XIX Symposium Neuroradiologicum Bologna, Italy, 5. – 9. October 2010 “Time is Brain” Still a valid concept for the treatment of acute stroke patients? Rüdiger von Kummer Department of Neuroradiology Dresden University Stroke Center (DUSC) Universitätsklinikum Carl-Gustav-Carus der TU Dresden www.tu-dresden.de/medneurorad

Disclosures Chair, Steering Committee, DIAS-3/4 Steering Committee, ECASS-2, ECASS-3 Safety Committee, DIAS, DEDAS, DIAS-2, FAST CT/MRI Reading Panel: ECASS, DIAS, FAST, IST3 Outcome Adjudiction: SPORTIF, MATCH, OPAL, ONYX Fees for services, travel grants from: AB Medica, Altana, Astellas, Bayer Schering, Boehringer Ingelheim, Lundbeck, NovoNordisk, Novartis, Paion, Penumbra, Pfizer, Sanofi, Siemens Disclosures

Time is brain. Is time really brain? Be quick, but use brain, not clock!

Response to IV tPA (NINDS, Marler et al.,Neurology 2000. 55:1649)

No Treatment Beyond 3 Hours?

Treatment of Acute Ischemic Stroke Challenging the Concept of a Rigid and Universal Time Window J.C. Baron, MD; R. von Kummer, MD G.J. del Zoppo, MD Stroke 1995; 26:2219-2221

The Time-is-Brain-Concept for Acute Ischemic Stroke acknowledges the high vulnerability of brain tissue for even short periods of ischemia, has fostered special and effective service for acute stroke patients (e.g. stroke units), but widely ignores the pathophysiology of individual patients and thus excludes many patients from treatment. The Time-is-Brain-Concept for Acute Ischemic Stroke

Minimal Diagnostics in Stroke Advantages Time not required Specialist not required Special institution not required Cheap and available Disadvantage Efficiency

Guideline “Time is Brain”: Therapeutic time window and minimal diagnostics Within 3h of stroke Exclusion ICH Vessel pathology? Brain pathology?? IV thrombolysis (rt-PA)

Prejustice Early treatment with IV thrombolytics means high benefit for the patient. The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain). The main reason for the failure of IV thrombolytics is the disappearance of penumbra. The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours).

Prejustice Early treatment with IV thrombolytics means high benefit for the patient. The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain). The main reason for the failure of IV thrombolytics is the disappearance of penumbra. The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours).

2001 - 2007 245 : 3908 = 6%

Effectivness of IV tPA The concept „time-is-brain“ excludes the majority of patients from treatment without a diagnosis of the individual disease. The effectiveness of IV tPA was tested in a minority of acute ischemic stroke patients. The beneficial effect of IV tPA in this minority was significant in 2 RCTs only, but minor as well.

Absolute Reduction of Disability/Mortality by IV tPA in RCTs *NINDS1: retrospective

Benefit from IV Thrombolytics (Alteplase) in Randomised Controlled Studies (RCTs) Only NINDS-2 and ECASS-3 showed a significant effect Maximal effect: Absolute reduction M/M: 7% Relative reduction M/M: 9,5% (NINDS-2), 12,7% (ECASS-3) Time-window NINDS-2: 3 hours Time-window ECASS-3: 3 to 4.5 hours

Prejustice Is time really brain? Early treatment with IV thrombolytics means high benefit for the patient. The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain). The main reason for the failure of IV thrombolytics is the disappearance of penumbra. The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours). Is time really brain?

Beneficial Outcome after IV tPA Pooled Analysis of all RCTs, N=3760 (Lees, Bluhmki, von Kummer et al. Lancet 2010;375:1695) 60 120 180 240 300 360

Potential Causes for Progressive Failure of IV tPA in RCTs Selection bias: Patients with poor prognosis were treated early Spontanous recovery: no arterial occlusion, spontaneous recanalization and tissue reperfusion Recanalisation and reperfusion not achieved Thrombolytics cannot reach the thrombus (tandem stenosis) Thrombus too big (too long) Thrombus constitution (calcified, no fibrine) Arterial obstruction not caused by thrombus, but by atheroscleosis, dissection Recanalisation without sufficient tissue reperfusion Re-Occlusion, thrombus migration Adverse events, e.g. symptomatic hemorrhage Reperfusion too late, brain already damaged to an extend that does not allow recovery

Good Clinical Outcome after Ischemic Stroke and Treatment with Placebo

Good Clinical Outcome in Trials on the Treatment with IV tPA Pooled Analysis of all RCTs, N=3760 (Lees, Bluhmki, von Kummer et al. Lancet 2010;375:1695)

Clinical deterioration (CD) In 44/374 patients (12%) Stroke 2007;38:69

51 y, m, Stroke 4 Days After Car Accident R Hemiparesis: 15:00 CT: 17:00 US: L ICA Occlusion IV rt-PA

51 y, m, Stroke 4 Days After Car Accident 1 d later after clinical deterioration

51 y, m, Stroke 4 Days After Car Accident 2 d later after clinical deterioration

Infarctpatterns after MCA Occlusion Zülch KJ Infarctpatterns after MCA Occlusion Zülch KJ. Über die Entstehung und Lokalisation der Hirninfarkte. Zbl Neurochir 1961;21: 158-178

ECASS II (N=792): Prevalence of Ischemic Edema after Stroke Onset

ECASS II (N=792): Large Ischemic Edema at Baseline % 3 11 15 14 8 1 hours after symptom onset

Infarct Core and Penumbra (CBF) in Patients with acute MCA Occlusion (Jovin et al. Stroke 2003;34:2426-2435)

Volumes of DW image (DWI) lesions (teal bars) and absolute mismatch volumes (red bars) for every patient in study Copen, W. A. et al. Radiology 2009;250:878-886 Copyright ©Radiological Society of North America, 2009

Infarctvolume and Time Minutes Hours Days Time

The ascending lenticulo-striatal arteries originate from the MCA-trunk and supply the basal ganglia. There is no collateral supply for this region.

In case of thrombo-embolic occlusion of the MCA-trunk, the basal ganglia become severely ischemic, whereas the cortical MCA territory

Prejustice Early treatment with IV thrombolytics means high benefit for the patient. The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain). The main reason for the failure of IV thrombolytics is the disappearance of penumbra. The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours).

Major Brain Hemorrhage after IV tPA Pooled Analysis of all RCTs, N=3760 (Lees, Bluhmki, von Kummer et al. Lancet 2010;375:1695)

74 y, m, Wake-up Stroke, R Hemiparesis 25. 07. 2003, 11:15

74 y, m, Wake-up Stroke, R Hemiparesis L ICA, 25. 07. 2003, 12:00

74 y, m, Wake-up Stroke, R Hemiparesis Carotis-Wallstent: 7 mm x 50 mm, 25. 07. 2003, 12:25

74 y, m, Wake-up Stroke, R Hemiparesis 25. 07. 2003 14:15

74 y, m, Recovered from Wake-up Stroke 26. 07. 2003

The earth is not flat and the treatment of stroke can be beneficial after 3 hours

New Concept Identification of patients who should not be treated with IV tPA No arterial obstruction/perfusion deficit No thrombotic obstruction Big thrombi in ICA, M1-segment, basilar artery Extended brain damage within the affected arterial territory No time limits Appropriate choice of treatment Assessment of recanalization/reperfusion

Diagnostic Keys of Ischemic Stroke Treatment Arterial Obstruction Identification of Infarction 3 h after stroke onset

Use your Brain, but not your Clock Be quick, however