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Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Bath, Philip M.W.; Christensen, L M; Woodhouse, Lisa J.; Bentsen, L; Appleton, Jason P.; Krarup Hansen, C; Beridze, M.; Thomsen, T T; Christensen, Hanne; Kruuse, C; Dineen, Robert A.; Jensen, H H; Duley, Lelia; Hansen, S S; England, Timothy J.; Petrovic, V; Flaherty, Katie; Beridze, N; Havard, Diane; Kakabadze, N; Heptinstall, Stan; Kherkheulidze, T; James, Marilyn; Kakabadze, D; Krishnan, Kailash; Toidze, I; Markus, H.S.; Lobjanidze, N; Montgomery, Alan A.; Akiashvili, N; Pocock, Stuart J.; ATevdoradze; Randall, Marc; Khizanishvili, N; Ranta, A.; Tsanava, T; Robinson, Thompson G.; Taylor, R; Scutt, Polly; Iniesta, I; Venables, Graham S.; Kok, J; Sprigg, Nikola; Duignan, J; Funnell, M; Cariga, P; Rodriguez, M; Watson, I J; Tennant, S; Macleod, M; Furnace, J; Gow, H; Irvine, J; Joyson, A; Nelson, S; Taylor, V; Smith, M; Bellfield, R; Hairsine, B; Davies, R; Dodd, A; Corrigan, J; Doherty, M; Ahmed, A; Denniss, C; Johnson-Holland, S; Kay, K A; Icart Palau, R; Auld, G; Daboo, P; Erande, R;...

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial Thumbnail


Authors

PHILIP BATH philip.bath@nottingham.ac.uk
Stroke Association Professor of Stroke Medicine

L M Christensen

L Bentsen

Jason P. Appleton

C Krarup Hansen

M. Beridze

T T Thomsen

Hanne Christensen

C Kruuse

ROBERT DINEEN rob.dineen@nottingham.ac.uk
Professor of Neuroradiology

H H Jensen

Lelia Duley

S S Hansen

V Petrovic

Katie Flaherty

N Beridze

Diane Havard

N Kakabadze

Stan Heptinstall

T Kherkheulidze

MARILYN JAMES MARILYN.JAMES@NOTTINGHAM.AC.UK
Professor of Health Economics

D Kakabadze

Kailash Krishnan

I Toidze

H.S. Markus

N Lobjanidze

ALAN MONTGOMERY ALAN.MONTGOMERY@NOTTINGHAM.AC.UK
Director Nottingham Clinical Trials Unit

N Akiashvili

Stuart J. Pocock

ATevdoradze

Marc Randall

N Khizanishvili

A. Ranta

T Tsanava

Thompson G. Robinson

R Taylor

Polly Scutt

I Iniesta

Graham S. Venables

J Kok

NIKOLA SPRIGG nikola.sprigg@nottingham.ac.uk
Professor of Stroke Medicine

J Duignan

M Funnell

P Cariga

M Rodriguez

I J Watson

S Tennant

M Macleod

J Furnace

H Gow

J Irvine

A Joyson

S Nelson

V Taylor

M Smith

R Bellfield

B Hairsine

R Davies

A Dodd

J Corrigan

M Doherty

A Ahmed

C Denniss

S Johnson-Holland

K A Kay

R Icart Palau

G Auld

P Daboo

R Erande

G Grimwood

D Hove

L Howaniec

O Redjep

R Rangasamay

G Butt

D Sandler

J Reddan

S Stafford

J McIlmoyle

S Maguire

P Murphy

J Chambers

L Guthrie

M Osborn

A Steele

M Burn

A Benford

A Misra

D Hilton

E O'Brien

E Amis

S Finlay

J Mitchell

O Geraghty

K Harvey

B Hazel

S Mashate

P Wilding

M Sajid

M Ball

R Gascoyne

R Sivakumar

A Wright

K Chatterjee

S Booth

H Eccleson

C Kelly

S Leason

C Perkins

D Bruce

E Brown

S Clayton

M Garside

G Rogers

E Lawrence

S Mahmood

C Watchurst

D Chadha

L Glover

L Holford

K Smith

D Walstow

R Williams

L O'Shea

J Goodsell

C Athulathmudali

E Barbon

R Namushi

P Jacob

L Johnson

D Morse

C McGhee

O Speirs

S Atkinson

A Peacocke

P Langhorne

R Graham

F Wright

C McAlpine

A Ravindrane

M Bajoriene

L Matter

S Windebank

E Giallombardo

D Dellafera

C Eglinton

J Wilson

D Broughton

K Chapman

L Dixon

M Zaidi

K Ayes

J Kessell

D Manawadu

O Adegbaju

J Aeron-Thomas

K Anderson

A Brigden

E Cattermole

J Good

S Hassan

E Khoromana

L Lee-Carbon

K Marks

E Mckenzie

N Sikondari

M Cooper

K Whysall

I Wynter

J Bamford

A Hassan

P Wanklyn

M Kambafwile

L Makawa

D Waugh

E Veraque

M G G Soliman

S Arif

R Brown

S Butler

C Hewitt

J Hindle

A Pusalkar

H Beadle

K Chan

M Siddiqui

P Dangri

S Buddha

A Asokanathan

A Mistri

D Eveson

K Musarrat

L Manning

S Anand

P Christian

S Khan

C Patel

M Sein

J Banns

E Gibson

T Gordon

Y Gruenbeck

S Wong

P Datta

G Bateman

L Jackson

A Needle

Y Duodu

R Oliver

C Padilla-Harris

M Barber

D Esson

F Brodie

C McInnes

K Fotherby

D Butler

D Morgan

K Preece

A Willberry

M Dent

F Hammonds

J Hunt

C Vernon

D O'Kane

F Faola

P Lai

J O'Callaghan

C Smith

C Price

R Lakey

V Riddell

A Smith

G Storey

S Munshi

A Buck

J Clarke

N Gilzeane

M Godfrey

R Keshvara

C Richardson

J Roffe

L Ryan

F Shelton

W Sunman

A Tittle

J Tomlinson

K Whittamore

G Wilkes

P Owusu-Agyei

N Temple

D Mangion

A Hardwick

K Netherton

A MohdNor

B Hyams

S Norman

N Persad

S Ragab

C Dickson

J Dube

E Jinks

K Knops

B Wadams

K Ali

J Gaylard

G Spurling

L Sztriha

T Ajao

M Alao

F KChan

P Webster

P HowardT JDobson

L Hyatt

D Sims

J Cunningham

B Esisi

T Cassidy

M Bokhari

B McClelland

B Mokoena

G Gunathilagan

S Jones

M Reader

G Thomas

S Tilby

P Findlay

F Barrett

F Leslie

S Ross

I Shread

J Okwera

J Howe

F Harrington

G Courtauld

C Schofield

R Donnelly

M Maddula

J Scott

J Beavan

K Muhidden

I Memon

M Clarke

A Hedstrom

L Mills

A Hemsley

A Bowring

L Boxall

H Kingwell

S Keenan

C Roughan

A Manoj

P Cox

G Fletcher

P Lopez

H Emsley

B Gregary

A McLoughlin

S Raj

C Roffe

N Abano

A Barry

A Butler

R Carpio

K Castro

K Finney

S Gomm

J Hiden

J Grocott

S Lyjko

H Maguire

A Remegoso

R Sanyal

S Stevens

I Natarajan

J Chembala

G Muddegowda

A Warusevitane

A Blight

O Balazikova

C Lawlor

L Shaw

D Button

D Howcroft

S Lucas

B Madigan

S McCann

A Dixit

A Barkat

J Davis

M Fawcett

L Finlay

H Guy

C Hays

V Hogg

E Horsley

C Hubbuck

C Pringle

C Stevenson

K Storey

T Thompson

S Woodward

A Banerjee

C Allcock

S Merotra

C Douglass

E Campbell

R Jarapa

M Johnes

C Keaveney

T Marsden

Z Naing

J Perez

K Shaw

T Black

A Anthony

C Clarke

J Paterson

K Deighton

E Temlett

C Blank

C Doyle

S Duty

K Gill

K Harkness

C Kamara

E Richards

K Elfandi

P Guyler

P Harman

C Khuoge

S Kunhunny

S Tysoe

B Moynihan

T Adedoyin

N Chopra

N Dayal

R Ghatala

N Jeyaraj

I Jones

F Kennedy

L Kerin

N Khanom

S Lewis

S Maheswaran

L Montague

M Niemierko

J O'Reilly

S Trippier

F Watson

P Wilkinson

E Young

K Dizayee

H Cochrane

J O'Connell

L Mokoena

E Osborne

A Nair

J Greig

C Jenkins

J Powell

F Price

M Chowdhury

S Brixey

L Hunt

N Rands

G Rose

S Stoddart

M Srinivasan

N Motherwell

R Shekhar

T Fuller

A Lankester

P Lingwood

C Rankin

H Webb

B Jupp

J Bell

G Hann

B Longland

C Ovington

B Bhaskaran

G Ayres

C Bailey

H Bearne

J Buxton

P Fitzell

C Hilaire

D Kelly

S Szabo

D Tomlin

E Gamble

B Charles

R Kumar

T Fluskey

Z Mellor

J Peters

V Sutton

A Kenton

I Martin

S Nyabadza

S Ghosh

M Henry

B Kumar

D Bruce

C Ambulo

S Crawford

T Nozedar

M Platton

V Cvoro

M Couser

K McCormick

D Wilkinson

K Javaid

S Hurdowar

T Attygalle

S Sundayi

O Orugun

H Crowther

R Jolly

U Poultney

A Azim

M Krasinska-Chavez

J White

N Sengupta

J Margalef

M G Metiu

S Meenakshisundaram

S Dealing

D Hargroves

E Beranova

L Cowie

H Rudenko

A Thomson

A Verrion

K Rashed

S Board

C Buckley

D Hayward

K Jenkins

E Keeling

R Rowland-Axe

C Vickers

D Wood

A Lehman

R Erande

M Patel

H Russell

H Rehman

D Forrest

P Farren



Abstract

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.
Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.
Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p

Citation

Bath, P. M., Christensen, L. M., Woodhouse, L. J., Bentsen, L., Appleton, J. P., Krarup Hansen, C., …Farren, P. (2018). Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet, 391(10123), 850-859. https://doi.org/10.1016/S0140-6736%2817%2932849-0

Journal Article Type Article
Acceptance Date Nov 2, 2017
Online Publication Date Dec 20, 2017
Publication Date Mar 3, 2018
Deposit Date Jan 9, 2018
Publicly Available Date Jan 9, 2018
Journal Lancet
Print ISSN 0140-6736
Electronic ISSN 1474-547X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 391
Issue 10123
Pages 850-859
DOI https://doi.org/10.1016/S0140-6736%2817%2932849-0
Public URL https://nottingham-repository.worktribe.com/output/918616
Publisher URL http://www.sciencedirect.com/science/article/pii/S0140673617328490
Contract Date Jan 9, 2018

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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