Pharmacology 101: Thrombolytics for Acute Ischemic Stroke

On average someone in the United States has a stroke every 40 seconds.¹

This dire statistic from the American Heart Association (AHA) represents the fact that every year approximately 795,000 Americans experience stroke, of which 87% are ischemic strokes. The AHA predicts that by 2030 nearly 4% of the adult population will have experienced a stroke at some point in their lives.¹

Stroke is an “abrupt neurological outburst caused by impaired perfusion through the blood vessels to the brain.”² An ischemic stroke happens when blood supply to brain cells is interrupted, depriving them of nutrients and oxygen and ultimately leading to necrosis.

One systematic review of the literature puts forth the estimate that “the typical patient loses 1.9 million neurons each minute in which stroke is untreated.”³ The author also makes this jarring observation: “Compared with the normal rate of neuron loss in brain aging, the ischemic brain ages 3.6 years each hour without treatment.”³ Clearly the phrase “time is brain” does indeed hold water!

How Thrombolytics Work

Because most ischemic strokes are caused by thromboses (blood clots) in the arteries, thrombolytics (or “clot busters”) may be employed with the hopes of restoring cerebral blood flow. In the 1980s researchers began to investigate the use of thrombolytics for ischemic stroke, and in 1996 the US Food and Drug Administration approved intravenous single-chain tPA (alteplase).⁴ Tenecteplase, also known as TNK, is noted in the most recent American Heart Association (AHA)/American Stroke Association (ASA) Guidelines for the Early Management of Patients With Acute Ischemic Stroke as an alternative thrombolytic that may be used in certain cases.

Thrombolytics work by binding to fibrin (a protein component of clots) and converting entrapped plasminogen to plasmin. The plasmin then breaks up fibrin, dissolving the clot.⁵

The problem with thrombolytics is that data indicate the risk/benefit ratio is less favorable as time goes by, and so a rapid door-to-needle time is important when thrombolytics are deemed appropriate.

The AHA/ASA guidelines specifically note that “in patients eligible for IV alteplase, benefit of therapy is time-dependent, and treatment should be initiated as quickly as possible” (emphasis added).⁶ The guidelines recommend alteplase for select patients who can be treated within 3–4.5 hours of ischemic stroke symptom onset or their last-known-well or baseline state. Emerging data indicate some patients may benefit outside this window under certain circumstances.⁶

EMS caregivers play a huge role in ensuring patients are evaluated and treated as quickly as possible. The data show that when patients use EMS, there are shorter times to ED arrival and evaluation and treatment with thrombolytics.⁶

Adverse Events and Contraindications

Thrombolytics are not for everyone. For example, they are not recommended for mild, nondisabling strokes due to the risks. While they can have incredible therapeutic potential for patients with acute ischemic stroke, thrombolytics also carry risks. The most concerning adverse event is hemorrhaging, particularly intracranial bleeding. Angioedema may also occur. Patients are monitored closely in the hospital setting following any thrombolytic administration.

Contraindications include intracranial or subarachnoid hemorrhage, acute or recent severe head trauma within 3 months, structural GI malignancy or recent GI bleed within 21 days, recent acute ischemic stroke within 3 months, and recent intracranial/intraspinal surgery within 3 months.

Coagulopathy is also a contraindication. Bleeding risks include a low platelet count or elevated INR, PTT, or PT. When on scene with a patient who may be having an acute ischemic stroke, it is important for EMS caregivers to ask whether the patient is on any anticoagulant medications (blood thinners) such as warfarin, heparin, enoxaparin (Lovenox), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa), or dabigatran (Pradaxa).

Communication Is Key

In terms of communication, it is extremely important to clarify both the time of symptom onset and the time the patient was last known well. While they may seem similar, they may not always coincide.

Corey Slovis, MD, FACP, FACEP, FAAEM, professor and chair emeritus of emergency medicine at Vanderbilt University Medical Center and medical director for the Nashville Fire Department, says, “In emergencies just like any other critical endeavor, it’s so important to be clear. The optimal thing to do rather than time-of-onset of stroke [symptoms] versus last-known-normal is to routinely describe specifically both. Then there can be no confusion between me and you.”

Elaborating further, Slovis says, “If you ask me, ‘What was the time of onset?’ and I say, ‘It was this morning,’ well, maybe it’s because I saw the stroke this morning. But the last known normal might have been 3 days ago, [meaning] the stroke could have happened 3 days ago.

“But if you say, ‘When was the last known normal and do you know the time of onset?’ I could say, ‘Well, Dad went to bed last night normal about 9:30, and when he woke this morning, he had slurred speech and a facial droop.’ Or ‘I don’t know when he was normal last. We came to his house and found him like this today, but we haven’t seen him in a week.’ That says something so totally different.”

In conclusion Slovis has this take-home point: “The very first step for a paramedic is, ‘When was the last known normal?’ and ‘When was the time of onset [of symptoms]?’ as separate and distinct entities. [Alteplase is] one of the very best drugs we have, and it’s one of the very worst drugs we have. When you have a medication that can remove a clot, dissolve a clot, lyse a clot, or begin the facilitation of lysis prior to thrombectomy, that is a lifesaving, stroke-saving drug. Yet that same drug can cause hemorrhagic strokes or death in up to 10% of patients.

“So what I believe is, we need to maximize the benefits and minimize the risks. And that can only be done by knowing what the time of onset was, or at least the last known normal, and then having experts decide what risk factors make the risk/benefit ratio for or against thrombolytics, and often with shared decision-making.”

The views and opinions expressed in this article are those of the author.

References

1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics—2020 update: A report from the American Heart Association. Circulation. Published online 2020:E139-E596. doi:10.1161/CIR.0000000000000757

2. Kuriakose D, Xiao Z. Pathophysiology and treatment of stroke: Present status and future perspectives. Int J Mol Sci. 2020; 21(20): 1–24. doi:10.3390/ijms21207609

3. Saver JL. Time is brain—Quantified. Stroke. 2006; 37(1): 263–6. doi:10.1161/01.STR.0000196957.55928.ab

4. Lyden PD. Thrombolytic Therapy for Acute Ischemic Stroke: A Very Great Honor. Stroke. 2019; 50(9): 2597–603. doi:10.1161/STROKEAHA.119.025699

5. Jilani TN, Siddiqui AH. Tissue Plasminogen Activator. StatPearls [Internet]. Accessed March 29, 2022. www.ncbi.nlm.nih.gov/books/NBK507917/

6. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50(12): E344–E418. doi:10.1161/STR.0000000000000211

Daniel Hu, PharmD, BCCCP, has Doctor of Pharmacy degree and is a critical care and emergency medicine pharmacist. He is a frequent speaker at conferences and has many publications in peer-reviewed journals.