Important Changes to Activase Contraindications

A version of this article originally appeared on the Emergency Medicine PharmD blog.

Changes to the prescribing information for alteplase (Activase rt-PA) pertaining to contraindications to the drug's use in acute ischemic stroke (AIS) recently flew in under the radar.

The contraindications now read as follows:

Do not administer Activase to treat AIS in the following situations in which the risk of bleeding is greater than the potential benefit:

• Current intracranial hemorrhage
• Subarachnoid hemorrhage
• Active internal bleeding
• Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma
• Presence of intracranial conditions that may increase the risk of bleeding, including some neoplasms, arteriovenous malformations, or aneurysms
• Bleeding diathesis
• Current severe uncontrolled hypertension

Without the old contraindications for comparison purposes, the changes may not be obvious. In a 2013 package insert, the contraindications read as follows (changes italicized):

Activase therapy in patients with AIS is contraindicated in the following situations because of an increased risk of bleeding, which could result in significant disability or death:

• Evidence of intracranial hemorrhage on pretreatment evaluation
• Suspicion of subarachnoid hemorrhage on pretreatment evaluation
• Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or previous stroke
• History of intracranial hemorrhage
• Uncontrolled hypertension at time of treatment, such as >185 mm Hg systolic blood pressure or >110 mm Hg diastolic blood pressure
• Seizure at the onset of stroke
• Active internal bleeding
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Known bleeding diathesis including but not limited to: Current use of oral anticoagulants, such as warfarin sodium, or an International Normalized Ratio (INR) >1.7 or a prothrombin time >15 seconds Administration of heparin within 48 hours preceding the onset of stroke and an elevated activated partial thromboplastin time at presentation. Platelet count <100,000/mm³

The changes, particularly the language introducing the contraindications, are significant. The consequences that used to be "significant disability or death" are now simply "situations in which the risk of bleeding is greater than the potential benefit."

If you didn't catch the specific changes, rt-PA is no longer contraindicated in patients with:

• History of intracranial hemorrhage
• Seizure at the onset of stroke
• Blood glucose assessment prior to rt-PA

Furthermore, the language describing specific bleeding diatheses and what constitutes as "uncontrolled hypertension" is now very vague.

At this point, it is unclear if or when practice guidlines will be updated based on the new prescribing information.