Ischemic stroke medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

Overview

Treatment of stroke is occasionally with thrombolysis ("clot buster"), but usually with supportive care (physiotherapy and occupational therapy) and secondary prevention with antiplatelet drugs (aspirin and often dipyridamole), blood pressure control, statins and anticoagulation (in selected patients).

Ischemic Stroke

Medical treatment	Drug class	Recommendations
		Acute	Long-Term
Reperfusion therapy	Tissue plasminogen activator (t-PA)	Recommended within 3-4.5 hours of onset of ischemic stroke in eligible patients	None
Antithrombotic agents	Antiplatelets	Oral administration of aspirin (initial dose is 325 mg) is recommended within 24 to 48 hours after stroke onset in most patients Aspirin is contraindicated in patients with ischemic stroke within 24 hours of t-PA administration DAPT therapy (aspirin and clopidogrel) is recommended for 90 days in patients with symptomatic intracranial large artery disease	Long term therapy with clopidogrel or aspirin extended release dipyridamole may be used for secondary prevention of non cardioembolic stroke
	Anticoagulants	Parenteral or oral anticoagulation is not recommended within 48 hours of onset of ischemic stroke	Oral anticoagulants may be used for secondary prevention of ischemic stroke in patients with atrial fibrillation or other cardioembolic disease
Antilipid therapy	Statins	Among patients already taking statins at the time of onset of ischemic stroke, continuation of statin therapy during the acute period is reasonable	Long term management of ischemic stroke with high intensity statins may be recommended for patients with atherosclerotic disease Patients who cannot tolerate high intensity dose, medium or low intensity statins may prove beneficial
Antihypertensive therapy	Labetolol, nitroprusside	May be used to control high blood pressure in patients with BP> before starting t-PA	Long term oral antihypertensives may be used after 24 hours of ischemic stroke in patients having history of hypertension
Antihyperglycemic agents	Insulin	May be used to control blood glucose between range of 140-180 mg/dl since hyperglycemia is associated with worst outcome in patients with acute ischemic stroke	Long term oral antidiabetic may be used for secondary prevention of ischmeic stroke in patients with diabetes mellitus

Antithrombotic agents

Antiplatelet drugs

Acute treatment
Long term treatment

Anticoagulants

Acute treatment
Long term treatment

Reperfusion therapy

Intravascular

Within 3 hours
3-4.5 hours
> 4 hours

Intraarterial

Mechanical thrombectomy

An ischemic stroke is due to a thrombus (blood clot) occluding a cerebral artery, a patient is given antiplatelet medication (aspirin, clopidogrel, dipyridamole), or anticoagulant medication (warfarin), dependent on the cause, when this type of stroke has been found. Hemorrhagic stroke must be ruled out with medical imaging, since this therapy would be harmful to patients with that type of stroke.

Whether thrombolysis is performed or not, the following investigations are required:

• Stroke symptoms are documented, often using scoring systems such as the National Institutes of Health Stroke Scale, the Cincinnati Stroke Scale, and the Los Angeles Prehospital Stroke Screen. The Cincinnati Stroke Scale is used by emergency medical technicians (EMTs) to determine whether a patient needs transport to a stroke center.
• A CT scan is performed to rule out hemorrhagic stroke
• Blood tests, such as a full blood count, coagulation studies (PT/INR and APTT), and tests of electrolytes, renal function, liver function tests and glucose levels are carried out.

Other immediate strategies to protect the brain during stroke include ensuring that blood sugar is as normal as possible (such as commencement of an insulin sliding scale in known diabetics), and that the stroke patient is receiving adequate oxygen and intravenous fluids. The patient may be positioned so that his or her head is flat on the stretcher, rather than sitting up, since studies have shown that this increases blood flow to the brain. Additional therapies for ischemic stroke include aspirin (50 to 325 mg daily), clopidogrel (75 mg daily), and combined aspirin and dipyridamole extended release (25/200 mg twice daily).

It is common for the blood pressure to be elevated immediately following a stroke. Studies indicated that while high blood pressure causes stroke, it is actually beneficial in the emergency period to allow better blood flow to the brain.

If studies show carotid stenosis, and the patient has residual function in the affected side, carotid endarterectomy (surgical removal of the stenosis) may decrease the risk of recurrence if performed rapidly after stroke.

If the stroke has been the result of cardiac arrhythmia with cardiogenic emboli, treatment of the arrhythmia and anticoagulation with warfarin or high-dose aspirin may decrease the risk of recurrence. Stroke prevention treatment for a common arrhythmia, atrial fibrillation, is determined according to the CHADS/CHADS2 system.

Anticoagulant Recommendations Following Ischemic Stroke

Currently, the European Stroke Organization recommends that anticoagulation should not be used after non-cardio-embolic ischemic stroke, except in some specific situations, such as aortic atheromas, fusiform aneurysms of the basilar artery, cervical artery dissection, or patent foramen ovale in the presence of proven deep vein thrombosis (DVT) or atrial septal aneurysm. Data suggest that oral anticoagulation after non-cardiac ischemic stroke is not superior to aspirin, but may be associated with more bleeding.

Antiplatelet Recommendations Following Ischemic Stroke

Although the combination of clopidogrel and aspirin is prescribed for patients with acute coronary syndromes (ACS), this combination has not been studied in the setting of acute ischemic stroke. No data are available about the use of other combinations of antiplatelet agents in the management of acute ischemic stroke. The current American Stroke Association (ASA) / American Heart Association (AHA) recommendations are the following:

"The administration of clopidogrel alone or in combination with aspirin is not recommended for the treatment of acute ischemic stroke (Class III, Level of Evidence C)."

The 2008 American College of Chest Physician (ACCP) Guidelines, similar to the AHA/ASA Guidelines, state the following:

4.1.3. "In most patients with a noncardioembolic stroke or transient ischemic attack, were recommend avoiding long-term use of the combination of aspirin and clopidogrel (Grade1B). In those with a recent acute myocardial infarction, other acute coronary syndrome, or a recently placed coronary stent, we recommend clopidogrel plus aspirin (75-100mg) [Grade1A]."

There is no data available regarding the safety and efficacy of dual antiplatelet therapy in addition to chronic anticoagulation for patients with non-cardio-embolic-ischemic stroke. It should be noted that more potent platelet inhibition with prasugrel was associated with a higher risk of adverse outcomes compared to clopidogrel in the Triton study among patients who had sustained a prior stroke or transient ischemic attack (TIA).

Thrombolysis

In increasing numbers of primary stroke centers, pharmacologic thrombolysis ("clot busting") with the drug tissue plasminogen activator, tPA, is used to dissolve the clot and unblock the artery. However, the use of tPA in acute stroke is controversial. On one hand, it is endorsed by the American Heart Association and the American Academy of Neurology as the recommended treatment for acute stroke within three hours of onset of symptoms as long as there are not other contraindications (such as abnormal lab values, high blood pressure, or recent surgery).

This position for tPA is based upon the findings of two studies by one group of investigators which showed that tPA improves the chances for a good neurological outcome. When administered within the first three hours, 39% of all patients who were treated with tPA had a good outcome at three months, only 26% of placebo controlled patients had a good functional outcome. However, in the NINDS trial 6.4% of patients with large strokes developed substantial brain hemorrhage as a complication from being given tPA. tPA is often misconstrued as a "magic bullet" and it is important for patients to be aware that despite the study that supports its use, some of the data were flawed and the safety and efficacy of tPA is controversial. A recent study found the mortality to be higher among patients receiving tPA versus those who did not. Additionally, it is the position of the American Academy of Emergency Medicine that objective evidence regarding the efficacy, safety, and applicability of tPA for acute ischemic stroke is insufficient to warrant its classification as standard of care. Until additional evidence clarifies such controversies, physicians are advised to use their discretion when considering its use. Given the cited absence of definitive evidence, AAEM believes it is inappropriate to claim that either use or non-use of intravenous thrombolytic therapy constitutes a standard of care issue in the treatment of stroke.

In 2014, a meta-analysis by the Cochrane Collaboration reported the following findings with the administration of recombinant tissue plasminogen activator (also known as alteplase or rt-PA) within 6 hours of the onset of stroke:

• Reduction in combined outcome of disability and death
• No increase in death

An individual patient meta-analysis by the Stroke Thrombolysis Trialists' Collaborative Group reported the following findings with the administration of recombinant tissue plasminogen activator (rt-PA):

• 10% absolute increase of a good outcome, defined as no significant disability at 3-6 months (modified Rankin Score of 0 or 1)
• 2% absolute increase risk of early death from intracranial hemorrhage

Embolic Stroke

Anticoagulation can prevent recurrent stroke. Among patients with nonvalvular atrial fibrillation, anticoagulation can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%.. However, a recent meta-analysis suggests harm from anti-coagulation started early after an embolic stroke.

Hemorrhagic Stroke

Anticoagulants and antithrombotics, key in treating ischemic stroke, can make bleeding worse and cannot be used in intracerebral hemorrhage. Patients are monitored and their blood pressure, blood sugar, and oxygenation are kept at optimum levels.

Contraindicated Medications

Stroke is considered an absolute contraindication to the use of the following medications:

• Abciximab
• Almotriptan
• Alteplase
• Conjugated estrogens/bazedoxifene
• Drospirenone and Ethinyl estradiol
• Eletriptan
• Eptifibatide
• Esterified estrogens
• Frovatriptan
• Norethindrone acetate and Ethinyl estradiol
• Norgestimate and Ethinyl estradiol
• Norelgestromin and Ethinyl Estradiol
• Phentermine
• Prasugrel
• Progesterone
• Rizatriptan
• Reteplase
• Streptokinase
• Urokinase
• Vorapaxar
• Norgestrel and Ethinyl estradiol
• Sumatriptan
• Zolmitriptan

The 2007 American Heart Association (AHA) / American Stroke Association (ASA) Guidelines (DO NOT EDIT)

Class III (Harm)

"1.Urgent anticoagulation with the goal of preventing early recurrent stroke, halting neurological worsening, or improving outcomes after acute ischemic stroke is not recommended for treatment of patients with acute ischemic stroke (Level of Evidence: A)This recommendation may change if additional data demonstrate the usefulness of very early intravenous administration of anticoagulants for treatment of patients with infarctions secondary to large-artery thrombosis or cardioembolism. Urgent anticoagulation should not be used in lieu of intravenous thrombolysis for treatment of otherwise eligible patients (Level of Evidence: A)"

"2.Urgent anticoagulation is not recommended for patients with moderate to severe strokes because of an increased risk of serious intracranial hemorrhagic complications (Level of Evidence: A)"

"3.Initiation of anticoagulant therapy within 24 hours of treatment with intravenously administered rtPA is not recommended (Level of Evidence: A)"