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Emergent Treatment of Acute
Ischemic Stroke, Including the
Intravenous Administration of
Thrombolytic Therapy
ACUTE ISCHEMIC STROKE
• Complex medical illness resulting from
thromboembolism
Parts of the brain irreversibly injured
Other areas dysfunctional (penumbra)
• Penumbra might be salvageable if
interventions started
• Time is an important variable in effective
management
• Time window might differ between
treatments
Yatsu FM, Villar-Cordova C. Atherosclerosis. In: Stroke. Pathophysiology, Diagnosis, and
Management. Barnett HJM et al (eds) Philadelphia. Churchill-Livingstone, 1998
THERAPIES TO TREAT ISCHEMIC STROKE
• Restoring, maintaining, or improving blood
flow
• Neuroprotective agents
Membrane stabilization
Counteract effects of excitatory transmitters
Antagonize free radicals
Halt apoptosis
Slow metabolism
NEUROPROECTIVE AGENTS
• Large number of agents tested in clinical
trials
• No evidence of efficacy in improving
outcomes
• Side effects are common
Disturbances of consciousness or behavior
Seizures
Cardiac arrhythmias or conduction defects
• At present, no neuroprotective agent can be
Neuroprotection in Cerebral Ischemia:
Clinical Trials
Drugs
Mode of action
Result
Nimodipine
Voltage-dependent Ca++ antagonist
no efficacy
Flunarizine
ditto
no efficacy
Isradipine
ditto
trial discontinued, no efficacy
Selfotel
Competitive NMDA antagonists
trial discontinued, adverse effects
Aptiganel
Noncompetitive NMDA antagonist
ditto
Dizolcipine
ditto
ditto
Dextrorfan
ditto
ditto
Racemide
ditto
phase III planned
Magnesium
noncompetitive NMDA
Antagonist, voltage-dependent Ca++
antagonist
pilot study (+), ongoing trial
(IMAGES study)
GV150526
glycine site antagonist
no efficacy
Eliprodil
polyamine site antagonist
no efficacy
Ca++ channel antagonists
NMDA receptor antagonists
Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001;11(Suppl 1):60-70
Presynaptic glutamate
release inhibitors
Lubelozole
Na*channel blockade,
modulates NOS
No efficacy
Fosphenytoin
Modulates Na+ channel
No efficacy
Propentophylline
Inhibits adenosine
transport
Adverse effects
Clomethiazole
GABA agonist,
modulates Cl channel
No overall clinical
efficacy, improvement in
TACl, ongoing trial
NBQX
AMPA receptor
antagonist
Trial discontinued,
adverse effects
Bay x 3702
5-HT agonist
Phase III trial
GM-1
Non-NMDA antagonist
No clinical efficacy
Nalmefene
K-selective opiate
antagonist
No clinical efficacy
BMS-204352
K channel agonist
Phase III clinical trial
Blood substitute
Phase II trial, adverse
effects
Other ionic channel
inhibitors
Hemodilution
DCLHb
Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001;11(Suppl 1):60-70
Antioxidants inhibiting
free radicals
Tirilizad
Inhibits lipid
peroxidation
No efficacy
Ebselen
Gluthatione peroxidaselike action
No efficacy
Enlimomab
Antiadhesion antibodies
Trial completed, no
clinical efficacy, adverse
effects
Hu23F2G
Antiadhesion antibodies
No efficacy
Piracetam
Membrane modulator
No clinical efficacy,
possible efficacy<7h,
new PASS II trial
Citiocline
Antioxidant,
phosphatidylcholine
synthesis
Possible benefit in
medium-sized infarets
(2,000 mg/day)
bFCF
Neurotropic factor
Trial discontinued,
adverse effects
Drugs acting against late
damage
Martinez-Vila & Irimia Sieira. Cerebrovasc Dis 2001;11(Suppl 1):60-70
MEASURES TO IMPROVE OR
RESTORE BLOOD FLOW TO THE BRAIN
• Carotid
endarterectomy
• Endovascular
treatment
• Induced
hypertension
• Antiplatelet agents
•
•
•
•
Other operations
Hemodilution
Anticoagulants
Thrombolytic
agents
SURGICAL AND ENDOVASCULAR
PROCEDURES
• Anecdotal evidence supports the use of
surgical procedures
Limited evidence means that no
recommendation
• Endovascular treatment shows great
promise
Angioplasty, stenting or mechanical
thrombolysis
Combined with intra-arterial thrombolysis
• Urgent endovascular therapy is a
consideration if available
HEMODILUTION AND INDUCED HYPERTENSION
• Altering blood flow by altering viscosity or
increasing perfusion pressure
Used successfully to treat vasospasm after
SAH
Can be complicated by myocardial ischemia,
heart failure, or pulmonary edema
LMW dextran complicated by allergic reactions
• Trials of hemodilution for treatment ischemic
stroke not successful
• At present, not recommended for treatment
of acute ischemic stroke
ANTICOAGULANTS
• Rationale for urgent administration of
heparin
Halt propagation of thrombus
Prevent early recurrent embolization
Maintain collateral flow
• Adjunct to mechanical or pharmacological
thrombolysis
• Until recently, limited evidence for safety
and efficacy
• Several recent trials provide strong
evidence
TRIALS OF ANTICOAGULATION
• Tested unfractionated heparin, LMW
heparin, danaparoid
• Most trials tested subcutaneous therapy –
only 1 trial of intravenous, adjusted dose
therapy
• Most trials have not used a weight-based
regimen
• Most trials have involved late entry (up to
48 hours)
• One large trial was unblinded and did not
require CT prior to treatment
HEMORRHAGIC COMPLICATIONS
EMERGENT ANTICOAGULATION
Placebo/control
Anticoagulant
1%
0
IST - heparin
0.3%
0.7% – 1.8%
TOAST - danaparoid
0.9%
2.9%
FISS-bis - nadroparin
2.8%
3.7% – 6.1%
HAEST - dalteparin
1.8%
2.8%
TAIST - tinzaparin
0.2%
0.6% – 1.4%
FISS - nadroparin
PREVENTION OF EARLY
RECURRENT STROKE
EMERGENT ANTICOAGULATION
Placebo/control
Anticoagulant
FISS - nadroparin
4.7%
1% - 1.9%
IST - heparin
2.2%
1.6% - 1.8%
TOAST - danaparoid
1.1%
1.1%
HAEST - dalteparin
7.5%
8.5%
TAIST - tinzaparin
3.1%
3.3% - 4.7%
FAVORABLE (best) OUTCOMES
EMERGENT ANTICOAGULATION
Placebo/control
Anticoagulant
FISS - nadroparin
35.2%
47.5% - 55.8%
IST - heparin
17.0%
17.1% - 17.3%
TOAST - danaparoid
47.0%
49.4%
FISS-bis - nadroparin
56.8%
57.2% - 59.2%
HAEST - dalteparin
21.3%
22.8%
TAIST - tinzaparin
42.5%
38.3% - 38.4%
CONCLUSIONS AND RECOMMENDATIONS
EMERGENT ANTICOAGULATION
• Emergent anticoagulant therapy causes a
modest increase of symptomatic intracranial or
systemic bleeding
• No evidence in lowering the risk of early
recurrent stroke
Including among patients with cardioembolism
• No evidence in halting neurological worsening
• No evidence in improving neurological
outcomes
• No data to recommend emergent
EFFECTS OF ASPIRIN
ON OUTCOMES AFTER STROKE
Lancet 1997 349:1641-49
CURE
• Randomized trial patient with unstable angina
pectoris or non-ST segment myocardial
infarction
• Enrolled within approximately 14 hours or
onset of symptoms
• All patients received aspirin 75 - 325 mg/day
• 1/2 - Clopidogrel 300 mg initial dose followed
by 75 mg/day
• Followed for approximately
9 months
N Engl J Med, 2001;345:494-502
OUTCOMES
Aspirin
and placebo
clopidogrel
n = 6259
%
Death, MI, or stroke
11.5
Vascular death
5.5
Myocardial infarct
6.7
Stroke
1.4
Major hemorrhage
2.7
Life threatening
1.8
Aspirin
and
n = 6303
%
9.3
5.1
5.2
1.2
3.6
2.1
ABCIXIMAB IN ACUTE STROKE STUDY
• Randomized, double-blind, dose-escalation study
that enrolled 74 patients
• Four dose tiers (abciximab bolus or bolus
followed by infusion)
• 54 patients assigned abciximab and 20 patients
assigned placebo
• Treated within 24 hours of onset of stroke - 38
sites
• One-half treated with 12 hours and others 12 - 24
hours
• Stratified enrollment baseline NIHSS score: 4 14, 15 and above
Stroke, 2000;31:601-609
• No cases of symptomatic intracranial
hemorrhage
• Asymptomatic hemorrhagic changes on CT abciximab: 10, placebo: 1
• Minor non-neurological bleeding –
abciximab: 10, placebo: 4
• Thrombocytopenia (non-serious) –
abciximab: 4
• Rankin score < 1 at 3 months –
abciximab: 19, placebo: 4
• Barthel index > 95 at 3 months –
CONCLUSIONS AND
RECOMMENDATIONS
ANTIPLATELET AGENTS
• Aspirin can be started within hours of stroke –
modest benefit
• Aspirin should not be considered as an
alternative to other interventions – such as rtPA
• The combination of aspirin and clopidogrel
holds promise but safety and efficacy in
stroke is not known
• The GP IIb/IIIa agents are being tested –
RATIONALE FOR
PHARMACOLOGICAL THROMBOLYSIS
• Ischemic stroke is usually due to
thromboembolic occlusion
• Natural clot lysins promote
recanalization – but effect delayed
• Thrombolytic agents
Speed clot lysis
Restore perfusion to the brain
Permit delivery of other medication
INTRA-ARTERIAL ADMINISTRATION
OF THROMBOLYTIC AGENTS
• Potential advantages
Higher concentration of medication at site
Lower systemic doses might improve safety
• Potential disadvantages
Facilities not widely available
Time required to mobilize resources
• No head-to-head comparisons with IV
therapy
INTRA-ARTERIAL PROUROKINASE
PROACT - II STUDY
Randomized, clinical trial - 54
centers
121 Patients - proUK and heparin
59 Patients - heparin
Outcomes measured at 90 days
Blinded to treatment allocation
Slight or no disability
Furlan et al, JAMA
1999; 282:2003-2011
OUTCOMES AT 90 DAYS
PROACT - II STUDY
Modified Rankin Scale 0 - 2
Baseline
NIHSS Score
ProUK
Heparin
%
Odds
n
%
n
%
Diff
Ratio
4-10 points
10/16
63
5/8
63
0
1.00
11-20 points
34/75
45
9/37
24
21
2.58
21-30 points
4/30
13
1/14
7
6
2.00
Furlan et al, JAMA
1999; 282:2003-2011
RECANALIZATION AND
INTRACRANIAL BLEEDING PROACT-II STUDY
Recanalization
ProUK (%) Heparin (%)
1 Hour
4%
--
2 Hours
19%
2%
Symptomatic hemorrhage
10%
2%
CT hemorrhage - 1 day
35%
13%
Furlan et al, JAMA
1999; 282:2003-2011
TRIALS OF STREPTOKINASE
Trial
MAST - E
Dead/disabled
Symptomatic hemorrhage
MAST - I
Dead/disabled
(with aspirin)
Symptomatic hemorrhage
(with aspirin)
ASK
Dead/disabled
Symptomatic hemorrhage
Placebo/control Streptokinase
81.8%
2.6%
79.5%
21.2%
68.0%
59.0%
64.0%
6.0%
10.0%
0.6%
43%
3%
48%
13%
NINDS PART 1
NINDS PART 2
Favorable Outcomes at Three Months
Persons Treated Within Ninety Minutes
rt-PA
n=157
Placebo
n=145
Odds
Ration
Relative
Risk
P-value
Barthel
53%
38%
1.8(1.2-2.9) 1.4(1.1-1.8)
0.010
Rankin
40%
28%
1.7(1.0-2.6) 1.4(1.0-1.9)
0.035
Glasgow
43%
32%
1.6(1.0-2.5) 1.3(1.0-1.8)
0.057
NIHSS
34%
20%
2.0(1.2-3.4) 1.7(1.1-2.5)
0.008
New England Journal of Medicine, 1995;333:1581-1587.
Favorable Outcomes at Three Months
Persons Treated Within 91-180 Minutes
rt-PA
n=157
Placebo
n=145
Odds
Ration
Relative
Risk
p-value
Barthel
51%
38%
1.6(1.1-2.5) 1.3(1.0-1.7)
0.026
Rankin
45%
25%
2.4(1.5-3.7) 1.8(1.3-2.4)
<0.001
Glasgow
47%
30%
2.0(1.3-3.2) 1.6(1.2-2.1)
0.002
NIHSS
34%
21%
2.0(1.2-3.2) 1.6(1.1-2.3)
0.008
New England Journal of Medicine, 1995;333:1581-1587.
TRIAL OF ALTEPLASE
GIVEN 3 - 5 HOURS AFTER ONSET OF
STROKE
Randomized, double-blind clinical trial at
140 centers in North America.
613 patients enrolled, 39 < 3 hours, 547 3-5
hours, 24 > 5 hours, 3 no Rx.
Received dose of alteplase used in NINDS
trials
Comparison of 272 patients - alteplase, 275
patients - placebo
Mean NIHSS score was 11 Clark et al, JAMA
1999; 282:2019-2026
OUTCOMES - ATLANTIS
Alteplase
Placebo
Excellent recovery - 90 days
34.0%
32.0%
Symptomatic ICH - 10 days
7.0%
1.1%
Asymptomatic ICH - 10 days
11.4%
4.7%
Mortality - 90 days
7.0%
4.4%
Clark et al, JAMA
1999; 282:2019-2026
CLEVELAND EXPERIENCE WITH
rt-PA
JULY 1997 - JUNE 1998
3,948 Patients seen at 29 hospital in
area
70 Patients (1.8%) received rt-PA
Treated only 10.4% of patients seen < 3
hours
Approximately one-half of hospital
Katzan et al, JAMA
2000; 283: 1151-1158
treated 0
OUTCOMES AND
EXPERIENCE
CLEVELAND, OHIO
Symptomatic hemorrhage in 11 of 70 cases
(15.7%)
In-hospital mortality among 70 cases - 15.7%
In-hospital mortality among non-treated cases 5.1%
Deviation in protocol in 50% of cases
Treated outside time - 12.9%
Katzan
et al, JAMA
Received anticoagulants or platelet
agents
2000; 283: 1151-1158
37.1%
TRIAL OF ALTEPLASE
ACUTE ISCHEMIC STROKE
0.9 mg/kg IV - 0 - 6 hours of onset
Placebo-controlled, 1-1 randomization
142 patients at 42 sites in North America
71 - alteplase, 71 - placebo
Mean NIHSS score of 13
Clark et al
Stroke, 2000
31:811-816
• To date, no head-to-head comparisons
of intravenous versus intra-arterial
therapy
Intravenous (rt-PA) < 3 hours
Intra-arterial (Pro UK) < 6 hours
• No evidence that intra-arterial therapy is
either more effective or safer
PHYSICIAN EXPERTISE
• Because time is critical, many patients will
need to be treated in a community setting
• Strategy of early treatment locally and transfer
to a major medical center
• Need to bring expertise to hospital
Telephone consultations
Teleradiology
Telemedicine
ALGORITHM FOR DECISIONS
ABOUT USE OF rt-PA TO TREAT ISCHEMIC
STROKE
QUESTION # 1 WHEN DID THE STROKE OCCUR?
 Ascertain
time of onset of stroke – must be < 3
hours
 Ask patient and observers – most conservative



time
Not time of last neurological worsening
If a prior TIA with resolution, time starts with new
event
Most patients with stroke during sleep are
excluded
QUESTION # 2 ANY RECENT MEDICAL
ILLNESSES THAT WOULD MAKE THE
ADMINSTRATION OF rt-PA PARTICULARLY
DANGEROUS?




Recent ischemic stroke – generally < 4 weeks
Recent trauma – including falls with the stroke
Recent myocardial infarction – generally < 4 weeks
Recent surgery – generally < 2 weeks
Severity of surgery
Consultation with surgeon
 Recent serious bleeding – generally < 4 weeks
QUESTION # 3 ANY MEDICATIONS THAT MIGHT
MAKE THE ADMINISTRATION OF rt-PA
PARTICULARLY DANGEROUS?
 Issues related primarily to the use of
anticoagulants
Warfarin – patients with atrial fibrillation
Level of anticoagulation
Heparin – administration for treatment of stroke
Heparin – administration to maintain IV line
 Will be influenced by baseline coagulation tests
 Antiplatelet aggregating agents are OK
QUESTION # 4 ANY ABNORMALITIES ON
BASELINE COAGULATION TESTS?
 Prothrombin time/ INR < 1.7, prefer < 1.4
 APTT < few seconds upper limits of normal
 Platelet count – normal
 Should not try to reverse anticoagulants
QUESTION # 5 ANY EVIDENCE OF ACTIVE
BLEEDING?
 Overt signs of bleeding are critical
 Do not screen urine or stool for occult bleeding
QUESTION # 6 ANY FINDING ON MEDICAL
EXAMINATION THAT WOULD MAKE
ADMINISTRATION OF rt-PA PARTICULAR
DANGEROUS?
 Arterial blood pressure is most critical
Systolic blood pressure < 185 mm Hg
and
Diastolic blood pressure < 110 mm Hg
 Monitor blood pressure repeatedly
 Can lower blood pressure if sufficient time
QUESTION # 7 WHAT IS THE PATIENT’S
NEUROLOGICAL STATUS?
 Decisions influenced by the NIHSS score.
 Would not treat a patient with mild neurological


deficit
Would not treat who has dramatic improvement
Complex issue of treating a patient with severe
deficit
Poor prognosis without treatment
Likely will not respond to treatment
Higher risk of hemorrhage
NIH STROKE SCALE
• Consciousness 0 - 3
Commands
Orientation
•
•
•
•
Language
Articulation
Neglect
Eye Movement
0-2
0-2
0-3
0-2
0-2
0-2
• Motor
Upper (R/L)
Lower (R/L)
Face
• Sensory
• Coordination
• Visual Fields
0-4
0-4
0-3
0-2
0-2
0-3
QUESTION # 8 WHAT ARE THE RESULTS OF
THE CT STUDY?
 Any evidence of intracranial hemorrhage

precludes treatment
Evidence of major infarction on CT – patients
with severe stroke





Dense artery sign
Obliteration of insular cortex
Hypodensity of the lenticular nuclei
Obliteration of hemispheric sulci
Loss of gray-white matter junction hemisphere
QUESTION # 9 DO THE PATIENT AND FAMILY
UNDERSTAND THE POTENTIAL BENEFITS
AND RISKS OF TREATMENT?
 At present, only effective therapy
 Therapy can not be given with impunity
Risk of hemorrhagic transformation
Seriously ill patients and elderly
 Alternative therapies not available
 Prognosis of patient without treatment
MANAGEMENT AFTER
ADMINISTRATION OF rt-PA
• Avoid central venous/arterial
punctures
• Avoid placing nasogastric tube
• Avoid placing indwelling bladder
catheter
• Monitor blood pressure carefully
• Admit to a skilled nursing facility
REGIMEN TO CONTROL HYPERTENSION
AFTER TREATMENT WITH rt-PA
BLOOD PRESSURE
DIASTOLIC
SYSTOLIC
RESPONSE
105 - 120 mm Hg or 180 - 230 mm Hg
IV labetalol - 10 mg
Repeat as needed
121 - 140 mm Hg or > 231 mm Hg
IV labetalol - 20 mg
Repeat as needed
IV sodium
nitroprusside
>140 mm Hg
nitroprusside
IV sodium
0.5 - 10 mg/kg/min
Thrombolytic therapy currently is the best
treatment for patients with acute stroke
There is considerable room for
improvement
Likely to have new therapies
Improving blood flow
Neuroprotective medications
Likely to have combinations of therapies
May select therapies on a case-by-case
basis
POTENTIAL STRATEGIES FOR
TREATMENT
OF PATIENTS WITH ACUTE
ISCHEMIC STROKE
• Combination of intravenous and intra-arterial
thrombolysis
• Combination of pharmacological and mechanical
thrombolysis
• Combination of thrombolysis and neuroprotective
agents
• Combination of thrombolysis and new antithrombotic
agents
• In the field administration of neuroprotective agents
NEW THERAPIES BEING TESTED
• New thrombolytic agents – plasminogen
activators
• New antithrombotic agents:
– Thrombin inhibitors
– Antiplatelet agents
• Volume expansion and hemodilution:
– Albumin
• Neuroprotective agents:
– Magnesium
STATEMENT ON THROMBOLYSIS
TREATMENT OF ACUTE STROKE
• Emergency Departments should work with
EMS and community so that all parties know
what the hospital’s capabilities are regarding
acute stroke care.
• Further studies are needed to define more
clearly those patients most likely to benefit
from fibrinolytic therapy in acute ischemic
stroke.
• Intravenous tPA may be an efficacious
therapy for the management of acute
ischemic stroke if properly use incorporating
the guidelines of NINDS.
American College of Emergency Physicians
26 March 2002
•There is insufficient evidence at this time to endorse the use of
intravenous tPA in clinical practice when systems are not in place to
ensure that the inclusion/exclusion criteria established b the NINDS
guidelines for tPA use in acute stroke are followed.
•The decision for an emergency department to use intravenous tPA
for acute stroke should begin at the institutional level with
commitments from hospital administration, the emergency
department, neurology, neurosurgery, radiology and laboratory
services to ensure that the systems for the safe use of fibrinolytic
agents are in place.
American College of Emergency Physicians
26 March 2002
Thrombolytic therapy is mandating
changes in treatment of stroke
Engine that is driving stroke care
Treating stroke like a life-threatening
disease
Time is brain