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Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke TARDIS – ISRCTN47823388

Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke TARDIS – ISRCTN47823388. TARDIS Team Philip Bath, Margaret Adrian University of Nottingham. www.tardistrial.org. Agenda: Morning. Welcome Philip Bath 5 Aims/objectives/design Philip Bath 45

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Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke TARDIS – ISRCTN47823388

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  1. Triple Antiplatelets for Reducing Dependency after Ischaemic StrokeTARDIS – ISRCTN47823388 TARDIS Team Philip Bath, Margaret Adrian University of Nottingham www.tardistrial.org

  2. Agenda: Morning Welcome Philip Bath 5 Aims/objectives/design Philip Bath 45 Interventions/protocol Marg Adrian 40 Lunch

  3. Agenda: Afternoon Paperwork, data Marg Adrian 60 SAEs / SUSARS Philip Bath 30 Imaging Philip Bath 30 Tea Site responsibilities Marg Adrian 45 Data Monitoring Cttee Philip Bath 15 Substudies Philip Bath 20 Tea

  4. TARDIS: People • Patients • Investigators • Trial Steering Committee • Trial Management Committee • Data Monitoring Committee • SAE / Events adjudication • Neuroimaging staff • Substudy staff www.tardistrial.org

  5. Trial Steering Committee • Helen Rodgers Newcastle Chair • Philip Bath Nottingham • Stan Heptinstall Nottingham • Hugh Markus London • Ossie Newell Nottingham Patient • Tom Robinson Leicester • Graham Venables Sheffield • Independent Experts • Sponsor’s representative • Funder’s representative www.tardistrial.org

  6. Trial Management Committee • Philip Bath Chief Investigator • Margaret Adrian Coordinator • Tim England Medic • Chamila Geeganage Medic • Sandeep Ankolekar Medic • TBA Statistician • Wim Clarke Financial www.tardistrial.org

  7. Other posts • Niki Sprigg Events adjudicator • TBA Neuroimaging www.tardistrial.org

  8. Funding The British Heart Foundation Sponsor University of Nottingham Adoption Stroke Research Network Live Website www.tardistrial.org Email tardis@nottingham.ac.uk Trial Bodies

  9. TARDIS: Identifiers • ISRCTN: 47823388 • EudraCT: 2007-006749 • MHRA ref: 03057/0027/001/0001 • MREC ref: 08/H1102/112 • Sponsor ref: 31350 www.tardistrial.org

  10. TARDIS: Background Philip Bath www.tardistrial.org

  11. Cellular: Platelets White cells Endothelial cells Soluble: Fibrinogen Thrombin Atherothrombosis

  12. Antiplatelets and Stroke: Monotherapy Aspirin: • Inhibitor of cyclooxygenase • Reduces recurrence (RRR) by 17% in patients with prior stroke or TIA Clopidogrel: • Adenosine diphosphate (ADP) receptor antagonist • Was slight more efficacious than aspirin in CAPRIE Dipyridamole: • Inhibits red cell uptake of adenosine • Reduced recurrence by 16% (vs placebo, ESPS II)

  13. Acute ischaemic stroke/TIA Stroke: • Aspirin IST, CAST, MAST-I √ • Dual PRoFESS (√) • Triple ? TIA: • Aspirin APT √ • AC FASTER (√)

  14. Stroke prevention: Antiplatelets Strategy RRR (%) Trial No. Aspirin (A) 18 ATT, ESPS II 18270 Dipyridamole (D) 16 ESPS II 6602 Clopidogrel (C) vs. A 7 CAPRIE 6431 AD vs. control 38 ESPS, ESPS II 9102 AD vs. A 23 ESPS II, ESPRIT 9341 AC vs. C ( 0) MATCH 7599 AC vs. A (20) CHARISMA 15603 AC vs. A (34) FASTER 392 AD vs. C (- 1) PRoFESS 20332 ACD vs. A N/A Triple 2 17 ACD vs. AD ? TARDIS

  15. In blood from volunteers Combined aspirin, AR-C69931 and dipyridamole reduce: Platelet aggregation (figures: ADP, PAF) Monocyte activation Neutrophil activation Platelet-monocyte conjugation Platelet-neutrophil conjugation Platelet p-selectin expression Platelet aggregation: In vitro Zhao et al. Br J Pharm 2001;134:353-8

  16. In volunteers and patients with previous stroke Combined aspirin, AR-C69931 and dipyridamole (not different from aspirin/clopidogrel) reduce: Platelet aggregation (figures) Monocyte activation Neutrophil activation Platelet-monocyte conjugation Platelet-neutrophil conjugation Platelet aggregation: Ex vivo Zhao et al. Thromb Haemost 2005;93:527-34

  17. Triple 2 trial: Design • Randomised controlled trial • Open label, blinded outcome, blinded adjudication • 50 patients, 1 centre • Event: ischaemic stroke or TIA <5 years • Primary outcome: tolerability (discontinuations) • ACD vs. A (standard of care) • Aspirin 75 mg od • Clopidogrel 75 mg od • Dipyridamole MR 200 mg bd • Stopped early at n=17 • Positive results of ESPRIT (AD > A) • Total exposure 282 months • ISRCTN83673558 Sprigg et al. PLoS 2008;3(8):e2852

  18. Triple trial: Patient characteristics Aspirin ACD Number 8 9 Age (years) 61 63 Sex, male (%) 75 67 Event, stroke (%) 88 89 Event  trial (months) 10 8 Lacunar syndrome (%) 63 78 Hypertension (%) 63 67 Diabetes (%) 13 11 Sprigg et al. PLoS 2008;3(8):e2852

  19. Triple trial: Discontinuations Aspirin ACD 2p n=8 n=9 Exposure (mo) 144 138 Discontinuations 0 (0) 4 (44) 0.08 bruising 1 GI 2 non-compliance 1 Sprigg et al. PLoS 2008;3(8):e2852

  20. Triple trial: Safety Aspirin ACD 2p n=8 n=9 Death 0 (0) 1 (11) 1.00 SAEs 0 (0) 3 (33) 0.47 treatment-related 1 AEs 2 (25) 7 (77) 0.06 Bleeding, any 0 (0) 3 (33) 0.21 Recurrent stroke 0 (0) 1 (11) 1.00 Sprigg et al. PLoS 2008;3(8):e2852

  21. Adverse events: ordinal P<0.01 Sprigg et al. PLoS 2008;3(8):e2852

  22. Triple trial: Other measures Aspirin ACD 2p Hb at end 13.9 13.4 0.76 Platelet agg. 84 70 0.05 Monocyte act. 165 96 0.02 Platelet-monocyte 118 74 0.04 BP, PP, HR, RPP No effects/differences Sprigg et al. PLoS 2008;3(8):e2852

  23. Triple trial: Conclusions • Trial very underpowered • Stopped early (17 vs. 50 patients) • ACD (vs. A) • Trends to increased discontinuations and AEs • Reduced platelet aggregation, monocyte activation, platelet monocyte conjugates • Patients at low risk of recurrence • Long time after stroke, lacunars, young • Benefit < hazard? • Future trials should concentrate on high risk patients so benefit > hazard Sprigg et al. PLoS 2008;3(8):e2852

  24. Triple therapy: Case series History Prior Rx Length Status (months) HT/PFO A AD 15 Stopped - PFO closed ICAS/HT/HL A AD 20 Continuing ICAS/IHD/HT A AD 23 Continuing IHD/HT/HL A AD 5 Continuing IHD/PE/HL A W WA CD 9 Stopped - further PE DM/HL/HT C AC 14 Continuing IHD/HL A AD 1 Stopped - haematuria DM/HT/HL A AD 7 Continuing IHD/ICAS/HT A AD 12 Continuing No strokes on ACD Willmot et al. J Stroke CVD 2004;13:138-40

  25. Triple therapy (SR): MI Geeganage et al. Unpublished

  26. Triple therapy (SR): Major bleeding Geeganage et al. Unpublished

  27. Triple therapy (SR): Absolute effects Geeganage et al. Unpublished

  28. Triple therapy (SR): Conclusions Short-term triple therapy: • Reduces MI and vascular events • Increases bleeding and transfusions • Absolute event - efficacy>hazard Stroke: • Minimal data on stroke events • Minimal data on effects in stroke/TIA patients • Need more data! Geeganage et al. Unpublished

  29. Any Questions?

  30. TARDIS: Aims, objectives Philip Bath www.tardistrial.org

  31. TARDIS: Aims (PICO) To assess: • Patients • With acute TIA or ischaemci stroke • Intervention • Short-term addition of clopidogrel to standard dual antiplatelet therapy (AD) • Comparator • Standard dual antiplatelet therapy (AD) • Outcomes • Efficacy - stroke and its severity • Safety – bleeding and its severity www.tardistrial.org

  32. TARDIS: Predications • Patients at high risk of recurrence • Acute stroke • Acute TIA (ABCD2>4, crescendo TIA) • Efficacy: AD >> A; bleeding AD ~ A • Efficacy: AC >> A; bleeding AC > A • AD is standard of care in UK (NICE) • Patients on AD still have strokes (‘failure’) • Efficacy: ACD >> AD? • Bleeding: ACD > AD? • High risk patients: benefit > hazard www.tardistrial.org

  33. TARDIS: Design • Prospective, randomised, open-label, blinded endpoint, parallel group controlled trial Reduce sources of bias: • Randomised • Concealment of allocation • Blinded endpoint assessment • Controlled • ACD vs AD (open-label) • Intention-to-treat www.tardistrial.org

  34. TARDIS: Design • Start-up phase of main phase III trial • 270 patients, 25+ SRN centres, 3 years • Intervention: Addition of clopidogrel to standard antiplatelet therapy • ACD vs. AD for one month Oral Nasogastric Aspirin 75 mg od = (150 mg pr alt) Dipyridamole 200 mg bd MR 100 mg qds, liq/tab Clopidogrel 75 mg od = www.tardistrial.org

  35. TARDIS: Outcomes (start-up) Primary outcome (day 30): • SAEs • 12% --> 30%, alpha 5%, power 90% Secondary (days 30, 90): • Events: Stroke, Vascular, MI • Function: mRS, BI, NIHSS Safety (days 30, 90): • Death, SICH, major bleeding www.tardistrial.org

  36. TARDIS: Outcomes (main phase) Use ordinal outcome for stroke to: • Shift analysis (as with mRS) • Reduce sample size, potentially by ~25% • Show effects of ACD on event severity • Fatal stroke • Non-fatal severe stroke • Non-fatal mild stroke • TIA • No event www.tardistrial.org

  37. Any Questions?

  38. TARDIS: Trial interventions, protocol Margaret Adrian www.tardistrial.org

  39. TARDIS: Inclusion criteria • Adults (aged >50) at high risk of recurrent ischaemic stroke, within 48hrs of onset: • Acute non-cardioembolic ischaemic stroke • Motor weakness and/or dysphasia present at randomisation • Acute TIA with one or more of • Crescendo TIA (>1 TIA within 1 week) • AND/OR Taking dual antiplatelet therapy (aspirin/dipyridamole, aspirin/clopidogrel, clopidogrel/dipyridamole) • AND/OR ABCD2 score >4 • AND Motor weakness/or dysphasia lasting at least 10 minutes for the randomising event www.tardistrial.org

  40. ABCD2 score

  41. Definitions • Stroke - WHO • A clinical syndrome characterised by rapidly developing clinical symptoms and/or signs of focal (and at times global) loss of cerebral function with symptoms lasting for more than 24 hours or leading to death, with no apparent cause other than that of vascular origin’ • Brain imaging required before trial entry • TIA • A sudden focal neurological deficit of the brain or eye, presumed to be of vascular origin and lasts less than 24 hours • Brain imaging is not required before trial entry

  42. TARDIS: Exclusion criteria, 1 • Age<50 • Motor weakness and/or aphasia lasting <10 minutes • Pure sensory, vertigo, dizziness, speech or visual symptoms without weakness • Contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole • Definite need for treatment with clopidogrel (e.g. recent MI - within 1yr) • Pre-morbid dependency (mRS>2) • No enteral access www.tardistrial.org

  43. TARDIS: Exclusion criteria, 2 • TIA not fulfilling inclusion criteria • Definite need for full dose oral (e.g. warfarin) or parenteral (e.g. heparin, GP IIb/IIIa inhibitor) anti-coagulation • AF, recent MI • Low dose heparin for DVT prophylaxis is allowed • Thrombolysis within last 30 hours • Severe high BP (BP>185/110 mmHg) • Bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage) www.tardistrial.org

  44. TARDIS: Exclusion criteria, 3 • Parenchymal haemorrhagic transformation (PH I/II), subarachnoid haemorrhage • Other non ischaemic cause for weakness • Known haemoglobin <10g/dL • Known platelet count <100 x 1E9/L • Known white cell count <3.5 x 1E9/L • Planned surgery during 3 month follow-up (e.g. carotid endarterectomy) • Concomitant acute coronary syndrome www.tardistrial.org

  45. TARDIS: Exclusion criteria, 4 • Stroke secondary to a procedure • e.g. carotid or coronary intervention • Coma (GCS<8) • Non-stroke life expectancy<6 months • Dementia • Participation in another drug trial • Observational studies or non-drug trials are OK • Not available for follow-up • e.g. no fixed address, overseas visitor • Females of childbearing potential, pregnancy or breastfeeding www.tardistrial.org

  46. TARDIS: Interventions / Trial Flow Stroke or TIA (<48) Triple Therapy Dual Therapy (ACD) for 1 month (AD) for 1 month ( Randomised 1:1) Assessment at days 7 and 35 for safety, efficacy, and tolerability 90 day central blinded telephone follow up and end of the trial www.tardistrial.org

  47. TARDIS: Trial Flow FBC Form Brain Imaging Form SAE / Outcome Form Hospital Events Form www.tardistrial.org

  48. TARDIS: Aspirin • Dose: • Loading dose: 300mg (whether or not already on aspirin) • Maintenance dose: 25mg bd to 75mg od • Protocol violation: maintained on 300mg aspirin • Route • Enteral (including via nasogastric tube): dispersible or crushed tablets • Rectal: 150mg suppository alternate days • Alternative if necessary • All authorised UK brands may be used www.tardistrial.org

  49. TARDIS: Dipyridamole • Dose: • Oral: 200mg modified release (MR) bd • Nasogastric tube (e.g. dysphagia): Dipyridamole suspension 75mg tds - 100mg qds • Headache from dipyridamole: Wean up from daily MR 200mg or standard release 75mg od to MR 200mg bd • Fixed combinations of A and D may be used • E.g. Asasantin Retard (aspirin 25mg, dipyridamole 200mg MR bd) • All authorised UK brands may be used www.tardistrial.org

  50. TARDIS: IMP - Clopidogrel • Dose: • Loading dose 300mg (day 0) • Maintenance dose: 75mg od (days 1 to 30) • Route: Enteral (including via nasogastric tube – tablets may be crushed) • The IMP is defined by active substance only, so all authorised UK brands may be used www.tardistrial.org

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