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Evidence-based Stroke Care Charles S. Yanofsky,MD Grand Rounds September 25, 2008 Pinnacle Health EVIDENCE-BASED STROKE CARE Charles S. Yanofsky, MD Pinnacle.

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Presentation on theme: "Evidence-based Stroke Care Charles S. Yanofsky,MD Grand Rounds September 25, 2008 Pinnacle Health EVIDENCE-BASED STROKE CARE Charles S. Yanofsky, MD Pinnacle."— Presentation transcript:

1 Evidence-based Stroke Care Charles S. Yanofsky,MD Grand Rounds September 25, 2008 Pinnacle Health EVIDENCE-BASED STROKE CARE Charles S. Yanofsky, MD Pinnacle Health Neurology Sept. 25, 2008

2 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 disability  5 yr recurrence30%-50 percent  >four million Americans living with the consequences of stroke

3 Counterintuitive Stroke Mngt  See stroke tables:  Comprehensive study list in table form ROKEAHA v1  Guidelines for the Early Mngt of Adults with Ischemic Stroke (2007) Adams et al

4 Stroke Ideal Topic for Evidence Based Approach Evidence Based = Empirical What You think is true, isn’t What Works, is

5 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

6 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.

7 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

8 Medicine =school of hard knocks. Utterly Empirical Experience teaches: Reasonable surmise is false. Stroke care is primary example Counterintuitive

9 Medical Wisdom Don’t think too much Stick to the Program Leave nothing undone Race goes to the meticulous

10 Stroke Care 1. Prevent complications  Aspiration  DVT  Complications 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

11 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

12 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

13 What Matters Cadre of Experienced Personnel.  Stroke Beds  Stroke Nurses  Stroke Team Prevention of Secondary Complications  Aspiration, DVT, Comorbidities Treat Processes that affect Outcomes

14 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.

15 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.

16 Empirical Treatments of Stroke Summary What you think is true is not. Don’t be smart. Be Meticulous. Follow the Rules. Develop Expertise

17 Fatal stroke

18 Issues Acute Stroke Management T-PA Exclusions Risk factors e.g. hypertension

19 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


21 T-PA for Acute Ischemic Stroke NEJM (1995)333:  624 patients randomized  3 hour window  at three mos. 30% more likely to have minimal or no disability  6.4% risk of hemorrhage  No change in mortality at 6 mos

22 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.

23 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:

24 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

25 Eligibility Ischemic stroke with clearly defined time of onset Clear deficit measurable on NIHSS Baseline CT negative for hemorrhage

26 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

27 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

28 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

29 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

30 HEMORRHAGE AND t-PA Symptomatic intracranial hemorrhage (ICH) occurred in 6.4% of patients treated with t-PA in the NINDS-sponsored study

31 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:

32 Mayo Clin Proc. 1997;72: © 1997

33 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.

34 Cleveland Study Jama ,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.


36 Left hemisphere stroke

37 MCA Sign


39 Modifiable stroke risks Smoking Heart disease (Afib) Hypertension TIA Increased RBC Cholesterol/lipids physical inacivity Etoh abuse

40 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).

41 Framingham Cohort relative 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 (1 st vs 4 th qtle) 1.82

42 Treatment of HTN Numbers Needed to Treat MRC [1) 17,354 individuals years diastolic mmHg, 5.5 years NNT=850 to prevent one stroke at one year SHEP [3] 4736 individuals 60 years or older systolic mmHg & diastolic <90 mmHg, 4.5 years RR=0.65 ( ), NNT=43 ( ) STOP [4]1627 individuals years systolic mmHg & diastolic 100 mmHg or diastolic mmHg 4 years, RR=.55 ( ), NNT=34 ( ) MRC [6] 4396 individuals years systolic mmHg diastolic <115 mmHg, 5.8 years RR=0.76 ( ), NNT=70 ( )

43 Diastolic BP Every 7 points doubles your stroke risk

44 HTN But consider lacunar strokes. Synergy of Diabetes L’etat lacunaire

45 Lessons Follow empirical rules Don’t stop thinking

46 Acute Treatment

47 Recommended Tests CT 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)

48 Radiology Ancillary Tests CT or MR Angio Perfusion/Diffusion studies  CT v. MRI  “Mismatch” – brain at risk

49 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

50 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

51 Transesophageal Echo Young Stroke Non-atherosclerotic cause suspected Look for anomalies often missed by TTE  PFO w/ atr septal aneurysm  Atrial myxoma  Subtle valve abns as in SBE  Aortic atheroma/anomalies

52 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

53 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

54 Stroke Dichotomy Atherosclerotic v. non-atherosclerotic (= esoteric) Even in young, atherosclerotic stroke predominate.

55 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.

56 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

57 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.

58 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

59 Blood Pressure (preferred agents) Preferred agents include intravenous labetalol or enalapril. Some investigators have also used nitropaste Nicardipine 5-15 mg/Hr iv

60 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).

61 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.

62 Goals for BP in Stroke <220/120 :Ischemic Stroke <200 :Heparin <185/110 :t-PA

63 Glucose Elevated levels enhance neuronal injury Human studies >180 increases infarct volume Maintain levels betw 60 and 180

64 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.

65 Temperature Increase temp increases percentage of poor outcome in stroke Increase cerebral oxygen/substrate consumption  Lancet 1996:422

66 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.

67 Fever: Treatment Treat any temperature elevations Data is not in as to whether hypothermia may be protective

68 CEREBRAL EDEMA Hypo-osmolar fluids, such as 5% dextrose in water, may worsen edema. 1/2NS or NS recommended

69 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

70 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.

71 Modifying Risks

72 Risks 1 Identified arterial lesion Atrial fibrillation (Framingham) Past vascular event Smoking

73 Risks 2 African American Diabetes Hypertension Family History Coronary Artery Disease

74 FRAMINGHAM ATRIAL FIBRILLATION Quadruples stroke risk Doubles Stroke Death Rate

75 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)

76 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.

77 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.

78 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)

79 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%

80 Carotid Endarterectomy :Evidence Based Review Neurology 2005;65: Symp >70% level A Symp 50-69% level B Not indicated <50% level A Assympt >60% iff stroke/death <3% level A ASA mg before and after endarterectomy Level A

81 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%

82 ACAS 1662 Patients, multiple centers >60% carotid stenosis <3% perioperative M/M 5 year risk of stroke/death 5.1% surgical patients 11% medical group 53% aggregate risk reduction

83 Antiplatelet Agents Aspirin Plavix (Clopidogrel) Ticlid (Ticlopidine) Aggrenox© Asa 25 mg + Dipyridamole 200 mg.

84 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%.

85 Ticlopidine © ADP induced platelet-fibrinogen binding Neutropenia and TTP Hematologic 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

86 CATS ticlopidine placebo 1072 patients 1 week to 4 months after stroke 2 years RR=0.61 ( ) NNT=15 (9 - 41)

87 Aggrenox © Large European trial  22% reduction on stroke Risk in pts who’d previously had stroke compared to ASA

88 Aggrenox © European Stroke Prevention Study 2 (ESPS2) 6,600 patients. 37% reduction compared to placebo 22% compared with ASA

89 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

90 Statins: HMGCoA reductase inhibitors decrease stroke risk by 31%  Stroke :944

91 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:

92 Pravastatin J Shepherd et al. Prevention of coronary heart disease with privastatin in men with hypercholesterolaemia. NEJM, : men years cholesterol over 6.5 mmol/L Pravastatin placebo  4.9 years  RR=0.90 ( )  NNT=641 (135 - no benefit)

93 Other Issues

94 Heparin Use Not generally recommended.

95 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

96 Heparin It is recommended that, bolus injections of heparin be avoided because of reported symptomatic hemorrhagic transformation.

97 Heparin for Cardioembolic Stroke: Afibr: Stroke recurrence is low, much less than 1%/day in first 2 weeks Large stroke: wait hours and repeat CT Small stroke: use judgment

98 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

99 Anticoagulant bridge Makes sense for  Mechanical valve  Angry lesions likely to embolize  Hi early risk of hemorrhage

100 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 (low molecular weight heparinoid) in the treatment of acute cerebral infarction. Neurology. 1989;39:

101 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 patients: result: heparin was not beneficial Lancet. 1997;349:

102 Heparinoids TOAST trial: indicated no benefit for a LMW heparinoid in stroke (ORG 10172) Stroke. 1998;29:286

103 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 Dec 14; 333(24):

104 Nimodipine Siesjo BK. Calcium and ischemic brain damage. Eur Neurol. 1986;24: Gelmers HJ, Gorter K, deWeerdt CJ, Wiezer HJA. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med. 1988;318:

105 STEROIDS IN STROKE No improvement in clinical trials. Infection more common “not indicated in the emergent management of cerebral edema complicating ischemic stroke.”

106 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

107 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

108 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.

109 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.

110 CEREBELLAR HEM & INFARCTION Surgical removal of an edematous cerebellum or a cerebellar hematoma may be life-saving and the residual neurologic deficit negligible

111 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:

112 Estrogen Increases thrombogenesis Decrease LDL Chronic effect vs. Acute effect

113 Estrogen Decrease risk of MI but only after 3 rd year  JAMA :605

114 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 pts ACAS: Assymp carotid artery study European Stroke Prevention Study 2 (ESPS2) 6600 patients

115 1.M Gent et al. The Canadian American ticlopidine study (CATS) in thromboembolic stroke. Lancet 1989 i: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Journal of the American Medical Association : B MRC trial of treatment of mild hypertension: principal results. British Medical Journal : Dahlöf et al. Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-hypertension). Lancet : Swedish aspirin low-dose trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet : MRC trial of treatment of hypertension in older adults: principal results. British Medical Journal : Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet : J Shepherd et al. Prevention of coronary heart disease with privastatin in men with hypercholesterolaemia. New England Journal of Medicine : HC Diener et al. European stroke prevention study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. Journal of Neurological Sciences : 1-13.

116 Evidence based Stroke Care Louis Caplan Arch Neuol 2008 “Tyranny of Majority” Single cases drowned in data of large patient numbers

117 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 UTIs No Evidence Pathways improve outcomes Cochrane: Kwan Sandercock, 2004 (

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