Steph’s Note: When trying to decide what to write about this week, I decided to at least start to try to fill another content hole on our site. If you haven’t noticed, we have very little…erm…next to nothing about acute ischemic strokes. Whoopsy. But I’m going to try to redeem us, so here goes, happy learning! (Also btw, big shout out to Joe Nissan, who helped to make sure this post is in tip top, current critical care practice shape for you guys. Thanks, Joe!)

You’re working in the emergency room, and you get the page that there’s a code stroke coming in 10 minutes. What do you do?

You start your checklist:

Does the bed in the planned room have a scale?
Ask for the patient’s name if it’s available to check any medical records, particularly medication records.
Listen for any info on vital signs and severity of symptoms.
Get ready to ask for a STAT point-of-care glucose check if you don’t hear the results of one already done.
Double check the formula for tPA dosing and have your calculator in your pocket.
Grab the tPA box for bedside preparation.
Wait for CT results.

Whew. There’s a lot to unpack there, and we’re going to pull out a couple major pieces to discuss. But first, we should back up for a little pathophysiology moment.

What is an ischemic stroke?

When the code stroke is called, it’s important to have an understanding of what’s going on with the patient clinically that makes EMS suspect a stroke. In simple terms, an ischemic stroke is basically a heart attack in the brain. That is, there’s a blockage in one of the blood vessels that supplies the brain, which leads to insufficient blood flow to those tissues…and eventually this can cause tissue death.

Ischemic strokes account for ~87% of all strokes. The blockage can be one of 2 types:

A cerebral thrombosis, which is a blood clot that forms locally in the brain at the site of an atherosclerotic plaque.
A cerebral embolism, which is a clot that forms elsewhere in the body and is pumped into the vessels that supply the brain. (The most common cause of this is an abnormal heart rhythm called atrial fibrillation, in which a clot may form in the heart due to pooling of blood. When this clot breaks off, it is pumped out into the vasculature.)

What are the symptoms of a stroke?

Symptoms of an ischemic stroke are directly related to what portions of the brain are being cut off by the blockage. The best way to remember major symptoms is the acronym BE FAST (which is also a good reminder to BE FAST when you do recognize these symptoms…TIME IS BRAIN!!!!)

This is a pretty simplified assessment of stroke symptoms, but it covers the gamut of major signs, especially from a patient’s perspective. As clinicians, we should also be thinking of less obvious symptoms like the following:

Acute changes or loss in any of the 5 senses
Clumsiness or ataxia
Dizziness/vertigo
Word-finding difficulty (aphasia), loss of speech, or slurred/garbled speech (dysarthria)
Confusion, mood changes/emotional lability, or personality changes
Memory loss
Nausea or vomiting

How are stroke patients assessed?

Severity of a stroke is graded according to the NIHSS (National Institute of Health Stroke Scale) scoring system. Components include measures of neurological function and deficits across 11 categories, and scores range from 0-42. Higher scores indicate a more severe stroke, whereas scores 1-5 indicate a minor stroke.

Diagnosis of a stroke requires imaging, specifically a CT scan. Usually, for the purposes of speed and availability, a non-contrasted CT is the mainstay for assessing an acute stroke. The CT will also show if there are areas of hemorrhage, which can be important when determining next steps for treatment.

This brings us to the meat of this post. While there are MANY other pieces of the acute stroke treatment puzzle, today we’re here to discuss tPA - what it is, how it works, how much to give, and who should get it (or not) and when.

What is tPA?

What you need to get from this is that the end point of the coagulation cascade is thrombin (Factor II) converting fibrinogen to fibrin, which cross links and forms clots. On the other side of the checks and balances, there’s plasminogen conversion to plasmin by plasminogen activator (aka tPA). Plasmin breaks down fibrin into fibrin-degradation products (FDPs here), thereby lysing clots. BOOM. *Fibrin*-o-*lytics*. (Image)

tPA, or tissue plasminogen activator, is a fibrinolytic. Alteplase and tenecteplase are two common tPA products. Another is reteplase, which is also fibrin-specific like alteplase and tenecteplase, meaning they don’t deplete systemic coagulation factors. (Older non-specific fibrinolytics are streptokinase and urokinase, and these do deplete systemic coagulation factors.)

As you might suspect from the name, these drugs aid in the break down fibrin. They do this by increasing the conversion of inactive plasminogen to active plasmin.

Forgot what that means? You’re not alone. Take a look at this simplified coagulation cascade for a refresher.

Now that we have that straight, let’s take a moment to discuss alteplase versus tenecteplase. When I was a young gun new grad working in the ER, everything was alteplase, alteplase, alteplase. It was the tPA of choice. And while it has certainly served its purpose, Joe (our critical care guru) brought it to my attention that it’s kinda like the old guy still trying to dunk on the twenty-somethings at the local gym… and bricking it hard. It’s just not as cool anymore. The new, hot tPA on the scene and set to replace alteplase is tenecteplase. Why, you ask?

Compared to alteplase…

Tencteplase has higher fibrin specificity → stronger clot busting ability
Tenecteplase has a longer half-life → allows for easier administration
Tenecteplase has higher resistance to plasminogen activator → decreased risk of clot stability and formation
And of course there’s the money factor. Tenecteplase is about $2000 cheaper per dose.

Seems like a win all around, right? Knowing these benefits of tenecteplase is great, but how does it stack up against alteplase in terms of clinical benefit. That’s really the bottom line.

Which brings us to the 2024 Lancet Neurology ATTEST-2 trial. This prospective, open-label, randomized, parallel-group trial evaluated 1777 patients in the UK who were given either alteplase or tenecteplase within the 4.5 hour time window for acute ischemic stroke. The primary outcome was the distribution of the modified Rankin Scale (mRS) score at day 90. If you’re not familiar with this score, it’s a way of measuring disability with scores ranging from 0-5 (with a score of 6 indicating death). It’s also the most common outcome measure of most stroke trials. They tested for non-inferiority first (with a lower 95% confidence limit of 0.75) and superiority next (if non-inferiority was demonstrated). Safety endpoints were as you’d expect: death and all the kinds of bleeding.

The modified Rankin Scale score system for assessing disability after strokes. (Image)

Tenecteplase was non-inferior to alteplase for mRS score distribution at 90 days, but it was not superior (odds ratio 1·07; 95% CI 0·90–1·27; p value for non-inferiority<0·0001; p=0·43 for superiority). Let’s pause here for a moment because this non-inferiority study is slightly different from what most of us are probably used to.

Often, for non-inferiority studies, we’re looking for the upper bound of the 95% confidence interval to be below the set non-inferiority limit because it’s usually a relative risk or a hazard ratio, where higher numbers indicate more risk of badness. Put another way, because the new treatment/intervention is supposed to just be “not worse” than the study standard, we just want to make sure that there’s not any chance (with 95% confidence, at least) that the risk of a bad outcome could be higher than what we already have. But did you notice that in the ATTEST-2 trial, non-inferiority was concluded when the lower bound of the 95% confidence interval (0.9) was larger than the limit of 0.75?

Well crud. How does that make sense?

In this case, it has to do with how the primary endpoint of the study was defined. Note that the primary endpoint was the distribution of the mRS scores, not the mRS scores themselves. This paper about regression analysis of ordinal stroke outcomes explains it best: “The summary odds ratio is a clinically interpretable parameter that represents ‘the odds of a higher versus lower mRS score’” between 2 treatment groups - at all mRS cut points.

So the summary odds ratio for the primary endpoint of the ATTEST-2 trial was 1.07, meaning there was a 7% higher chance of achieving a particular desired distribution of mRS scores at 90 days with tenecteplase versus alteplase. So higher odds ratios would be better here because that represents a higher likelihood of a desired distribution (NOT a higher likelihood of higher mRS scores, which would be clinically worse!).

Taking this a step further, that’s why a confidence interval above the non-inferiority limit is desirable for demonstrating non-inferiority in this case. That means the odds of achieving this desired mRS score distribution is no less than 75% with tenecteplase compared with alteplase. Would you want to play a lottery if your odds of winning were less than 75%?

I mean, I guess it depends on the price of the ticket versus the size of the prize. But in this case, no, you don’t want to play with odds less than 75% of getting your desired outcome.

Long story short, tenecteplase was deemed non-inferior to alteplase in terms of 90 day outcomes. In terms of safety, there were no significant differences with regards to hemorrhages or angioedema. Sounds like a win to me!

Now that we’ve gone down this little biostats rabbit hole, back to the task at hand - treating acute ischemic stroke. So in the case of an acute ischemic stroke, in which there’s a clot blocking a blood vessel somewhere in - or on the way to - the brain, it would make sense that you might need something to open the road back up, right?

Considerations for Administering tPA in Ischemic Stroke

That’s exactly the idea. According to the 2019 American Heart Association Guidelines for Stroke, alteplase is indicated in patients presenting within 4.5 hours of stroke symptom onset. The guidelines even state that it is reasonable to use alteplase if the exact time of stroke symptom onset is unknown, so it could even be beneficial outside of the 4.5 hour time window.

Essentially, the idea is tPA administration ASAP for CT-confirmed stroke because TIME IS BRAIN. That being said, there are several caveats to this “universal” proclamation that we pharmacists should be aware of as we’re going through our checklist, whether your institution uses alteplase or tenecteplase.

First, what is the patient’s blood pressure? Although not a forever contraindication, blood pressures >185/110 require attention prior to tPA administration. The risk of hemorrhage after tPA is greater in patients with severe hypertension, so take a moment to bring those pressures down before starting the infusion.

There are several options, all of which work pretty darn quickly (like, within minutes). So the benefit of waiting just a smidge longer to get the blood pressure down outweighs the risk. Intravenous labetalol, nicardipine, and clevidipine are all on the table as first line choices. While hydralazine is also listed as an option, it’s onset of action is longer (on the order of 20-30 minutes), and TIME IS BRAIN. Why wait that long when you have other, faster options?

Second, what is the patient’s blood glucose? Symptoms of hypoglycemia (and actually hyperglycemia, too) can mimic those of a stroke, so ruling out glycemic abnormalities with a simple glucose stick that results in seconds is well worth it to save the risks of unnecessary alteplase.

Warfarin patients…they DO exist! (Image)

Third, does the patient have a known or suspected coagulopathy? This could be a history of hemophilia found in the chart, platelets <100,000 on labs in the ER, or it could be an acquired coagulopathy. We’re pharmacists, so the acquired coagulopathy that should come to mind is medication-induced. Ahhh, those anticoagulants! Does the patient have a history of atrial fibrillation? Could they be on warfarin, and should we run a STAT INR? Have they taken a DOAC in the last 48 hours (or longer if they have impaired renal function)?

Now, I want to be clear. Just because a patient takes an anticoagulant at home or has one on the med list does NOT mean they’re automatically excluded from receiving tPA! We should be assessing that INR or aPTT or time from last dose to make sure we’re not inappropriately ruling out patients who are otherwise eligible.

Also, on a similar note, use of antiplatelets (regardless of last dose timing) is NEVER a contraindication unless baseline platelets are <100,000. This is a common question, and it’s tempting to rule out tPA because a patient is on clopidogrel and they took their dose 3 hours ago. Yes, it’s true. Antiplatelets increase the chances of a possible bleed when given with tPA, but they are NOT absolute contraindications.

Fourth, does the patient have an increased risk of bleeding with tPA? This could be a GI bleed 2 weeks ago, a history of an intracranial hemorrhage, a brain tumor, etc. Check out the full list of alteplase contraindications from the 2019 AHA Guidelines below. There are a lot of non-pharmacological conditions that may alter eligibility for alteplase when weighing risk of bleeding versus benefit in ischemic stroke.

So let’s say your code stroke patient DOES meet the eligibility criteria for IV tPA. Their non-contrasted CT demonstrated an infarct and no hemorrhage. Blood pressure is normal, and glucose is normal. You’re fortunate enough to have some history on this patient (rather than him being a John Doe), and there are no interacting medications. Labs and medical history are a go. How should you dose tPA?

Dosing and Administration of tPA for Ischemic Stroke

Alteplase dosing is straight-forward and standard (for once). The total dose is 0.9mg/kg of total body weight (max total dose for any patient is 90 mg). Ten percent of that total dose is administered as an IV bolus over 1 minute, and the remaining 90% follows as a continuous infusion over an hour.

Let’s practice for kicks.

Your code stroke patient is transferred to the weigh bed in the room, and the nurse tells you his weight is 91 kg. You do your quick math on your calculator (that you had ready, right?!):

0.9 mg/kg x 91 kg = 82 mg total dose

0.1 x 82 mg = 8.2 mg —> 8 mg IV bolus

82 - 8 mg = 74 mg IV infusion over 1 hour

And voila! There you have it. IV alteplase dosing for acute ischemic stroke.

When you can’t find what you need to draw up a drug in the middle of a code. Raise your hand if you’ve ever been there…*raises hand* (Image)

As far as preparation and administration, this is often prepped at the bedside by a pharmacist in the ER since TIME IS BRAIN. With that in mind, many facilities combine everything that is needed for alteplase administration into a “code stroke box” to make it easier. There’s nooooothing more fuuuuun than having to run around the ER opening supply carts trying to find the syringe or needle that you need in an emergency. Noooothing at all. So rather than deal with that hot mess, the medication and all the supplies are boxed and put in an automated dispensing cabinet as a kit.

Preparation of alteplase vials is pretty specific, but the beauty is that once reconstituted, the solution is 1 mg/mL. Depending on vial size, it’s either a 50 mg/50 mL vial or 100 mg/100 mL vial. Makes it super easy, right, when you’re trying to draw up doses quickly?

The bolus dose is drawn into a syringe from the reconstituted vial. So from our example case, we would need a 100 mg/100 mL vial since our total dose is > 50mg. We would draw 8 mg = 8 mL into a syringe, leaving 92 mg = 92 mL in the vial at this point. Give the bolus syringe to the nurse to administer. Then, our infusion is only 74 mg = 74 mL, so we would remove (92-74 =) 18 mL from the vial, leaving only the 74 mL needed. Spike the vial with an infusion set, prime the line, turn that baby upside down, and give it to the nurse to connect to the patient for their infusion.

So there’s no need to make bags, etc, unless that’s your institution’s policy. Everything may done right from the reconstituted vial, which makes things faster. Which is great for TIME IS BRAIN.

Now let’s take a moment for tenecteplase dosing and administration. It’s even easier than alteplase!! It is dosed as 0.25 mg/kg of ACTUAL body weight (max dose: 25 mg) given as an IV bolus over 5 seconds. Preparation is super easy. Dilute the tenecteplase vial with 10 mL sterile water for a final concentration of 5 mg/mL, and then draw up the dose. Hand it to the nurse to administer along with two 10 mL saline flushes, one for before the tenecteplase and one for after.

Bada bing, bada boom! Easy peasy, right?

Mmmm. Sorry. If this all seems a little too easy, you’re right. We haven’t talked about the downsides, but we’re about to.

Adverse Reactions of tPA Administration

You’ve probably guessed the biggest risk of administering a fibrinolytic that works to dissolve clots… Yup, bleeding. While the risk is dose-dependent and increases significantly with alteplase doses >150mg, it is still possible for bleeding to occur at normally recommended stroke doses. But yes, this is why the alteplase and tenecteplase doses for stroke are capped, no matter the patient’s weight.

Bleeding may occur at any site - internal or external. Internal can literally be anywhere…from intracranial to retroperitoneal to GI to genitourinary. External could be from wounds or IV puncture sites. In stroke patients who received alteplase, intracranial hemorrhages were noted in about 15% of patients within 90 days and 6% within 36 hours of administration. Now that’s a broad scope and begs questions of stroke location, patient characteristics, etc, but for a 10,000 foot view, that tells you this is not an insignificant occurrence.

So that’s the adverse reaction you would expect. The somewhat surprising one is angioedema. This hypersensitivity reaction is reported in up to 5% of stroke patients receiving thrombolysis. While it’s certainly not a common occurrence, 5% isn’t nothing, and the swift onset and potentially fatal outcome makes this a reaction to log away as a possibility. Interestingly, a patient’s use of ACE-inhibitors (also known for a risk of angioedema) seems to increase risk of this reaction with thrombolysis 3-4 fold.

Hello, importance of pharmacy and medication histories!

Next Steps after Giving tPA for Ischemic Strokes

Monitoring of a patient’s hemostasis labs and vital signs is essential, as well as a clinical assessment of any new symptoms (don’t want that “worst headache of my life” report…). Along with severe headache, acute spikes in blood pressure, worsening neurological function, or new nausea/vomiting could indicate hemorrhagic transformation. That’s when the STAT CT is warranted.

Just like blood pressure may have required treatment in order to initiate tPA, it should continue to be maintained less than 180/105 during and for 24 hours after tPA is administered. All those options previously discussed are still on the table. Still trying to prevent the big, bad, scary hemorrhage!

Any and all procedures should be avoided, if possible. This means holding off on that nasogastric tube placement or the in-dwelling catheter. Procedures may mean trauma, which equals possible blood loss. And tPA will just exaggerate any and all blood loss.

Finally, a follow up CT scan or MRI should be obtained 24 hours after tPA is given, especially prior to starting or resuming any antiplatelets or anticoagulants. Don’t want to double up on any ongoing bleeding!

The tl;dr of Using tPA for Acute Ischemic Stroke

There you have it. The basics of what you need to know about using tPA for acute ischemic strokes. Here are a couple key takeaways:

Ischemic strokes are heart attacks in the brain and may originate from clots formed in the brain or those that travel from elsewhere.
Symptoms reflect the part of the brain not being perfused and may range from sensory to motor to emotional to GI. The best way to remember major stroke symptoms is the BE FAST pneumonic.
The NIHSS scale is used to assess severity of a stroke. Higher numbers indicate more severe strokes.
tPA is a fibrinolytic therapy that is meant to bust up a clot and aid with reperfusion of affected tissues. TIME IS BRAIN, so the faster this can be administered, the higher chances of recovery.
Blood pressure and blood glucose should be assessed prior to tPA administration. Labs for clearance are nice to have but not required unless there’s a reason to suspect an anomaly.
Monitor, monitor, monitor for any signs of hemorrhage or hypersensitivity after giving tPA!

We’ve covered the acute management of ischemic strokes, but don’t worry, we haven’t forgotten about secondary prevention. Stay tuned for a literature-happy review of those therapies, coming soon!

The Pharmacist's Quick Guide to tPA for Acute Ischemic Strokes