SGEM#297: tPA Advocates Be Like – Never Gonna Give You Up

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. At least one other reanalysis has questioned the 2009 reanalysis (Saver et al Ann Emerg Med 2010).  Thus, there is a degree of uncertainty in the NINDS-II results. 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: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes