Acute Ischemic Stroke
2014; Lippincott Williams & Wilkins; Volume: 45; Issue: 2 Linguagem: Inglês
10.1161/strokeaha.113.003798
ISSN1524-4628
AutoresNathan Manning, Bruce Campbell, Thomas J. Oxley, René Chapot,
Tópico(s)Traumatic Brain Injury and Neurovascular Disturbances
ResumoHomeStrokeVol. 45, No. 2Acute Ischemic Stroke Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBAcute Ischemic StrokeTime, Penumbra, and Reperfusion Nathan W. Manning, MBBS, FRANZCR, Bruce C.V. Campbell, MBBS, BMedSc, PhD, FRACP, Thomas J. Oxley, MBBS, BMedSc and René Chapot, MD Nathan W. ManningNathan W. Manning From the Florey Institute of Neuroscience and Mental Health (N.W.M., B.C.V.C., T.J.O.) and Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (B.C.V.C., T.J.O.), University of Melbourne, Parkville, Australia; and Department of Intracranial Endovascular Therapy, Alfried-Krupp Krankenhaus Hospital, Essen, Germany (R.C.). , Bruce C.V. CampbellBruce C.V. Campbell From the Florey Institute of Neuroscience and Mental Health (N.W.M., B.C.V.C., T.J.O.) and Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (B.C.V.C., T.J.O.), University of Melbourne, Parkville, Australia; and Department of Intracranial Endovascular Therapy, Alfried-Krupp Krankenhaus Hospital, Essen, Germany (R.C.). , Thomas J. OxleyThomas J. Oxley From the Florey Institute of Neuroscience and Mental Health (N.W.M., B.C.V.C., T.J.O.) and Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (B.C.V.C., T.J.O.), University of Melbourne, Parkville, Australia; and Department of Intracranial Endovascular Therapy, Alfried-Krupp Krankenhaus Hospital, Essen, Germany (R.C.). and René ChapotRené Chapot From the Florey Institute of Neuroscience and Mental Health (N.W.M., B.C.V.C., T.J.O.) and Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (B.C.V.C., T.J.O.), University of Melbourne, Parkville, Australia; and Department of Intracranial Endovascular Therapy, Alfried-Krupp Krankenhaus Hospital, Essen, Germany (R.C.). Originally published7 Jan 2014https://doi.org/10.1161/STROKEAHA.113.003798Stroke. 2014;45:640–644Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 IntroductionCurrent guidelines advocate intravenous thrombolysis for patients with ischemic stroke 6 hours) showed no significant difference in favorable clinical response to reperfusion.8 This suggests that patients who are able to maintain a penumbra longer, presumably relating to good collateral vessels, represent a subpopulation who will benefit the most from reperfusion. A similar finding has also been demonstrated in functional outcomes using CT perfusion–based selection.16 The significance of this time-insensitive patient selection with respect to improving access to therapy for patients presenting beyond the current time limits or with unclear symptom onset cannot be overstated.Recently, the first randomized controlled trial using penumbral imaging before IA therapy has been published, MR-RESCUE (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy).17 Both MRI and CT perfusion were used to screen patients again with automated postprocessing software, RescueOnSite. Disappointingly, MR-RESCUE failed to demonstrate a favorable response to endovascular therapy based on penumbral patterns.17Significant differences in imaging protocols between DEFUSE-2 and MR-RESCUE may explain the contrasting outcomes. Patients in DEFUSE-2 had a median time from imaging to femoral puncture of 42 minutes. A median time from imaging to completion of intervention and therefore reperfusion of 90 minutes was reported. Reperfusion assessment was performed acutely, with median time from baseline MRI to follow-up MRI being 222 minutes.18 In contrast, MR-RESCUE reported a mean time from imaging to femoral puncture of 120 minutes. Unfortunately, no indication of procedure times has been given. The long time delay likely relates, in part, to randomization in MR-RESCUE. However, stroke is a dynamic condition, and penumbral status could have changed significantly during that time delay. Furthermore, reperfusion was not assessed until day 7, by which time spontaneous reperfusion is common but may have occurred too late to save brain.The mismatch criteria used by the RAPID software in DEFUSE-2 were optimized based on DEFUSE6 and EPITHET7 data. In this work, determinants of the ischemic core and penumbra were based on longitudinal MRI studies in the presence or absence of reperfusion. Critically, reperfusion was assessed by perfusion imaging at a relatively early time point.19 Although the analysis was rigorous, the determinants were relatively simple. Ischemic core was defined using MR diffusion (apparent diffusion coefficient 6-second threshold based on analysis of the best baseline perfusion lesion threshold to predict follow-up infarction in patients who did not reperfuse.8 These seemed to be robust on analysis of the DEFUSE-2 data set.18 MR-RESCUE used a remarkably complex multiparametric algorithm to estimate ischemic core that even included baseline National Institutes of Health Stroke Scale (NIHSS) in the case of CT perfusion.20 Maximum core volume for penumbral pattern was 90 mL in contrast to 70 mL in DEFUSE-2, and the penumbra in MR-RESCUE was estimated using Tmax >4 seconds (which generates significantly larger volumes than Tmax >6 seconds). These 2 factors would increase the likelihood of patients being classified as having mismatch in MR-RESCUE versus DEFUSE-2.The primary analysis of DEFUSE-2 was reperfusion versus no reperfusion, whereas in MR-RESCUE it was embolectomy versus standard care. This meant that, although similar endovascular techniques were used in both trials, the low thrombolysis in cerebral infarction (TICI) 2b/3 successful revascularization rate of 27% in MR-RESCUE made it difficult to show benefit of treatment. MR-RESCUE did show trends toward improved functional outcomes in patients who achieved revascularization in both penumbral and nonpenumbral groups, but numbers were too small for detailed statistical comparison. Only 13.6% of patients achieved good functional outcomes (mRS, 0–2) in the absence of revascularization at day 7, all of which were from the penumbral group. In patients achieving revascularization, 28.4% also achieved good functional outcomes. The relatively small difference in good outcome between those with a penumbral pattern versus those without (34% versus 21%)17 suggests that the algorithm used in this trial had only modest success in identifying treatment responders.In both DEFUSE-2 and MR-RESCUE, lack of investigator equipoise seems to be an issue. In DEFUSE-2, an average of 5.1 patients per site per year were enrolled versus 0.8 patients per site per year in MR-RESCUE. In contradistinction to DEFUSE-2, MR-RESCUE had larger initial ischemic core volumes despite a narrower time window (≤8 versus ≤12 hours). The low rate of enrollment and the larger ischemic cores imply that investigators, possibly because of personal convictions about the efficacy of IA therapy, did not randomize patients with smaller cores. Whereas the converse may be true for DEFUSE-2, investigators may have deemed reperfusion futile in patients with larger cores and not enrolled them. In fact, MR-RESCUE penumbral patients had similar cores to nontarget DEFUSE-2 patients (36 versus 45 mL). This likely explains the similarities in the functional outcomes in these 2 apparently contradictory groups (mRS, 0–2; ≈19% in both).6,17The significance of baseline ischemic core volume has only recently been refined.21–23 Current generation trials give this issue considerably greater emphasis (SWIFT-PRIME [ClinicalTrials.gov NCT01657461] <50mL and EXTEND-IA24 [NCT01492725] <70 mL). The results of MR-RESCUE and DEFUSE-2, which at first seem to be contradictory, highlight the significance of ischemic core volume and its importance in patient selection. Furthermore, they highlight the importance of appropriate penumbral selection, particularly in patients treated later. Current trials are in a position to benefit from this experience, and this is reflected in their design.Endovascular Reperfusion TherapyRapid and complete reperfusion is the goal of AIS intervention.25–27 Although the rates of reperfusion achieved with IV-tPA are modest in major vessel occlusion,6,7 particularly compared with more aggressive modern techniques,28,29 it remains the only treatment with proven clinical benefit. The results of Prolyse in Acute Cerebral Thromboembolism Trial II (PROACT II)30 propelled intra-arterial thrombolysis forward and may be responsible for the developments in endovascular intervention today. PROACT II reported marked benefit compared with heparin control with a 15% treatment effect, surpassing even the National Institutes of Neurological Disorders and Stroke (NINDS) trial.31 At the time, it was felt that IA-tPA would lead to significantly improved reperfusion and thus better outcomes. Recently, 2 large multicenter randomized controlled trials have reported results comparing intravenous with IA thrombolysis. Both failed to demonstrate an advantage of an IA approach. These trials highlight the importance of patient selection, the need for speed, and the shortcomings of thrombolysis-based reperfusion.The Italian SYNTHESIS trial32 compared endovascular therapy (the majority of patients receiving IA-tPA) with IV-tPA. It failed to show an advantage of IA compared with IV-tPA (odds ratio, 0.71; 95% confidence interval, 0.44–1.14).32 There was considerable delay in IA treatment (225 versus 165 minutes; P<0.001) and concerns about the intention-to-treat analysis and patient crossover. More significantly, the trial design underestimated the relevance of imaging-based patient selection. Patients were randomized based only on noncontrast CT brain to exclude hemorrhage. Noninvasive angiography was not performed to determine the presence of a vascular occlusion, and the absence of an occlusion on digital subtraction angiography was not a contraindication to IA-tPA. Furthermore, no attempt was made to exclude patients unlikely to have a target lesion clinically. Consequently, patients randomized to endovascular therapy had NIHSS of only 13 (median) with mild strokes (NIHSS as low as 2) included. In PROACT II, there was no significant difference between IA thrombolysis and heparin-treated controls in patients with NIHSS 7 with a defined vessel occlusion).34 Obviously, the critical factor is time to reperfusion rather than time to starting intervention. No direct indication of procedural times is available for IMS III; however, relatively lengthy procedures can be inferred given the use of IA-tPA in 80% of patients. The IMS III protocol allowed for IA-tPA infusions ≤120 minutes, and in DEFUSE-2, the median IA-tPA procedure time was 90 minutes.8 In comparison, in the largest series published on the current-generation stentriever devices, procedure times are reported at 40 minutes (median).28 Furthermore, an endovascular bypass is often achieved, at least temporarily, at the time of first deployment, which was reported at only 26 minutes (median).28IMS III illustrates the absolute importance of quality reperfusion, building on reperfusion data from the previous IMS trials.37 Partial or complete reperfusion (TICI, 2–3) was achieved in 65% of internal carotid artery, 81% of M1, and 70% of M2 occlusions. On the surface, this would seem to compare with success rates using stentrievers.28,38 However, these figures include patients who achieved reperfusion of less than half the affected vascular territory (TICI 2a). If TICI 2a patients are excluded, the IMS III rates of TICI 2b-3 reperfusion are 38% for internal carotid artery, 44% for M1, and 44% for M2 occlusions.34 This effectively halves the quoted reperfusion rate and is in stark contrast to stentrievers that achieve TICI 2b-3 in >75% of patients in less than half the time.28,38The prognostic relevance of quantifying the degree of reperfusion was investigated in DEFUSE-2. In patients with favorable penumbral imaging, the degree of reperfusion, assessed on early follow-up MRI, was divided into quartiles. A strong relationship between favorable clinical response and the degree of reperfusion was seen with rates increasing across each successive quartile: Q1 29%, Q2 44%, Q3 65%, and Q4 94%.8 Similar results were seen on analysis of IMS III reperfusion data.34 The degree of reperfusion (TICI) achieved directly correlated with good functional outcomes at 90 days (Figure). It seems that too few patients achieved quality reperfusion fast enough to save brain. In line with this interpretation, several recent studies have demonstrated that clinical outcomes after TICI 2a align closely with TICI 0 to 1 and that good outcomes usually require TICI 2b or preferably TICI 3.39,40 Subsequently, a recent position statement has recommended that procedures be performed with a view to a minimum reperfusion of TICI 2b.41 The hope for the future is that modern devices may more than double the rate of quality reperfusion in less than half the time.Download figureDownload PowerPointFigure. Rates of good functional outcome (modified Rankin scale [mRS], 0–2) at day 90 stratified by thrombolysis in cerebral infarction (TICI) reperfusion grade. Data derived from IMS-III.Currently, stentrievers are the most appropriate first-line endovascular intervention supported by the literature, with technical results that seem superior to most other techniques and devices.42–45 Recently, stentrievers have been demonstrated to improve functional outcomes compared with either IA-tPA or Merci Retriever.46 This suggests a direct translation from technical success to clinical success. The recent Solitaire Flow Restoration Thrombectomy for Acute Revascularization registry has demonstrated compelling technical success rates.29 Quality reperfusion was achieved, with 79.2% achieving TICI 2b-3 as adjudicated by the core laboratory. Significantly, the majority of these patients achieved TICI 3 reperfusion (54.7%). These results were achieved with a maximum of 3 Solitaire passes and a mean procedure time of 32 minutes from puncture to reperfusion. The importance of shaving off minutes once a patient reaches the site of care has already been well demonstrated for thrombolysis.47,48 Although there was no control group, the 58% rate of mRS 0 to 2, 7% mortality, and 1.5% symptomatic hemorrhage rate are impressive. It compares favorably with a recent study of IV-tPA in a similarly severe stroke population (median NIHSS=17) in which the rate of mRS 0 to 2 was 35%.14 Certainly, this is encouraging for current randomized trials involving stentrievers that use more sophisticated imaging selection strategies.ConclusionsRapid reperfusion of the penumbra should be at the core of all AIS interventions. The highly individualized nature of the pathophysiology in AIS patients and the variability in achieving quality reperfusion among the various noninvasive and invasive interventions are becoming apparent. Technical advances in clot retrieval offer exciting prospects when combined with thoughtful patient selection and highly organized systems of care to expedite therapy. The current generation of randomized trials appear to acknowledge this complexity and will hopefully demonstrate clear advantages to aggressive strategies able to achieve timely, high-quality reperfusion to the ischemic penumbra.DisclosuresDr Campbell, Co-PI EXTEND-IA, received speakers' honoraria from Boehringer Ingelheim and is a consultant for Lundbeck; Dr Chapot is a consultant for Covidien, Microvention, and Balt. The other authors report no conflicts.FootnotesCorrespondence to Nathan Manning, MBBS, FRANZCR, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Grattan St, Parkville, Victoria 3010, Australia. E-mail [email protected]References1. Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJB, Demaerschalk BM, et al. 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