Refinement of the Magnetic Resonance Diffusion-Perfusion Mismatch Concept for Thrombolytic Patient Selection

Abstract

Background and Purpose-The DIAS-2 study was the only large, randomized, intravenous, thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore, a reevaluation of the penumbra selection strategy is warranted. Methods-In post hoc analyses we assessed the relationships of magnetic resonance imaging-measured lesion volumes with clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch with the clinical effect of desmoteplase in DIAS-2 and in pooled data from DIAS, DEDAS, and DIAS-2. Results-In DIAS-2, lesion volumes correlated with National Institutes of Health Stroke Scale (NIHSS) at both baseline and final time points (PϽ0.0001), and lesion growth was inversely related to good clinical outcome (Pϭ0.004). In the pooled analysis, desmoteplase was associated with 47% clinical response rate (nϭ143) vs 34% in placebo (nϭ73; Pϭ0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size. The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% confidence interval, 1.16 -6.94; Pϭ0.023) for MMV Ͼ60 mL. Increasing the minimum NIHSS score for inclusion did not affect treatment effect size. Key Words: acute cerebral infarction Ⅲ desmoteplase Ⅲ diffusion-weighted imaging Ⅲ magnetic resonance imaging Ⅲ mismatch Ⅲ perfusion Ⅲ stroke Ⅲ thrombolysis R eperfusion of the ischemic penumbra (ie, at-risk but salvageable ischemic brain) is the goal of thrombolytic stroke therapy. Up to 4.5 hours from symptom onset, thrombolytic treatment efficacy is demonstrable in patients with clinical ischemic stroke syndrome. 1,2 Imaging confirmation of the ischemic penumbra has not been required in this treatment period because virtually all patients are assumed to have salvageable tissue in the early period after symptom onset. However, spontaneous recanalization and reperfusion as well as progression of penumbral tissue to infarction occur at variable rates and cannot be predicted by clinical features. After 4.5 hours, many patients may no longer have the target ischemic penumbra that would justify thrombolysis, and their inclusion into clinical trials would confound the detection of therapeutic benefit. A rational approach to expanding the indication for thrombolytic stroke therapy would be selection of only those patients who have evidence of ischemic penumbra. Magnetic resonance imaging (MRI) diffusion-weighted imaging and perfusion-weighted (PWI-DWI) mismatch permits a clinical trial strategy to select patients with ischemic penumbra and to monitor drug effects on the probability of reperfusion and infarct expansion. [3][4][5] On MRI, the ischemic penumbra is approximated by a region of mismatch between a larger perfusion defect relative to a smaller region of acute ischemic DWI change, an...

Perfusion-Based Selection for Endovascular Reperfusion Therapy in Anterior Circulation Acute Ischemic Stroke

“…[24][25][26] However, post hoc analyses suggested that a minimal mismatch volume of 60 mL would have led to a benefit in favor of desmoteplase. 27 Other intravenous thrombolytic phase 2 trials confirmed potential benefit in delayed treatment by using MR diffusion-perfusion imaging-based patient selection. 28,29 In the DEFUSE-2 trial, endovascular reperfusion was associated with a 5-fold increase in favorable clinical outcomes among patients with target mismatch (defined as ratio of Ͼ1.8), while no benefit was seen among patients without target mismatch.…”

Relationships Between Imaging Assessments and Outcomes in Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke

“…Some prior data sets, including a post hoc analysis of the Desmoteplase in Acute Ischemic Stroke (DIAS) studies, demonstrated a treatment effect with an intravenous thrombolytic that was only present in patients with larger mismatch volumes. 19 Further studies of the benefit of endovascular therapy in patients with small mismatch volumes are warranted.The increased rate of PH in patients with the malignant profile confirms the findings of previous studies. 4,5 The trend toward fewer PH1 or PH2 hemorrhages in patients who did not have successful reperfusion is compatible with the established association between PH and large volume infarctions.…”

MR Imaging for Acute Stroke

“…However, the several multicentric studies which had been conceptualized around the mismatch hypothesis and its benefit for selecting patients for thrombolysis (DEFUSE, DIAS, DIAS II) also pointed to the many pitfalls of perfusion imaging, the first one being the very definition of mismatch. The initially popular idea that a sufficient mismatch was a difference of 20 % or more between PI and DWI soon proved too lenient [19] and likely played a pivotal role in ensuring the negative outcome of the DIAS II trial (published in 2009). Additionally, unlike DWI, perfusion imaging is not straightforward as the depiction (and subsequent potential volumetric assessment) of hypoperfusion is based on an array of different parameter maps and underlying calculation methods.…”

“…However, the rather small number of patients with no target mismatches in their study greatly limited any ability to characterize the response to reperfusion in nonmismatch individuals. As a conclusion, the mismatch concept appears to function and provide useful information, but only under certain conditions, one of them being a large enough absolute mismatch volume, of somewhere between 15 and 60 ml, providing a sufficient amount of tissue to be saved in order for the results of successful reperfusion to be demonstrated [19]. Another would be a strict enough definition of hypoperfusion, serving to prevent areas of benign oligemia from being misinterpreted as tissue at risk of infarction [21,22].…”