SGEM#333: Do you gotta be starting something – like tPA before EVT?

Date: May 25th, 2021 Guest Skeptic: Dr. Garreth Debiegun is an emergency physician at Maine Medical Center in Portland, ME and clinical assistant professor with Tufts University School of Medicine. He also works at an urgent care and a rural critical access hospital. Garreth is interested in wilderness medicine and is the co-director of the wilderness medicine clerkship at Maine Med, and the medical director for Saddleback Ski Patrol and for Maine Region NSP. At work Garreth imagines himself as a student of evidence-based medicine trying to provide the best care based on the best evidence. References: Suzuki et al. Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial. JAMA 2021 Zi et al. Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial. JAMA 2021 Case: A 74-year-old woman presents to your emergency department with 1.5 hours of right-sided weakness, aphasia, and neglect. On rapid bedside assessment you calculate the National Institute of Health Stroke Score/Scale (NIHSS) of 11 and a Field Assessment for Stroke Triage for Emergency Destination (FAST-ED) score of 7; you suspect a large vessel occlusion (LVO) based on the high NIHSS and FAST-ED score >3. 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 thrombolytics. You wonder if you gotta be starting something?  Specifically, you wonder if you should give the thrombolytics while waiting for your neurointerventional/endovascular team? Background: Management of acute ischemic stroke has been discussed on the SGEM ever since this knowledge translation project was launched in 2012. My position remains that there is uncertainty as to whether tPA provides a patient-oriented outcome and this was summarized in the downgrading of the NNT recommendation to “yellow” with Dr. Justin Morgenstern from First10EM. The world of stroke management has changed in the last few years the more robust evidence to support endovascular therapy (EVT) for large vessel occlusion (LVO) strokes. The tipping point came with the publication of MR. CLEAN in 2015. It was a multicenter, randomized, unblinded trial of patients with an LVO stroke in the anterior circulation treated in less than six hours after onset of symptoms. The primary outcome was good neurologic function defined as a modified Rankin Scale (mRS) score of 0-2 at 90 days. The trial included 500 patients and reported an absolute risk reduction of 14% (33% EVT vs 19% control) with a NNT of 7. Four other RCTs were stopped early due to the publication of MR. CLEAN.  All of these were published in the NEJM in the following six months. SWIFT PRIME (n=196) NNT of 4 EXTEND-IA (n=70) NNT of 2-5 depending on which outcome you picked REVASCAT (n=206) extended the window to eight hours NNT 6.5 ESCAPE (n=316) extended to 12 hours NNT 4 There are dangers with stopping trials early. Dr. Gordon Guyatt wrote in the BMJ that it can introduce bias towards efficacy. He said you should have a high level of skepticism regarding the findings of trials stopped early for benefit, particularly when those trials are relatively small, and replication is limited or absent. A systematic review and meta-analysis (SRMA) was published by Badhiwala, JH et al in JAMA 2015 looking at EVT for stroke. The first three RCTs reported no superiority. Then came MR. CLEAN and those four additional studies that were stopped early. The forest plot shows a point estimate that favors EVT and the 95% confidence interval does not cross the line of no statistical difference. We do need to be careful in not over interpreting this data because the bias of stopping trials early could have been compounded in the SRMA process. A couple more RCTs were published since the 2015 SRMA: DAWN 2018 (n=206) NNT 3 between 6-24 hours, stopped early DEFUSE 2018 (n=182) NNT 4 between 6-16 hours, stopped early Here is a lists all the studies and the number of patients enrolled/center/year put together by friend of the SGEM, Dr. Salim Rezaie (REBEL EM). The average was 4.6 patients/year from these stroke centres. While the NNT for EVT looks very impressive, it is suffering from denominator neglect. Once the patient is getting the intervention the NNT is in the single digits. However, how many possible stroke patients were screened, and code strokes were called to get the impressive NNTs of the EVT trials? Most of these trials didn’t tell us how many patients they screened to get the patients they registered.  Only one did – EXTEND-IA.  In that RCT, they screened ~7,800 patients, and registered 70. That’s 0.9%, or about 1/110, that were eligible for the treatment. The NNT in MR CLEAN, the largest and arguably the most methodologically sound of these trials, was 7.  If you must screen 110 patients to find one eligible, and need to treat 7 to benefit one, then about one out of every 770 patients having a potential stroke would benefit from this therapy. Therefore, we think the NNT provided by the RCTs suffer from denominator neglect. An NNT of 770 is not nearly as impressive as an NNT of 7. The agenda is in the numerator, but the devil is in the denominator. 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. There is a SRMA by Mistry et al published in Stroke 2017 on the issue of EVT +/- tPA. They included 13 studies (n=1,769) with three RCTs (which accounted for only 25% of patients) and ten observational studies (which accounted for the other 75% of the patients). They reported an NNT of 17 for good neurologic outcome (defined as mRS 0-2) with EVT + tPA compared to EVT alone. However, it was not statistically significant if you just looked at the RCT data. This is a problem of combining lower quality observational studies with higher-quality RCTs. We looked at a 2020 RCT by Yang P et al published in the NEJM on SGEM#292. This trial asked if EVT alone was non-inferior to EVT + tPA in stroke patients with LVOs presenting withing 4.5 hours of symptoms. The cohort consisted of 654 patients and the key results was EVT alone was not non-inferior to EVT plus tPA. Our SGEM bottom line was that there does not appear to be a role for systemic thrombolysis in acute ischemic stroke for appropriate patients when EVT is readily available. Two more trials have been published and that is what we are going to review today on the SGEM. Clinical Question: Does intravenous thrombolysis prior to mechanical thrombectomy increase the percentage of patients with LVO who achieve mRS of 0-2 (functional independence) at 90 days? Reference #1:  Suzuki et al. Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial. JAMA 2021 Population: Patients aged 18-85 evaluated at one of 23 stroke centers in Japan within 4.5 hours of onset, who were found to have: NIHSS ≥6, CTA or MRA proven ICA or M1 occlusion, minimal imaging changes of ischemic stroke. Patients had to be previously independent (mRS 0-2) and meet Japanese criteria for thrombolysis. Exclusions: Contraindication for contrast agent or EVT, contraindication for IVT, presence of severe renal disorder, pregnancy or possibility of pregnancy, unlikely to complete the study, such as due to progressive malignant tumor, judged incompatible with the study by the investigators Intervention: Mechanical thrombectomy of LVO without additional thrombolytics Comparison: Alteplase given at a dose of 0.6 mg/kg in addition to mechanical thrombectomy performed within 30 minutes of randomization Outcome: Primary Outcome: mRS evaluated by physical exam or phone interview at 90 days. Secondary Outcomes: Ordinal shift analysis of mRS, mRS 5-6, mRS 0-1, mRS 0-3, 90-day mortality, successful reperfusion, recanalization and adverse events (ICH) Authors’ Conclusions: “Among patients with acute large vessel occlusion, mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority.” 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 treated (per-protocol analysis for non-inferiority trials). 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. Unsure 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