management of acute ischaemic stroke

Management of Acute Ischaemic StrokeRecommended Practice Guidelinesas a Component of Disease Management

Søren Paaske Johnsen, Steen Elkjær Husted and Anne ThomassenAarhus County Hospital, Aarhus University Hospital, Aarhus, Denmark

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3111. Magnitude of the Stroke Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3122. Organisation of Healthcare Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

2.1 Public Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3132.2 Emergency Medical Systems (EMS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3132.3 Hospital Admission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

3. Evaluation of the Stroke Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3143.1 Computerised Tomography (CT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3153.2 Magnetic Resonance Imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3153.3 Imaging of the Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

4. Treatment of Acute Ischaemic Stroke (IS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3164.1 Thrombolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3164.2 Anticoagulant/Antiplatelet Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3174.3 Neuroprotective Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

5. Treatment and Prevention of Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3185.1 Cardiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3185.2 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3185.3 Hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3195.4 Hyper/Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3195.5 Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3195.6 Complications of Immobilisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3195.7 Neurological Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

6. Rehabilitation and Discharge Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3207. Prevention of Recurrent Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

7.1 Risk Factor Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3217.2 Antiplatelet Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3227.3 Anticoagulant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3237.4 Carotid Endarterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3237.5 Carotid Angioplasty and Stenting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

Abstract Stroke is a leading cause of death and disability and continues to have a greatpublic health impact worldwide. Management of patients with acute ischaemicstroke (IS) has been, until recently, primarily supportive care. A better under-

REVIEW ARTICLE Dis Manage Health Outcomes 1999 Jun; 5 (6): 311-3271173-8790/99/0006-0311/$08.50/0

© Adis International Limited. All rights reserved.

standing of the mechanisms of stroke has stimulated a far more aggressive andactive treatment strategy, and stroke is now considered a state of medical emer-gency.Evidence-based protocols for the management of patients with stroke should

be implemented in all hospital departments involved in the diagnosis and treat-ment of such individuals. These protocols should include assessment, investiga-tion, immediate treatment and rehabilitation, as well as secondary prevention andrisk factor management strategies.Specialised stroke units are well documented initiatives for optimising the

management of patients with stroke and are central to the future of acute strokemanagement. Establishment of stroke units should receive top priority in strategicplanning within the area of stroke management.Immediate and precise evaluation of patients with assumed stroke, including

a computerised tomography scan of the brain followed by close monitoring, areessential for preventing medical and neurological complications and for achiev-ing the optimal outcome.Primary treatment of acute IS with thrombolysis is a therapy with substantial

risks, but at present is essentially the only available therapy for reversing orreducing effects of acute IS. Antiplatelet therapy with aspirin (acetylsalicylicacid) in the acute phase of IS also has a small but significant effect. Anticoagulanttherapy with heparin has not yet proven any net long term benefit in the treatmentof acute IS. Likewise, there are currently no convincing data on the efficacy ofneuroprotective drugs in a clinical setting.Every patient should have disability needs assessed as soon as possible and a

well conceived rehabilitation plan should be made based on the patient’s owngoals.To reduce the incidence of a subsequent stroke, secondary prevention is es-

sential. Prevention should primarily focus on detection and management of riskfactors for stroke, which in many cases influence both the risk of ischaemic andhaemorrhagic stroke. These risk factors include hypertension, atrial fibrillation,smoking, diabetes mellitus, alcohol abuse and hyperlipidaemia. In patients withIS, secondary prevention also includes antiplatelet therapy with aspirin and di-pyridamole or clopidogrel and the possibility of carotid endarterectomy.

1. Magnitude of the Stroke Problem

Stroke is a leading cause of death and disabilitythroughout the world. In the US alone 500 000 in-dividuals each year have a stroke and more than143 000 die.[1] Between 3 and 4million individualsin the US are stroke survivors. The economic con-sequences of stroke are considerable, with total costsin 1996 exceeding $US40 billion in the US eachyear if both direct costs (e.g. those associated withtreatment) and indirect costs (e.g. the value of lostproductivity) are included.[2] Stroke is thus an on-going burden to society, to the patients and to theirfamilies, and measures to lower the risk of stroke

and to limit the consequences of the acute illnessitself have major public health implications.Stroke is defined as a state of rapidly developing

focal or global neurological deficit due to a vascu-lar lesion which lasts longer than 24 hours or leadsto the patient’s death. This syndrome can be subdi-vided into different categories of which ischaemicstroke (IS) by far is themost common type account-ing for 80% of strokes or approximately 400 000cases each year in the US.[1]A transient ischaemic attack (TIA) is an acute

episode with focal neurological deficit lasting lessthan 24 hours followed by complete clinical recov-

312 Johnsen et al.

© Adis International Limited. All rights reserved. Dis Manage Health Outcomes 1999 Jun; 5 (6)

ery. Approximately one-third of patients with TIA,of which there are 50 000 a year in the US, willsubsequently develop an IS.[3]Management of patients with stroke has under-

gone dramatic changes in recent years owing toresults from numerous animal studies and clinicaltrials demonstrating the efficacy of acute diagnosisand treatment in reducing stroke morbidity andmortality. Stroke is now considered a state of med-ical emergency. This development has major im-plications for the medical system in general con-cerning early recognition, rapid transportation tohospital, immediate and precise evaluation andtreatment of patients with acute stroke.Systematic and comprehensive implementation

of clinical guidelines is needed if clinical researchis to result in increased quality of healthcare. How-ever, the traditional approaches, e.g. publication injournals and presentation at educational meetings,have proven to be insufficient.[4,5] Clinical guide-lines are defined as systematically developed state-ments designed to help clinicians make decisionsabout appropriate healthcare for specific circum-stances.[6] Use of clinical guidelines has increas-ingly been recognised as a valuable tool for over-coming the difficulties of closing the gap betweenresearch evidence and daily clinical practice. Dis-tribution of clinical guidelines in itself is, of course,of limited value, if it is not followed by a wellorganised local effort, e.g. continued education andtraining of doctors and other healthcare workers,or appropriate organisation of healthcare systems.Thus the guidelines presented in this article are anattempt to provide a basis for rational and evi-dence-based management of patients with strokefrom which protocols adjusted to local conditionscan be developed (table I).

2. Organisation of Healthcare Systems

Recognition of stoke as a medical emergencyimplies that changes are needed in the logistics ofstroke treatment if effective therapy is to be madeavailable to as many patients as possible.[7] Severalstudies of early intervention in stroke cases havedemonstrated that earlier intervention provides

better results than later intervention.[8,9] Many strokepatients, however, arrive at the hospital too late toreceive maximum benefit from the new inter-ventional stroke therapies. Studies evaluating timeto arrival for stroke patients have shown that onlya minority of patients arrive at hospital at a timewhen they are still eligible to receive thrombolytictherapy, especially outside the US.[10-14] Althoughonly a minority of patients will ever be eligible forthrombolysis they will all benefit from a more ex-peditious treatment. In order to achieve a rapidmedical response in the diagnosis and treatment ofpatients with acute stroke, a multilevel effort is re-quired as outlined in the following subsections.

2.1 Public Education

Firstly, it is essential that the general public isaware of symptoms and warning signs of strokeand are able to react rationally to this. Several stud-ies have documented a major lack of knowledge ofstroke in the general public and especially amongthe elderly, which is the group at the highestrisk.[15,16] Thus, public education programmes areneeded using the experience from previous educa-tion campaigns.[17] Public education should focuson the entire community with special attentiongiven to high risk populations. Information high-lighted should include a description of stroke symp-toms and approaches to modifying risk factors. Ifa person identifies stroke symptoms the local emer-gency number should be called immediately with-out further delay.[18]

2.2 Emergency Medical Systems (EMS)

Secondly, stroke management should be repriori-tised in emergency medical service systems as an

Table I. Components of a rational evidence-based managementstrategy for acute ischaemic stroke

Organisation of healthcare systemsEvaluation of the stroke patientTreatment of acute ischaemic strokeTreatment and prevention of complicationsRehabilitation and discharge planningPrevention of recurrent stroke

Guidelines for Managing Patients with Stroke 313


acute medical emergency. Patients with strokesymptoms should be treated with the same degreeof urgency as patients with acute myocardial in-farction or major trauma. To achieve these objec-tives, improved training of emergencymedical sys-tems (EMS) personnel (including dispatchers)should be conducted, focusing on early recognitionof symptoms, assessment and transport of patientswith stroke.[18]

2.3 Hospital Admission

For 3 decades the question of the most effectiveway of providing care for patients with stroke whoare admitted to hospital has been controversial.[19]However, recent data have shown the value ofspecialised stroke units beyond all reasonabledoubt.[20-22] The stroke unit staff includes physicians,nurses, physiotherapists, social workers, speech-language therapists and others. A recent systematicreview found that the stroke units are characterisedby coordinated multidisciplinary team care, special-ist interests among the staff in stroke and/or reha-bilitation, involvement of caregivers in the rehabil-itation process, and the provision of education andtraining in stroke.[19] The outcome of organisingstroke care in specialised stroke units is impres-sive: a long term (median follow up time 1 year)19% reduction of deaths [odds ratio (OR) = 0.81;95% confidence interval (CI) 0.68 to 0.96] primar-ily due to a lower mortality rate from complicationsof immobility and cardiovascular disease.[19] Forthe combined poor outcome of death or institu-tional care and death or dependency the resultswere even more in favour of stroke unit care (OR= 0.75; 95% CI 0.65 to 0.87 and OR = 0.71; 95%CI 0.60 to 0.84). In 100 patients treated in a strokeunit instead of receiving conventional care, 4deaths (95% CI –7 to 0) will be prevented, 1 patient(95% CI –4 to 1) less requires long term institu-tional care and 5 additional patients (95% CI 1 to8) return to their homes and can function inde-pendently. Furthermore, length of hospital admis-sion is reduced by 8% (95% CI 3 to 13%). All pa-tient categories appears to benefit from stroke unitcare regardless of gender, age and stroke sever-

ity.[19] Thus, better organisation of inpatient strokecare improves patient outcome and is likely to becost effective; therefore, it should receive top pri-ority in the future as stated in the Helsingborg Dec-laration on Stroke Management.[23] In areas or athospitals without the above mentioned expertise,transfer of stroke patients to stroke care units isrecommended.

3. Evaluation of the Stroke Patient

The first evaluation of an assumed stroke patientshould primarily focus on excluding other dis-eases/conditions which can be mistaken for stroke,e.g. hypoglycaemia, craniocerebral trauma, intra-cranial tumour, epilepsy or migraine. Secondly, theimportant differentiation between infarction andhaemorrhage should be made, and thirdly the strokemechanism should be established as a basis for fur-ther treatment.The basis of this evaluation is the patient history

and medical examination. Patient history shouldinclude information on the type and developmentof stroke signs, including the time of the first signsof stroke. Furthermore, information on pre-strokefunctional ability, medication, previous cerebro-vascular disease and risk factors should be ob-tained. A careful medical examination should beconducted to assess the general condition and neuro-logical status of the patient in order to estimate apreliminary prognosis and initiate an appropriatetreatment plan.[7] The neurological status includesa standardised level of consciousness (e.g. GlasgowComa Scale), a stroke deficit scale (e.g. NationalInstitutes of Health or Scandinavian Stroke Scale)and a measure of global disability (e.g. modifiedRankin Scale), with special attention to focal neuro-logical signs such as hemiparesis, aphasia, dysar-thria or hemianopsia combined with assessment ofswallowing, bladder and bowel function and thepossibility of development of pressure sores.[18]A number of clinical investigations are relevant

to the stroke patient. Some of these should be per-formed on an emergency basis for almost every pa-tient, whereas others are not routine. Table II liststhe investigations that are of value in the initial

314 Johnsen et al.


stroke evaluation, whereas table III lists additionalinvestigations.Since the clinical features of ischaemic and

haemorrhagic stroke do not permit a reliable diag-nosis on clinical examination alone, supplementaryinvestigations are needed. These include variousimaging techniques which are essential to definethe type and localisation of the stroke as well as thesize and age of the lesion.[24]

3.1 Computerised Tomography (CT)

Anon-contrast enhanced CT scan of the head isrecommended as the initial brain imaging proce-dure.[7,18,24] The ability of this test to detect intra-cerebral haemorrhage (sensitivity: 100%) andsubrachnoid haemorrhage (sensitivity: 96%) is im-pressive.[24] Sensitivity is more modest when itcomes to detecting ischaemic infarction, but thesensitivity rises sharply with time after stroke on-set. Afollow-up CT scan after 2 to 7 days can there-fore be of relevance if the initial scan is nega-tive.[24] CT scan of the head should be performedon all patients with acute stroke unless the patientis terminal. The test should be performed on anemergency basis if intracerebral or subarachnoidhaemorrhage is suspected, if there are progressivesymptoms, if there is a history of recent head traumaor if the patient is eligible for thrombolysis. Otherpatients should have a CT scan within 24 hours.

3.2 Magnetic Resonance Imaging (MRI)

MRI is more sensitive than CT for detecting is-chaemic infarction, brain stem infarction, post-infarct oedema and early signs of haemorrhagicinfarction.[24] The test is, however, limited by rel-atively high costs and low availability as well asbeing less sensitive in detecting early intracerebralhaemorrhage. Thus, MRI is not recommended as aroutine test for acute stroke but can be used as asupplement in specific situations.[24]

3.3 Imaging of the Vessels

Imaging of cervicocerebral vessels can provideessential information on the mechanism of strokeor TIA. Different techniques are available, e.g. ultra-sound, MRI angiography, CT angiography, con-ventional angiography and single-photon emissioncomputed tomography (SPECT), but none of theseare necessary in the initial diagnostic phase andshould not delay treatment.[24] Anoninvasive screen-ing test like carotid duplex or Doppler ultra-sonography is indicated for patients with TIA andpatients with confirmed IS, who have recovered.When noninvasive tests indicate a ≥70% stenosisin the appropriate carotid artery, a conventional ra-diographic angiography should be considered as aprerequisite before endarterectomy.[24]Lumbar puncture for detection of blood in the

cerebrospinal fluid is only rarely indicated if CT ofthe head is negative but should be performed with-

Table II. Tests in the initial evaluation of acute stroke

Non-contrast enhanced computerised tomography of the head12-lead ECGChest x-rayBlood testscomplete blood countplatelet countinternational normalised ratiopartial thromboplastin timeglucose levelserum electrolyte levelsarterial blood gas measurements (if hypoxia is suspected)liver function tests (if hepatoencephalopathy is suspected)

Blood pressureBody temperature

Table III. Additional tests after the initial phase

Magnetic resonance imaging of the brainCarotid duplex scanArteriographyTransthoracic echocardiographyTransesophageal echocardiographyFasting lipid profileScreening for a prothrombotic state in patients <55 years of age(e.g. anticardiolipin antibodies, lupus anticoagulants, antinuclearantibodies, protein C and S,a antithrombin,a serum fibrinogenlevel, plasma homocystine, factor V Leiden, prothrombin 20210Amutationa)Ambulatory electrocardiographic monitoringSyphilis serologya Only in patients with a family history of thromboembolic disease.



out delay if subarachnoid haemorrhage is still sus-pected.[7,18]Blood pressure, body temperature and a limited

number of basic blood tests, including arterial bloodgas (if hypoxia is suspected), should be obtainedtogether with a 12-lead ECG and a chest x-ray.

4. Treatment of Acute IschaemicStroke (IS)

4.1 Thrombolysis

Primary treatment of IS with thrombolysis isbased on the perception that rapid reperfusionthrough an occluded cerebral artery can restorenormal function in the ischaemic neural tissue andthus minimise the consequences of stroke. Six largerandomised trials of thrombolysis in stroke havebeen published in recent years, 3 with intravenousstreptokinase and 3 with alteplase (rt-PA).[25-27]The streptokinase trials were all terminated beforecompletion due to a high frequency of complica-tions among patients treated with the thrombolyticagent compared with those who received placebo.Of the 3 major alteplase trials, 2 were equivocal[EuropeanCooperativeAcuteStrokeStudy (ECASS)and ECASS II] and one had a positive outcome[National Institute of Neurological Disorders andStroke Study (NINDS)].[8,9,28] Compared with thealteplase trials, the streptokinase trials were com-promised by inclusion of patients with more severestroke, greater use of antithrombotic therapy, e.g.heparin and aspirin (acetylsalicylic acid), higherdoses of therapy and longer interval to treatmentwith thrombolytic therapy.[25]ECASS compared alteplase with placebo in 620

patients with acute IS treated within 6 hours anddemonstrated no effect on 90-day disability out-come, but a significantly higher mortality at 3months in the alteplase group (22.4 vs 15.8%, p =0.04).[8] There was also a 3-fold increase in largeparenchymal haemorrhages in the alteplase group(19.8 vs 6.5%, p < 0.001). Protocol violations in 109of 620 patients were an important contributing fac-tor to the overall negative outcome.[8,27]

NINDS was a 2-part study that compared al-teplase with placebo in 624 patients with acute IStreated within 3 hours. At 90 days there was a 12%absolute increase in the number patients exhibitingfavourable outcome (i.e. minimal or no neurologi-cal deficits or disabilities) in the alteplase groupcompared with the placebo group. Odds ratio forfavourable outcome was 1.7 (95% CI: 1.2 to 2.6).There were significantly more brain haemorrhagesamong alteplase recipients than placebo recipients(6.4 vs 0.6%, p < 0.001), but no increase in mortal-ity (17 vs 21%, p < 0.3).[9] The results fromNINDSled the US Food and Drug Administration to ap-prove the use of alteplase within 3 hours of acute IS.ECASS II used a lower dose of alteplase and

more rigorous inclusion criteria than ECASS, butthe same time window of ≤6 hours from onset ofsymptoms for administration of study treatment.[28]There was no significant difference for the primaryendpoint, which was favourable outcome on themodified Rankin scale (0 or 1) [40.3 vs 36.6%, p <0.277]. However, a post-hoc analysis of the outcomeindependence (modified Rankin scale ≤2) found asignificant benefit of alteplase treatment (54.3 vs46.0%, p < 0.024).A recently presented meta-analysis of ECASS,

ECASS II and NINDS on the outcome death ordisability (modified Rankin scale ≥3) demonstrateda significant benefit of alteplase, especially if givenwithin 3 hours (OR3h = 0.55, OR6h = 0.68). Num-bers needed to treat to prevent 1 death or disabilitywere 7 and 11 patients, respectively, in the 3-hourand 6-hour groups.[29]Several new studies have recently been presented,

including the Atlantis rt-PA (alteplase) AcuteStroke Trial (ATLANTIS), a studywhich evaluatedintravenous alteplase administered within 3 to 5hours of the onset of symptoms. The results wereneutral for all end-points except formore intracran-ial haemorrhages in the alteplase group (7.4 vs0.7%, p = 0.001).[30] Another study, RecombinantPro-urokinase in Acute Cerebral Thromboembolism(PROACT II) tested treatment with local interarter-ial pro-urokinase (r-ProUK) within a 6-hour timewindow in 180 patients with angiographically

316 Johnsen et al.


proven middle cerebral artery occlusion. 12 323patients were screened for this study. A significantbenefit was demonstrated for r-ProUK comparedwith placebo (40 vs 25%, p < 0.05) in terms of theprimary end-point (modified Rankin score ≤2).[31]There was a significant excess of symptomatic in-tracranial haemorrhages in the active treatmentgroup (10.2 vs 1.8%, p < 0.01). In a study of 500patients treated within 3 hours from onset of strokewith ancrod, a selective defibrinogenating agentderived from the venom of Malayan pit viper. Pri-mary end-point was independence at 90 days, andancrod was associated with a positive outcome(41.1 vs 35.3%, p = 0.041).[32] There was no sig-nificant excess of intracranial haemorrhages in thistrial in contrast to the trials with alteplase and r-ProUK.Thrombolysis is thus a therapy with substantial

risks but also the potential of major benefits. Atpresent it is our only available therapy for revers-ing or reducing the effects of acute IS.The use of thrombolysis within 3 hours after

stroke in selected patients is supported by recenttrials, whereas the documentation of a net benefitof thrombolysis therapy started beyond 3 hours isstill limited. However, major issues remain unre-solved before routine use can be initiated. For ex-ample, we need to define the subgroups of patientswhomight benefit most from thrombolysis, as wellas the type of agent and optimummode of delivery.Strict eligibility criteria is of decisive importancein order to achieve positive results with this ther-apy. In the future, a combination of thrombolytictherapy with neuroprotective agents and maybealso new antithrombotic drugs, like glycoproteinIIb/IIIa complex antagonists, may extend the timewindow for administration of thrombolytic agentsand markedly improve outcomes for patients withacute IS.[27]

4.2 Anticoagulant/Antiplatelet Therapy

The effect of aspirin (acetylsalicylic acid) in theacute phase of IS has been evaluated in 2 recentmegatrials with a total of more than 40 000 pa-tients, the International Stroke Trial (IST) and the

Chinese Acute Stroke Trial (CAST).[33,34] A com-bined analysis of IST and CAST showed a smallbut statistically significant effect, with 9 (SD ± 3)avoided deaths or nonfatal strokes per 1000 treatedpatients within the first few weeks (p = 0.001).These trials suggest that aspirin should be startedas soon as possible after the onset of acute IS inhospitalised patients. Furthermore, immediate treat-ment with aspirin is likely to increase the propor-tion of patients who are discharged on an antiplate-let drug. Use of aspirin in the acute phase inpatients undergoing thrombolytic therapy is notrecommended, at least not with streptokinase, be-cause of an increased risk of bleeding.[35]The use of antithrombotic agents like unfraction-

ated heparin (UFH), low-molecular-weight hepa-rin (LMWH) and heparinoids in the treatment ofIS has been the source of discussion for severalyears, partly because of lack of sufficient data onthe efficacy and safety of these agents. Earlier trialshave been very small, but in recent years severallarger trials have been published.Besides evaluating aspirin, IST was also de-

signed to evaluate the benefit of low-dose [5000IUsubcutaneously (SC) twice daily] or medium-dose(12 500IU SC twice daily) UFH alone or in com-bination with aspirin. The study showed a nonsig-nificant trend towards fewer deaths within 14 daysamong UFH-allocated patients (9 vs 9.3%), corre-sponding to 3 (SD ± 4) fewer deaths per 1000 pa-tients. At 6 months, the percentage of dead or de-pendent patients was identical (62.9%) with orwithout UFH therapy. Treatment with UFH within48 hours of an IS prevented 9 recurrent strokes per1000 patients, but also caused 8 more cases of in-tracranial haemorrhages.[33] Medium-dose UFHtreatment was associated with a significantlyhigher number of transfused patients or patientswith fatal extracranial bleeding, more haemor-rhagic strokes, and more deaths or non-fatal strokeswithin 14 days (12.6 vs 10.8%) compared withlow-dose UFH treatment. There were no signifi-cant differences at 6 months between low- andmedium-dose UFH-allocated patients.



Nadroparin, a LMWH, was evaluated in a smallerrandomised, double-blind, controlled study of 308patients.[36] The study showed a significant dose-dependent effect of LMWH in lowering the risk ofdeath or dependency at 6 months (p = 0.005). Nosignificant differences, however, were present at10 days or at 3 months. The changes in outcomesbetween 3 and 6 months may be attributable to pro-gressive recovery in the LMWH-treated patients ow-ing to treatment-induced smaller infarct volumes,[36]but the delay in benefit sheds doubt on whether theeffects are directly related to the LMWH treatment.TheTrial ofORG10172 inAcuteStrokeTreatment

(TOAST) was a randomised, double-blind, placebo-controlled trial evaluating danaparoid sodium (alow molecular weight heparinoid) in the treatmentof 1281 patients with acute IS. The trial demon-strated an early apparent positive effect of treatmentat 7 days with ‘favourable outcome’ rated as thecombination of a Glasgow Outcome Scale Score of Ior II, and a modified Barthel Index of 12 or greateron a scale of 0 to 20 and ‘very favourable outcome’rated as the combination of a Glasgow OutcomeScale of I and a Barthel Index of 19 or 20. However,a significant improvement in favourable or veryfavourable outcomes at 3 months was not found.[37]Treatment with UFH or LMWH thus clearly re-

duces the incidence of deep vein thrombosis (DVT)in immobilised stroke patients,[7,18,38,39] but has notyet shown any convincing net long term benefit inthe treatment of acute IS.

4.3 Neuroprotective Therapy

The basic mechanisms of ischaemic neural in-jury have been identified in recent years. Anumberof biochemical reactions constitute the so-calledneuronal injury cascade, which offers multiple tar-gets for pharmacological protection with neuro-protective drugs. Several new agents have been de-veloped and testedwith promising results in animalstudies.[27,30] These medications may not only beeffective in limiting the extent of brain injurycaused by IS, but also in expanding the time win-dow available for administration of thrombolyticdrugs.[27] Although convincing data are not yet avail-

able demonstrating the efficacy of any neuropro-tective drug in a clinical setting, new trials are under-way that were designed taking into considerationthe experiences obtained in earlier negative stud-ies.[27,40,41]

5. Treatment and Preventionof Complications

Close monitoring is essential for optimising careand preventing the development of neurologicaland other medical complications in patients withacute stroke. During the first 24 hours the monitor-ing should ideally include continuous ECG, oxygensaturation, blood pressure and body temperature.[38]Level of consciousness, neurological function, bloodglucose level, fluid balance and haematocrit shouldbe monitored intermittently.[38] The intensity of themonitoring should, of course, be individualised ac-cording to the patient’s needs.

5.1 Cardiac Disease

The association between heart disease and strokeis strong, e.g. more than 40% of post-stroke deathsover 5 years are related to cardiac disease.[38,42,43]It is well known that cardiac arrhythmias, e.g. atrialfibrillation (AF), can be the cause of stroke on acardioembolic basis, but arrhythmias can also beinduced by stroke.[38,42] Moreover, myocardial in-farction can present clinically as an acute IS.[18] Thus,close monitoring is required during at least the first24 hours and can, on an individual basis, be supple-mented with transthoracic or transoesophageal echo-cardiography and serum levels of troponin T or cre-atine kinase (MB fraction).

5.2 Hypertension

Arterial hypertension is very common in patientswith acute stroke, but despite years of debate, dis-agreement still exists concerning the managementof hypertension in the acute phase of stroke.[44,45]No definite data from controlled clinical trials areavailable. Most guidelines,[7,18,38] however, recom-mend a non-aggressive approach towards elevatedarterial pressure in acute stroke.

318 Johnsen et al.


Loss or impairment of autoregulatory mecha-nisms of cerebral blood flow owing to a longstand-ing history of hypertension, or the infarction it-self[46,47] makes cerebral perfusion very sensitiveto even modest reductions in arterial pressure inmany patients with acute stroke. A decrease inmean arterial blood pressure exceeding 15mmHg/24 hours has been shown to decrease cerebralperfusion.[48] Furthermore, elevated blood pres-sure has a tendency to spontaneously decline dur-ing the first days after a stroke.[49] Thus, it is rec-ommended that high blood pressure should not betreated routinely in the acute phase of stroke, un-less there is hypertensive encephalopathy, whichcan be diagnosed with ophthalmoscopy, or a sys-temic cardiovascular emergency.[46] However, ifthe blood pressure is markedly elevated, e.g. meanpressure 140mm Hg or systolic pressure 220mmHg, at consecutive measurements, cautious treat-ment with an easily titrated drug that has minimalinfluence on cerebral blood flow (e.g. labetalol,metyldopa) could be started.[38] Special guidelinesregarding the management of hypertension areavailable for patients undergoing thrombolysis.[50]

5.3 Hyperthermia

Even moderate elevations in body temperaturemay markedly worsen neural injury followingacute stroke or head injury.[51] For each 1°C in-crease in body temperature the relative risk ofdeath or disability has been reported to rise by afactor of 2.2, independent of initial stroke sever-ity.[52] There have not been any randomised trialsof body temperature reduction in acute stroke, butit seems justified to recommend that body temper-ature should be maintained within the normother-mic range. To achieve this, antipyretics may beused and sources of infection should be identifiedand treated with antibiotics.[18,38,53] The effect oftherapeutic hypothermia in acute stroke is currentlybeing evaluated.

5.4 Hyper/Hypoglycaemia

Increased blood glucose levels in non-diabeticpatients with acute stroke are correlated with in-

creased mortality.[54,55] The effect of reducing ele-vated blood glucose levels is uncertain at present.Therefore, management of elevated blood glucoselevels including close monitoring in patients withacute stroke should be similar to that in patients withother diseases until further data are presented.[7,18,38]Intravenous administration of isotonic glucose(dextrose) solution is not recommended during thefirst few days of hospital admission in patients withacute stroke. However, in patients who are hypo-glycaemic, intravenous glucose should be admin-istered at once because hypoglycaemia is a wellknown cause of neurological deficit.[7,18]

5.5 Hypoxia

Patients with acute stroke are at great risk ofdeveloping hypoxia owing to hypoventilation, as-piration pneumonia or atelectasis.[7,18] There is noreason to routinely administer oxygen to patientswith acute stroke, but if hypoxia is evident it shouldbe given (although caution is advised for patientswith chronic bronchitis and emphysema). Earlymobilisation and close monitoring of body temper-ature are essential for reducing the risk of aspira-tion pneumonia and in the early treatment of pa-tients who develop this complication.[7]For patients with depressed levels of conscious-

ness, airway support and ventilatory assistancemay be appropriate to maintain adequate tissue oxy-genation. These patients should be admitted to anintensive care unit.

5.6 Complications of Immobilisation

Besides pneumonia, immobilisation results inan increased risk for development of DVT, pulmo-nary embolism and pressure sores. Routine use ofUFH or LMWH for prevention of DVT in patientswith acute IS is not recommended because of thepotential risk of intracranial haemorrhage. Instead,compression stockings, early mobilisation, frequentturning and careful positioning are recommendedin immobilised patients[7,18,19,38,39] in order to re-duce mortality from immobilisation-related com-plications.[56,57]



5.7 Neurological Complications

Following acute IS at least 20% of patients de-velop neurological deterioration primarily due tocerebral oedema, haemorrhagic conversion or re-infarction.[58,59] Brain oedema is the most frequentcause, with development of symptoms of raised in-tracranial pressure (ICP) during the first days afterstroke including headache, vomiting, gaze paresisand papilloedema.[38,59] Treatment is aimed towardsreducing ICP, maintaining adequate cerebral perfu-sion and preventing brain herniation.[7,18] Clinicalmonitoring and brain imaging are essential for earlydiagnosis. Initial treatment includes modest fluidrestriction, avoidance of hypotonic fluids and ele-vation of the head by 30°.[7,18,38] Further treatmentincludes osmotherapy, hyperventilation and even-tually surgical decompression, which can be life-saving if performed early.[60] Corticosteroids are notrecommended, as no beneficial effect has beenfound in clinical trials and treatment carries a riskof infection.[7,18,61,62]Seizures are common in patients with acute

stroke especially in the acute phase; however, nodata support the prophylactic administration of an-ticonvulsants in seizure-free patients.[18] Patientsexperiencing partial seizures can be treated withcarbamazepine or phenytoin, whereas status epi-lepticus can be treated with lorazepam or diaze-pam.[18,63]Depression in the acute phase of stroke, whichmay

pose serious problems for the rehabilitation process,has been reported in 17 to 64% of patients.[64,65]Treatment with a selective serotonin reuptake in-hibitor (citalopram) seems effective.[66] Citalopramhas also been reported to immediately abolish cry-ing episodes in patients with pathological crying,another frequent sequelae in stroke patients.[67]

6. Rehabilitation andDischarge Planning

Stroke rehabilitation is an active process startedat hospital admission and continued throughout ad-mission and after discharge.[68] The goal of reha-bilitation is to assist the patient in achieving and

preserving the maximum possible functional inde-pendency through an organised coordinated effort.Every patient should have disability needs assessedas soon as possible and a well conceived rehabili-tation plan should be made based on the patient’sown goals.[23,68] The qualifications for rehabilita-tion are significant functional disability, an abilityto learn, a reasonable medical stability and a min-imal level of physical endurance.[68]As mentioned in section 2.3, the stroke unit

model for care with a multidisciplinary team con-sisting of, for example, a physician, a nurse expe-rienced in stroke rehabilitation, a physiotherapist,an occupational therapist and a speech-languagetherapist will constitute the most effective basis forpatient rehabilitation.[19,21-23] It is not possible torecommend specific techniques but it seems impor-tant to use task specific techniques in an intensiveand patient-centred way.[23,69,70] Furthermore, therehabilitation should be planned in collaborationwith the patient’s family in order to supplement theformal training sessions with training by familymembers or friends.[23] This aspect of rehabilita-tion is particularly important after hospital dis-charge.Planning of discharge should be conducted in

close cooperation between the hospital and com-munity-based social services in order to achieve anunbroken chain of care. Moreover, a long term fol-low-up by local services is recommended with afollow-up referral to rehabilitation services ifneeded.[23]The area of stroke rehabilitation is unfortunately

filled with major gaps in knowledge and thus guide-lines within this area cannot claim to be evidencebased. Well conducted randomised trials on the ef-fectiveness of different techniques and strategiesare very much needed.

7. Prevention of Recurrent Stroke

Patients with IS have a markedly elevated riskfor recurrent atherothrombotic ischaemic eventsand death; 19% have a new event at the same or anew arterial site within a year, and the approximate1-year mortality is about 29%.[71-73] Secondary

320 Johnsen et al.


prevention is therefore essential for patients withstroke. Prevention should primarily focus on de-tection and management of risk factors forstroke,[74-77] which in many cases influence boththe risk of ischaemic and haemorrhagic stroke. Therelevant risk factors are well documented for theirrole in primary prevention of IS, but although theknowledge about predictive factors for stroke re-currence is growing, there is still a lack of clinicaltrial data on the effect of secondary prevention formost risk factors.Secondary prevention for IS also includes spe-

cific medical or surgical therapy, i.e. therapy withantiplatelet agents or warfarin and carotid endar-terectomy.

7.1 Risk Factor Intervention

7.1.1 HypertensionHypertension is the single most important mod-

ifiable risk factor for first IS,[74-77] and it has beenestimated that hypertension is responsible for al-most 50% of all IS.[77] The association betweenfirst IS and hypertension is found in both men andwomen, in all ages and ethnic groups and for alldegrees of elevated blood pressure.[78] Both dias-tolic and systolic blood pressure are independentrisk factors, although the relative risk is greaterwith an elevated systolic blood pressure.[78] In gen-eral, the relative risk of stroke is 3- to 4-fold greaterfor hypertensive than for normotensive individu-als. However, this rises to a 10-fold differencewhen comparing those in the highest blood pres-sure level range with those in the lowest bloodpressure level range, despite a difference of nomore than 30mm Hg between these groups.[79] Arise in diastolic blood pressure of just 7.5mm Hgalmost doubles the risk of IS.[79]Treatment of hypertension has a well docu-

mented effect and reduces the risk of first stroke by40%.[80] The effect is also seen among elderly pa-tients.[81,82]The association of blood pressure and the risk

of secondary stroke in individuals with a history ofcerebrovascular disease is not well established.[75,76]However, data from the United KingdomTransient

Ischaemic Attack Aspirin Trial (a trial aimed at as-sessing the effects of aspirin on the risk of second-ary stroke and other vascular events) indicate thatthe strength of the association between blood pres-sure and stroke in patients with a history of TIA orminor stroke is similar to that among individualswithout cerebrovascular disease.[83] Thus, a 5mmHglower diastolic blood pressure is associated with a34% reduction in risk of recurrent stroke.Four randomised clinical trials evaluating the

effects of blood pressure lowering on the risk ofsecondary stroke have been published.[84] These 4trials involved a total of 2742 patients, and com-bined results indicate that the risk of stroke wasnonsignificantly reduced by 19% for patients allo-cated to active treatment. Although this is a prom-ising result, it is not definitive evidence of an effectand further information is needed. Hopefully, in afew years the major Perindopril Protection AgainstRecurrent Stroke Study (PROGRESS) trial willprovide this information. PROGRESS is a rand-omised trial on the effects of an ACE inhibitor-based blood pressure lowering regimen on the riskof secondary stroke in 6000 patients with a historyof cerebrovascular disease.[84,85]

7.1.2 SmokingThe relative risk of primary IS associated with

cigarette smoking is 1.9 (95% CI 1.7 to 2.2).[86]The risk is higher for women than for men, higherfor younger than older persons and increases withthe number of cigarettes smoked.[86] Cessation ofsmoking results in a significant risk reduction by 2years and after 5 years is at the same level as non-smokers.[87] However, there are no data availableon patients with established prior IS.

7.1.3 Diabetes MellitusThe relative risk of IS is increased 2 to 3-fold in

patients with diabetes mellitus compared with non-diabetic individuals,[88,89] and diabetes may also in-crease the risk of stroke recurrence.[76] There exist,however, no data which demonstrate that optimis-ing glycaemic control reduces the risk of stroke inpatients with diabetes mellitus.



7.1.4 AlcoholFive percent of all strokes are attributed to

heavy alcohol consumption, and evidence suggestthat excessive alcohol use is a risk factor for bothischaemic and haemorrhagic cerebrovascular dis-ease.[77,90] Moderate alcohol consumption, however,seems to reduce the risk of both stroke and coro-nary artery disease, i.e. the relative risk of stroke inindividuals taking ≤2 drinks/day has been reportedto be 0.3 to 0.5 compared with nondrinkers.[91]

7.1.5 HyperlipidaemiaThe association between stroke and hyperchol-

esterolaemia is uncertain in the reported observa-tional studies,[92] and hypercholesterolaemia hasnot been considered a well documented risk factorfor stroke.[74] However, recently published meta-analyses[93,94] on the effect of therapy with thelipid-lowering statins (HMG-CoA reductase inhib-itors) in both primary and secondary prevention ofcardiovascular disease have supported a possibleassociation. Hebert et al.[93] found an average re-duction in serum levels of total- and low densitylipoprotein-cholesterol of 22 and 30%, respec-tively, and a 29% reduction in stroke risk in anoverview of 16 trials including about 29 000 pa-tients. Separate analyses were conducted for theprimary and secondary prevention trials, demon-strating a large and significant risk reduction of32% [risk ratio (RR) 0.68; 95% CI 0.55 to 0.85] inthe secondary prevention trials and a smaller non-significant risk reduction of 20% (RR 0.80; 95%CI 0.54 to 1.16) in the primary prevention trials.Bucher et al.[94] found a RR for fatal and non-fatalstroke with HMG-CoA reductase inhibitors of 0.76(95% CI, 0.62 to 0.92) in 8 trials. Whether the ben-eficial effect of statin therapy is mediated throughthe lipid-lowering effect alone or also through amore specific antiatherogenic effect is presently amatter of discussion,[95] but it seems possible thatstatins will have an important role in primary andsecondary stroke prevention.

7.2 Antiplatelet Therapy

Antiplatelet therapy has a well established ef-fect in reducing risk of stroke, myocardial infarc-

tion and vascular death in high risk patients.[96] As-pirin is the most widely used agent, but is of limitedeffectiveness for secondary stroke prevention.Thus, a recent meta-analysis on 10 trials evaluatingaspirin therapy as secondary prevention in patientswith TIAor stroke found a 13% relative risk reduc-tion for a recurrent vascular event, regardless ofdosage regimen.[97]The European Stroke Prevention Study (ESPS-

2) evaluated dipyridamole alone and in combina-tion with aspirin in 6602 patients with IS. On theirown, aspirin and dipyridamole were almost equallyeffective in preventing stroke, the risk reductionbeing 18.1% (p = 0.013) and 16.3% (p = 0.039),respectively. In combination, the 2 agents showedan additive effect with a risk reduction of 37.0%(p < 0.001). The results imply prevention of 25strokes per 1000 patients receiving either aspirin ordipyridamole for 2 years, but prevention of 58strokes per 1000 patients if the agents are given incombination.[98]Clopidogrel is an ADP receptor antagonist which

is similar to ticlopidine but with a better tolerabilityprofile. The agent was evaluated and comparedwith aspirin in the Clopidogrel versus Aspirin inPatients at Risk of Ischaemic Events (CAPRIE) trialin 19 185 patients with recent IS, recent myocar-dial infarction or symptomatic peripheral arterialdisease. The combined end-point was stroke, myo-cardial infarction or vascular death. The annualevent rate was 5.83% in the aspirin-treated groupand 5.32% in the clopidogrel-treated group, corre-sponding to an 8.7% relative risk reduction (95%CI, 0.3 to 16.5%) in favour of clopidogrel.[99] Nosignificant difference was seen in the subset of pa-tients with IS in a post hoc analysis (relative riskreduction 7.3%; 95% CI 5.7 to 18.7%). However,an additional analysis of those patients with IS orperipheral arterial disease with a previous historyof myocardial infarction demonstrated clear bene-fits for clopidogrel over aspirin (relative risk reduc-tion 22.7%; 95%CI 4.9 to 37.2%).[99] The CAPRIEresults demonstrate that aspirin would have to bereplaced with clopidogrel in 200 patients per year

322 Johnsen et al.


to prevent one case of IS, myocardial infarction orvascular death.There are no trials comparing the efficacy of

aspirin plus dipyridamole with clopidogrel, so un-til further data are available the antiplatelet therapywill be based on the above-mentioned trials. Costsof treatment will be central in choosing betweentreatments.

7.3 Anticoagulant Therapy

AF is a strong risk factor for IS, and more than9% of IS cases can be attributed to the presence ofAF.[77] The attributable risk of stroke from AF in-creases significantly with age, from 1.5% for pa-tients aged 50 to 59 years to 23.5% for patientsaged 80 to 89 years (p < 0.01).[100] The relative riskof stroke is 3- to 4-fold higher in patients with non-rheumatic AF than in individuals without this con-dition, and the relative risk is even greater for pa-tients with rheumatic valvular disease.[100,101]Data from 5 major recent trials evaluating anti-

thrombotic therapy with warfarin in patients withAF demonstrate that increasing age, hypertension,diabetes mellitus and previous TIA or stroke areindependent risk factors for stroke in patients withAF.[102] Warfarin therapy with dosage adjustmentsto an international normalised ratio (INR) of 2.0 to3.0 resulted in an absolute annual risk reduction of3.1% corresponding to a relative risk reduction of68% (95% CI 50 to 79%).[102] European Atrial Fi-brillation Trial (EAFT) is the only major trial onsecondary prevention in non-rheumatic atrial fi-brillation after TIA or minor stroke.[103] The find-ings of this study were similar to those of the 5primary prevention studies,[102] i.e. anticoagulanttreatment reduces the risk of recurrent stroke bytwo-thirds. However, since the absolute risk ismuch higher in patients with a history of TIA/minor stroke, the absolute benefit of treatment isconsequently also greater, i.e. 90 vascular events(mainly strokes) would be prevented if 1000 pa-tients with AF and recent TIA/minor stroke weretreated with anticoagulation for 1 year.[103] Thus,in patients with CT-proven IS and AF warfarintreatment should be initiated if clear contraindica-

tions are not found. The alternative is aspirin treat-ment but the risk reduction of aspirin is only one-third of warfarin therapy. The importance of anti-thrombotic treatment is accentuated by the fact thatstroke in patients with AF has been found to bemore severe and the outcomemarkedly poorer thanin patients with sinus rhythm.[104] Despite these re-sults, anticoagulation therapy appears to be widelyunderutilised in patients with AF.[18,105,106]Few data are available on the use of anticoagu-

lants for secondary prevention of IS in patientswithout AF. The Stroke Prevention In ReversibleIschemia Trial (SPIRIT) trial compared the effi-cacy and safety of oral anticoagulant therapy (INR3.0 to 4.5) and aspirin 30mg daily in 1316 patientswith a recent TIA or non-disabling IS of presumedarterial (non-cardiac) origin.[107] The trial wasstopped at the first interim analysis because of anexcess of major bleeding complications in the anti-coagulated group. The bleeding incidence in-creased by a factor of 1.43 (95% CI, 0.96 to 2.13)for each unit increase of the achieved INR. In con-clusion, high-intensity anticoagulant therapy is notsafe in secondary prevention of IS in patients with-out AF and cannot be recommended. The efficacyof a lower intensity anticoagulation regimen ispresently not determined but results on the subjectare underway in the Warfarin-Aspirin RecurrentStudy (WARSS) and European and AustralianStroke Prevention in Reversible Ischaemia Trial(ESPRIT).

7.4 Carotid Endarterectomy

Two major trials have evaluated the effect ofcarotid endarterectomy in patients with recent non-disabling carotid artery ischaemic events.[43,108]Although the 2 trials used different methods formeasuring carotid artery stenosis, results were con-sistent in terms of the degree of stenosis at whichbenefit of surgical therapy can be achieved. Formost patients with >70% stenosis and a recent non-disabling event, carotid endarterectomy is indi-cated, resulting in a 65% relative reduction in therisk of stroke. 17 strokes are prevented over a 2-year period per 100 patients treated.



The risk of IS is much smaller in patients withasymptomatic carotid stenosis, i.e. an annual inci-dence of 1.3%.[109] The value of carotid endarter-ectomy in this patient group is therefore limited. Toprevent 1 IS a year, 85 operations are needed and192 operations are needed to prevent 1 case of se-rious or fatal stroke.[110] This marginal benefit wasachieved under strict trial conditions which may behard to translate into everyday practice.[111]

7.5 Carotid Angioplasty and Stenting

The use of carotid angioplasty and stenting asan alternative to carotid endartectomy has receiveda great deal of interest recently due to the relativetechnical ease and cost effectiveness of the proce-dures.[112,113] Until now in contrast to carotid end-arterectomy, which has a proven benefit at least insymptomatic patients, no controlled prospectiverandomised trials on the use of carotid angioplastyand stenting have been published. However, re-cently, results from the Carotid and Vertebral Ar-tery Transluminal Angioplasty Study (CAVATAS),a randomised, multicentre trial comparing the ben-efits and risks of angioplasty were presented.[114]The study included 504 patients with a mean ca-rotid stenosis of 86% who were randomised totreatment with either endartectomy or angioplastywith or without stenting. Minimum follow-up timewas 1 year. There was no significant difference on30-day risk of stroke or death nor was there anydifference in long term efficacy. A significant ex-cess of restenosis was, however, noted in the an-gioplasty group after 12 months. The complicationrate in CAVATAS did not differ significantly fromNASCET and ESCET. Thus, carotid angioplastymay well be a safe an effective approach in patientswith carotid artery stenosis in the future. Furthertrials are underway, e.g. Carotid RevascularizationEndarterectomy versus Stent Trial (CREST).

8. Conclusions

Management of patients with acute IS has untilnow largely been supportive care, but advances inour understanding of the mechanisms of stroke

have stimulated a far more aggressive and activetreatment strategy.Evidence-based protocols for management of

patients with stroke including, assessment, inves-tigation and immediate treatment and rehabilita-tion of acute stroke as well as secondary preventionand risk factor management should be developedin all involved hospital departments.Specialised stroke units are well documented

initiatives for optimising management of patientswith stroke and are central in the changes of logis-tics in acute IS management. Establishment ofstroke units should receive top priority in futurestrategic planning within the stroke area. Immedi-ate and precise evaluation of patients with assumedstroke including a CT scan of the brain followed byclose monitoring are essential for preventing med-ical and neurological complications and for achiev-ing the optimal outcome.Primary treatment of acute IS with thrombolytic

therapy administered within a 3-hour time periodis supported by recent trials, whereas the documen-tation of a net benefit of thrombolytic therapystarted after 3 hours is limited. Antiplatelet therapywith aspirin in the acute phase of IS has a small butsignificant effect. Anticoagulation therapy withheparin has not yet proven any net long term ben-efit in the treatment of acute IS. Likewise, there areno convincing data, at present, on the efficacy ofneuroprotective drugs in a clinical setting. Everypatient should have disability needs assessed assoon as possible and a well conceived rehabilitationplan should bemadebased on the patient’s owngoals.To reduce the incidence of second stroke, sec-

ondary prevention is essential. Prevention shouldprimarily focus on detection and management ofrisk factors for stroke, which in many cases influ-ence both the risk of ischaemic and haemorrhagicstroke, i.e. hypertension, atrial fibrillation, smok-ing, diabetes mellitus, alcohol abuse and hyper-lipidaemia. In patients with IS, secondary preven-tion also includes antiplatelet therapy with aspirinand dipyridamole or clopidogrel and the possibilityof carotid endarterectomy.

324 Johnsen et al.


An essential area for future research in the man-agement of acute IS will be more effective strate-gies for identification of those patients who willbenefit the most from a specified therapy, i.e. dis-tinction between different subtypes of acute IS anddocumentation of perfusion deficits. Other impor-tant areas will be development of multiple targettherapies, e.g. thrombolytic therapy combined withneuroprotective and new antithrombotic agents andexpanding knowledge of stroke rehabilitation. Thus,strong efforts are needed to further develop andrefine the area of acute IS management if the goalof optimising patient outcome is to be achieved.

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About the Authors: Søren Paaske Johnsen, MD, is ResearchFellow at the Section on Clinical Epidemiology, Depart-ment of Epidemiology, Aarhus University. His clinical andresearch interests are risk factors and prevention of stroke,acute treatment of stroke and clinical cardiology.Steen Elkjær Husted, MD, DMSc, is Chief of Department ofInternal Medicine and Cardiology, Aarhus County Hospi-tal, Aarhus University Hospital. He has published 120 orig-inal and review articles, mainly receptor pharmacology,clinical pharmacology of antithrombotic drugs, plateletfunction, clinical studies with antithrombotic drugs andhaemostatic markers for vascular thrombosis. He was theformer president for the Danish Society on Thrombosis andHaemostasis.Anne Thomassen, MD, DMSc, is Medical Director atAarhus County Hospital, Aarhus University Hospital,Aarhus, Denmark. She has published 60 original and re-view articles mainly concerning ischaemic heart diseaseand myocardial metabolism. She was the former presidentof the Danish Society of International Medicine, secretaryof the Danish Society of Cardiology and chairman of theRegional Scientific Ethical Committee.Correspondence and reprints: Dr Anne Thomassen, Depart-ment of Administration, Aarhus County Hospital, AarhusUniversity Hospital, Tage Hansensgade 2, DK-8000 AarhusC, Denmark.



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