Code Stroke: Alteplase, Icatibant and Labetalol

There are two stroke subgroups: ischaemic and haemorrhagic. An ischaemic stroke is caused by the blockage of a blood vessel in the brain (i.e. a blood clot), whereas haemorrhagic stroke is caused by a bleed into the brain (i.e. from a ruptured blood vessel). The medications discussed in this article are used to treat ischaemic stroke.

Acute Ischaemic Stroke

When patients present with any signs of potential stroke (facial drooping, one sided weakness, slurred speech, etc.) it is deemed a medical emergency as assessment and treatment within certain time frames can greatly affect patient outcomes. Clinical assessment using a stroke scale is still considered gold standard (many scales are presented in Therapeutic Guidelines: Neurology). Brain imaging, usually with computed tomography (CT), is used to exclude haemorrhage and may also detect early signs of ischaemia.

Selected patients may benefit from intravenous thrombolytic therapy (medication that breaks down clots) if initiated within 4.5 hours of stroke symptom onset. Thrombolysis can increase the chance of the patient being independent on discharge by 30%, with better outcomes the earlier the treatment is started. Thrombolysis beyond 4.5 hours is not currently recommended; however the efficacy and safety of different thrombolytic agents up to nine hours after stroke onset is currently being researched.

Table 1. Overview of medications used in a “Code Stroke”.

^{*In Australia, labetalol in the intravenous form is an unlicensed product and can only be obtained under individual contract (with a TGA approved manufacturer) with the pharmacy at each hospital.}

Alteplase

Alteplase (Actilyse^®) is a thrombolytic agent; a recombinant tissue plasminogen activator (rt-PA) which mimics endogenous plasminogen activator. It is the only agent of its class that is indicated for thrombolysis in acute stroke. It is also indicated for acute myocardial infarction and acute pulmonary embolus (along with other agents such as tenecteplase). Other than bleeding, the main risk associated with its use is anaphylaxis.

Alteplase activates fibrin-bound plasminogen, converting it back into plasmin which catalyses the deactivation of fibrin resulting in clot breakdown. It has a low affinity for circulating plasminogen but a high affinity for fibrin-bound plasminogen, resulting in highly effective local fibrinolysis with limited systemic effects.

The benefit and risks associated with the use of alteplase need to be evaluated for each patient on an individual basis. Further information can be found in the product information, in the Therapeutic Guidelines and in local hospital protocols.

Patient selection criteria should be considered before initiating alteplase. Some key examples are:

Do not use if:

• There is uncertainty about time of stroke onset (must be within 4.5 hours)
• Patient is under 18 years old
• CT scan shows any signs of haemorrhagic stroke
• Patient shows only a minor stroke deficit that is rapidly improving
• Patient is having, or has had, a seizure in the period since stroke onset
• International Normalised Ratio (INR) > 1.5
• Patient has a low platelet count
• Patient has an elevated activated partial thromboplastin time (APTT)

Use with caution if:

• Patient is over 80 years old
• Patient has a severe neurological impairment
• Patient has experienced recent stroke or serious head trauma
• Patient has had major surgery within the last 14 days
• Recent myocardial infarction (heart attack)
• Advanced or terminal illness that may pose a risk to treatment

Alteplase is cleared rapidly by the liver, with more than 50% cleared within five minutes of ceasing the infusion. Approximately 80% of the drug is cleared within ten minutes. The dose is calculated as per the patient’s weight, with an initial bolus and then hour long infusion.

Many guidelines and protocols have been created to streamline the calculation process and reduce the scope for error in emergencies. SA Health’s Stroke Management Procedures and Protocols offer one example of an alteplase dosing schedule.

Angioedema is a rare (1-2%) but potentially life-threatening complication of thrombolysis, usually occurring towards the end of the infusion. It is more common in patients on pre-existing angiotensin converting enzyme inhibitor therapy and commonly involves the tongue, but can manifest as rash, stridor, bronchospasm or hypotension. In the event of evolving angioedema, an urgent medical review is warranted and icatibant potentially indicated (discussed below).

Icatibant

Icatibant (Firazyr^®) is a highly effective, although expensive, treatment for acute attacks of hereditary angioedema (HAE), for example non-allergy/bradykinin mediated angioedema. It is subsidised by the Pharmaceutical Benefits Scheme for this indication and not for alteplase-induced angioedema. However, it may be listed in local stroke guidelines, such as the SA Health Code Stroke Protocol, where the drug is considered an option for alteplase-induced angioedema under the direction of an immunologist.

Icatibant is a selective competitive beta-2 receptor antagonist leading to inhibition of bradykinin release and relief of angioedema symptoms. It has a half-life of approximately one to two hours with approximately 90% of the drug converted to inactive metabolites in the liver.

A single 30mg subcutaneous injection (3mL via slow push) is usually sufficient to treat an attack. Icatibant’s bioavailability is approximately 97% with peak concentration reached in 30 minutes. It contains no antimicrobial agent and should be used immediately. A maximum of three doses should not be exceeded within 24 hours.

Labetalol

Alteplase is contraindicated if a patient’s blood pressure remains above 185/110mmHg. This is called pre-treatment hypertension and is where labetalol is indicated in the SA Health Code Stroke Protocol. Labetalol is also used if there is uncontrolled hypertension during the alteplase infusion.

Labetalol has mixed beta-blocking and alpha1-blocking activity which provides an additional arteriolar vasodilating action. This unique combination of actions (alpha and beta blocking in heart, lungs and vasculature) decreases systemic blood pressure and vascular resistance without markedly affecting cardiac output, renal haemodynamics, or cerebral blood flow.

Labetalol is metabolised in the liver. Its effect occurs within five minutes, peaks within 15 minutes, and persists for at least two to four hours (effects lasting 24 hours has been reported). It has a half-life of approximately 5.5 hours.

Conclusion

Alteplase, icatibant and labetalol are not common medications, but they have an important role to play in the management of patients presenting with acute ischaemic stroke. Clinicians should be aware of the accessibility of these products at their hospital, their role in local stroke protocols (including patient selection criteria), and the cost to benefit ratio associated with their use.