LCD L38709: Computed Tomography Cerebral Perfusion Analysis (CTP)

CTP (using automated post-processing software algorithmic analysis) is medically reasonable and necessary in patients with acute ischemic stroke (AIS) caused by unilateral large vessel occlusion (LVO) in the proximal anterior circulation evaluated at stroke centers; CTP can be used to aid in selection for endovascular mechanical thrombectomy (EVT) if one of the following other conditions is fulfilled:

• Treatment (femoral puncture) can be started within 6-24 hours of the time last known to be at neurologic baseline and who meet the pre-CTP inclusion/exclusion criteria as defined by the DAWN trial 1 , or

• Treatment (femoral puncture) can be started within 6-16 hours of the time last known to be at neurologic baseline and who meet the pre-CTP inclusion/exclusion criteria as defined by the DEFUSE 3 trial 2

*excluding criteria purely related to study mechanics (e.g., able to return for protocol required follow-up visits, etc.)

Table 1: Key Inclusion Criteria for DAWN and DIFUSE 3

Parameter

DAWN

DEFUSE 3

Prestroke baseline mRS (0-6)

mRS ≤1 (no significant disability)

mRS ≤2 (slight disability)

Last known well to treatment time

6-24 h

6-16 h

Minimum NIHSS score (0-42)

10 (moderate stroke)

6 (moderate stroke)

LVO by MR or CT angiography

ICA (intracranial) and/or M1 segment of MCA

ICA (cervical or intracranial) and/or M1 segment of MCA

mRS= modified Rankin scale, NIHSS= National Institutes of Health Stroke Scale, ICA= internal carotid artery, MCA= middle cerebral artery

Background

Stroke is the leading cause of adult disability in the United States with limited treatment options 3 . The FDA approved treatment for stroke is intravenous tissue plasminogen activator (tPA) within three hours after onset of symptoms. Often treatment is not initiated since most patients do not present within this narrow time window, resulting in only 4% of patients receiving tPA treatment. Even with treatment, only 12-25% benefit as irreversible injury may have already occurred, or the treatment fails to recanalize the occluded artery with reported recanalization rate of 10-50% 2,4. Endovascular stroke therapy involves mechanical removal of blood clots or intra-arterial administration of thrombolytics. This offers an alternative to patients who fail tPA or are not eligible. Recanalization rates are as high as 82% for thrombectomy 5 . Initial studies on EVT failed to demonstrate clinical benefits 2. Further investigation suggested the lack of benefit was related to patient selection. Subsequent studies identified imaging criteria to determine patients with potentially salvageable tissues and improved outcomes from EVT 6-8 . In stroke victims, there is the ischemic penumbra, potentially salvageable tissue, and ischemic core, which is irreversibly injured. Patients with >50% reperfusion have been shown to have an improved outcome compared to those with 2,9 . CPT plays a role as it can be used to calculate the ischemic penumbra and help to identify which patients may benefit from EVT. Reperfusion treatment was found to be more common in patients who had imaging with CTA (13%) or CTP (17.6%) 10 .

Noncontrast CT (NCCT) is the mainstay for initial AIS imaging due to widespread availability, rapid scan times, and detection of intracranial hemorrhage (which leads to very different management from infarction). Multimodal CT includes NCCT, CT angiography (CTA) (to assess the site of vascular occlusion), and CT Perfusion Imaging (CTP). CTP is typically performed after NCCT and consists of a temporal sequence of head CT scans obtained during the wash-in and wash-out of an IV bolus of iodinated contrast agent. Post-acquisition data analysis by dedicated software allows the creation of multiple hemodynamic parametric maps (based on contrast time-density curves) for clinical interpretation. Hemodynamic parameters include time to maximum contrast intensity (Tmax), mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV), mathematically related by the equation CBF = CBV/MTT 11. The CBV is calculated as the milliliters of blood per 100g of brain tissue. These maps can estimate brain regions with a high probability of irreversible infarction (ischemic core) versus areas of potentially reversible ischemia (penumbra). Both core and penumbra are estimates of probabilistic tissue fate. Penumbra imaging has been proposed as a useful predictor of hemorrhagic transformation (HT) in AIS 12 . HT occurs in up to 40% of stroke patients and is related to rapid deterioration and poor outcomes. CTP has been studied in acute ischemic stroke for decades 13 , only recently was it found likely to influence treatment decision 14 . Subsequently, two level I randomized controlled trials (RCTs) (DAWN and DEFUSE 3) found CTP helped determine eligibility for EVT in the late time period (6-24 hr.) of an acute ( 2,9 , a paradigm shift away from confinement to the early window ( CTP has the advantage of being able to be performed by most multi-slice scanners and add minimal time, usually less than 10 minutes, to the evaluation. There are limitations to CPT technology, emphasizing that CTP must be performed in properly selected patients. There are potential technical issues such as patient movement and poor contrast bolus that can impact results. While experienced providers can typically recognize abnormalities caused by artifacts, calculations provided by the software may include artifacts, risking overestimating the penumbral volume. This requires manual correction to avoid miscalculations. Another challenge is there are multiple CTP vendor software and postprocessing techniques, which may lead to variations in calculated core and mismatch 11,15 . Ideally, the software programs would be standardized, but given the variability, providers must be familiar with the software package being used and potential variations in calculated values. Automation has the potential to reduce human variability; however, even with fully automated software, a significant clinician interpretation learning curve remains 16 . Limitations of arterial flow, which can be caused by low cardiac output, arrhythmias, chronic carotid stenosis, may result in overestimations. Chronic infarction, vascular stenosis, chronic white matter changes, seizures, and vasospasm can demonstrate abnormal CTP patterns and potentially mimic acute ischemia, so the provider must consider the full medical picture when interpreting results 11,17 . CTP requires contrast, so those with renal failure or known serious allergy to iodine and previously refractory to pretreatment medications may not be candidates. Protocols should include care to avoid excess radiation exposure and avoid treatment delays.

CTP for AIS

CTP in acute stroke management: A 2020 systematic review aimed to evaluate the diagnostic accuracy of CTP in the prediction of hemorrhagic transformation and patient outcome in AIS reported CTP sensitivity as 85.9%, a specificity of 73.9%, positive predictive value 60.3% and negative predictive value of 92.9% 12 . A 2017 systematic review identified 27 studies with a total of 2168 patients. The pooled sensitivity of CTP for acute ischemic stroke was 82% (95% CI 75–88%), and the specificity was 96% (95% CI 89–99%). They determined CTP was more sensitive than NCCT and had a similar accuracy with CTA, but also that the evidence was not strong, and there is a need for high-quality evidence to confirm results [18]. Older systematic reviews report mixed results with a wide range in sensitivity and specificity of CTP for the detection of AIS 18 . A 2019 systematic review and meta-analysis comparing imaging modalities for evaluation of AIS concludes that while CTP was more accurate than NCCT for detection of AIS, it was less accurate than diffusion-weighted imaging (DWI) MRI (sensitivity 82%, specificity 96% vs. sensitivity 15-86%, specificity 100%, respectively) 19 .

A 2020 systematic review reported prediction of the HT could guide decision making in regards to consideration at thrombolysis decision point and concludes CTP is a useful prognostic tool for clinicians at the point of intervention decision making for AIS 12 . This review, however, consisting of three prospective and nine retrospective studies, is subject to inaccuracy given the risk of bias and a high degree of heterogenicity in the selected studies. On the contrary, a large prospective trial with 545 patients treated with IV tPA or thrombectomy had CTP at admission, and day three follow-up looked at the ability of the technology to predict HT (by measurement of the blood-brain barrier permeability (BBBP). While univariate analysis associated BBBP measured by CTP as an independent predictor of HT, the multivariant analysis did not reproduce those findings, and the addition of BBBP as a variable did not change the AUC (0.77, 95% CI 0.71–0.83) of the model. The authors concluded BBBP measured by CTP did not improve prediction of HT, and improvements are needed before being considered “a useful addition to decision making” 20 .

Most studies evaluating the role of CTP in AIS are retrospective with variability in inclusion and exclusion criteria, outcomes reported, and sampling procedures, which introduces a high risk for bias, heterogenicity, and overall reduced quality of evidence. The evidence for routine use of CTP for evaluation for AIS is low quality, and there is a need for high-quality evidence to determine the role it may play in AIS evaluation. The exception is the role of CTP for evaluation for patient selection for EVT.