To Lyse or Not to Lyse: The Great tPA Debate

It’s been a few months since I’ve posted (a little over six, whoops), but as they say – new year new me. I’m planning on trying to stick to a once a month or so posting schedule so hopefully that goes well!

I’m kicking 2024 off with a real doozy – does thrombolysis really work in stroke?

Got your attention, maybe? Yes, this debate is withered and old and the same arguments from both sides get circulated routinely about the putative risks and benefits of providing a guideline-supported therapy with decades of supporting evidence to patients who are experiencing a neurologic emergency which has the potential to permanently alter their entire life. Ok, ok – that is the only bit of sass I’ll allow myself.

Key Points

  • Thrombolysis for eligible acute ischemic stroke patients is guideline-recommended and backed by strong evidence, but controversy remains over the merits of the evidence
  • Objection #1: There is No Positive Data for Thrombolysis
    • Re-analyses of positive trials have distinct flaws themselves. Pooled patient-level analyses of all trials and registry studies of tens of thousands of patients demonstrate clear benefit with thrombolysis in eligible patients that consistently outweighs the risks.
  • Objection #2: The Harms are Undersold to Patients
    • While it is difficult to capture and characterize the exact level of risk that is discussed or the amount of risk patients want to hear, evidence suggests that risk is the predominant theme in many consent conversations. Some suggest a move to informed refusal of thrombolysis would be preferable in most scenarios.
  • Objection #3: Unacceptable Excess Harm is Caused After Misdiagnosis
    • Thrombolysis is rarely administered to patients with stroke mimics. While it does occur, patients with stroke mimics are significantly less likely to experience adverse effects and not administering thrombolysis to a potential stroke patient is likely more harmful.
  • Objection #4: Legal Risk of Adverse Effects
    • Several studies of legal cases involving acute stroke therapy have shown physicians are significantly more likely to be sued for not administering thrombolysis, rather than be sued for the toxicities of administering it.

Every few months or so, a variant of a particular post appears on Twitter. This is how it typically goes down: someone asks what everyone’s “hot take” in medicine is, someone inevitably states that either thrombolytics don’t work or there is “no evidence” supporting their use in stroke, and a back and forth occurs on differing interpretations of the same three to four studies and a debate on the value of different medical specialties, and rarely anything productive is accomplished. I have historically not engaged in these debates, mainly because my opinion is that it is just not a debate worth having, and engaging reminds me too much of this classic xkcd comic:

Thrombolysis is effective in acute ischemic stroke, and this fact is supported by numerous international treatment guidelines.1–3 Of course, the decision to administer thrombolysis is not straightforward, and concluding that "thrombolysis works for all strokes" without considering indications and exclusions obviously misses the nuance of the treatment. Like any therapy, there are risks associated with the potential benefit, and this is magnified by the fact that the main risks associated with administration can produce devastating consequences that would negate its potential benefit. However, these considerations form the basis of who is and who is not eligible to receive treatment. Over the last 30 years, the population who is most likely to benefit and least likely to be harmed has been refined and with refinement, a clear criteria list has been formed. Despite this, this debate continues to come up, suggesting clinician opinion fall somewhere on this spectrum:

It's important to recognize that this debate is largely artificial, and in the real world, stroke guidelines are applied appropriately and eligible patients are treated with thrombolysis in a thoughtful manner. Clinician opinion on thrombolysis, like many things, falls on a bell curve and most people fall in the middle:

How Did We Get Here?

It is worth briefly revisiting the history of thrombolysis in stroke and explore how we got to where we are today. If you're not interested in a history lesson, feel free to jump to the discussion of Where Were Now.

Since at least the late 1930s, the primary pathophysiologic model of acute ischemic stroke has been known to be some form of thrombosis of the cerebral circulation.4,5 Interest in developing therapies that could dissolve these thrombi thus emerged as early as the 1950s, predating much of the understanding of the nuance of stroke pathophysiology and predating imaging technologies which would allow better stroke characterization and risk stratification. Even without the guide of CT or MRI, early stroke neurologists recognized the critical relationship between time from symptom onset and initiation of treatment. Bernard Sussman and Thomas Fitch, describing three patients with angiographically observed cerebral thrombi, stated “what has been needed is an agent, known to be effective in reversing thrombosis, which can be administered immediately on the appearance of symptoms by the first physician on the scene.”6 In the case of their three patients, this involved treatment with fibrinolysin, a bovine-derived plasmin derivative, of which one patient with a documented MCA occlusion experienced reperfusion.

Fibrinolysin specifically never quite gained steam and its subsequent use was limited mostly to case reports,7–9 but when streptokinase was demonstrated to be effective in coronary ischemia, interest grew in using it for cerebral ischemia. Early trials were less than encouraging, however – a 1963 RCT of 40 patients with anterior cerebral thrombosis randomized to streptokinase and SQ heparin plus warfarin vs placebo and SQ heparin plus warfarin within 72 hours of symptom onset revealed no significant difference in functional improvement (after 10 days) but, somewhat surprisingly, no differences in adverse effects.10 The authors did, however, note that patients who experienced clinical improvement tended to exhibit markers of enhanced fibrinolytic activity, regardless of the arm they were randomized to, suggesting that identifying a dosing regimen of streptokinase which could reliably induce a state of fibrinolysis could replicate the improvement. A larger trial was thus initiated and published in 1964 using a higher dose of streptokinase, but unfortunately analysis of the 73 randomized patients demonstrated a significantly higher rate of early death (35.1% vs 11.1%) which dampened enthusiasm to the strategy.11 Notably, these trials predated the existence of CT, so while they did perform an LP to “rule out” ICH (and then gave a lytic! Yikes!), it is not possible to know for sure whether some of the randomized patients presented with hemorrhagic strokes.

The 1970s introduced CT technology to vascular neurology12 and allowed neurologists to easily identify one of the issues with thrombolytic administration (this time with urokinase) - hemorrhagic conversion. A pilot study of urokinase in 31 patients with ischemic stroke presenting within 36 hours of last known well demonstrated urokinase could sustainably induce fibrinolysis, but no unequivocal early neurologic improvement was noted.13 Furthermore, at least four patients experienced early hemorrhagic conversion, with the cases distinctly discussed in a separate paper.14 A 1981 review article on stroke therapeutics notes that thrombolysis remains an attractive theory, but notes the limitations of the evidence discussed above. The authors conclude that “the ability to make a more accurate diagnosis… and improved technology to administer and measure thrombolytic agents might make this form of treatment feasible in the future.”15

Well, the technology came – first, incorporation of CT imaging in the routine evaluation of stroke revealed that nearly a quarter of patients with primary ICH may have been incorrectly diagnosed as primary ischemic stroke prior to the availability of CT imaging.16 Second, improvements in the rapidity of diagnosis, identification of target lesions, and selection of dosing given more extensive experience with thrombolysis in MI and PE led to some of the first definitive reports of improved outcomes with thrombolytic therapy. A 1988 retrospective review of 65 cases, 43 of whom received intra-arterial thrombolysis (urokinase or streptokinase) and 22 of whom received conventional therapy (antiplatelets and anticoagulants) for vertebrobasilar occlusion revealed patients who experienced recanalization with thrombolysis (44% of treated patients) had significantly improved outcomes compared to conventional therapy – 31.6% mortality vs 86.3% mortality (p = 0.0005) and 52.6% vs 13.6% favorable outcome (p = 0.017). While thrombolysis without recanalization had dismal outcomes (100% mortality, remember these were vertebrobasilar strokes so this is not terribly unexpected), this was not found to be statistically significantly different than conventional therapy (p = 0.10 for both mortality and functional outcomes).17 A pilot study from the same year found similar results – patients treated with intra-arterial thrombolysis within 8 hours of last known well (note the time window of eligibility has been gradually narrowing) tended to experience neurologic improvement when vessel recanalization occurred, and neurologic demise was only observed in those without recanalization. Interestingly, 4 of the 15 patients in this trial experienced hemorrhagic conversion but did not experience neurologic decline (in fact 2 of the 4 completely or nearly completely recovered), providing an early example of how hemorrhagic conversion is not a universally poor outcome.18

In sum, the field of stroke neurology spent decades continuously refining the theoretical basis for who may benefit from thrombolysis. Up until the late 1980s, the strategy had yet to be proven effective in large scale trials, but the lessons learned included that universal application of thrombolysis (especially in combination with anticoagulation) was generally harmful, earlier initiation was likely better than late, and that neurologic improvement seemed closely linked with vessel recanalization. A comprehensive review published in 1987 outlined the theoretical basis for thrombolysis in cerebrovascular disease and reviewed all available clinical and experimental data published to date, ultimately concluding that with advances in imaging techniques, understanding of fibrinolysis, and improves selection of cases, thrombolysis will likely become a viable treatment option for stroke.19

The viability of thrombolysis for stroke treatment was demonstrated perhaps for the first time in a landmark meta-analysis of early clinical data in 1992. By narrowing in to just the effects of thrombolysis revealed in studies conducted when CT technology was available, the overall effect of thrombolysis on death and neurologic deterioration was reported to be about a 6% improvement (p = 0.007).20

The first meta-analysis to demonstrate improvements in outcomes with thrombolytics, but only when data from the pre-CT era were excluded.

This, in combination with an improved understanding that long term functional outcomes, rather than just death or short-term improvement, was most meaningful to patients, prompted the initiation of the lytic study design which we know today.21 The MAST-I,22 MAST-E,23 and ASK24 trials were the first major streptokinase trials conducted using “traditional” thrombolysis methods – patients were enrolled within 4 (ASK) or 6 (MAST-I and MAST-E) hours of last known well to receive streptokinase or placebo, excluding patients with evidence of ICH, recent anticoagulant therapy, and patients with only mild deficits or very severe deficits. Overall, the three trials demonstrated the high risk of bleeding and early mortality with streptokinase. Over 1200 patients were randomized across the three trials and rates of symptomatic hemorrhagic conversion and early mortality were higher in treated patients across all three trials. The silver lining, however, was that in patients that survived, patients treated with streptokinase had better functional outcomes, especially if they were treated earlier. Now, this could easily be confounded by the fact that more severe patients likely expired earlier and thus were excluded from the 6-month outcome analysis, but it suggested that a more selective agent, one with a lower likelihood of systemic and intracerebral bleeding, might be able to capture that functional outcome benefit without the overwhelming risk of bleeding and poor early outcomes. 

Functional outcomes from the MAST-E trial. Note that outcomes excluding mortality were significantly improved with streptokinase. The Rankin disability score would later be modified to include death to account for this limitation.

This is where alteplase enters the story. Alteplase, as a true “tissue” plasminogen activator, provides a number of theoretical advantages over the far less specific fibrinolytics streptokinase and urokinase and had already been demonstrated to be a viable option for stroke in animal models by the time the streptokinase trials were underway.25,26 Alteplase had also recently been demonstrated to be superior to streptokinase for MI in the GUSTO trial,27 further supporting the notion that not all lytic agents could be considered equal and that the pharmacodynamic advantages of alteplase over streptokinase could lead to measurable clinical differences. The first meaningful trials of alteplase in stroke, by Brott and Haley, revealed two important findings – stroke patients could be rapidly triaged and randomized to acute therapies, and that both the risk and benefit of thrombolytic therapy was a function of time to treatment and the dose of the agent.28,29 These findings, demonstrating that alteplase at a dose of 0.9 mg/kg given within 180 minutes of last known well appeared to balance clinical improvement and risk of hemorrhage, formed the basis of the NINDS trial which went on to be the first large-scale positive trial of thrombolysis in acute ischemic stroke.30 This trial prompted the FDA to approve alteplase for the treatment of AIS within 3 hours of last known well and the debate of exactly how beneficial alteplase is has raged on every since.    

Where We Are Now

Since the publication of the NINDS trial, alteplase has been evaluated in at least 8 RCTs for stroke, which I have briefly summarized below.


Inclusion Criteria and Treatment

Functional Outcomes




Stroke onset within 3 hours


Standard exclusion criteria


Alteplase 0.9 mg/kg vs placebo

624 patients randomized across two arms


Global OR for improved functional outcome:

OR 1.7, 95% CI 1.2-2.6 (favoring tPA)

Alteplase vs placebo


6.4% vs 0.1%, P<0.001



17% vs 21%, P=0.30

Arm 1 designed to assess early improvement, arm 2 designed to assess functional outcomes


Moderate to severe stroke onset within 6 hours


Key exclusion criteria: very severe stroke, improving symptoms, bleeding diathesis, recent trauma or surgery, ICH present on CT, malignant MCA ischemia


Alteplase 1.1 mg/kg vs placebo

620 patients randomized


Median mRS at 90 days:

Intention to treat:

3 (tPA) vs 3 (placebo), P=0.41

Per protocol:

2 (tPA) vs 3 (placebo), P=0.035

Alteplase vs placebo

Parenchymal hematoma:

Intention to treat:

19.8% vs 6.5%, P<0.001

Per protocol:

19.4% vs 6.8%, P<0.001



Intention to treat:

22.4% vs 15.8%, P=0.04

Per protocol:

19.4% vs 14.8%, P=0.17

Protocol violations contributed to findings significantly


Most violations related to degree of ischemia seen on initial CT


tPA dose higher than current recommendation


Moderate to severe stroke onset within 6 hours


Standard exclusion criteria


Alteplase 0.9 mg/kg vs placebo

800 patients randomized


mRS 0-1 at 90 days

40.4% (tPA) vs 36.6% (placebo), P=0.277


mRS 0-2 at 90 days

54.3% (tPA) vs 46.1% (placebo), P=0.024

Alteplase vs placebo

Parenchymal hematoma:

8.1% vs 0.8% (no P value provided)



10.3% vs 10.5%, P=0.816

Outcomes in 0-3 and 3-6 hours strata not different, but n very small for 0-3 hours


8.3% reduction in death or dependency (mRS 3-6) noted


Stroke onset within 6 hours


Standard exclusion criteria


Alteplase 0.9 mg/kg vs placebo


Stopped early due to safety concerns in the 5-6 hour group

142 patients randomized


Median mRS at 90 days:

5 (tPA) vs 2 (placebo), P=0.05

Alteplase vs placebo


11.3% vs 0%, P=0.003



22.5% vs 7.0%, P=0.009

Poor outcomes mostly limited to patients randomized between 5-6 hours from LKW and with baseline NIHSS of >20


Randomization continued to part B, restricting to LKW <5 hours


Stroke onset within 5 hours


Standard exclusion criteria


Alteplase 0.9 mg/kg vs placebo

613 patients randomized


mRS 0-1 at 90 days:

41.7% (tPA) vs 40.5% (placebo), P=0.77

Alteplase vs placebo


6.7% vs 1.3%, P<0.001



10.9% vs 6.9%, P=0.08

Analysis restricted to patients enrolled within 3 hours of LKW demonstrated significant benefit with tPA: mRS 0-1 61% vs 26%, P=0.0135


Stroke onset within 3-4.5 hours


Standard exclusion criteria, additionally excluded patients with a history of stroke and diabetes


Alteplase 0.9 mg/kg vs placebo

821 patients randomized


mRS 0-1 at 90 days:

52.4% (tPA) vs 45.2% (placebo), P=0.04

Alteplase vs placebo


2.4% vs 0.2%, P=0.008



7.7% vs 8.4%, P=0.68

sICH definition more restrictive than in prior publications


Stroke onset within 3-6 hours and could undergo baseline MRI


Standard exclusion criteria


Alteplase 0.9 mg/kg vs placebo

101 patients randomized


mRS 0-1 at 90 days:

35% vs 24%, P=0.265

Alteplase vs placebo


7.7% vs 0% (no P value provided)



25% vs 14%, P=0.102

Primary endpoint was percent infarct growth; functional outcomes were a secondary outcome


Stroke onset within 6 hours and general uncertainty about whether the patient would benefit


Standard exclusion criteria


Alteplase 0.9 mg/kg vs placebo


Only pilot study was double blind

3035 patients randomized


OHS 0-1 (similar to mRS) at 180 days:

24% (tPA) vs 21% (placebo), P=0.018


Ordinal shift in OHS:

OR 1.17 (95% CI 1.03-1.33)

Alteplase vs placebo


7% vs 1%, P<0.001


Mortality (at 6mo):

27% vs 27%, P=0.672


Several protocol changes and lack of double blinding may limit external generalizability


OHS 0-1 significant only after adjustment for confounding; OHS 0-2 not significant in unadjusted or adjusted analyses


Stroke onset between 4.5 and 9 hours and MRI or CT perfusion demonstrating a penumbra:core ratio of at least 1.2 with an absolute difference between penumbra and core of 10 mL and an absolute core volume of <70 mL


Standard exclusion criteria plus patients undergoing thrombectomy were excluded


Alteplase 0.9 mg/kg vs placebo

225 patients enrolled


mRS 0-1 at 90 days:

35.4% (tPA) vs 29.5% (placebo), P=0.04


Common odds for shift towards improved outcomes:

OR 1.55, 95% CI 0.96-2.49

Alteplase vs placebo


6.2% vs 0.9%, P=0.053



11.5% vs 8.9%, P=0.67

Primary outcome significant after adjustment for confounders



Stroke onset unknown, but at least greater than 4.5 hours, and MRI demonstrating no FLAIR change within the area of DWI restriction


Standard exclusion criteria plus patients undergoing thrombectomy and whose baseline NIHSS were >25 were excluded


Alteplase 0.9 mg/kg vs placebo


Enrollment halted due to lack of funding

503 patients randomized


mRS 0-1 at 90 days:

53.3% (tPA) vs 41.8% (placebo), P=0.02

Alteplase vs placebo


2.4% vs 0.4% (ECASSIII), P=0.21



4.1% vs 1.2%, P=0.07

Primary outcome significant after adjustment for confounders


Rates of sICH were not significantly different between arms regardless of definition used


There is, understandably, a lot going on in all of these trials, and not all of it can be captured in a broad overview table. Some of the nuance I will discuss throughout this post, but attempting to distill the cumulative knowledge produced from over 20 years of clinical trials is no small feat. Rather, to focus the rest of the text, I will try to identify the main objections tPA skeptics make when interpreting these trials, and provide some commentary on a more nuanced way of thinking about thrombolysis in stroke.

Objection #1: There is No Positive Data for Thrombolysis

A common and somewhat baffling argument against thrombolysis in stroke is that there is “no positive prospective data” for thrombolysis in stroke. At face value, this is a bit perplexing – just a glance at the table above suggests there are at least 4 trials with positive top-line results with alteplase vs placebo. Two of these are the EXTEND and WAKE-UP trials, which realistically can be excluded from most general thrombolytic discussions because they require advanced imaging modalities and neuroradiology expertise to interpret them, which is often only available at comprehensive stroke centers. That leaves NINDS and ECASS-3 which form the primary basis of thrombolytic recommendations (we’ll get to the 2014 Lancet meta-analysis in a moment). The reason skeptics are doubtful even these are positive is because their findings are particularly “fragile”41 and two specific re-analyses, one of the NINDS trial42 and one of the ECASS-3 trial,43 have suggested the findings of the primary analysis, when viewed through a different lens, may not be positive after all. Both have different limitations than the trials they aim to refute, however, and both miss the big picture of thrombolysis in acute ischemic stroke.

The NINDS Re-Analyses

Hoffman and Schriger approached the re-analysis of the NINDS trial aiming to more fully characterize the trial dataset using a wide number of data visualizations.42 The central thesis is valid in that the original trial contained some 60,000 variables and the original publication was physically limited by journal space and could not fully represent the dataset. A 2004 re-analysis conducted after concerns of baseline imbalance were raised had confirmed (and strengthened) the primary findings of the original publication,44 but the lack of detailed visualizations left additional questions about the distribution of the data. The 2009 re-analysis plotted several key variables against each other, including baseline NIHSS vs 90-day improvement in NIHSS, Bathel index, and mRS, as well as plots evaluating time to treatment. In all plots, the effects favored alteplase, but the authors note that effects were less consistent when baseline NIHSS was <5 or >22, which only confirms current practice to generally avoid thrombolysis in minor stroke and consider the risks in severe stroke. Notably, conclusions were only gained by visually assessing the shape of the curve, which is naturally subject to bias from axis scaling and the degree of jitter introduced to scatterplots. The authors also conclude that no evidence of a time-is-brain effect was present, but do not visualize the effect of door-to-needle time on functional outcomes, only on change in 90-day NIHSS. 

The only figure in the Hoffman re-analysis which places mRS, rather than NIHSS, on the Y-axis

In response to this re-analysis, a third re-analysis of the trial data was conducted in 2010. Saver and colleagues (who practice at the same center as Hoffman and Schriger; I can only imagine what those workplace conversations were like…) point to notable limitations in plotting the NIHSS continuously and as the primary marker of functional improvement.45 The NIHSS itself is a flawed scale, with biases towards anterior circulation strokes and strokes affecting the left (dominant) hemisphere.46,47

A graphical representation of the expected 
benefits and harms of alteplase by
 Saver and colleagues

Additionally, attaining an NIHSS of >32 is outstandingly rare given the extreme severity of the scores and thus regression lines drawn between values of 32 and 42 (death) are effectively meaningless. Incremental one-point changes in the NIHSS do not represent equal degrees of functional change given the scale is ordinal, and thus plotting changes in values with this assumption blunts the appearance of meaningful clinical improvement. The description of these limitations by Saver and colleagues does border on condescension (but is an entertaining read) but proves an important point – visualization alone does not capture the full picture (no pun intended). The authors ultimately produce a different kind of visualization, visually representing the concept of NNT and NNH. The ultimate conclusion is that the summary statistics reported by the original NINDS trial and its 2004 reanalysis are accurate, and that the visual depiction of delta-NIHSS scores alone simply serves to represent an impossibly biased view of stroke recovery.

The ECASS-III Re-analysis

The next article skeptics point to when suggesting no positive data exist for thrombolysis is a 2020 re-analysis of the ECASS-III data. In this article, Alper and colleagues re-analyze the ECASS-III dataset using a variety of imputation and categorization methods and come to conclusions which differ modestly from the original publication.43 The primary thesis of the authors here is valid – following the exact statistical methods described in the body of the text with the data provided to the re-analysis authors does not produce precisely the same results. This, of course, is problematic. The entire purpose of reporting methods is to ensure reproducibility, and a lack of reproducibility jeopardizes the confidence in the original publication’s methods. The authors clarified several points with the original study sponsor and ultimately discover a few errors – one, the modified NIHSS used in the study (ranging from 0-46) which is described in the study protocol was mis-transcribed to the original NIHSS (ranging from 0-42) in the manuscript, and two, several ordinal variables were analyzed categorically rather than continuously. Changing the methods of adjustment yielded an odds ratio with a 95% confidence interval that crosses 1, casting doubt on the confidence of the ECASS-III findings.

The 16 models trained by Alper and colleagues. Significant results in bold.

This itself, however, is also problematic – repeatedly running the primary analysis with different types of confounders is bound to result in findings which fail to reject the null. There is no correct model here and any of the models included in this table could be perfectly valid on its own. As with the Hoffman NINDS analysis, considering NIHSS as purely continuous is likely problematic, as it assumes each 1-point change in the scale represents an equal degree of neurologic change, which it does not. Using door-to-needle time as categorical is probably also problematic, but is not invalid per se. Regardless, one thing is universal to all models – the effect size for all favors alteplase, and when considered in the context of the overall body of evidence (as the authors suggest), it is consistent with benefit with alteplase when used in the 3-to-4.5-hour window.

The Overall Body of Evidence

The conclusion I just made above may seem a bit cheap, but I would argue the context is important here. Much of the skepticism of the evidence supporting thrombolysis emerges from concerns at the trial level, meaning that concerns over baseline imbalances, selection bias, or reporting methods may yield inconclusive or incorrect results. While we could journal club each of these trials to death, focusing on the individual trials runs a substantial risk of missing the forest from the trees given the body of evidence available to date. Time and time again, improvements in the implementation, efficiency, and selection process of thrombolysis has been associated with improvements in patient outcomes and safety. Early observational data aimed to assess the safety of increased thrombolysis implementation found consistent functional outcome improvements in 6483 treated patients compared to untreated patients from clinical trials48 and analyses from the Get With the Guidelines registry has demonstrated a clear correlation between time to treatment and functional outcomes in over 50,000 treated patients.49,50 It is astoundingly unlikely that the clear improvements in patient outcomes related to time to treatment with thrombolysis can be entirely ascribed to confounding; in the real world, thrombolysis works, and there is data to prove it.

Of course, guideline-level treatment recommendations cannot be made on observational evidence alone. Luckily, the same pattern seen in the real-world evidence is seen when patient-level trial data is pooled. A landmark 2014 patient-level meta-analysis of alteplase trials published in Lancet evaluated the cumulative effect of alteplase on functional outcomes across all the major alteplase trials published to date.51 This publication illustrates a few crucial points. First, by combining the baseline and treatment data from 9 clinical trials including nearly 7,000 patients, it substantially increases the precision of treatment effects. Second, because of the size of the study, effect can be illustrated across the continuous axis of time, providing a clearer method of adjusting assumed benefits to patient-specific characteristics. This figure from the paper nicely demonstrates how the likelihood of attaining an mRS of 0-1 at 90 days is strongly correlated with door-to-needle time, a relationship consistently seen in nearly all trials and all real-world evidence to date.

The odds of achieving an mRS of 0-1 at 90 days is linearly associated with time to treatment from symptom onset which provides strong evidence for the beneficial effect of alteplase.

Now, there is a small elephant in the room here worth discussing – exactly what does “benefit” mean to the average patient? On a philosophical basis, the purpose of clinical trials is to inform our understanding of what the likelihood of benefit is for an individual patient. Thrombolysis in stroke is an enormously complex decision and cannot be captured by a simple benefit/no benefit decision. The likelihood thrombolysis will benefit an individual patient experiencing stroke depends on at least these variables:

  • The time from stroke symptom onset to treatment initiation
  • The severity of the stroke symptoms at baseline
  • The patient’s baseline level of function or disability
  • The degree/extent of ischemia present at the time of evaluation
  • More, potentially undiscovered, effect modifiers

Additionally, the use of the term “benefit” also makes several assumptions. Most clinical trials dichotomize the mRS into “excellent” (0-1) or “good” (0-2) as their primary outcome which substantially limits the power of detecting differences across the ordinal scale.52,53 Dichotomization makes interpreting study results easier, but misses important clinical changes which represent meaningful outcomes for patients, such as improvement from an mRS of 4 (the patient needs assistance for most ADLs) to an mRS of 3 (the patient needs some assistance for daily tasks, but can walk independently).54 Not only is shift analysis a more efficient clinical trial design method, consideration of the entire ordinal scale provides a more holistic and accurate assessment of patient outcomes and cost of treatment.55 The point being – point estimates from clinical trials that only report the difference in rates of attainment of dichotomous lumps of mRS may incompletely represent the benefit a patient may expert to see.

Disability, or more specifically how disability is defined, is also a key assumption in the assessment of presumed benefit from thrombolysis. Benefit in stroke trials has traditionally been limited to attainment of specific mRS thresholds in patients who present with symptoms exceeding certain NIHSS thresholds. This is conceptually restricting, as not all meaningful (read: “disabling”) symptoms are equally represented on the NIHSS (as discussed above), and the mRS, while reasonably reflective of function, does not fully capture impairment.56 The ultimate point I am building to is making the decision to administer thrombolysis to a patient needs to be based on a continuous understanding of the risks and benefits of treatment, rather than static effect sizes provided by clinical trials. The clear time-to-treatment benefit provides not only evidence that there is (broadly speaking) "positive" data for thrombolysis, but gives a continuous estimate of just how much benefit an individual patient might expect to see, whatever that benefit might mean to that patient.

Objection #2: The Harms are Undersold to Patients

This very well may be true, depending on the specific conversation that is had with patients and surrogates, but there is no compelling evidence that the risk of thrombolysis is underreported to patients. In fact, evidence suggests it may be the opposite – because emergency medicine guidelines provide a level B recommendation for thrombolysis and a level C recommendation for utilizing a shared decision model with patients regarding the use of thrombolysis, there may be a perception that the risks and benefits are equivocal, and thus no “best” decision exists.57 One semi-structured interview study of medical professionals in a safety net hospital revealed that clinicians focused heavily on the risks, and the emphasis on the potential for harm may have confused or scared patients and posed a barrier to treatment.58 While patients absolutely retain the right to refuse treatment, it is very challenging to accurately communicate the short term risks in the context of the long term benefits, especially in the setting of acute ischemic stroke. While patient refusals do occur, it is rare and has decreased over time – one single center experience reported 30 patient refusals over an 8-year period, representing a 4.2% refusal rate. However, refusal steadily declined over the study period from 2004 to 2011 – each additional year in the study was associated with a 37% reduction in the odds of patient refusal. While the nature of the discussions with these patients was not described, patients ultimately diagnosed with stroke mimics and with lower baseline NIHSS were significantly more likely to refuse treatment, suggesting patients with milder symptoms may be less willing to accept the risk of treatment.59

Now, there are realistically two issues worth discussing here – one, the content of the conversation had with patients or their surrogates, and two, the nature of the conversation had with patients or their surrogates, namely whether the conversation should involve “informed” consent, assent, shared decision making, or simply informed refusal.

The Content of the Conversation

It is challenging to characterize the content of real discussions had with patients about thrombolysis, both because the discussions occur in time sensitive environments and observation of the conversation will suffer from the Hawthorne effect. Undoubtedly, however, there is substantial variation in exactly what conversation is had. A survey of 101 resident and attending neurologists in the Netherlands revealed that only 33% of residents and 21% of attendings “always” ask for explicit consent prior to alteplase administration, and 62% of respondents reported they spent less than a minute on the conversation, if they had one at all.60 Similar findings were reported in a survey of 199 neurologists and emergency medicine physicians in the US, with only 36.7% of respondents reporting universal informed consent and 54.8% spent less than 5 minutes on the conversation. Over 90% of respondents noted that the risk of intracranial hemorrhage was a dominant theme in the conversation, while the time-dependent benefit was discussed by 76.4% of respondents and that a third of patients will see significant benefit by 61.3% of respondents.61

Semi-structured interviews of clinicians who have these conversations with patients and their surrogates confirm that the risk of treatment is an intensive focus of the consent process. One interview study of 13 clinicians in the UK revealed risk communication to be a dominant theme of discussions clinicians had with patients. One participant focused on the challenge of risk communication and the time-dependent nature of the intervention, stating “you’ve just given them this whole raft of information about risks and possible side-effects…and you’re almost pushing them into a decision…because you know you’re under time pressure.”62 The enormous pressure to communicate both the benefits and the risks of treatment to patients or their surrogates makes it challenging to universally satisfy the acceptable criteria of consent. A study of the adequacy of consent of 14 tele-stroke consent conversations found that acceptable patient or family understanding was observed in 78.6% of cases as rated by a neurologist, an emergency medicine physician, a layperson, an ethicist, and a lawyer, but agreement about the degree of adequacy was poor across raters despite the use of a relatively consistent consent script which contained information about the risk of the treatment.63

Ultimately, though, any assessment of the “adequacy” of risk discussion assumes what level of risk is acceptable to patients. A semi-structured interview study of stroke survivors and their caregivers revealed participants preferred a balanced presentation of risks and benefits, and that decision-making aids would be beneficial in the context of making a consent decision. When clinicians were interviewed in the same study, though, clinicians reported that risks dominated their conversations. One nurse practitioner stated “I usually spend a fair amount of time going into the negatives about it. Then [I] go over the percentages of [the] likelihood of getting better.”64 Patients may not value a statistics-heavy approach to discussing risk, however – one survey study of a convenience sample of 184 patients, visitors, and employees recruited from a hospital’s cafeteria revealed that after reading three sample scripts on alteplase’s risks and benefits, a technical approach to discussing risks and benefits was the preferred by only 29% of respondents. A “parental” approach, where general statements about how while risks existed, the benefits outweighed risks but the clinician would give this medication to their loved one, was preferred by 55% of respondents.65

Perhaps the largest challenge with assessing these conversations is that as a species, we place much greater emphasis on shorter term risk than we do on longer term risks and benefits. While any conversation with patients or their family should contain a fair and balanced discussion of both the risks and benefits of thrombolysis, the abstract perception of “benefit” is very difficult to grasp while the immediate risks of hemorrhage and angioedema can be felt intrinsically. This is likely why this particular concern is so real to so many individuals who are skeptical of the benefits of thrombolysis – seeing and managing the oftentimes catastrophic hazard of thrombolysis is an immediate experience after administering a thrombolytic, while the benefits are not seen for months and only seen by the individuals caring for the patient at home or in clinic. This is likely why the bulk of individuals skeptical of thrombolytics are from the emergency medicine specialty – these individuals only see the consequences, and never see the benefits. Granted, it’s not possible to “see” the benefits at an individual level, but those of us who work with stroke survivors during their recovery can find it very easy to ascribe at least part of the recovery process to the benefits of thrombolysis. I have the opportunity to work in an interdisciplinary neurorecovery clinic which sees patients months to years after their injury, and the benefits of thrombolysis can feel very real.

The Nature of the Conversation

I will preface this further discussion with an obvious caveat – I, as a neurocritical care pharmacist, have never and likely never will have the direct conversation with a patient or their loved one about the risks and benefits of thrombolysis. I have not felt the anxiety about helping a patient or family member make the right individual decision. I can, though, highlight some of the evidence which has evaluated how exactly this conversation could be had, and whether the way many institutions currently conduct this conversation is best for patients. The 2022 AAN Policy Statement on consent issues in the management of acute ischemic stroke states that when patients retain decision making capacity or when surrogates are available, they should be informed about the stroke diagnosis and rationale for therapy, the prospects for a good functional recovery with and without treatment, and the risks of treatment. However, when surrogates are not present, the authors state “it may be reasonable to proceed with treatment on the presumption of consent when patients’ cases fit extant inclusion/exclusion criteria, contraindications (particularly, absolute contraindications) are absent, and the overall balance of risks and benefits strongly favors intervention” (emphasis mine).66 The statement suggests verbal consent or refusal should be documented, but does not mandate any particular structure to the consent process.

This vagueness has led to substantial variation in exactly how consent/assent is obtained. One survey of New York stroke centers found that written consent was required at 27.9% of centers when patients present within 3 hours of last known well but in 51.4% when patients presented after 3 hours, while documentation of consent was not required at all at 18.4% and 7.2% of centers for patients presenting within or after 3 hours, respectively.67 The variation in consent practices stems from the challenging bioethical nature of thrombolysis in acute ischemic stroke. The time sensitivity of acute therapy, uncertainty regarding patient-specific preferences in the moment particularly when patients are decisionally impaired, potential gaps in the understanding of thrombolysis in special populations, and potentially devastating consequences of both treating or not treating with thrombolysis make a universal approach to consent challenging.68 Several groups have proposed informed refusal as a way to balance the time-sensitive nature of treatment with the right of patient autonomy. This appears to be reasonable from a patient perspective, as surveys including representative samples of the US population have revealed that 76.2% of adults would want thrombolysis if they experienced an ischemic stroke, which is a similar rate to the desire to receive CPR (75.9%), another time-sensitive intervention where a type of informed refusal is used (presumption of consent unless DNR status is known).69,70 The rates of acceptance were similar when participants were asked what their decision would be if they could not make the decision for themselves – when asked whether they would want thrombolysis in a hypothetical scenario when they or a surrogate was not available to make the decision, 78.1% of respondents stated they would want thrombolysis.70 Advance directives regarding thrombolysis are also feasible, with one study of 121 patients in Ireland at risk for stroke revealing that 82.6 and 89.3% of patients would opt for thrombolysis if presenting with a stroke within 4.5 and 3 hours of last known well, respectively. Over 75% of respondents preferred their physician make the final decision to treat if they were decisionally impaired, with one participant stating “I don’t think it’s fair to put the responsibility on someone who’s had a stroke.”71

“Getting the gist across” and allowing patients to refuse therapy if not within their goals of care may be a safe and more efficient way of approaching the decision to treat.58,72 Patients only remember about 55% of the information shared with them about thrombolysis after 90 minutes, so the confidence in a patient’s ability to make an informed decision at the time of stroke is questionable.73 A verbal informed refusal method may also be significantly more efficient as well and could reduce door to needle time, which might translate to distinct clinical benefits. After four hospitals in Singapore changed from a written consent to verbal consent process, door-to-needle times declined by 5.6 minutes and the percent of patients who received thrombolysis within 60 minutes of arrival increased from 35.6% to 66.1% (p = 0.01).74 Incremental improvements in time to thrombolysis are associated with measurable improvements in patient outcomes,75 and if patients are given the opportunity to refuse treatment after a reasonable discussion of the risks and benefits rather than a lengthy written consent process, this may allow for those improvements to occur.

Objection #3: Unacceptable Excess Harm is Caused After Misdiagnosis

Stroke is a challenging diagnosis and is generally made based on clinical criteria alone. While advanced imaging techniques like MRI and CT perfusion can produce more definitive results, delaying treatment to obtain these results particularly at centers who do not have them readily available can cause unacceptable delays to treatment and thus the pressure to treat can be overwhelming even in the face of diagnostic uncertainty. Because of this, there is sometimes a concern that a more liberal approach to thrombolysis in borderline cases causes excess harm. Of course, any adverse effect of a medication given to a patient who ultimately is found to have not been indicated for it is unacceptable, but not giving a time-sensitive acute therapy for a potentially devastating diagnosis when some uncertainty exists is equally unacceptable. Luckily, patients who present with stroke mimics ultimately have a degree of built in safety – the most concerning adverse effect, hemorrhagic conversion, has a risk profile directly linked to the severity of the underlying stroke. Because patients who are ultimately found to have stroke mimics have no ischemic brain tissue, they are at a significantly lower risk of hemorrhagic conversion than a traditional stroke patient.

It's important to frame this discussion from the perspective of making the decision to administer a thrombolytic in the moment, rather than retrospectively wondering if the decision that was made was the right one. In other words, if faced with a patient where the diagnosis could either be ischemic stroke or a mimic (complex migraine, Todd’s paralysis, functional neurologic disorder, etc), what is the risk-to-benefit ratio of thrombolysis for that individual patient? First, it is helpful to understand how often thrombolysis is given to stroke mimics. This depends partly on how a stroke mimic is defined and reported, but registry studies have estimated around 1.4-3.5% of thrombolytic administrations are given to patients with an ultimate diagnosis of a stroke mimic.76–79 One single-center cohort study reported a stroke mimic rate of 27.9%, but a third of “stroke mimics” were classified as having transient ischemic attack, which is arguably disingenuous to refer to as a stroke mimic and thus this center's true stroke mimic rate is likely lower than reported.80 Other cohorts have reported rates of stroke mimics up to 7-10.4%, but the higher rates of stroke mimics are likely a function of smaller sample sizes than multicenter registry studies.81,82 Another group of patients that is often grouped with stroke mimics are those with ischemia-negative imaging, where no definitive ischemic lesion is identified on MRI or follow-up CT. It is more difficult to disentangle whether these patients represent true stroke mimics or an “aborted” stroke, but one cohort reported a 7% rate of “neuroimaging negative cerebral ischemia” in all patients who received thrombolysis at their center.83

Pooled Data76,78–85



Patients who Received Thrombolysis



Patients Diagnosed with Stroke Mimic



Complex Migraine



Functional neurologic disorder









Pooled incidence of stroke mimics who receive thrombolysis and their ultimate diagnosis

Putting this together, lysing stroke mimics is a relatively uncommon occurrence and fear of misdiagnosing a stroke mimic should not prevent one from administering a thrombolytic because the harms of not treating a true ischemic stroke far outweigh the risks of inappropriately treating a stroke mimic. Because patients with stroke mimics do not have any fresh ischemic cerebral tissue, they are somewhat protected from the risks of thrombolysis as well. Patients who present as stroke mimics who receive a thrombolytic experience symptomatic intracranial hemorrhage at significantly lower rates than patients with stroke (rates of 0%,76 0.4%,77 and 2%78 have been reported, all significantly lower than patients with stroke) and experience angioedema vanishingly rarely (0% in the two studies that distinctly report it).78,83 This of course does mean that everyone who presents with symptoms that could be vaguely suggestive of stroke should receive thrombolysis, of course, but it does suggest that if there is a lack of a clear alternate explanation for stroke-like symptoms, thrombolysis is reasonable more often than not if the patient otherwise meets criteria for thrombolysis. Interestingly, patient intuition may play a role here, too – studies of informed refusal of thrombolysis have found that patients with stroke mimics are significantly more likely to refuse treatment than those with actual strokes.59,86,87

Objection #4: Legal Risk of Adverse Effects

Unfortunately, an additional hesitation about thrombolysis in AIS stems from concerns over litigation because of the risk of harm caused by thrombolysis. Thrombolysis is of course high risk, and with it comes the risk of potentially life-threatening hemorrhagic conversion. While this is a known and expected risk, there is the concern that families and caregivers could view the harms caused by thrombolysis as the fault of the physician who prescribed the treatment. One semi-structed interview of emergency medicine physicians in the UK highlighted the cognitive dissonance faced by providers discussing the risks and benefits of thrombolysis, with one participant noting a memorable case: “I told them about risk of bleeding…and despite the fact that 2 CTs showed he didn’t have any bleeding at all… he just took a massive brain swelling [sic]. When he died the family turned around and said that we had killed him basically.”62 Undoubtedly, many clinicians may have experienced similar sentiments and could feel that extreme caution to avoid liability in the case complications occur.

Interestingly, this has not been observed to be the case in the US medicolegal system. Multiple evaluations of available legal cases have shown that litigation related to acute stroke care is uncommon, and providers are more likely to be sued for not administering thrombolysis rather than for complications of therapy. At least four analyses of legal cases have found this consistent result, and patterns of litigation have remained consistent over the decades as the strength of the evidence supporting thrombolysis has grown. A summary of the four publications is provided below:


Legal Cases Reviewed

Cases Related to tPA Identified


Liang 200888



66.7% of cases involved delay in diagnosis

87.9% related to failure to treat with tPA

9.1% related to harms caused by tPA


Of cases ruled in favor of the plaintiff (n=12), 83.3% were related to failure to administer tPA

Bhatt 201389



70% related to failure to treat with tPA

5% related to harms caused by tPA


Factors associated with a verdict favoring the defendant included consent documentation, expert witness testimony, patients falling out of the time window, or lack of tPA availability


Factors associated with a verdict favoring the plaintiff included failure to treat, failure to diagnose, failure to transfer, or failure to document consent

Haslett 201990

1.3 million

246 (AIS)

Included all cases related to acute  stroke, not just tPA

26% (of all cases) related to failure to treat with tPA, of which 62% ruled in favor of defendant

0.4% (n=1, of all cases) related to harms caused by tPA, which was ruled in favor of the defendant

Ganti 202291



100% related to failure to treat with tPA


Ultimately, while litigation is rare, it is much more likely to be because of a lack of treatment rather than because of complication of treatment. In cases where litigation is pursued as a result of adverse effects, the decision if most often in favor of the defendant. Clinicians should treat patients according to the most up to date literature rather than practice defensively to avoid litigation to begin with, and in this case avoiding thrombolysis as a method of defensive medicine is a lose-lose situation – not only is it a disservice to the patient, the avoidance itself is a risk of legal action by not follow evidence based care.


If you’ve stuck it out all the way here, thank you for taking the time to read my thoughts on thrombolysis in stroke and my opinion on the “debate” of its merits. Thrombolysis is one of the most effective therapies available for acute ischemic stroke along with thrombectomy, and endlessly debating the merits of the RCTs supporting its use while ignoring the overwhelming body of evidence demonstrating clear and measurable improvements in stroke outcomes with improving utilization of thrombolysis ultimately leads to confusion and does nothing to benefit patients. Thrombolysis has real risks and these need to be communicated to patients to ensure therapy is within goals of care, but these risks are far outweighed by the benefits, benefits that are far more meaningful to patients than the risks. 

           Andrew Webb, PharmD, BCCCP

Clinical Pharmacist, Neurocritical Care

Massachusetts General Hospital



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