What medications can be used for stroke treatment?
Drugs for Initial Treatment of Ischemic Stroke
Intravenous thrombolytics. clot-busting, or thrombolytic drugs, normally used for breaking up existing clots in people who have had heart attacks, are now administered intravenously for ischemic (not hemorrhagic) stroke. The standard thrombolytic drug used for stroke is tPA or alteplase (Activase). Streptokinase is also sometimes used, and other drugs are
under investigation. The following steps are critical before administering these agents.
Before tPA is given, a CT scan must also first confirm that the stroke is not hemorrhagic.
Thrombolytics must be administered within three hours of a stroke (but not after that period) to have any effect. Unfortunately, most stroke patients arrive at the hospital more than three hours after an attack and therefore are not eligible for treatment. This delay is the primary reason why only 1% to 2% of stroke patients are receiving these agents.
Because of an association with a risk of hemorrhage, tPA may not be appropriate for patients with existing risk factors for bleeding. They should not be used in patients who are experiencing seizures. However, thrombolytics may be appropriate in more patients than previously thought, however, including older people, those with a history of stroke, and those with high blood pressure. More research is needed to confirm this.
Thrombolytics are used less frequently than they should be in certain groups, particularly African-Americans.
Intra-Arterial tPA. Researchers are investigating a tPA agents injected directly into an artery in the brain. Early studies suggest this approach may allow effective treatment up to six hours after a stroke and improve recovery in more patients. The risk for bleeding is increased, however.
Ancrod. Ancrod is an agent derived from the venom of a pit viper snake that reduces the amount of a blood-clotting factor called fibrinogen. Although it is not actually a clot-busting drug, some experts believe it might be a possible alternative to thrombolytics. Studies are reporting less disability in patients who are given ancrod within three hours of the stroke. (It is not clear yet whether the agent improves survival.) As with all anticlotting agents, there is a slightly higher risk for hemorrhage.
Anticlotting Medications for Preventing a Recurring Stroke
Medications that prevent blood from coagulating or clotting are used to prevent a recurring or second stroke. They are generally either antiplatelet agents or anticoagulants. Typically, an antiplatelet agent -- most often aspirin -- is initiated within 48 hours of an ischemic stroke and continued in low doses as maintenance. Studies suggest that antiplatelet therapy can reduce the risk for a second stroke by 25%. Specific anticlotting agents may be warranted in some patients with high-risk conditions for a first stroke.
Aspirin. Aspirin has some modest effect in preventing a second stroke and is recommended within 48 hours of a first stroke, usually in doses of between 50 and 325 mg. However, aspirin should not be taken at home or before the cause of the stroke has been determined. Aspirin increases the risk for bleeding in patients with hemorrhagic stroke, and taking it would preclude important clot-busting drugs in appropriate patients with ischemic stroke. It is not clear if aspirin should be used after a first stroke in patients who have been taking it before the stroke for heart attack prevention or other medical problems. Experts now recommend that most patients take a daily low-dose aspirin to prevent a second stroke. (A 2000 review of four trials found no evidence that aspirin can prevent a first ischemic stroke, although the studies reviewed in the report had been conducted using subjects at risk for heart disease, not stroke.)
Thienopyridines. Clopidogrel (Plavix) and ticlopidine (Ticlid) are antiplatelet agents known as thienopyridines. They may be slightly more protective against stroke than aspirin, but they are costly. Typically, thienopyridines are options for patients who cannot tolerate or do not respond to aspirin. Clopidogrel has been preferred over ticlopidine because of its better safety record.
Glycoprotein IIB/IIIa Inhibitors. Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors are potent drugs that reduce clotting by blocking platelets (clotting factors in the blood). They are administered intravenously in the hospital and include abciximab (ReoPro, Centocor), eptifibatide (Integrilin), tirofiban (Aggrastat), and lamifiban. They are being investigated along or as add-on agents to thrombolytic drugs.
Anticoagulants. Anticoagulants thin blood and may be useful under certain circumstances.
Warfarin. The anticoagulant warfarin (Coumadin) is a potent anticoagulant and needs to be monitored carefully. Studies have mixed on its value for protecting against future stroke. A 2001 study found no additional benefits for patients with ischemic stroke compared to aspirin. Warfarin is, however, very important in high-risk patients with atrial fibrillation, and may be useful in other situations, such as patients with patent foramen ovale (PFO), those whose stroke followed a heart attack, or in high-risk patients who do not respond to or cannot take other antiplatelet drugs.
Heparin. Of note, intravenous heparin, a potent antiplatelet agent, has been used for ischemic stroke since 1941. Although many physicians continue to use it, five out of six major studies have reported no clear protective benefits compared to aspirin with the use of standard heparin or any other heparin-like agents. For example, heparins do not appear to protect against stroke recurrence, brain injury, or post-stroke complications. They pose a much higher risk for hemorrhagic stroke than aspirin does. Experts now recommend heparins only for preventing thromboembolism in stroke patients at risk for this condition.
All anticlotting drugs carry a risk for bleeding and a slightly increased risk for hemorrhagic stroke.
ACE Inhibitors and Diuretics
Angiotensin converting enzyme (ACE) inhibitors are used to treat high blood pressure. Studies suggest that they have additional properties that protect against stroke. For example, they appear to help prevent plaque build-up on the blood vessel walls and blood clotting. Importantly, evidence is increasing that ACE inhibitors may prevent a first and second stroke in high-risk patients -- even those with normal blood pressure. An important 2002 study used subjects older than 55 with a history of heart disease, stroke, or diabetes and an additional risk factor for heart disease or stroke. Those who took the ACE inhibitor ramipril (Altace) experienced greater protective benefits against stroke itself and disabilities from stroke than those who took placebo. (The protective effects of ACE inhibitors against hemorrhagic stroke are mixed, with a 2001 study showing significant protection and the 2002 study showing none.)
Adding a diuretic, another important antihypertensive drug, has increased protection in some studies. It should be noted that it is still unclear then if the stroke-protective benefits from ACE inhibitors are simply from lowering blood pressure, including in people with normal pressure. Some experts believe, then, that both an ACE inhibitor and a diuretic should be given to patients with a history of stroke or TIA regardless of blood pressure. Of note is research suggesting that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the effects of ACE inhibitors.
Drugs for Hemorrhagic Stroke
Antifibrinolytic Drugs. Drugs called antifibrinolytics (e.g., tranexamic acid, epsilon amino-caproic acid or an equivalent) are used to stop bleeding. They have been investigated for years for subarachnoid hemorrhagic stroke with mixed results. Some patients even get worse with their use. They may be beneficial in certain circumstances, such as in patients with a low risk for spasms or when surgery is delayed. It is not clear, however, whether they have any long-term benefits even in these cases. Combinations with other agents may prove to be helpful.
Calcium Channel Blockers. One of the most common and serious dangers after a subarachnoid hemorrhagic stroke is spasm of the blood vessels near the ruptured site, which closes off oxygen to the brain. Calcium causes contraction of the smooth muscles of the blood vessels, and calcium channel blockers are drugs that relax the blood vessels. One, nimodipine (Nimotop), has been tested in a number of trials with considerable success. The drug works best if it is administered within six hours of the stroke. Calcium channel blockers are not useful for ischemic stroke.
Investigative Therapies to Protect or Restore Nerve Cells after a Stroke
Hyperbaric Oxygen. To improve oxygenation of brain tissue investigators have been studying the use of hyperbaric oxygen (oxygen administered under pressure) in stroke patients. Results have been mixed with some risk of significant adverse effects using this approach. One animal study suggested that simply delivering oxygen under normal pressure may protect nerve cells if it is started less than 30 minutes after stroke.
Hypothermia. Hypothermia -- reducing body temperature -- is being investigated for reducing mortality rates in patients with severe stroke and swelling in the brain. Cooling is done through special cooling blankets, ventilators, or infusion of cool fluids. Risks include pneumonia, blood clotting disorders, heart rhythm disturbances, and others. This approach may not be as affective as hemicraniectomy, a surgical procedure used to relieve pressure.
Nerve-Protecting Agents. Researchers are currently working to develop medications that may slow down or prevent the cascading process that destroys nerve cells after a stroke. Many investigative drugs are targeting the excitatory amino acids, such as glycine and glutamate, which are known to destroy nerve cells after a stroke.
Other nerve-protecting agents being investigated that have shown some promise include citicoline, piracetam, and ebselen. Piracetam, for example, is showing promise in helping patients improve speech defects after a stroke.
Investigative Agents for Nerve Regeneration. It has been thought that when cells in the brain were destroyed, new ones could not grow to replace them. Scientists have now observed, however, that nerve regrowth (neurogenesis) is possible in the adult brain. This exciting discovery opens the way for new agents that might in the future stimulate nerve growth and repair damage done by many neurologic diseases, including stroke. For example, a 2002 study reported nerve regeneration in animals whose brains were treated with the agent inosine. More research is under way.