Lancet Neurol Annual Inventory: Stroke of the 2022 Neurology Summary

The 2022 stroke clinical trial has many new answers and new questions
.
The journal Lancet Neurology conducts an annual inventory
of stroke studies.

Yimaitong compiles and arranges, please do not reprint
without authorization.

In 2022, several clinical trials answered important research questions about indications for revascularization and endovascular embolectomy, but their answers raised more questions
.
FOR EXAMPLE, TWO MULTICENTER, OPEN-LABEL, RANDOMIZED TRIALS (DIRECT-SAFE AND SWIFT-DIRECT) COMPARED ENDOVASCULAR THROMBECTOMY ALONE WITH COMBINATION OF INTRAVENOUS THROMBOLYSIS AND ENDOVASCULAR THROMBECTOMY TO DETERMINE WHETHER PATIENTS WITH LARGE VESSEL OCCLUSION (CALLED DIRECT TRANSPORT PATIENTS) WHO WENT DIRECTLY TO A HOSPITAL WHERE ENDOVASCULAR EMBOLECTOMY COULD BE PERFORMED COULD AVOID INTRAVENOUS ALPLASE THERAPY
。 The trials did not show non-inferiority of the primary outcome of functional independence (defined as a modified Rankin Scale [mRS] score of 0 to 2) by endovascular embolectomy alone, with an adjusted risk difference of -0.
051 (95% CI -0.
160 to 0.
059) in DIRECT-SAFE and -7.
3 (95% CI -16.
6 to -2.
1)
in SWIFT-DIRECT 。 HOWEVER, SOME UNCERTAINTY SURROUNDING THESE FINDINGS REMAINS, AS THE NON-INFERIORITY BOUNDARY CHOSEN BY DIRECT-SAFE (10%) AND SWIFT-DIRECT (12%) DIFFERS FROM PREVIOUS TRIALS INVESTIGATING THE SAME RESEARCH QUESTION WITH A HIGHER
ODDS RATIO BOUNDARY.
Overall, DIRECT-SAFE and SWIFT-DIRECT suggest that intravenous alteplase therapy
should not be discontinued when endovascular embolectomy is performed in direct transport mode.
However, these findings raise the question of whether there should be guidelines on acceptable non-inferior thresholds, and who should contribute to these guidelines (e.
g.
, doctors, patients, or policymakers)?

The randomized ACT trial used a 5% non-inferiority boundary to investigate whether intravenous tenecteplase was not inferior to alteplase
in achieving excellent functional results (90-day mRS 0-1 score).
Tenecteplase was shown to be non-inferior to alteplase (risk difference 2.
1%, 95% CI -2.
6 to 6.
9).

However, because tenecteplase is easier to use than alteplase, the results of ACT raise several other questions
.
For example, if tenecteplase is to replace altenecteplase, should previous trials with alteplase be repeated with tenecteplase? However, this question can be answered in other ways: for example, the In-Silico trial
.

The CHOICE trial investigated whether adjuvant intraarterial alteplase therapy improves the incidence of
good functional outcomes (mRS 0 to 1) in patients with successful end-vascular embolectomy and angiographic reperfusion.
Due to registration issues related to the COVID-19 pandemic and the absence of placebo available, this randomized, double-blind, placebo-controlled trial was discontinued
before planned registration was completed.
Although an adjusted risk difference of 18.
4% (95% CI 0.
3 to 36.
4) supported the superiority of intraarterial alpeplase over placebo, the reliability of these findings is questionable given that target sample sizes were not met
.
When taking into account limitations in ACT trial results, CHOICE may need to be replicated
in another study investigating tenecteplase.

In the RESCUE-JAPAN open-label randomized controlled trial, the objective was to investigate the benefits
of endovascular embolectomy and optimal medical management over optimal medical management alone in patients with large vessel occlusion and large core infarction (defined as an early CT score of 3-5 at baseline [i.
e.
, when first imaging after stroke onset]) of Alberta stroke program 。 The functional results (defined as mRS 0-3 points) in the endovascular thrombectomy group were better than those in the control group (relative risk 2.
4, 95% CI 1.
4-4.
4), but the rate of intracranial hemorrhage (relative risk 3.
5, 95% CI 1.
8~7.
0) was higher than that in the control group
.
Although most centers worldwide use CT for imaging of acute ischemic stroke, in RESCUE-JAPAN, most patients are enrolled on the basis of MRI, which is considered to overestimate core infarction compared to CT
.
In addition, the approved dose of Japanese alpleplase (0.
6 mg/kg) for intravenous thrombolysis differs from
the approved dose in North America (0.
9 mg/kg).
Therefore, these results may vary if CT is used as a means of imaging, and the use of low-dose altenplase may lead to an underestimation of the risk of
intracranial hemorrhage.

Similar to the RESCUE-Japan trial, the ATTENTION and BAOCHE randomized trials also investigated the benefits
of endovascular embolectomy beyond optimal medical management.
The two trials included people with basilar artery occlusive stroke, whose primary outcome was an mRS score of 0 to 3, as outcomes were worse
in this patient population than in patients with anterior circulation and macrovascular occlusive stroke.
An MRS score of 3 can be considered a meaningful improvement in patients
with an mRS score of 4-5.
However, we do not know what the most appropriate outcome is
for stroke patients in different subgroups.
The choice of results can be left to researchers, but seeking consensus on this issue can be beneficial
.
There may also be a need to focus more on patient-centered outcomes
.

So while these findings provide valuable guidance for clinicians and guideline committees, the question remains whether these results apply to patients now, who often receive more aggressive medical treatment
than those of patients in 2016.

The randomised CASSISS trial investigated whether stenting is beneficial
in addition to medical therapy in people with severe symptomatic intracranial atherosclerotic disease.
There was no difference in the primary composite outcome of stroke or death (stenting 8.
0% versus medical therapy 7.
2%, p=0.
82).

During enrollment (2014-16), most centers started antiplatelet and statin therapy immediately after stroke, particularly in patients with
intracranial atherosclerotic disease.
So while these findings provide valuable guidance for clinicians and guideline committees, the question remains whether these results apply to patients now, who are receiving more aggressive medical treatment
than they did in 2016.

The research questions answered by these well-designed, rigorous trials raise new and critical questions that remain to be answered
.
Some debates are ongoing, and others remain, such as about the benefits
of intra-arterial thrombolysis after endovascular thrombectomy.
Medical management is likely to remain the mainstay of treatment for intracranial atherosclerotic disease, but clinicians and researchers are not yet fully certain
.