Consensus Statements 2008

 

Consbar

Should the time window for intravenous thrombolysis be extended?

The Consensus Statement includes two parts, the Consensus Statement itself, and the Recommendation to the European Stroke Organisation (ESO) on revision of ESO Guidelines. Please note that the final text of the Guidelines, is decided by ESO and that the recommendation in this document may not be the final guidelines version. As soon as the guidelines are confirmed, they will appear on this website as well as on the ESO website www.eso-stroke.org

 

A. Karolinska Stroke Update Consensus Statement

Should the time window for intravenous thrombolysis be extended?

The following Consensus Statement was adopted by the 7th Karolinska Stroke Update meeting on November 18, 2008.
The consensus statement was proposed by the chairman of the session, Professor Markku Kaste, Helsinki, the co-chair Dr Robert Mikulik, Brno, and the session secretary Dr Nikolaos Kostulas, Stockholm, together with the speakers of the session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.
The speakers in this session were Professor Kennedy R Lees, Glasgow, Professor Nils Wahlgren, Stockholm, Professor Danilo Toni, Rome,   Professor Antoni Davalos, Barcelona, and Professor Peter Sandercock, Edinburgh. 


Controversy to discuss at the 2008 consensus session:

Is there sufficient evidence to support the conclusion that routine use of intravenous thrombolysis is effective and safe from 3 to 4.5 hours after the onset of stroke symptoms?

 

Background


The combined analysis of data from six randomized trials, the pooled analysis, showed that a favourable outcome was achieved even if the treatment was given between 3 and 4.5 hours, with an odds ratio of 1.4 for a favourable outcome with alteplase treatment as compared with placebo. This analysis already considered data from a neutral trial in that time window, ATLANTIS. The pooled analysis also suggested that the longer time window compared with the shorter one was not associated with higher rates of symptomatic intracranial haemorrhage or death[1]. When thrombolysis for ischaemic stroke was approved by the European Medicines Agency (EMEA), the licence was granted with two requests: to perform a new randomized trial, the European Cooperative Acute Stroke Study (ECASS III)[2] with a therapeutic window extended beyond 3 hours and to set up an observational safety registry, the Safe Implementation of Thrombolysis in Stroke-monitoring Study (SITS-MOST)[3,4], to assess the safety profile of alteplase in routine clinical practice within 3 hours of the onset of stroke symptoms. The results of ECASS III trial and data from SITS-ISTR (ISTR – International Stroke Treatment Registry)[5] are discussed below.

The results of ECASS III showed that 219 of 418 patients in the alteplase group (52.4%) had a favourable outcome, which was defined as a score of 0 or 1 on the modified Rankin Scale (mRS) compared with 182 of the 403 patients in the placebo group (45.2%) representing an absolute improvement of 7.2% (odds ratio, 1.34; 95% CI, 1.02 -1.76)[2]. In the global analysis of ECASS III data based on the mRS, Barthel index and the National Institutes of Health Stroke Scale (NIHSS), the outcome was also improved with alteplase when compared with placebo (odds ratio, 1.28; 95% CI, 1.00-1.65). The pooled analysis had revealed an almost identical effect size[1].  In ECASS III with the extended time window, the number needed to treat (NTT) for one additional patient to achieve a favourable outcome (mRS 0-1) was 14[2]; and it would be even lower if only patients actually given alteplase were considered (e.g. NNT 10 based on per protocol analysis)[2].


In ECASS III trial, the incidence of intracranial haemorrhage was higher with alteplase than with placebo (for any intracranial haemorrhage 27.0% vs. 17.6 %; p=0.0001; and for symptomatic intracranial haemorrhage 2.4% vs. 0.2%; p=0.008. Symptomatic haemorrhage was defined as any intracranial bleeding that was the predominant cause of clinical deterioration, as defined by an increase of 4 points or more in the NIHSS score, or death[2].


In both study groups 29 patients had symptomatic brain oedema. The rate did not differ significantly between the study groups. It was 6.9% in the alteplase group and 7.2% in the placebo group (odds ratio, 0.96; 95% CI, 0.56-1.64)2.
Mortality did not differ significantly between the alteplase and placebo groups. In the alteplase group 32 of 418 patients (7.7%) and in the placebo group 34 of 402 (8.4%) died (P=0.68). There was no significant difference in the rate of other serious adverse events[2].


In the post hoc intention to treat analysis adjusted for confounding baseline variables, treatment with alteplase remained significantly associated with a favourable outcome (odds ratio, 1.42; 95% CI, 1.02-1.98; P=0.04)[2].


SITS-ISTR is a part of SITS collaboration providing information about the safety of thrombolytic treatment in patients treated in a clinical routine setting in agreement with the European marketing licence for alteplase. SITS-ISTR also included off-label use, e.g. when treatment is provided beyond 3 hours. The SITS investigators compared 664 patients with ischaemic stroke treated between 3 and 4.5 hours otherwise compliant with the European summary of the product characteristics criteria with 11 865 patients treated within 3 hours. Outcome measures were symptomatic intracerebral haemorrhage defined as parenchymal haemorrhage type 2 associated with NIHSS > 4 points deterioration, mortality, and independence defined by modified Rankin scale of 0-2 at 3 months[5].


The data from SITS-ISTR showed that in the 3-4.5-hour cohort, treatment was started on average 55 minutes later after symptom onset (195 min (IQR 187-210) vs. 140 min (IQR 115-165); p< 0.0001), median age was 3 years younger (65 years (55-77) vs. 68 (58-74); p<0.001), and stroke severity was lower (NIHSS score 11 (7-16) vs. 12 (8-17); p<.00001) than in the 3-hour cohort[5]. There were no significant differences between the 3-4.5-hour cohort and the 3-hour cohort for any outcome measures: symptomatic intracerebral haemorrhages 2.2% (14 of 649) vs. 1.6% (183 of 11681), odds ratio, 1.18; 95% CI, 0.89-1.55; adjusted odds ratio, 1.32, 95% CI, 1.00-1.75, mortality 12.7% (70 of 551) vs. 12.2% (1263 of 10368), odds ratio, 1.02; 95% CI, 0.90-1.17; adjusted odds ratio, 1.15; 95% CI, 1.00-1.33, and independence 58.0% (314 of 541) vs. 56.3% (5757 of 10231), odds ratio, 1.04; 95% CI, 0.95-1.13; adjusted odds ratio, 0.93; 95% CI, 0.84-1.03)[5].


The results revealed that the rates of symptomatic intracerebral haemorrhage, mortality and independence at 3 months follow-up in routine clinical practice are similar in patients for whom the treatment was started between 3 and 4.5 hours and for those treated within 3 hours after the onset of ischaemic stroke. The interpretation of the SITS investigators was that alteplase remains safe when given between 3 and 4.5 hours after the onset of symptoms in ischaemic stroke patients who otherwise fulfil the European summary of product characteristics criteria[5].

 

Discussion


The results of ECASS III[2] and SITS-ISTR registry study[5] showed that intravenous alteplase given between 3 and 4.5 hours (median 3 hours 59 minutes in ECASS III and 3 hours 15 minutes in SITS-ISTR registry) after stroke onset is associated with an improvement in clinical outcome (absolute difference 7.2% and NNT up to 14 in ECASS III), in patients who otherwise meet the licensing criteria, without a higher rate of symptomatic intracerebral haemorrhage than reported previously among patients treated within 3 hours. The effect size of thrombolysis is time-dependent. The NNT to get one more favourable outcome drops from two during the first 90 minutes through seven within 3 hours and towards 14 between 3 and 4.5 hours[1,2].
Early treatment remains essential but a longer time window offers an opportunity for patients who cannot be treated within the previously approved 3-hour time window. The results of ECASS III and SITS-ISTR registry should not slow the efforts to facilitate early treatment. Patients should be treated as early as possible to maximize the benefit.

 

Conclusion


The results of ECASS III and the SITS-ISTR registry confirm the conclusion drawn from the pooled data from prior randomised controlled trials (RCTs), that intravenous alteplase started between 3 and 4.5 hours after stroke onset is effective, and that although the risk of intracranial haemorrhage is increased compared to placebo, this treatment from 3 up to 4.5 hours remains as safe as when commenced within the approved 3-hour time window.

 

References:

  1. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774
  2. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, for the ECASS Investigators. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med 2008; 359: 1317-1329.
  3. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Külkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G: Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282
  4. Wahlgren N, Ahmed A, Eriksson N, Aichner F, Bluhmki E, Dávalos A, Erilä T, Ford GA, Grond M, Hacke W, Hennerici M, Kaste M, Köhrmann M, Larrue V, Lees KR, Machnig T, Roine RO, Toni D, Vanhooren G, for the SITS-MOST investigators. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials; Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST). Stroke 2008; 39: 3316-3322.
  5. Wahlgren N, Ahmed N, Dávalos A, Hacke W, Millán M, Muir K, Roine RO, Toni D, Lees KR. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008; 372: 1303-1309.

 

 

B. Recommendation by Karolinska Stroke Update participants to ESO Guidelines Committee to revise ESO guidelines:


Specific treatment:


Recommendations

  1. Intravenous rtPA (0.9 mg/kg body weight, maximum 90 mg), with 10% of the dose given as a bolus followed by a 60-minute infusion, is recommended within 3 hours of onset of ischaemic stroke (Class I, Level A)
  2. There is clear evidence that intravenous rtPA is also beneficial if given between 3 and 4.5 hours after stroke onset (CLASS I, Level A). It is recommended that treatment is considered in patients who otherwise meet the licence criteria.
  3. The use of multimodal imaging criteria may be useful for patient selection for thrombolysis but is not recommended for routine clinical practice (Class III, Level C)
  4. It is recommended that blood pressures of 185/110 mmHg or higher is lowered before thrombolysis (Class IV, GCP)
  5. It is recommended that intravenous rtPA may be used in patients with seizures at stroke onset, if the neurological deficit is related to acute cerebral ischaemia (Class IV, GCP)
  6. It is recommended that intravenous rtPA may also be administered in selected patients under 18 years and over 80 years of age, although this is outside the current European labelling (Class III, Level C)
  7. Intra-arterial treatment of acute MCA occlusion within a 6-hour time window is recommended as an option (Class II, Level B)
  8. Intra-arterial thrombolysis is recommended for acute basilar occlusion in selected patients (Class III, Level B). Intravenous thrombolysis for basilar occlusion is an acceptable alternative even after 3 hours (Class III, Level B) 
  9. It is recommended that aspirin (160–325 mg loading dose) be given within 48 hours after ischaemic stroke (Class I, Level A) 
  10. It is recommended that if thrombolytic therapy is planned or given, aspirin or other antithrombotic therapy should not be initiated within 24 hours (Class IV, GCP)
  11. The use of other antiplatelet agents (single or combined) is not recommended in the setting of acute ischaemic stroke (Class III, Level C) 
  12. The administration of glycoprotein-IIb-IIIa inhibitors is not recommended (Class I, Level A)
  13. Early administration of unfractionated heparin, low molecular weight heparin or heparinoids is not recommended for the treatment of patients with acute ischaemic stroke (Class I, Level A)
  14. Currently, there is no recommendation to treat ischaemic stroke patients with neuroprotective substances (Class I, Level A)

 


Thrombolytic therapy:

(Please note that the numbered references are in agreement with the ESO Guidelines paper for ischaemic stroke and TIA 2008. New references are indicated by the first author and year of publication. Full details are given in the reference list. The new references will be included in the next revision of the paper, planned for 2013).

Intravenous tissue plasminogen activator

Thrombolytic therapy with rtPA (0.9 mg/kg body weight, maximum dose 90 mg) given within 4.5 h after stroke onset significantly improves outcome in patients with acute ischaemic stroke [126, Hacke 2008]. By contrast, the ECASS (European Cooperative Acute Stroke Study) and ECASS II studies did not show statistically significant superiority of rtPA for the primary endpoints when treatment was given within 6 h [384, 385]. A pooled analysis of individual data of rtPA trials involving a total of 2,889 patients suggested a benefit up to 4.5 h, although, even within a 3-hour window, earlier treatment results in a better outcome (0–90 min: OR 2.11; 95% CI 1.33–3.55; 90–180 min: OR 1.69; 95% CI 1.09–2.62, 180-270 min: OR 1.40; 95% CI 1.05-1.85) [387]. The recently published trial European Cooperative Acute Stroke Study III  (ECASS III) has shown that intravenous alteplase administered between 3 and 4.5 hours (median 3 h 59 min) after the onset of symptoms significantly improves clinical outcomes in patients with acute ischemic stroke compared to placebo [Hacke 2008]; the absolute improvement was 7.2% and the adjusted OR of favorable outcome (mRS  0-1) was 1.42, 1.02-1.98. Mortality did not differ significantly (7.7% versus 8.4%), but alteplase increased the risk of SICH (2.4% vs 0.2%). Treatment benefit is time-dependent. The number needed to treat to get one more favourable outcome drops from two during the first 90 minutes through seven within 3 hours and towards 14 between 3 and 4.5 hours [387; Hacke et al 2008]. 

The SITS investigators compared 664 patients with ischaemic stroke treated between 3 and 4.5 hours otherwise compliant with the European summary of the product characteristics criteria with 11 865 patients treated within 3 hours [Wahlgren 2008a]. 
In the 3-4.5-hour cohort, treatment was started on average 55 minutes later after symptom onset. There were no significant differences between the 3-4.5-hour cohort and the 3-hour cohort for any outcome measures, confirming that alteplase remains safe when given between 3 and 4.5 hours after the onset of symptoms in ischaemic stroke patients who otherwise fulfil the European summary of product characteristics criteria [Wahlgren 2008a].

European regulatory agencies do not advocate rtPA treatment in patients with severe stroke (NIHSSS >25), extended early ischaemic changes on CT-scan, or age above 80 years (unlike the US labelling). However, the NINDS (National Institute of Neurological Disorders and Stroke) Study showed that the extent of early ischaemic changes (using the ASPECT score) had no effect on treatment response within the 3-hour time window [387]. Moreover, observational studies suggest that rtPA given within 3 h of stroke onset is safe and effective in patients over 80 years of age [389–391], but more randomized data are pending.

Thrombolytic therapy appears to be safe and effective across various types of hospitals, if the diagnosis is established by a physician with stroke expertise and brain CT is assessed by an experienced physician [393-395, Wahlgren 2008b]. Whenever possible, the risks and benefits of rtPA should be discussed with the patient and family before treatment is initiated. 
 
Blood pressure must be below 185/110 mmHg before, and for the first 24 hours after, thrombolysis. Management of high blood pressure is required [126]. Protocol violations are associated with higher mortality rates [396, 397]. 

Continuous transcranial ultrasound was associated with an increased rate of early recanalization after rtPA in a small randomized trial [398]; this effect may be facilitated by the administration of microbubbles [399]. However, a randomized clinical trial has recently been stopped for undisclosed reasons. 

The use of multimodal imaging criteria may be useful for patient selection. Several large observational studies suggest improved safety and possibly improved efficacy in patients treated with iv rtPA beyond 3 hours based on advanced imaging findings [131, 160, 400, 401]. However, available data on mismatch, as defined by multimodal MRI or CT, are too limited to guide thrombolysis in routine practice (see also the section on imaging) [153].
 
Patients with seizures at stroke onset have been excluded from thrombolytic trials because of potential confusion with post-ictal Todd’s phenomena. Case series have suggested that thrombolysis may be used in such patients when there is evidence for new ischaemic stroke [389].

Post hoc analyses have identified the following potential factors associated with increased risk of intracerebral bleeding complications after rtPA use [402]:

  1. elevated serum glucose
  2. history of diabetes
  3. baseline symptom severity
  4. advanced age
  5. increased time to treatment
  6. previous aspirin use
  7. history of congestive heart failure
  8. low plasminogen activator inhibitor activity
  9. NINDS protocol violations.

However, none of these factors reversed the overall benefit of rtPA.
 

References:

New references:


[Hacke 2008] Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, for the ECASS Investigators. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med 2008; 359: 1317-1329.

[Wahlgren 2008a] Wahlgren N, Ahmed N, Dávalos A, Hacke W, Millán M, Muir K, Roine RO, Toni D, Lees KR. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008; 372: 1303-1309.

[Wahlgren 2008b] Wahlgren N, Ahmed A, Eriksson N, Aichner F, Bluhmki E, Dávalos A, Erilä T, Ford GA, Grond M, Hacke W, Hennerici M, Kaste M, Köhrmann M, Larrue V, Lees KR, Machnig T, Roine RO, Toni D, Vanhooren G, for the SITS-MOST investigators. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials; Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST). Stroke 2008; 39: 3316-3322.

Existing references:

126. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. New Engl J Med 1995;333:1581-1587.

131. Chalela J, Kidwell C, Nentwich L, Luby M, Butmann J, Demchuk A, Hill M, Patronas N, Latour L, Warach S: Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369:293-298.

153. Kane I, Sandercock P, Wardlaw J: Magnetic resonance perfusion diffusion mismatch and thrombolysis in acute ischaemic stroke: a systematic review of the evidence to date. JNNP 2007;78:485-490.

160. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, Bammer R, Kakuda W, Lansberg MG, Shuaib A, Coplin W, Hamilton S, Moseley M, Marks MP: Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508-517.

384. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Scheider D, Diez-Tejedor E, Trouilas P: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998;352:1245-1251

385. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerici M: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute stroke. JAMA 1995;274:1017-1025.

387. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774

389. Sylaja PN, Cote R, Buchan AM, Hill MD: Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry 2006;77:826-829.

390. van Oostenbrugge RJ, Hupperts RM, Lodder J: Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch centre. J Neurol Neurosurg Psychiatry 2006;77:375-377.

391. Ringleb PA, Schwark C, Köhrmann M, Külkens S, Jüttler E, Hacke W, Schellinger PD: Thrombolytic therapy for acute ischaemic stroke in octogenarians: selection by magnetic resonance imaging improves safety but does not improve outcome. J Neurol Neurosurg Psychiatry 2007;78:690-693.

393. Hill MD, Buchan AM: Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study (CASES). CMAJ 2005;172:1307-1312.

394. Bateman BT, Schumacher HC, Boden-Albala B, Berman MF, Mohr JP, Sacco RL, Pile-Spellman J: Factors associated with in-hospital mortality after administration of thrombolysis in acute ischemic stroke patients: an analysis of the nationwide inpatient sample 1999 to 2002. Stroke 2006;37:440-446.

395. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Külkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G: Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282.

396. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM: Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke 2003;34:799-800.

397. Graham GD: Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke 2003;34:2847-2850

398. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW: Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170-2178.

399. Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, Arenillas JF, Huertas R, Purroy F, Delgado P, Alvarez-Sabin J: Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006;37:425-429.

400. Köhrmann M, Jüttler E, Fiebach JB, Huttner HB, Siebert S, Schwark C, Ringleb PA, Schellinger PD, Hacke W: MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006;5:661-667.

401. Schellinger PD, Thomalla G, Fiehler J, Kohrmann M, Molina CA, Neumann-Haefelin T, Ribo M, Singer OC, Zaro-Weber O, Sobesky J: MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1,210 patients. Stroke 2007;38:2640-2645.

402. Lansberg MG, Thijs VN, Bammer R, Kemp S, Wijman CA, Marks MP, Albers GW: Risk factors of symptomatic intracerebral hemorrhage after tPA therapy for acute stroke. Stroke 2007;38:2275-2278

 

 

 

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