1 / 303

Prevention Of Decline in Cognition After Stroke Trial (PODCAST)

Prevention Of Decline in Cognition After Stroke Trial (PODCAST). www.podcast-trial.org. PODCAST: Agenda, day 1. Welcome Philip Bath, John O’Brien Background Philip Bath Aims & design overview Philip Bath Protocol: inclusion/exclusion Sandeep Ankolekar Approvals Sheila O’Malley

fleta
Download Presentation

Prevention Of Decline in Cognition After Stroke Trial (PODCAST)

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Prevention Of Decline in Cognition After Stroke Trial(PODCAST) www.podcast-trial.org

  2. PODCAST: Agenda, day 1 Welcome Philip Bath, John O’Brien Background Philip Bath Aims & design overview Philip Bath Protocol: inclusion/exclusion Sandeep Ankolekar Approvals Sheila O’Malley Interventions: BP/lipid lowering I Philip Bath, Nathalie Bailey- Flitter Tea Interventions: BP/lipid lowering II Philip Bath, John Reckless Cognitive outcome measures Philip Bath, Clive Ballard Funders’ perspective Susanne Sorensen Delegates Practice data entry (Room A41) Trial Steering Committee (Room A42)

  3. PODCAST: Agenda, day 2 Serious Adverse Events Philip Bath Outcomes, dementia & vascular Clive Ballard Philip Bath Electronic data entry I Sandeep Ankolekar Coffee Electronic data entry II Sandeep Ankolekar Imaging: definitions/upload Sandeep Ankolekar, Tanya Jones Site responsibilities Sally Utton Site monitoring Lynn Stokes Data monitoring Philip Bath Close Philip Bath Lunch

  4. PODCAST: Background to the trial Philip Bath

  5. Definitions Post stroke dementia (PSD): • Dementia following symptomatic stroke Vascular dementia (VaD): • Dementia in presence of cerebrovascular disease Mixed dementia: • Coexisting VaD and AD Post stroke cognitive impairment (PSCI): • Cognitive impairment following symptomatic stroke Cognitive impairment/no dementia (CIND) Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  6. Post-stroke dementia High risk of vascular cognitive impairment and dementia after stroke Dementia 15-30% within 5 years of stroke Strategic infarcts – rapid Lacunar/white matter – insidious Attentional/executive dysfunction before memory Mechanisms Stroke lesion(s): strategic lesions Cortical, lacunar, white matter disease Atherosclerosis & risk factors High BP, high cholesterol Blood brain barrier breakdown Toxic blood components: white matter disease Low blood flow, …

  7. Prevalence of pre-stroke dementia Pendlebury & Rothwell. Lancet Neurol 2009;8:1006

  8. Prevalence of post-stroke dementia By 1 year Pendlebury & Rothwell. Lancet Neurol 2009;8:1006

  9. Incidence of post-stroke dementia Hospital-based cohorts/any stroke Community-based cohorts/first stroke Pendlebury & Rothwell. Lancet Neurol 2009;8:1006

  10. Lessons: Observational data PSD higher: If dementia prevalent at time of stroke Self-evident! After recurrent stroke than first stroke Predictable In hospital series, relative to community Predictable Preventing recurrence may be a key way to prevent PSD

  11. ENOS: Cognitive decline post stroke High BP, <48 hours of onset Ischaemic stroke, ICH 5 continents, 16 countries, 105 centres RCT of GTN v control; continue v stop Blinded telephone outcomes at day 90 Primary: modified Rankin Scale Cognitive: sMMSE (n = 465) sMMSE 0-18/18, mean 13.4, SD 4.7 sMMSE <14 = 178 (38.3%) Secondary: Barthel Index, EuroQoL, Zung www.enos.ac.uk

  12. ENOS: Associations with low sMMSE + p<0.001 Univariate Multivariate Age + + Female sex + + Previous stroke + - AF + + PICH + + TACS + + Severe stroke + + High SBP + + Diabetes - Temperature - Glucose - Ankolekar et al, for ENOS, UK Stroke Forum 12/2009

  13. ENOS: sMMSE and other outcomes Measure Scale r p Dependency mRS -0.368 <0.001 Disability BI 0.432 <0.001 QoL EuroQoL 0.314 <0.001 Mood Zung -0.135 0.004 So, influencing one may alter the others Ankolekar et al, for ENOS, UK Stroke Forum, 12/2009

  14. ENOS: Implications Poor cognitive function at day 90 post stroke Common, 38% Associated with: Multiple baseline factors including high BP Outcome - poor functional outcome, QoL, mood Lowering BP acutely is a potential target for reducing early poor cognition Ankolekar et al, for ENOS, UK Stroke Forum, 12/2009

  15. PODCAST: Predications • High risk of cognitive decline and dementia after stroke • Dementia 15-30% within 5 years of stroke • Biological rationale and some evidence that lowering BP reduces cognitive decline and dementia • Syst-Eur, PROGRESS • Biological rationale but no good evidence that lowering lipids reduces cognitive decline

  16. Prevention/treatment of PSCI & PSD Prevention Treatment VaD AD PSD AD CEI ?+ + BP ?+ Lipid - ? Antiplatelet NSAID - SSRI ?+ Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  17. Dementia: BP lowering trials Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  18. Cognitive decline: BP lowering trials Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  19. Cognitive change: BP lowering trials Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  20. Dementia: BP lowering trials Trial Rx N OR ΔSBP LoFU month Syst-Eur CCB 2418 0.51 -10.0 24 PROGRESS ACE-I+D 3544 0.77 -12.3 49 * SHEP Diuretic 4736 0.84 -11.9 54 HYVET Diuretic 3336 0.89 -15.0 25 PRoFESS ARA 15049 1.00 -3.8 30 * PROGRESS ACE-I 2561 1.08 -4.9 49 * SCOPE ARA 4886 1.08 -3.2 45 * Post stroke Note: no data ALLHAT, ASCOT, PATS Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  21. Prevention: Dementia vs BP Meta-regression Log odds ratio vs. SBP Weighted: inverse of variance Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  22. Cognition: Treatment, Statins But: • LEADe: Neutral (n=640) • No MMSE: PROSPER, HPS • No data: ASCOT, ALLHAT, SPARCL Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press

  23. Lessons: Trial data BP lowering associated with reduction in dementia/cognitive decline Effect related to magnitude in fall in BP Potential BP class differences But pattern not clear Data from mix of hypertension and post-stroke trials Insufficient data on lipid lowering Missed opportunities Must include cognitive measures in non-cognitive trials

  24. PRoFESS: Dementia over 2.5 years RCT post ischaemic stroke, n=20,223 Dementia (%) All Recurrence Telmisartan 5 13 Placebo 5 10 Aspirin/dipyridamole 5 12 Clopidogrel 5 11 Diener et al. Lancet2008;27 Aug

  25. PRoFESS: Recurrent Stroke Mean follow-up 2.5 yrs Telmisartan 8.7% Placebo 9.2% HR 0.95, 95%CI 0.86-1.04 P=0.23 Cox covariates: age, baseline ACE-inhibitor use, modified Rankin Scale, and baseline diabetes status Yusuf et al. New Engl J Meds2008;27 Aug

  26. Analysis of cognition: Suboptimal Ignore baseline Comparison of on-treatment means Comparison of on-treatment medians Ignore continuous nature of data Comparison of proportions of cognitive impairment Comparison of proportions of cognitive decline Ignore ordinal nature of cognition/dementia Ignore death Poor methods for dealing with missing data Imputation of missing data Last value carried forward

  27. OAST-Cog: Analysis of cognition Optimising analysis: Binary vs ordinal vs continuous Proportions vs Shift in scores vs Gradient (repeated measures) vs ANCOVA vs … Include death – part of cognitive continuum Deal with missing data – multiple measures

  28. Advantages: Ordinal vs Binary More powerful statistically: Smaller p-value / confidence intervals [1] Smaller sample size [2] Smaller NNT (i.e. more favourable) [3] Also worth including co-variates [4] 1. OAST. Stroke 2007;38:1911-5 2. OAST. Int J Stroke 2008;3:78-84 3. OAST. To be submitted 4. OAST. Stroke 2009;40:888-94

  29. ECASS III: Modified Rankin Scale mRS 0,1 vs 2-6: 52.4% vs. 45.2%; ARR 7.2% Odds ratio 1.34 (95% CI 1.02-1.76, P = 0.04) Hacke et al. New Engl J Med 2008;359:1317-29

  30. Ordered categorical outcomes Such ordered categorical outcomes could be more powerful statistically, reduce sample size, reduce numbers-needed to treat, and improve health economic arguments Bath et al. Stroke 2008

  31. Stroke, 4 levels: NASCET ‘p’ 2 level 0.002, 3 level 0.001, 4 level 0.0009 Geeganage, Bath, Gray, Collier, Pocock. British Hypertension Society 2006

  32. PROGRESS: Cognition (severity) Binary, dementia: p=0.22 NNT 129 (49-∞) Ordinal ‘shift’: p=0.021 NNT 47 (28-138) Ankolekar, Geeganage, Bath. In preparation

  33. OAST-Cog: Relevant trials Vascular: BP: HOPE, HYVET, ONTARGET, PROGRESS, PRoFESS, SCOPE, Syst-Eur, TRANSCEND, … Lipid: HPS, LEADe, PROSPER, … Cholinesterase inhibitors: Antiplatelets: PRoFESS, … NSAIDs: philip.bath@nottingham.ac.uk

  34. Lessons: Trial design Interventions: Limited Cholinesterase inhibitors, lipid/BP lowering, … Prevention vs. treatment Risk factor difference: often small (BP, lipid) Follow-up: usually too short (months) Size: usually too small Analysis: often suboptimal Outcomes: varying, some non-ideal MMSE, TICS, … Cognition: secondary/tertiary outcome

  35. Secondary Prevention of Small Subcortical Stroke trial N=2,500 with MR+ve lacunar stroke/TIA (<6/12), age 40+ US, Canada, Mexico, Latin America, Spain Interventions (for mean 3 years) – factorial design: Aspirin + clopidogrel vs. aspirin + placebo SBP lowering: <130mmHg vs. <150 mmHg Primary outcomes: Ischaemic stroke recurrence Haemorrhagic stroke (PICH, SAH) Secondary outcome: Rate of cognitive decline (for AC vs. A) SPS3 www.sps3.org/ NCT00059306

  36. PODCAST: Addressing lessons Cognition (inc. dementia) is primary outcome Intensive vs guideline BP lowering Force big difference, A(B)/CD rule Factor in lipid lowering (ischaemic stroke) Recruit 3-7/12 post stroke Cognition stable, exclude prevalent dementia/early PSD Recruit from hospital Long follow-up (years) Large sample size (1,000s) Optimise statistical analysis www.podcast-trial.org/ IRCTN85562386

  37. PODCAST: Background Any questions?

  38. PODCAST: Trial aims & overview Philip Bath

  39. PODCAST Prevention of Dementia & Cognitive decline After Stroke trial Randomised controlled partial factorial trial Open label, blinded outcome, blinded adjudication Phases: Start-up: 600 patients, 40 SRN centres, 3 years Main: ~3,500 patients over 5 years 100+ centres – UK, France? Singapore? …

  40. PODCAST: Interventions All stroke Intensive vs. guideline BP lowering <125 mmHg vs. <140 mmHg Ischaemic stroke only Intensive vs. guideline lipid lowering <4/2 mmol/l vs. <5/3 mmol/l (Statins associated with increased bleeding) Trial of management trial, not specific drugs

  41. PODCAST: Sample size per group Assumes ~90% of patients are ischaemic ICH Ischaemic stroke No lipid Lipid Total Lip int Lip guide BP int 30 135 135 300 BP guide 30 135 135 300 Total 60 270 270 600

  42. PODCAST: Primary outcome • Comparison of cognition using the standardised ’Addenbrooke’s Cognitive Examination’ between treatment groups • Proportion with reduction in ACE at end of trial; or • Shift in ordinal cognition/dementia • Method of analysis subject to results of OAST-Cog and other studies • ACE includes ‘Mini-Mental State Examination’ (MMSE)

  43. PODCAST: Secondary outcomes Individual cognitive domains: • Global TICS, MOCA • Attention Trail making A/B • Attention/executive Stroop • Memory MMSE • Informant IQCODE Vascular: • Stroke recurrence, MI Function • mRS, QoL, mood

  44. PODCAST: Safety • Death • Falls (leading to fracture or hospitalisation) • Postural hypotension • Myositis, rhabdomyolysis • SAEs Notes: • AEs will not be collected since drugs are licensed • Outcomes and SAEs will be entered using a common form to facilitate data collection

  45. PODCAST: Other aims CT/MR scanning: • Index event • Characterise patients at baseline • On-treatment clinical scan (dementia, vascular) • Characterise clinical event Health economics • Costs of dementia/cognitive impairment • Carer, institutionalisation • Costs of excess treatment • BP drugs, lipid drugs • Cost/event (cognitive decline) prevented • Cost/QALY

  46. PODCAST: Recruiting centres Start-up phase: • Recruitment over 2 years • 40+ sites x 1 patient/site/month = ~400 pa • Follow-up over 1-2.5 years • Recruitment: • SRN hospital sites • Follow-up: • Primary care (guideline management, blood tests) • SRN hospitals (DeNDRoN)

  47. PODCAST: Status Approvals: • Eudract, MHRA, MREC, SSI • ISRCTN 85562386 • SRN adoption (with DeNDRoN, PCRN) • User/consumer support • AS QRD, TSA, Nottingham Forum Documents: • Protocol, PIS/RIS http://www.podcast-trial.org/ • Data forms, database, algorithms https://www.nottingham.ac.uk/~nszwww/podcast/podcasttrialdb/demo/podcast_login.php

  48. PODCAST: Time lines, start-up Start-up -6-0 0-2 3-6 7-18 19-24 25-30 31-36 Protocol <> Approvals <> Site id < = > Funding < = = = = > Recruit patients < = = > Review <> main phase?

  49. PODCAST: Promotion • UK Investigator meeting • Sept 2010, … • Stroke Res. Network Annual meeting • 2009, 2010, … • SRN Local Research Networks • Thames, West Midlands, … • UK Stroke Forum • 2009, Dec 2010 (Glasgow) • European Stroke Conference • 2010, May 2011 (Hamburg) • Other meetings • Int Geriatrics Society (Sept 2010), … • Trial protocol publication

More Related