Division of Cerebrovascular Diseases, Department … P. Adams Jr, M.D. Division of Cerebrovascular...

Harold P. Adams Jr, M.D. Division of Cerebrovascular Diseases, Department of Neurology Carver College of Medicine UIHC Stroke Center University of Iowa

o  I adjudicate events in clinical trials sponsored by Merck and I serve on the DSMB for a clinical study funded by Medtronic. I am a consultant to Pierre Fabre (France)

o  I receive grant support from NINDS and St Jude Medical

o  I will discuss therapies for treatment of stroke that are not approved by the FDA

o  A leading cause of death and disability among Americans o  Approximately 800,000 new strokes annually o  Affects men, women, and children of all ages o  More common in Blacks, Hispanics

o  A leading cause of long-term disability o  The most common acute neurological illness

o  Leading neurological reason for hospitalization o  The frequency of stroke is increasing

o  Aging of the American population o  Survival of high-risk patients with heart disease

Iowa  Stroke  Registry  Design  Project   4  

o  4th most common cause of death – 1,627 deaths o  5 Iowans die from stroke every day o  3rd most common cause of death among women o  14% of the men dying of stroke are < 65 o  The mortality rate from stroke has been declining

o  In 2009, 8140 admissions for stroke in Iowa hospitals

o  In 2008, average inpatient costs for stroke were $9282

o  Total inpatient hospital costs are $78.2 million

¡  Number  of  patients  =14,483  

¡  Source  of  data    §  IHA  Discharge  Data  

SAH,  176,  1%   ICH,  546,  

4%  Other  ICH,  314,  2%  

Occlusion  Precerebral,  4281,  30%  

Occlusion  Cerebral,  2871,  20%  

TIA,  1413,  10%  Acute,  21,  

0%  

Other,  1362,  9%  

Late,  3499,  24%  

o  Important  issue  in  Iowa    o  Approximately  25%  of  Americans  

o  Rural  areas  or  small  communities  o  Risk  of  stroke  is  1.34  greater  than  urban  areas  

o  Elderly,  poor,  minorities  o  Outcomes  among  rural  patients  

o  Relative  increase  in  mortality  –  18%  o  Many  problems  not  unique  to  rural  America  

o  Suburban  and  non-­‐academic  hospitals  o  Non-­‐availability  of  technology/expertise  

o  Large distances to hospitals o  Hospitals – limited resources

o  Critical access hospitals o  Limited experience with stroke

o  Non-availability of stroke specialists o  Neurology o  Interventional

o  Interventions used in this setting o  Time in transfer to medical center

o  Current  approach  to  early  treatment  of  ischemic  stroke  o  Change  attitude  of  the  public  and  health  care  system  o  Increase  the  number  of  persons  treated    o  Core  message  

o  Stroke  is  a  life-­‐threatening  or  life-­‐changing  disease  o  Stroke  is  an  emergency  o  Stroke  may  be  successfully  treated  and  outcomes  

improved  o  Time  is  brain    

o  Public  education  to  recognize  stroke  and  best  responses  

o  Organize  medical  resources  to  treat  stroke  

o  Public  recognition  of  symptoms  o  Sudden  onset  of  neurological  symptoms  o  May  not  be  recognized  by  patient,  observers  are  key  o  Family,  friends,  neighbors,  co-­‐workers  

o  Response  –  immediately  seek  medical  attention  o  Do  not  wait  for  symptoms  to  resolve  o  Call  911  or  brought  to  the  hospital  o  Arriving  by  EMS  expedites  early  hospital  care    o  If  not  stroke,  many  be  another  serious  neurological  

disease    

o  Treatment  of  stroke  modeled  on  treatment  of  MI  o  Vascular  events  secondary  to  arterial  occlusion  o  Need  rapid  treatment  to  limit  organ  injury  o  Treatment  centers  on  reperfusion  o  Best  managed  in  specialized  centers  o  Most  important  early  treatment  occurs  in  the  community  

o  Emergency  cardiac  care  system  is  well-­‐developed  o  Need  to  think  of  stroke  in  the  same  way  and  add  

stroke  care  to  the  emergency  cardiac  care  system  

o  Most patients are not treated with reperfusion therapy

o  Most patients arrive too late for treatment or their strokes are considered to be mild

o  Overall impact of intravenous thrombolysis is limited

o  Impact of intra-arterial interventions is very small

o  4750  hospitals  with  495,000  patients  with  ischemic  stroke  o  64%  of  hospitals  had  not  treated  a  single  patient  o  0.9%  of  hospitals  had  treated  10  or  more  patients  

o  Low  utilization  of  rtPA  o  Smaller  (<  95  beds)  hospitals  o  Less  densely  populated  areas  in  South  and  Midwest  o  Areas  that  involve  40%  of  the  American  population  

   Kleindorfer  et  al,  Stroke,  2009;  40:  3580    

o  Ischemic stroke is a common and serious disease o  Potential for death or severe incapacity o  Affects patient and family

o  An approved therapy of proven value is available o  Intravenous thrombolysis is approved by the FDA

o  Success is linked to early treatment o  Guidelines provide recommendations for care

o  Improve safety and efficacy of treatment o  Failure to follow guidelines associated with poorer

outcomes

o  Not treating a patient may violate the rule of “doing no harm”

o  The primary legal issue is not prescribing rtPA o  Need a well-documented reason for not treating o  Clearly state reasons in the medical record

o  Medication may be prescribed by any physician o  Neurological consultation helps comfort levels of primary

care or emergency medicine physician o  Plans for consultation should have these plans in place

o  The size of the hospital is not a defense o  Expected to have a plan for emergency treatment of

stroke

o  Organize emergency medical services o  Certification of stroke centers

o  Primary stroke centers o  Comprehensive stroke centers

o  Time goals for emergency treatment o  Development of regional stroke programs

o  Hub-and-spoke system o  Drip-and-ship strategy o  Use of technologies to increase availability of

neurological expertise o  Get With The Guidelines

o  First step in stroke management o  The time the stroke is most “acute” o  Meets the need of early intervention o  Matches the approach for MI

o  More than just assessment – start treatment o  Guidelines proved recommendations

o  General emergency care o  Hemorrhage or infarction

o  100% use of validated pre-hospital screening tools o  Compare to final diagnoses o  Use to improve first responder and EMS training o  Complete minimum of 2 hours of training/year o  Use stroke history checklists

o  Assure that response time is < 9 minutes o  Dispatch time < 1 minute, travel time same as

for MI o  Assure pre-arrival notification of hospitals o  Protocols for transfer of patients from non-

stroke hospitals to stroke centers Jauch et al, Stroke 2013

o  Assess and manage ABCs o  Do not treat hypertension unless directed by physician

o  Initiate cardiac monitoring o  Provide O2 to maintain O2 saturation > 94% o  Establish IV access with saline

o  Do not give excess volume of fluid o  Do not administer glucose-containing fluids unless patient has

hypoglycemia o  Check blood glucose and treat accordingly o  Determine time of onset of stroke o  Obtain family information, preferably a cell phone

Jauch et al, Stroke, 2013

o  Diversion of patients to hospitals that can treat stroke o  Emergency medical services o  Hospitals that are not ready to treat stroke are bypassed

o  Regulations that route patients with acute stroke to primary stroke centers or stroke-ready hospitals o  Initiated in 2000 in Alabama and Texas o  End of 2010: 16 states and regional areas in 3 additional states

o  Covered population o  2000 4,471,933 1.5% o  2010 164,705,389 53%

o  Efforts continue to expand this system Song & Saver, Stroke, 2012; 43: 1975

o  Recognize the wide range of EMS programs in the state of Iowa o  Full-time paramedics o  Part-time, unpaid volunteers

o  Levels of expertise and experience vary o  Reflect numbers of patients with stroke seen

o  Develop programs that will provide core information to EMS directors and personnel

o  Key features o  Recognition of stroke manifestations o  Early stabilization and obtain key history o  Prompt notification and transport to stroke-ready hospital

o  Recognize the common neurological findings o  FAST – face, arm, speech

o  Obtain key historical information o  FAST – time of onset of symptoms (last normal) o  Medications or other recent illness o  Cell phone # of next-of-kin or family member

o  Stabilization o  As with other critically ill people

o  Emergency transport o  Bypass a hospital that cannot treat patient

o  Notification of stroke ready hospital – Code Stroke Jauch et al, Stroke, 2013

o  Hospitals that have the capability to give emergency stroke care o  Focus on care in emergency department o  Communication closely linked to EMS o  Rapid evaluation and treatment of stroke o  Administration of intravenous thrombolysis o  Communities across the United States

o  Protocols in place o  Certified by Joint Commission or states o  Another group of hospitals – stroke capable

o  Integrated between smaller and larger hospitals o  Hub-and-spoke system

o  Increase availability of neurological expertise o  In person, telephone consultation, telemedicine

o  Develop protocols that can be used in community hospitals o  Emergency evaluation o  General emergency treatment o  Administration of intravenous rtPA o  Drip and ship (emergency transfer to larger hospital)

o  Increase the number of patients treated with rtPA

o  Develop stroke care protocols for the network o  Used at both the hub and spokes o  Emergency diagnostic studies and therapies o  Indications for evacuation to the hub o  Returning the patients back to the community

o  Professional educational programs o  Physicians and hospital personnel o  Emergency medical services personnel

o  Public educational programs o  Coordinate research

o  Emergency Medical Services o  Treat stroke as a level 1 emergency o  Dispatchers and rescue services o  Emergency assessment, transportation and notification

o  Primary Stroke Centers or Stroke-Ready Hospitals o  Protocols for emergency management of stroke o  Potential collaboration with comprehensive center o  Community outreach programs o  Public education, health screening and stroke prevention o  Maintaining continuity of care

o  Limited neurological coverage in most small to medium sized communities o  Non-availability of a neurologist o  Even less availability of a vascular neurologist

o  Develop close links with a comprehensive stroke center o  Crucial time lost during transfer to center o  Treatment started locally

o  Choices o  Telephone consultation o  Teleradiology o  Telemedicine (telestroke)

o  Nationwide inpatient sample o  22,243 patients treated with IV thrombolysis o  4,474 patients treated using drip-and-ship approach

o  81% referred to teaching hospitals o  7% had subsequent endovascular treatment

o  States using drip-and-ship had higher rates of use of thrombolytic therapy o  5.4% vs. 3.3% (p < 0.001)

o  Outcomes (home and self care) o  Drip-and-ship vs. primary emergency department o  Odds ratio 1.198 (95% CI 1.019-1.409, p = 0.028)

Tekle et al, Stroke, 2012; 43: 1971

o  Hospital plan to respond to a patient with acute stroke o  Coordinate emergency assessment and treatment o  Emergency alerts to the code stroke team o  Emergency department is usual site for treatment

o  Development of a code stroke toolbox o  Initial assessment including orders and laboratory

supplies o  Screening assessment for stroke and rtPA o  General emergency management o  Stroke-specific management and availability of rtPA

o  Based on Brain Attack Recommendations o  Door-to-needle time 60 minutes

o  First contact in the emergency department o  Clinical assessment and diagnosis o  Results of diagnostic studies o  Decisions about treatment o  Starting bolus dose of rtPA

o  Results of diagnostic studies 45 minutes o  Time of arrival to hospital o  CT, laboratory, and ECG

o  Are the neurological symptoms due to stroke?

o  Is the stroke hemorrhagic or ischemic?

o  Are there acute medical or neurological complications that affect early treatment?

o  Is the patient eligible for intravenous thrombolytic treatment?

o  Hemorrhagic stroke o  Seizures with post-ictal signs o  Migraine (may or may not have headache) o  Metabolic disorder

o  Hypoglycemia o  Occult trauma o  Intracranial mass

o  Subdural hematoma o  Tumor

o  Somatization disorder

o  Sudden onset of focal neurological symptoms o  Usually maximal at onset o  May wax and wane or slowly progress

o  Signs should fit within a defined vascular territory o  Cerebral hemisphere – hemiparesis, sensory loss, visual

field defect, aphasia, neglect o  Brainstem/cerebellum – ataxia, cranial nerve palsy,

dysarthria, bilateral motor signs, crossed signs o  Rarely associated with loss of consciousness o  Approximately 20% of patients have headache o  Nausea and vomiting occur with brainstem or

cerebellar infarction

Consciousness 0 - 3 Orientation 0 - 2 Commands 0 - 2 Gaze 0 - 2 Visual fields 0 - 3 Facial paresis 0 - 3 Arm motor (x2) 0 - 4 Leg motor (x2) 0 - 4 Limb ataxia 0 - 2 Sensory 0 - 2 Language 0 - 3 Dysarthria 0 - 2 Inattention 0 - 2

Brott et al, Stroke. 1989; 20: 864-70.

0%10%20%30%40%50%60%70%80%90%

100%

0-3 points n = 170

4-6 points n = 409

7-10 points n = 323

11-15 points n = 205

16-22 points n = 103

23+ points n = 059

excellentgoodpoordead

Adams Jr HP, et al. Neurology. 1999;53:126.

Impact of NIHSS Scores on Outcomes

o  Brain imaging o  May be either CT or MRI o  CT generally more readily available in community

hospitals o  Quick, non-invasive, and relatively inexpensive o  Gives key information for emergency care

o  Electrocardiogram o  Complete blood count and platelet count o  INR and aPTT o  Cardiac enzymes, renal studies, glucose o  Pulse oximetry

o  Similar to other acutely and seriously ill patients o  ABC of life support

o  Airway protection if decreased consciousness or brainstem dysfunction

o  Oxygen supplementation not needed unless hypoxic o  Monitor vital signs and neurological status o  Intravenous access with normal saline o  Treat fever and look for source of fever o  Treat serious cardiac arrhythmias o  Symptomatic treatment – pain, nausea,

agitation

o  Elevations in blood pressure common – underlying risk factor, stress, physiological response for perfusion

o  Management is controversial because of lack of clinical trial evidence

o  Aggressive lowering of blood pressure is not recommended because of risk of worsening of stroke

o  Need to lower blood pressure to treat rtPA o  IV administration of short-acting medications

o  Labetalol, nicardipine, apresoline, sodium nitroprusside

Jauch et al, Stroke, 2013  

o  Approved medical therapy for treatment of carefully selected patients with acute ischemic stroke

o  Engine that is driving acute stroke care o  Improve neurological outcomes o  May “cure” patients o  Efficacy is time-linked o  Cannot be given with impunity – does cause

bleeding o  Effective therapy of limited usefulness because

too few patients are being treated

 Pooled analyses of clinical trials

Time Odds of Favorable Outcomes < 90 minutes 2.55 (1.44 – 4.52) 91 – 180 minutes 1.64 (1.12 – 2.40) 180 – 270 minutes 1.34 (1.06 – 1.68) 270 – 360 minutes 1.22 (0.92 – 1.61) Lees et al, Lancet, 2010; 375: 1695

o  IV administration of rtPA is recommended o  0.9 mg/Kg (maximum dose is 90 mg) o  10% as bolus, remainder infused over 1 hour

o  Carefully selected patients < 3 (4.5) hours o  Can be associated with side effects

o  Overall risk of bleeding is 6%, higher with severe strokes

o  Does not increase mortality o  Uncommon risk of angioedema

o  Success in clinical settings is similar to that achieved in trials

o  Success is linked to compliance with guidelines Jauch et al, Stroke, 2013

o  Goal remains to treat as quickly as possible o  Expansion of time window from 3 to 4.5 hours o  This expansion in time not approved by FDA

o  Require a similar study in the US o  Dosage of rtPA and ancillary care similar o  Some differences in criteria for treatment (3 – 4.5

hours) o  Age less than 81 o  Maximum NIHSS score – 25 o  Diabetes and history of prior stroke o  Warfarin use (regardless of level of INR)

Del Zoppo et al, Stroke, 2009; 40: 2945 & Jauch et al, Stroke, 2013

o  Impact on the numbers treated is relatively small o  Approved by European Regulatory Authorities o  Not approved by FDA

o  Did not find the data compelling o  Requested another study in the US o  Such a study is not likely to be done

o  Marketing of the medication for this indication o  Influence CMS decisions about reimbursement for

treatment in time window o  Guidelines continue to recommend the

administration of rtPA up to 4.5 hours after onset of stroke

Wechsler and Jovin, Stroke, 2012; 43: 2517

o  Did the stroke happen in the last 3 – 4.5 hours? o  Stroke upon awakening or unwitnessed stroke o  Minor symptoms with subsequent worsening o  TIA followed by a second (new) event

o  Remember the difference in criteria for those treated < 3 hours and those treated 3 – 4.5 hours

o  If the stroke is > 3 hours but < 4.5 hours o  Age must be < 81 for treatment in 3 – 4.5 hours o  No age restriction for treatment < 3 hours  

o  Any co-morbid disease or recent illness that could be associated with a high risk of bleeding complications? o  History of prior cerebral hemorrhage o  Recent stroke or myocardial infarction o  Recent major trauma or surgery o  Recent major bleeding

o  Is the patient taking oral anticoagulants? o  If taking warfarin, do not treat in 3 – 4.5 hours o  If taking warfarin, treat in < 3 hours if INR is < 1.8 o  Aspirin, clopidogrel, dipyridamole, ticlopidine o  Safety with use of thrombin or direct Xa inhibitors is

not known. Interim plan: not to treat if drug was given < 48 hours

o  Are baseline coagulation tests normal? o  Primary issue is anticoagulant use or a history of bleeding o  Abnormal coagulation tests preclude treatment o  Tests take time to perform and may treat in some instances if

tests are delayed o  Finger stick test for INR o  Prolonged aPTT as a marker for dabigatran effect

o  Is the patient a diabetic and has a history of a previous stroke? o  May treat < 3 hours but not in 3 – 4.5 hour time period

o  Is the patient taking an ACE-inhibitor? o  Not a contraindication o  May be associated with increased risk of angioedema

o  What is the score on the NIH Stroke Scale? o  No minimum score for treatment o  Mild stroke may worsen subsequently o  Composition of score may influence decision o  A patient may be disabled despite a low score

o  No maximum score for treatment < 3 hours o  Use caution with very severe stroke o  Higher risk of bleeding complications o  No increase risk in mortality

o  Maximum score for treatment in 3 – 4.5 hours o  NIHSS score < 25

o  What are the findings on brain imaging? o  Presence of a hemorrhage – contraindication o  Stroke appears to be older than 3 – 4.5 hours o  Very large ischemic lesion is detected o  Presence of a dense artery sign – usually a severe stroke

o  Are the patient/family aware of risks of treatment? o  Overall risk of symptomatic bleeding is approximately 6% o  Hemorrhagic transformation of infarction or hematoma o  Risk of bleeding greater in patients with severe strokes o  FDA approved therapy and guidelines available

o  A number of variables have identified those patients at the highest risk for bleeding following intravenous thrombolysis o  Elderly, severe strokes, elevated glucose, serious

comorbid diseases, cardioembolism o  None of these variables is an absolute

contraindication to treatment o  Many of these variables also portend a poor

outcome without treatment o  The presence of multiple “risk factors” for a

hemorrhagic complication should lead to a careful discussion with the patient and family about the risks and benefits of treatment

o  Close observation and monitoring during first hours o  Neurological status o  Blood pressure and vital signs

o  Aggressively treat arterial hypertension o  If systolic > 180 mm Hg or diastolic > 110 mm Hg o  Parenterally administered, short-acting medications

o  Delay placement of devices associated with bleeding o  Nasogastric tube o  Bladder catheter o  Central venous line

o  Stroke now is being treated as the emergency it is o  Requires coordination and collaboration

o  Public o  All components of the health care system o  Government and third-party payers

o  Need to address hurdles to early treatment o  Each community or region has its own issues to address o  Overcome these hurdles with careful and proactive

planning

o  Likely will have new interventions for treating stroke

o  Combinations of interventions o  Thrombolysis and neuroprotective agents o  Intravenous and intra-arterial interventions o  Adjunctive use of antithrombotic agents

o  Improved selection of patients for specific therapies o  Treatments that could be started in ambulance or

helicopter o  Regardless of advances, the success of future

stroke treatment will remain time-linked and time-limited