Since its approval in 1987, controversy has surrounded a drug that we all know is near and dear to my heart, recombinant tissue Plasminogen Activator (insert eye roll).  In similar discreetness of a Hollywood wedding, the FDA updated the prescribing information of tPA with important changes made to the contraindications to the use of tPA in the setting of acute ischemic stroke.  It is unclear as to what prompted these updates and why.  There have been no recent studies of significance published to support these modifications.

 

2/2015 updated prescribing info:

“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”

 

Now contrast the new package insert to the 2013 package insert.  Pay special attention to the omissions of the exclusion of contraindications in patients with history of intracranial hemorrhage and seizure at onset of stroke.   It is pertinent to note that the wording regarding the contraindications has also changed.  The previous consequences being “significant disability or death” have now been replaced with “situations in which the risk of bleeding is greater than the potential benefit.”

 

From the 2013 package insert (changes are 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:

o       Current use of oral anticoagulants (e.g., warfarin sodium) or an International Normalized Ratio (INR) > 1.7 or a prothrombin time (PT) > 15 seconds

o       Administration of heparin within 48 hours preceding the onset of stroke and have an elevated activated partial thromboplastin time (aPTT) at presentation.

o       Platelet count < 100,000/mm3”

 

The new 2/2015 update does provide some vague conditions in which the risks of bleeding must be outweighed against the anticipated benefits (however, note that these are not firm contraindications):

• Recent major surgery or procedure, (e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels)

• Cerebrovascular disease

• Recent intracranial hemorrhage

• Recent gastrointestinal or genitourinary bleeding

• Recent trauma

• Hypertension: systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg

• High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation

• Acute pericarditis

• Subacute bacterial endocarditis

• Hemostatic defects including those secondary to severe hepatic or renal disease

• Significant hepatic dysfunction

• Pregnancy

• Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions

• Septic thrombophlebitis or occluded AV cannula at seriously infected site

• Advanced age [see Use in Specific Populations (8.5)]

• Patients currently receiving anticoagulants (e.g., warfarin sodium)

• Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

 

Currently the guidelines have not updated their list of contraindications to tPA in acute stroke, but I wouldn’t be surprised to see them included when the guidelines are updated.

 

So like Oprah says, you get tPA! You get tPA! Everyone gets tPA!