 0.001) as was the 30-day mortality (Crete: 25.4%; n 307; Boston: 39.4%; n 510; P 0.001; Table 1). Similarly, the 3-month mortality rate was significantly lower on Crete than in Boston (Table 1). After excluding patients on anticoagulants from both centers, the in-hospital and 30-day mortality were again lower on Crete (19.2%; n 291 and 20.8%; n 259, respectively) than in Boston (35.4% and 37.0%; respectively; n 359; P 0.001; Table 2). Limiting the analysis to patients admitted in Crete over the same time period as in Boston (January 2003 to September 2009) gave similar results (Tables 1 and 2). Differences in AHS mortality remained significant even when all 391 patients with AHS admitted to the University Hospital of Heraklion, Crete were included (intention-to-treat analysis, Supplemental Table III). The functional status of AHS survivors, as judged by the discharge modified Rankin Scale, was better on Crete (Tables 1 and 2; and Supplemental Figure II). However, the average in-hospital stay was longer on Crete than in Boston (Tables 1 and 2), because the Cretan patients needed to stay in the hospital for their IVDxM course to be completed. Multiple logistic regression analysis adjusting for various factors revealed that IVDMx decreased the risk of death at 30 days (OR, 0.357; 95% CI, ; Figure A). The beneficial effect of IVDMx occurred 3 days after treatment initiation (Supplemental Figure III). Analyses based on ICH location revealed that the decreased mortality on Crete was mainly due to improved outcomes for thalamic and basal ganglia, but not for lobar, hemorrhages (Figure B; Supplemental Table IV). IVDxM was relatively well tolerated with serious noninfectious adverse events occurring rather rarely (Supplemental Table V). Discussion This retrospective, multivariable-adjusted 2-center study revealed that patients with AHS treated acutely with IVDxM had lower mortality rates and better functional outcomes than Table 2. Clinical Outcomes for Patients With Acute Hemorrhage Stroke Not Receiving Anticoagulants Boston (n 359) Crete (n 291) Crete (n 159) Death in the hospital, no. (%) 127 (35.4%) 56 (19.2%) (20.8%) Death at 30 d, no. (%) 133 (37.0%) 54 (20.8%) (22.0%) Death at 90 d, no. (%) 143 (39.8%) 65 (27.7%) (28.9%) Average hospital stay, d (mean SD) Modified Rankin Scale on discharge (mean SD) SD indicates standard deviation; d, days.

Zaganas et al The Crete Boston Study 3 Downloaded from http://stroke.ahajournals.org/ by guest on May 8, 2018 Figure. A, OR for death at 30 days. B, Thirty-day mortality according to the ICH location.

3 Zaganas et al The Crete Boston Study 3 Downloaded from by guest on May 8, 2018 Figure. A, OR for death at 30 days. B, Thirty-day mortality according to the ICH location. Numbers in parentheses above each column represent the total number of patients per category. *P ICH indicates intracerebral hemorrhage; OR, odds ratio; IV, intraventricular. those managed without corticosteroids. We acknowledge, however, that the 2 cohorts differed in their genetic and cultural background and variations in patient care of the 2 hospitals may have affected the observed outcomes. Notwithstanding these limitations, the mortality of IVDxM-treated Cretan patients is still better than that of other Greek Centers in which ICH is managed without steroids. 8 Although our results are at variance with those of studies from the United States, 4 Thailand, 5 India, 6 and Nigeria, 7 these previous reports included small AHS patient samples. Because we observed decreased mortality rates 3 days after starting the IVDxM treatment and because this effect was more pronounced for deep-seated hemorrhages, it is possible that this beneficial outcome relates to the well-known action of steroids on vasogenic edema or on inflammation. 3 Such edema and/or inflammation is shown to complicate ICH. 1,9 Although we cannot exclude that factors other than IVDxM could be operational, the encouraging results of this retrospective analysis support controlled clinical trials using this approach. Acknowledgments The help of Irini Tzanaki and Drs Minas Tzagournissakis, Mihalis Mavridis, Vassilios Mastorodemos, and Martha Spilioti is cordially acknowledged. Source of Funding Supported by the Association for Research and Treatment of Neurologic Disorders of Crete EY ZHN (I.Z., A.P.) and grant 2R01 AG26484 from the National Institutes of Health (S.M.G.). None. Disclosures References 1. Qureshi A, Mendelow D, Hanley D. Intracerebral hemorrhage. Lancet. 2009;373: Feigin V, Anderson N, Rinkel G, Algra A, van Gijn J, Bennett D. Corticosteroids for aneurysmal subarachnoid hemorrhage and primary intracerebral hemorrhage. Cochrane Database Syst Rev. 2005;3:CD Davis SM, Donnan GA. Steroids for stroke: another potential therapy discarded prematurely? Stroke. 2004;35: Tellez H, Bauer R. Dexamethasone as treatment in cerebrovascular disease. A controlled study in intracerebral hemorrhage. Stroke. 1973;4: Poungvarin N, Bhoopat W, Viriyavejakul A, Rodprasert P, Buranasiri P, Sukondhabhant S, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med. 1987;316: Desai P, Prasad K. Dexamethasone is not necessarily unsafe in primary supratentorial intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1998;65: Ogun S, Odusote K. Effectiveness of high dose dexamethasone in the treatment of acute stroke. West Afr J Med. 2001;20: Vemmos K, Takis C, Georgilis K, Zakopoulos N, Lekakis J, Papamichael CM, et al. The Athens stroke registry: results of a five-year hospital-based study. Cerebrovasc Dis. 2000;10: Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2006;27:

Downloaded from http://stroke.ahajournals.org/ by guest on May 8, 2018 A Comparison of Acute Hemorrhagic Stroke Outcomes in 2 Populations: The Crete Boston Study Ioannis Zaganas, Amy P.

Christina Valatsou, Efrosini Papadaki, Antonios Vakis, Karen L. Furie, Steven M. Greenberg and Andreas Plaitakis Stroke.

4 Downloaded from by guest on May 8, 2018 A Comparison of Acute Hemorrhagic Stroke Outcomes in 2 Populations: The Crete Boston Study Ioannis Zaganas, Amy P. Halpin, Alexandra Oleinik, Athanasios Alegakis, Dimitra Kotzamani, Spiros Zafiris, Chryssanthi Chlapoutaki, Dimitris Tsimoulis, Emmanouil Giannakoudakis, Nikolaos Chochlidakis, Aikaterini Ntailiani, Christina Valatsou, Efrosini Papadaki, Antonios Vakis, Karen L. Furie, Steven M. Greenberg and Andreas Plaitakis Stroke. published online October 20, 2011; Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2011 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Stroke is online at:

5 ONLINE SUPPLEMENT A Comparison of Acute Hemorrhagic Stroke Outcomes in two Populations: The Crete-Boston Study Ioannis Zaganas, MD, PhD 1, Amy P Halpin, BS 2, Alexandra Oleinik, BA 2, Athanasios Alegakis, PhD 3, Dimitra Kotzamani, MD 1, Spiros Zafiris, MD 1, Chryssanthi Chlapoutaki, MD 1, Dimitris Tsimoulis, MD 1, Emmanouil Giannakoudakis, MD 1, Nikolaos Chochlidakis, MD 4, Aikaterini Ntailiani, MD 5, Christina Valatsou, MD 5, Efrosini Papadaki, MD, PhD 5, Antonios Vakis, MD, PhD 4, Karen L Furie, MD 2, Steven M Greenberg, MD, PhD 2, Andreas Plaitakis, MD, PhD 1 1 Neurology, 3 Toxicology, 4 Neurosurgery and 5 Radiology Department, University Hospital of Heraklion, Crete, Greece; 2 Stroke Service, Massachusetts General Hospital, Boston, MA, USA Address correspondence to: Andreas Plaitakis, MD, PhD, Professor and Chairman, Department of Neurology Tel ; Fax ; plaitakis@yahoo.com 1

6 Supplemental Methods Imaging studies All patients included in this study had CT-documented acute ICH. Brain imaging studies, obtained in the Cretan and Boston center, were compared directly regarding the location and volume of the ICH. For this, scans from Boston were sent to Crete in digital form, after removal of all patient-related information. The location of the ICH was independently determined (by EP, AN and CV) taking into consideration the following: hematomas located either entirely in the basal ganglia or in the thalamus or those extending to adjacent structures (cerebrum or brainstem) were included under basal ganglia and thalamus categories, respectively; hematomas spanning both the basal ganglia and the thalamus were included under the basal ganglia category; hemorrhages involving the cerebral lobes, the brainstem or the cerebellum were assigned to these categories only when confined to these structures. Hematoma volume was calculated using the ABC/2 formula, which has been shown to offer a good approximation of the actual hematoma volume. 1 Assessment of adverse outcomes Significant medical events during hospitalization of Cretan patients, such as pulmonary embolism, deep venous thrombosis, gastrointestinal tract hemorrhage, and infections requiring intravenous antibiotics, were recorded. Also, blood glucose levels were closely monitored. Statistical analysis Multiple logistic regression analysis was performed with backward selection in an initial dataset of variables that included sex, age (per 5-year increments), volume (in a logarithmic scale) and location (lobar versus non-lobar) of ICH, GCS on admission, hypertension, diabetes mellitus, coronary artery disease, antiplatelet, anticoagulant and statin use, smoking in the previous five years and dexamethasone administration. 2

7 Supplemental Tables Table I.A. Dexamethasone dosing of Cretan patients (n=340) Total DxM Dosage received (mg) Mean ± SD ± 83.3 Treatment duration (days) Mean ± SD 9.0 ± 5.7 Initial DxM Dose: no of patients treated (%) 8 mg 12 mg 16 mg 24 mg 32 mg 5 (1.8%) 12 (4.2%) 121 (42.6%) 88 (31.0%) 58 (20.4%) Table I.B. Patient characteristics and initial dexamethasone dosing 16 mg P 24 mg (n=88) 32 mg (n=58) (n=121) Age-yrs: Mean ± SD 72.3 ± ± ± Male sex no. (%) 69 (57.0%) 48 (54.5%) 37 (63.8%) GCS score-mean ± SD 12.5 ± ± ± 4.4 <0.001 mrankin-mean ± SD 4.0 ± ± ± Hematoma volume (ml) Mean ± SD 21.3 ± ± ± 67.5 <

8 Table II. Baseline characteristics of AHS patients on admission Crete-Dex Boston-No Dex (n=340) (n=510) p Age (yr) - Mean ± SD 73.1 ± ± Male sex no. (%) 204 (60 0%) 281 (55.1%) Transfer from another hospital no. 45 (16.0%) 339 (68.5%) <0.001 (%) Time from onset to ER (h)-mean±sd 9.8 ± ± Time from onset to CT (h)-mean±sd 11.7 ± ± Admission SAP (mmhg)-mean±sd ± ± Admission DAP (mmhg)-mean±sd 91.5 ± ± Admission Glucose (mg/dl)-mean±sd ± ± GCS score-mean ± SD 11.6 ± ± Location of hemorrhage-no. (%) Lobes 102 (30.0%) 194 (38.0%) Basal ganglia 134 (39.4%) 159 (31.2%) Thalamus 52 (15.3%) 71 (13.9%) Brainstem 12 (3.5%) 20 (3.9%) Cerebellum 28 (8.2%) 40 (7.8%) Multiple/IV 12 (3.5%) 26 (5.1%) Intraventricular blood no. (%) 140 (41.9%) 252 (49.6%) Hematoma volume (ml) Mean ± SD Median (range) 35.1 ± ( ) 40.1 ± ( ) Hematoma max diameter (cm) Mean ± SD 4.3 ± ± 2.3 Anticoagulants-no. (%) 34 (10.5%) 151 (29.6%) <0.001 Antiplatelets-no. (%) 64 (19.8%) 254 (49.8%) <0.001 Atrial Fibrillation-no. (%) 45 (13.9%) 143 (28.3%) <0.001 Diabetes Mellitus -no. (%) 62 (19.1%) 109 (21.6%) Hypertension-no. (%) 251 (76.5%) 421 (83.2%) Coronary Artery Disease-no. (%) 40 (14.3%) 105 (21.4%) Smoking-no. (%) 44 (19.0%) 73 (21.7%) Statin use-no. (%) 20 (8.4%) 168 (33.9%) <0.001 Previous ICH-no. (%) 30 (9.7%) 31 (6.1%)

9 Outcome Table III. Intention to treat analysis Boston (n=510) Crete-all (n=391) Death in hospital-no. (%) 194 (38.0%) 99 (25.3%) <0.001 Death (30 days) no. (%) 201 (39.4%) 95 (26.8%) <0.001 Death (90 days) no. (%) 223 (43.7%) 110 (33.7%) Average in hospital stay Days (mean ± SD) Mod. Rankin on discharge (mean ± SD) Mod. Rankin on discharge-no. (% of known) Serious adverse events-no. (%) Pulmonary Embolism Gastrointestinal Hemorrhage DVT Infection 8.8 ± ± ± ± (1.4%) 17 (3.5%) 23 (4.7%) 75 (15.3%) 142 (29.0%) 32 (6.5%) 194 (39.6%) (3.6%) 38 (11.3%) 33 (9.9%) 42 (12.5%) 79 (23.6%) 32 (9.6%) 99 (29.6%) 2 (0.6%) 4 (1.3%) 1 (0.3%) 118 (34.1%) P <0.001 <0.001 <0.001 Includes all AHS patients admitted to the University hospital of Crete during the reporting period, irrespectively whether their IVDxM treatment status is known. 5

10 Table IV. In-hospital and 30 day-mortality according to the location of the hemorrhage In-hospital, n (%) 30-day, n (%) Location Crete Boston P Crete Boston P Lobar 29/102 (28.4%) 63/194 (32.5%) /92 (30.4%) 66/194 (34.0%) Basal Ganglia 33/134 (24.6%) 74/159 (46.5%) < /119 (26.1%) 75/159 (47.2%) <0.001 Thalamic 5/52 (9.6%) 17/71 (23.9%) /47 (12.8%) 20/71 (28.2%) Cerebellar 5/28 (17.9%) 11/40 (27.5%) /27 (18.5%) 11/40 (27.5%) Brainstem 4/12 (33.3%) 13/20 (65.0%) /11 (36.4%) 13/20 (65.0%) Multiple Territories/ Intra-ventricular 5/12 (41.7%) 16/26 (61.5%) /11 (36.4%) 16/26 (61.5%)

11 Table V. Clinical outcomes Boston (n=510) Crete (n=340) Crete (n=190) Blood Glucose (mg/dl) (mean ± SD) At 3 days post admission At 6 days post admission At 9 days post admission ± ± ± ± ± ± ± ± ± Serious adverse events-no. (%) Pulmonary Embolism Gastrointestinal Hemorrhage DVT Infection (0.7%) 3 (1.1%) 1 (0.3%) 105 (33.2%) 1 (0.6%) 2 (1.2%) 1 (0.6%) 59 (33.1%) 7

12 Supplemental Figures 391 HS patients (365 in Acute Stroke Unit of the Neurology Department and 26 in the Neurosurgery Department of the University Hospital of Heraklion, Crete) 25 Dex use unknown 366 Dex use known 340 Dex used 26 Dex not used Figure I. Flow chart of patients from Crete included in the analysis. Dex: Dexamethasone. 8

13 Figure II. mrankin Scale on discharge for patients with AHS in Boston (upper panel) and Crete (lower panel). 9

14 40 35 (20) Crete Boston % of Total 10-day deaths (18) (38) (13) (6) (29) (4) (24) (14) (4) (17) (11) (3) (3) (9) (2)(5) (2) (2) (3) Days post admission Figure III. Daily death rates as percentage of the 10-day mortality in Crete and Boston (total number of deaths 60 and 167, respectively). Each successive doublet of columns represents different days post admission (shown under the x axis). The numbers in parentheses above each column represent the number of deaths. 10

15 Supplemental References 1) Kothari R, Brott T, Broderick J, Barsan W, Sauerbeck L, Zuccarello M, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 1996; 27:

Intracerebral hemorrhage (ICH) is associated with poor outcome,

Intracerebral hemorrhage (ICH) is associated with poor outcome, Low Serum Calcium Levels Contribute to Larger Hematoma Volume in Acute Intracerebral Hemorrhage Yasuteru Inoue, MD; Fumio Miyashita, MD; Kazunori Toyoda, MD; Kazuo Minematsu, MD Downloaded from http://stroke.ahajournals.org/