A Comparison of Acute Hemorrhagic Stroke Outcomes in 2 Populations
The Crete–Boston Study
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 2009. 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, 0.174–0.732).
Conclusions—This study suggests that intravenous dexamethasone improves outcome in acute hemorrhagic stroke and supports a randomized clinical trial using this approach.
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.
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; http://stroke.ahajournals.org). These were compared with all patients with AHS admitted to the Stroke Service of Massachusetts General Hospital, Boston, from January 2003 to September 2009. 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 2 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 χ2 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.
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, 0.174–0.732; 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).
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 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.
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.).
The help of Irini Tzanaki and Drs Minas Tzagournissakis, Mihalis Mavridis, Vassilios Mastorodemos, and Martha Spilioti is cordially acknowledged.
Ralph L. Sacco, MD, was the Guest Editor for this paper.
The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.632174/-/DC1.
- Received July 11, 2011.
- Accepted July 28, 2011.
- © 2011 American Heart Association, Inc.
- Davis SM,
- Donnan GA
- Tellez H,
- Bauer R
- Desai P,
- Prasad K