Targeting the Right Patients for the Right Treatment

Updated:Jun 4,2014

Targeting the Right Patients for the Right Treatment: The Critical Role of Neurovascular Imaging to Advance Acute Stroke Treatment in the Next Decade

Disclosure: Dr. Demchuk has a modest research grant from Novo Nordisk Canada.
Pub Date: Thursday, September 24, 2009
Author: Andrew Demchuk, MD, FRCPC

Citation

Latchaw RE, Alberts MJ, Lev MH, et al. on behalf of the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, and the Interdisciplinary Council on Peripheral Vascular Disease. Recommendations for imaging of acute ischemic stroke: a scientific statement from the American Heart Association. Stroke 2009. Published online before print, September 24, 2009. 10.1161/STROKEAHA.108.192616.


Article Text

Acute ischemic stroke treatment advances have been limited due to a paucity of positive pivotal Phase 3 efficacy trials.[1] During this time, however, there has been an explosion of technologic advances in the field of neurovascular imaging that has generated much enthusiasm.

Latchaw and colleagues provide a very comprehensive assessment of these various neurovascular imaging tools in acute stroke diagnosis, investigation, and treatment.[2] They thoroughly evaluate each imaging modality and modality-specific techniques for accuracy in correctly identifying the four critical elements in acute stroke: (a) the presence of hemorrhage; (b) presence of an intravascular thrombus that can be treated with thrombolysis or thrombectomy; (c) presence and size of a core of irreversibly infarcted tissue; and (d) presence of hypoperfused tissue at risk for subsequent infarction unless adequate perfusion is restored.

Computed tomography (CT) and magnetic resonance imaging (MRI) represent the two most widely available/applicable neurovascular imaging modalities. Both provide accurate "snapshots in time" regarding the four critical elements. MRI would generally be considered the more ideal modality compared with CT but remains less commonly used because of additional preparatory time requirements, contraindications, and more limited 24-hour availability than CT.

The choice between the two imaging approaches is not a simple one. CT is much faster to perform and possible in all patients, with CT-angio providing excellent visualization of the entire arterial tree. MRI can better identify small ischemic or chronic hemorrhage lesions and provides whole brain perfusion imaging. Transcranial Doppler (TCD) shouldn't be compared to either MRI or CT as a snapshot tool. TCD has the inherent advantage of being a "dynamic" tool capable of continuous or repeated studies at bedside that is ideal for real-time thrombolysis monitoring, 1-hour emboli detection, daily vasospasm monitoring, and yearly sickle cell vasculopathy screening. Transcranial ultrasound may also have a therapeutic effect on recanalization when combined with intravenous tissue plasminogen activator (IV tPA) [3], which requires confirmation in a large multicenter study. Single photon emission computed tomography and xenon-CT modalities are in very limited use with little evidence of a resurgence expected.

It is very clear that future advances in acute stroke treatment will require these exciting neurovascular imaging tools. The simplicity of the NINDS and ECASS thrombolysis trial design using only noncontrast CT (NCCT) was possible because of robust treatment effect of IV tPA in achieving early recanalization.[4,5] The next generation of stroke treatments are unlikely to be so robust. Therefore, to combat the extreme heterogeneity of stroke, either megatrials involving thousands of patients must be performed or highly selected imaging-based approaches adopted. Multimodal MRI or NCCT/CT bolus-based evaluation both hold great potential in imaging-based selection trials. Clinical trials so far have been generally encouraging. Multimodal MRI uses a perfusion imaging/diffusion-weighted imaging (PI/DWI) volume mismatch to define the target population with salvageable penumbra. This PI/DWI volume mismatch is the differential volume where PI indicates the hypoperfused tissue and DWI shows the ischemic core.[6] A mismatch volume of 20% (PI greater than DWI) has been widely accepted as an indicator of penumbra. A major barrier to this PI/DWI mismatch-based selection strategy has been slow recruitment, with an average one subject per center per year recruitment rate in the three MR-based randomized clinical trials of systemic thrombolysis.[7-9] CT-angiography (CTA) or CT-perfusion (CTP)-focused randomized trials have not been performed to date to compare recruitment rates. The DIAS-2 trial is the only trial to date to involve both multimodal MRI and CT perfusion for patient selection. Recently published, DIAS-2 trial used an "eyeballing" approach of 20% MRI PI/DWI volume mismatch or a 20% CTP PI/cerebral blood volume (CBV) mismatch for patient selection at the discretion of the individual centers. Results of this trial were largely disappointing due to a number of possible factors.[10] Concerns were also raised regarding whether multimodal MRI and CT perfusion results were interchangeable because of significant differences in core lesion volume, mismatch lesion volume, and core lesion growth seen by modality.[11] The profound differences may be explained in part by constraints associated with CT brain coverage using CTP. Further standardization and refinements of perfusion measurements and penumbral definition are needed.[10] A mismatch volume of only 20% (PI greater than DWI) may not be the correct definition for clinically relevant salvageable penumbra.[12-14]

An alternative for image-based selection trials not addressed in the American Heart Association statement is simply applying a NCCT/CTA: "good CT"-occlusion paradigm. This unsophisticated approach uses NCCT visualization of early ischemic changes (EIC) known as hypoattenuation for predicting extent of infarct core in the region supplied by the occluded artery. Brain tissue appearing normal on NCCT in this region gives an estimate of penumbra and benign oligaemia.[15] DWI is more sensitive to ischemia detection compared to NCCT [16] due to better discrimination of small volume infarcts; however, when a systematic approach is used in disabling stroke, NCCT is similar to DWI for measuring extent.[17] We use the Alberta Stroke Programme Early CT Scoring (ASPECTS) scoring system to evaluate the extent of EIC within the middle cerebral artery (MCA) territory.[18] Baseline ASPECTS scores correlate closely with final infarct volumes.[19] When the extent of EIC is modest (high ASPECTS score) and a proximal MCA occlusion is present, there is a small ischemic core relative to a large surrounding oligaemic region with a potentially large "penumbra" that is ideal for recanalization treatment. The main disadvantages to our simplified paradigm is the difficulty visualizing early ischemic changes due to image quality issues with spiral CT acquisition [20,21] and inexperience resulting in variable accuracy.[22,23] There are also difficulties in applying this paradigm to occlusions distal to the M1 MCA. CTA source images provide an alternative to NCCT for ischemic core detection that could also be used in clinical trial design by providing a qualitative CBV map of ASPECTS regions.[24] Supporting the "good CT"-occlusion approach is the reevaluation of baseline NCCT scans in the PROACT-2 clinical trial. Patients with a proximal MCA occlusion (M1 or M2) and a baseline NCCT ASPECTS greater than 7, had a three times greater likelihood of a good outcome after intra-arterial treatment with a number needed to treat of 3 to 5.[25] This was further confirmed post hoc in the IMS-1 trial, where high ASPECTS identified the group most likely to benefit from combining IV tPA with neurointerventional treatment.[26] A variation of this simplified NCCT/CTA paradigm is being adopted for patient selection in two new randomized clinical trials (DIAS-3 and DIAS-4) based on compelling data from DIAS-2 that the treatment effect was most robust in patients with a target occlusion. Only patients with visible intracranial arterial occlusion or high-grade stenosis by CT-angio or MRA and absence of extensive early infarction in the affected area (NCCT or MRI) will be enrolled in both trials.[27,28]

The most pressing treatment approach requiring pivotal efficacy data is the early neurointerventional treatment of ischemic stroke. There are now two approved devices in the United States gaining market acceptance without randomized trials. The approved MERCI Retriever clot extraction device [29,30] and PENUMBRA clot aspiration catheters [31] both have very high arterial recanalization rates although this has not translated to good clinical outcomes in many cases, likely due to patient selection issues.[32] Future randomized trials using these improved recanalization techniques with optimized imaging-based patient selection are sure to be successful.

With this scientific statement, the authors have presented the state of the evidence for the role of neurovascular imaging in the diagnosis, investigation, and treatment of acute ischemic stroke. The advances in imaging are compelling. The true "acid test," however, will be demonstrating value from these imaging tools in targeting the right patients for the right treatments in image-based clinical trials. Although promising data exist, much clinical trial work remains before broad implementation of these exciting tools can be justified.

References

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-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --
 

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