CardioExchange Archive

This post was originally published on Craig Cocchio‘s blog, Emergency Medicine PharmD.

Flying in under the radar recently were the changes to the Alteplase (rt-PA) prescribing information. These changes pertain to the contraindications to use of the drug in acute ischemic stroke. It’s hard to find anything—and puzzlingly so—on the particulars about why the FDA authorized such changes.

The updated contraindications now read as follows: Link
Do not administer Activase to treat acute ischemic stroke 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 (e.g., some neoplasms, arteriovenous malformations, or aneurysms)
• Bleeding diathesis
• Current severe uncontrolled hypertension

Without the old contraindications to compare to side by side, the changes may not be obvious. From a 2013 package insert, the contraindications read as follows (changes italicized):

Activase therapy in patients with acute ischemic stroke 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 (e.g., > 185 mm Hg systolic or > 110 mm Hg diastolic)
• 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 (e.g., warfarin sodium) or an International Normalized Ratio (INR) > 1.7 or a prothrombin time (PT) > 15 seconds
  • Administration of heparin within 48 hours preceding the onset of stroke and have an elevated activated partial thromboplastin time (aPTT) at presentation.
  • Platelet count < 100,000/mm3

The changes can be significant, particularly the language introducing the contraindications. The consequences which were previously “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

Furthermore, the language describing specific bleeding diatheses (drugs: warfarin, diabigatran, rivaroxaban, etc.; thrombocytopenia or prolonged bleeding times) and describing what constitutes “uncontrolled hypertension” are now very vague.

At this point the guidelines have not updated their list of contraindications… for now.