Evidence-based Stroke Care
Charles S. Yanofsky,MDGrand RoundsSeptember 25, 2008Pinnacle Health
EVIDENCE-BASED STROKE CAREEVIDENCE-BASED STROKE CARE
Charles S. Yanofsky, MDPinnacle Health NeurologySept. 25, 2008
Stroke: magnitude of Problem in U.S. 730,000 people / Yr The third leading cause of death
160,000 deaths/yr 570,000 stroke survivors
Leading cause of disability5 yr recurrence30%-50 percent>four million Americans living with the
consequences of stroke
Counterintuitive Stroke Mngt
www.strokecenter.orgSee stroke tables: Comprehensive study list in table form
www.susqneuro.com http://stroke.ahajournals.org/cgi/reprint/
STROKEAHA.107.181486v1Guidelines for the Early Mngt of Adults with
Ischemic Stroke (2007) Adams et al
Stroke
Ideal Topic for Evidence Based Approach Evidence Based = Empirical What You think is true, isn’t What Works, is
Reasonable surmise is false
Blocked arteries need anticoagulant (heparin) Use Decadron (steroids) for ischemic or hemorrhagic
cerebral edema Elevated blood pressure needs to be controlled (in acute
stroke) Increased blood pressure leads to cerebral hematoma
expansion Prothrombotics decrease cerebral bleed volume (EACA,
Factor VllA) and thus improve outcomes
Assymptomatic “significant” carotid stenoses require surgery
What you think, isn’t true
Lower Very High blood pressures immediately!! IV glucose is a good substrate for brain with poor blood supply Hemorrhagic Strokes should never be anticoagulated Total occluded carotids can be treated by STA-MCA bypass Warfarin is “stronger” than antiplatelets. Use warfarin when
antiplatelets fail Warfarin works better than aspirin for intracranial arterial stenosis Warfarin and antiplatelets act synergistically to reduce stroke
occurrence. Use both together.
What you think is true is not
Heparin worsens arterial dissection Thrombolytics (clot busters) cause hemorrhages Cooling the brain diminishes stroke damage We have minutes to restore bloodflow to the brain. Vasodilators increase blood flow to ischemic brain Certain Drugs stop the cascade of Apoptosis (cell death) and are
neuroprotective. Hemodilution (rheostasis) increases blood flow to ischemic brain Calcium channel blockers increase brain blood flow Use Rehab to Maximize unaffected functions Surgical evacuation of Cerebral hematoma improves
survival/outcome. Refer brain hemorrhages to neurosurgeon
Medicine =school of hard knocks. Utterly Empirical Experience teaches: Reasonable surmise
is false. Stroke care is primary example Counterintuitive
Medical Wisdom
Don’t think too much Stick to the Program Leave nothing undone Race goes to the meticulous
Stroke Care
1. Prevent complicationsAspirationDVTComplications of Immobility
2. Make sure all relevant studies are done to determine etiology e.g. cocaine if a possibility
3. Identify and treat risk factors
AHA Stroke Levels of Evidence
Level I: Data from randomized trials with low false-
positive (alpha) and low false-negative (beta) errors Level II: Data from randomized trials with high
false-positive (alpha) or high false-negative (beta) errors
Level III: Data from nonrandomized concurrent cohort studies
Level IV:Data from nonrandomized cohort studies using historical controls
Level V: Data from anecdotal case series
AHA Stroke Strength of Recomendation
Grade A:Supported by Level I evidence Grade B:Supported by Level II evidence Grade C:Supported by Levels III, IV, or V
evidence
What Matters
Cadre of Experienced Personnel. Stroke BedsStroke NursesStroke Team
Prevention of Secondary ComplicationsAspiration, DVT, Comorbidities
Treat Processes that affect Outcomes
Stroke units: State of the Art
Admission to a unit that is dedicated to the care of stroke patients helps to reduce mortality and morbidity.
Stroke Units
Early admission of most patients to a unit that has a specialized interest in the treatment of stroke is strongly recommended (Level of Evidence I, Grade A Recommendation). A team of physicians, nurses, and technicians that is devoted to the early care of patients with stroke should be assembled. Rapid transfer of a patient to a hospital that has a specialized stroke care unit is strongly recommended.
Empirical Treatments of Stroke Summary What you think is true is not.
Don’t be smart. Be Meticulous.
Follow the Rules. Develop Expertise
Fatal stroke
Issues
Acute Stroke Management T-PA Exclusions Risk factors e.g. hypertension
T-PA
If a 3-hour window of treatment can be met, thrombolytic therapy with intravenous t-PA can be beneficial for each of the major categories of ischemic stroke: (85%)
atherothrombotic/atheroembolic, cardioembolic, and small vessel occlusive (lacunar) stroke
T-PA for Acute Ischemic Stroke
NEJM (1995)333:1581-87624 patients randomized3 hour windowat three mos. 30% more likely to have minimal
or no disability6.4% risk of hemorrhageNo change in mortality at 6 mos
NIH Study In 624 patients studied within 3 hours
after symptom onset, the chance of a total or near total recovery for a patient in the tissue plasminogen activator (t-PA [Activase]) group was 1.7 times greater than in the placebo group.
NIH Study - 2
All four outcome measures used (Barthel index, modified Rankin scale, Glasgow outcome scale, and the National Institutes of Health Stroke Scale showed a beneficial effect of t-PA at three months.
The National Institute of Neurological Disorders and Stroke re-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM. 1995; 333:1581-1587
t-PA Protocol
.9 mg/Kg, 10% as bolus of t-PA, 90% over 60 minutes
no anticoags or antiplatelet agents for 24 hrs
maintain bp in normal range repeat CT in 24 hours and stat if ICH
suspected
Eligibility
Ischemic stroke with clearly defined time of onset
Clear deficit measurable on NIHSS Baseline CT negative for hemorrhage
EXCLUSIONS
Stroke or head injury in past 3 mos major surgery within past 14 days History of ICH Bp >185/110 that can’t be rapidly reduced rapidly improving or minor symptoms symptoms suggesting SAH, severe HA, Sz, LOC INR>=1.2 Unknown time of onset of sx or > 3 hr
T-PA After Three Hours
1. Not proven Beneficial
2 European Cooperative Acute Stroke Study (ECASS): no benefit of later treatment
3.Patients with CT evidence infarction of more than one third of the territory of MCA had excess risk of hemorrhagic stroke and death when treated with a higher dose of t-PA
Poor Outcomes
Early CT finding of Thrombus NIHSS score >20 >30% MCA territory or MCA opacified Glucose >400
Source: Taney & Kasner et al post t-PA data
Bleeding Suspected
D/C t-PA Stat CT Stat bleeding time, PT/PTT, Plts,
Fibrinogen, Cryoprecipitate 6-8 Units Platelets 6-8 Units Neurosurgery and Hematology Consult
HEMORRHAGE AND t-PA
Symptomatic intracranial hemorrhage (ICH) occurred in 6.4% of patients treated with t-PA in the NINDS-sponsored study
Arterial Thrombinolysis
During cerebral angiography it has been found that it is possible to thread a fine guidewire and infusion catheter to and through an intravascular clot. It has been effective in the internal carotid artery or its branches and in the vertebrobasilar system for administration of intra-arterial thrombolytic agents to restore blood flow.
Sasaki O, Takeuchi S, Koike T, et al. Fibrinolytic therapy for acute embolic stroke: intravenous, intracarotid and intraarterial local approaches. Neurosurgery. 1995; 36:246-253
Mayo Clin Proc. 1997;72:1005-1013 © 1997
Non t-PA
If thrombolytic therapy is not feasible, treatment should be carefully evaluated by repeated neurologic examination over the next few hours to be sure the stroke is not progressing. If there is progression, anticoagulants may be considered after a repeat CCT to be certain the cause is progression and not hemorrhage.
Cleveland Study Jama 2000
3,948 stroke patients. Only 70 –1.8% got t-PA Treatment guidelines violated in half Increased Hemorrhage
15.7 percent – 3X rate in other studies 15.7% Mortality The bottom line - Stick with the guidelines. Experience is impt.
Left hemisphere stroke
MCA Sign
Modifiable stroke risks
Smoking
Heart disease (Afib)
Hypertension
TIA
Increased RBC
Cholesterol/lipids
physical inacivity
Etoh abuse
PROGRESS Trial
Effect: The PROGRESS trial, including 6105 patients, demonstrated that an ACE inhibitor and a diuretic, mainly in combination, are beneficial after ischemic and hemorrhagic stroke. The relative risk of stroke is reduced by 28 %, and the relative risk of major cardiac events by 26 % over 4 years (Grade B evidence).
Framingham Cohortrelative stroke risks Age (per year) 1.06 Syst. BP (per 20mm incr) 1.16 Smoking 1.52 Diabetes 1.90 Atrial fibrillation 2.29 Coronary heart disease 1.49 Homocysteine level (1st vs 4th qtle) 1.82
Treatment of HTNNumbers Needed to Treat
MRC [1)17,354 individuals 36-64 years diastolic 90-109 mmHg, 5.5 years NNT=850 to prevent one stroke at one year
SHEP [3] 4736 individuals 60 years or older systolic 160-219 mmHg& diastolic <90 mmHg, 4.5 years RR=0.65 (0.51 - 0.83), NNT=43 (27 - 95)
STOP [4]1627 individuals 70-84 years systolic 180-230 mmHg & diastolic 100 mmHg or diastolic 105-120 mmHg 4 years, RR= .55 (0.30 - 0.97), NNT=34 (20 - 123)
MRC [6] 4396 individuals 65-74 years systolic 160-209 mmHg diastolic <115 mmHg, 5.8 yearsRR=0.76 (0.59 - 0.98), NNT=70 (36 - 997)
Diastolic BP
Every 7 points doubles your stroke risk
HTN
But consider lacunar strokes. Synergy of Diabetes L’etat lacunaire
Lessons
Follow empirical rules Don’t stop thinking
Acute Treatment
Recommended TestsCT of the brain without contrast
Electrocardiogram and rhythm monitoring
Carotid Doppler
Echocardiogram
Lumbar puncture (if subarachnoid hemorrhage is suspected and CT is negative)
Electroencephalogram (if seizures are suspected)
Radiology Ancillary Tests
CT or MR Angio Perfusion/Diffusion studies
CT v. MRI“Mismatch” – brain at risk
Recommeded Tests cont’d :Bloods
Complete blood count
Platelet count
PT-PTT
Electrolytes, glucose
Hypercoagulable profile if coagulopathy suspected
Collagen vasc workup, selected patients
Cocaine drug screen in selected cases
Doppler
Ultrasonography. extracranial Doppler: can be useful noninvasive techniques to screen for internal carotid artery stenosis.
Differentiation between stenosis of 95% and complete occlusion is usually not possible but demonstration of stenosis >60% is quite accurate
Transesophageal Echo
Young Stroke Non-atherosclerotic cause suspected Look for anomalies often missed by TTE
PFO w/ atr septal aneurysmAtrial myxomaSubtle valve abns as in SBEAortic atheroma/anomalies
Cerebral Arteriogram
Unusual cause such as vasculitis suspected Dissection, fibromuscular hyperplasia, moya
moya or other unusual process suspected Often MRA or CT angio are sufficient Risks may outweigh benefits. Needed for arterial throminolysis/clot retrieval
Young Stroke
Pregnancy, estrogens
Angiography
TEE
Cocaine/drug screen
Phospholipid (cardiolipin) antibody profile
Consider inflammatory/col vasc disease
Factor V, but Antithrombin III, protein C & S and C resistance of limited utility
Stroke Dichotomy
Atherosclerotic v. non-atherosclerotic (= esoteric)
Even in young, atherosclerotic stroke predominate.
Blood Pressure
An elevation of blood pressure may be a compensatory response to maintain cerebral perfusion pressure in a patient with a markedly elevated intracranial pressure. In such instances antihypertensive agents, particularly those that induce cerebral vasodilation, are avoided.
Hypertension/treatment
In general, antihypertensive drugs should be withheld unless the calculated mean blood pressure (the sum of the systolic pressure plus double the diastolic pressure, divided by three) is greater than 130 mm Hg or the systolic blood pressure is greater than 220 mm Hg
Blood Pressure
Elevated blood pressure usually declines spontaneously over the first 24 hours after stroke onset and overzealous use of a calcium antagonist and other antihypertensive drugs should be avoided because they can further reduce cerebral perfusion.
Blood Pressure
Minimal or no treatment of mildly to moderately elevated blood pressure during the first hours of ischemic stroke is supported by human and animal data. Because of the partial or complete loss of autoregulation in ischemic brain, cerebral blood flow in these regions depends almost entirely on the arterial blood pressure to maintain cerebral perfusion
Blood Pressure (preferred agents)
Preferred agents include intravenous labetalol or enalapril. Some investigators have also used nitropaste
Nicardipine 5-15 mg/Hr iv
Blood Pressure and hemorrhage
Control of elevated blood pressure has never been shown to decrease the risk of ongoing or recurrent bleeding in patients with intracerebral hemorrhage.
Recommend treatment of moderate and severe elevations of blood pressure (systolic blood pressure of greater than 180 mm Hg or mean arterial pressure of greater than 130 mm Hg).
Antithypertensive Rx
Indicated for: aortic dissection acute myocardial infarction heart failure acute renal failure hypertensive encephalopathy thrombolytic therapy
When systolic pressure is 180 mm Hg or higher or the diastolic pressure 105 mm Hg or higher.
Goals for BP in Stroke
<220/120 :Ischemic Stroke <200 :Heparin <185/110 :t-PA
Glucose
Elevated levels enhance neuronal injury Human studies >180 increases infarct
volume Maintain levels betw 60 and 180
Blood Glucose
There is general agreement to recommend control of hypoglycemia or hyperglycemia after stroke (Levels of Evidence III through V, Grade C).
Do not use D5W
“free water” incr edema
Incr glucose.
Temperature
Increase temp increases percentage of poor outcome in stroke
Increase cerebral oxygen/substrate consumptionLancet 1996:422
Fever
There is general agreement to recommend treatment of the sources of fever and use of antipyretics to control an elevated body temperature (Levels of Evidence III through V, Grade C). There are insufficient clinical data about the use of hypothermia to recommend this therapy.
Fever: Treatment
Treat any temperature elevations
Data is not in as to whether hypothermia may be protective
CEREBRAL EDEMA
Hypo-osmolar fluids, such as 5% dextrose in water, may worsen edema.
1/2NS or NS recommended
Mannitol
Mannitol (0.25 to 0.5 g/kg IV) given over 20 minutes rapidly lowers intracranial pressure and can be given every 6 hours.57 The usual maximum daily dose is 2 g/kg.57
Mannitol
Dose: - 25 to 50 g I.v. q 3-5 hrs. Maximal dose of 2 g /KG/D. Furosemide I.v. 20 to 80 mg q 4 to 12
hours to supplement mannitol. Replacement fluids to maintain the
calculated serum osmolality at 300 to 320 mOsm per kilogram of water.
Modifying Risks
Risks 1
Identified arterial lesion
Atrial fibrillation (Framingham)
Past vascular event
Smoking
Risks 2
African American
Diabetes
Hypertension
Family History
Coronary Artery Disease
FRAMINGHAM ATRIAL FIBRILLATION
Quadruples stroke risk
Doubles Stroke Death Rate
Coumadin & AF
Reduction in strokes of 60% 5.8% /yr - placebo to 2.3% - warfarin. NNT = 18 (14 to 27). (18 patients treated with warfarin
1.6 years to prevent one stroke. Also one-year NNTs to prevent one stroke of 37 for primary prevention, 12 for secondary prevention for adjusted dose warfarin compared with placebo.
All-cause mortality was decreased by 1.6% a year in patients receiving warfarin.
Source: Bandolier on Web (British)
Aspirin For AF
6 trials with 3225 patients and 349 strokes. Mean duration 1.5 years, Placebo stroke rate= 5.2% /yr
with no previous stroke, 13% /yr w/ previous stroke. Reduction in strokes of 20%, from 7.9%/yr-
placebo to 6.5%/yr, aspirin. NNT was 48 (23 to >1000).
One-year NNTs 67 for primary prevention and 40 for secondary prevention for aspirin compared with placebo.
All-cause mortality was not significantly reduced by aspirin.
Warfarin vs. ASA in AF
Reduction in strokes of 35%, from a rate of 4.0%/Yr aspirin to 2.6% /yr warfarin. NNT= 35 (21 to 104).
One-year NNTs to prevent one stroke = 167 for primary prevention and 14 for secondary prevention for warfarin compared to aspirin.
All-cause mortality was similar for both treatments.
Warfarin v. ASA for intracranial stenosis 569 pts with angiog proven ic stenosis Assigned to ASA 1300 mg v. warfarin Hazard ratios for death and hemorrhage
about half those in asa group v. warfarin Concl: ASA superior to warfarin for
intracranial stenosis NEJM 352:1305 (3/05)
Carotid Endarterectomy
Surgical M/M < 6%
TIAs in the past 6 months
Carotid stenosis > or = 70%
Stroke within 6 months and a carotid stenosis > or = 70%
Carotid Endarterectomy:Evidence Based Review Neurology 2005;65:794-801
Symp >70% level A Symp 50-69% level B Not indicated <50% level A Assympt >60% iff stroke/death <3% level
A ASA 51-325 mg before and after
endarterectomy Level A
Endarterectomy Questionable
TIAs + stenosis 50% to 69%
Progressive stroke and a stenosis > or = 70%
Mild or moderate stroke in the past 6 months and a stenosis 50% to 69%
ACAS
1662 Patients, multiple centers
>60% carotid stenosis
<3% perioperative M/M
5 year risk of stroke/death5.1% surgical patients11% medical group
53% aggregate risk reduction
Antiplatelet Agents
Aspirin
Plavix (Clopidogrel)
Ticlid (Ticlopidine)
Aggrenox© Asa 25 mg + Dipyridamole 200 mg.
Aspirin
Preliminary results from the International Stroke trial suggest that aspirin use within 24 hours of stroke onset is associated with a reduction of recurrent ischemic stroke from 2.7% to 3.5%.
Ticlopidine ©
ADP induced platelet-fibrinogen binding
Neutropenia and TTPHematologic monitoring required
TASS: Reduction in stroke risk compared to ASA was 34% for 5 yrs. In pts w/prev event
CATS: Reduction after stroke 33% over 3 years compared to placebo
CATS
ticlopidine placebo 1072 patients 1 week to 4 months after
stroke 2 years RR=0.61 (0.44 - 0.84) NNT=15 (9 - 41)
Aggrenox ©
Large European trial22% reduction on stroke Risk in pts who’d
previously had stroke compared to ASA
Aggrenox ©
European Stroke Prevention Study 2 (ESPS2)6,600 patients. 37% reduction compared to placebo22% compared with ASA
Plavix © European Trial:
No significant reduction of stroke alone risk compared with ASA, but trend.
But 7% reduction in 3 endpoints as group: stroke, MI, Periph vasc occl
ASA “failures”, Persons unable to use ASA
? ASA + Plavix
Statins:
HMGCoA reductase inhibitors decrease stroke risk by 31%Stroke 1997 28:944
SPARCL Study
4731 post stroke/TIA patients 80 mg atorvastatin, 4.9 yy average LDL signif lowering 73 v 129 for placebo 22% reduction in subsequent strokes 55 v 33 hemorrhagic strokes diff to explain NEJM (2006) 355:549 Amarenco P, et al Statins in stroke prevention and
carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35:2902-2909.
Pravastatin
J Shepherd et al. Prevention of coronary heart disease with privastatin in men with hypercholesterolaemia. NEJM, 1995 333:1301-7.
6595 men 45-64 years cholesterol over 6.5 mmol/L
Pravastatin placebo 4.9 years RR=0.90 (0.61 - 1.34) NNT=641 (135 - no benefit)
Other Issues
Heparin Use
Not generally recommended.
But: Use Heparin for Specific circumstances Mechanical heart valve, Afibr, atr or ventr
thrombus, ventr aneurysm “cardiogenic stroke” Arterial dissection, threatening thrombus Venous sinus thrombosis with or w/o
hemorrhage. Serious basilar stroke Stroke in progress/crescendo TIA
Heparin
It is recommended that, bolus injections of heparin be avoided because of reported symptomatic hemorrhagic transformation.
Heparin for Cardioembolic Stroke: Afibr: Stroke recurrence is low, much less
than 1%/day in first 2 weeks Large stroke: wait 48-72 hours and repeat
CT Small stroke: use judgment
Heparin “bridge”: Controversial
Use of heparin in hospital until Coumadin alters clotting may slightly decrease early stroke
But it increases early hemorrhage Lovenox (enoxaparin) at home. Similar
thoughts
Anticoagulant bridge
Makes sense forMechanical valveAngry lesions likely to embolizeHi early risk of hemorrhage
Low molecular heparin
One study of low molecular weight heparin administered within 48 hours of symptom onset showed a decrease in death or dependency 6 months after stroke.
Biller J, et al. A dose escalation study of Org 10172 (low molecular weight heparinoid) in the treatment of acute cerebral infarction. Neurology. 1989;39:262-265.
Heparin
There is no large clinical trial in the literature comparing i.v. heparin as traditionally administered to placebo
International Stroke Trial: compared s.q. heparin at comparable doses to asa and neither in 19435 patients: result: heparin was not beneficialLancet. 1997;349:1569-81
Heparinoids
TOAST trial: indicated no benefit for a LMW heparinoid in stroke (ORG 10172)Stroke. 1998;29:286
Low Mol Wgt Heparin
Studies indicate Variable Effectiveness
Jury is Still Out
Low-molecular-weight heparin for the treatment of acute ischemic stroke [see comments]CM: Kay-R; Wong-KS; et al. N-Engl-J-Med. 1995 Dec 14; 333(24): 1588-93
Nimodipine
Siesjo BK. Calcium and ischemic brain damage. Eur Neurol. 1986;24:45-56.
Gelmers HJ, Gorter K, deWeerdt CJ, Wiezer HJA. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med. 1988;318:203-207.
STEROIDS IN STROKE
No improvement in clinical trials.
Infection more common
“not indicated in the emergent management of cerebral edema complicating ischemic stroke.”
Thrombophlebitis
Prophylactic administration of heparin or low-molecular-weight heparins or heparinoids to prevent deep vein thrombosis is strongly recommended for immobilized patients
Stockings and mechanical motion devices
Physical therapy
Mobilization
Early mobilization and measures to prevent the subacute complications of stroke (aspiration, malnutrition, pneumonia, deep vein thrombosis, pulmonary embolism, decubitus ulcers, contractures, and joint abnormalities) are strongly recommended
SURGERY FOR ICH
The best candidates for surgery may be patients with moderate to large hematomas who are still awake. At the present time there is no definitive proof of the value of early evacuation of deep intracranial hematomas.
CEREBELLAR HEM. AND INFARCTION
Hemorrhage or an infarction can rapidly produce critical brainstem compression and threaten the life of the patient. They are often surgical emergencies.
CEREBELLAR HEM & INFARCTION
Surgical removal of an edematous cerebellum or a cerebellar hematoma may be life-saving and the residual neurologic deficit negligible
Aspiration
Consider it early to prevent pneumonia
NPO for patients with significant deficit or those at risk for progression
Speech Therapy Evaluation
Water swallow test DePippo KL, Holas MA, Reding MJ. Validation of the 3 oz. water swallow
test for aspiration following stroke. Arch Neurol. 1992;49:1259-1261.
Estrogen
Increases thrombogenesis Decrease LDL Chronic effect vs. Acute effect
Estrogen
Decrease risk of MI but only after 3rd yearJAMA 1998 280:605
Some Stroke Studies WASID trial: Warfarin v. asa TASS: Ticlopidine ASA stroke Trial CATS: Canadian ASA Ticlopidine Study ECASS: European Cooperative Acute Stroke Study IST: International Stoke Trial CAPRIE: Clopidigrel vs. ASA in Pts at Risk of Ischemic
Events 19185 pts ACAS: Assymp carotid artery study European Stroke Prevention Study 2 (ESPS2) 6600
patients
1. M Gent et al. The Canadian American ticlopidine study (CATS) in thromboembolic stroke. Lancet 1989 i: 1215-20.
2. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Journal of the American Medical Association 1991 265: 3255-64.
3. B MRC trial of treatment of mild hypertension: principal results. British Medical Journal 1985 291: 97-104.
4. Dahlöf et al. Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-hypertension). Lancet 1991 338:1281-5.
5. Swedish aspirin low-dose trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991 338:1345-9.
6. MRC trial of treatment of hypertension in older adults: principal results. British Medical Journal 1992 304:405-12.
7. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994 344: 1383-9.
8. J Shepherd et al. Prevention of coronary heart disease with privastatin in men with hypercholesterolaemia. New England Journal of Medicine 1995 333:1301-7.
9. HC Diener et al. European stroke prevention study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. Journal of Neurological Sciences 1996 143: 1-13.
Evidence based Stroke Care
Louis Caplan Arch Neuol 2008 “Tyranny of Majority” Single cases drowned in data of large
patient numbers
Cochrane Review of Evidence based Acute Stroke Pathways:
No difference in Outcomes or Discharge Destinations
Pathway: More neuro-imaging Less Satisfaction, Quality of Life Less UTIsNo Evidence Pathways improve outcomes
Cochrane: Kwan Sandercock, 2004 (Cochrane.org)
