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Lancet. 2019 Jun 29;393(10191):2613-2623. doi: 10.1016/S0140-6736(19)30840-2. Epub 2019 May 22.

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial.

Collaborators (955)

Al-Shahi Salman R, Dennis MS, Sandercock P, Sudlow C, Wardlaw JM, Whiteley WN, Murray GD, Stephen J, Newby DE, Sprigg N, Werring DJ, White PM, Baigent C, Lasserson D, Sullivan F, Carrie J, Rojas J, Amoils S, Bamford J, Armitage J, Rinkel G, Lowe G, Emberson J, Innes K, Dinsmore L, Drever J, Williams C, Perry D, McGill C, Buchanan D, Walker A, Hutchison A, Matthews C, Fraser R, McGrath A, Deary A, Anderson R, Walker P, Hansen C, Parker R, Rodriguez A, Macleod MR, Gattringer T, Palmer J, Sakka E, Adil-Smith J, Minks D, Mitra D, Bhatnagar P, du Plessis J, Joshi Y, Lerpiniere C, O'Brien R, Burgess S, Mead G, Paulton R, Doubal F, McCormick K, Hunter N, Taylor P, Parakramawansha R, Perry J, Blair G, MacRaild A, Parry-Jones A, Johnes M, Lee S, Shaw KM, Burger I, Punter M, Ingham A, Perez J, Naing Z, Morell J, Marsden T, Hall A, Marshall S, Harrison L, Jarapa R, Wood E, O'Loughlin V, Cohen D, Davies S, Njoku K, Mpelembue M, Burgess L, Licenik R, Ngwako M, Nisar N, Niranchanan R, Roganova T, Bathula R, Devine J, David A, Oshodi A, Guo F, Owoyele E, Sukdeo V, Ballantine R, Abbdul-Saheb M, Chamberlain A, Chandrakumar A, Poku P, Harkness K, Blank C, Richards E, Ali A, Kibutu F, Balitska O, Birchall K, Bayliss P, Doyle C, Stocks K, Majis A, Howe J, Kamara C, Barron L, Maatouk A, Lindert R, Dakin K, Redgrave J, Bhaskaran B, Salih I, Kelly D, Szabo S, Tomlin D, Bearne H, Buxton J, Fitzell P, Ayres G, Saulat A, Horan K, Garfield-Smith J, Bhakri H, Guyler P, Sinha D, Loganathan T, Siddiqui A, Siddiqui A, Coward L, Kunhunny S, Tysoe S, Orath Prabakaran R, Kelavkar S, Rashmi S, Ngo D, Ng KX, Menon N, Shah S, Barber M, Esson D, Brodie F, Anjum T, Wani M, Krishnan M, Quinn L, Spencer J, Jones T, Thompson-Jones H, Dacey L, Chenna S, Storton S, Thomas S, Beaty T, Treadwell S, Davies C, Tucker S, Connor L, Slade P, Gainard G, Muddegowda G, Sanyal R, Remegoso A, Abano N, Causley C, Carpio R, Stevens S, Butler A, Varquez R, Denic H, Alipio F, Moores A, Barry A, Maguire H, Grocott J, Finney K, Lyjko S, Roffe C, Hiden J, Ferdinand P, Cvoro V, Ullah K, Chapman N, Couser M, Pound S, McCormick K, Mcauley S, Raghunathan S, Shelton F, Hedstrom A, Godfrey M, Havard D, Buck A, Krishnan K, Gilzeane N, Roffe J, Clarke J, Whittamore K, Sheikh S, Keshvara R, Jordan C, Jackson B, Wilkes G, Appleton J, Law Z, Matias O, Vasileiadis E, Mason C, Parry A, Landers G, Holden M, Aweid B, Rashed K, Balian L, Vickers C, Keeling E, Board S, Allison J, Buckley C, Williams-Yesson B, Board J, Pitt-Kerby T, Tanate A, Wood D, Kini M, Chadha D, Walstow D, Fong R, Luder R, Adesina T, Gallagher J, Bridger H, Murali E, Bhargava M, van Someren C, Harrington F, Mate A, James A, Courtauld G, Schofield C, Adie K, Lucas L, Bond K, Maund B, Ellis S, Mudd P, James M, Keenan S, Bowring A, Cageao J, Kingwell H, Roughan C, Hemsley A, Sword J, Strain D, Miller K, Goff A, Gupwell K, Thorpe K, Emsley H, Punekar S, McLoughlin A, Sultan S, Gregory B, Raj S, Doyle D, Muir K, Smith W, Welch A, Moreton F, Cheripelli BK, El Tawil S, Kalladka D, Huang X, Day N, Ramachandran S, Crosbie C, Elliot J, Rudd T, Marks K, Bhalla A, Birns J, Kullane S, Weir N, Allen C, Pressly V, Crawford P, Battersby-Wood E, Blades A, Egerton S, Walters A, Evans S, Marigold JR, Smith F, Howard G, Gartrell I, Smith S, Creeden R, Cox C, Boxall C, Hewitt J, Nott C, Sarah P, Whiteman J, Buckle S, Wallace R, Mardania R, Gray J, Triscott C, Nair A, Greig J, Rana P, Robinson M, Alam MI, Wilson D, Watchurst C, Brezitski M, Crook L, Jones I, Banaras A, Patel K, Erande R, Hogan C, Hostettler I, Ashton A, Feerick S, Francia N, Oji N, Elliott E, Al-Mayhani T, Lerpiniere C, Fraser R, Dutta D, Brown P, Ward D, Davis F, Turfrey J, Hughes C, Collins K, Bakawala R, O'Connell S, Glass J, Broughton D, Tryambake D, Dixon L, Chapman K, Young A, Bergin A, Sigsworth A, Manoj A, Fletcher G, Lopez P, Cox P, Wilkinson M, Fitzsimmons P, Sharma N, Choulerton J, Button D, Dow L, Gbadamoshi L, Avis J, Madigan B, McCann S, Shaw L, Howcroft D, Lucas S, Stone A, Cluckie G, Lovelock C, Clarke B, Chopra N, Clarke N, Patel B, Kennedy K, Williams R, Blight A, O'Reilly J, Orefo C, Dayal N, Ghatala R, Adedoyin T, Watson F, Trippier S, Choy L, Moynihan B, Khan U, Jones V, Jeyaraj N, Kerin L, Thavanesan K, Tiwari D, Cox C, Ljubez A, Tucker L, Iqbal A, Bagnall C, Keltos M, Roberts J, Jupp B, Ovington C, Rogers E, David O, Bell J, Longland B, Hann G, Cooper M, Nasar M, Rajapakse A, Wynter I, Anwar I, Skinner H, Nozedar T, McArdle D, Kumar B, Crawford S, Annamalai A, Ramshaw A, Holmes C, Caine S, Osborn M, Dodd E, Murphy P, Devitt N, Baker P, Steele A, Guthrie LB, Clarke S, Hassan A, Waugh D, Veraque E, Makawa L, Kambafwile M, Randall M, Papavasileiou V, Cullen C, Peters J, Thant H, Ingram T, Zoe M, Durairaj R, Harrison M, Stevenson S, Shackcloth D, Ewing J, Sutton V, McCarron M, McKee J, Doherty M, McVerry F, Blair C, MacLeod M, Irvine J, Gow H, Furnace J, Joyson A, Jagpal B, Ross S, Klaasen K, Nelson S, Clarke R, Crouch N, MacLennan B, Taylor V, Epstein D, Jones I, Shukla A, Krishnamurthy V, Nicholas P, Qureshi S, Webber A, Penge J, Ramadan H, Maguire S, Patterson C, Bellfield R, Hairsine B, Stewart K, Hooley M, Quinn O, Richard B, Moseley S, Nott C, Buckle S, Sarah P, Whiteman J, Edwards M, Lawson H, Wallace R, Triscott C, Tayler M, Pai Y, Dhakal M, Esisi B, Dima S, Smith GM, Garside M, Naeem M, Baliga V, Rogers G, Brown E, Bruce D, Hayman R, Clayton S, Gamble E, Grue R, Charles B, Hague A, Blane S, Lambert C, Chaudhry A, Harrison T, Saastamoinen K, Hove D, Howaniec L, Grimwood G, Redjep O, Humphries F, Argandona L, Cuenoud L, Erumere E, Amlani S, Auld G, Salek-Haddadi A, Schulz U, Kennedy J, Ford G, Mathieson P, Reckless I, Teal R, Lenti G, Harston G, O'Brien E, Mcgee J, Mitchell J, Amis E, Handley D, Kelly S, Zachariah G, Francis J, Crisp S, Sesay J, Finlay S, Hayhoe H, Hannon N, Hughes T, Morse B, De Berker H, Tallantyre E, Osman A, White S, Schwarz S, Jelley B, Yadava R, Azhar K, Reddan J, Sangombe M, Stafford S, Fotherby K, Morgan D, Baig F, Jennings-Preece K, Butler D, Ahmad N, Willberry A, Stevens A, Rai B, Siddegowda P, Howard P, Saulat A, Hyatt L, Dobson T, Jarrett D, Ponnambath S, Tandy J, Harrington-Davies Y, Butler R, James C, Valentine S, Suttling A, Langhorne P, Kerr G, Wright F, Graham R, McAlpine C, Iqbal MS, Humphreys L, Pasco K, Balazikova O, Nasim A, Peixoto C, Gallagher L, Shahmehri S, Ghosh S, Barrie E, Gilmour D, Henry M, Webb T, Cowie L, Rudenko H, McDonald S, Schumacher N, Walker S, Cosier T, Verrion A, Beranova E, Thomson A, Venter M, Kar A, Mashate S, Harvey K, Gardener L, Nguyen V, Halse O, Geraghty O, Hazel B, Wilding P, Tilley V, Esisi B, Cassidy T, McClelland B, Bokhari M, England T, Hedstrom A, Maddula M, Donnelly R, Findlay P, Macaden A, Shread I, Barr C, Mohd Nor A, Brown C, Persad N, Eglinton C, Weinling M, Hyams B, Shah A, Baker J, Byrne A, McGhee C, Smart A, Copeland C, Carpenter M, Walker M, Davey R, Needle A, Fathima R, Bateman G, Datta P, Stanners A, Jackson L, Ball J, Davis M, Atkinson N, Fawcett M, Thompson T, Guy H, Hogg V, Hays C, Woodward S, Haque M, Hakim E, Symonds S, Maanoosi M, Herman J, Black T, Miriam S, Clarke C, Anthony A, Tribbeck M, Cronin J, Mead D, Fennelly R, McIlmoyle J, Dickinson C, Jeffs C, Anwar S, Howard J, Jones K, Dhar S, Clay C, Siddiq M, Ivatts S, Baird Y, Sally M, Amey I, Newton S, Clayton-Evans L, Chadbourn I, Rayessa R, Naylor C, Rodgers A, Wilson L, Wilson S, Clarkson E, Davies R, Owings P, Sangster G, Gott V, Little V, Weir P, Cherian S, Jose D, Moroney H, Downham S, Dodd A, Vettimootal Johnson V, Codd L, Robinson N, Ahmed A, Albazzaz M, Johnson S, Denniss C, Cunningham M, Zahoor T, Webster T, Leason S, Haider S, Chatterjee K, Nallasivan A, Perkins C, Seagrave S, Jenkins C, Price F, Hughes C, Mercer L, Hussain M, Brown S, Harvey M, Homan J, Khan M, Whiting R, Foote L, Hunt N, Durman H, Brotherton L, Foot J, Pawley C, Foster E, Whitcher A, Metcalf K, Jagger J, McDonald S, Waterfield K, Sutton P, Shinh N, Anversha A, Ravenhill G, Greenwood R, Saada J, Wiltshire A, Perfitt R, Andole S, Gadapa N, Dunne K, Krommyda M, Burssens E, King S, Plewa C, Smyth N, Wilson J, Giallombardo E, Eglinton C, Sykes L, Kumar P, Barker J, Huggett I, Dunn L, Culmsee C, Thomas P, Myint M, O'Brien R, Brew H, Majmudar N, O'Connell J, Bunea G, Fox C, Gulliver D, Smith A, Mokoena B, Sattar N, Krishnamurthy R, Osborne E, Wilson D, Wroath B, Dynan K, Power M, Thompson S, Adell V, Orugun E, Poultney U, Glover R, Crowther H, Thornthwaite S, Wiggam I, Wallace A, Kerr E, Fulton A, Hunter A, Tauro S, Cuddy S, Mangion D, Hardwick A, Markova S, Lawrence T, Constantin C, Fletcher J, Thomas I, Pettitt K, Sekaran L, Tate M, Bharaj K, Simon R, Justin F, Sethuraman S, Phiri D, Mohammed N, Chauhan M, Elfandi K, Khan U, Stafford S, Reddan J, Eveson D, Mistri A, Manning L, Khan S, Patel C, Moqsith M, Sattar S, Lam MY, Musarrat K, Stephens C, Kalathil L, Miller R, Salehin M, Gautam N, Bailey D, Amor K, Meir J, Nicolson A, Imam J, Wood L, White J, Sajid M, Ghaly G, Ball M, Gascoyne R, Proeschel H, Sharpe S, Horton S, Beaves E, Jones S, Yip B, Bell M, MacLiver L, MacInnes B, Esson D, Sims D, Hurley J, Willmot M, Sutton C, Littleton E, Maiden S, Jones R, Cunningham J, Green C, Bates M, Shekhar R, Waterfield K, Gilham E, Ahmed I, Crown R, Fuller T, Goorah N, Bell A, Kelly C, Singh A, Walford J, Tomlinson B, Patel F, Duberley S, Kane I, Rajkumar C, Gaylard J, Breeds J, Gainsborough N, Pitt-Ford A, Barbon E, Latter L, Thompson P, Hervey S, Krishnamoorthy S, Vassallo J, Walter D, Cochrane H, Srinivasan M, Campbell R, Donaldson D, Motherwell N, Hurford F, Mukherjee I, Kenton A, Nyabadza S, Martin I, Hunt B, Hassan H, O'Toole S, Dallol B, Putterill J, Jha R, Gallifent R, Kakar P, Pusalkar A, Chan K, Dangri P, Beadle H, Cook A, Crabtree K, Subramonian S, Owusu-Agyei P, Temple N, Butterworth-Cowin N, Ragab S, Knops K, Jinks E, Dickson C, Gleave L, Dube J, Leggett J, Garcia T, Ispoglou S, Evans R, Ankolekar S, Hayes A, Ni H, Rahman B, Milligan J, Graham C, Jose J, Keegan B, Doherty M, Kelly J, Blair C, Dewar R, White J, Thomas K.

Abstract

BACKGROUND:

Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.

METHODS:

The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).

FINDINGS:

Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92).

INTERPRETATION:

These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.

FUNDING:

British Heart Foundation.

PMID:
31128924
PMCID:
PMC6617509
DOI:
10.1016/S0140-6736(19)30840-2
[Indexed for MEDLINE]
Free PMC Article

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