1. UCLA Stroke Center Implications for Clinical Practice Jeffrey L. Saver, MD Professor of Neurology Director, UCLA Stroke Center --All slides in presentation are freely available under a Creative Commons “Share Freely with Attribution” License – Saver

2. Talk Outline Implications for clinical practice guidelines » Statistical significance Implications for clinicians at bedside » Clinical significance » Systems of care Implications for future UCLA Stroke Center

3. Guidelines UCLA Stroke Center

4. European EUSI Recommendations 2006 UCLA Stroke Center

5. US AHA/ASA Guidelines 2010 UCLA Stroke Center

6. INTERACT 2: A Near Win Trial TrialInterventionORP primary P ordinal INTERACT 2BP↓ for ICH0.87 (0.75-1.01)0.060.04 UCLA Stroke Center

7. Stroke and Near Win Trials TrialInterventionORP primary P ordinal INTERACT 2BP↓ for ICH0.87 (0.75-1.01)0.060.04 IST 3TPA to 6 hours1.13 (0.95-1.35)0.180.001 SPS3 BP ArmBP↓ prevent recurrent stroke 0.81 (0.64-1.03)0.08 UCLA Stroke Center

8. Meta-Analysis of INTERACT 1, 2 and ATACH Trials UCLA Stroke Center

10. Clinical Significance “A difference, to be a difference, must make a difference” UCLA Stroke Center

11. INTERACT 2 UCLA Stroke Center

12. INTERACT 2 UCLA Stroke Center

13. INTERACT 2 UCLA Stroke Center

14. Benefit on Dichotomized Outcome 52.0% vs 55.6% ARR 3.6% Benefit per Thousand: 36 NNT: 27.8 UCLA Stroke Center

15. INTERACT 2 UCLA Stroke Center

16. INTERACT 2 UCLA Stroke Center

17. Automated Algorithmic Joint Outcome Table Analysis UCLA Stroke Center --Saver et al, Stroke 2009;40:2433-7

18. Benefit Over All Health State Transitions Benefit per Thousand: 81 NNT: 12.3 UCLA Stroke Center

19. Benefit in INTERACT 2 vs Other Acute Stroke Interventions InterventionNet Benefit per Thousand TPA under 3h290 IA Pro-UK208 Coiling in SAH169 TPA 3-4.5h136 BP lowering for ICH 81 Clinician worthwhile 50 Socioeconomic model worthwhile 20 UCLA Stroke Center --Samsa et al, Am Heart J 1998;136:703-13 --Saver, Stroke 2007;38:3055-3062 --Saver et al, Stroke 2009;40:2433-7

20. Door to BP Control in Community Practice in ICH 100 patients, 32 Emergency Departments At ED arrival » NIHSS 18 » Time from LKW 63 mins » Mean BP 176/94 54% received BP therapy in ED Among the 48 patients with SBP ≥ 180 » Control (<180) never achieved in 19% » Median door to control 118 mins » Door to control ≤ 90m in 31% UCLA Stroke Center --Sanossian et al, Ann Emerg Med 2012;60: S56

21. Other Treatment Recommendations for ICH ICU monitoring Antipyretics in febrile patients Early mobilization ICP management » Head of bed, analgesia, sedation » Osmotic diuretics, CSF drainage, hyperventilation Maintain serum glucose < 185 Seizures » Prophylactic antiepileptics for lobar ICH » Antiepileptics for clinical seizures » Antiepileoptics for electrographic seizures DVT prophylaxis » Intermittent compression on arrival » SQ LMWH or UH after 3-4d For DVT, consider vena cava filter Reversal of coagulopathies » Protamine for heparin » Vitamin K, PCC, rF7 for warfarin Surgery » Definite for select cerebellar » Consider for lobar » Consider minimally invasive for deep UCLA Stroke Center --Morgenstern et al, Stroke 2010

22. ICH Critical Pathway Identify Signs of Possible Stroke Critical EMS Assessments & Actions Immediate General Assessment/Stabilization Immediate Neurologic Assessment (stroke team or designee) Does CT scan show hemorrhage? No Hemorrhage Hemorrhage Possible ischemic stroke Consult neurologist or neurosurgeon If not available, consider transfer BP Management ICP Management Seizure Prevention and Management Fluid Management Body Temperature Management Surgical Treatment of ICH  Cerebellar hemorrhage >3 cm with neurologic deterioration or brain stem compression and/or hydrocephalus  Consider in lobar clots <1 cm of surface AHA Adult Stroke Guidelines. Circulation. 2005;112(suppl 24):IV-111-IV-120; Broderick J, et al. Stroke. 2007;38:2001-2023; Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460. NINDS Time Goals Monitor Blood Glucose and Treat (if needed) Begin ICH Pathway  Admit to stroke unit (if available) or ICU  Monitor BP and treat (if indicated)  Monitor neurologic status (emergent CT if deterioration)  Monitor blood glucose & treat (if needed)  Supportive therapy  Treat comorbidities

23. ICH Critical Pathway Sample Checklist EMSED (60 min)ICU/NCCUSurgical Intervention Medical history (risk factors, similar recent events) Determine any medications currently taken Cincinnati Prehospital Stroke Scale Los Angeles Prehospital Stroke Screen ABCs Time of onset Medic Alert tag ABCs Vital signs Medical history Time of onset Blood pressure Neurologic status (GCSS) Blood glucose ABCs Vital signs Blood pressure Intracranial pressure Neurologic status Blood glucose Body temperature Routine evacuation of supratentorial ICH with standard craniotomy within 96 hours not recommended Surgical candidates (cerebellar hemorrhage >3 cm with neurologic deterioration; consider with lobar clots <1 cm from surface) Vital signs Support ABCs (oxygen if needed) Transport (consider triage to stroke center) Vital signs Obtain IV access & blood samples Support ABCs Intubation(?) Supportive therapy Treat comorbidities Vital signs Support ABCs Intubation(?) Supportive therapy Treat comorbidities Fluid management (euvolemia) Positional factors (head at midline, raise head of bed 30º) Blood glucose (if possible) 12-lead ECG (if possible) CT/MRI Neurologic examination (NIH Stroke Scale, Canadian Neurologic Scale) Blood pressure Electrolytes Blood glucose 12-lead ECG on admission CBC, PT, aPTT, INR, electrolytes Toxicology Platelet function CXR Blood pressure – MAP, SAP, CPP ICP (ventriculostomy, fiberoptic ICP monitor, etc) Blood glucose 12-lead ECG CT/MRI Assessment Nursing Testing ICH Critical Pathway Sample Checklist

24. ICH Critical Pathway Sample Checklist (cont.) EMSED (60 min)ICU/NCCUSurgical Intervention OxygenOxygen (if hypoxemic) Treat blood glucose abnormalities Blood pressure (labetalol, esmolol, nitroprusside, hydralazine, enalapril) Blood pressure (labetalol, esmolol, hydralazine, enalapril, nicardipine) ICP (head elevation, osmotic diuretics, CSF drainage; neuromuscular blockade, hyperventilation) Seizures (lorazepam, diazepam, phenytoin, fos- phenytoin) Warfarin coagulopathy (PCC, FFP, Vitamin K, Factor VIIa) Treat blood glucose abnormalities Alert hospitalActivate stroke team Consult neurologist or neurosurgeon Consider transfer to stroke center Consult neurologist or neurosurgeon Begin stroke pathway Admit to stroke unit (if available) or ICU Follow stroke pathway Adapted from AHA Adult Stroke Guidelines. Circulation. 2005;112(suppl 24):IV-111-IV-120; Broderick JP, et al. Stroke. 1999;30:905-915; Broderick J, et al. Stroke. 2007;38:2001-2023; Marik PE, et al. Chest. 2002;122:699-711; Passero S, et al. Epilepsia. 2002;43:1175-1180; Qureshi AI, et al. Stroke. 2001;33:1916-1919. ABCs = airway-breathing-circulation aPTT = activated partial thromboplastin time CBC = complete blood count CPP = cerebral perfusion pressure CXR = chest x-ray ED = emergency department FFP = fresh frozen plasma GCSS = Glascow Coma Scale score ICP = intracranial pressure INR = international normalized ratio MAP = mean arterial pressure NCCU = neuro-critical care unit PCC = prothrombin complex concentrate PT = prothrombin time SAP = systolic arterial pressure Medications Consults Pathways ICH Critical Pathway Sample Checklist (cont.)

25. Next Steps UCLA Stroke Center

26. Time is Brain for Hemorrhagic Stroke UCLA Stroke Center --Arima et al, Stroke 2012;43:2236-8

27. Dynamics of Hyperacute Hematoma Growth 0-120 Minutes: Not Well Delineated --Kazui et al, Stroke 1996;27:1783-1787

28. Intracerebral Hemorrhage and the Golden Hour Narrow therapeutic time window Early intervention critical Prehospital personnel » 35-70% of stroke patients arrive by ambulance » Unique position: first medical professional to come in contact with stroke patient UCLA Stroke Center

29. Time in minutes from onset of symptoms Volume of Hematoma in mL Rupture of blood vessel Onset of Symptoms Activation of EMS EMS Arrival EMS Transport EMS Arrival in ED Initial ED Evaluation CT scan obtained CT scan evaluated Hospital Treatment initiated Final Hematoma Volume Established Sanossian, FAST-BP Trial

30. Time in minutes from onset of symptoms Volume of Hematoma in mL Rupture of blood vessel Onset of Symptoms Activation of EMS EMS Arrival EMS Transport EMS Arrival in ED Initial ED Evaluation CT scan obtained CT scan evaluated Hospital Treatment initiated Final Hematoma Volume Established Field Treatment Initiated Goal: Control Hematoma expansion Earlier in Course Sanossian, FAST-BP Trial

31. Time in minutes from onset of symptoms Volume of Hematoma in mL Rupture of blood vessel Onset of Symptoms Activation of EMS EMS Arrival EMS Transport EMS Arrival in ED Initial ED Evaluation CT scan obtained CT scan evaluated Hospital Treatment initiated Final Hematoma Volume Established Field Treatment Initiated Goal: Control Hematoma expansion Earlier in Course Sanossian, FAST-BP Trial

32. Onset to Treatment Times in Recent Trials Enrolling ICH Patients TrialSettingInterventionOnset to Treatment INTERACT 1HospitalTarget SBP ≤ 1404h 00m ATACH 1HospitalNicardipine4h 17m INTERACT 2HospitalTarget SBP ≤ 1404h 00m RIGHTPrehospitalGlyceryl trinitrate 55m PIL-FASTPrehospitalLisinopril1h 17m FAST-MAGPrehospitalMagnesium 47m UCLA Stroke Center

33. Preserve / Treat / Cure ConditionEMSEDOR/Cath Lab Acute ischemic stroke NeuroprotectionTPAEndovascular recanalization Acute intracerebral hemorrhage BP loweringHemostatic agentMinimally invasive hem evacuation UCLA Stroke Center

34. Preserve / Treat / Cure ConditionEMSEDOR/Cath Lab Acute ischemic stroke NeuroprotectionTPAEndovascular recanalization Acute intracerebral hemorrhage BP loweringHemostatic agentMinimally invasive hem evacuation UCLA Stroke Center