eMedicine Specialties > Physical Medicine and Rehabilitation > Stroke
Medical Treatment of Stroke
Updated: Jun 3, 2009
Introduction
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
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
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).
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 research has suggested that aspirin is not effective in primary stroke prevention.1,2 Research has also indicated that 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 reportedly 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.
The Antithrombotic Trialists’ (ATT) Collaboration conducted meta-analyses of serious vascular events, including myocardial infarction, stroke, and vascular death, as well as of major bleeds, in 6 primary prevention trials of long-term aspirin use. These trials utilized 95,000 individuals at low-average risk for the above events.5
In a 2009 report on the study, aspirin was associated with significant reduction (12% proportional reduction) of serious vascular events (0.51% aspirin vs 0.57% control annually, p = 0.0001). However, this decrease resulted mainly from a 20% reduction in nonfatal myocardial infarctions (0.18% vs 0.23% annually, p <0.0001), while the net effect on stroke was not significant. Aspirin increased the risk for major gastrointestinal and extracranial bleeding.
According to the report, "the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women."
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.6
Exercise
A Finnish study showed that the likelihood of stroke in men with the lowest degree of physical fitness (VO2 max <25.2 mL/kg/min) was more than 3 times greater than in men with the highest degree of physical fitness (VO2 max >35.3 mL/kg/min).7
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.
Related eMedicine topic:
Stroke, Ischemic
Secondary Prevention
Secondary prevention refers to the treatment of individuals who have already had a stroke. As in primary stroke 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.8
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.9 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.10 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).11 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.12
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.13 Furthermore, ESPS-2 and the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) trial showed that dipyridamole was more effective in combination with aspirin than aspirin alone.14,15 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 for the secondary prevention of ischemic stroke or transient ischemic attacks (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.16 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).17
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.18
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.19
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).20
A Greek study showed a 10-year risk reduction for recurrent stroke when statin therapy was administered after a first stroke.21 Statin use also reduced the risk of mortality, even after adjustment for potential confounders, such as blood pressure control, reported investigators. The study, which used linked hospitalization and death records, was a retrospective observational analysis of 794 patients from the Athenian Stroke Registry who had been hospitalized for a first-time ischemic stroke. The analysis included a period, starting in January 1997, during which the use of poststroke statin therapy was not common medical practice.
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.22 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.23 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.24
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.25
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.26 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 clinician, as their condition may be based on other underlying disorders (eg, valvular disease, prosthetic valve replacement).27
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.28
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.29
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.30
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.31
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.32
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.33 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.34 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.35
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
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).36 Within 3 months following a stroke, approximately 12% more patients in the tPA group had experienced a symptomatic cure than had those in the non-tPA group. The risk of intracerebral hemorrhage in the tPA group was 6% (50% lethal), compared with 0.6% in the placebo group. Despite the difference 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.37,38 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.39
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 agents40
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.41
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.42
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.43 Another study found that the use of calcium channel blockers acutely lowered diastolic BP and was associated with worse outcomes.44
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.
Related eMedicine topics:
Acute Stroke Management
Magnetic Resonance Imaging in Acute Stroke
Mechanical Thrombolysis in Acute Stroke
Neuroprotective Agents in Stroke
Stroke Anticoagulation and Prophylaxis
Thrombolytic Therapy
Thrombolytic Therapy in Stroke
Subacute and Long-term Treatment
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.45 Another agent, citalopram, also appears to improve outcome.46 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.47,48,49
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.50
Related eMedicine topic:
Motor Recovery In Stroke
Stroke Motor Impairment
Stroke Units
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.51,52,53 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 clinicians, optimized protocols of care, improved and coordinated rehabilitation services, and patient and family education.
Related eMedicine topic:
Stroke Team Creation and Primary Stroke Center Certification
Keywords
medical treatment of stroke, stroke, strokes, aspirin, heparin, warfarin, anticoagulant, anticoagulation, tPA, Plavix, anticoagulants, statins, after stroke, ACE inhibitors, ischemic stroke, clopidogrel, stroke rehabilitation, thrombolytic, stroke treatment, stroke therapy, Persantine, tissue plasminogen activator, dipyridamole, cerebrovascular accident, CVA, prevention of stroke, acute therapy following stroke, subacute/chronic therapy following stroke, cerebral ischemia, medical treatment of CVA, antiplatelet therapy
More on Medical Treatment of Stroke |
| References |
References
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Further Reading
Keywords
medical treatment of stroke, stroke, strokes, aspirin, heparin, warfarin, anticoagulant, anticoagulation, tPA, Plavix, anticoagulants, statins, after stroke, ACE inhibitors, ischemic stroke, clopidogrel, stroke rehabilitation, thrombolytic, stroke treatment, stroke therapy, Persantine, tissue plasminogen activator, dipyridamole, cerebrovascular accident, CVA, prevention of stroke, acute therapy following stroke, subacute/chronic therapy following stroke, cerebral ischemia, medical treatment of CVA, antiplatelet therapy
