Date: June 30th, 2020

Guest Skeptic: Professor Daniel Fatovich is an emergency physician and clinical researcher based at Royal Perth Hospital, Western Australia. He is Head of the Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research; Professor of Emergency Medicine, University of Western Australia; and Director of Research for Royal Perth Hospital.

Reference: Alper et al. Thrombolysis with alteplase 3–4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evidence Based Medicine 2020

Case: A 65-year-old man arrives from home to the emergency department by EMS with right-sided weakness beginning three hours prior. Advance neuroimaging demonstrates he does not qualify for endovascular clot retrieval. He has an NIHSS score of 11 and no contra-indications for systemic thrombolysis.

Background: Thrombolysis for acute ischemic stroke has to be one of, if not the most, controversial subjects of my career. The debate dates back to the classic NINDS paper published in the NEJM in 1995. We reviewed that publication with Dr. Anand Swaminathan on SGEM#70.

Some people might argue that it’s less relevant now because of endovascular clot retrieval, but it’s a living example of issues with research methodology, critical appraisal, bias, conflicts of interest, etc. These elements are continuously present in medicine – look at all the COVID-19 literature – made worse by the preprint archives of non-peer reviewed papers.

  • Thrombolysis in acute ischaemic stroke. The Lancet 2012
  • Truth, thinking and thrombolysis. EMA 2016
  • Response from Prof. Fatovich to Stroke thrombolysis: Leaving the past, understanding the present and moving forward. EMA 2013
  • The “Fragility” of Stroke Thrombolysis. TMJ 2020
  • Believing is seeing: Stroke thrombolysis remains unproven after the third international stroke trial (IST-3). EMA 2012
  • Don’t Just Do Something, Stand There! The Value and Art of Deliberate Clinical Inertia. EMA 2018

Dr. Jerome Hoffman

It was Dr. Jerome Hoffman that introduced me to this issue and was a basis of my skepticism. I used to think if the study was published in a high-impact journal it must be true. His mentorship and teaching are why I consider Dr. Hoffman a legend of emergency medicine.

We have covered the issue of thrombolysis for acute ischemic stroke a number of times on the SGEM. I have also published a review on the topic of thrombolytics for stroke beyond three hours (Carpenter et al JEM 2011). More recently, I published a pro/con debate on the subject with Dr. Eddy Lange looking at the evidence (Milne et al CJEM 2020).

  • SGEM#29: Stroke Me, Stroke Me
  • SGEM Xtra: Walk of Life
  • SGEM Xtra: No Retreat, No Surrender
  • SGEM#269: Pre-Hospital Nitroglycerin for Acute Stroke Patients?
  • SGEM#290: Neurologist Led Stroke Teams – Working 9 to 5

There has been a lot of skepticism around thrombolysis in acute ischemic stroke since the beginning. A reanalysis of the NINDS data by Dr. Hoffman and Dr. Schriger was published in Annals of Emergency Medicine in 2009.

The major takeaway from this reanalysis was that the baseline imbalance in stroke severity led to the difference in outcomes. If tPA really works, we should see a bigger change in the NIHSS score in the tPA group vs. the placebo group. Yet the difference was 0.0. People can forget that a clinical trial has internal validity if and only if the imbalance between groups, bias in the assessment of outcome, and chance, have been excluded as possible explanations for the difference in outcomes. Baseline imbalance is a recurring theme. So, replication studies are hugely important.

It was the NINDS trial that changed guidelines and practices to provide thrombolysis in patients with stroke symptoms less than three hours after onset. This despite the multiple other trials that did not show efficacy and reported an increase in harm (bleeding). The increase in adverse events prompting some to be stopped early (SGEM Xtra:Thrombolysis for Acute Stroke).

The only other randomized control trial claiming benefit for the primary outcome was ECASS III (Hacke et al NEJM 2008). ECASS I and II did not show a benefit with thrombolysis. ECASS III reported a 7% absolute benefit of improved mRS at 90 days compared to placebo, 9% increase in intracranial hemorrhage, 2% increase in symptomatic intracranial hemorrhage and no significant difference in mortality.

The American College of Emergency Physicians (ACEP) is the largest organization of EM physicians in the world. ACEP has a clinical policy statement on the issue (Brown et al AEM 2015). They looked at the <3 hour time frame and the 3-4.5 hour time frame.

ACEP made no level “A” recommendations but did make level B and C recommendations.

  • Is IV tPA safe and effective for patients with acute ischemic stroke if given within 3 hours of symptom onset?
    • Level B Recommendations: With a goal to improve functional outcomes, IV tPA should be offered and may be given to selected patients with acute ischemic stroke within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication. The increased risk of symptomatic intracerebral hemorrhage (sICH) should be considered when deciding whether to administer IV tPA to patients with acute ischemic stroke.
    • Level C Recommendations: When feasible, shared decision-making between the patient (and/or his or her surrogate) and a member of the health care team should include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA for acute ischemic stroke. (Consensus recommendation)
  • Is IV tPA safe and effective for patients with acute ischemic stroke treated between 3 to 4.5 hours after symptom onset?
    • Level B Recommendations: Despite the known risk of sICH and the variability in the degree of benefit in functional outcomes, IV tPA may be offered and may be given to carefully selected patients with acute ischemic stroke within 3 to 4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication.
    • Level C Recommendations: When feasible, shared decision-making between the patient (and/or his or her surrogate) and a member of the health care team should include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA for acute ischemic stroke. (Consensus recommendation)

ECASS III was published in 2008. Now, 12 years later there is a reanalysis of the trial similar to the reanalysis of the NINDS 14 years after it was published.


Clinical Question: Is thrombolysis for acute ischaemic stroke in the 3-4.5 hour time frame post symptom onset, safe and effective?


Reference: Alper et al. Thrombolysis with alteplase 3–4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evidence Based Medicine 2020

  • Population: Adult patients age 18-80 years of age with at least 30 minutes of acute ischemic stroke symptoms presenting between 3-4.5 hours after onset of symptoms with no significant improvement.
    • Main Exclusion: Intracranial hemorrhage, time of symptom onset unknown, symptoms rapidly improving or only minor before start of infusion, severe stroke as assessed clinically (e.g., NIHSS score >25) or by appropriate imaging techniques*, seizure at the onset of stroke, stroke or serious head trauma within the previous 3 months, combination of previous stroke and diabetes mellitus, administration of heparin within the 48 hours preceding the onset of stroke, with an activated partial-thromboplastin time at presentation exceeding the upper limit of the normal range, platelet count of <100,000/mm2, systolic >185 mmHg or diastolic pressure >110 mmHg, or aggressive treatment (IV medication) necessary to reduce BP to these limits. blood glucose < 50 mg/dL or > 400 mg/dL, symptoms suggestive of subarachnoid hemorrhage, even if CT scan was normal, oral anticoagulant treatment, major surgery or severe trauma within the previous 3 months or other major disorders associated with an increased risk of bleeding.
  • Intervention: tPA 0.9 mg/kg; initial 10% bolus, remainder over 60 minutes
  • Comparison: Placebo
  • Outcome:
    • Primary Outcome: Modified Rankin Scale (mRS) score 0-1 (favourable) vs. 2-6 (unfavourable) at 90 days
    • Secondary Outcomes: Global outcome measure that combined 90 day outcomes of mRS 0-1, >=95 Barthel index, NIHSS score 0-1, score of 1 GOS; mortality at 90 days; any ICH, symptomatic ICH, symptomatic edema (defined as brain edema with mass effect as the predominant cause of clinical deterioration), and other serious adverse events.

Authors’ Conclusions: “Reanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3–4.5 hours after stroke onset. Clinicians, patients and policy makers should reconsider interpretations and decisions regarding management of acute ischaemic stroke that were based on ECASS III results.”

2008 ECASS III Conclusions: “As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. No
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They included 821 patients in the trial with a mean age of 65 years and 60% male.


After adjusting for baseline imbalances, multiple methods failed to find statistically significant benefits with thrombolysis given 3-4.5 hours after stroke onset and confirmed significant increase in harm.


1. Inter-Rater Reliability (IRR): The IRR of outcome assessments using the mRS are moderate at best [1,2]. A clinical trial has internal validity if and only if the imbalance between groups and bias in the assessment of outcome and chance, have been excluded as possible explanations for the observed difference in outcomes.

2. Fragility Index (FI): The FI is a method to understand how statistically reproducible a study is [3]. It is the minimum number of patients who would need to have a different outcome to change the p value from < 0.05 to > 0.05, ie from statistically significant to insignificant (the 0.05 threshold as a measure of statistical significance is problematic).

A low FI means that only a small number of patients would have to have their outcome change for the trial to lose statistical significance. It is simply calculated by repeatedly applying Fisher’s exact test, while successively reallocating patients, one at a time, from the favourable outcome group to the other (control) group. The FI of the original ECASS-III data is 1. So, only one patient would have to have a different outcome to change the result of the study. This fragility is consistent with the new re-analysis study by Alper, which found no significant benefit for tPA [4].

IST-3 was the largest RCT looking at tPA for acute ischemic stroke in treated patients up to 6 hours. It failed to show a benefit for its primary outcome. In the 3-4.5 hour subgroup (n = 1,177), no difference in functional outcomes in those randomized to tPA vs. placebo (32% tPA vs 38% placebo (OR 0.73) was reported.

However, this was obtained by using a 99% confidence interval (0.50-1.07). Readers will be aware that the conventional reporting approach is the 95% CI. Using the traditional 95% CI results in a statistically significant association with placebo for good functional outcome compared to tPA

3. Baseline Imbalances: A strong predictor of how someone will do after a stroke is how bad their symptoms were at presentation. There was an important baseline imbalance in stroke between the two groups in the ECASS III trial. This is a feature seen before in stroke studies (eg with studies on Factor VII for intracranial hemorrhage). This was first highlighted by Shy in 2014, who noted that the online version of the ECASS III paper was changed in 2013 to reflect the actual p value of 0.003, vs. the originally published p 0.03 [5]. The authors had originally defined significant p values for these comparisons as < 0.004, so the correction marked stroke history as a significant difference between the two groups. Clinically, it is known that recurrent strokes have a worse outcome than first strokes. So, the difference in outcome could be fully explained by the baseline imbalance.

4. NINDS Reanalysis:The re-analysis of ECASS III by Alper in BMJ EBM is similar to the re-analysis of NINDS by Hoffman & Schriger who found that baseline imbalance in stroke severity was likely responsible for the difference in outcome [6].

5. Time is Not Brain: In 2018, the author of the original phrase “time is brain” wrote: “It is no longer reasonable to believe that the effect of time on the ischaemic process represents an absolute paradigm. It is increasingly evident that the volume of injured tissue within a given interval after the estimated time of onset shows considerable variability in large part due to the beneficial effect of a robust collateral circulation.” [7]

The effect of any intervention in stroke is due to factors such as the precise automated measurement of a small ischaemic core, a large reversible penumbra, and the use of thrombectomy in highly selected patients with detailed consent,coupled with absence of treatment harm [8]. The endovascular trials have demonstrated that it is possible to identify a cohort of patients who will benefit from revascularization, independent of time of onset, when perfusion imaging is paired with an effective treatment modality. This has not been achieved for stroke thrombolysis using tPA.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the conclusions made by the Alper et al who reanalyzes ECASS III affirming the lack of benefit for tPA. We also agree that replication studies are needed [9,10].

We do not agree with the conclusion of the original ECASS III authors.


SGEM Bottom Line: Reanalysis of the original ECASS III data does not support the potential benefit of tPA given between 3-4.5 hours after onset of stroke symptoms and confirms the known potential harm.


Case Resolution: You provide the man with the latest information on thrombolysis for stroke. He decides not to move forward with systemic tPA administration.

Dr. Fatovich

Clinical Application: This furthers our skepticism about the thrombolytic literature for acute ischemic stroke especially in this later time frame. It will modify how we present the information to patients. On a broader scale, you decide locally to discuss this with your EM group and advocate for policy makers to re-consider their recommendations.

What Do I Tell My PatientYou are having a stroke. It is being caused by a clot in the brain. There is a drug that has been used to try and dissolve clots. Older data showed that 7% of people may do better by 3 months. The drug does cause a potential 10% increase in bleeding in the brain. Two percent more of people getting this drug will have symptoms of the brain bleeding. It is not a life-saving drug and the same number of people die from this type of stroke (~8%). The existing guidelines say this medication may be offered to patients like you. However, a new look at the original data has raised some concerns. When re-analyzing the evidence, it showed the increase in harm was the same (bleeding in the brain). However, the potential benefits were unfortunately not confirmed. That means we are not confident this drug will have any benefit. We are confident that puts you at greater risk for bleeding.

Keener Kontest: Last weeks’ winner was Dr. Mark McManus an Emergency Consultant from Queensland, Australia. He knew the German thermometrist was Wunderlich and that eponymous Wunderlich syndrome describes atraummatic intracapsular renal bleeding.

Listen to the SGEM podcast to hear this weeks’ question. Send your answer to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.


Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.


References: 

  1. Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. Stroke 2009; 40(10): 3393-5.
  2. Wilson JT, Hareendran A, Hendry A, Potter J, Bone I, Muir KW. Reliability of the modified Rankin Scale across multiple raters: benefits of a structured interview. Stroke 2005; 36(4): 777-81.
  3. Farkas J. What is the fragility index of the NINDS trial? PulmCrit (EMCrit), 5 July 2016. http://emcrit.org/pulmcrit/fragility-index-ninds/(accessed 12 July 2016).
  4. Alper BS, Foster G, Thabane L, Rae-Grant A, Malone-Moses M, Manheimer E. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid Based Med 2020.
  5. Shy BD. Implications of ECASS III error on emergency department treatment of ischemic stroke. The Journal of emergency medicine 2014; 46(3): 385-6.
  6. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med 2009; 54(3): 329-36, 36 e1-35.
  7. Gomez CR. Time Is Brain: The Stroke Theory of Relativity. J Stroke Cerebrovasc Dis 2018; 27(8): 2214-27.
  8. Mosely M. IV tPA is Still a Naked Emperor. Emergency Medicine News 2019; 41(7): 30.
  9. Donaldson L, Fitzgerald E, Flower O, Delaney A. Review article: Why is there still a debate regarding the safety and efficacy of intravenous thrombolysis in the management of presumed acute ischaemic stroke? A systematic review and meta-analysis. Emerg Med Australas 2016; 28(5): 496-510.
  10. Fatovich DM. Truth, thinking and thrombolysis. Emerg Med Australas 2016; 28(5): 490-2.