U.S. Pharmacist

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Pharmacologic Management of Stroke

Shari N. Allen, PharmD
Assistant Professor of Pharmacy Practice
Philadelphia College of Osteopathic Medicine School of Pharmacy
Suwanee, Georgia

DeAna Augustus, PharmD
Clinical Pharmacy Specialist, Blind Rehabilitation/MHRRTP
Gulf Coast Veterans Health Care System
Biloxi, Mississippi



2/17/2012

US Pharm.
2012;37(2):HS-12-HS-15.

Stroke (also called cerebrovascular accident) is a condition that reduces blood flow to the central nervous system—specifically, the brain. While its incidence has fallen since the 1980s, stroke is currently the fourth leading cause of death in the United States, and it claimed the lives of nearly 136,000 people in 2007. Each year, about 795,000 people (on average, 1 person every 40 seconds) will experience a new or recurrent stroke. Incidence is highest in African Americans aged 18 years and older (3.2%), with the next highest incidences in the white (2.5%) and Asian (1.3%) populations.1,2

PATHOPHYSIOLOGY

The reduction in blood flow that occurs during a stroke is due primarily to either ischemia or hemorrhage. Of the two major types of stroke (ischemic and hemorrhagic), the ischemic form is more common, accounting for 85% to 87% of stroke cases.3 Ischemic stroke occurs when an artery supplying the brain is occluded, leading to decreased blood flow to the affected area. A variety of diseases can cause occlusion, most commonly large-artery disease, small-vessel disease, and cardioembolism.4 The causes of an ischemic stroke may be more generally categorized as embolism and thrombosis, with thrombosis occurring more frequently. Thrombotic stroke occurs when a clot forms in a vessel and reduces blood flow to the brain from the location where the clot originates. In embolic stroke, the clot forms in an area apart from the brain, loosens, and travels until it reaches a blood vessel that is too narrow to allow it to pass. This occlusion impedes the flow of blood to the brain.

Hemorrhagic stroke occurs when a blood vessel in the brain becomes weak and ruptures. The blood then leaks into other parts of the brain, damaging the surrounding tissue. Hemorrhagic stroke may be classified in one of two ways, depending upon the location of the bleed. Subarachnoid hemorrhage results from a ruptured blood vessel between the surface of the brain and the skull. Eighty-five percent of subarachnoid hemorrhages are caused by the rupture of saccular aneurysms at the base of the brain. Intracerebral hemorrhage, most commonly the result of small-vessel disease, occurs when a blood vessel inside the brain ruptures. Intracerebral hemorrhages may be further categorized as lobar hemorrhages (involving the cortex) and subcortical hemorrhages (involving the area beneath the cortex).4,5

SIGNS AND SYMPTOMS

The brain contains more than 100 billion neurons. For each minute that a patient with a large-vessel ischemic stroke goes untreated, an average of 1.9 million neurons are lost.6 Stroke is a time-sensitive condition, making it important for patients, caregivers, and health professionals to recognize its signs and symptoms. Symptoms may vary depending upon the area of the brain affected, but the National Institute of Neurological Disorders and Stroke (NINDS) lists five key signs and symptoms (TABLE 1) that should be identified.7 If a person is experiencing any of these signs and symptoms, 911 should be called without delay.

The acronym F.A.S.T. may be used for determining whether a person may be experiencing a stroke: Face—Ask the person to smile; this will help identify numbness or weakness on one side of the face. Arms—Ask the person to raise both arms; notice whether one arm drifts lower than the other. Speech—Ask the person to repeat a simple phrase; this will indicate whether he or she is having trouble speaking or understanding speech. Time—Call 911 immediately if the person evidences any of these signs and symptoms.8

PHARMACOTHERAPY

Pharmacologic therapy for stroke may be divided into stroke-specific treatment and stroke prevention.9 The pharmacologic treatment of a stroke depends upon whether the stroke is ischemic or hemorrhagic. Pharmacotherapeutic options for primary ischemic stroke are tissue plasminogen activator (tPA) and—under defined conditions—antiplatelet agents. Pharmacotherapeutic treatment for hemorrhagic stroke is aimed at controlling the patient’s blood pressure and intracranial pressure.

Treatment of Ischemic Stroke

tPA: Of the available IV tPA agents, alteplase is the only one that is FDA approved to treat ischemic stroke. This indication was granted after the drug’s efficacy was demonstrated in the NINDS rt-PA Stroke Study. This study, which included 624 patients randomized to receive 0.9 mg/kg (maximum 90 mg) of IV tPA or placebo, found that those receiving tPA (£3 hours of symptom onset) were at least 30% more likely than those receiving placebo to have minimal or no disability 3 months after treatment.10

The Safe Implementation of Thrombolysis in Stroke–International Stroke Registry (SITS-ISTR) 3- to 4.5-hour study found no differences between patients treated within 3 hours and those treated within 3 to 4.5 hours with regard to symptomatic intracerebral hemorrhage, mortality, or modified Rankin Scale (which measures degree of disability/dependence in daily activities of stroke patients) score of 0 to 2 at 90 days.11 While stroke patients eligible for IV tPA should be treated within 3 hours, the stroke-treatment guidelines published by the American Heart Association/American Stroke Association (AHA/ASA) in 2007 recommend that tPA may still be administered to eligible patients 3 to 4.5 hours after the stroke.11,12 Because bleeding is the most frequently reported adverse reaction associated with alteplase, it is extremely important to follow the prescribing guidelines (TABLE 2). Other adverse reactions reported with the use of alteplase for ischemic stroke include cerebral edema, cerebral herniation, seizure, and new ischemic stroke.13


Antiplatelet Agents: Aspirin is the only oral antiplatelet agent that has been evaluated for the treatment of acute ischemic stroke. Aspirin therapy (325 mg) should begin within 24 to 48 hours of an ischemic stroke, but not within 24 hours of completion of alteplase therapy.12 Alternatively, it is recommended that patients who are ineligible for treatment with a thrombolytic agent receive early aspirin therapy (starting dose 150-325 mg). Although there is an increased risk of bleeding with aspirin use, a beneficial role is seen when aspirin is administered during acute ischemic stroke.14

Secondary Prevention: Treatment of ischemic stroke does not stop once the acute concern is addressed. Secondary treatment addresses the prevention of recurrences by controlling metabolic risk factors, namely blood pressure and lipids. Lowering the blood pressure has been shown to reduce the risk of stroke by 30% to 40%, with no clear evidence favoring a specific antihypertensive class.15 A joint AHA/ASA publication summarized a meta-analysis of seven randomized clinical trials and the MOSES and PRoFESS trials. Based on findings from these trials, the AHA/ASA recommends blood pressure reduction with or without a documented history of hypertension. While the optimal blood pressure goal is undetermined and should be individualized, a benefit has been seen with a reduction of 10/5 mmHg.15

The specific blood pressure regimen also remains uncertain. The use of diuretics alone or in combination with an angiotensin-converting enzyme inhibitor has been shown to confer a benefit. AHA/ASA guidelines recommend that the regimen be based on pharmacologic properties, the mechanism of action, and a consideration of specific patient characteristics. Elevated LDL and total cholesterol are associated with an increased risk of ischemic stroke. Statin therapy has the most support in the literature for the prevention of recurrent ischemic stroke, but niacin, fibrates, and cholesterol-absorption inhibitors also may be used in patients who cannot tolerate statin therapy. Statin therapy is recommended in patients with ischemic stroke with atherosclerosis, LDL ³100 mg/dL, and no known coronary heart disease. A reduction of at least 50% or LDL £70 mg/dL is targeted to provide optimal benefit. Ischemic stroke patients with elevated cholesterol or comorbid coronary artery disease should be managed according to National Cholesterol Education Program ATP III guidelines.15

Treatment of Hemorrhagic Stroke

Treatment Options: While hemorrhagic stroke accounts for about 15% of stroke occurrences per year, the death rate for these patients is disproportionately high (50%).2 Pharmacologic treatment options for hemorrhagic stroke are limited. Treatment of any patient who has experienced a hemorrhagic stroke includes the following steps: determining the cause of bleeding; controlling the patient’s blood pressure; stopping any medications that may heighten the risk of further bleeding; and controlling the patient’s intracranial pressure.16

Subarachnoid hemorrhage is most often caused by an aneurysm. In such cases, surgical treatment (clipping or coil embolization) may be employed.17 Warfarin-related intracerebral hemorrhage is relatively common, with an annual risk of about 2%. This form of hemorrhagic stroke often carries a grim prognosis because it typically affects older patients and results in a larger volume of bleeding. All medications that increase the risk of bleeding, such as warfarin, aspirin, and heparin, should be discontinued in a patient having a hemorrhagic stroke. If the intracranial hemorrhage is caused specifically by warfarin, the patient’s international normalized ratio (INR) may be corrected through the administration of IV vitamin K and fresh-frozen plasma.17 The administration of 10 mg of IV vitamin K will potentially normalize the INR in 6 to 24 hours; additional doses of 5 to 10 mg every 12 hours may be given, to a maximum dose of 25 mg. The amount of fresh-frozen plasma to be administered is based on the patient’s INR, body weight, and target INR after correction.18

An elevation in blood pressure commonly occurs during the acute phase of hemorrhagic stroke. This rise in blood pressure has been linked to increased mortality, disability, and the risk of hematoma development. Numerous agents, including thiazide diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers, have been shown to effectively lower blood pressure during a stroke. Management of the patient’s blood pressure also reduces the patient’s risk of another stroke.17

There are several ways to decrease intracranial pressure. A ventriculostomy may be performed to drain blood that has collected in the brain. In severe cases, a decompressive craniotomy, in which part of the cranium is removed and blood is evacuated to relieve the intracranial pressure, may be performed.16

Secondary Prevention of Intracerebral Hemorrhagic Stroke: The recurrence rate of intracerebral hemorrhage is 2.1% to 3.7% per patient-year.19 Factors that contribute to the recurrence rate are location of the previous hemorrhage, older age, and anticoagulation therapy post intracerebral hemorrhage. Hypertension remains a modifiable risk factor that may help reduce the risk of primary intracerebral hemorrhage, as well as its recurrence. While the target blood pressure goal has not been ascertained, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a blood pressure of <140/90 mmHg or <130/80 mmHg in patients with chronic kidney disease or diabetes; this also may be an attainable goal for the prevention of secondary intracerebral hemorrhage. Oral anticoagulants are a risk factor for recurrent intracerebral hemorrhage. The AHA/ASA guidelines suggest that antiplatelets are a safer alternative after primary intracerebral hemorrhage.19

CONCLUSION

Stroke is a time-sensitive condition regardless of whether it is ischemic or hemorrhagic. Although pharmacotherapeutic treatment options are limited, they have been shown to reduce the complications associated with stroke. Pharmacotherapeutic treatment options also reduce the risk of recurrent stroke.

REFERENCES

1. National Center for Health Statistics. Health, United States, 2010: With Special Feature on Death and Dying. Hyattsville, MD: US Department of Health and Human Services; 2011. DHHS Pub No 2011-1232.
2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18-e209.
3. Hinkle JL, Guanci MM. Acute ischemic stroke review. J Neurosci Nurs. 2007;39:285-293,310.
4. Markus H. Stroke: causes and clinical features. Medicine. 2004;32:57-61.
5. American Stroke Association. Types of stroke. www.strokeassociation.org/
STROKEORG/AboutStroke/ TypesofStroke/Types-of-Stroke_ UCM_308531_SubHomePage.jsp. Accessed August 12, 2011.
6. Saver J. Time is brain—quantified. Stroke. 2006;37:263-266.

7. National Institute of Neurological Disorders and Stroke. Know stroke. Know the signs. Act in time. www.ninds.nih.gov/disorders/stroke/knowstroke.htm. Accessed December 28, 2011.
8. National Stroke Association. Warning signs of stroke. www.stroke.org/site/PageServer?pagename=symp. Accessed December 28, 2011.
9. Piechowski-Józwiak B, Bogousslavsky J. Pharmacotherapy of stroke. Eur Neurol Dis. 2006;1:52-62.
10. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587.
11. del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009;40:2945-2948.
12. Adams HP Jr, del Zoppo G, Alberts MJ. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655-1711.
13. Activase (alteplase) package insert. South San Francisco, CA: Genentech, Inc; April 2011.
14. Hirsh J, Guyatt G, Albers GW, et al. Antithrombotic and thrombolytic therapy. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:71S-105S.
15. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:227-276.
16. Caplan LR. Patient information: hemorrhagic stroke treatment. www.uptodate.com/contents/patient-information-hemorrhagic-stroke-treatment. Accessed October 3, 2011.
17. Marsh JD, Keyrouz SG. Stroke prevention and treatment. J Am Coll Cardiol. 2010;56:683-691.
18. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc. 2007;82:82-92.
19. Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41:2108-2129.

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