The correct answer is:

Adding endovascular therapy results in significantly better functional recovery without a statistically significant increase in symptomatic hemorrhages.

Educational Objective:

Discuss recent (April 2022) study findings with regards to endovascular treatments in patients with severe strokes and ASPECTS scores of 3-5, which is a group of patients for whom current stroke guidelines discourage endovascular treatments.

Key Point:

Due to a lack of data, guidelines currently do not recommend endovascular treatments for patients with severe strokes and an ASPECTS score < 6. However, a recent trial (conducted in Japan) now fills in some of the missing data. They found that among patients with acute stroke and a large ischemic region (ASPECTS 3-5), functional outcomes at 90 days were  - though overall not great (as to be expected after a severe stroke) – nonetheless significantly better with endovascular treatment than with medical treatment alone (which incl. thrombolysis where applicable).

Even though the addition of endovascular therapy resulted in a significant increase in intracranial hemorrhage as compared to medical care alone, the rate of symptomatic intracranial hemorrhage within 48 hours or death at 90 days was NOT statistically different between the two groups.

Explanation:

Editor’s Note: in order to follow the author’s data, it helps to understand three common stroke scoring systems: mRs, NIHSS, and ASPECTS. 

For both the mRs and NIHSS, LARGER scores signify WORSE strokes. For ASPECTS, the opposite is true: a score of 10 is the best score. Smaller scores signify incrementally WORSE strokes:

• mRs quantifies the patient’s pre-stroke level of independence (0 = fully independent; 6 fully dependent). This score is important because a patient with a previous stroke and a high mRs score (significant disability) prior to the current stroke will not be able to recover from the current stroke to any significant degree.
• NIHSS is a scoring tool that clinically (pre-imaging) quantifies the severity of the current stroke. This score correlates well with the likelihood of a good versus increasingly poorer outcome (loss of independence). NIHSS ≥6 is considered the transition point between a likely good versus poorer outcome. Even though the maximum score is 42 points, most scores > 6 correlate with a significant loss of independence.
• ASPECTS quantifies the imaging result in terms of the location/size/severity of a stroke, with 10 signifying normal imaging results and 0 being a severe stroke of essentially the entire brain.

Patients with large infarctions (e.g., those with an ASPECTS value of <6) have been generally excluded from clinical trials of endovascular therapy due to concerns that bleeding will occur in the area of infarction after reperfusion. This has led to a lack of data and therefore also a lack of recommendations regarding endovascular treatments in this group of patients.

A recent Japanese study investigated the open question of endovascular treatment in patients with large ischemic strokes and an ASPECTS of 2-5 (extremely severe strokes with ASPECTS 0-1 were excluded).

The percentage of patients who presented with large ischemic stroke (ASPECTS value of 3 to 5) and achieved a good functional recovery at 90 days (mRs score of 0 to 3) was significantly higher (31%) when endovascular therapy was added to medical care than with the same medical care alone (12.7%).

In terms of safety, there was a significantly higher total number of intracranial hemorrhages in the endovascular-therapy group than in the medical-care group; however, there was no statistically significant difference between the two groups in symptomatic intracranial hemorrhage or death.

The percentage of patients who had recurrence of an ischemic stroke within 90 days was similar in the both groups, as was the percentage of those who had decompressive craniectomy within 7 days.

Other safety outcomes (not part of the primary or secondary outcome measures) showed that the endovascular group had 8.9% procedural complications (vessel perforation being the most common one) versus – logically – none in the medical group (since they did not undergo the procedure).

The endovascular group also had 33.7% other adverse events (cardiovascular events being the most common one) whereas the medical group had 18.6% such events (pneumonia being the most common one). The study was not powered to determine if these differences in other adverse events were statistically significant.

STUDY DESIGN:

Patients were eligible for enrollment if they:

(1)   DIAGNOSIS: had acute ischemic stroke,

(2)   AGE: were 18 years of age or older,

(3)   NIHSS: had a score of at least 6 on the NIHSS at admission (significant stroke),

(4)   mRs: had a score of 0 or 1 on the mRs before the onset of stroke (no disability or no clinically significant disability),

(5)   ASPECTS: had an ASPECTS value of 3 to 5 (large area of ischemia), as determined with the use of computed tomography (CT) or diffusion-weighted magnetic resonance imaging (MRI),

(6)   STROKE LOCATION: had an occlusion of the internal carotid artery or M1 segment of the middle cerebral artery on computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) that was amenable to endovascular treatment,

(7)   TIMELY STUDY ENTRY: were randomized within 6 hours after the time the patient was last known to be well or within 6 to 24 hours after the time the patient was last known to be well and there was no signal change in the initial image on fluid-attenuated inversion recovery (FLAIR) indicating that the infarction was recent, and

(8)   TIMELY ENDOVASCULAR THERAPY: if endovascular therapy could be initiated within 60 minutes after randomization.

Patients were excluded if they had a clinically significant cerebral mass effect with midline shift or an acute intracranial hemorrhage on CT or MRI or if site investigators considered that there was a high risk of hemorrhage.

The study and control groups were balanced in terms of age (<75 versus ≥75 years), interval between the time that a patient was last known to be well and the time of hospital arrival (<120 versus ≥120 minutes), NIHSS score at admission (<21 versus ≥21), and use of recombinant tissue plasminogen activator (rt-PA or no rTPA).

Medical care in both groups was in line with the guidelines from the 2019 American Heart Association and the American Stroke Association stroke guidelines with the caveat that in Japan, a lower dose of rTPA is given than in the USA and fewer patients in Japan than the USA receive rTPA.

The method of endovascular therapy was selected by the treating physicians and could include stent retriever, aspiration catheter, balloon angioplasty, intracranial stent, and carotid-artery stent.

MAIN OUTCOME MEASURES:

(1)   The primary outcome measure was a score of 0 to 3 on the mRs at 90 days after the onset of stroke.

(2)   Various secondary outcome measures were: mRs score ranges of 0 to 2 and 0 or 1, a shift in mRs scores toward a better outcome at 90 days and/or an improvement of at least 8 points on the NIHSS at 48 hours after randomization.

(3)   Safety (adverse) outcome measures were symptomatic intracranial hemorrhage (parenchymal hematoma type 2, defined as clots in at least 30% of the infarcted area with space-occupying effect) in combination with worsening of NIHSS score by at least 4 points within 48 hours after randomization, any intracranial hemorrhage within 48 hours after randomization, death within 90 days after the onset of stroke, recurrence of ischemic stroke within 90 days after randomization, and need for decompressive craniectomy within 7 days after randomization.

References:

Yoshimura, N. Sakai, H. Yamagami, et al. Endovascular Therapy for Acute Stroke with a Large Ischemic Region. N Engl J Med 2022; 386:1303-1313  DOI: 10.1056/NEJMoa2118191

Powers WJ, Rabinstein AA, et al; on behalf of the American Heart Association Stroke Council 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50:e344–e418

LeCouffe NF, Kappelhof M, Treurniet KM, et al. A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke. New Engl J Med 2021; 385:1833-1844. DOI: 10.1056/NEJMoa2107727

Ciccone A. Alteplase and Thrombectomy - Not a Bridge to Dismantle. Editorial. N Engl J Med 2021; 385:1904-1905. Nov 11, 2021 DOI: 10.1056/NEJMe2112663

Suzuki K, Matsumaru Y, Takeuchi M, 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; 325:244-253.

Si W, QIU Z, Li F, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular treatment of functional independence in patients with acute ischemic stroke: the DEVT randomized clinical trial. JAMA 2021; 325:234-243.