AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

INTRODUCTION

Section 2 of 8  

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

The following discussion divides stroke treatment into 3 phases (ie, prevention, acute treatment, subacute/chronic treatment). The order of presentation reflects the sequence in which the intervention occurs (ie, before, during, and after stroke).

For excellent patient education resources, visit eMedicine's Stroke Center, Cholesterol Center, and Statins Center. Also, see eMedicine's patient education articles Stroke, High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

PRIMARY PREVENTION

Section 3 of 8  

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

Primary prevention refers to the treatment of individuals with no previous history of stroke. Measures may include the use of platelet antiaggregants; 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (ie, statins); and exercise.

Platelet antiaggregants

In otherwise healthy men older than 50 years, aspirin 325 mg every other day prevents myocardial infarction (MI; at a rate of 2 men per 1000) but not stroke.^{1, 2} In otherwise healthy women older than 45 years, aspirin 100 mg every other day prevents ischemic stroke (at a rate of 3 women per 1000) but not MI.^{3, 4} This reduction in ischemic stroke is more pronounced among women older than 65 years (10 women per 1000). The reason for the sex-related differences in cardiovascular and cerebrovascular prevention is not clear.

Platelet antiaggregants pose a small but definite increase in the risk of gastrointestinal bleeding (8 cases per 1000 individuals) and the need for transfusion (2 cases per 1000 individuals).

Other antiaggregants, including dipyridamole, ticlopidine, and clopidogrel, have not been tested in primary prevention.

HMG-CoA reductase inhibitors (statins)

Although pravastatin had a beneficial effect in preventing coronary heart disease in the West of Scotland Coronary Prevention Study (WOSCOPS), no statistically significant difference in stroke prevention was seen for men with moderate hypercholesterolemia and no history of MI.⁵

Exercise

A Finnish study showed that the likelihood of stroke in men with the lowest degree of physical fitness (VO₂max <25.2 mL/kg/min) was more than 3 times greater than in men with the highest degree of physical fitness (VO₂max >35.3 mL/kg/min).⁶

In this analysis, level of physical fitness was a more powerful risk factor than low-density lipoprotein (LDL) cholesterol level, body mass index, and smoking and was nearly comparable to hypertension as a risk factor.

SECONDARY PREVENTION

Section 4 of 8  

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

Secondary prevention refers to treatment of individuals who have had a stroke. As in primary prevention, measures may include the use of platelet antiaggregants, antihypertensives, HMG-CoA reductase inhibitors (statins), and lifestyle interventions.

Platelet antiaggregants

Aspirin

A 15% relative risk reduction in vascular events (stroke, death, and MI) has been documented for aspirin compared with placebo.⁷

No clear evidence suggests that high doses (eg, 1300 mg/d) are more effective than low doses (eg, 50 mg/d). Doses prescribed vary worldwide.⁸ The usual dose in North American practice varies from 81 to 325 mg daily.

Adverse effects of aspirin include gastritis (common to most antiplatelet agents), tinnitus, and hearing loss (especially at high doses).

Ticlopidine (Ticlid)

A relative risk reduction of approximately 9% for stroke, death, and MI has been reported for ticlopidine compared with aspirin.⁹ Blood monitoring is required (a complete blood count assessed every 2 wk for 3 mo).

The recommended dose is 250 mg twice daily (bid). Adverse effects include diarrhea (20%), skin rash (14%), and reversible agranulocytosis (1%). High discontinuation rates are common because of adverse effects.

Clopidogrel (Plavix)

A relative risk reduction of approximately 9% for stroke, death, and MI has been reported for clopidogrel compared with aspirin (an absolute risk reduction of about 0.25% per year).¹⁰ No blood monitoring is required with clopidogrel (unlike ticlopidine).

The recommended dose is 75 mg daily. The adverse effects are similar to those of aspirin. Thrombotic thrombocytopenic purpura is seen in rare circumstances with clopidogrel.¹¹

Dipyridamole (Persantine)

The European Stroke Prevention Study 2 (ESPS-2) showed that extended-release dipyridamole is more effective than placebo in preventing stroke when given as an extended-release formulation at a dosage of 200 mg bid.¹² Furthermore, ESPS-2 and the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) trial both showed that dipyridamole was more effective in combination with aspirin than aspirin alone.¹³ The typical dose of aspirin in these studies was less than 100 mg/d. At this time, evidence that short-acting dipyridamole is as efficacious as extended-release dipyridamole is insufficient. The combination of extended-release dipyridamole and aspirin reduces the relative risk of stroke, death, and MI by about 20% (approximately a 1% absolute risk reduction per year). A combination capsule of aspirin 25 mg and extended-release dipyridamole 200 mg is marketed in the United States as Aggrenox forthesecondarypreventionofischemicstrokeortransientischemicattacks(TIAs).

The adverse effects profile is similar to that of aspirin with the exception of an increased incidence of headache and gastrointestinal disturbance.

The Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy suggested that the combination of extended-release dipyridamole and aspirin was more efficacious than clopidogrel based on indirect comparisons.¹⁴ The ongoing Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is comparing extended-release dipyridamole directly with clopidogrel for secondary stroke prevention. Results will be available in 2008.

The combination of clopidogrel with aspirin for long-term stroke prevention is discouraged based on the negative findings of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) studies. In the MATCH study, life-threatening bleedings were higher in the group receiving aspirin and clopidogrel than in the group receiving clopidogrel alone (an absolute risk increase of about 1% per year).¹⁵

HMG-CoA reductase inhibitors (statins)

In patients with a history of coronary artery disease, pravastatin decreases the risk of future stroke (relative risk reduction of 32% compared with placebo), even in those with normal serum cholesterol levels.¹⁶

In patients with a history of coronary disease, other vascular disease, or diabetes, the British Heart Study showed a 25% reduction in the risk of stroke with simvastatin at 40 mg/d (an absolute risk reduction of about 1.4% over 5 years). The benefit was independent of the baseline serum cholesterol level, down to a level of 140 mg/dL. The reduction in stroke risk was uniformly reduced after the first year through the end of the study at 5 years.¹⁷

The Stroke Prevention by Aggressive Reduction in Cholesterol levels (SPARCL) trial, which looked at patients without a history of coronary artery disease and serum LDL cholesterol level of 100-180 mg/dL, found that 80 mg/d of atorvastatin reduced the risk of recurrent stroke by about 16% over 5 years (an absolute risk reduction of about 2.2% over 5 years).¹⁸

No direct comparisons have been made of different statins or doses in stroke patients.

Antihypertensives

BP-lowering medications include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs).

In the Heart Outcomes Prevention Evaluation (HOPE) study, the addition of the ACE inhibitor (ramipril) to all other medical therapy, including antiplatelet agents, reduced the relative risk of stroke, death, and MI by 32% compared with placebo.¹⁹ Only 40% of the efficacy of ramipril could be attributed to its BP-lowering effects. Postulated mechanisms included endothelial protection.

In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a regimen based on perindopril, an ACE inhibitor, was superior to placebo. However, perindopril alone was not superior to placebo, but the combination of perindopril with indapamide (a thiazide diuretic) substantially reduced the recurrence of stroke.²⁰ Much of the effect in reducing stroke recurrence was due to the lowering of BP, in contrast to findings from the HOPE study.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed slight superiority of chlorthalidone (a thiazide diuretic) compared with lisinopril (an ACE inhibitor) in terms of stroke occurrence.²¹

The Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE) demonstrated that an ARB (losartan) was superior to a beta blocker (atenolol) in reducing the occurrence of stroke.²²

The Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study found that the ARB eprosartan was superior in the secondary prevention of stroke and TIA compared with the calcium channel blocker nitrendipine. This was true despite comparable reductions in blood pressure.²³ The absolute annual difference in stroke and TIA risk was approximately 4%. The study was relatively small, and most events were TIAs.

Whether the beneficial effect of ramipril represents a class effect of ACE inhibitors or whether it is a property unique to ramipril is unclear. Adverse effects of ACE inhibitors include cough (10%), which is less common with ARBs.

At this time, first-line agents for the treatment of hypertension in stroke include thiazide diuretics, calcium channel blockers, ACE inhibitors, and ARBs. Beta blockers are considered second-line agents given their inferiority in preventing events despite similar reductions in blood pressure.

Thrombin inhibitors

Warfarin

Warfarin is an indirect thrombin inhibitor.

For high-risk patients with atrial fibrillation (ie, atrial fibrillation and 1 other risk factor), warfarin (with a target international normalized ratio [INR] of 2-3) versus placebo in primary stroke prevention reduces the incidence of stroke from 4.5% to 1.4% per year (relative risk reduction of 68%). The risk of lone atrial fibrillation on aspirin is 2.2% per year.

In secondary stroke prevention, the incidences of stroke with warfarin, aspirin, and placebo are 4%, 10%, and 12% per year, respectively. The relative risk reduction of warfarin was 70% compared with placebo.

Recommendations of the American College of Chest Physicians (ACCP) in cases of atrial fibrillation are the following:

• Warfarin should be used for all high-risk patients and all patients older than 75 years regardless of their risk.
• Low-risk patients (ie, those with only atrial fibrillation) and patients younger than 65 years should be treated with aspirin.
• Patients aged 65-75 years without risk factors may or may not be given warfarin at the discretion of the treating physician, as their condition may be based on other underlying disorders (eg, valvular disease, prosthetic valve replacement).²⁴

The dose is variable. The target INR is 2-3. Adverse effects include excessive bleeding. The major concern is intracranial hemorrhage.

The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) found that the combination of clopidogrel plus aspirin was less effective for stroke prevention than warfarin (INR 2-3). Further, intracranial hemorrhage was more common in the dual antiplatelet group.²⁵

Antiphospholipid antibody syndrome is the presence of lupus anticoagulant and/or cardiolipin antibody. The Antiphospholipid Antibodies and Stroke Study (APASS) showed no advantage of warfarin (INR of 1.4-2.8) over aspirin for secondary stroke prevention in patients with antiphospholipid antibodies. Further, the risk of stroke did not appear to be increased in patients with positive antibodies.²⁶

Patients with the antiphospholipid antibody syndrome and previous thrombosis are treated with warfarin. An INR of 2.0-3.0 is an appropriate therapeutic target. An INR of 3.1-4.0 is not superior.²⁷

An interesting observation is that arterial events follow arterial events and that venous events follow venous events in 91% of patients.

Regarding intracranial atherosclerosis, the Warfarin Aspirin Symptomatic Intracranial Disease (WSAID) investigators compared warfarin with aspirin for secondary stroke prevention in patients with stroke and intracranial stenosis documented on angiography. The study was stopped prematurely when an increased risk of major hemorrhage, MI, and death was found with no difference in prevention of ischemic stroke.²⁸

Regarding noncardioembolic stroke, the Warfarin Versus Aspirin Recurrent Stroke Study (WARSS) compared warfarin with aspirin for secondary stroke prevention in patients with assorted causes of noncardioembolic stroke. The risk of hemorrhage was greater with warfarin, and no advantage was seen relative to aspirin.²⁹

In patients with a mean age of 59 years who had patent foramen ovale (PFO), with or without an atrial septal aneurysm, the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) showed no advantage of warfarin over heparin for the secondary prevention of stroke.³⁰ These cardiac features did not seem to affect the risk of stroke. A prospective study in France showed that, in a stroke population with a mean age of 40.3 years, isolated PFO or isolated atrial septal aneurysm did not increase the risk of stroke, but the presence of both findings increased the risk of stroke more than 4-fold.³¹ Ongoing randomized studies are comparing best medical management and percutaneous closure of PFOs for secondary stroke prevention.

A meta-analysis of data from small, nonrandomized series suggested that anticoagulation may be superior to antiplatelet therapy in cases of arterial dissection but at the expense of increased bleeding risk. The conclusion of the meta-analysis was that a large, randomized study was necessary to determine optimal therapy.³²

Lifestyle interventions

Smoking cessation, BP control, diabetes control, a low-fat diet (eg, Dietary Approaches to Stop Hypertension [DASH] or Mediterranean diets), weight loss, and regular exercise should be encouraged as strongly as the medications described above. Written prescriptions for exercise and medications for smoking cessation (nicotine patch, bupropion, varenicline) increase the likelihood of success with these interventions.

Secondary stroke prevention can be summarized by the mnemonic A, B, C, D, E as follows: A indicates antiaggregants (aspirin, clopidogrel, extended-release dipyridamole, ticlopidine) and anticoagulants (warfarin); B, blood pressure–lowering medications; C, cessation of cigarette smoking and cholesterol-lowering medications; D, diet; and E, exercise.

ACUTE TREATMENT

Section 5 of 8  

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

Acute treatment is that administered within 0-24 hours of stroke onset and may include the use of thrombolytics, antiplatelet agents, anticoagulants, antihypertensives, and neuroprotectants.

Thrombolytics

Tissue-type plasminogen activator

The efficacy of intravenous (IV) tissue-type plasminogen activator (tPA) was established in 2 randomized, double-blind, placebo-controlled studies conducted in combination by the National Institute of Neurological Disorders and Stroke (NINDS).³³ At 3 months after stroke, approximately 12% more patients in the tPA group than in the non-tPA group had symptomatic cure. Therefore, 8 patients need to be treated to achieve 1 cure. The risk of intracerebral hemorrhage in the tPA group was 6% (50% lethal) compared with 0.6% in the placebo group. Despite the differences in hemorrhage rates, mortality rates did not differ (17% for tPA vs 21% for placebo).

Key points are as follows:

• Thrombolytics must be given within 3 hours of symptom onset. In patients who wake up with symptoms or those who cannot accurately describe the time of their symptom onset, the window is timed according to when they were last known to be well.
• Head computed tomography (CT) scanning or magnetic resonance imaging (MRI) must be performed before treatment to rule out hemorrhage as a cause of symptoms.
• BP should be <185/100 mm Hg. Agents such as labetalol may be used to lower BP for treatment.
• Platelet counts >100 X 10⁹/L; many recommend an INR <1.6; many recommend an activated partial thromboplastin time <40 seconds; glucose levels should be 50-400 mg/dL.
• Recent surgery, trauma, and bleeding diatheses should be screened in the history (as in the MI protocol).
• The earlier treatment is administered, the better the outcomes may be. The patient should be treated within 90 minutes of symptom onset if possible.

The protocol for treatment is as follows:

• IV tPA (0.9 mg/kg) is administered (maximum of 90 mg).
• The first 10% is given as a bolus over 1 minute. The remaining 90% is delivered over the next hour.
• No anticoagulants or antiplatelet agents are used for the next 24 hours.
• BP is monitored closely over the next 24 hours and aggressively managed, if excessive (eg, systolic pressure >185 mm Hg, diastolic pressure >100 mm Hg).
• Opportunities for neurosurgical consultation and reversal of bleeding (eg, with cryoprecipitate, fresh frozen plasma) should be available if intracerebral hemorrhage complicates treatment.

Adverse effects include systemic and intracranial hemorrhage.

Prourokinase

Prourokinase is also known as recombinant prourokinase or r-proUK. This intra-arterial therapy requires the involvement of a skilled interventionist. The time window is 6 hours from symptom onset.

In 1 study, and in contrast to findings from the NINDS tPA study, a CT scan showing more than one-third involvement of the territory of the middle cerebral artery (MCA) was an exclusion criterion, and heparin was administered afterward. The absolute increase in patients with slight or no disability at 3 months was 15% in the prourokinase group compared with the placebo group. Therefore, 7 patients need to be treated for 1 to achieve benefit. The hemorrhage rate in the prourokinase group was 10%, versus 2% in subjects who received placebo. However, no difference was noted in mortality (25% for prourokinase vs 27% for placebo). Therefore, this therapy may be especially useful for patients who arrive later than 3 hours from symptom onset and who have less than one-third involvement of the MCA territory on initial scans.

The recommended dose is 9 mg.

Adverse effects include systemic and intracranial hemorrhage.

The US Food and Drug Administration (FDA) did not approve this medication on the basis of the single study above. No further trials are planned.

Some clinicians use intra-arterial tPA, but this treatment has not been tested in a large, randomized trial. The ongoing Interventional Management of Stroke III (IMS III) study is comparing the effectiveness of intravenous tPA combined with intra-arterial tPA versus the effectiveness of intravenous tPA alone when both treatments are initiated within 3 hours of stroke.

Antiplatelet agents

Aspirin

The Chinese Acute Stroke Trial (CAST) and the International Stroke Trial (IST) are 2 large studies in which investigators evaluated aspirin 160-300 mg/d within 48 hours of ischemic stroke symptom onset. Compared with no treatment, aspirin resulted in a 1% absolute reduction in risk of stroke and death in the first few weeks. At later time points (eg, 6 mo), aspirin had absolute reduction of approximately 1% for death or dependence.

The recommended dose is 160-300 mg. Adverse effects include gastritis.

Abciximab

An ongoing phase III study of the efficacy of abciximab (ReoPro) in acute stroke was terminated due to efficacy and safety issues. Previously, a phase II study of 400 patients had found an 8% absolute reduction in poor outcomes at 3 months (P <.05). Symptomatic intracranial hemorrhage occurred in 3.6% of patients on abciximab and in 1% of patients on placebo.³⁴

Anticoagulants

Heparin and heparinoids

Only 1 randomized trial has shown benefit for heparins or heparinoids in acute ischemic stroke. In that study, benefit was seen only at 6 months and not at 10 days or 3 months.³⁵

Other large studies have failed to show the benefit of heparin or heparinoids, given either intravenously or subcutaneously (SC), at 3 months, including in the setting of atrial fibrillation. An exploratory post hoc analysis of data from randomized study suggested benefit with a low-molecular-weight heparin in patients with severe large vessel (eg, carotid) atherosclerosis. However, the authors concluded that these findings must be properly evaluated in a prospective, randomized trial.

Neuroprotectants

Various classes tested include calcium channel antagonists, potassium channel openers, glutamate antagonists, antiadhesion molecules, N-methyl-D-aspartate (NMDA) receptor antagonists and modulators, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, membrane stabilizers, growth factors, glycine-site antagonists, and free radical scavengers.

Many early studies of neuroprotectants showed no effect in the treatment of acute stroke. The Stroke Acute Ischemic NXY-059 Treatment (SAINT-I) study, which tested the free radical scavenger NXY-059, was the first to show an effect in acute ischemic stroke. However, the effect was seen only in 1 of the 2 scales used for outcome measures (ie, in the Rankin scale but not in the National Institutes of Health [NIH] stroke scale). A second study failed to confirm a benefit, and further development was stopped in 2006.

Antihypertensives

One prospective study found a hazard ratio of 1.89 for the risk of poor outcome for each decrease in systolic BP of 10% in the first 24 hours.³⁶ Another study found that the use of calcium channel blockers acutely lowered diastolic BP and was associated with worse outcomes.³⁷

Current recommendations include avoiding more than 10% reduction of BP within the first 24 hours unless values exceed certain thresholds. These values, which are not based on any specific randomized studies, are 220 mm Hg systolic (some recommend 200 mm Hg systolic) and 115 mm Hg diastolic. Suggested agents for use in the acute setting are beta blockers (eg, labetalol) and ACE inhibitors (eg, enalapril). For more refractory hypertension, agents such as nicardipine, nitroprusside, and hydralazine are used.

SUBACUTE AND LONG-TERM TREATMENT

Section 6 of 8  

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

Depression is common after stroke, occurring in 30-40% of patients. This rate is higher than that expected among patients with chronic illness, suggesting a role of the disease itself in the process of depression.

A depressed mood may hinder recovery, which has prompted studies to evaluate the effects of psychotropic agents on functional recovery. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, appear to improve functional recovery.

Which agent is superior is not clear. Findings from a single randomized trial suggested that nortriptyline was superior to fluoxetine in the treatment of poststroke depression and in recovery of activities of daily living.³⁸ Another agent, citalopram, also appears to improve outcome.³⁹ Nortriptyline has been shown to be effective in treating depression after stroke. Various other agents and procedures are under investigation for the improvement of functional outcome. These include constraint-induced therapy, mirror therapy, and electrical stimulation of the cortex.^{40, 41, 42}

A study that compared treatment of 10 mg of dextroamphetamine coupled with physiotherapy twice a week for 5 weeks in the early poststroke period provided no additional benefit in motor or functional recovery compared with physiotherapy alone.⁴³

STROKE UNITS

Section 7 of 8  

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

Several European randomized studies have shown the efficacy of admitting patients with acute stroke to specific stroke units versus nonstroke units for treatment. Mortality rates are consistently reduced at 10 days and at 1, 5, and 10 years.^{44, 45, 46} The absolute risk reduction is about 7%. In addition, hospitalizations are reduced, and most patients have improved quality of life.

Putative reasons for the differences in outcomes between stroke units and nonstroke units may include focused treatment from expert nurses and physicians, optimized protocols of care, improved and coordinated rehabilitation services, and patient and family education.

REFERENCES

Section 8 of 8

• Authors and Editors
• Introduction
• Primary Prevention
• Secondary Prevention
• Acute Treatment
• Subacute and Long-term Treatment
• Stroke Units
• References

1. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed). Jan 30 1988;296(6618):313-6. [Medline]. [Full Text].
2. Steering Committee of the Physicians'' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians'' Health Study. N Engl J Med. Jul 20 1989;321(3):129-35. [Medline].
3. Iso H, Hennekens CH, Stampfer MJ, et al. Prospective study of aspirin use and risk of stroke in women. Stroke. Sep 1999;30(9):1764-71. [Medline]. [Full Text].
4. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. Mar 31 2005;352(13):1293-304. [Medline]. [Full Text].
5. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. Nov 16 1995;333(20):1301-7. [Medline].
6. Kurl S, Laukkanen JA, Rauramaa R, et al. Cardiorespiratory fitness and the risk for stroke in men. Arch Intern Med. Jul 28 2003;163(14):1682-8. [Medline].
7. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. Jan 8 1994;308(6921):81-106. [Medline].
8. Tijssen JG. Low-dose and high-dose acetylsalicylic acid, with and without dipyridamole: a review of clinical trial results. Neurology. Sep 1998;51(3 Suppl 3):S15-6. [Medline].
9. Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med. Aug 24 1989;321(8):501-7. [Medline].
10. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. Nov 16 1996;348(9038):1329-39. [Medline].
11. Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. Jun 15 2000;342(24):1773-7. [Medline].
12. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. Nov 1996;143(1-2):1-13. [Medline].
13. ESPRIT Study Group; Halkes PH, van Gijn J, Kappelle LJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. May 20 2006;367(9523):1665-73. [Medline].
14. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. Sep 2004;126(3 Suppl):483S-512S. [Medline]. [Full Text].
15. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. Jul 24-30 2004;364(9431):331-7. [Medline].
16. Plehn JF, Davis BR, Sacks FM, et al. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators. Circulation. Jan 19 1999;99(2):216-23. [Medline]. [Full Text].
17. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. Jul 6 2002;360(9326):7-22. [Medline].
18. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. Aug 10 2006;355(6):549-59. [Medline].
19. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. Jan 20 2000;342(3):145-53. [Medline].
20. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. Sep 29 2001;358(9287):1033-41. [Medline].
21. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. Dec 18 2002;288(23):2981-97. [Medline].
22. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. Mar 23 2002;359(9311):995-1003. [Medline].
23. Schrader J, Luders S, Kulschewski A, et al. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. Jun 2005;36(6):1218-26.
24. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. Sep 2004;126(3 Suppl):429S-456S. [Medline]. [Full Text].
25. ACTIVE Writing Group on behalf of the ACTIVE Investigators; Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. Jun 10 2006;367(9526):1903-12. [Medline].
26. Levine SR, Brey RL, Tilley BC, et al. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA. Feb 4 2004;291(5):576-84. [Medline].
27. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. Sep 18 2003;349(12):1133-8. [Medline].
28. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. Mar 31 2005;352(13):1305-16. [Medline].
29. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. Nov 15 2001;345(20):1444-51. [Medline].
30. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation. Jun 4 2002;105(22):2625-31. [Medline]. [Full Text].
31. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. Dec 13 2001;345(24):1740-6. [Medline].
32. Lyrer P, Engelter S. Antithrombotic drugs for carotid artery dissection. Cochrane Database Syst Rev. 2003;(3):CD000255. [Medline].
33. Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. Dec 14 1995;333(24):1581-7. [Medline].
34. Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke. Apr 2005;36(4):880-90. [Medline]. [Full Text].
35. Kay R, Wong KS, Yu YL, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. Dec 14 1995;333(24):1588-93. [Medline].
36. Oliveira-Filho J, Silva SC, Trabuco CC, et al. Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset. Neurology. Oct 28 2003;61(8):1047-51. [Medline].
37. Ahmed N, Näsman P, Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke. Jun 2000;31(6):1250-5. [Medline]. [Full Text].
38. Lipsey JR, Robinson RG, Pearlson GD, et al. Nortriptyline treatment of post-stroke depression: a double-blind study. Lancet. Feb 11 1984;1(8372):297-300. [Medline].
39. Andersen G, Vestergaard K, Lauritzen L. Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke. Jun 1994;25(6):1099-104. [Medline].
40. Wolf SL, Winstein CJ, Miller JP, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA. Nov 1 2006;296(17):2095-104. [Medline].
41. Garry MI, Loftus A, Summers JJ. Mirror, mirror on the wall: viewing a mirror reflection of unilateral hand movements facilitates ipsilateral M1 excitability. Exp Brain Res. May 2005;163(1):118-22. [Medline].
42. Profice P, Pilato F, Dileone M, et al. Use of transcranial magnetic stimulation of the brain in stroke rehabilitation. Expert Rev Neurother. Mar 2007;7(3):249-58. [Medline].
43. Gladstone DJ, Danells CJ, Armesto A, et al. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: a randomized, double-blind, placebo-controlled trial. Stroke. Jan 2006;37(1):179-85. [Medline]. [Full Text].
44. Indredavik B, Bakke F, Slørdahl SA, et al. Stroke unit treatment improves long-term quality of life: a randomized controlled trial. Stroke. May 1998;29(5):895-9. [Medline]. [Full Text].
45. Indredavik B, Bakke F, Slordahl SA, et al. Stroke unit treatment. 10-year follow-up. Stroke. Aug 1999;30(8):1524-7. [Medline]. [Full Text].
46. Indredavik B, Bakke F, Solberg R, et al. Benefit of a stroke unit: a randomized controlled trial. Stroke. Aug 1991;22(8):1026-31. [Medline].
47. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. Sep 7 1996;348(9028):633-8. [Medline].
48. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry. Feb 1996;60(2):197-9. [Medline].
49. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. Jun 7 1997;349(9066):1641-9. [Medline].
50. Cleland JG, Freemantle N, Kaye G, et al. Clinical trials update from the American Heart Association meeting: Omega-3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE. Eur J Heart Fail. Jan 2004;6(1):109-15. [Medline].
51. Collaborative systematic review of the randomised trials of organised inpatient (stroke unit) care after stroke. Stroke Unit Trialists' Collaboration. BMJ. Apr 19 1997;314(7088):1151-9. [Medline]. [Full Text].
52. Dam M, Tonin P, De Boni A, et al. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke. Jul 1996;27(7):1211-4. [Medline]. [Full Text].
53. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. Jun 11 1994;343(8911):1454-9. [Medline].
54. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. Dec 1 1999;282(21):2003-11. [Medline].
55. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet. Jun 3 1989;1(8649):1215-20. [Medline].
56. Gustafson Y, Nilsson I, Mattsson M, et al. Epidemiology and treatment of post-stroke depression. Drugs Aging. Oct 1995;7(4):298-309. [Medline].
57. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med. Mar 4 1999;340(9):685-91. [Medline].
58. Jørgensen HS, Kammersgaard LP, Nakayama H, et al. Treatment and rehabilitation on a stroke unit improves 5-year survival. A community-based study. Stroke. May 1999;30(5):930-3. [Medline]. [Full Text].
59. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. Apr 13 1995;332(15):993-7. [Medline].
60. Laupacis A, Albers G, Dalen J, et al. Antithrombotic therapy in atrial fibrillation. Chest. Oct 1995;108(4 Suppl):352S-359S. [Medline]. [Full Text].
61. Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med. Feb 9 2006;354(6):588-600. [Medline].
62. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA. Apr 22-29 1998;279(16):1265-72. [Medline].
63. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. Nov 19 1994;344(8934):1383-9. [Medline].
64. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. Jul 11 1994;154(13):1449-57. [Medline].
65. Robinson RG, Schultz SK, Castillo C, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry. Mar 2000;157(3):351-9. [Medline]. [Full Text].
66. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med. Aug 15 1992;117(4):303-8. [Medline].
67. Rønning OM, Guldvog B. Stroke units versus general medical wards, I: twelve- and eighteen-month survival: a randomized, controlled trial. Stroke. Jan 1998;29(1):58-62. [Medline]. [Full Text].
68. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. Jan 4 2001;344(1):3-10. [Medline].
69. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet. Nov 20 1993;342(8882):1255-62. [Medline].
70. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. Aug 1991;84(2):527-39. [Medline].
71. Swinburn BA, Walter LG, Arroll B, et al. The green prescription study: a randomized controlled trial of written exercise advice provided by general practitioners. Am J Public Health. Feb 1998;88(2):288-91. [Medline]. [Full Text].
72. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. May 31 1997;349(9065):1569-81. [Medline].
73. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. Dec 14 1995;333(24):1581-7. [Medline].
74. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. Aug 16 2001;345(7):494-502. [Medline].

Article Last Updated: Feb 26, 2008