Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow)

Abstract

BackgroundThe relevance of impaired microvascular tissue-level reperfusion despite complete upstream macrovascular angiographic reperfusion (no-reflow) in human stroke remains controversial. We investigated the prevalence and clinical-radiological features of this phenomenon, and its associations with outcomes in three international randomized controlled thrombectomy trials with pre-specified follow-up perfusion imaging.MethodsIn a pooled analysis of the EXTEND-IA (ClinicalTrials.gov number NCT01492725), EXTEND-IA TNK (NCT02388061) and EXTEND-IA TNK Part-two (NCT03340493) trials, patients undergoing thrombectomy with final angiographic extended Thrombolysis In Cerebral Ischemia 2c-3 score for anterior circulation large vessel occlusion and 24-hour follow-up CT or MRI perfusion imaging were included. No-reflow was defined as regions of visually demonstrable persistent hypoperfusion on relative Cerebral Blood Volume or Flow maps within the infarct and verified quantitatively by >15% asymmetry compared to a mirror homologue in the absence of carotid stenosis or re-occlusion.ResultsRegions of no-reflow were identified in 33 of 130 patients (25.3%), encompassed a median of 60.2% (Interquartile range 47.8-70.7%) of the infarct volume, and involved both subcortical (n=26/33,78.8%) and cortical (n=10/33,30.3%) regions. Patients with no-reflow had a median 25.2% ([Interquartile range 16.4-32.2%],p<0.00001) relative Cerebral Blood Volume interside reduction and 19.1% (Interquartile range 3.9-28.3%,p=0.00011) relative Cerebral Blood Flow reduction but similar mean-transit-time (median -3.3%, Interquartile range -11.9-24.4%,p=0.24) within the infarcted region. Baseline characteristics were similar between patients with and without no-reflow. The presence of no-reflow was associated with hemorrhagic transformation (aOR=1.79,95%CI2.32-15.57,p=0.0002), greater infarct growth (ß=11.00,95%CI5.22-16.78,p=0.00027), reduced National Institutes of Health Stroke Score improvement at 24-hours (ß=-4.06,95%CI-6.78--1.34,p=0.004) and being dependent or dead at 90-day as assessed on the modified Rankin Scale (aOR=3.72,95%CI1.35-10.20,p=0.011) in multivariable analysis.ConclusionCerebral no-reflow in humans is common, can be detected by its characteristic perfusion imaging profile using readily available sequences in the clinical setting, and is associated with post-treatment complications and being dependent or dead. Further studies evaluating the role of no-reflow in secondary injury after angiographic reperfusion are warranted.Classification of evidenceThis study provides Class II evidence that cerebral no-reflow on CT/MRI perfusion imaging at 24-hours is associated with post-treatment complications and poor 3-month functional outcome.

Safety and efficacy of periprocedural antithrombotics in patients with successful reperfusion after endovascular stroke treatment

“…This could reverse the effect of the "no-reflow phenomenon", which has been associated to a greater infarct growth. 5,17 However, we found no interaction of the post-EVT reperfusion status with periprocedural treatment with aspirin on the final infarct volume. We did find an interaction between post-EVT reperfusion status and periprocedural treatment with unfractionated heparin on the final infarct volume.…”

Intra-arterial thrombolytics during endovascular thrombectomy for acute ischaemic stroke in the MR CLEAN Registry

“…The IA thrombolytics administered were urokinase (n=63/95 (66%)) or alteplase (n=32/95 (34%)), and the median doses were 250 000 IU (IQR, 1 93 750-2 50 000) and 20 mg (IQR, [12][13][14][15][16][17][18][19][20], respectively (table 2).…”

“…Despite the success of EVT, approximately 55% of the patients are functionally dependent or deceased at 90 days after EVT 11. This may be partially explained by incomplete macrovascular recanalisation or incomplete microvascular reperfusion 12. Incomplete macrovascular recanalisation may be due to technical difficulties regarding clot removal, such as thrombus fragmentation to inaccessible distal territories,13 fibrin-rich thrombus composition14 and anatomical challenges, such as tortuous arteries 15.…”

Efficacy of Cerebrolysin Treatment as an Add-On Therapy to Mechanical Thrombectomy in Patients With Acute Ischemic Stroke Due to Large Vessel Occlusion: Study Protocol for a Prospective, Open Label, Single-Center Study With 12 Months of Follow-Up

“…Efficacy of MT is related to multiple reasons e.g., time from stroke onset to reperfusion (OTR), secondary intracerebral hemorrhages (ICH) due to reperfusion injury, and the lack of successful recanalization or reflow. The mechanism underlying no-reflow phenomenon has not been fully established, but there is now class II evidence of no-reflow in human stroke ( 7 ). However, this phenomenon is probably independent of MT technique, can persist despite proximal recanalization, and results from altered microvascular circulation, proinflammatory state, and thrombosis, and represents a potential therapeutic target ( 8 ).…”