The Paper of the Month December01 Dec 2021
A new WSA feature highlighting original research in the field of neurology, selected by WSA Editor in Chief, Dr. Gustavo Saposnik
Title: EUREKA: Thrombolysis, Endovascular Thrombectomy or both?
Author: Dr. Gustavo Saposnik, EiC, WSA
“There are no secrets to success. It is the result of preparation, hard work, and learning from failure.” Colin Powell (American politician, statesman, diplomat)
In a recent open-label, multicenter, randomized trial in Europe, MR CLEAN-NO IV randomly assigned 539 stroke patients in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care).1 The primary outcome was the modified Rankin scale at 90 days. The trial was designed to test noninferiority of thrombectomy alone by a margin of 0.8 and also to test superiority (see brief explanation and figure below). The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28) showed neither superiority nor noninferiority of EVT alone. There were no significant differences in mortality, symptomatic intracerebral hemorrhage, Barthel index, successful recanalization or reperfusion rates, or final infarct volume between groups. The authors concluded that “EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke”.1
Commentary: EVT became standard of care in the management of acute ischemic stroke for eligible patients with large vessel occlusions.2-6 Several meta-analyses compared the benefits of intravenous thrombolysis (IVT) prior to EVT vs. tPA alone or EVT alone with conflicting results.7-10 In fact, this is the fourth trial to test the non-inferiority of EVT vs. IVT + EVT.1, 11-13 In other words, these trials compared whether thrombolysis can be avoided prior to thrombectomy (See a comparative table of baseline characteristics and hypothesis testing below).
Table: Comparison of clinical trial design and baseline characteristics between studies testing EVT alone vs intravenous thrombolysis + EVT
|DIRECT-MT11||DEVT12||SKIP13||MR CLEAN-NO IV1|
|N° subjects enrolled||656||234||204||539|
|Age, median[IQR]||69 [61-76]||70 [60-78]||75 [67-80]||70 [61-80]|
|NIHSS, median[IQR]||17 [12-22]||16 [12-20]||18 [12-23]||16 [10-20]|
|Pre-stroke mRS 1-2 (%)||51 (7.7)||17 (7.3)*||30 (14.7)||149 (27.6)|
|Pre-stroke mRS ≥3 (%)||0||0||2 (1.0)||15 (2.8)|
|Primary outcome||Shift at mRS score||mRS score 0-2||mRS score 0-2||Shift at mRS score|
|Alteplase dose (mg/Kg)||0.9||0.9||0.6||0.9|
|Inclusion criteria||All intracranial ICA, M1, proximal M2||All intracranial ICA, M1||All intracranial ICA, M1||ICA-T, M1, proximal M2|
|Median door-toneedle time (IQR) in minutes||
|% difference in mRS 0-2 between treatments||-0.4%||+7.7%||+2.1%||-2%|
|Hypothesis tested||Non-inferiority||Non-inferiority||Non-inferiority||Superiority and non-inferiority|
|P for non-inferiority||0.04||0.003||0.18||0.28|
* only patients with a mRS 0-1 were included in this trial.
What have we learned from the results of these 4 trials?
1) Heterogeneity: Despite the similarities in baseline characteristics, there was a variation in the non-inferiority margin among trials and the proportion of randomized patients with pre-existing disability (mRS 1 to 3) (See table).
2) How can clinicians better understand the concept of non-inferiority vs. superiority in the design of clinical trials?. Superiority trials were traditionally designed to show that treatment A was better than placebo, whereas non-inferiority trials tested the hypothesis that treatment A is similar or not worse than treatment B (usually an active control).14
Figure 1 illustrates different results and points estimates (95%CI) comparing the benefits of a new treatment vs. a standard one. The legend provides a simple explanation to help clinicians understand the meaning of each scenario (A to G). An important consideration is the determination of the non-inferiority margin. Readers can also refer to recent publications that illustrate these differences, including a document from the FDA. 14
Legend: Forest plot showing hypothesis testing and possible outcomes of non-inferiority trials. The solid vertical line indicates a relative risk of 1. The dashed vertical line indicates the predefined non-inferior margin. The dotted and dashed vertical lines indicate the equivalence margins (for equivalence trials). The horizontal lines represent the 95% CIs of the possible results of non-inferiority trials. A: the 95% CI does not overlap 1 and lies entirely on the left side of 1. Therefore, the new treatment is superior to standard treatment. B: the 95% CI overlaps 1 but the upper bound of the 95% CI does not exceed the predetermined non-inferior margin. Therefore, the new treatment is not superior but is non-inferior to standard treatment. C: the 95% CI overlaps 1 and lies entirely within the equivalence margins. Therefore, the new treatment is equivalent to standard treatment. D: the 95% CI does not overlap 1 and lies entirely on the right side of 1, Therefore, the new treatment is inferior to standard treatment. However, the upper bound of the 95% CI does not exceed the predetermined non-inferior margin. Therefore, the new treatment is also non-inferior to standard treatment. This scenario is unlikely but theoretically possible. E: the 95% CI overlaps 1 and the upper bound of the 95% CI exceeds the predetermined non-inferior margin. Therefore, the new treatment is neither inferior nor non-inferior to standard treatment. F and G: the 95% CIs lie entirely to the right side of 1 and the upper bound of the 95% CIs exceed the predetermined non-inferior margin. Therefore, the new treatment is inferior to standard treatment (reproduced with permission from Leung et al; Heart 2020;106:99-104).
3) What do we know so far?: Prior to the publication of CLEAN-NO IV1, a meta-analysis comprising 1092 patients from 3 trials15 (included in the comparative table), showed no difference between the EVT alone vs. Alteplase + EVT for all clinical outcomes (mRS score of 0-2 (OR 1.08, 95% CI 0.85-1.38; adjusted OR 1.11, 95% CI 0.76-1.63), mRS score of 0 to 1 (OR 1.10, 95% CI 0.84-1.43; adjusted OR 1.16, 95% CI 0.84-1.61), and functional improvement at 3 months (common OR 1.08, 95% CI 0.88-1.34; adjusted common OR 1.09, 95% CI 0.86-1.37).15 The table above illustrates the comparison of 4 trials comparing EVT alone vs. Alteplase preceding EVT. DIRECT-MT11 and DEVT12, both conducted in China, showed that EVT alone was not worse than Alteplase followed by EVT. The smaller study conducted in Japan (SKIP)13 failed to demonstrate non-inferiority of EVT alone. Finally, in CLEAN-NO IV showed no evidence of superiority or non-inferiority of EVT alone. For clinicians, there were no differences in the achieving independency between EVT alone vs Alteplase+EVT (49.1% vs. 51.1%; adj OR 0.95 (95%CI 0.65 to 1.39).1
In summary, what this information tell us is that for patients with LVO that would fulfill the entry criteria in these trials, EVT alone would achieve similar clinical outcomes if the procedure can be done within 60-90 min.
4) An important reminder: Large vessel occlusions (LVO) only represents 1 out of 3 or 4 patients with an acute ischemic stroke presenting to an ED.16-18 In other words, the great majority of acute stroke patients do not have LVO, and therefore are not candidates for EVT. For those patients, intravenous thrombolysis remains standard of care.
5) Are there any specific characteristics that would favor direct EVT vs. mothership bridging with iv thrombolysis?. As eloquently described by our colleagues Dr. Raul Nogueira and Dr. Giorgios Tsivgoulis19, patients with long clots (>8mm), more proximal occlusions, large infarct core, and factors associated with higher risk of intracerebral hemorrhage with iv thrombolysis would favor direct EVT, among others (See figure 2 below- reproduced with permission).
In conclusion, the initial clinical assessment and brain imaging will help classify stroke patients and estimating the best treatment. Intravenous thrombolysis remains as the first line option among patients with an acute ischemic stroke without contraindications and absence of a LVO. Some colleagues advocate for another clinical trial given the results of CLEAN-NO IV. In my personal view, EVT alone can be considered for those with a LVO who are nearby a tertiary stroke center that can deliver EVT in timely manner (ideally less than 60 min from door to groin puncture), and specially when there are higher risk of complications with iv thrombolysis. Bridging therapy (iv thrombolysis prior to EVT) would remain as the optimal option to improve the likelihood of achieving independency when expecting delays in undergoing EVT, drip and ship from a primary stroke center with prologued time between inter-facility transfers, or when there is uncertainty regarding the timing of EVT.
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Prof. Y. B. W. E. M. Roos
1. WHAT DID YOU SET OUT TO STUDY?
The clinical effect of direct endovascular treatment (EVT) in stroke patients as compared to patients treated with the combination of thrombolysis (IVT) with alteplase and EVT.
2. WHY THIS TOPIC?
After the original Mr Clean trial, published in 2015, which showed clinical efficacy of EVT in patients with an ischemic stroke of the anterior circulation, the remaining question was whether standard IVT treatment was still useful in patients with EVT. The point estimate of the effect in the original trial was similar in patients with and those without IVT treatment. So, the question was whether direct EVT was superior or at least non-inferior to the standard combination therapy of IVT and EVT.
3. WHAT WERE THE KEY FINDINGS?
In patients presenting directly to centres capable of providing both treatments EVT alone was neither superior nor non-inferior to IVT followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral haemorrhage was similar in the two groups.
4. HOW MIGHT THESE RESULTS IMPACT CLINICAL PRACTICE?
We now know that the combination therapy should remain the standard. However, knowing that the results look quite similar, in specific cases the treating physician can decide to treat with direct EVT.
5. WHAT SURPRISED YOU MOST?
That the incidence of symptomatic intracerebral haemorrhage was similar in the two groups. This suggests that the haemorrhagic effect of IVT is at least partly attributable to the opening of the blood vessel, not so much an effect of the thrombolytic drug itself.
6. WHAT’S NEXT FOR THIS RESEARCH?
The IRIS project has just started – in IRIS we are going to pool the individual patient data of all the trials similar to the Mr Clean NoIV. In IRIS we can analyse different subgroups of patients where one might expect that the effect of direct EVT is different as compared to the combination treatment. For instance, patient with a large proximal clot might not so much benefit from pre-treatment with IVT as compared to patients with a smaller more distal clot. We don’t know right now -hopefully IRIS will give us some answers.
7. IS THERE ANYTHING YOU’D LIKE TO ADD?
Many thanks to all PhD’s, all trial nurses, all investigators and above all – all patients who participated in this trial.