EBM Acute Stroke

Pedagogical disambiguation: Emergency Medicine Lecture Notes and Evidence Based emergency medicine principles from Professor A.F.T Brown and the Life in the Fast Lane team.

Epidemiology

• Stroke is the second commonest cause of death (10-12%), consumes >4% total healthcare costs, and is commonest cause of adult disability in western world.
• 80-85% are ischaemic (thrombotic or embolic) and 15-20% the more lethal haemorrhagic stroke (including 5% SAH), of which over 50% will die by 1 month.

Donnan G, Fisher M, Macleod M et al. Stroke. Lancet 2008;371:1612-23. [Reference]

Active Management

Early notification system

• Face Arm Speech Test (FAST), priority transportation, high Triage category, rapid referral for imaging and or to Acute Stroke Team, preferably within three hours of stroke onset.

Early CT scan

• Ideally within 1 hour ED arrival, if any of: indications for lysis or early anticoagulation; on warfarin; known bleeding tendency; depressed GCS <13; unexplained progressive or fluctuating symptoms; suspected meningitis; severe headache at onset.
• Otherwise within 24 hours (see later).

General supportive care

• Airway protection, correction of hypoxia, treatment of hypoglycaemia or hyperglycaemia, avoidance of aspiration with NBM until swallowing assessment in first 24 hours, maintenance of normothermia, treatment of infection, and pressure area care if unconscious.
• Consider BP control with an ischaemic stroke if BP elevated > 220/120 mmHg, though no agent significantly affected outcome from the 43 suitable trials reviewed. Be cautious with no more than a 10-20% change maximum (i.e. not lower than 180/100 mmHg initially).
  • Beta blockers, calcium channel blockers (nimodipine / nicardipine), ACEI, and GTN all have been used. Note thrombolysis requires SBP  185/ DBP  110 mmHg to qualify.
  • Avoidance of hypotension equally important.

Geeganage C, Bath P. Vasoactive drugs for acute stroke. Cochrane Database Syst Rev 2010, Issue 7. CD 002839 [Reference]

Weeraratne J, Lenstra A, Lee A et al. The NICS care bundle: aiming to improve the initial care of patients with stroke and transient ischaemic attack. Med J Aust 2010;193:381-2. [Reference]

Antiplatelet treatment

• Aspirin 300 mg orally (or via NGT / PR) early and then daily if stroke is non-haemorrhagic on CT or for TIA, ideally within first 24-48 hours. Far greater benefit (15-fold) with less risk than use of lysis or anticoagulation (see later). Continue for at least 2 weeks.
• Addition of dipyridamole 200 mg po bd for TIAs and minor ischaemic stroke preferred, but note more side effects including headache!
• Clopidogrel only for aspirin allergy or associated ACS.

Sudlow C. Give dipyridamole with aspirin instead of aspirin alone to prevent vascular events after ischaemic stroke or TIA. BMJ 2007;334:901. [Reference]

The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367:1665-73. [Reference]

Anticoagulant treatment

• No net advantages of heparin over antiplatelet agents in 24 trials. No clear advantages of LMWH / heparinoids over UFH. None supported. LMW or UF heparin did reduce DVT/PE, but not stroke deaths or dependency.

Sandercock P, Counsell C, Kamal M. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. The Cochrane Collaboration 2009. [Reference]

• Glycoprotein IIb/IIIa inhibitors had no +’ve effect in 2 small trials.

Ciccone A, Abraha I, Santilli I. Glycoprotein IIb/IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev 2006:4:CD 005208. [Reference]

Thrombolysis

• Treatment with tPA ideally within 3 hr of onset, possibly up to 4.5 hr in adults > 18 and < 80 years most promising in overall reduction in death / disability, when given in experienced centres in selected patients. Still is not recommended for general / widespread clinical use
• Even though safe and effective use of lysis within 3 hours of symptom onset in ‘routine’ clinical use appears validated by SITS-MOST post-marketing surveillance (rather than just in trial hospitals).
• However, note SITS-MOST excluded patients who were very elderly > 80 years, the most severe with NIHSS scores > 25, hypertensive > 185/110 mmHg, and if treated outside of 3 hours.

Wahlgren N, Ahmed N, Davalos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-82. [Reference] (Editorial: Albers G, Olivot J-M. Lancet 2007;369:249- 50.[Reference])

• Cochrane database reports 26 randomised trials to 2008 with 7152 patients studied (of which 55 % received tPA), using urokinase, streptokinase, recombinant tPA, recombinant pro-urokinase or desmoteplase, although very few patients over 80 years (0.5%).
• Overall significant net reduction in death or dependency at 3-6 months with lysis (OR 0.81). However, this was with an increase in death in first 7-10 days from ICH (4.34%, or 3.60% for tPA), and of symptomatic ICH (OR 3.49). Also noted an increase in deaths at follow up at 3-6 months (OR 1.31). Treatment within 3 hr most effective.

Wardlaw J, Murray V, Berge E et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2009 Oct 7;(4):CD000213. [Reference]

• Protagonists’ are dismayed that “a clear benefit” of tPA in trials and in routine practice “…with an absolute benefit that exceeds lysis in AMI…” has not translated into more enthusiastic adoption of this therapy.

Davis S, Hand P, Donnan G. Tissue plasminogen activator for ischaemic stroke: highly effective, reasonably safe and grossly underused. MJA 2007;187:548-9. [Reference]

• Others believe benefit of tPA is unproven, at best marginal with significant safety issues, and that ‘effectiveness’ in a community setting is far different from ‘efficacy’ in a trial situation. Also that the NINDS data on the 624 patients are still misrepresented.

Hoffman J, Schriger D, A graphical reanalysis of the NINDS trial. Ann Emerg Med 2009;54:329-36. [Reference] and correspondence (from Australia!) Ann Emerg Med 2010;55:226-9 [Reference].

Hurley J. MJA 2008;188:488. Toncich G. MJA 2008;188:489. Fatovich D MJA 2008;188:489.

• National Institute of Neurological Disorders and Stroke (NINDS) study 1995 traditionally the main positive outcome trial, using tPa (note MRIs were not utilised).
• NINDS results included
  • 12 % additional patients improved neurological outcome at 3 months over placebo.
  • 6 % additional symptomatic intracerebral haemorrhage, of which half died, although no overall mortality difference versus placebo at 3 months.
  • Majority ( 80%) no difference.

Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. NEJM 1995; 333: 1581-7 [Reference]

• However, lysis was only offered in 28% acute hospitals, and overall less than 3% of all ischaemic stroke patients received lysis in 2008 in Australia, as needed to:
  • present and have CT demonstrating absence of intracerebral haemorrhage ie. an ischaemic stroke, within 3 hours of onset of symptoms. MRI may become the standard imaging necessary…
  • have no contraindications to lysis.  These include minor symptoms only (ie. ataxia, minor sensory loss, dysarthria alone); major symptoms that are rapidly improving; SBP 185 / DBP 110 mmHg; previous ICH/SAH/neoplasm; seizure at stroke onset; recent trauma/surgery; bleeding diathesis/use of heparin or warfarin; other GI/urinary bleeding etc.
• Numbers of hospitals treating with rt-PA is increasing (50 by 2009), with Australian outcomes similar to rest of world. However only a minority of centres (42%) were participating in SITS reporting.

Simpson M, Dewey H, Churilov L et al. Thrombolysis for acute stroke in Australia: outcomes from the Safe Implementation of Thrombolysis in Stroke registry (2002-2008). Med J Aust 2010;193:439-43. [Reference] Editorial Fitzgeral M, Gerraty R. Med J Aust 2010;193:436-7. [Reference]

• Dose is tPA 0.9 mg/kg IV (not to exceed a total 90mg dose, regardless of the patient’s weight). A 10% bolus is given intravenous push over one minute. The remaining 90% is infused over 60 minutes via an infusion pump.

Khaja A, Grotta J. Established treatments for acute ischemic stroke. Lancet 2007; 369: 319-30. (Good overview) [Reference]. Editorial. Albers G, Olivot J-M. Lancet 2007; 369: 249-50. [Reference]

Neuroprotective agents

• Glutamate (excitatory amino acids) receptor antagonists or glutamate release inhibitors, magnesium as an NMDA blocker, other ion channel blockers, free radical scavengers, NO donors or NO synthase inhibitors, gangliosides, fibrinogen depleting agents, membrane stabilisers, monoclonal antibodies to adhesion molecules and spin trap agents.
• No definitive success yet despite promising animal studies, but combination therapies may be shown to have greater value.
• Induced hypothermia being investigated to ‘buy time’.
• Any agent used must be given as part of a randomised trial.

Sacco R, Prabhakaran S, Elkind M. Experimental treatments for acute ischemic stoke. Lancet 2007; 369:331-41. [Reference]

OTHER CONSIDERATIONS

Acute Stroke Team +/- dedicated, multidisciplinary Stroke Unit.

• Streamlining of care is single most important recommendation. Stroke Teams/Unit reduce death or dependency at 1 year from 62% to 56.4% (NNT 18), with an absolute risk reduction for mortality of 3% and need for institutional care by 2%.
• Features studied in trials include assessment and monitoring with protocols for medical, nursing and therapy; early management including physiological management, early mobilisation and nursing care; and multidisciplinary team rehabilitation.
• Currently, Stroke Unit Care is only available in one third of hospitals around Australia.

Candelise L, Gattinoni M, Bersano A et al. Stroke-unit care for acute stroke patients: an observational follow-up study. Lancet 2007; 369: 299-305. [Reference]

Langhorne P, Dennis M. Stroke units: the next 10 years. Lancet 2004;363: 834-5. [Reference]

• Co-operation between emergency medicine, neurology, general and geriatric medicine, neuroradiology, neurosurgery, intensive care, as well as nursing, OT, physio, speech therapy, rehab plus public education programs ensuring rapid recognition, liaison with GPs and EMS are necessary.
• 24 hour access to high resolution CT and/or MRI with experienced personnel reporting. Also availability of ECG, Doppler USS, echocardiography, ICP monitoring are ideal.

Primary prevention

• Treatment of high risk patients with significant hypertension or AF, and by reducing risk factors in the general population such as smoking.
• Non-valvular AF may be treated to reduce risk of stroke with aspirin (ARR 1.7%, NNT 59) or warfarin (ARR 3.1%, NNT 32), although warfarin causes over twice as many ICH, especially age over 75 years. Also need to keep INR in optimum range 2.0 – 3.0, only obtained in 40-77% patients on warfarin over time.
• Interest in newer agents such as oral direct thrombin inhibitor dabigatran 110 – 150 mg bd, as fixed dose with no need for laboratory control.

Wallentin L, Yusuf S, Ezekowitz M et al. Efficacy and safety of dabigatran compared with warfarin at different levels of INR control for stroke prevention in AF: an analysis of the RE-LY trial. Lancet 2010;376:975-83. [Reference] (Lane D, Lip G. Editorial. Lancet 2010;376:935-7 [Reference]).

Secondary prevention.

• Stop smoking, BP control, antiplatelet therapy (aspirin plus dipyridamole), statin, glucose control, anticoagulation (warfarin) only for AF or cardioembolic stroke, carotid endarterectomy (consult specialist vascular surgeon) etc.

Lancet. Stroke – prevention is better than cure. Lancet 2007;369:247. [Reference]

Transient ischaemic attack (TIA).

• TIA  with stroke symptoms and signs (numbness, weakness or paralysis, slurred speech, blurred vision, confusion) that resolve within 24 hours has forward risk of stroke of 3.9% at 2 days, 5.5% at 7 days and 9.2% at 90 days.

Hankey G. The ABCD, California and unified ABCD2 risk scores predicted stroke within 2, 7, and 90 days after TIA. Evid Based Med 2007;12:88. [Reference]

• 15-30% patients presenting with ischaemic stroke recall a history of a preceding TIA, and in these 17% had the stroke on the same day,  9% the day after the TIA and 43% the stroke followed the TIA within 7 days.

Rothwell P, Warlow C. Timing of TIAs preceding stroke. Neurology 2005; 64:817-20. [Reference]

• ABCD2 TIA Scoring Tool scores 2 for unilateral weakness, or duration of symptoms ≥ 60 mins; and 1 for each of age ≥ 60 yrs, SBP ≥140 mmHg or DBP ≥90 mmHg, speech disturbance without motor  weakness, duration of symptoms 10-59 mins, or diabetes.

Johnston S, Rothwell P, Nguyen-Huynh M et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369: 283-92. [Reference] Editorial Kernan W. Lancet 2007; 369: 251-2. [Reference]

• High risk’ ABCD2 Scoring Tool group with score 6-7 have 2-day stroke risk of 8.1%, ‘moderate risk’ with score 4-5 have 4.1% stroke risk, so ideally need immediate admission (ie. not sent home). Cost-utility of  admission proven. Also admit patients with ‘crescendo TIAs’, AF,  carotid territory symptoms.
• ‘Low risk’ have score 0-3 with a 1.0% 2-day stroke rate. May be managed on aspirin and dipyridamole as an outpatient, ideally seen within one week.
• These data have major implications for the timing of urgent out  patient medical assessment including Doppler carotids +/- stroke  clinic review.

Additional references:

• Clinical Guidelines for Stroke Management 2010. National Stroke Foundation. (172 pages. Covers every aspect of stroke and TIAs from ‘hyper-acute care’, hospital care to discharge planning and aftercare). [Website]
• Jauch E, Cucchiara B, Adeoye O et al. Part 11: Adult stroke: 2010 AHA Guidelines for CPR and ECC. Circulation 2010;120(suppl 3):S818-S828. [Reference]
• National Institute of Clinical Studies (NICS). Emergency Department Stroke and Transient Ischaemic Attack Care Bundle. 2009. [Website Reference]
• National Institute for Health and Clinical Excellence. Stroke. Diagnosis and initial management of acute stroke and transient ischaemic attack (TIA). Quick reference guide. NICE Clinical Guideline 68. July 2008 [PDF Reference]
• Editorial. Swain S, Turner C, Tyrrell P et al. Diagnosis and initial management of acute stroke and transient ischaemic attack: summary of NICE guidance. BMJ 2008;337:291-3 [Reference].
• Lancet 2007;369: Jan 27th (whole issue on stroke management) www.thelancet.com
• The Cochrane Library. Currently there are 275 guidelines or reviews are listed under ‘Stroke’, and 17 under ‘TIA’