With the increasing use of MRI, cerebral white matter

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1 Telmisartan on Top of Antihypertensive Treatment Does Not Prevent Progression of Cerebral White Matter Lesions in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) MRI Substudy Ralph Weber, MD, MSc; Christian Weimar, MD; Jon Blatchford, BSc, MSc, CStat; Karin Hermansson, DMSc; Isabel Wanke, MD, PhD; Claudia Möller-Hartmann, MD; Elke R. Gizewski, MD; Michael Forsting, MD; Andrew M. Demchuk, MD, FRCPC, PhD; Ralph L. Sacco, MD; Jeffrey L. Saver, MD; Steven Warach, MD, PhD; Hans-Christoph Diener, MD, PhD; Anke Diehl, MD, PhD; for the PRoFESS Imaging Substudy Group* Background and Purpose High blood pressure is one of the main risk factors for cerebral white matter lesions (WMLs). There is limited evidence from one randomized trial that blood pressure-lowering is able to slow WML progression. We investigated whether telmisartan prevents WML progression in the imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. Methods This predefined substudy comprised 771 patients (mean age, 65 years) with recent ischemic stroke of noncardioembolic origin who received telmisartan or placebo during a mean follow-up of 27.9 (SD, 7.6) months and had 2 evaluable MRI examinations after index stroke and at study closeout. All MRI scans were centrally adjudicated for progression of periventricular and subcortical WML by 2 neuroradiologists blinded to treatment allocation. Results Mean blood pressure was 3.0/1.3 mm Hg lower with telmisartan compared with placebo at follow-up MRI. There was no statistically significant difference in progression of the mean periventricular WML score (least squares mean difference, 0.14; 95% CI, 0.12 to 0.39; P 0.29) and mean subcortical WML diameter (least squares mean difference, 0.35 mm; 95% CI, 1.00 to 0.31 mm; P 0.30) during follow-up between patients on telmisartan and placebo. Conclusions Treatment with telmisartan on top of existing antihypertensive medication did not result in significant blood pressure-lowering and did not prevent the progression of WML in patients with a recent ischemic stroke in this patient cohort. Our analysis is limited by the relatively short follow-up period. Clinical Trial Registration URL: Unique Identifier: NCT (Stroke. 2012;43: ) Key Words: antihypertensive treatment cerebral small vessel disease ischemic stroke magnetic resonance imaging secondary prevention telmisartan white matter lesion With the increasing use of MRI, cerebral white matter lesions (WMLs) are frequently detected both in healthy elderly individuals and symptomatic patients with cerebrovascular diseases. The exact pathophysiology of WML is not yet fully understood. WMLs are considered to reflect mainly ischemic small-vessel disease in the deep white matter resulting in a loss of myelin and axons and mild gliosis. 1 3 Genetic factors appear also to play a significant role, 4 and genomewide association studies in communitybased cohorts of individuals of European descent recently identified 6 novel risk-associated single nucleotide polymorphisms in one locus on chromosome According to a systematic review and meta-analysis, WMLs increase with age and are risk factors for stroke, Received December 18, 2011; final revision received May 10, 2012; accepted May 31, From the Departments of Neurology (R.W., C.W., H.C.D.) and Neuroradiology (I.W., C.M.-H., E.R.G., M.F., A.D.), University of Duisburg-Essen, Essen, Germany; Boehringer Ingelheim Ltd, Bracknell, UK (J.B.); Boehringer Ingelheim AB, Stockholm, Sweden (K.H.); Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (A.M.D.); Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL (R.L.S.); Los Angeles Stroke Center, University of California, Los Angeles, CA (J.L.S.); and Stroke Diagnostics and Therapeutics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (S.W.). Bruce Ovbiagele, MD, MSc, was the Guest Editor for this paper. *Participating investigators of the PROFESS Imaging substudy are listed in the online-only Data Supplement. The online-only Data Supplement is available with this article at STROKEAHA /-/DC1. Correspondence to Hans-Christoph Diener, MD, PhD, Department of Neurology, University Duisburg-Essen, Hufelandstr. 55, Essen, Germany. hans.diener@uni-duisburg-essen.de 2012 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Weber et al Telmisartan Does Not Slow WML Progression 2337 dementia, and depression. 6 Apart from age, elevated blood pressure has been identified as a main risk factor for presence, severity, and progression of WML in prospective crosssectional and longitudinal studies Data from a large population-based cohort study showed that antihypertensive treatment was significantly associated with a smaller increase in WML volume compared with no treatment. 13 Only one small randomized, placebo-controlled trial has been performed to date to investigate the effect of antihypertensive treatment on the progression of WML; the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) MRI substudy included 192 patients treated with the angiotensinconverting enzyme inhibitor perindopril with or without addition of the diuretic indapamide or placebo. 14 After a mean follow-up period of 36 months, active blood pressurelowering resulted in a significantly reduced volume of new WML. We therefore investigated whether treatment with the angiotensin II receptor blocker telmisartan on top of existing medical antihypertensive treatment is able to slow progression of WML in the prespecified imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. Methods Study Design and Participants The PRoFESS trial protocol and primary results have been published elsewhere In brief, patients who were at least 50 years of age with recent ischemic stroke of noncardioembolic origin within 120 days of study entry were randomized to either aspirin (25 mg twice a day) plus extended-release dipyridamole (200 mg twice a day) or clopidogrel (75 mg daily) and telmisartan (80 mg daily) or placebo in a 2 2 factorial design and treated for 2 years. All patients received best medical care independent of treatment assignment, including medications for blood pressure control at the discretion of the investigators. Concomitant use of open-label angiotensin II receptor blockers was not allowed. Arterial hypertension was defined in PRoFESS as systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg. In addition to inclusion and exclusion criteria of the main trial, participants in the imaging substudy had to undergo an MRI of the brain after their qualifying stroke and a follow-up MRI at the final study visit. The imaging substudy was approved by the ethics committees of all participating centers. Participating patients gave informed consent for the main PRoFESS trial as well as a separate consent for the imaging substudy. The PRoFESS trial was registered as follows: clinicaltrials.gov identifier: NCT WML Assessment on MRI All MRI data were sent to the Central Adjudication Center at the University Duisburg-Essen where presence, location, and severity of WML were rated independently by 2 experienced neuroradiologists blinded to clinical data and treatment allocation using the semiquantitative Rotterdam Scan Study scale. 18,19 WMLs were defined as hyperintense lesions on T2-weighted and/or fluid-attenuated inversion recovery images and no correspondent hypointense signal on T1-weighted images. WMLs were further stratified as subcortical or periventricular if adjacent to the ventricles. Periventricular WMLs were visually rated as 0 (none), 1 (pencil-thin lining), 2 (smooth halo), or 3 (large confluent) in 3 different regions of interest (frontal caps, adjacent to frontal horns; bands, adjacent to the wall of lateral ventricles; and occipital caps, adjacent to occipital horns). The overall degree of periventricular WML was calculated by adding up the scores of the 3 regions of interest to a total periventricular WML score (range, 0 9). Subcortical WMLs were visually rated according to their presence and maximum diameter as 0 (none), 1 (1 3 mm diameter), 2 ( 3 10 mm diameter), or 3 ( 10 mm diameter) in the frontal, parietal, temporal, and occipital lobes. A total subcortical WML volume (in millimeters) was approximated based on number and diameter of all detected lesions. The Pearson interrater correlation coefficients for the assessment of the total periventricular WML score and subcortical WML diameter were 0.96 at baseline and 0.94 and 0.92 at follow-up MRI, respectively. Outcomes and Statistical Analysis Progression of periventricular WML score and subcortical WML diameter from baseline to follow-up MRI were the prespecified primary outcome parameters in the PRoFESS MRI follow-up substudy. Comparison of baseline characteristics between both treatment groups (telmisartan/placebo) was performed with Student t test for quantitative variables. The number and proportion of patients in the PRoFESS imaging substudy who had an increase in total periventricular WML score or subcortical WML diameter from baseline to follow-up MRI was compared with the number and proportion of patients with no increase by presence/absence of hypertension using the continuity-corrected 2 test. Linear logistic regression was performed to assess the relationship between treatment and increase in total periventricular WML score or subcortical WML diameter at follow-up MRI. We conducted analysis of covariance to compare the total periventricular WML score and subcortical WML diameter between the telmisartan and placebo groups. In both linear logistic regression and analysis of covariance, baseline total periventricular WML score or baseline subcortical WML diameter and age served as continuous covariates, and adjustments were made for sex, presence of hypertension, and qualifying stroke Trial of ORG in Acute Stroke Treatment criteria. We further performed stratified summaries of the periventricular WML score and subcortical WML diameter by baseline severity of WML load using tertiles. We used Pearson correlation to investigate the relationship between change in systolic/diastolic blood pressure and change in total periventricular WML score/subcortical WML diameter from baseline to follow-up MRI. This relationship was further investigated by unadjusted linear regression analyses and analysis of covariance adjusted for use of telmisartan, history of hypertension, age group, gender, history of diabetes, Trial of ORG in Acute Stroke Treatment classification, use of angiotensin-converting enzyme inhibitors, diuretics, or calcium antagonists, and use of statins at baseline. Statistical significance was set at P Analyses were performed with SAS Version 8.2. Results A total of 1057 patients who were randomized in the PRoFESS study had given consent to enter the imaging substudy of which 1014 (95.9%) patients had an evaluable baseline MRI examination performed within 120 days of their qualifying stroke. Mean time from index stroke to baseline MRI was 8.0 (SD, 15.7) days and did not differ between both treatment groups. T1-weighted images at baseline were present for evaluation in 928 patients (91.5%), T2-weighted images in 954 (94.1%), fluid-attenuated inversion recovery sequence in 926 (91.3%), diffusion-weighted images in 887 (87.5%), T1-weighted contrast-enhanced images in 186 (18.3%), and gradient echo MRI in 204 (20.1%). Seven hundred seventy-one patients had an evaluable follow-up MRI examination at the last study visit and could therefore be included in the PRoFESS MRI follow-up substudy (see the Figure for patient inclusion). Table 1 describes baseline and

3 2338 Stroke September 2012 Figure. Flowchart of participants in the follow-up analysis of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Imaging substudy. clinical characteristics of the 1014 patients in the PRoFESS imaging substudy and 771 patients in the comparison between treatment groups at follow-up. The characteristics in this analysis were broadly similar in both treatment groups and only one patient in each treatment group did not receive study medication during the complete follow-up period due to noncompliance or incorrect intake of trial medication, respectively. Periventricular and subcortical WMLs were significantly larger in patients aged 75 years and patients with arterial hypertension at baseline (Table 2). The mean periventricular WML score was significantly higher in patients whose qualifying ischemic stroke had been classified as small-artery occlusion on Trial of ORG in Acute Stroke Treatment classification as compared with patients classified as largeartery atherosclerosis. In contrast, there was no statistically significant difference in total subcortical WML diameter by qualifying stroke Trial of ORG in Acute Stroke Treatment criteria at baseline. Follow-up MRI in the 771 patients was performed on average 27.9 (SD, 7.6) months after baseline MRI ( months in the telmisartan group and months in the placebo group). At the time of the follow-up MRI, mean systolic blood pressure was mm Hg (SD, 20.5) in the telmisartan group and mm Hg (SD, 18.2) in the placebo group. Mean diastolic blood pressure was 79.1 mm Hg (SD, 11.7) in the telmisartan group and 80.4 mm Hg (SD, 11.0) in the placebo group. The mean decrease of both systolic ( 11.0 mm Hg [SD, 22.2] in the telmisartan group compared with 8.0 mm Hg [SD, 21.9] in the placebo group; P 0.057) and diastolic ( 6.2 mm Hg [SD, 13.7] in the telmisartan group compared with 4.9 mm Hg [SD, 13.1] in the placebo group; P 0.119) blood pressure from baseline was not significantly different between the 2 treatment groups. There was no statistically significant difference in progression of the mean periventricular WML score during follow-up between patients on telmisartan and patients on placebo (0.54 in the telmisartan group versus 0.40 in the placebo group; least squares mean difference, 0.14; 95% CI, 0.12 to 0.39; P 0.29). The proportion of patients with an increase of periventricular WMLs was 52.8% in patients treated with telmisartan compared with 49.6% in placebo patients (adjusted OR, 1.14; 95% CI, ; P 0.39). Similarly, we did not observe any statistically significant difference in progression of the subcortical WML diameter during follow-up (0.34 mm in the telmisartan group versus 0.83 mm in the placebo group; least squares mean difference, 0.35 mm; 95% CI, 1.00 to 0.31 mm; P 0.30). The proportion of patients with an increase of the subcortical WML diameter for telmisartan was 55.4% compared with 55.1% for placebo (adjusted OR, 1.03; 95% CI, ; P 0.86). There was no significant interaction of treatment by age group or arterial hypertension, respectively. Table 3 shows the mean periventricular WML score and subcortical WML diameter at follow-up by treatment group and further stratified by baseline severity of WML load using tertiles, showing that there were no differences between both treatment groups. We did not observe any significant correlation between change from baseline to follow-up periventricular WML score/subcortical WML diameter and change from baseline to follow-up systolic and diastolic blood pressure, respectively. The corresponding linear regression and analyses of covariance also indicated that there was no relationship between WML progression and change in blood pressure (data not shown). During the follow-up period, 63 patients experienced a recurrent stroke (32 in the telmisartan group versus 31 in the placebo group; P 0.97). Discussion Treatment with the angiotensin II receptor blocker telmisartan on top of existing medical antihypertensive treatment did not result in a slower progression of periventricular and subcortical WML in patients with a previous ischemic stroke over a mean follow-up period of 27.9 months in the PRoFESS MRI substudy. Progression of periventricular and subcortical WML occurred in approximately half of the patients treated with telmisartan or placebo. Although based on the estimation of the European Task Force on Age-Related white Matter Changes, 20 the number of 771 included patients who had 2 evaluable MRI examinations was adequate to study a potential protective effect, treatment duration may not have been long enough and/or the difference in blood pressure reduction may have been too low. Our results therefore did not find evidence that pleiotropic mechanisms of angiotensin II receptor blockers reduce the course of WML progression independently of blood pressure-lowering. 21

4 Weber et al Telmisartan Does Not Slow WML Progression 2339 Table 1. Patient Characteristics of Participants With Baseline and Follow-Up MRI Stratified by Treatment and All Patients in the PRoFESS Imaging Substudy Characteristic Telmisartan (n 390) Placebo (n 381) MRI Substudy (n 1014) Demographics Age, y, mean (SD) 65.5 (8.1) 65.2 (8.1) 66.1 (8.4) Age group, no. (%) 75 y 343 (87.9) 337 (88.5) 862 (85.0) 75 y 47 (12.1) 44 (11.5) 152 (15.0) Sex, male, no. (%) 255 (65.4) 241 (63.3) 648 (63.9) Ethnicity, no. (%) Asian 257 (65.9) 260 (68.2) 644 (63.5) White 105 (26.9) 84 (22.0) 264 (26.0) Black 8 (2.1) 9 (2.4) 30 (3.0) Other 20 (5.1) 28 (7.3) 76 (7.5) Clinical history, no. (%) TIA 33 (8.5) 41 (10.8) 97 (9.6) Hypertension 299 (76.7) 283 (74.3) 774 (76.3) Hypertension, treated 168 (43.1) 146 (38.3) 428 (42.2) Atrial fibrillation 8 (2.1) 6 (1.6) 28 (2.8) Diabetes mellitus 126 (32.3) 104 (27.3) 320 (31.6) Hyperlipidemia 192 (49.2) 185 (48.6) 502 (49.5) Smoker Current 96 (24.6) 92 (24.1) 245 (24.2) Former 133 (34.1) 122 (32.0) 331 (32.6) Never 161 (41.3) 167 (43.8) 438 (43.2) Clinical details Baseline NIHSS score, median (range) 2 (0, 16) 2 (0, 15) 2 (0, 23) Body mass index, kg/m 2, mean (SD) 25.8 (3.9) 26.0 (4.2) 26.0 (4.3) Systolic blood pressure, mm Hg, mean (SD) (16.3) (16.3) (16.6) Diastolic blood pressure, mm Hg, mean (SD) 85.4 (10.3) 85.3 (10.5) 85.0 (10.6) Regular alcohol consumption per week, no. (%) 0 drinks 259 (66.4) 280 (73.5) 719 (70.9) 1 14 drinks 114 (29.2) 77 (20.2) 247 (24.4) 15 drinks 15 (3.8) 24 (6.3) 44 (4.3) Exercise Sedentary 129 (33.1) 144 (37.8) 362 (35.8) Some 118 (30.3) 108 (28.3) 301 (29.7) Intense 143 (36.7) 129 (33.9) 349 (34.4) TOAST classification of qualifying stroke, no. (%) Large-artery atherosclerosis 137 (35.1) 116 (30.4) 327 (32.2) Cardioembolism 5 (1.3) 3 (0.8) 17 (1.7) Small-artery occlusion 203 (52.1) 216 (56.7) 539 (53.2) Other determined etiology 4 (1.0) 6 (1.6) 18 (1.8) Undetermined etiology 41 (10.5) 39 (10.2) 112 (11.0) Antihypertensive medication, open-label, no. (%) ACE inhibitor 110 (28.2) 103 (27.0) 294 (29.0) Alpha receptor antagonist 0 (0.0) 1 (0.3) 1 (0.1) Beta receptor antagonist 0 (0.0) 0 (0.0) 0 (0.0) Calcium channel blocker 99 (25.4) 89 (23.4) 255 (25.1) Diuretic 64 (16.4) 45 (11.8) 151 (14.9) Missing values in 1% of variables. PRoFESS indicates Prevention Regimen for Effectively Avoiding Second Strokes; TIA, transient ischemic attack; NIHSS, National Institutes of Health Stroke Scale; TOAST, Trial of ORG in Acute Stroke Treatment; ACE, angiotensin-converting enzyme.

5 2340 Stroke September 2012 Table 2. Baseline Characteristics of Patients in the PRoFESS Imaging Substudy and Their Association With the Periventricular WML Score and Subcortical WML Diameter No. Mean Periventricular WML Score (SD) P Value Mean Subcortical WML Diameter (SD) P Value Sex Male (2.3) 8.1 (5.9) Female (2.4) 8.3 (6.2) Age, y (2.3) 7.8 (5.8) (2.5) 10.2 (6.5) Hypertension Yes (2.4) 8.6 (6.0) No (2.3) 6.6 (5.7) Diabetes mellitus Yes (2.3) 7.6 (5.3) No (2.4) 8.4 (6.3) TOAST classification 0.018* 0.13* Large-artery atherosclerosis (2.3) 7.8 (5.7) Small-artery occlusion (2.4) 8.5 (6.1) Other etiology (2.4) 7.8 (6.1) PRoFESS indicates Prevention Regimen for Effectively Avoiding Second Strokes; WML, white matter lesion; TOAST, Trial of ORG in Acute Stroke Treatment. *Comparison between large-artery atherosclerosis and small-artery occlusion by 2-sample t test. Higher age and a history of arterial hypertension were the only factors that were associated with both periventricular and subcortical WML load at baseline, which was in correspondence to previous cross-sectional studies on WML in participants without a history of stroke. 7,8,22 24 In contrast to previous prospective observational and randomized trials describing a slowing of progressing of WML with antihypertensive medication, treatment with 80 mg telmisartan on top of existing antihypertensive medication resulted in a modest but nonsignificant lowering of systolic and diastolic blood pressure in the MRI substudy. At the time of the second MRI, the mean systolic and diastolic blood pressure was 3.0/1.3 mm Hg lower in the telmisartan group than in the placebo group. In contrast, the PROGRESS MRI substudy showed a significant blood pressure reduction of 11.2/4.3 mm Hg with perindopril alone or in combination with indapamide compared with placebo at the time of the second MRI. Although the volume of new WML was the Table 3. White Matter Lesion (WML) Load at Baseline and Follow-Up MRI by Treatment Group and Stratified by Baseline Severity Using Tertiles Telmisartan Group (n 390) Placebo Group (n 381) WML load at baseline MRI Total periventricular WML score, mean (SD) 2.9 (2.3) 2.9 (2.3) Subcortical WML load diameter, mm,, mean (SD) 8.2 (6.2) 7.8 (5.9) WML load at follow-up MRI Total periventricular WML score, mean (SD) 3.5 (2.6) 3.3 (2.5) Subcortical WML load diameter, mm, mean (SD) 8.6 (5.5) 8.7 (6.1) WML load at follow-up MRI stratified by baseline severity of WML load Total periventricular WML score, mean (SD) Percent of Patients Percent of Patients None (1.9) (1.5) Mild to moderate (1.8) (1.8) Severe (2.2) (2.2) Subcortical WML load diameter, mm, mean (SD) None (2.8) (3.4) Mild to moderate (4.1) (4.5) Severe (5.4) (5.6)

6 Weber et al Telmisartan Does Not Slow WML Progression 2341 primary end point in the PROGRESS MRI substudy, the fact that only 24 of 192 included patients developed new WML during the mean 3-year follow-up period limited the power of the PROGRESS MRI substudy as indicated by the authors. Besides the longer treatment period and more intensive blood pressure-lowering in PROGRESS, the aggressive medical preventive treatment in PRoFESS might have blunted some effects of telmisartan. All PRoFESS patients received treatment with an antiplatelet agent and almost half of the patients received lipid-lowering therapy with a statin. A stratified analysis in the population-based Three-City- Dijon MRI Study showed that antihypertensive treatment started within 2 years seems to significantly influence the progression of WML only in subjects with high baseline systolic blood pressure levels 160 mm Hg. 13 Another possible explanation is the ethnic background of the included participants. All participants in the PROGRESS MRI substudy and the Three-City-Dijon MRI Study were recruited in France (and probably whites), whereas the majority of our included patients were Asians. Our MRI substudy has some shortcomings. Mean follow-up duration in our study was substantially shorter compared with a mean follow-up of 36 months in the PROGRESS MRI substudy, and the overall increase of both periventricular and subcortical WML was only modest in both treatment groups and in the analysis stratified by baseline severity of WML load. There was no difference in periventricular and subcortical WML load at the follow-up measurement between both treatment groups even in patients with a severe baseline grade of WML. Follow-up periods in the Three-City-Dijon MRI Study (4 years) and the Atherosclerosis Risk in Communities (ARIC) Study (median follow-up of 10.6 years between both MRI measurements) were even longer. 13,25 Furthermore, adjustment for baseline subcortical and periventricular WML load could result in a bias of regression coefficient estimates because WML progression is associated with baseline health status and the dependent variable measurement might be unreliable or unstable. 26 Assessment of static clinic blood pressure measurements at single time points might have resulted in a lower reproducibility compared with ambulatory measurements. A recent prospective cohort study of older people averaging 82 years of age showed that only increased 24-hour ambulatory systolic blood pressure, but not office systolic blood pressure, was associated with volumetric WML progression after 24 months of observation. 27 Another potential limitation of our study is the use of semiquantitative visual rating scales. 28 When the PRoFESS MRI substudy was designed, the Rotterdam Scan Study scale was one of the established visual rating scales. Previous studies had shown a good intra- and interobserver agreement for the Rotterdam Scan Study scale. 18,29 Automated volumetric assessment of WML was difficult to assess in our multicenter study because of different MRI scanners used. However, a significant correlation with volumetric changes has been found for the subcortical part of the Rotterdam Scan Study scale. 30 A strength of our study was central adjudication of all MRI scans by 2 experienced and blinded neuroradiologists. In summary, antihypertensive treatment with telmisartan over 2 years did not result in a significant reduction of both systolic and diastolic blood pressure and did not slow the progression of WML in high-risk patients with a recent ischemic stroke of noncardioembolic origin. The results of our study do not support a pleiotropic or protective effect of angiotensin II receptor blockers on vascular WML and reinforce the finding that only a substantial blood pressurelowering and longer treatment periods might be able to reduce the course of WML progression. Source of Funding Boehringer Ingelheim sponsored and funded the PRoFESS trial and the imaging substudy. Disclosures C.W. received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Bayer, Boehringer Ingelheim, Brainsgate, Bristol-Myers Squib, Co-Axia, D-Pharm, Photothera, Sanofi-Aventis, Syngis, and Thrombogenics. He served on the end point adjudication committee of the PRoFESS trial. J.B. and K.H. are employees of Boehringer Ingelheim. A.M.D. received honoraria for contribution to advisory boards or oral presentations from Boehringer Ingelheim and Merck. R.L.S. received grants from the National Institute of Neurological Disorders and Stroke for the Northern Manhattan Study. He served as a consultant to Boehringer Ingelheim during the conduct of the PRoFESS trial. J.L.S. is an employee of the University of California, which received payments based on clinical trial contracts for the number of subjects enrolled from Boehringer Ingelheim and AGA Medical and received payments for faculty participation on scientific advisory boards from AGA Medical. H.-C.D. received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Abbott, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, D-Pharm, Fresenius, GlaxoSmithKline, Janssen- Cilag, MSD, MindFrame, Novartis, Novo-Nordisk, Paion, Parke- Davis, Pfizer, Sanofi-Aventis, Sankyo, Servier, Solvay, Thrombogenics, Wyeth, and Yamaguchi. Financial support for research projects was provided by Astra/Zeneca, GSK, Boehringer Ingelheim, Novartis, Janssen-Cilag, and Sanofi-Aventis. A.D. received honoraria for contribution to advisory boards or oral presentations from Boehringer Ingelheim and Bristol-MyersSquib. References 1. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke. 1997;28: Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43: Pantoni L. 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