The No-Reflow Paradox: Unblocking the Vessel, Not the Damage?

 Well shit, you're describing Capillaries that don't open due to pericytes;

 known since September 2011. The whole stroke medical world IS COMPLETELY FUCKING INCOMPENT FOR NOT SOLVING THAT PROBLEM!

The No-Reflow Paradox: Unblocking the Vessel, Not the Damage?

• Shravan Sivakumar , MD , @sshravanMD

Rivet S, Churilov L, Yassi N, Kleinig TJ, Thijs V, Wu T, Dewey H, Desmond PM, Parsons MW, Donnan GA, et al. Persistent Tissue-Level Hypoperfusion (No-Reflow) Negates the Clinical Benefit of Successful Thrombectomy. Stroke. 2025.

In real-world clinical practice, a substantial number of ischemic stroke patients fail to achieve functional independence, even after technically successful thrombectomy with excellent angiographic reperfusion scores (TICI 2C-3). This discordance has been described as futile recanalization and may be attributable to a phenomenon referred to as “no-reflow.” This has been conceptualized as the failure of downstream microvascular reperfusion at the tissue level despite successful macrovascular recanalization. Several mechanisms including microvascular obstruction by microthrombi, edema-related microvascular compression, and pericyte-induced capillary contraction may be at play.¹ Its clinical relevance is magnified in the context of recent trials expanding thrombectomy to patients with large core infarcts and perfusion mismatch — groups where optimizing tissue-level perfusion may be especially crucial. Prior research supports use of CTP imaging as a better predictor of outcomes following successful recanalization than CT angiogram alone and was even utilized as an indicator of therapeutic success in recent thrombolytic trials.

The authors Rivet et al. aimed to investigate the clinical impact of this no-reflow mechanism on functional outcomes by comparing patient characteristics between patients with “no-reflow” mechanism on perfusion imaging and varying degrees of angiographic recanalization (TICI scores). They conducted a post hoc analysis on the data from three clinical trials: EXTEND-IA (Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection) and EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Thrombectomy for Ischemic Stroke) part 1 and 2 trials. Both qualitative and quantitative evidence of tissue perfusion evaluation for “no-reflow” were evaluated in a two-step process through application of commercially available fully automated software (RAPID; iSchemaView, Menlo Park, CA) on post-thrombectomy follow-up 24-hour perfusion imaging (CTP or MR Perfusion). The authors identified 2 distinct regions of interest (ROI) which were superimposed into perfusion maps and excluded signals associated with hemorrhagic transformation of infarct. No-reflow was defined when both qualitative and quantitative criteria were met — that is, visually demonstrable reduced intralesional rCBV or rCBF and >15% interside reduction in median rCBV or rCBF value² (Figure 1). It is worth noting that since the primary studies were not primarily designed to evaluate for this phenomenon, not all patients had both MRP and CTP.

Figure 1. Imaging analysis method.

They compared both clinical and radiological characteristics of patients with combinations of no-reflow or completeFlow with different levels of angiographic success (full-TICI 2c3, partial-2b, unsuccessful-0-2a). No significant difference in the rate of no-reflow detection according to imaging modality (CT perfusion 13.6% [n=9/66] versus MRP 25.0% [n=21/84]; P=0.10) was observed. No-reflow mechanism occurred more frequently in successful angiographic recanalization (TICI 3) (n=17/30, 56.7%). Among patient characteristics across varying degrees of technical success, it is worth noting a statistically significant difference among time of onset and proportion of patients receiving thrombolytic (alteplase or tenecteplase).

The primary outcome of functional independence (mRS score of 0–2) was achieved in 43.33% (n=13/30) of patients with eTICI 2c3–NoReflow, versus 67.50% (n=81/120) of patients with eTICI 2c3–CompleteFlow, 63.03% (n=150/238) of patients with eTICI 2b and 50.00% (n=34/68) of patients with unsuccessful thrombectomy. In unadjusted analysis, patients with no-reflow  were less likely to experience functional independence despite technical success, TICI 2c-3 compared to completeFlow (odds ratio [OR], 0.37 [95% CI, 0.16–0.83]; P=0.02) or those with eTICI 2b (OR, 0.45 [95% CI, 0.21–0.97]; P=0.04) but had similar rate to patients with unsuccessful thrombectomy (OR, 0.76 [95% CI, 0.32–1.82]; P=0.54). When adjusted for age, premorbid mRS, baseline NIHSS, and baseline core volume, multivariable analysis confirmed lower odds of functional independence with no-reflow and full/partial recanalization, and similar odds of functional independence with unsuccessful thrombectomy. Furthermore, exploratory analysis of functional infarct volumes (FIV) showed that despite similar volumes, patients with no-reflow had worse outcomes despite full recanalization compared to partial recanalization.

These findings suggest that “no-reflow” phenomenon negates benefit of macrovascular recanalization in achieving favorable clinical outcome. The authors further caution that no-reflow mechanism tends to occur more frequently with prolonged periods of ischemic injury, suggesting that this prevalence could be underestimated by this study given the inclusion of patients within the 4.5-hour time window. Their major strength includes use of prospectively collected data from clinical trials. As we push the boundaries of thrombectomy eligibility, tackling the no-reflow phenomenon may be the next frontier in improving patient-centered outcomes — representing a crucial step not only in restoring macrovascular blood flow but also in minimizing downstream ischemic injury, thereby broadening the therapeutic benefit for patients with acute ischemic stroke.