Can patients be too mild, too severe or too old for thrombolysis?

21
Can patients be too mild, too severe or too old for thrombolysis? Professor Peter Sandercock University of Edinburgh ESC Hamburg 27 th May 2011 Disclosures I am co-chief investigator of the IST3 trial I chair the DMC for the SYNTHESIS trial

description

Can patients be too mild, too severe or too old for thrombolysis?. Professor Peter Sandercock University of Edinburgh ESC Hamburg 27 th May 2011. Disclosures I am co-chief investigator of the IST3 trial I chair the DMC for the SYNTHESIS trial. Outline. - PowerPoint PPT Presentation

Transcript of Can patients be too mild, too severe or too old for thrombolysis?

Page 1: Can patients be too mild, too severe or too old for thrombolysis?

Can patients be too mild, too severe or too old for

thrombolysis?

Professor Peter SandercockUniversity of Edinburgh

ESC Hamburg 27th May 2011

DisclosuresI am co-chief investigator of the IST3 trialI chair the DMC for the SYNTHESIS trial

Page 2: Can patients be too mild, too severe or too old for thrombolysis?

Outline

• ‘Opinion-’ or ‘evidence-based’ practice?

• ‘Routine’ iv thrombolysis, influence of – age

– severity

• Evidence from randomised trials– Meta-analyses

– Unanswered questions: current trials

Page 3: Can patients be too mild, too severe or too old for thrombolysis?

‘Opinion-’ or ‘evidence-based’ practice?

• 15 million acute strokes/ year world wide -> we need RELIABLE evidence

• Expert opinion varies about whether to treat – patients over 80 years – Mild (NIHSS 0-5) / severe (NIHSS > 25)

• Routine practice varies between centres

• ‘Best evidence’ comes from randomised trials and systematic reviews of trials

Page 4: Can patients be too mild, too severe or too old for thrombolysis?

Routine care: the older you are, the less likely you are to get rt-PA for stroke:

Germany (similar in USA)

0.01.02.03.04.05.06.07.08.09.0

10.0

25–34 35–44 45–54 55–64 65–74 75–84 85+ allages

Per

cent

age

Förch. Stroke 2009;40:1900-2

Age

Page 5: Can patients be too mild, too severe or too old for thrombolysis?

Randomised controlled trial (RCT) evidence

Subgroup analyses:

What is the effect of age & NIHSS on response to iv rt-PA?

Page 6: Can patients be too mild, too severe or too old for thrombolysis?

Trials need to be large!

…It is still not sufficiently widely appreciated just how large clinical trials need to be to detect reliably the sort of moderate, but important, differences in major outcomes’ that might exist (especially if effects in different subgroup are to be assessed reliably)’.

Collins, Lancet 2001; volume 357: 373

Page 7: Can patients be too mild, too severe or too old for thrombolysis?

RCT’s of iv thrombolysis vs control in acute myocardial infarct (MI) and in acute strokePlacebo-controlled trials of thrombolysis in acute MI

Total 1994 60,000

Placebo-controlled trials of thrombolysis in acute stroke

All agents (26 trials) 2009 7,100

rt-PA (11 trials) 2009 4,000*

*Largest stroke trial included just 800 patients RCT data on only 67 patients aged >80

Page 8: Can patients be too mild, too severe or too old for thrombolysis?

Ingall, T. J. et al. Stroke 2004;35:2418-2424

NINDS subgroups: effect of baseline NIHSS on likelihood of favourable outcome (mRS)

Page 9: Can patients be too mild, too severe or too old for thrombolysis?

Mishra, N. K. et al. Stroke 2010;41:2612-2617

Non-randomised data: VISTAfunctional outcomes x baseline NIHSS

Page 10: Can patients be too mild, too severe or too old for thrombolysis?

Conclusion?• Very few mild and severe strokes included in

randomised trials

• Effects in mild and severe strokes UNCLEAR– NINDS– Non-randomised VISTA database analysis

• European approval for iv rtPA excludes mild and severe strokes

• Pooled analysis of RCTs would be helpful…

Page 11: Can patients be too mild, too severe or too old for thrombolysis?

Pooled analysis of 7 rt-PA trials (n= 3670) Time to treatment and odds of ‘good outcome’ (mRS 0-1)

Lees et al Lancet 2010

Page 12: Can patients be too mild, too severe or too old for thrombolysis?

Pooled analysis, authors conclusions:

• ‘We need to understand better the factors that prevent alteplase from being effective in individual patients… clinical variables e.g.: age, stroke severity, …

• ‘..these factors must have a role in the success of thrombolysis, but are poorly understood’

• No analyses were performed to assess effects of age / NIHSS on response to rtPA in specific subgroups

Lees et al Lancet 2010

Page 13: Can patients be too mild, too severe or too old for thrombolysis?

Two views• We already know who to treat: ‘There is

no need to continue with randomised trials, we now can treat at any age, any severity and up to 4.5 hours (or even beyond)’

• The evidence is not as clear as some experts make out: ‘We need randomised evidence on the effects in: – people > 80yrs– NIHSS 15, NHSS >25’

• Conclusion: We need both clinical experience and RCT evidence

Page 14: Can patients be too mild, too severe or too old for thrombolysis?

Ongoing randomised trials iv rt-PA vs control

Trial name Age (y) Time from onset (h)

Imaging Sample size

EXTEND 18+ 3-9 Mismatch

DWI/PWI

400

TESPI 80+ 0-3 CT or MR 600150 to date

IST3 18+ 0-6 CT or MR* 3100

PRISMS

Planned

18 0-6 CT or MR

NIHSS <6

1500

*CT, MR perfusion/angiography optional

Page 15: Can patients be too mild, too severe or too old for thrombolysis?

Third International Stroke Trial. A large randomised trial to answer the

question: can a wider variety of patients be treated with iv thrombolytic therapy?

Page 16: Can patients be too mild, too severe or too old for thrombolysis?

Main features of IST - 3

• Randomised, open, blinded outcomes study of i.v. rt-PA vs control,

• Target 3100 patients < 6 h of acute ischaemic stroke (n=2902 by today)

• No age or severity exclusion criteria• Primary outcome: the proportion of patients

alive and independent at six months• Randomisation by telephone or internet• Imaging: CT or MR, perfusion/angio data if

available. • Blinded central review of all scans

Page 17: Can patients be too mild, too severe or too old for thrombolysis?

Age

0

200

400

600

800

1000

18-50 51-60 61-70 71-80 81-90 91-100

Age

Nu

mb

er

Already over 1200 patients aged > 80 years in study!

Page 18: Can patients be too mild, too severe or too old for thrombolysis?

NIHSS

0

100

200

300

400

500

600

700

0 to 5 6 to 10 11 to 15 16 to 20 21 to 35

Page 19: Can patients be too mild, too severe or too old for thrombolysis?

IST-3 will report its results at ESC 2012 in Lisbon

Main results• Primary outcome all cases 0-6hMain subgroups• Effect x time 0- 6h• Effect x age

~ 1500 patients aged > 80 years).

• Effect x severity: ~ 600 with NIHSS < 5 (mild) ~ 400 with NIHSS > 24 (severe)

Page 20: Can patients be too mild, too severe or too old for thrombolysis?

Conclusion: iv thrombolysis

• There is no reliable randomised trial evidence about optimum stroke severity or age limit for iv treatment

• Uncertainty about– Age: how old is ‘too old’ ?– Severity: too mild ? / too severe?

• Current trials (IST-3, TESPI, ?PRISM) will help resolve these uncertainties

Page 21: Can patients be too mild, too severe or too old for thrombolysis?

Acknowledgements:

The patients, the >115 hospitals in the IST-3 group, who have recruited at least 1 patient, the Data

Monitoring Committee, the MRC Steering Committee, Image reading panel, International Advisory Board,

Event adjudication panel