s afe i mplementation of t hrombolysis in s troke

Safe

Implementation

of Thrombolysis

in Stroke

Slide presentation adapted from http://www.acutestroke.org/

http://www.acutestroke.org/

In 2002, European Union regulatory authority EMEA approved rt-PA for stroke CONDITIONALLY

• Age 18-80

• In high quality stroke centres with stroke units with certain monitoring requirements

• Within 3 hours of anischaemic stroke

There were two major conditions for this approval:

• Safety monitoring of all treated patients in

SITS (SITS-MOST) until 2005 (prolonged to April 2006)

• RCT to study effectof rt-PA in patients with symptoms onset since 3–4.5h (ECASS III)

EU approval with conditions:

Recruitment

SITS-MOST2003-2006: 6,483 patients285 active centres

2003:1

2003:2

2004:1

2004:2

2005:1

2005:2

2006:1

0

50

100

150

200

250

300

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

Patients

Centres

Results, baseline:

Variables

Data are median (IQR) or %

SITS-MOST

n=6483

Pooled RCT Placebo 0-

3h

n=465

Pooled RCT

Alteplase 0-3h

n=464

Age, years 68 (59-75)67.1 (60-

74)69.6 (61-

75)

Females 39.8 40.2 40.1

Hypertension 58.7 60.7 59.7

Diabetes Mellitus 16.0 18.9 21.1

Atrial Fibrillation 23.9 20.0 20.7

Congestive heart failure 7.5 15.3 13.2

Previous stroke 10.1 12.7 13.8

Aspirin 29.8 28.8 36.4Lancet 2007; 369: 275-282.

Results, baseline:

Variables

Data are median (IQR) or %

SITS-MOST

n=6483

Pooled RCT Placebo 0-

3h

n=465

Pooled RCT

Alteplase 0-3h

n=464

NIHSS, excluding item 12

12 (8-17) 14 (9-19) 13 (8-18)

Blood glucose (mg/dl)

116 (101-139)

124 (106-151)

119 (104-158)

Weight in kg 75 (68-85) 79.4 (66-

90.7)75 (65-84)

Systolic blood pressure (mm Hg)

150 (137-166)

152 (140- 170)

156 (140-170)

Diastolic blood pressure (mm Hg)

81 (74-90) 86 (77-95.5) 84 (78-92)

Stroke onset to treatment time (minutes)

140 (115-165)

138 (90-165) 140 (90-168)Lancet 2007; 369: 275-282.

Type of haemorrhages at 22-36h imaging:

5.4

4.02.6

2.5

1.7

1.1

HI 1

HI 2

PH 1

PH 2

PHr 1

PHr 2

Lancet 2007; 369: 275-282.

HI 1: small petechiae along the margins of the infarct

HI 2: a more confluent petechiae within the infarct area but without space-occup. effect

PH 1: blood clot(s) not exceed. 30% of the infarct area w. some mild space-occup. effect

PH 2: blood clots exceeding 30% of the infarct area with significant space occup. effect

SICH107/ 6444 1.41.72.0

RCT Active arm

Preliminary Clinical Outcome, 95% CI

0% 6% 10%

15%

20%

25%

40%

50%

55%

45%

2%4% 8%

Lancet 2007; 369: 275-282.

SITS-MOST Results

*at post-treatment imaging 22-36h

SITS-MOST main outcomes 2003-2006, compared with active arms of randomised controlled trials (proportions and 95% confidence intervals)

SITS definition of SICH:PH2* +NIHSS ≥ 4 points or death within 24 hours

RCT Active arm

0% 6% 10%

15%

20%

25%

40%

50%

55%

45%

2%4% 8%

Lancet 2007; 369: 275-282

SITS-MOST Results

*at post-treatment imaging <7d



SICH296/ 6442 4.1 4.6 5.1

ECASS definition of SICH:Any haemorrhage +NIHSS ≥ 4 points or death within 7 days

RCT Active arm

0% 6% 10%

15%

20%

25%

40%

50%

55%

45%

2%4% 8%

Lancet 2007; 369: 275-282

SITS-MOST Results

*at post-treatment imaging <7d



SICH468/ 6438 6.7 7.3 7.9

RCT definition of SICH:Any haemorrhage +NIHSS ≥ 1 points or death within 7 days

RCT Active arm

0% 6% 10%

15%

20%

25%

40%

50%

55%

45%

2%4% 8%

Lancet 2007; 369: 275-282.

SITS-MOST Results



Mortality701/ 6218

SICH (any worsening + any

bleeding)468/ 6438

6.7 7.3 7.9

10.511.312.1

53.554,856.0

Independence 3 months (mRankin0-

2)3362/ 6136

Result of SITS-MOST compared with randomisedcontrolled trials – modified Rankin Scale at 3 months

Red colours: ADL*-independentBlue colours: ADL*-dependentBlack colour: Dead

19

20

13

19,9

22

16

15,9

8

11

14,7

14

14

13,9

12

20

5,3

7

7

11,4

18

18

SITS-MOST

RCT active rt-PA

RCT placebo

mRS 0

mRS 1

mRS 2

mRS 3

mRS 4

mRS 5

mRS 6

0% 20% 40% 60% 80% 100%

DeadRecovered

+10%

+4,8%

*Activities of daily living Lancet 2007; 369: 275-282.

6% 8% 10% 12% 14% 16% 18% 20%

45% 50% 55% 60%

1% 2% 3%

SITS-MOST RCT

Experienced New

SICH rates per SITS-MOST

1.6 (1.3-2.0) 1.7 (1.2- 2.6) NA

SICH rates per NINDS/Coch

rane

7.3 (6.6- 8.0) 7.3 (6.1- 8.7) 8.6 (6.3- 11.6)

Mortality within 3 months

10.6 (9.8- 11.6) 13.3 (11.6- 15.1) 17.3 (14.1- 21.1)

Independence (mRS, 0-2) at

3 months

54.4 (53.0- 55.8) 56.0 (53.4- 58.5) 50.1 (45.5- 54.7)

Main outcome by site’s previous experience with thrombolysis in stroke before joining SITS-MOST

Pooled RCT

SITS-MOST, Experienced

SITS-MOST, New

Lancet 2007; 369: 275-282.

Conclusions:

These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3h of stroke onset, even by centres with limited prior experience of thrombolytic therapy for acute stroke.

SITS-MOST has fulfilled its purpose outlined by EMEA to show that i.v stroke thrombolysis is safe under the treatment conditions

Now it is also important that ECASS 3 is completed successfully so that we can receive a permanent licence for rt-PA

The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.

Further conclusions: safe but still underused

Although the recruitment to SITS-MOST and SITS-ISTR (more than 12,000) is beyond expectations, less than 2% of all stroke patients receive thrombolysis in EU

Following the publication of SITS-MOST main outcomes national publications for each EU country are planned to state the current level of thrombolysis implementation

This will also be the starting point for the projectSITS 2009 @ 5% , which aims to reach this level of implementation (or more) in 3 years – all current SITS centres and those not yet active are invited to participate

Why should clinicians spend time putting patients into SITS?

Ongoing audit of local results against national and international standards

Especially important when starting a thrombolysis service

Instant summaries of outcomes for the local centre downloadable form the site

But: important to include all patients. Selective use of the database will bias outcomes.


SITS thrombolysis register Jun 2009Stoke UK World

No registered 105 3,194 27,988% much better in 24 h 40% 33% 31%% much better at 7d 54% 43% 41%% no symptoms at all at 3 mo 25% 15% 18%

% SICH* 0% 1% 1%% signif. deterioration<=24 h 9% 9% 12%% deaths 22% 22% 14%

Door to needle time 82 min** 66 min 65 minOnset to needle time 150 min 150 min 145 min

Age 67 68 67Baseline NIHSS 14 14 12TACI 51% 48% 36%

*defined as confluent haemorrhage (not just petechial) and clinical deterioration e.g. NIHSS change>4 within 24 h or death and PH2 or PHr2 at 22-36 h.

** 98 min to Jan 2008! 85 min to March 2008! And 62 min from May 2009

ECASS IIIRCT alteplase versus placebo 3-4.5 h post stroke onset

N=821

Median time to treatment 3:59 h:min

tPA Placebo

Favourable outcome 52% 45% p=0.04

e.g.Rankin 0-1 at 3 mo

Symptomatic ICH 2.4% 0.2% P=0.008

Mortality 7.7% 8.4% P=0.7

ECASS III caveats

• Baseline imbalance NIHSS 1 point worse in placebo group at randomization

• SC heparin was allowed

EPITHET Study

• 101 patients, median NIHSS 14• mismatch in perfusion-weighted MRI (PWI) and

diffusion-weighted MRI (DWI) before and 3-5 d after rx

• alteplase 3-6 h after stroke onset• non-significantly lower infarct growth and

significantly increased reperfusion in patients who had mismatch

• Phase III trials beyond 3 h warranted

Davis et AK, Lancet Neurol. 2008;7(4):299-309.

What % of stroke patients received thrombolysis for stroke in USA in 2007?

• rt-PA approved for stroke since 1995

• Audit of 4,750 hospitals, ~ 500,000 patients with ischaemic stroke (2005-7)

• ~12,000 (2.4%) patients treated with rt-PA

• Proportion treated varied: 0-23%

• 60% of hospitals did not give rt-PA at all.

Kleindorfer et al AHA Stroke Conference 2009Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

Cochrane systematic review of of thrombolysis with rt-PA

Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (in Press)

• 11 trials, including ECASS-3

• 3977 patients tpa vs control

• RCT data on only 42 patients > 80 yrs • Follow-up short: primary outcome @

3months.

Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009

IV rt-PA < 6h. ~4000 patients, 1920 outcome events ‘death or dependency (mRS 3-6)’

Odds ratio = 0.78 (0.68-.88)Heterogeneity (Chi2 p=0.007) I2 = 62%

Test for overall effect p=0.0001Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (submitted)

926 999


Third International Stroke Trial. A large Third International Stroke Trial. A large randomised trial to answer the question: can a randomised trial to answer the question: can a

wider variety of patients be treated?wider variety of patients be treated?

Target: 6000 patients from 300 centres in 36 Countries

IST-3 collaborators meeting Capetown 2006

IST3 IST3 Why another trial?Why another trial?

Areas of Uncertainty to exploreAreas of Uncertainty to explore RisksRisks

• Symptomatic cerebral haemorrhage Symptomatic cerebral haemorrhage • DeathDeath

BenefitsBenefits• Reduced ‘death or dependency’Reduced ‘death or dependency’• ?reduction in massive cerebral oedema??reduction in massive cerebral oedema?

Subgroup analyses: effect ofSubgroup analyses: effect of• Time to treatmentTime to treatment• AgeAge• Stroke severityStroke severity• Risk factors for intracerebral haemorrhageRisk factors for intracerebral haemorrhage• Appearance of CT scanAppearance of CT scan

Mild, or rapidly improving strokes (NIHSS < 4)

• 2 hours ago, this man developed right hemiparesis, now rapidly improving.

• NIHSS < 4, so rt-PA not approved

• Many such patients recover without rt-PA,

• BUT 15-30% later deteriorate suddenly -> disabling stroke

• IST-3 will include ~ 600 with NIHSS < 5


Vertebro-basilar territory ischaemic strokes

• Acute cerebellar infarct• Excluded from previous

trials of iv rt-PA• Time window for

treatment unclear• Is there benefit from iv

thrombolysis for such patients?

• IST-3 will include ~ 200


Stroke patients > 80 years• Patients over 80 have

been excluded from randomised trials and the licence

• In the UK 30% of all strokes are aged > 80 = 31,000 ischaemic stroke patients each year automatically excluded from thrombolysis

• IST-3 will recruit > 1000 patients > 80


Severe stroke (NIHSS > 25)

• This man had a large MCA infarct

• NIHSS > 25,

• rt-PA not approved for him

• He spent many months in hospital

• He was very disabled

• IST-3 will include ~ 300 such patients


Impact of iv rt-PA on symptomatic cerebral oedema

Odds ratio 0.79 (0.62- 1.01) p = 0.06

Wardlaw et al 2008Slide from IST-3 presentation P. Sandercock ESC

Stockholm 27 05 2009

Taking part in IST-3Taking part in IST-3

Support form IST-3 teamSupport form IST-3 team

Extends therapeutic window, more Extends therapeutic window, more experience in thrombolysisexperience in thrombolysis

Consent for IST-3Consent for IST-3

10% (one in 10) will make a better 10% (one in 10) will make a better than expected recoverythan expected recovery

5% (one in 20) will have a fatal brain 5% (one in 20) will have a fatal brain haemorrhagehaemorrhage

If IST-3 positive, how many stroke patients per If IST-3 positive, how many stroke patients per year in UK might avoid being ‘dead or year in UK might avoid being ‘dead or

dependent’ with each treatment? dependent’ with each treatment? UK has 130,000 strokes/yrUK has 130,000 strokes/yr

% treated% treated Number Number treated treated

per year per year

Number Number avoiding avoiding

death/dep.death/dep.

AspirinAspirin 80%80% 104000104000 13501350

Stroke UnitStroke Unit 60%60% 7800078000 43704370

Thrombolysis < 3hThrombolysis < 3h11 2.4%2.4% 31003100 200200

Thrombolysis < 6hThrombolysis < 6h22 30%30% 3900039000 18001800

1. USA 2004 MEDPAR average. Kleindorfer. Stroke 2008: 39: 924-82. If IST-3 widens treatment indication?


Hacke W et al. 16th European Stroke Conference; June 1, 2007; Glasgow, Scotland.

DIAS-2: Clinical response rates at 90 days

End point Placebo, n=63 (%)

90 µg/kg, n=57 (%)

125 µg/kg, n=66 (%)

Clinical response rate 46.0 47.4 36.4

All-cause mortality at 90 days

4 (6.3) 3 (5.3) 14 (21.2)

ICH at 72 h 0 (0) 2 (3.5) 3 (4.5)

DIAS-4

• Desmoteplase 90ug/kg bolus

• Within 9 h of symptom onset

• All patients need CT angio before randomization

• Inclusion depends on results of CT angio

LINKS

http://www.acutestroke.org/ for SITS

google sits stroke

http://www.dcn.ed.ac.uk/ist3/ for IST3

google ist3

http://www.thrombolysis.info/ for thrombolysis docs

google thrombolysis.info


http://www.dcn.ed.ac.uk/ist3/

http://www.thrombolysis.info/

Research and Governance

SITS Register

ECASS-3

IST-3

DIAS-3

C. Roffe

4-day Thrombolysis Course Stafford University 10 06 09

s afe i mplementation of t hrombolysis in s troke

Documents

sits sits

effect sits

result of sits

posttreatment imaging

sitsmostpooled rctsits

main outcomes

h of stroke onset

stroke units