Last updated on July 2019

DWI and CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention (DAWN)

Brief description of study

DWI and CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention (DAWN)

Detailed Study Description

Stroke represents the fourth leading cause of death in industrialized nations, after heart disease, cancer, and chronic lower respiratory disease. Each year approximately 795,000 people experience a new or recurrent stroke (ischemic or hemorrhagic) in the U.S. Also, in 2009, stroke caused approximately 1 of every 18 deaths in the United States. On average, every 40 seconds, someone in the United States has a stroke and dies of one approximately every four (4) minutes.

Proximal intracranial arterial occlusions are common, cause the most disabling types of ischemic strokes, and are predictive of poor neurological outcomes at hospital discharge. [3] Stroke survivors constitute the majority of disabled people nationally in the United States. Approximately one-quarter of the patients suffering a stroke die within one year after the initial event. Stroke brings a dramatic financial and personal burden to society. Direct medical costs related to stroke in the United States is an estimated $28.3 billion per year. Stroke is a leading cause of serious long-term disability. [4]

Intravenous (IV) tPA (alteplase) remains the only approved therapy for acute ischemic stroke (AIS). However, IV tPA has many limitations, including a short therapeutic window, with administration being restricted in the United States to 3 hours post known symptom onset, and in other parts of the world to 4.5 hours post known symptom onset, and a strong time-dependency. [5-8] The efficacy of IV tPA is limited by the large thrombus burden that occurs in the setting of acute ischemic strokes caused by proximal intra-cranial arterial occlusions. [9] [10]

In the 0-8 hours post symptom onset, endovascular revascularization by mechanical embolectomy has been shown to be safe and effective in numerous studies, including the MERCI and Multi MERCI trials [11-12], the Penumbra Pivotal trial [13], and the SWIFT and TREVO 2 trials [14-15]. Clinical outcomes in ischemic stroke have been shown to be strongly linked to revascularization. [16-18] Thus, in cases where patients are ineligible for IV tPA or where IV tPA fails to result in a clinical improvement, endovascular treatment with mechanical thrombectomy devices is a viable treatment option. Mechanical endovascular therapy has been linked to higher recanalization rates as compared to IV tPA, and is considered standard of care in many institutions within the 0-8 hour time window. [19-21]

Acute ischemic stroke due to large vessel occlusion (LVO) is a potentially devastating event, with a poor prognosis in the absence of timely revascularization. The sub-population of interest in this study is subjects with intracranial ICA or MCA-M1 vessel occlusions. Evidence from prior and ongoing studies suggests that patients with a blockage in these vessels, when managed medically, do worse compared to those who are treated with pharmacologic or mechanical reperfusion therapies.

In a single center study conducted in Badalona, Spain of consecutively screened patients within 6-24 hours of symptom onset or time they were last seen well, the subset of medically managed patients with confirmed intracranial ICA or MCA-M1 occlusions, 17.5% of patients experienced a good clinical outcome, defined as a modified Rankin Score (mRS) of 0, 1 or 2. [22]

In the multi-center STOPSTROKE study, good outcomes in a clearly defined subset of medically managed patients with CTA confirmed intracranial ICA or MCA-M1 occlusion was 18.4%. Although treated patients in this study presumably had more favorable imaging at baseline and therefore their natural history may be more favorable than untreated patients, the evidence is suggestive of worse outcomes in untreated patients. [23]

The ongoing Penumbra FIRST study includes subjects presenting within 0-8 hours from symptom onset with documented ICA or M1 occlusions who would normally be candidates for endovascular thrombectomy, but for whom the procedure is unavailable. The interim outcomes data for the first 63 subjects enrolled demonstrate a good outcome rate of 20.4%. [24]

The seminal PROACT II trial control arm, which included subjects with MCA-M1 and M2 occlusions, is often referenced as a comparator for results of treatment with pharmacological or mechanical revascularization therapies. In PROACT II, the control arm subjects were treated with intra-arterial heparin within 0-6 hours of symptom onset. This group of subjects experienced good clinical outcomes in 25% of the cases. [25-26] However, in the more proximal MCA-M1 occlusion subset of the control arm (n=37) good outcomes were only 22%. [27]

Together, these data support an overall grim prognosis for medically managed intracranial ICA or MCA-M1 occlusions, with low rates of good outcomes ranging from 17.5-25%.

In contrast to patients who are medically managed, those with similar clinical presentation who are revascularized experience higher rates of good clinical outcomes. In the SWIFT and TREVO 2 trials, Stentrievers™ were used to restore blood flow to the neurovasculature in subjects with intracranial large vessel occlusions. Subjects treated within 0-8 hours of symptom onset experienced good clinical outcomes in 37% and 40% of cases respectively. [14-15] In a retrospective analysis of stroke patients, who were selected by CT Perfusion or MRI for endovascular treatment, regardless of time from symptom onset or time last seen well, Nogueira et al reported good outcomes of 40% within the subset of patients with confirmed intracranial ICA or MCA-M1 occlusions. [28]

The current guidelines for treatment, including the use of thrombolysis and/or thrombectomy are based on time last seen well (TLSW). [29] Yet, the majority of patients presenting with AIS symptoms are beyond 8 hours from symptom onset or of unknown onset. [30] It is estimated that in between 14-28% of AIS patients, the onset of stroke symptoms is un-witnessed or occurs during sleep. [31-36] It has also been demonstrated that as many as 71.4% of the patients with proximal intra-cranial arterial occlusion may have a significant MRI (DWI/PWI) mismatch as far as 9 to 24 hours post stroke onset. [37]

There is limited data in the literature on the relative risks versus benefits of performing mechanical thrombectomy in patients within 6-24 hours from symptom onset or time last seen well. The current AHA/ASA guidelines recommend standard medical management only (supportive care) for these patients. [29] The AIS stroke population is heterogeneous by nature and though some patients may do better than others, in general the more proximal the occlusion and the later the patient arrives, the worse the anticipated outcome.

Clinical Study Identifier: TX143977

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Recruitment Status: Open

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