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Date: May 19th, 2020
Reference: Yang P et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. NJEM 2020.
Guest Skeptic: Dr. Anand Swaminathan is an Assistant Professor of Emergency Medicine at St. Joseph’s Regional Medical Center in Paterson, NJ. Managing editor of EM:RAP and Associate Editor at REBEL EM.
Case: A 53-year-old previously healthy man presents with 1.5 hours of right sided weakness as well as slurred speech. A rapid bedside assessment gives you a National Institute of Health Stroke Score/Scale (NIHSS) of 9 and you are concerned about a large vessel occlusion (LVO) based on the high NIHSS as well as the presence of both an upper extremity drift and the speech abnormality. A non-contrast CT shows no evidence of intracranial hemorrhage. A CT angiogram plus CT perfusion demonstrate a clot in the left proximal middle cerebral artery (MCA) with a small infarcted area and a large penumbra. Based on your institution’s current guidelines, the patient is a candidate for endovascular therapy, but they are also within the current window for the administration of alteplase. You wonder if you should give the alteplase while waiting for your neurointerventional team?
Background: The issue of thrombolytics for stroke has been debated since at least 1995. This is the year that the famous NINDS trial was published. We cover this as an SGEM classic that all EM physicians should know about on SGEM#70. Our bottom line was that we were skeptical thrombolysis has a net patient-oriented benefit for acute ischemic strokes.
We have covered this issue of thrombolysis for acute ischemic stroke a number of times on the SGEM
- SGEM#29: Stroke Me, Stroke Me
- SGEM Xtra:Thrombolysis for Acute Stroke
- SGEM#290: Neurologist Led Stroke Teams – Working 9 to 5
You also had the Legend of Emergency Medicine, Dr. Jerome Hoffman on to reflect upon the last 25 years and the thrombolysis for acute ischemic stroke debate (No Retreat, No Surrender)
I also invited my EBM friend, Dr. Eddy Lang onto the SGEM to discuss his perspective on the issue (SGEM Xtra). This led to a pro/con publication in the Canadian Journal of Emergency Medicine (CJEM) tPA should be the initial treatment in eligible patients presenting with an acute ischemic stroke (Milne et al CJEM April 2020).
The publication of the MR CLEAN trial in January 2015 changed the face of ischemic stroke care. This was the first study demonstrating a benefit to endovascular treatment of a specific subset of ischemic stroke patients: those with LVOpresenting within sixhours of symptom onset. MR CLEAN was followed by a flurry of publications seeking to replicate and refine treatment as well as expand the window for treatment. The REBEL EM team reviewed this literature back in 2018 and, with the help of Dr. Evie Marcolini, created the below workflow:
One major component of LVO management is the use of systemic thrombolytics in patients presenting within the current thrombolytic treatment window prior to endovascular intervention. However, it’s unclear if systemic thrombolytic administration results in better outcomes or if it simply exposes the patient to increased risks at a higher cost.
Limited evidence questions the utility of the current approach with thrombolytics plus endovascular therapy (Phan 2017, Rai 2018). There is a clear need for further research into systemic thrombolytics dosing and use.
Clinical Question: Is endovascular therapy alone non-inferior to endovascular therapy plus systemic thrombolytics in the treatment of patients with large vessel occlusion strokes presenting within 4.5 hours of onset?
Reference: Yang P et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. NJEM 2020.
- Population: Adult patients (18 years of age or older) presenting within 4.5 hours of ischemic stroke symptom onset and with cerebral vascular occlusion on CT angiography of the intracranial internal carotid artery or middle cerebral artery (first and/or second segments) and an NIHSS > 1 and if endovascular thrombectomy was intended to be performed.
- Exclusions: Disability from a previous stroke or contraindication to IV alteplase and any contra-indication for thrombolysis according to American Heart Association (AHA) guidelines.
- Intervention: Endovascular thrombectomy alone
- Comparison: Endovascular thrombectomy + systemic alteplase 0.9 mg/kg
- Outcomes:
- Primary Outcome: Modified Rankin Scale (mRS) score assessed at 90 days after randomization looking for non-inferiority (defined as a lower end of the odds ratio > 0.80)
- Secondary Outcomes: Death from any cause at 90 days, successful reperfusion before thrombectomy, recanalization at 24-72 hours (assessed by CTA), NIHSS score at 24 hours, and 5-7 days, final lesion volume on CT and mRS comparisons
- Safety Outcomes: All hemorrhages and symptomatic intracranial hemorrhages according to the Heidelberg criteria, occurrence of pseudoaneurysm and groin hematoma at the site of arterial puncture used for thrombectomy, cerebral infarction in a new vascular territory at five to seven days, and mortality within 90 days.
Authors’ Conclusions: “In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset.”
Quality Checklist for Randomized Clinical Trials: 
- The study population included or focused on those in the emergency department. Unsure
- The patients were adequately randomized. Yes
- The randomization process was concealed. Yes
- The patients were analyzed in the groups to which they were randomized. Yes
- The study patients were recruited consecutively (i.e. no selection bias). Unsure
- The patients in both groups were similar with respect to prognostic factors. Yes
- All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
- All groups were treated equally except for the intervention. Unsure
- Follow-up was complete (i.e. at least 80% for both groups). Yes
- All patient-important outcomes were considered. Yes
- The treatment effect was large enough and precise enough to be clinically significant. No
Key Results: They screened 1,586 patients for eligibility and 654 were included in the final analysis. The median age was 69 years and slightly more were male. The median NIHSS score was 17.
- Primary Outcome: Adjusted odds ratio for the mRS
- aOR = 1.07 (95% CI 0.81 TO 1.40)
- Demonstrates non-inferiority as lower limit of non-inferiority was set at 0.80
- Secondary Outcomes:
1) Consecutive Patients and External Validity – The manuscript did not explicitly say patients were recruited consecutively. Without this information it is hard to comment on whether or not there was selection bias. We are also concerned about the external validity of a stroke trial conducted in China compared to the care provided in the USA.
2) Declined to Participate – Of eligible patients, 15% (240/1,586) declined to participate. There was no information provided on this group in the published paper or supplementary material. Patients deciding to participate could have been different from those who decided not to participate. This too could have introduced some selection bias.
3) Lack of Blinding: The treating physicians and study participants were not blinded to group allocation. This could have biased the study towards the EVT alone if that hypothesis was known to these two groups.
4) Intention-To-Treat (ITT): You will often hear us comment about whether or not the trial has used an ITT analysis. This is a quality indicator for superiority designs. However, for non-interiority trials a per-protocol analysis is the more conservative approach to minimize bias.Using an ITT can bias the results toward the null hypothesis. The per-protocol analysis could only be found in the supplemental appendix.
A non-inferiority design seeks to establish a novel treatment is not worse than a standard treatment by more than a predetermined acceptable amount. The null hypothesis for a non-inferiority study states for a given outcome, treatment A (a novel treatment) is worse than treatment B (an accepted, validated treatment) by more than a non-inferiority margin called the delta (∆). In contrast, the alternate hypothesis states for a given outcome, treatment A is not worse than treatment B by more than ∆.This type of study design is often used when two circumstances are met: a placebo trial would be unethical, due to the existence of a treatment proven superior to placebo, and the novel treatment offers other advantages (e.g., cost, ease of use, less invasiveness, fewer adverse effects, etc.).
Setting the non-inferiority margin should be specified a priori. It can be set at a statistically significant difference or a clinically significant difference. Subjectivity can be introduced when determining what is considered clinically significant. A number of guidelines exist like the CONSORT extension statement to help researcher properly design non-inferiority trials.
5) Outcomes: Outcome data was obtained via interviews performed in person or by phone. Phone interviews are suboptimal for assessing functionality. This could add more statistical noise into the data and bias the results to finding non-inferiority. We could not find how many assessments were done in person and how many were done by phone. It would be interesting to see if there were any differences in outcome that could be attributed to the method of assessing the outcome.
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.
SGEM Bottom Line: There does not appear to be a role for systemic thrombolysis in acute ischemic stroke for appropriate patients when EVT is readily available.
Case Resolution: Based on the best available evidence and the potential for harm, you decide to hold off on administration of systemic thrombolytics. Your neurointerventional team calls for the patient 20 minutes after you get the report from radiology and you bring him up to the interventional suite. The patient has a clot retriever deployed which returns circulation to the affected area. Although they have a long road to recovery, the patient is discharged to a rehab setting with only a mild weakness in the arm and fully recovered speech.
Dr. Anand Swaminathan
Clinical Application: Additional studies are needed but, given the potential harms of systemic thrombolytics, there should be careful consideration about their use in patients with LVO strokes who are proceeding to endovascular therapy.
What Do I Tell My Patient? The scan of your head shows you are having a stroke. It is being caused by a clot in a large blood vessel in your brain. We have a team that can get the clot out. This will give you a good chance of having a good recovery. The team will be here soon to tell you more details about the potential benefits and potential risks of the surgery.
Keener Kontest: Last episode’s winner was Jake Price. On average it takes eight minutes for EMS to arrive but 14 minutes in a rural area.
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.
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