Delayed recanalization in acute ischemic stroke patients: Late is better than never?

Abstract

Successful recanalization of the occluded vessel as early as possible has been widely accepted as the key principle of acute ischemic stroke (AIS) treatment. Unfortunately, for many years, the vast majority of AIS patients were prevented from receiving effective recanalization therapy because of a narrow therapeutic window. Recently, a series of inspiring clinical trials have indicated that more patients may benefit from delayed recanalization during an expanded therapeutic window, even up to 24 h after symptom onset. However, could potentially salvageable brain tissue (penumbra) in patients who do not receive medication within 24 h still possible to be saved?

Restoration of blood flow to a level above the functional threshold in brain tissue after acute ischemic stroke (AIS), in theory, could reverse neurological deficits without severe permanent damage. For many years, intravenous thrombolysis with alteplase was regarded as the only effective drug therapy for AIS, but this treatment should be administered within a very narrow therapeutic window (3 h). Even though the ECASS 3 trial expanded the thrombolysis time window to 4.5 h, the vast majority of AIS patients were still excluded from receiving effective recanalization therapy, resulting in permanent large vessel occlusion. The outcome of AIS patients was primarily based on whether they presented within the therapeutic window, the so-called “golden hour”. To improve the outcome of AIS patients, neurologists have strived for early identification, rapid transportation and efficient diagnostic imaging techniques for AIS. Actually, these efforts have resulted in substantial improvement but not to the expected level.

Advances in imaging have recently allowed better characterization of tissue and vessel status in AIS. Perfusion-weighted imaging/diffusion-weighted imaging (PWI/DWI) mismatch and DWI/fluid attenuated inversion recovery (DWI/FLAIR) mismatch on magnetic resonance imaging (MRI) are markers of brain ischemia. MRI scanning with PWI or computed tomography (CT) perfusion (CTP) scanning tends to show different extents of hypoperfusion after AIS.Given these developments in imaging techniques and intravascular interventional devices, the concept of a therapeutic window for AIS patients has been expanded. It is clear that the central consideration of AIS therapy is the salvageable ischemic penumbra, which is poorly perfused but not yet infarcted. The penumbra is affected to a greater extent by the collateral circulation status other than the traditional time length after ischemia onset. Hence, the concept of a “tissue window” was developed to represent the salvageable brain tissue, namely the penumbra or the mismatch area between the ischemic hypoperfusion area and the infarct core on imaging findings.

This concept provided a theoretical basis for delayed recanalization in AIS patients with target imaging mismatch but who were beyond the traditional narrow time-based therapeutic window. Fortunately, an increasing number of randomized studies have demonstrated that delayed recanalization has beneficial effects on 90-day outcomes. Two high-quality, randomized controlled clinical trials (DAWN and DEFUSE 3) of endovascular mechanical thrombectomy reported that selective delayed recanalization based on imaging mismatch improved patients’ 90-day outcomes, even when performed at 16 to 24 h after symptom onset. ¹

These data provided evidence for the first time for broadening the time window for delayed recanalization in patients with AIS. Recently Ma et al. reported in the EXTEND trial that within 4.5–9 h of symptom onset, alteplase treatment resulted in a significantly higher probability of a good prognosis than that in the placebo group. ² Campbell et al. also argued that even though the rate of symptomatic intracerebral hemorrhage was higher with alteplase treatment, this increase did not negate the overall net benefit of thrombolysis in patients with salvageable brain tissue treated 4.5–9 h from symptom onset. ³ Evidence from studies of perfusion CT/MRI-based selection for the use of tenecteplase for thrombolysis even supported an extended time window of 24 h. ⁴ These studies indicate that more patients may benefit from an extended therapeutic window of up to 24 h. However, should 24 h be the final time limit for AIS patients? Can patients with reversible brain tissue damage who are admitted beyond 24 h still benefit from delayed recanalization?

Although some AIS patients are not treated within the therapeutic window, it may be possible to save those with sufficient collateral circulation. A study reanalyzed the data of the DEFUSE 3 trial and suggested that approximately 20% of patients with a middle cerebral artery (MCA) or internal carotid artery occlusion who are not treated with thrombectomy have a persistent mismatch for at least an additional 24 h. ⁵ Besides, an increasing number of studies have reported that delayed recanalization based on imaging mismatch successfully improves the outcome, even at three days or longer after symptoms onset. ⁶

More importantly, the long-term outcomes of patients who received delayed recanalization were reported to be improved as well. A one-year follow-up study of the REVASCAT trial revealed that the 12-month outcomes of patients were strongly associated with the outcomes at both 5 days and 90 days. ⁷ A two-year follow-up study of the MR CLEAN trial demonstrated that the difference in the mortality rate between the endovascular therapy group and standard therapy group continued to increase from three months to two years. ⁸ If whether patients present in the limited therapeutic window matters so much, why does recanalization have such a long-term effect on patient outcome?

Once large vessel occlusion occurs, pathophysiological changes in brain tissue will persist. McBride et al. demonstrated that delayed recanalization promoted functional recovery in rats following permanent MCA occlusion. In this study, delayed recanalization restored cerebral blood flow, led to sensorimotor recovery, improved learning and memory, and reduced infarct volume. Even restoring cerebral blood flow at 14 days after permanent MCA occlusion allowed rats to regain some sensorimotor function. ⁹ Zheng et al. also reported that delayed recanalization at three days after permanent MCA occlusion attenuated neuronal apoptosis in a rat model. ¹⁰

An important factor of these above-mentioned clinical trials is the “tissue window” evaluated by specific imaging protocols or image processing software. In theory, the therapeutic window could be extended as long as patients meet the imaging criterion. However, the relationships among neurologic outcomes, collateral circulation, imaging mismatch and patient heterogeneity are complex and dynamic in stroke patients. Patients with low perfusion volume/an infarct core rate >1.8 and a maximum infarct core ≤70 ml were included in the DEFUSE 3 trial. In the DAWN trial, the mismatch between severe clinical symptoms (NIHSS score) and small infarct volume were examined. In the EXTEND trial, the criteria for penumbra mismatch were defined as low perfusion volume/infarct core rate >1.2 and an ischemic core lesion ≤70 ml. Which criterion should be used in clinical practice? How much penumbra area or what perfusion volume/infarct core rate is suitable for delayed recanalization? Currently, the major concern regarding delayed recanalization is the hemorrhagic risk. What will occur if delayed recanalization is performed a few days into the late phase with a more stable vascular condition and lower hemorrhagic potential?

All in all, given the current developments in imaging techniques and comprehensive management for AIS, delayed recanalization without a time limit may be beneficial as long as patients meet some “tissue window” criterion. Further studies are needed before these questions are addressed. Studies involving multiparametric MRI or CT scanning-based patient selection may be useful.