Washington University Emergency Medicine Journal Club – April 15, 2021
You’re working a shift in TCC one afternoon when you get a page that EMS is bringing in a 67-year-old woman with right-sided weakness and hemiplegia. Her last known normal was one hour ago. She arrives and you immediately begin to perform your NIH stroke scale. She has right arm, and leg hemiplegia and severe aphasia, and her score on the scale is 13. A non-contrast head CT is negative, though there is a possible hyper-dense “MCA sign” per the preliminary read. CT angiography reveals a left M1 occlusion and CTP demonstrates a large penumbra and small infarct core. All labs are unremarkable and no contraindications to IV thrombolysis were elicited from her husband. Alteplase has already been mixed up your astute nurses and neurology is on the phone with neuro-interventional radiology, who plans to take the patient for an endovascular procedure as soon as possible (see previous journal club on endovascular stroke treatment). As the nurse begins the alteplase bolus, you wonder whether systemic thrombolysis is really necessary if the patient is immediately going to undergo clot retrieval. You remember hearing that there is some evidence that systemic thrombolysis might not be helpful in such cases. As the alteplase infuses and the patient is whisked away, you decide to go online and check the literature yourself…
Population: Adult patients presenting to the ED with acute stroke who are eligible for endovascular thrombectomy AND systemic thrombolysis
Intervention: Endovascular therapy alone (without systemic thrombolysis)
Comparison: Endovascular therapy with systemic thrombolysis
Outcome: Functional recovery, recanalization, quality of life, mortality, intracranial hemorrhage
Article 1: Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Dávalos A, Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, Diener HC, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millán M, Davis SM, Roy D, Thornton J, Román LS, Ribó M, Beumer D, Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG; HERMES collaborators. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016 Apr 23;387(10029):1723-31. doi: 10.1016/S0140-6736(16)00163-X. Epub 2016 Feb 18. PMID: 26898852. Answer Key.
Article 2: Zi W, Qiu Z, Li F, 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;325(3):234–243. doi:10.1001/jama.2020.23523. Answer Key.
Article 3: Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, Peng Y, Han H, Wang J, Wang S, Yin C, Liu S, Wang P, Fang Q, Shi H, Yang J, Wen C, Li C, Jiang C, Sun J, Yue X, Lou M, Zhang M, Shu H, Sun D, Liang H, Li T, Guo F, Ke K, Yuan H, Wang G, Yang W, Shi H, Li T, Li Z, Xing P, Zhang P, Zhou Y, Wang H, Xu Y, Huang Q, Wu T, Zhao R, Li Q, Fang Y, Wang L, Lu J, Li Y, Fu J, Zhong X, Wang Y, Wang L, Goyal M, Dippel DWJ, Hong B, Deng B, Roos YBWEM, Majoie CBLM, Liu J; DIRECT-MT Investigators. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. N Engl J Med. 2020 May 21;382(21):1981-1993. doi: 10.1056/NEJMoa2001123. Epub 2020 May 6. PMID: 32374959. Answer Key.
Article 4: Suzuki K, Matsumaru Y, Takeuchi M, Morimoto M, Kanazawa R, Takayama Y, Kamiya Y, Shigeta K, Okubo S, Hayakawa M, Ishii N, Koguchi Y, Takigawa T, Inoue M, Naito H, Ota T, Hirano T, Kato N, Ueda T, Iguchi Y, Akaji K, Tsuruta W, Miki K, Fujimoto S, Higashida T, Iwasaki M, Aoki J, Nishiyama Y, Otsuka T, Kimura K; SKIP Study Investigators. 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 Jan 19;325(3):244-253. doi: 10.1001/jama.2020.23522. PMID: 33464334; PMCID: PMC7816103. Answer Key.
While initial studies evaluating neurointerventional thrombectomy for acute stroke due to anterior large vessel occlusion failed to demonstrate significant benefit (IMS-3, MR RESCUE, SYNTHESIS), subsequent trials using newer generation clot retrieval devices were quickly undertaken. Five important trials, all published in 2015, were able to demonstrated improved functional outcomes as measured by the modified Rankin Scale (mRS) at 90 days among select patients treated with thrombolysis and thrombectomy when compared to thrombolysis alone (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA).
The authors of these trials subsequently published a meta-analysis of their results in 2016 (HERMES collaboration). The pooled data demonstrated a reduced chance of disability at 90 days among patients treated with thrombectomy with an adjusted odds ratio (OR) of 2.49 (95% CI 1.76 to 3.53) and a number needed to treat (NNT) to have one patient with reduced disability of at least 1 point on the mRS of 2.6. There was no difference in rates of intracranial hemorrhage (ICH) or mortality between the groups. More significantly, this meta-analysis confirmed the benefit of endovascular thrombectomy among important subgroups, including the elderly, patients not receiving intravenous alteplase, and patients who presented later than 300 min from stroke symptom onset. While these findings are of significant interest, the authors of this meta-analysis performed a cursory literature search that did not identify any research outside of their five published articles (publication bias). They also failed to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, primarily by failing to report:
- A detailed search strategy.
- Inclusion/exclusion criteria for study selection.
- A flow diagram detailing the selection process.
- Details regarding how data was collected and analyzed.
- A risk of bias assessment (such as the Cochrane Tool).
- Measures of heterogeneity between studies or Forest plots for visual estimation.
Despite limited reporting, the HERMES meta-analysis and its included trials helped make thrombectomy the standard of care for stroke due to anterior large vessel occlusion. The obvious next question to emerge was whether systemic thrombolytics provide any added benefit among patients undergoing thrombectomy, or whether thrombectomy alone was sufficient to provide revascularization in these patients. We reviewed three studies comparing thrombectomy alone to thrombectomy plus systemic thrombolysis in such cases.
Three trials (DEVT, DIRECT-MT, and SKIP) were identified by our search strategy. These studies were all similar, in that they were all multicenter, randomized controlled, noninferiority trials enrolling adult patients with acute ischemic stroke and imaging-confirmed occlusion of proximal anterior vessels who were eligible to receive intravenous alteplase. Patients with significant functional disability prior to the stroke (pre-stroke modified Rankin Scale (mRS) score > 2) were excluded. The primary differences in the studies was that DEVT and DIRECT-MT were both conducted in China, where patients or their families had to consent to pay for treatment prior to enrollment, while SKIP was conducted in Japan, where a controversial lower dose of alteplase (0.6 mg/kg) is used.
In the DEVT trial, the risk difference for functional independence (mRS 0-2) was 7.7%, favoring thrombectomy alone. The lower bound of the 97.5% confidence interval (CI) was -5.1%, well above the prespecified noninferiority margin of -10%. Noninferiority was also demonstrated in the DIRECT-MT trial, in which the adjusted OR for the proportion of patients with a mRS score of 0 to 2 at 90 days was 1.07, with a lower bound of the 95% CI of 0.81 (above the prespecified margin of 0.80). Only the Japanese SKIP trial failed to demonstrate noninferiority; in this trial, the OR for a favorable neurologic outcome was 1.09, and the lower bound of the 1-sided 97.5% CI was 0.63 (below the prespecified non inferiority margin of 0.74). There was no significant difference in the rates of symptomatic ICH or death in any of the studies.
Overall, this data is highly promising, with a trend toward improved outcomes in all 3 studies. While the SKIP trial failed to prove noninferiority for thrombectomy alone, and it could be argued that the potential benefit of systemic thrombolysis was diluted by the use of low-dose alteplase, the results of the other two trials suggest that alteplase adds little benefit in patients undergoing early thrombectomy. The MR CLEAN-NO IV trial, a superiority trial conducted in the Netherlands, France, and Belgium, has been completed by not yet formally reported. Its results may further bolster the findings of these three previous trials, and may provide a sufficient body of evidence to change practice, allowing those patients undergoing timely endovascular therapy to forego systemic thrombolysis and its associated risks.