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
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.
Acute ischemic stroke treatment advances have been limited due to a paucity of positive pivotal Phase 3 efficacy trials. 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. 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) , 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. 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. 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. 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. 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. DWI is more sensitive to ischemia detection compared to NCCT  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. 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. Baseline ASPECTS scores correlate closely with final infarct volumes. 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. 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. 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. 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  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. 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.
- Kidwell CS, Liebeskind DS, Starkman S, et al. Trends in acute ischemic stroke trials through the 20th century. Stroke 2001;32:1349-1359.
- 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. 2009.
- Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170-2178.
- Tissue plasminogen activator for acute ischemic stroke. The National Institute Of Neurological Disorders and Stroke Rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587.
- Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329.
- Fiebach JB, Schellinger PD. MR mismatch is useful for patient selection for thrombolysis: Yes. Stroke 2009;40:2906-2907.
- Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36:66-73.
- Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): Evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006;37:1227-1231.
- Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): A placebo-controlled randomised trial. Lancet Neurol 2008;7:299-309.
- Davis SM, Donnan GA. MR mismatch and thrombolysis: Appealing but validation required. Stroke 2009;40:2910.
- Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): A prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8:141-150.
- Butcher KS, Parsons M, MacGregor L, et al. Refining the perfusion-diffusion mismatch hypothesis. Stroke 2005;36:1153-1159.
- Miteff F, Levi CR, Bateman GA, et al. The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke. Brain 2009;132:2231-2238.
- Olivot JM, Mlynash M, Thijs VN, et al. Optimal tmax threshold for predicting penumbral tissue in acute stroke. Stroke 2009;40:469-475.
- Jovin TG, Yonas H, Gebel JM, et al. The cortical ischemic core and not the consistently present penumbra is a determinant of clinical outcome in acute middle cerebral artery occlusion. Stroke 2003;34:2426-2433.
- Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: A prospective comparison. Lancet 2007;369:293-298.
- Barber PA, Hill MD, Eliasziw M, et al. Imaging of the brain in acute ischaemic stroke: Comparison of computed tomography and magnetic resonance diffusion-weighted imaging. J Neurol Neurosurg Psychiatry 2005;76:1528-1533.
- Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Aspects study group. Alberta stroke programme early ct score. Lancet 2000;355:1670-1674.
- Demchuk AM, Coutts SB. Alberta stroke program early ct score in acute stroke triage. Neuroimaging Clin N Am 2005;15:409-419, xii.
- Heiken JP, Brink JA, Vannier MW. Spiral (helical) CT. Radiology 1993;189:647-656.
- Bahner ML, Reith W, Zuna I, et al. Spiral CT vs incremental CT: Is spiral CT superior in imaging of the brain? Eur Radiol 1998;8:416-420.
- Wardlaw JM, Mielke O. Early signs of brain infarction at CT: Observer reliability and outcome after thrombolytic treatment--systematic review. Radiology 2005;235:444-453.
- Mak HK, Yau KK, Khong PL, et al. Hypodensity of >1/3 middle cerebral artery territory versus Alberta Stroke Programme Early CT Score (ASPECTS): Comparison of two methods of quantitative evaluation of early CT changes in hyperacute ischemic stroke in the community setting. Stroke 2003;34:1194-1196.
- Coutts SB, Lev MH, Eliasziw M, et al. Aspects on CTA source images versus unenhanced CT: Added value in predicting final infarct extent and clinical outcome. Stroke 2004;35:2472-2476.
- Hill MD, Rowley HA, Adler F, et al. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using aspects. Stroke 2003;34:1925-1931.
- Hill MD, Demchuk AM, Tomsick TA, et al. Using the baseline CT scan to select acute stroke patients for IV-IA therapy. AJNR Am J Neuroradiol 2006;27:1612-1616.
- http://clinicaltrials.Gov/ct2/show/nct00790920?Term=desmoteplase&rank=2 (opens in a new window)
- http://clinicaltrials.Gov/ct2/show/nct00856661?Term=desmoteplase&rank=3 (opens in a new window)
- Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: Results of the MERCI trial. Stroke 2005;36:1432-1438.
- Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: Final results of the multi merci trial. Stroke 2008;39:1205-1212.
- The penumbra pivotal stroke trial: Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke 2009;40:2761-2768.
- Coutts SB, Goyal M. When recanalization does not improve clinical outcomes. Stroke 2009;40:2661.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --