Medical treatment of stroke

The author: Professor Yasser Metwally

http://yassermetwally.com

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).

PREVENTION

PRIMARY PREVENTION (for those with no previous history of stroke)

Aspirin

  • In otherwise healthy patients, no resounding benefit is seen with aspirin for the primary prevention of stroke. Because benefits are relatively small and side effects significant, there is no compelling reason at this time to recommend aspirin routinely in this population.

  • In high-risk patients (ie, those with some vascular disease or other condition that implies an increased risk of occlusive vascular disease), aspirin is beneficial in reducing the risk of stroke.

Thienopyridines (ticlopidine, clopidogrel) and angiotensin-converting enzyme inhibitors

  • No available evidence associated with these medications exists for stroke prevention in this population.

HMG-CoAse reductase inhibitors

  • 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 myocardial infarction (MI).

Exercise

  • A Finnish study found that men with the highest degree of physical fitness (V02 max 35.3 mL/kg/min) were more than 3 times less likely to have a stroke than men with the lowest degree of physical fitness (VO2 max <25.2 mL/kg/min).>

  • In this analysis, physical fitness was a more powerful risk factor than LDL cholesterol, body mass index, and smoking and nearly comparable to hypertension.

SECONDARY PREVENTION (for those who already have had a stroke)

Platelet antiaggregants

Aspirin

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

  • No clear evidence exists to support the idea that higher doses (eg, 1300 mg/d) are more effective than lower doses (eg, 50 mg/d).

  • Doses prescribed vary worldwide. The usual dose in North America is 325 mg qd though the usual practice is now changing such that 81 mg qd is the usual dose.

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

Ticlopidine (Ticlid)

  • Approximately 9% relative risk reduction has been reported, compared with the use of aspirin in the occurrence of stroke, death, and MI.

  • Blood monitoring is required (CBC every 2 wk for 3 mo).

  • The recommended dose is 250 mg bid.

  • Side effects include diarrhea (20%), skin rash (14%), and reversible agranulocytosis (1%). High dropout rates are common because of side effects.

Clopidogrel (Plavix)

  • Approximately a 9% relative risk reduction has been reported compared with aspirin in the occurrence of stroke, death, and MI.

  • No blood monitoring is required (compare with ticlopidine).

  • The daily cost is approximately US $3.83 per day, compared with US $0.13 per day for aspirin.

  • The recommended dose is 75 mg qd.

  • The side effects are similar to those of aspirin.

Dipyridamole (Persantine)

  • The European Stroke Prevention Study 2 (ESPS-2) showed that dipyridamole is more effective than placebo in preventing stroke when given as an extended release formulation at 200 mg bid.

  • Further, dipyridamole was shown to be more effective in combination with 50 mg of aspirin compared to 50 mg of aspirin alone (relative risk reduction of stroke, death, and MI by 23%). A combination capsule of 25 mg of aspirin and 200 mg of extended-release dipyridamole is marketed in the US under the name Aggrenox and is advertised for secondary prevention of transient ischemic attacks (TIA) or ischemic stroke. The recommended dose is one capsule bid. The daily cost is approximately US $3.60 per day, compared with US $0.13 per day for aspirin.

  • The recommended dose is 200 mg bid (extended release formulation).

  • The side effects profile is similar to that of aspirin with the exception of a higher incidence of headache and gastrointestinal disturbance.

HMG-CoAse reductase inhibitors (statin agents)

  • In patients with a prior coronary history, pravastatin has been shown to decrease the risk of future stroke (relative risk reduction of 32% compared with placebo), even in patients with normal serum cholesterol. A previous study showed a beneficial effect of simvastatin in the secondary prevention of stroke in patients with coronary heart disease and elevated cholesterol.

  • The recommended dose is 40 mg qd.

  • In patients with a prior history of stroke and coronary artery disease, the British heart study found a 25% reduction in the risk of stroke with simvastatin at 40 mg daily. 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 through the end of the study at 5 years.

  • An ongoing study is being conducted with atorvastatin versus placebo in patients with a history of stroke only (ie, no previous cardiac history). Results are expected in 2005.

Blood pressure–lowering medications including thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers

  • In the Heart Outcomes Prevention Evaluation (HOPE) study, the addition of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, to all other medical therapy, including antiplatelet agents, resulted in a relative risk reduction of stroke, death, and MI by 32% compared with placebo.

  • Only 40% of the efficacy of ramipril could be attributed to its blood pressure–lowering effects. Postulated mechanisms included endothelial protection.

  • In the PROGRESS trial, a regimen based on perindopril, an ACE inhibitor, was superior to placebo.
     

  • Of note, however, was the finding that perindopril alone was not superior to placebo but the combination of perindopril with indapamide (a thiazide diuretic) substantially reduced the recurrence of stroke.

  • Much of the effect in reduction of stroke recurrence was due to lowering of blood pressure, in contrast to the HOPE study.

  • Further, the ALLHAT study found slight superiority of chlorthalidone (a thiazide diuretic) compared with lisinopril (an ACE inhibitor) for stroke occurrence.

  • Finally, the LIFE study found that an angiotensin receptor blocker (ARB), losartan, was superior to a beta-blocker, atenolol, for the reduction in stroke occurrence.

  • At this time, whether the beneficial effect seen with ramipril represented a class effect (ie, ACE inhibitors) or a property unique to ramipril is unclear.

  • While still controversial, most authorities agree that when selecting agents for blood pressure lowering in stroke patients, regimens that incorporate thiazide diuretics, ACE inhibitors, and ARBs are considered first-line agents, especially if diabetes is present.

  • Side effects of ACE inhibitors include cough (10%). This side effect is less common with ARBs.

Thrombin inhibitors

Warfarin (an indirect thrombin inhibitor)

  • For high-risk patients with atrial fibrillation (patients who have atrial fibrillation and one 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 68%).

    • The risk of lone atrial fibrillation on aspirin is 2.2% per year.

    • In secondary stroke prevention (ie, after a stroke already has occurred), the incidence of stroke while on warfarin, aspirin, and placebo is 4%, 10%, and 12% per year, respectively. The relative risk reduction of warfarin was 70% over placebo.

    • The American College of Chest Physicians (ACCP) recommendations in cases of atrial fibrillations) include the following:

    • Warfarin should be used for all high-risk patients and for those patients aged older than 75 years, regardless of risk.

    • Low-risk patients (ie, lone atrial fibrillation) and patients younger than 65 years should be treated with aspirin.

      • Patients aged 65-75 years without risk factors are subject to the choice of warfarin versus placebo at the discretion of the treating physician, as their condition may be based on other underlying disorders (eg, valvular disease, prosthetic valve replacement).

    • The dose is variable. The target INR is 2-3.

    • Side effects include excessive bleeding. The major concern is intracranial hemorrhage.

  • Antiphospholipid antibody syndrome (eg, lupus anticoagulant and/or cardiolipin antibody)

    • The APASS study found no advantage of warfarin (INR 1.4-2.8) over aspirin for the secondary prevention of stroke in patients with antiphospholipid antibodies.

    • Further, the risk of stroke did not appear to be increased in patients with positive antibodies.

    • Previous nonrandomized, retrospective studies found the risk of re-thrombosis in patients with a history of thrombosis and positive antibodies on high intensity warfarin (INR greater than of equal to 3) versus low intensity warfarin (INR less than 3) plus aspirin versus aspirin (retrospective cohorts) is 1.3% versus 23% versus 18% per year, respectively (relative risk reduction of 94% of high intensity warfarin versus low intensity warfarin plus aspirin).

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

  • Intracranial atherosclerosis

    • The Warfarin Aspirin Symptomatic Intracranial Disease (WSAID) study compared warfarin with aspirin for secondary stroke prevention in patients with stroke and intracranial stenosis documented by angiography.

    • The study was stopped prematurely when an increased risk of major hemorrhage and death was found, and no difference in efficacy was noted.

  • Noncardioembolic stroke

    • Warfarin versus Aspirin Recurrent Stroke (WARRS) was a study comparing 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.

  • Patent foramen ovale (PFO) with or without atrial septal aneurysm

    • THE PICSS study found no advantage of warfarin over heparin for the secondary prevention of stroke in patients with PFO with or without an atrial septal aneurysm in patients with a mean age of 59.0. The risk of stroke did not appear to be affected by the presence of these cardiac features.

    • A prospective evaluation in France found that in a stroke population with a mean age of 40.3, the presence of isolated PFO or isolated atrial septal aneurysm did not increase the risk of stroke relative to those without such findings, but the presence of both findings increased the risk of stroke over 4-fold.

  • Arterial dissection

    • A meta-analysis of small nonrandomized series suggested that anticoagulation may be superior to antiplatelet therapy in cases of arterial dissection but comes 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.

Ximelagatran (a direct thrombin inhibitor)

  • Two large studies have demonstrated the noninferiority of ximelagatran to warfarin for the prevention of stroke in high-risk patients.

  • A lower overall and major systemic bleeding risk is seen with ximelagatran compared with warfarin while the rate of major intracranial hemorrhage is similar and low.

  • The dose is 36 mg PO bid.

  • No blood monitoring is required.

  • The main side effect is transient elevation of liver function enzymes during the first 6 months, and this is reversible with drug discontinuation.

  • The daily drug cost is unknown at this time.

  • FDA approval is expected in the summer of 2004.

Lifestyle interventions

Smoking cessation, blood pressure control, diabetes control, low-fat diet (eg, DASH or Mediterranean diets), weight loss, and regular exercise should be encouraged as strongly as the above described medications. Written prescriptions for exercise and certain medications for smoking cessation increase the likelihood of success with these interventions.

ACUTE TREATMENT (0-24 HOURS)

Thrombolytics

Tissue plasminogen activator (tPA) (also known as recombinant tPA or rt-PA)

  • The efficacy of intravenous tPA was established in 2 randomized double-blind placebo-controlled studies published in combination by the National Institute of Neurological Disorders and Stroke (NINDS).

  • At 3 months after stroke, approximately 12% more patients in the tPA group experienced a cure of symptoms relative to those who did not receive it. Therefore, 8 patients need to be treated to achieve one cure.

  • The risk of intracerebral hemorrhage in the tPA group was 6% (50% of which were fatal), compared to 0.6% in the placebo group.

  • Despite the differences in hemorrhage rates, there were no differences in mortality (17% in the tPA group versus 21% in the placebo group).

  • Key points about the administration of thrombolytic agents include the following:

    • They must be administered within 3 hours of symptom onset. Patients who wake up with symptoms or those who cannot describe accurately the time of their symptom onset are timed to when they were last known to be well.

    • An imaging study of the head (CT scan or MRI) must be performed prior to treatment to rule out hemorrhage as a cause of symptoms.

    • Blood pressure should be lower than 185 systolic and 110 diastolic. Agents such as labetalol may be used to lower the blood pressure for the purposes of treatment.

    • Blood must be tested for platelet count (should be over 100,000), INR (many recommend under 1.6), PTT (many recommend less than 40), and glucose (should be 50-400).

    • Recent surgeries, traumas, and bleeding diatheses should be screened in the history (like in the MI protocol).

    • The earlier treatment is administered, the better. The patient should be treated within 90 minutes of symptom onset if at all possible.

  • Protocol for treatment

    • Intravenous tPA (0.9 mg/kg) is administered (maximum 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.

    • Blood pressure is monitored closely over the next 24 hours and aggressively managed, if excessive (eg, systolic pressure over 185, diastolic pressure over 100).

    • Opportunities for neurosurgical consultation and reversal of bleeding (eg, cryoprecipitate, fresh frozen plasma) should be available if intracerebral hemorrhage complicates treatment.

  • The recommended dose is 0.9 mg/kg IV.

  • Side effects include systemic and intracranial hemorrhage.

Prourokinase (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 addition, and in contrast to the NINDS tPA study, a CT scan showing over one third involvement of the MCA territory was an exclusion criterion.

  • In contrast to the NINDS tPA study, heparin was administered afterward.

  • The absolute percentage 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.

  • No difference was noted, however, in mortality (25% in the prourokinase group versus 27% in the placebo group).

  • 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 scan.

  • The recommended dose is 9 mg.

  • Side effects include systemic and intracranial hemorrhage.

  • The medication was not approved by the FDA on the basis of this single study. No further trials are planned.

  • Some clinicians use intra-arterial tPA, but this agent has not been tested in this fashion in a large randomized trial.

Antiplatelet agents

Aspirin

  • The Chinese Acute Stroke Trial (CAST) and the International Stroke Trial (IST) are 2 large studies evaluating the use of aspirin (160-300 mg/d) within 48 hours of ischemic stroke symptom onset.

  • Compared to no treatment, there was approximately a 1% absolute reduction in stroke and death in the first few weeks.

  • At further time points (eg, 6 months), there was a similar absolute reduction of approximately 1% in death or dependence.

  • The recommended dose is 160-300 mg.

  • Side effects include gastritis.

Abciximab

  • An ongoing phase III study of the efficacy of abciximab (Reopro) in acute stroke is being conducted. A phase II study of 400 patients found an 8% absolute reduction in poor outcomes at 3 months.

Anticoagulants

Warfarin

  • No studies have evaluated use of warfarin for the acute treatment of stroke.

Heparin and heparinoids

  • At this time, only one randomized trial has shown benefit for heparins or heparinoids in acute ischemic stroke. In that study, no benefit was seen at 10 days or 3 months, only at 6 months.

  • Other large studies have failed to find benefit of heparin or heparinoids, either IV or SC, at 3 months. An exploratory post hoc analysis of one intravenous low molecular randomized study suggested benefit in patients with severe large vessel (eg, carotid) atherosclerosis; however, the authors conclude that these findings need to 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-isoxazol propionic acid (AMPA) receptor antagonists, membrane stabilizers, growth factors, and glycine site antagonists.

  • At this time, no neuroprotectant has shown efficacy in the treatment of acute stroke.

Stroke Units

  • Several European randomized studies have shown the efficacy of admission to a specific stroke unit compared with nonstroke units in the treatment of patients with acute stroke. Mortality is reduced consistently at 10 days, 1 year, 5 years, and 10 years. The absolute risk reduction is about 7%. In addition, fewer patients are institutionalized, and a greater percentage of patients have a better quality of life.

  • The putative reasons for the differences in outcomes between stroke units and nonstroke units may include focused expert nursing/physician treatment, optimized protocols of care, better coordinated rehabilitation services, and patient/family education.

Blood Pressure Management

  • One prospective study found a hazard ratio of 1.89 for the risk of poor outcome for each drop in systolic blood pressure of 10% in the first 24 hours.

  • Another study found that the use of calcium channel blockers acutely lowered diastolic blood pressure and was associated with worse outcomes.

  • Current recommendations recommend avoiding more than 10% reduction of blood pressure within the first 24 hours unless values exceed certain thresholds. These values are not based on any specific randomized studies and 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, labetolol) and ACE inhibitors (eg, enalapril).

SUBACUTE AND CHRONIC TREATMENT

Depression is common after stroke and occurs in 30-40% of patients. This rate is higher than 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 re-uptake inhibitors (SSRIs) such as fluoxetine appear to improve functional recovery. It is not clear which agent is superior. A single randomized trial suggested that nortriptyline was superior to fluoxetine in the treatment of post-stroke depression and recovery of activities of daily living. Another investigational agent, citalopram, also appears to improve outcome. Nortriptyline has been shown to be effective in the treatment of depression following stroke. Various other agents and procedures are under investigation for the improvement in functional outcome.

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