South Yorkshire thrombolysis training day

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South Yorkshire thrombolysis training day

• Thrombolytic therapy

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Outline

• Context
• Evidence
• Implementation
• Delivery

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of Sites with Acute Stroke Units With 5-6 key
features
RCP Stroke Audit 2006
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of Sites with CT waits of lt24 hours - weekdays
RCP Stroke Audit 2006
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Output from the ASSET Toolkit at National Level
by new Health Authority Potential improved
outcome from four key stroke interventions
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Outline

• Context
• Evidence
• Implementation
• Delivery

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British Medical Bulletin 1964

• The reader of these papers will be left in no
  doubt that fibrinolysis is a manifestation of an
  enzyme system of great potential power, normally
  kept in check but ready to be unleashed by stress
  or injury.
• He will appreciate that this system can be
  stimulated or inhibited artificially and that
  clinical advantage can be taken of this
  situation. But if he also wonders about the
  function of the mechanism in the normal body, he
  will still be left in doubt.
• The evidence that fibrin formation and
  destruction proceed simultaneously in the normal
  circulation is persuasive but not conclusive.
• If it is proved to be the case, then it may well
  be that imbalance in one direction or the other
  does potentiate haemorrhage or thrombosis, and
  the lytic mechanism will take its place as the
  natural counterpart of coagulation in our picture
  of homeostatic equilibria.
• R G MacFarlane

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Thrombolysis before imaging

• Meyer JS, Gilroy J, Barnhart MI, Johnson JF.
  Therapeutic thrombolysis in cerebral
  thromboembolism. Double-blind evaluation of
  intravenous plasmin therapy in carotid and middle
  cerebral artery occlusion. Neurol
  196313927-937.
• Meyer JS, Gilroy J, Barnhart MI, Johnson JF.
  Anticoagulants plus streptokinase therapy in
  progressive stroke. J Amer Med Assn 1964
  189373.
• Not mentioned in the British Medical Bulletin
  1964.

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CTA and CTP before
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CTA and CTP 24 hrs later
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DWI-MRI 1 week later
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Thrombolysis

• Where is the evidence
• Urokinase
• Streptokinase
• Stroptokinase and aspirin
• Recombinant tissue plasminogen activator
• Mechanical clot disruption

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UROKINASE
Death from all causes
Fatal intracranial haemorrhage
Death or dependency at end of follow up
Favours treatment ? favours control
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STREPTOKINASE
Death from all causes
Fatal intracranial haemorrhage
Death or dependency at end of follow up
Favours treatment ? favours control
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STREPTOKINASE and ASA
Death from all causes
Fatal intracranial haemorrhage
Death or dependency at end of follow up
Favours treatment ? favours control
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tRPA
Death from all causes
Fatal intracranial haemorrhage
Favours treatment ? favours control
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tRPA
Death or dependency at end of follow up
Favours treatment ? favours control
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• 624 patients with clinical diagnosis of stroke
• CT to exclude a bleed or mimic
• treatment within 3 hours of stroke onset using
  i.v. rt-PA 0.9mg/kg over 1 hour

• 120-160 more independent survivors per 1,000
  treated
• and 14 years later?

NINDS 1995
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ECASS II - 1998

• 800 patients 18 to 80 years within 3 hours of
  onset
• CT to exclude ICH, mimic or lt 1/3 MCA ischaemia
• Treatment with i.v. rt-PA 0.9mg/kg over 1 hour
• 3.7 absolute difference in favour of tPA
• 37 more independent survivors / 1,000 treated
• 11 years later treatment being implemented

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Reduction in death or dependency in people
treated with i.v. rTPA within 6 hours of onset of
stroke
20 (95 CI 7-23) reduction in death /
dependency significant heterogeneity (I262)
results unreliable
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Favorable Outcome Adjusted odds ratio with 95
CI by stroke onset to treatment time
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lt 3 hrs
gt 3 hrs

• Does the treatment effect decline with time?
• clustering at 90 minutes
• wide confidence interval
• unreliable conclusion

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SITS - MOST

• 6483 patients were recruited from 285 centres in
  14 countries between 2002 and 2006 for this
  prospective, open, monitored, observational
  study.
• Primary outcomes were symptomatic ICH (a
  deterioration in NIH stroke scale score of 4)
  within 24 h and mortality at 3 months.
• Mortality rate, the proportion of patients with
  SICH and functional outcome at 3 months were
  compared with relevant pooled results from
  randomised controlled trials.

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SITS Monitoring Cohort
SICH any haemorrhage and NIHNS 1 Independence
mRS 0 - 2
Lancet 2007
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Proportion of patients with modified Rankin Score
of 0 - 5 or dead in monitoring cohort and the
active and placebo arms of available RCTs
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Thrombolysis with Alteplase 3 to 4.5 Hoursafter
Acute Ischemic Stroke

• ECASS 3
• NEJM 2008

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ECASS III

• Patients from multiple centres across Europe
• Double-blind, parallel-group trial
• Age 18 to 80 years
• Clinical diagnosis of acute ischemic stroke
• Symptoms present lt 30 minutes without improvement
• Intracranial hemorrhage or major ischemic
  infarction excluded by CT
• Able to receive the study drug within 3 to 4.5
  hours after the onset of symptoms

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Exclusion

• Intracranial hemorrhage and severe stroke on
  imaging
• Unknown time of symptom onset
• Rapidly improving, minor symptoms or severe
  stroke, NIHSS gt25
• Seizure at the onset
• Stroke, major surgery or serious head trauma
  within the previous 3 months
• Combination of previous stroke and diabetes
  mellitus
• Heparin lt 48 hours preceding the onset of stroke,
  with increased APPT or oral anticoagulant
  treatment
• Platelet count of less than 100,000 / mm3
• SBP gt 185 mm Hg or DBP gt 110 mm Hg, or aggressive
  treatment to reduce blood pressure to these
  limits
• Blood glucose lt 50 mg/dl or gt 400 mg/dl
• Other major disorders associated with an
  increased risk of bleeding

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Modified RankinIntention to treat
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Outcomes

• Day 90 Day 30
• mR 0 1 1.34 (1.02-1.7) 1.42 (1.05 1.0)
• mR 0 2 1.3 (0.55-1.71) 1.21 (0.93-1.44)
• Barthel 1.23 (0.93-1.42) 1.25 (0.95-1.09)

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Adverse events ()

• tpa placebo OR and CL
• Any ICH 27 17.6 1.73 (1.24-2.42)
• Symptomatic ICH 7.9 3.5 2.38 (1.25-4.52)
• NINCDS defn.
• Oedema 6.9 7.2 0.96 (0.56-1.64)
• Death 7.7 8.4 0.90 (0.54-1.49)

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• No Consensus
• 3 4.5 hour time window
• Patient age
• Timing of recent major surgery
• Timing of recent arterial puncture
• Rate of improvement
• Blood pressure reduction

• Consensus
• Previous stroke lt 1.5 months
• Head trauma within 2 months
• Gastrointestinal surgery lt 14 days
• Urinary tract haemorrhage lt 14 days
• Stroke severity gt NIH 3
• SBP gt 185 and DBP gt 110
• Platelet count lt90
• Glucose gt 2.6 and lt 22 mmol/L
• INR gt1.5 and APPT lt50

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What do the trials tell us

• 70 / 1000 more fatal and non fatal ICH
• 60 / 1000 more early deaths
• 120 / 1000 fewer deaths or dependent people
  overall but significant heterogeneity meaning
  that results are unreliable
• 1 extra patient alive and independent for every 7
  treated

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Impact of stroke treatments (USA)

• ASA SU tPAlt3 h rtPAlt 6r
• treated 80 60 2 30
• No Treated 480000 360000 11000 144000
• Benefit / 1000 13 56 63 47
• No. not dead or 6250 20200 700 6800
• dependent

Kleindorfer. Stroke 2008
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Outline

• Context
• Evidence
• Implementation
• Delivery

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• 4750 hospitals
• 500,000 patients with IS over 2 years
• 12000 (2.4) treated with tPA
• 0 23 patients
• 60 hospitals not treating

Kleindorfer et al AHA Stroke Conf. 2009
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Variation in use of rt-PA for acute ischaemic
stroke within licence in Europe recorded in
SITS-MOST registry 2007
SITS register November 2005
SITS-MOST 29/1/2007
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Who is not being treated

• No patients treated in 35 of hospitals.
• Less use
• No neurologist present
• Female 0.8 (0.7-1.0) 0.09
• Black 0.5 (0.3-0.9) 0.03
• Increasing age compared with age 60
• Age 60-69 0.7 (0.5-1.0) 0.07
• Age 70-79 0.7 (0.5-0.9) 0.003
• Age 80-89 0.4 (0.2-0.6 lt 0.001
• Age 90 0.2 (0.1-0.4 lt 0.001

Reed et al. Stroke 2001 32 1832-44 23,058
acute stroke patients in 137 US community
hospitals
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PATIENTS INCLUDED
All hospitals in Sweden 2003-08 144 195 patients
registered in Riks-Stroke
67 014 with ischemic stroke, age 18-80 years
64 462 not treated with thrombolysis
2 552 treated with thrombolysis
82 of all admitted for acute stroke
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THROMBOLYSIS FOR ISCHEMIC STROKE IN SWEDEN
2003-2008
Proportion of patients with ischemic stroke,
18-80 years treated with thrombolysis
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TYPE of SERVICE
University Large non-teaching Small
Type of hospital
Reference
1.21 (1.04-1.41)
0.92 (0.78-1.08)
Type of department
Reference
Internal medicine Neurology
2.06 (1.77-2.40)
Type of care
Stroke unit General ward
Reference
0.57 (0.53-0.62)
Odds ratio
Less ? likely ? More
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CHANCE OF THROMBOLYSIS BASIC PATIENT
CHARACTERISTICS
0.91 (0.83-1.00)
Women vs. men
Higher age, per 10 years
0.82 (0.78-0.86)
Cohabitant vs. living alone
1.91 (1.72-2.12)
Odds ratio
Less ? likely ? More
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CHANCE OF THROMBOLYSIS - COMORBIDITY
Previous stroke
0.51 (0.45-0.58)
0.91 (0.83-1.00)
Hypertension Diabetes Atrial fibrillation
0.62 (0.55-0.70)
0.67 (0.60-0.75)
Odds ratio
Less ? likely ? More
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SYMPTOMATIC ICH
ICH
No difference between sexes, hospital size or
department
data on SITS-MOST and pooled RCTs from Wahlgren N
et al. Stroke 2008393316-22
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SUMMARY

• Nationwide implementation slow but now
  accelerating
• Patient safety preserved
• Patients admitted to a stroke unit / neurology
  are more likely than others to be treated
• Implementation fragmented with regional inequity
• Strategic decisions to introduce thrombolysis
  result in rapid uptake over 2 years

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Number of older patients with acute stroke per
year in UK

• 87,000 patients aged gt 70 years
• 47,000 patients aged gt 80 years
• A big problem for acute medical services!

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280 patients aged gt 80 yrs have increased world
evidence base x 7
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Outline

• Context
• Evidence
• Implementation
• Delivery

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Barriers to introducing thrombolytic therapies

• Individual
• Institutional
• National

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Time Window for thrombolysis in Acute MI
60,000 patients from mega-trials

• Fibrinolytic Therapy Trialists Group. Lancet
  1994343311-322

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Effect of publication of large trials of
thrombolysis in MI on clinical practice
GISSI
ISIS-2
GISSI
AIMS
ISIS-2
ASSET
Ketley and Woods Lancet 1993 342 891-4
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Minimise the risk

• Patient MUST be
• able to be treated within 3 hours
• aged under 80
• not have a history of prior stroke Diabetes
• not have any of the standard exclusions
• NIHSS lt 25
• No extensive infarction on CT
• There must be a discussion of risk/consent

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When not to call.

• Symptoms not consistent with stroke, minor or
  rapidly improving
• Patient woke from sleep with stroke or gt 3 hrs
  since onset
• Age under 18 or over 80
• Patient dependant for ADLs prior to stroke
• Known coagulation disorder or on warfarin /
  heparin
• Blood glucose lt 3 or gt 22 mmol/l
• Systolic BP gt 220 or diastolic gt130
• Arterial or large vein cannulation lt 7 days ago
• Known neoplasm / life threatening illness / major
  surgery / trauma / GI bleed past 21 days
• Haemorrhage on CT

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Diagnosis

• Early diagnosis of stroke is difficult
• Get the history from patient and / or carer
• Examine the patient including NIH score
• Have your antennae switched for both functional
  and non stroke disease including intoxication

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Treat stroke

• Accurate clinical diagnosis
• Focal neurological deficit
• Known time of onset
• Exclude stroke mimics (hypo, fits, migraine, etc)
• Identify clinical contraindications to rt-PA
• Measure deficit (NIHSS)
• Careful assessment of CT
• Exclude haemorrhage and non-stroke mimics
• Identify early signs of ischaemia
• Does the CT match the clinical features?

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CLINICAL pointers for safe treatment

• Probably ELIGIBLE for thrombolysis
• Known time of onset
• Unilateral neurological signs
• Increasing NIH score (gt4)
• Abnormal vascular signs (AF, PVD)
• Probably NOT ELIGIBLE
• Deficit first noted on waking from sleep
• Prior cognitive impairment
• Loss of consciousness at/soon after onset
• Seizure
• Can walk now ( too mild)

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Safe imaging
Also often missed on CT scans investigating
acute confusion
Davenport BMJ, Jul 2006 333 235 - 240
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Use the right drug
IV urokinase
IV streptokinase
IV rt-PA
IV streptokinase aspirin
IA pro-urokinase
IA urokinase
IV desmoteplase
Total
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Effects on main outcomes.

• SICH Dead Dead or
• (incl fatal) dependent
• All drugs 3.3 1.3 0.8
  
• n7152 2.7 - 4.1 1.1 - 1.5
  0.7 - 0.9
• plt0.00001 p0.06
  plt0.0001
• rt-PA 3.1 1.1 0.8
• n3977 2.3 - 4.0 1.0 - 1.4
  0.7 - 0.9
• plt0.00001 p0.16 plt0.0001
• Significant heterogeneity confounds
  interpretation
• meta-regression on a variety of factors does not
  explain it

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Thrombolysis box and what to do if? sheets
Box has everything you need drug, infusion pump,
disposables, monitoring protocols, forms
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Ensure there are protocols formanagement of

• Intracerebral Haemorrhage
• Suspected major extracranial bleeding
• Anaphylactoid reactions
• Oro-lingual oedema

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Proportions of patients with symptomatic
intracerebral haemorrhage, including fatalities,
and mortality and independence at 3 months
inexperienced and new SITS-MOST centres and
pooled randomised controlled trials
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Risk fatal haemorrhage 3
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Intracerebral haemorrhages detected by CT or MRI
study at 2236 h after treatment and
anypost-treatment imaging scans
SITS-MOST
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ICH in ECASS 3
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Symptomatic ICH

• ?GCS
• New headache
• New nausea or vomiting.
• ?BP or new acute ? BP
• Abnormal ventilation pattern

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Treatment of ICH

• Call the doctor
• Stop tPA
• Urgent CT scan
• Check coagulation
• prothrombin time,
• activated partial thromboplastin time,
• fibrinogen,
• full blood count and group and save serum.
• Monitor IV fluids
• Do not correct coagulation abnormality

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Asymptomatic ICH on CT _at_ 24 hrs

• Haemorrhagic transformation of the infarct
• Parenchymatous haematoma
• No specific action
• ? Delay the start of long-term antiplatelet or
  anticoagulant therapy

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Extracranial haemorrhage

• ?BP
• ?thready pulse
• Obvious bleeding
• haematuria,
• melaena etc.

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Management of ECH

• Call doctor
• Stop tPA
• Mechanical compression
• Check coagulation and group or X match
• IV Fluids
• Discuss with haematologists consider
• 500000 kallikrein inactivator units of aprotinin
  over 10 minutes followed by 200000 units over 4
  hours
• tranexamic acid 1 gm iv over 15 mins 8 hourly as
  needed
• FFP / Cryoprecipitate
• Delay surgery until coagulopathy corrected

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Anaphylaxis

• Urticaria
• Facial Swelling
• Rash
• Difficulty breathing
• ?BP
• ?thready pulse

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Severe orolingual angioedema during rT-PA
treatment for stroke
Angioedema during rt-PA caused tongue swelling
and airway obstruction. CT shows diffuse ETT and
severe tongue swelling
unilateral tongue swelling still present post
extubation
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Management

• Call doctor
• Stop tPA
• ABC
• Adrenaline 0.5 ml 11000 im or sc
• Hydrocortisone 200 mgm iv
• Chlorpheniramine 10 mgm iv
• Salbutamol nebuliser 5 mgm
• Fluids

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Hypertension pre thrombolyis

• Monitor blood pressure every 15 minutes.
• Do not treat with tPA unless lt 185/110 mm Hg.
• If gt 185/110, give
• Sublingual lisinopril
• nitroglycerin paste
• one or two 10-20mg doses i.v. labetalol
• If this does not maintain BP lt 185/110 do not
  thrombolyse the patient.

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Hypertension during treatment

• Monitor blood pressure for the first 24 hours
  after starting treatment
• every 15 minutes for 2 hours after starting the
  infusion, then
• every 30 minutes for 6 hours, then
• every hour for 18 hours.
• Further discussion in cases

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BMs

• Inform duty ward doctor if BM gt 10 mmols or lt 3
  mmols
• On arrival on ward
• QDS for 48 hours
• BD after 48 hours

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GENERAL

• Will the patient need NG and urinary catheter,
• pass tube / catheter before treatment
• Or avoid NG tube or urinary catheter for 24 hours
• No wet shaving for 24 hours
• Do not remove cannulas unless absolutely
  necessary for 24 hours.
• Give gentle mouth care with soft swabs for 24
  hours
• Set pump rate at mls required for the dose
  prescribed over 1 hour

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MEDICAL PROTOCOLSGeneral

• NIH training and CT reading course before
  initiating thrombolysis.
• Ward managers decide on the basis of capacity and
  staffing.
• All patients have CT at 24 hrs.
• Start ASA 300 mgm daily after 24 hrs

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Will PCI mean primary carotid intervention