Kat Dakay, DO
If 2014 was the year of the thrombectomy, 2017 to early 2018 was the era of the extended time window. While earlier endovascular trials set the bar at 6 hours (still more permissive than the 4.5-hour limit for IV tPA), there still remained a large proportion of patients for whom we had no acute stroke intervention.
Cue DEFUSE 3 and DAWN. These trials confirmed that there was a benefit in patients up to 16 hours (for DEFUSE 3) and 24 hours (for DAWN) from last known normal (LKN) who received endovascular therapy. Both trials were stopped early at interim analysis, as the results were consistent with a benefit from mechanical thrombectomy (MT) compared to medical treatment. Specifically, in DAWN, 49% of patients in the MT group were functionally independent at 90 days compared to 13% in the control group with a posterior probability of superiority of >0.999. In DEFUSE 3, patients who underwent MT had a 45% rate of functional independence versus 17% in the medical group, with p<0.001. For those of us at the International Stroke Conference in January 2018 (or the European Stroke Organisation Conference in 2017), the applause and cheers as the study results were announced were an unforgettable moment, as we now knew that there was a whole new subset of patients for which endovascular therapy would become the standard of care.
This enthusiasm, however, was tempered by the inclusion criteria, which limits the patients that are eligible. For one, strict parameters were specified regarding the volume of infarction and penumbra, excluding patients with larger infarcts. Additionally, patients with some functional deficits at baseline were excluded from the trial due to premorbid modified Rankin scale even though their stroke may be causing profound worsening of their baseline. Patients with M2 occlusions were also not included in DEFUSE 3 and DAWN, though proximal M2 occlusions are often accessible and can cause severe disability such as aphasia, hemiparesis, or neglect.
In this retrospective single-center study from the University of Pittsburgh Medical Center, the authors explored patients who underwent MT in the extended time window who were not candidates based on DEFUSE 3/DAWN criteria. 204 patients with ELVO in the anterior circulation presented from 6-24 hours, 142 of which were neither DAWN- or DEFUSE 3-eligible (trial ineligible, or TI). Common reasons for TI included large infarct volume in 38%, premorbid MRS of 2 or greater in 27%, absence of imaging mismatch in 23%, and distal occlusion in 22%. Of those 142 patients, 37 received off-label MT. Of the TI-MT patients, 30% were functionally independent at 90 days compared to only 12% in the medical management group (p= 0.007). More symptomatic hemorrhages occurred in the TI-MT group compared to the trial-eligible patients from the study center (8% in the trial ineligible group compared to only 4% each in the DAWN and DEFUSE 3 enrolled groups); however the numbers were small.
Additionally, the hemorrhage rate was similar in the TI-MT patients (8%) compared to those who did not get MT (5%). In particular, patients <80 years old seemed to have the highest likelihood of benefitting from MT outside of DEFUSE 3 or DAWN criteria. Notably, the infarct volume was small in the TI-MT group (7 cc) compared to the trial-ineligible non-MT group (83 ccs) suggesting that patients with a large infarct were generally not offered MT. Nearly 1/4 of the TI-MT group had a premorbid baseline MRS of >2 and nearly 1/5 of the TI-MT group had distal occlusions — these are two groups of patients in which one may intuitively expect the rate of complication not to be markedly higher than the trial-eligible patients.
The study has some limitations, however. This is a single-center study from a large treatment center where recanalization outcomes were high, >88% in all three groups (DEFUSE 3, DAWN, and TI-MT) — smaller volume centers may not necessarily have the same outcomes. Additionally, the retrospective nature and the lack of a predefined treatment protocol meant that treating the large vessel occlusion with thrombectomy was left to the discretion of the treating physicians, opening the door for selection bias. It is likely that patients selected to undergo thrombectomy are those who have a higher likelihood of doing well and were thought to be a lower procedural risk. The reason for TI was reported for the 142 patients who did not fulfill DAWN or DEFUSE 3 criteria, but the specific reasons for exclusion of the 37 patients who did receive MT were not reported (some had more than one exclusion criterion) — thus, it is not clear what the exact subgroup of patients to target for TI treatment are. It is notable that the patients offered MT had relatively small infarct burdens, so it is unclear if patients with a large core benefit from off-label MT as they generally weren’t included in the TI-MT group. It is also notable that nearly 1/5 of the patients treated with TI-MT had a distal occlusion, suggesting maybe these patients should be targeted for further study to confirm the benefit.
Altogether, these findings suggest that patients who present in the extended time window who do not fulfill DAWN or DEFUSE 3 criteria can still benefit from MT. In particular, if the patient is younger than 80 years old or has a small core, they may benefit. Although the treatment effect is not as robust as the treatment effect in DAWN- or DEFUSE 3-eligible patients, it is still better than the outcome with medical treatment alone, especially given the poor natural history of large vessel occlusion. These results suggest that perhaps distal occlusions in the extended window are worthy of further study, and that perhaps a more permissive approach to patients with premorbid functional impairment or small penumbra should be considered. With regards to patients with a large core infarct, this study did not specifically address this population, and more data is warranted given the concern for hemorrhagic transformation.
Table: Trial Inclusion Criteria.
- Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018;378(8):708-718.
- Desai SM, Rocha M, Molyneaux BJ, et al. Thrombectomy 6-24 hours after stroke in trial ineligible patients. J Neurointerv Surg. 2018.
- Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018;378(1):11-21.