studies and registries march 2012. disclaimer please be aware that legal provisions governing the...

Studies and RegistriesMarch 2012

Disclaimer

Please be aware that legal provisions governing the advertising of pharmaceutical preparation may differ from country to country, as a consequence of which this document has not been checked against all jurisdictions.

It is the responsibility of the Boehringer Ingelheim OPU to check on a local basis.

Studies and Registries

Studies and Registries

ECASS 3

Imaging studies (MRI-based patient selection)

Meta- and pooled analyses

SITS register

SITS-MOST

SITS-ISTR

SITS-NEW

VISTA

ECASS 3

ECASS 3: Background

Thrombolysis with rt-PA initiated within 3 h of symptom onset is the only approved treatment for acute ischaemic stroke

Efficacy is highest if initiated within 90 min

Many stroke victims do not reach a centre equipped to administer rt-PA in time

Worldwide, <5% of acute ischaemic stroke patients are treated with rt-PA within 3 hours of stroke symptom onset

NINDS Trialists N Engl J Med 1995;333:1581-1587.Hacke et al. Lancet 2004;363:768-774.

Ingall. Stroke 2009;40:2264-2265.

ECASS 3: Rationale

rt-PA was approved by the EU regulatory authority EMEA in 2002 for use within 3 h of ischaemic stroke with two post-approval requirements:

All patients should be registered in the SITS internet database and entered into an observational safety study, SITS-MOST

A randomised trial of rt-PA versus placebo, with an extended therapeutic window greater than 3 hours

The pooled analysis of individual patient data (N=2,775) from 6 trials of i.v. rt-PA vs. placebo showed that the effective treatment window may extend to 4.5 hours

Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.Hacke et al. Lancet 2004;363:768-774.

ECASS 3: Overview

Objective

To assess efficacy and safety of rt-PA between 3 and 4.5 hours after stroke onset in the European setting

Primary Endpoint: Disability at day 90

Favourable (mRS ≤1) vs. unfavourable outcome (mRS 2-6)

Secondary Endpoint

Global outcome analysis at day 90, combining mRS (0-1), Barthel Index ≥95, NIHSS (0-1), Glasgow Outcome Scale (1)

Safety Endpoints

Included mortality at 90 days, any ICH, SICH

Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

ECASS 3: Primary Endpoint (ITT)

Disability at Day 90, mRS ≤1


Analysis rt-PA n/N (%)

Placebon/N (%)

OR(95% CI)

p

Unadjusted 219/418 (52.4%) 182/403 (45.2%)

1.34(1.02−1.76)

0.04‡

Adjusted* − − 1.42(1.02−1.98)

0.04§

0.5 1 1.5

Favours placebo Favours rt-PA

ITT, intent-to-treat*Adjusted for NIHSS score at presentation and the time to start of treatment‡ p value was obtained by the Pearson chi-square test of proportions§p value was obtained by stepwise logistic regression

ECASS 3: Secondary Endpoint (ITT)

Day 90: NINDS global endpoint statistic(mRS 0-1; BI ≥95; NIHSS ≤1 or >8 point improvement; GOS 1)


rt-PA

(N=418)

Placebo

(N=403)

OR

(95% CI)

p

Global outcome n/a n/a 1.28

(1.00–1.65)

0.05

mRS score ≤1 219 (52.4%) 182 (45.2%) 1.34

(1.02–1.76)

0.04‡

BI score ≥95 265 (63.4%) 236 (58.6%) 1.23

(0.93–1.62)

0.16‡

NIHSS score ≤1 210 (50.2%) 174 (43.2%) 1.33

(1.01–1.75)

0.04‡

GOS score 1 213 ( 51.0%) 183 (45.4%) 1.25

(0.95–1.64)

0.11‡

0.5 1 1.5

Favours placebo Favours rt-PAITT, intent–to-treat; ‡ p value was obtained by the Pearson chi-square test of proportions

ECASS 3: Functional Efficacy Endpoints at 90 Days (PP Population)

730 patients (out of 821 randomised)

Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

Endpoint day 90

rt-PA(N=375)

Placebo (N=355)

OR(95% CI)

p

mRS score 0-1 206 (54.9%) 161 (45.4%) 1.47(1.10−1.97)

0.01‡

Global outcome statistic (unadjusted)

n/a n/a 1.39(1.07−1.80)

0.02

0.5 1 1.5

Favours placebo Favours rt-PA

mRS, modified Rankin ScalePP, per protocol‡ p value was obtained by the Pearson chi-square test of proportions

ECASS 3: Distribution of Scores on the mRS at 90 Days for the Per-Protocol Populations


Patients

‡stratified on Cochran–Mantel–Haenszel test, adjusted for baseline NIHSS scores and time-to-treatment onset

p=0.016

Per-protocol population

ECASS 3 - Efficacy: Summary

rt-PA administered 3-4.5 hours after stroke symptom onset is effective

Significantly more patients benefitted vs. placebo in terms of:

• Disability at day 90, mRS 0-1

• Overall greater functionality/independence (global outcome statistic) at day 90

• Improved neurological functioning (NIHSS 0-1 or >8 point improvement) at day 30

• Independence (mRS 1-2) at day 30 in the PP population


mRS, modified Rankin Scale PP, per protocolNIHSS, National Institute of Health Stroke Scale

ECASS 3 – Safety Endpoints: Mortality (ITT)


rt-PA(N=418)

Placebo(N=403)

OR (95% CI)

p

Overall mortality 32 (7.7%) 34 (8.4%) 0.90

(0.54–1.49)

0.68

0.5 1 1.5

Favours rt-PA Favours placebo

After day 90 (7 deaths) Days 8–90 (34 deaths) Days 1–7 (25 deaths)

Mortality by time interval

0%

2%

4%

6%

8%

10%

rt-PA Placebo

1.0%

3.8%

2.9%

0.7%

4.5%

3.2%

Dea

th (

%)

ITT, intent-to-treat

ECASS 3 – Safety Endpoints: Summary

sICH (symptomatic intracranial haemorrhage)

Significant difference in sICH rates (2.14% absolute difference), although the incidence of sICH among rt-PA-treated patients was low (2.4%)

Mortality

Low overall mortality rate (approximately 8%), not different between treatment arms

Probably due to the mild to moderate initial stroke severity

Consistent with results from other randomised controlled trials of thrombolysis in acute ischaemic stroke

No safety concerns in the longer time windowHacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

ECASS 3:

Further Analyses

ECASS 3: Further Analyses

Additional outcome analyses included functional endpoints at day 90 or day 30

mRS 0-1 [day 30], mRS 0-2, Barthel Index ≥85, and global outcome statistic [day 30] and treatment response (8-point improvement from baseline or 0-1 score on NIHSS)

A stratified responder analysis by baseline NIHSS

The subgroup analyses were based on the mRS 0-1 at day 90, sICH, and death


mRS, modified Rankin ScalesICH, symptomatic intracranial haemorrhageNIHSS, National Institutes of Health Stroke Scale

ECASS 3 – Subgroup Analysis of Favourable Outcome (mRS 0-1): Demographics (ITT)

rt-PA

% (n/N)

Placebo

% (n/N)

OR

(95% CI)

p

NIHSS at baseline0-9

10-19

≥20

73% (156/215)

34% (57/166)

16% (6/37)

67% (128/190)

31% (50/161)

8% (4/52)

1.28 (0.84-1.96)

1.16 (0.73-1.84)

2.32 (0.61-8.9)

0.631

Age<65

≥65

57% (105/184)

49% (144/234)

45% (70/155)

45% (112/247)

1.61 (1.05-2.48)

1.15 (0.80-1.64)

0.230

GenderMale

Female

53% (139/264)

52% (80/154)

42% (97/231)

50% (85/171)

1.54 (1.08-2.19)

1.09 (0.71-1.69)

0.237

Time to treatment181-210 min

211-240 min

241-270 min

58% (23/40)

49% (93/191)

56% (98/174)

40% (17/42)

47% (91/193)

43% (64/148)

1.99 (0.83-4.79)

1.06 (0.71-1.59)

1.69 (1.09-2.63)

0.212


1

Favours placebo Favours rt-PAmRS, modified Rankin scaleITT, intent-to-treat

ECASS 3 – Subgroup Analysis of Favourable Outcome (mRS 0-1): Risk factors (ITT)

rt-PA

% (n/N)

Placebo

% (n/N)

OR

(95% CI)

p

Diabetes

No

Yes

54% (191/356)

45% (28/62)

44% (149/335)

49% (33/67)

1.45 (1.07-1.95)

0.85 (0.42-1.70)

0.167

Prior stroke

No

Yes

52% (199/387)

63% (20/32)

47% (163/345)

33% (19/57)

1.19 (0.89-1.59)

3.33 (1.35-8.22)

0.033

Hypertension

No

Yes

57% (90/157)

49% (129/261)

44% (66/149)

46% (116/253)

1.69 (1.07-2.66)

1.15 (0.82-1.63)

0.190

Atrial flutter/ fibrillation

No

Yes56% (205/365)

26% (14/53)

47% (163/347)

35% (19/55)

1.45 (1.08-1.94)

1.69 (0.30-1.55)

0.092


1

Favours placebo Favours rt-PAmRs, modified Rankin scaleITT, intent-to-treat

ECASS 3 – Further Analyses: Summary

Subgroup results

For mRS 0-1 all subgroups were in favour of rt-PA; most notably no interaction by age and stroke severity was established

Additional endpoints

mRS 0-1, 0-2, Barthel index ≥85 and global outcome statistic and treatment response (8 point improvement from baseline or 0-1 on the NIHSS) stratified responder analysis


mRS, modified Rankin scaleNIHSS, National Institutes of Health Stroke Scale

ECASS 3:

Conclusions

ECASS 3: Conclusions

Intravenous rt-PA initiated 3-4.5 h after onset of stroke symptoms is:

An effective treatment for patients with AIS, who cannot be thrombolysed within 3 h, with no relevant increase in intracranial bleeding compared with treatment within 3 h

A viable therapeutic option for the many patients previously excluded from thrombolysis by missing the narrow treatment time-frame

Favourable across a broad range of subgroups of patients

This finding opens a window of opportunity for later-arriving stroke patients

However …

Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329. Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

AIS, acute ischaemic stroke

ECASS 3: Conclusions (cont)

… having more time does not mean we should take more time

Patients need to be treated as early as possible with rt-PA, to maximise the benefit therefore networks have to work fast!

Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329. Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

There may be more time for the patients,but not for the treating physicians

Clinical Implications of ECASS 3

Provides a better understanding of stroke systems of care for patients with acute ischaemic stroke

A multidisciplinary team is required to implement changes, including healthcare professionals and professional organisations

Extension of the treatment window to 4.5 hours will impact all stages of stroke networks from dispatchers and emergency medicine services to acute stroke units and imaging facilities

The balance of costs and benefits (in terms of gain in QALYs) favours treatment with rt-PA in the 3-4.5 hour time window after stroke onset vs. non-thrombolytic therapy

Tung et al. Stroke 2011;42:2257-2262.Ingall. Stroke 2009;40:2264-2265.

Impact of ECASS 3 on Time to Thrombolysis

Minnerup et al. Stroke 2011;42:2838-2843.

Following confirmation by ECASS 3 of the extended time window to 4.5 hours for the administration of rt-PA to patients with an acute ischaemic stroke, delays in administration were not confirmed and the proportion of patients with a DTN <60 min increased

Guidelinepublication

ECASS 3publication

Imaging studies

(MRI-based Patient Selection)

MRI-Based Patient Selection

Mismatch concept

Mismatch decreases over time, but may be found in individual patients as late as 24 hours or more, depending on individual symptoms

This may help to increase the time window and also allow treatment in patients without known onset of stroke

Practical issues

15-20 minutes scan time

Some patients do not tolerate MR study

Overall feasibility in experienced centres >90%

Warach et al. Ann. Neurol 2000;48:713-722.Kidwell et al. Stroke 2002;33:95-98.

Jansen et al. Der Nervenarzt 1998;69:465-471.Schellinger, Fiebach. In Fiebach, Schellinger 2003;6:31-34.

What is Mismatch?

Historically defined on MRI as the difference in volume of DWI lesion and PWI lesion

PWI > DWI by at least 20% Uncorrected / unthresholded time-based perfusion parameter map

(TTP, MTT) Isotropic DWI

Limitations

DWI lesion reversibility in a minority of patients Therefore, DWI lesion is an approximation of infarct PWI without any thresholding identifies all brain tissue with

hypoperfusion

MRI, magnetic resonance imaging; DWI, diffusion weighted imaging; PWI, perfusion weighted imaging

TTP, time to peak; MTT, mean transit time

Other Mismatch Definitions

Clinical DWI mismatch Higher NIHSS score than DWI lesion size would

suggest

MRA DWI mismatch MRA vessel occlusion more proximal and involving

more brain tissue than infarcted on DWI

FLAIR DWI mismatch Positive lesion on DWI but not seen on FLAIR images

Paradigm: MRI-Based Studies andIndividual Therapeutic Approach

Baseline

Acute ischaemic

stroke

Acutetissue at risk

4-8h after rt-PA

Reperfusion

No reperfusion

Interimlesion

30 days

Finallesion

Tissue at risk(penumbra)

Dead brain(ischaemic core)

Healthy brain

Higher chance for better outcome

Higher chance for poorer outcome

Example: Imaging on Presentation of Acute Ischaemic Stroke

Example: Imaging After rt-PA

Rationale for (MRI-)Mismatch Based Thrombolysis

Time from symptom onset and (more or less) normal CT is an excellent tool to screen for patients likely responsive to rt-PA The earlier the time, the smaller the core The earlier the time, the likelier no demarcation as also seen on normal CT The earlier the time, the larger the tissue at risk

Note: After 3-4.5h patients still have a reduced benefit

Unselected treatment (CT, NIHSS, time 4.5-9h) leads to low or no benefit with higher risk of bleeding and mortality (pooled analyses)

Therefore, selection of suitable patients beyond established time windows is a worthwhile target

This includes patients with unknown time window

DEFUSE

Objective

To determine whether MRI profiles can help to predict clinical response in patients with ischaemic stroke treated with iv thrombolysis at 3-6 hours after onset

Key Results

Target Mismatch pattern was associated with substantial benefit from early reperfusion in 67%

Malignant MRI pattern was associated with high risk of fatal SICH following reperfusion

Small DWI and PWI lesions are associated with favourable outcomes

Albers et al; the DEFUSE Investigators. Ann Neurol 2006;60:508-517.

DEFUSE: MRI Profile and Clinical Outcome

MRI profile N Mean age (y)Median

baseline NIHSS score

Favourable clinical

response*

Target mismatch with early reperfusion

15 78.3 1467%** (42-84)

Target mismatch without early reperfusion

16 68.0 1319% (7-43)

Malignant profile 6 68.3 18.517% (3-56)

Albers et al. Ann Neurol 2006;60:508-517.

* Improvement of 8 points or more in the NIHSS score between baseline and 30 days or a score of 0-1 at 30 days

** p≤0.01, compared with target mismatch without early reperfusion

Target mismatch excludes patients with malignant mismatch

Take 5: Multicentre Study (N=1,210 Patients)

Large dataset

More than 500 MRI-based rt-PA treated patients

Comparison

Standard CT based rt-PA <3 hours

MR-based rt-PA <3 hours

MR-based rt-PA >3 hours (-17 hours)

Schellinger et al. Stroke 2007;38:2640-2645.

Take 5: Safety and Efficacy Multivariate

Symptomatic ICH

Age OR=1.033, 95% CI 1.006-1.060, p=0.016NIHSS OR=1.057, 95% CI 1.010-1.106, p=0.016Use of MRI OR=0.520, 95% CI 0.270-0.999, p=0.05

Good outcome

Age and NIHSS OR=0.973 and 0.862, for both, p<0.001Use of MRI >3h OR=1.467, 95% CI 1.017-2.117, p=0.040Use of MRI <3h OR=1.36, 95% CI 0.841-1.534, p=NS

Conclusion

MRI-based thrombolysis within and beyond the 3-h time window is at least as safe and possibly more effective than CT-based thrombolysis

Schellinger et al. Stroke 2007;38:2640-2645.

EPITHET

Hypotheses

PI/DWI mismatch represents potentially salvageable tissue in the ischaemic penumbra

rt-PA will attenuate infarct growth by increased perfusion of the penumbra

Objective

To determine whether rt-PA administered 3-6 hours after stroke onset decreases infarct growth in patients with a known PI/DWI mismatch

Design

Randomised, double-blind, placebo-controlled trial

Davis et al. Lancet Neurol 2008;7:299-309.

EPITHET Outcomes: Infarct Growth

Primary measure p

Ratio of geometric means (rt-PA/placebo) 0.24

Secondary growth measures

Median relative growth 0.05

Growth >0% 0.03

Geometric mean growth (baseline lesion >5 ml)0.01


EPITHET Clinical Outcomes:Rankin Day 90 in Mismatch Patients


Patients

Functional outcome in mismatch patients

mRS, modified Rankin Scale

EPITHET Clinical Outcomes:Rankin Day 90 in Mismatch Patients

rt-PA (N=42)

Placebo (N=43)

p

mRS 0-245%

(19/42)40%

(17/43)0.60

mRS 0-136%

(15/42)21%

(9/43)0.13

NIHSS improvement ≥8 or NIHSS ≤150%

(21/42)37%

(16/43)0.23


Results suggest, in mismatch patients a Phase III trial of rt-PA vs placebo 3-6 hours could be powered

with <200 patients per arm


Reperfusion and Mismatch

EPITHET study confirms the results of DEFUSE

Reperfusion is associated with a better outcome and a reduced infarct growth


Reperfusion No reperfusion p

Infarct growth N=30 N=47

Median relative growth0.86

(0.34 to 1.75)2.07

(1.19 to 3.65)<0.0001

Median absolute growth-1.0

(-9.0 to 11.2)43.6

(4.0 to 92.3)<0.0001

Clinical outcomes N=30 N=47

Good neurological outcome22

(73%)13

(27%)<0.0001

Good functional outcome19

(63%)15

(32%)0.007

Imaging Studies: Conclusions

CT is sufficient for exclusion of intracranial haemorrhage and therefore decision making for or against thrombolysis

Infarct detection <3h is achieved in only a third of ischaemic strokes

MRI is more sensitive than CT

Perfusion/diffusion MRI can add more information about the penumbra and potentially salvageable tissue after acute ischaemic stroke

Specific patient profiles on MRI can help to identify subgroups of patients that may benefit from early reperfusion with thrombolytic therapy outside of approved time windows

Albers et al; the DEFUSE Investigators. Ann Neurol 2006;60:508-517.Davis et al. Lancet Neurol 2008;7:299-309.

Schellinger et al. Neurology 2010;75:177-185.

Meta- and Pooled Analyses

Cochrane Meta-Analysis of IV rt-PA Versus Control (including ECASS 3)

Wardlaw et al. Cochrane Database of Systematic Reviews 2009;4: CD000213. DOI: 10.1002/14651858.CD000213.pub2.

Mori 1992 13/19 10/12 0.4% 0.43 [0.07, 2.62]

ECASS 1995 201/313 217/307 11.3% 0.74 [0.53, 0.68]

NINDS 1995 179/312 229/312 11.3% 0.49 [0.35, 0.68]

ECASS II 1998 244/409 248/391 15.8% 0.85 [0.64, 1.13]

ATLANTIS B 1999 161/307 162/306 12.8% 0.98 [0.71, 1.35]

ATLANTIS A 2000 64/71 56/71 1.4% 2.45 [0.93, 6.44]

Wang 2003 29/67 26/33 1.4% 0.21 [0.08, 0.54]

EPITHET 2008 34/52 37/49 1.7% 0.61 [0.26, 1.46]

ECASS 3 2008 140/418 155/403 15.7% 0.81 [0.61, 1.07]

Subtotal (95% Cl) 1968 1884 71.7% 0.76 [0.66, 0.87]

Total events: 1065 (Thrombolysis), 1140 (Control)Heterogeneity: Chi2=23.25, df=8 (p=0.003); I2=66%Test for overall effect: Z=4.03 (p=0.000055)

Favours thrombolysis Favours control

0.1 1.0 10

Updated Pooled Analysis(Including ECASS 3 and EPITHET)

Data from ECASS 3 and EPITHET were added to the pool of common data elements from the 6 previous trials of rt-PA for acute ischaemic stroke

N=3,670 patients (old analysis N=2,779)

1,850 patients treated with rt-PA;1,820 patients given placebo

Men: 60%

Median age: 68 years (IQR 59-74)

Median NIHSS: 11 (IQR 7-16)

Median time-window: 240 min (IQR 180-284)

Separate analyses at four OTT intervals (0-90 min, 91-180 min, 181-270 min, 271-360 min) were undertaken

Hacke et al. Lancet 2004;363:768-774. Lees et al. Lancet 2010;375:1695-1703.

Comparison of Pooled Analysis Data with ECASS 3

Time Window

Adjusted OR (95% CI)

0-90 2.81 (1.75-4.50)

91-180 1.55 1.12-2.15)

181-270 Pooled 1.40 (1.05-1.85)

ECASS 3 1.42 (1.02-1.98)

271-360 1.15 (0.90-1.47)

Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.Hacke et al. Lancet 2004;363:768-774.

0.1 1.0 10.0Odds Ratio (95% CI)

Pooled data analysis of NINDS, ATLANTIS and ECASS I and II trials (green) showing odds ratios and 95% confidence intervals for favourable outcome in different time windows from onset, adjusted for prognostic confounders, with ECASS 3 outcome superimposed (blue)

The earlier you treat, the greater the benefit

Updated Pooled Analysis:Favourable Outcome (mRS 0-1) vs. Time

Lees et al. Lancet 2010;375:1695-1703.

5

60 120 150 210 240 300 3300

1

2

3

4

Odds ratio (OR)

OTT (min)

Odd

s ra

tio a

nd 9

5% C

I

NNT 4-5

OR 2.55

NNT 9

OR 1.64

NNT 14

OR 1.34

NNT 21

OR 1.22

270 36018090

NNT, Number needed to treatOTT, Time from stroke onset to start of treatmentmRS, modified Rankin Scale

Updated Pooled Analysis:Mortality

Placebon/N (%)

rt-PAn/N (%)

OR*(95%CI)

p

0-90 min31/151 (20.5%)

3/161(18.6%)

0.78 (0.41-1.48)

0.440

91-180 min49/315(15.6%)

51/303(16.8%)

1.13 (0.70-1.82)

0.608

181-270 min82/811(10.0%)

89/809(10.6%)

1.22 (0.87-1.71)

0.252

271-360 min55/542(10.2%)

86/757(15.0%)

1.49 (1.00-2.21)

0.050

0-360 min217/1820(11.9%)

257/1849(13.9%)

1.19 (0.96-1.47)

0.108

Lees et al. Lancet 2010;375:1695-1703.

*OR adjusted for NIHSS, age, diastolic blood pressure

Updated Pooled Analysis:Interpretation

Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous rt-PA when treated up to 4.5 h

No increase in mortality with rt-PA use up to 4.5 h

The earlier treatment with rt-PA is administered, the greater the benefit

To maximise benefit, every effort should be taken to shorten delay in initiation of treatment

Beyond 4.5 h, risk might outweigh benefit

Lees et al. Lancet 2010;375:1695-1703.

SITS Register

SITS Register

SITS (Safe Implementation of Treatments in Stroke) is an internet-based interactive thrombolysis register

The SITS register is an instrument for clinical centres to follow their own treatment results and compare them with other centres in their own or in collaborating countries

The SITS register is the technical basis for the International Stroke Treatment Register (SITS-ISTR) and SITS Stroke Monitoring Study (SITS-MOST)

www.sitsinternational.org

SITS Register


>60,167 patients added into theSITS register by December 2011

Recruitment is ongoing

Now 1,273 registered centres

55 participating countries in four continents


SITS-MOST

SITS-MOST: Rationale

Randomised controlled trials show thrombolysis to be beneficial when given within 3 hours of ischaemic stroke

rt-PA was approved by the EU regulatory authority EMEA in 2002 for use within 3 hours of ischaemic stroke on two conditions:

That patients be registered in the SITS internet database and entered into an observational safety study, SITS-MOST

AND

A new, randomised trial of rt-PA versus placebo, ECASS 3, be launched, with an extended therapeutic window greater than 3 hours

Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:275-282.

SITS-MOST: Overview

An observational safety monitoring study within the EU, plus Norway, Iceland, and Switzerland

A cohort of the existing online stroke register SITS-International Stroke Thrombolysis Register (SITS-ISTR)

Objective

To assess whether intravenous rt-PA, when given as thrombolytic therapy within 3 hours of the onset of ischaemic stroke is as safe and effective in routine clinical practice as reported in randomised controlled clinical trials


SITS-MOST: Outcomes

Primary outcome

Symptomatic intracerebral haemorrhage*

Death within 3 months

Secondary outcome

Functional independence (mRS ≤2 at 3 months)

SICH according to NINDS and Cochrane reviews§

SICH according to ECASS (I + II)#

Complete recovery (mRS ≤1 at 3 months)


*Defined as local or remote parenchymal haemorrhage type 2 on the 22–36 hour post-treatment imaging scan; plus deterioration of NIHSS by ≥4 points; or leading to death§ Any haemorrhage + deterioration of NIHSS ≥1# Any haemorrhage + deterioration of NIHSS ≥4

Modified Rankin Scores at 3 Months

Modified Rankin scores (mRS) at 3 months in SITS-MOST and RCTs for placebo and rt-PA patients


Pooled placebo 0–3 h (N=465)

Pooled rt-PA0–3 h (N=463)

SITS-MOST (N=6,136)

RCT, randomised controlled trial

mRS

SITS-MOST: Summary

Mortality rates within the first 3 months were lower in SITS-MOST (11.3%) than in RCTs (17.3%)

Functional independence at 3 months was higher in SITS-MOST (54.8%) than in RCTs (50.1%)

The results of SITS-MOST confirm that routine use of rt-PA within 3 hours of ischaemic stroke has a safety profile at least as good as that seen in RCTs

SITS-MOST showed that safety could be maintained across centres, regardless of experience in acute stroke thrombolysis

SITS-MOST demonstrates the advantage of establishing stroke centres for treating stroke patients and the need for a multidisciplinary approach to ensure recognition of symptoms, rapid transportation, accurate diagnosis, & effective treatment

Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:275-282.Wahlgren et al. Lancet 2007;369:826.

RCT, randomised controlled trial

SITS-MOST: Conclusion

SITS-MOST, the largest monitored stroke register to date, with over 6,000 patients, demonstrated that broad implementation of thrombolysis with rt-PA in acute stroke treatment is as safe and effective as in randomised controlled clinical trials

SITS-MOST confirmed the existing European labelling of rt-PA for thrombolysis of acute ischaemic stroke


SITS-ISTR

Updated Analysis of SITS-ISTR

Centres participating in the SITS database are required to enter all patients into SITS-ISTR (International stroke treatment register), regardless of whether they fulfil the SITS-MOST criteria or not

Between December 2002 and February 2010, SITS-ISTR looked at a cohort of patients (N=2,376) treated with rt-PA within 3-4.5 hours after the onset of ischaemic stroke and compared the outcome with that of patients treated within the 3-hour time window (N=21,566)

Outcome measures were:

sICH within 24 hours

Mortality

Independence (mRS 0-2) at 3 monthsAhmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874.

SITS-ISTR: Results

No significant difference for any outcome measure between patients treated within 0-3 hours or at 3-4.5 hours after stroke onset

Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874.

0 - 3 h 3 - 4.5 h Unadjusted results Adjusted results

n/N (%) n/N (%) Odds ratio (95% CI)

p value

Odds ratio (95% CI)

p value

sICH (SITS-MOST definition)

352/21204 (1.7%)

52/2317(2.2%)

1.36 (1.01-1.83)

0.04 1.44(1.05-1.97)

0.02

sICH (ECASS II definition) 1020/21206(4.8%)

121/2304 (5.3%)

1.10(0.90-1.33)

0.35 1.27 (1.03-1.55)

0.02

sICH (NINDS definition) 1515/21245(7.1%)

171/2317(7.4%)

1.04(0.88-1.22)

0.66 1.18(0.99-1.41)

0.06

Mortality at 3 months 2287/18583(12.3%)

218/1817(12.0%)

0.97(0.84-1.13)

0.70 1.26(1.07-1.49)

0.005

Mortality at 7 days 1307/20956(6.2%)

132/2259(5.8%)

0.93(0.78-1.12)

0.46 1.22 (1.00-1.48)

0.052

Functionally independent at 3 months (mRS 0-2)

10531/18317(57.5%)

1075/1784(60.3%)

1.12(1.02-1.24)

0.02 0.84(0.75-0.95)

0.005

Minimal or no disability at 3 months (mRS 0-1)

7467/18317(40.8%)

793/1784(44.5%)

1.16(1.05-1.28)

0.003 0.92 (0.83-1.03)

0.17


22%

20%

22%

20%

16%

17%

12%

13%

11%

12%

5%

5%

12%

12%

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

Within 3 h(n=18,317)

3−4.5 h(n=1,784)

Patients (%)

0 1 2 3 4 5 6

SITS-ISTR: mRS at 3 Months

Functional independence at 3 months was almost identical in the 2 treatment groups

Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874.

Proportion of patients in the 3-4.5 h and within 3 h cohorts according to the modified Rankin scale (mRS) score at 3 months

mRS

SITS-ISTR: Conclusions

Early treatment with thrombolysis has been confirmed and leads to better outcomes

SITS-ISTR confirms the safety and efficacy of rt-PA for the thrombolysis of ischaemic stroke within the approved 3-hour time window as well as in the 3-4.5 hour time window

SITS-ISTR confirms the results of SITS-MOST and reinforces the results of ECASS 3

These results should provide more patients with access to thrombolysis which should be administered as early as possible

However, “time is brain” and patients should be treated as early as possible after stroke

Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874. Wahlgren et al. SITS Investigators. Lancet 2008;372:1303-1309.

SITS-NEW

SITS NEW: Background

Patients >80 years are underrepresented in approval relevant studies

SITS NEW focused on Asian patients (48 stroke centres from Korea, China, India and Singapore participated)

Objective was to evaluate if the results for the use of intravenous rt-PA within 3 hours of symptom onset are consistent compared to rest of the world

The Virtual International Stroke Trials Archive(VISTA)

VISTA: Rationale and Objective

Rationale

The datasets from many studies investigating risk factors, aetiology, prevalence, ethnic disparity and potential benefits of stroke treatment regimens reside in industry and academic archives long after the studies have been published

The importance of this stored information is often underestimated

By collating these datasets, a large and rich pool of information can be utilised for novel analyses of the natural history of homogeneous subgroups of stroke patients

Objective

To establish a comprehensive resource comprising patient data from acute stroke clinical trials, on which novel analyses to inform clinical trial design could be performed

Ali et al. Stroke 2007;38:1905-1910.

VISTA: Overview

VISTA contains 29 anonymised acute stroke clinical trials and one acute stroke registry

Over 27,500 patients with either ischaemic or haemorrhagic stroke

Patients aged 18-103 years

Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials

Outcome measures include Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale

Ali et al. Stroke 2007;38:1905-1910.

NIHSS at baseline

Forest plot OR (95%Cl) CMHp

Sample size Alteplase/Control

1-4 1.14 (0.30, 4.35) 0.82 8/161

5-8 1.25 (0.98, 1.59) 0.04 278/934

9-12 1.32 (1.07, 1.62) 0.01 404/942

13-16 1.63 (1.30, 2.05) < 0.05 342/814

17-20 1.67 (1.32, 2.12) < 0.05 311/736

21-24 1.56 (1.14, 2.14) < 0.05 178/466

≥ 25 1.12 (0.66, 1.90) 0.08 64/179

0.2 0.5 1 2 5

Favours control Favours alteplase

VISTA: Baseline Stroke Severity Predicts Outcome with Thrombolysis

In a non-randomised comparison of 5,817 patients from the VISTA database, outcomes with thrombolysis were significantly better across baseline NIHSS levels 5 to 24

Mishra et al; VISTA Collaborators. Stroke 2010;41:2612-2617.

rt-PA/Control

Age decile

Forest plot OR (95%Cl) CMHp

Sample size rt-PA/Control

21-30 1.14 (0.30, 4.35) 0.82 8/161

31-40 1.25 (0.98, 1.59) 0.04 278/934

41-50 1.32 (1.07, 1.62) 0.01 404/942

51-60 1.63 (1.30, 2.05) < 0.05 342/814

61-70 1.67 (1.32, 2.12) < 0.05 311/736

71-80 1.56 (1.14, 2.14) < 0.05 178/466

81-90 1.12 (0.66, 1.90) 0.08 64/179

91-100

0.01 0.1 0.2 0.5 1 2 5

Favours control Favours rt-PA

VISTA: Outcomes by Age Group

Odds ratios (OR) with 95% confidence intervals for better outcome are estimated from ordinal logistic regression, adjusted for age and NIHSS

Mishra NK, et al. Stroke 2010;41:2840-2848.

VISTA: Diabetes and Prior Stroke

Mishra et al, for VISTA & SITS Collaborators. Cerebrovascular Diseases 2010 [abstract from ESC];Mishra et al, for VISTA Collaborators. Diabetes Care 2010 PMID 20843977.

0.5 1 2 5

Diabetes & prior stroke

NIHSS

mRS

Previous stroke

Diabetes

NIHSS

mRS

NIHSS

mRS

0.5 1 2 5

SITS recorded only Rankin

Favours ThrombolysisFavours Control Favours ThrombolysisFavours Control



No diabetes/stroke interaction: p=0.9 No diabetes/stroke interaction: p=0.5

VISTA: Summary

rt-PA is an approved* and recommended treatment

Age restriction Age >80 years does not appear to influence response to rt-PA No loss of benefit or enhanced ICH with age <90 years

Severity restriction Efficacy extends across NIHSS up to 24

Diabetes and prior stroke restriction No interaction between diabetes and prior stroke

* Marketing approval does not extend to >25 NIHSS; diabetes with prior stroke; or in some countries, >80 years (e.g. EU, although relaxed to a warning in others, e.g. Australia)

Prescribing information

Actilyse®

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.

1. NAME OF THE MEDICINAL PRODUCT Actilyse® Powder and solvent for solution for injection and infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 vial with powder contains: 10 mg alteplase (corresponding to 5,800,000 IU) or 20 mg alteplase (corresponding to 11,600,000 IU) or 50 mg alteplase (corresponding to 29,000,000 IU), respectively. Alteplase is produced by recombinant DNA technique using a Chinese hamster ovary cell-line. The specific activity of alteplase in-house reference material is 580,000 IU/mg. This has been confirmed by comparison with the second international WHO standard for t-PA. The specification for the specific activity of alteplase is 522,000 to 696,000 IU/mg. For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Powder and solvent for solution for injection and infusion. The powder is presented as a colourless to pale yellow lyophilizate cake.

4. CLINICAL PARTICULARS 4.1 Therapeutic indications: Thrombolytic treatment in acute myocardial infarction -90 minutes (accelerated) dose regimen (see section 4.2): for patients in whom treatment can be started within 6 h after symptom onset-3 h dose regimen (see section 4.2): for patients in whom treatment can be started between 6 - 12 h after symptom onset provided that the diagnosis has been clearly confirmed. Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction. Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instability The diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning. There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism. Fibrinolytic treatment of acute ischaemic stroke Treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques (e.g. cranial computerised tomography or other diagnostic imaging method sensitive for the presence of haemorrhage). The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome.

SUMMARY OF PRODUCT CHARACTERISTICS


4.2 Posology and method of administration Actilyse should be given as soon as possible after symptom onset. The following dose guidelines apply. Under aseptic conditions the content of an injection vial of Actilyse (10 mg or 20 mg or 50 mg) is dissolved with water for injections according to the following table to obtain either a final concentration of 1 mg alteplase/ml or 2 mg alteplase/ml:


Actilyse vial 10 mg 20 mg 50 mg

Volume of water for injections to be added to dry powder:

Final concentration(a) 1 mg alteplase/ml (ml)

10 20 50

(b) 2 mg alteplase/ml (ml) 5 10 25

The reconstituted solution should then be administered intravenously. It may be diluted further with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg/ml. A dilution of the reconstituted solution with sterilised water for injections or in general, the use of carbohydrate infusion solutions, e.g. dextrose is not recommended. Actilyse should not be mixed with other medicinal products neither in the same infusion-vial nor the same catheter (not even with heparin). For further practical instructions for preparation and handling see sections 6.2 and 6.6. The experience in children and adolescents is limited. Actilyse is contraindicated for the treatment of acute stroke in children and adolescents (see section 4.3).


Myocardial infarction a) 90 minutes (accelerated) dose regimen for patients with myocardial infarction, in whom treatment can be started within 6 hours after symptom onset:


In patients with a body weight below 65 kg the dose should be weight adjusted according to the following table:

Concentration of alteplase

1 mg/ml 2 mg/ml

15 mg as an intravenous bolus 15 7.5

50 mg as an infusion over 30 minutes 50 25

followed by an infusion of 35 mg over 60 minutes until the maximal dose of 100 mg 35 17.5


1 mg/ml 2 mg/ml

15 mg as an intravenous bolus 15 7.5

ml/kg bw ml/kg bw

and 0.75 mg/kg body weight (bw) over 30 minutes (maximum 50 mg) 0.75 0.375

followed by an infusion of 0.5 mg/kg body weight (bw) over 60 minutes (maximum 35 mg)

0.5 0.25


b) 3 h dose regimen for patients, in whom treatment can be started between 6 and 12 hours after symptom onset:


In patients with a body weight below 65 kg the total dose should not exceed 1.5 mg/kg.The maximum dose of alteplase is 100 mg.Adjunctive therapy:Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction; acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with lifelong treatment unless it is contraindicated.


1 mg/ml 2 mg/ml

10 mg as an intravenous bolus 10 5

50 mg as an infusion over the first hour 50 25

ml/30 min ml/30 min

followed by infusions of 10 mg over 30 minutes until the maximal dose of 100 mg over 3 hours

10 5


Pulmonary embolismA total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available with the following dose regimen:


The total dose should not exceed 1.5 mg/kg in patients with a body weight below 65 kg.Adjunctive therapy: After treatment with Actilyse heparin therapy should be initiated (or resumed) when aPTT values are less than twice the upper limit of normal. The infusion should be adjusted to maintain aPTT between 50 - 70 seconds (1.5 to 2.5 fold of the reference value).

Acute ischaemic stroke Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care, see sections 4.3 and 4.4. The recommended dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) infused intravenously over 60 minutes with 10% of the total dose administered as an initial intravenous bolus. Treatment with Actilyse must be started as early as possible within 4.5 hours of the onset of symptoms. Beyond 4.5 hours after onset of stroke symptoms there is a negative benefit risk ratio associated with Actilyse administration and so it should not be administered (see section 5.1). 5 Adjunctive therapy: The safety and efficacy of this regimen with concomitant administration of heparin and acetylsalicylic acid within the first 24 hours of onset of the symptoms have not been sufficiently investigated. Administration of acetylsalicylic acid or intravenous heparin should be avoided in the first 24 hours after treatment with Actilyse. If heparin is required for other indications (e.g. prevention of deep vein thrombosis) the dose should not exceed 10,000 IU per day, administered subcutaneously.


1 mg/ml 2 mg/ml

10 mg as an intravenous bolus over 1 - 2 minutes 10 5

followed by an intravenous infusion of 90 mg over 2 hours 90 45


4.3 ContraindicationsHypersensitivity to the active substance or to any of the excipients.Additional contraindications in acute myocardial infarction, acute pulmonary embolism and acute ischaemic stroke:Actilyse is contraindicated in cases where there is a high risk of haemorrhage such as: •significant bleeding disorder at present or within the past 6 months •known haemorrhagic diathesis •patients receiving oral anticoagulants, e.g. warfarin sodium •manifest or recent severe or dangerous bleeding •known history of or suspected intracranial haemorrhage •suspected subarachnoid haemorrhage or condition after subarachnoid haemorrhage from aneurysm •any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery) •recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture) •severe uncontrolled arterial hypertension •bacterial endocarditis, pericarditis •acute pancreatitis •documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial-aneurysm, arterial/venous malformations •neoplasm with increased bleeding risk •severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis •major surgery or significant trauma in past 3 months.Additional contraindications in acute myocardial infarction:•any known history of haemorrhagic stroke or stroke of unknown origin •known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 3 hours.Additional contraindications in acute pulmonary embolism:•any known history of haemorrhagic stroke or stroke of unknown origin •known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 3 hours.



Additional contraindications in acute ischaemic stroke:•symptoms of ischaemic attack beginning more than 4.5 hours prior to infusion start or symptoms for which the onset time is unknown and could potentially be more than 4.5 hours ago (see section 5.1) •minor neurological deficit or symptoms rapidly improving before start of infusion •severe stroke as assessed clinically (e.g. NIHSS>25) and/or by appropriate imaging techniques •seizure at onset of stroke •evidence of intracranial haemorrhage (ICH) on the CT-scan•symptoms suggestive of subarachnoid haemorrhage, even if CT-scan is normal •administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory •patients with any history of prior stroke and concomitant diabetes •prior stroke within the last 3 months •platelet count of below 100,000/mm3 •systolic blood pressure > 185 or diastolic BP > 110 mm Hg, or aggressive management (intravenous pharmacotherapy) necessary to reduce BP to these limits •blood glucose < 50 or > 400 mg/dl.Use in children and, adolescentsActilyse is not indicated for the treatment of acute stroke in paediatric patients under 18 years.Use in elderly patientsActilyse is not indicated for the treatment of acute stroke in adults over 80 years of age.

4.4 Special warnings and precautions for use Special warnings and precautions in acute myocardial infarction, acute pulmonary embolism and acute ischaemic stroke: Thrombolytic/fibrinolytic treatment requires adequate monitoring. Actilyse should only be used by physicians trained and experienced in the use of thrombolytic treatments and with the facilities to monitor that use. It is recommended that when Actilyse is administered standard resuscitation equipment and pharmacotherapy be available in all circumstances. The risk of intracranial haemorrhage is increased in elderly patients, therefore in these patients the risk/benefit evaluation should be carried out carefully. As yet, there is only limited experience with the use of Actilyse in children and adolescents. As with all thrombolytic agents, the expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with •small recent traumas, such as biopsies, puncture of major vessels, intramuscular injections, cardiac massage for resuscitation •conditions with an increased risk of haemorrhage which are not mentioned in section 4.3. The use of rigid catheters should be avoided.



Additional special warnings and precautions in acute myocardial infarction: A dose exceeding 100 mg of alteplase must not be given because it has been associated with an additional increase in intracranial bleeding. Therefore special care must be taken to ensure that the dose of alteplase infused is as described in section 4.2. There is limited experience with readministration of Actilyse. Actilyse is not suspected to cause anaphylactic reactions. If an anaphylactoid reaction occurs, the infusion should be discontinued and appropriate treatment initiated. The expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with systolic blood pressure > 160 mm Hg. GPIIb/IIIa antagonists: Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

Additional special warnings and precautions in acute pulmonary embolism: same as for acute myocardial infarction (see above)

Additional special warnings and precautions in acute ischaemic stroke: Special precautions for use: Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care. Special warnings / conditions with a decreased benefit/risk ratio: Compared to other indications patients with acute ischaemic stroke treated with Actilyse have a markedly increased risk of intracranial haemorrhage as the bleeding occurs predominantly into the infarcted area. This applies in particular in the following cases: •all situations listed in section 4.3. and in general all situations involving a high risk of haemorrhage •small asymptomatic aneurysms of the cerebral vessels •with later time-to-treatment from onset of stroke symptoms the net clinical benefit is reduced and may be associated with a higher risk of ICH and death compared to patients treated earlier. Therefore, the administration of Actilyse should not be delayed. •patients pre-treated with acetyl salicylic acid (ASA) may have a greater risk of intracerebral haemorrhage, particularly if Actilyse treatment is delayed.Blood pressure (BP) monitoring during treatment administration and up to 24 hours seems justified; an intravenous antihypertensive therapy is also recommended if systolic BP > 180 mm Hg or diastolic BP > 105 mm Hg. The therapeutic benefit is reduced in patients that had a prior stroke or in those with known uncontrolled diabetes, thus the benefit/risk ratio is considered less favourable, but still positive in these patients.In patients with very mild stroke, the risks outweigh the expected benefit (see section 4.3). Patients with very severe stroke are at higher risk for intracerebral haemorrhage and death and should not be treated (see section 4.3). Patients with extensive infarctions are at greater risk of poor outcome including severe haemorrhage and death. In such patients, the benefit/risk ratio should be thoroughly considered.



In stroke patients the likelihood of good outcomes decreases with increasing age, increasing stroke severity and increased levels of blood glucose on admission while the likelihood of severe disability and death or relevant intracranial bleedings increases, independently from treatment. Patients over 80, patients with severe stroke (as assessed clinically and/or by appropriate imaging techniques) and patients with blood glucose levels < 50 mg/dl or >400 mg/dl at baseline should not be treated with Actilyse (see section 4.3). Data available from ECASS III and the pooled analysis indicate that the net clinical benefit becomes smaller in elderly with increasing age compared to younger patients as benefit from treatment with Actilyse appears to decrease and the risk of mortality appears to increase with increasing age. Other special warnings: Reperfusion of the ischaemic area may induce cerebral oedama in the infarcted zone.Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase.

4.5 Interaction with other medicinal products and other forms of interactionNo formal interaction studies with Actilyse and medicinal products commonly administered in patients with acute myocardial infarction have been performed.The risk of haemorrhage is increased if coumarine derivatives, oral anticoagulants, platelet aggregation inhibitors, unfractionated heparin or LMWH or active substances which interfere with coagulation are administered (before, during or within the first 24 hours after treatment with Actilyse) (see section 4.3).Concomitant treatment with ACE inhibitors may enhance the risk of suffering an anaphylactoid reaction, as in the cases describing such reactions a relatively larger proportion of patients were receiving ACE inhibitors concomitantly.Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

4.6 Pregnancy and lactationThere is very limited experience with the use of alteplase during pregnancy and lactation. Studies in animals have shown reproductive toxicity (see section 5.3). In cases of an acute life-threatening disease the benefit has to be evaluated against the potential risk. It is not known if alteplase is excreted into breast milk.

4.7 Effects on ability to drive and use machinesNot relevant.



4.8 Undesirable effectsAdverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).Except for intracranial haemorrhage as adverse reaction in the indication stroke and reperfusion arrhythmias in the indication myocardial infarction, there is no medical reason to assume that the qualitative and quantitative adverse reaction profile of Actilyse in the indications pulmonary embolism and acute ischaemic stroke is different from the profile in the indication myocardial infarction.HaemorrhageThe most frequent adverse reaction associated with Actilyse is bleeding resulting in a fall in haematocrit and/or haemoglobin values:very common: bleeding from damaged blood vessels (such as haematoma), injection site haemorrhage (puncture site haemorrhage, catheter site haematoma, catheter site haemorrhage)common: intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute ischaemic stroke. Symptomatic intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke (up to 10 % of patients without any increase of overall mortality and without any relevant increase in overall mortality and severe disability combined, i.e. mRS of 5 and 6), respiratory tract haemorrhage (such as pharyngeal haemorrhage, epistaxis, haemoptysis), gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, haemorrhage, rectum, haematemesis, melaena, mouth haemorrhage, gingival bleeding), ecchymosis, urogenital haemorrhage (such as haematuria, haemorrhage urinary tract), blood transfusion (necessary)uncommon: intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute myocardial infarction and acute pulmonary embolism, ear haemorrhage, haemopericardium, retroperitoneal haemorrhage (such as retroperitoneal haematoma)rare: bleeding in parenchymatous organs (such as hepatic haemorrhage, pulmonary haemorrhage)very rare: eye haemorrhageDeath and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.If a potentially dangerous haemorrhage occurs in particular cerebral haemorrhage, the fibrinolytic therapy must be discontinued. In general, however, it is not necessary to replace the coagulation factors because of the short half-life and the minimal effect on the systemic coagulation factors. Most patients who have bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume replacement, and manual pressure applied to an incompetent vessel. Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative.



Immune system disordersuncommon: hypersensitivity reactions / anaphylactoid reactions (e.g. allergic reactions including rash, urticaria, bronchospasm, angio-oedema, hypotension, shock or any other symptom associated with allergic reactions)very rare: serious anaphylaxisTransient antibody formation to Actilyse has been observed in rare cases and with low titres, but a clinical relevance of this finding could not be established.Nervous system disordersvery rare: events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia, speech disorder, delirium, acute brain syndrome, agitation, confusion, depression, psychosis) often in association with concurrent ischaemic or haemorrhagic cerebrovascular events.Cardiac disordersAs with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and / or thrombolytic administration.very common: recurrent ischaemia / angina, hypotension and heart failure / pulmonary oedema, reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block I° to complete, atrial fibrillation / flutter, bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia / fibrillation, electromechanical dissociation [EMD])common: cardiac arrest, cardiogenic shock and reinfarctionuncommon: mitral regurgitation, pulmonary embolism, other systemic embolism / cerebral embolism, ventricular septal defectThese cardiac events can be life-threatening and may lead to death.Vascular disordersuncommon: embolism (thrombotic embolisation), which may lead to corresponding consequences in the organs concernedGastrointestinal disorderscommon: nausea, vomitingInvestigationsvery common: blood pressure decreasedcommon: body temperature increasedInjury and poisoning and procedural complicationsrare: fat embolism (cholesterol crystal embolisation), which may lead to corresponding consequences in the organs concerned

4.9 OverdoseThe relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other blood coagulation components may occur after overdosage. In most cases, it is sufficient to await the physiological regeneration of these factors after the Actilyse therapy has been terminated. If, however, severe bleeding results, the infusion of fresh frozen plasma or fresh blood is recommended and if necessary, synthetic antifibrinolytics may be administered.



5.PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: antithrombotic agent, ATC code: B 01 A D 02 The active ingredient of Actilyse is alteplase, a recombinant human tissue-type plasminogen activator, a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot. Due to its relative fibrin-specificity alteplase at a dose of 100 mg leads to a modest decrease of the circulating fibrinogen levels to about 60 % at 4 hours, which is generally reverted to more than 80 % after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to about 20 % and 35 % respectively after 4 hours and increase again to more than 80 % at 24 hours. A marked and prolonged decrease of the circulating fibrinogen level is only seen in few patients. In a study including more than 40,000 patients with an acute myocardial infarction (GUSTO) the administration of 100 mg alteplase over 90 minutes, with concomitant intravenous heparin infusion, led to a lower mortality after 30 days (6.3 %) as compared to the administration of streptokinase, 1.5 million U over 60 minutes, with subcutaneous or intravenous heparin (7.3 %). Actilyse-treated patients showed higher infarct related vessel patency rates at 60 and 90 minutes after thrombolysis than the streptokinase-treated patients. No differences in patency rates were noted at 180 minutes or longer. 30-day-mortality is reduced as compared to patients not undergoing thrombolytic therapy. The release of alpha-hydroxybutyrate-dehydrogenase (HBDH) is reduced. Global ventricular function as well as regional wall motion is less impaired as compared to patients receiving no thrombolytic therapy.

Myocardial infarction A placebo controlled trial with 100 mg alteplase over 3 hours (LATE) showed a reduction of 30-day-mortality compared to placebo for patients treated within 6-12 hours after symptom onset. In cases, in which clear signs of myocardial infarction are present, treatment initiated up to 24 hours after symptom onset may still be beneficial.

Pulmonary embolism In patients with acute massive pulmonary embolism with haemodynamic instability thrombolytic treatment with Actilyse leads to a fast reduction of the thrombus size and a reduction of pulmonary artery pressure. Mortality data are not available.

Acute stroke In two USA studies (NINDS A/B) a significant higher proportion of patients, had a favourable outcome with alteplase, compared to placebo (no or minimal disability). These findings were confirmed in the ECASS III trial (see paragraph below), after in the meantime two European studies and an additional USA study had failed to provide the respective evidence in settings essentially not compliant with the current EU product information.



The ECASS III trial was a placebo-controlled, double-blind trial conducted in patients with acute stroke in a time-window of 3 to 4.5 hours in Europe. Treatment administration in the ECASS III study was in line with the European SmPC for Actilyse in its stroke indication, except the upper end of the time of treatment window i.e. 4.5 hours. The primary end point was disability at 90 days, dichotomized for favourable (modified Rankin scale [mRS] 0 to 1) or unfavourable (mRS 2 to 6) outcome. A total of 821 patients (418 alteplase/403 placebo) were randomized. More patients achieved favourable outcome with alteplase (52.4%) vs. placebo (45.2%; odds ratio [OR] 1.34; 95% CI 1.02 - 1.76; P=0.038). The incidence of symptomatic intracranial haemorrhage was higher with alteplase vs. placebo (27.0% vs 17.6%, p=0.0012; Mortality was low and not significantly different between alteplase (7.7%) and placebo (8.4%; P=0.681). Subgroup results of ECASS III confirm that a longer OTT is associated with an increasing risk for mortality and symptomatic intracranial haemorrhage. The results of ECASS III show a positive net-clinical benefit for ACTILYSE in the 3 to 4.5 hour time window, while pooled data demonstrate that the net-clinical benefit is no longer favourable for alteplase in the time window beyond 4.5 hours.

The safety and efficacy of ACTILYSE for acute ischaemic stroke treatment up to 4.5 hours time stroke onset time to start of treatment (OTT) has been assessed by an ongoing registry (SITS-ISTR: The Safe Implementation of Thrombolysis in Stroke registry). In this observational study safety outcome data of 21.566 treated patients in the 0 to 3 hour time window were compared with data from 2.376 patients treated between 3 to 4.5 hours after onset of AIS. The incidence of symptomatic intracranial haemorrhage (according to the SITS-MOST definition) was found to be higher in the 3 to 4.5 hour time window (2.2%) as compared with the up to 3 hour time window (1.7%). Mortality rates at 3 months were similar comparing the 3 to 4.5 hour time window (12.0%) with the 0 to 3.0 hours time window (12.3%) with an unadjusted OR 0.97 (95% CI: 0.84-1.13, p=0.70) and an adjusted OR 1.26 (95% CI: 1.07-1.49, p=0.005. The SITS observational data support clinical trial evidence of stroke onset time to start of treatment (OTT) as an important predictor of outcome following acute stroke treatment with alteplase.

5.2 Pharmacokinetic properties Alteplase is cleared rapidly from the circulating blood and metabolised mainly by the liver (plasma clearance 550 - 680 ml/min.). The relevant plasma half-life t1/2 alpha is 4-5 minutes. This means that after 20 minutes less than 10 % of the initial value is present in the plasma. For the residual amount remaining in a deep compartment, a beta-half-life of about 40 minutes was measured.

5.3 Preclinical safety data In subchronic toxicity studies in rats and marmosets no unexpected undesirable effects were found. No indications of a mutagenic potential were found in mutagenic tests. In pregnant animals no teratogenic effects were observed after intravenous infusion of pharmacologically effective doses. In rabbits embryotoxicity (embryolethality, growth retardation) was induced by more than 3 mg/kg/day. No effects on peri-postnatal development or on fertility parameters were observed in rats with doses up to 10 mg/kg/day.



6.PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder for solution: Arginine Phosphoric acid, dilute Polysorbate 80 Solvent: Water for injections The pH of the reconstituted solution is 7.3 ± 0.5

6.2 Incompatibilities The reconstituted solution may be diluted with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg alteplase per ml. Further dilution, the use of water for injections for dilution or in general the use of carbohydrate infusion solutions, e.g. dextrose, is not recommended due to increasing formation of turbidity of the reconstituted solution. Actilyse should not be mixed with other medicinal products neither in the same infusion vial nor the same catheter (not even with heparin).

6.3 Shelf life 10 mg, 20 mg and 50 mg pack sizes: 3 years After reconstitution, an immediate use is recommended. However, the in-use stability has been demonstrated for 24 hours at 2 °C – 8 °C and for 8 hours at 25 °C

6.4 Special precautions for storage Store in the original package in order to protect from light. For 10 mg, 20 mg and 50 mg pack sizes: Do not store above 25 °C. For storage conditions of the reconstituted medicinal product, see section 6.3.



6.5 Nature and contents of container Powder for solution: 10 ml, 20 ml or 50 ml sterilised glass vials, sealed with sterile siliconised grey butyl-type stoppers with aluminium/plastic flip-off caps. Solvent: For the 10 mg, 20 mg and 50 mg pack sizes, the water for injections is filled into either 10 ml, 20 ml or 50 ml vials, depending on the size of the powder vials. The water for injections vials are sealed with rubber stoppers and aluminium/plastic flip-off caps. Transfer cannulas (included with pack sizes of 20 mg and 50 mg only) Pack sizes: 10 mg: 1 vial with 467 mg powder for solution for injection and infusion 1 vial with 10 ml of water for injections 20 mg: 1 vial with 933 mg powder for solution for injection and infusion 1 vial with 20 ml of water for injections 1 transfer cannula 50 mg: 1 vial with 2333 mg powder for solution for injection and infusion 1 vial with 50 ml of water for injections 1 transfer cannula Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling For reconstitution to a final concentration of 1 mg altpelase per ml the full volume of solvent provided should be transferred to the vial containing the Actilyse powder. To this purpose a transfer cannula is included with the 20 mg and 50 mg pack sizes, which is to be used. For the 10 mg pack sizes a syringe should be used. For reconstitution to a final concentration of 2 mg alteplase per ml only half of the solvent provided should be used. In these cases always a syringe should be used to transfer the required amount of solvent to the vial containing the Actilyse powder. A table giving the volumes of solvent required for reconstitution to the final concentrations for each pack size is provided in section 4.2. When reconstituting the product from the respective amount of powder and solvent, the mixture should only be agitated gently until complete dissolution. Any vigorous agitation should be avoided to prevent foam formation. The reconstituted preparation is a clear and colourless to pale yellow solution. Prior to administration it should be inspected visually for particles and colour. The reconstituted solution is for single use only. Any unused solution should be discarded.

7. MARKETING AUTHORISATION HOLDERBoehringer Ingelheim International GmbH, Binger Str. 173, D-55216 Ingelheim am Rhein, Germany


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studies and registries march 2012. disclaimer please be aware that legal provisions governing the...

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