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Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension–Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial

Zanchetti, Albertoa,b; Liu, Lishengc,d; Mancia, Giuseppea,e; Parati, Gianfrancoa,e; Grassi, Guidoe,f; Stramba-Badiale, Marcoa; Silani, Vincenzoa,b; Bilo, Grzegorza; Corrao, Giovannie; Zambon, Antonellae; Scotti, Lorenzae; Zhang, Xinhuad; Wang, HayYand; Zhang, Yuqingc,d; Zhang, Xuezhongc,d; Guan, Ting Ruid; Berge, Eivindg; Redon, Joseph; Narkiewicz, Krzysztofi; Dominiczak, Annaj; Nilsson, Peterk; Viigimaa, Margusl; Laurent, Stéphanem; Agabiti-Rosei, Enricon; Wu, Zhaosuo; Zhu, Dingliangp; Rodicio, José Luisq; Ruilope, Luis Miguelr; Martell-Claros, Nievess; Pinto, Fernandot; Schmieder, Roland E.u; Burnier, Michelv; Banach, Maciejw; Cifkova, Renatax; Farsang, Csabay; Konradi, Alexandraz; Lazareva, Irinaaa; Sirenko, Yuriyab; Dorobantu, Mariaac; Postadzhiyan, Armanad; Accetto, Rokae; Jelakovic, Bojanaf; Lovic, Draganag; Manolis, Athanasios J.ah; Stylianou, Philipposai; Erdine, Serapaj; Dicker, Drorak; Wei, Gangzhial; Xu, Chengbinam; Xie, Henggean; Coca, Antonioao; O’Brien, Johnap; Ford, Garyaq

doi: 10.1097/HJH.0000000000000254
ORIGINAL PAPERS: Therapeutic aspects

Background and objectives: The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether ‘the lower the better’ or the ‘J-curve’ hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design.

Protocol design: The European Society of Hypertension–Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145–135; 2, <135–125; 3, <125 mmHg); two different LDL-C targets (target A, 2.8–1.8; target B, <1.8 mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1–6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly.

Outcomes: Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety.

Sample size calculation: It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.

aIstituto Auxologico Italiano

bUniversità di Milano, Milan, Italy

cFuWai Hospital and Cardiovascular Institute

dBeijing Hypertension League Institute, Beijing, China

eUniversità Milano-Bicocca

fIRCCS Multimedica, Sesto San Giovanni, Milan, Italy

gOslo University Hospital, Oslo, Norway

hUniversity of Valencia, Madrid, Spain

iMedical University of Gdansk, Gdansk, Poland

jUniversity of Glasgow, Glasgow, UK

kLund University, Scania University Hospital, Malmö, Sweden

lTallinn University of Technology, Tallinn, Estonia

mEuropean Hospital Georges Pompidou, Paris, France

nUniversità di Brescia, Spedali Civili, Brescia, Italy

oBeijing Anzhen Hospital, Beijing

pShanghai Hypertension Institute, China

qComplutense University

rHospital 12 de Octubre

sHospital Clínico San Carlos, Madrid, Spain

tCentro Hospitalar de Entre o Douro e Vouga, E.P.E., Portugal

uNephrology and Hypertension, University Hospital, Erlangen, Germany

vUniversity Hospital of Lausanne, Lausanne, Switzerland

wMedical University of Lodz, Poland

xCharles University Medical School I and Thomayer Hospital, Prague, Czech Republic

ySt. Imre University Teaching Hospital, Budapest, Hungary

zAlmazov Federal Heart, Blood and Endocrinology Center, St. Petersburg, Russia

aaRSPC Cardiology, Minsk, Belarus

abNSC ‘Institute of Cardiology named after N.D. Strazhesko’ of NAMS, Kiev, Ukraine

acEmergency Hospital of Bucharest, Romania

adUniversity Hospital Saint Anna, Sofia, Bulgaria

aeDr Peter Drzai Hospital, Ljubljana, Slovenia

afUniversity Hospital Center Zagreb, Croatia

agClinic for Internal Medicine InterMedic, Nis, Serbia

ahCardiology Department, Asklepeion General Hospital, Athens, Greece

aiNicosia General Hospital, Nicosia, Cyprus

ajIstanbul University Cerrahpaşa School of Medicine, Istanbul, Turkey

akHasharon Hospital – Rabin Medical Center, Petach-Tikva, Israel

alBeijing Xuanwu Hospital

amSecond Affiliate Hospital, Beijing University

anMilitary General Hospital, China

aoHospital Clinic. University of Barcelona, Barcelona, Spain

apUniversity of Cambridge, Cambridge

aqOxford University Hospital NHS Trust, Oxford, United Kingdom

Correspondence to Professor Alberto Zanchetti, Istituto Auxologico Italiano, Via L. Ariosto 13, 20145 Milan, Italy. Tel: +39 02 619112237; e-mail: alberto.zanchetti@auxologico.it

Abbreviations: ABP, ambulatory blood pressure; ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACEI, angiotensin-converting enzyme inhibitor; ALT, alanine aminotransferase; ANCOVA, analysis of covariance; ARB, angiotensin receptor blocker; AST, aspartate aminotransferase; BP, blood pressure; CHD, coronary heart disease; CHL, Chinese Hypertension League; CI, confidence interval; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CT, computed tomography; CVE, cardiovascular event; D, diuretic; DAD, disability assessment for dementia; DBP, diastolic blood pressure; DSMB, Data Safety and Monitoring Board; ECG-LVH, electrocardiographic left-ventricular hypertrophy; eCRF, electronic case report form; ESC, European Society of Cardiology; ESH, European Society of Hypertension; ESH-CHL-SHOT, European Society of Hypertension–Chinese Hypertension League Stroke in Optimal Hypertension Treatment; HbA1C, glycated haemoglobin; IQCODE, Informant Questionnaire on Cognitive Decline in the Elderly; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; PROBE, prospective randomized open blind endpoint; PROFESS, Prevention Regimen for Effectively Recurrent Stroke Study; PROGRESS, Perindopril Protection against Recurrent Stroke Study; PWV, pulse wave velocity; R, randomization; S, screening; SAE, serious adverse event; SCAST, Scandinavian Candesartan Acute Stroke Trial; SHOT, Stroke in Hypertension Optimal Treatment; TIA, transient ischaemic attack; TOAST, Trial of Org 10172 in Acute Stroke Treatment

Received 20 January, 2014

Revised 29 April, 2014

Accepted 29 April, 2014

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