No-reflow in clinical studies: Causes, rates and implications for patient outcomes

Adnan Mujanovic

In a guest article for NeuroNews, Adnan Mujanovic (Bern, Switzerland) discusses a relatively unknown but potentially significant factor in stroke patients experiencing poor clinical outcomes following a successful endovascular therapy (EVT) procedure—the ‘no-reflow’ phenomenon.

EVT has revolutionised the treatment for patients with acute ischaemic stroke. Yet, despite these advancements, more than half of patients undergoing EVT end up with a poor clinical outcome. Researchers are looking into different causes of this ‘reperfusion failure’, and one potential reason for having a poor outcome despite successful reperfusion could be due to the no-reflow phenomenon.1,2,3

This phenomenon occurs when, despite successful macrovascular reperfusion and restoration of the blood flow in principle blood vessels, flow is not fully restored on the microvascular level in the affected brain tissue. The compromised microcirculation in affected areas results in persistent ischaemia, exacerbating neuronal injury and impaired tissue recovery, which all leads to a poor outcome. Therefore, a comprehensive understanding of the underlying mechanisms of no-reflow is crucial.

Voyage into microvasculature

Several proposals have been put forward to explain the pathophysiology of no-reflow. Damage to the microvasculature can lead to the capillary vasospasm and constriction of the pericapillary pericytes. Conversely, sudden restoration of the blood flow can trigger an inflammatory response, which leads to the aggregation of neutrophiles and leucocytes that can obstruct the capillary lumen. Lastly, clots can get fragmented during the intervention and distal emboli may cause downstream occlusion leading to hypoperfusion of distal regions. These different hypotheses on the cause of no-reflow have made it hard to identify molecules and biomarkers that may be targeted for prognostic or therapeutic purposes.

From angiograms to echoes

Another topic of discussion regarding the no-reflow phenomenon is how to detect it. Perfusion imaging has been widely accepted to detect changes in tissue blood flow; however, it is not yet clear which perfusion maps might be most suitable to detect subtle changes in the microvasculature. Digital subtraction angiography imaging has also been suggested as an imaging modality for detection of no-reflow due to its widespread use and convenience, although its potential to show tissue-level changes is uncertain. Others have reported the use of transcranial Doppler and laser speckle contrast imaging for measurement of microvascular resistance and blood flow. This diverse array of imaging modalities makes it challenging to estimate true prevalence of no-reflow.

Chronological currents

The choice over the timing for measurements of no-reflow is also one of the crucial points for its accurate assessment. Prevalence of no-reflow seems to be highest when measured immediately after the intervention, followed by a decreasing tendency until reaching a plateau once 24 hours have passed since the intervention. However, a serial assessment of no-reflow at different timepoints is still lacking. In an ideal study, a patient would systematically undergo imaging at several timepoints—starting from immediately after the intervention until the 24-hour threshold. Timepoints for estimating no-reflow in current studies seem to be guided more by institutional stroke-imaging protocols rather than by research-driven motives to discover the natural evolution of no-reflow.

Clinical compass

Despite these uncertainties, one thing on which the vast majority seem to agree is the notion that there is a clear association between no-reflow and poor outcomes. No-reflow has been associated with reduced rates of functional independence in multiple studies, and a recent meta-analysis of clinical data has also shown this association (odds ratio [OR], 0.2; 95% confidence interval [CI] 0.1–0.3).4

This should further motivate strokeologists to define a comprehensive definition of what constitutes a ‘no-reflow’, including clear outlines on imaging modalities, potential biomarkers and post-interventional timepoints that can be used for its assessment. This journey into the waters of no-reflow is a dynamic one, but having a clear definition will help us effectively tackle this next frontier in acute stroke therapy.



  1. Sperring C P, Savage W M, Argenziano M G et al. No-Reflow Post-Recanalization in Acute Ischemic Stroke: Mechanisms, Measurements, and Molecular Markers. Stroke. 2023; 54(9): 2472–80.
  2. Zhang Y, Jiang M, Gao Y et al. “No-reflow” phenomenon in acute ischemic stroke. J Cereb Blood Flow Metab. 2024; 44(1): 19–37.
  3. Schiphorst A T, Turc G, Hassen W B et al. Incidence, severity and impact on functional outcome of persistent hypoperfusion despite large-vessel recanalization, a potential marker of impaired microvascular reperfusion: Systematic review of the clinical literature. J Cereb Blood Flow Metab. 2024; 44(1): 38–49.
  4. Mujanovic A, Ng F, Meinel TR et al. No-reflow phenomenon in stroke patients: A systematic literature review and meta-analysis of clinical data. Int J Stroke. 2024; 19(1): 58–67.


Adnan Mujanovic works as a clinical research fellow at the University Hospital Bern Inselspital in Bern, Switzerland. He is part of the TECNO trial core team, a board member of the Swiss Association of Young Neurologists (SAYN), and a country representative of young neurologists at the European Academy of Neurology (EAN).


The author declared no relevant disclosures.


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