Utility of Computed Tomographic Perfusion in Thrombolysis for Minor Stroke
Background and Purpose—The use of thrombolysis in acute minor ischemic stroke (MIS) remains controversial. We sought to determine the safety and efficacy of intravenous tissue-type plasminogen activator (IV-tPA) in acute MIS patients with demonstrable penumbra on computed tomographic perfusion study.
Methods—Consecutive MIS patients with National Institutes of Health Stroke Scale ≤3 were identified from a prospective single tertiary-center database over a 4.5-year period (2011–2015). Cases with demonstrable penumbra were analyzed according to treatment received: IV-tPA versus standard stroke-unit care without thrombolysis.
Results—Seventy-three patients of 195 acute MIS admissions had a demonstrable penumbra (34 IV-tPA versus 39 standard stroke-unit care). Overall median National Institutes of Health Stroke Scale and premorbid modified Rankin Scale were 2 and 0, respectively. Median age was 73.2 (interquartile range, 67.3–82.8) years. There were no differences in baseline demographics, risk factors, stroke localization and cause, rates of vascular occlusion (38.2% versus 38.5%; P=1.000), or mean penumbral volume (41.3 versus 25.1 mL; P=0.150; IV-tPA versus standard stroke-unit care) between groups. There were no symptomatic intracerebral hemorrhages in either group. Patients treated with IV-tPA were more likely to have an excellent functional outcome at discharge (88.2% versus 53.9%; P=0.002) and 90 days (91.2% versus 71.8%; P=0.042). Ordinal analysis demonstrated a favorable shift in modified Rankin Scale with IV-tPA both at discharge (odds ratio, 5.23; 95% confidence interval, 1.83–12.20) and 90 days (odds ratio, 4.35; 95% confidence interval, 1.77–11.36).
Conclusions—In selected MIS patients with demonstrable penumbra on computed tomographic perfusion, IV-tPA is safe and associated with significant improvement in functional outcome at discharge and 90 days.
- cerebrovascular disorders
- intracranial embolism
- tissue-type plasminogen activator
The use of intravenous tissue-type plasminogen activator (IV-tPA) in acute minor ischemic stroke (MIS) is controversial. Despite mild neurological symptoms, an intra-arterial occlusion is evident on computerized tomographic angiogram (CTA) in 10% to 54% of MIS patients, and 30% have persistent disability at 90 days.1–3 Mild clinical deficits with low National Institutes of Health Stroke Scale (NIHSS) scores remain a frequent reason for IV-tPA exclusion. This represents a missed opportunity to administer an effective therapy to an at-risk population.
CT perfusion (CTP) provides real-time evaluation of cerebral hemodynamics and has an increasing role in selecting eligible candidates for intra-arterial treatment.4,5 We sought to determine whether selected MIS patients with demonstrable penumbra on CTP have better clinical outcomes when treated with IV-tPA compared with those who received standard stroke unit care without thrombolysis.
Materials and Methods
Consecutive patients identified from a prospective stroke and transient ischemic attack hospital database over a 4.5-year period (2011–2015) with the following criteria were included: (1) diagnosis of ischemic stroke as defined by a stroke neurologist; (2) presentation to the emergency department within 4.5 hours of symptoms onset; (3) NIHSS ≤3; (4) premorbid modified Rankin Scale (mRS) ≤1; (5) demonstrable penumbra on CTP at presentation; (6) complete follow-up data at 90 days. The primary outcomes were safety as assessed by rate of intracranial hemorrhage and efficacy as measured by mRS at discharge and 90 days. Secondary outcomes included inpatient length-of-stay, rate of inpatient stroke progression, and discharge destination. All patients with acute stroke were managed in a standardized management protocol (Methods in the online-only Data Supplement). Our institutional Human Research Ethics Committee approved the study.
Stroke localization, pathogenic subtype classification6, and inpatient stroke progression were determined by review of individual medical records. All remaining data were collected prospectively. Inpatient stroke progression was defined as any inpatient worsening of initial neurological symptoms. Symptomatic intracranial hemorrhage was defined according to the European Cooperative Acute Stroke Study protocol.7
All imaging data were independently reviewed by 2 experienced readers (F.N. and P.C.) blinded to treatment received. Discrepancies were resolved by consensus. Demonstrable penumbra was defined as an area, regardless of size, of prolonged time-to-peak on visual inspection with preserved cerebral blood volume that corresponded to cerebral vascular territories and the presenting symptoms. In addition, CTP volumetric analysis was performed on fully automated RAPID software (noncommercial research version; Stanford University)8 on scans performed after 2012. Perfusion lesion and ischemic core volume were defined as Tmax>6 seconds and cerebral blood volume (mL/100 g) <30% of normal tissue, respectively.4 Mismatch volume was defined as the difference between penumbra and ischemic core volumes.
We used 2-tailed t test and Mann–Whitney U test for group-wise comparisons among numeric outcomes and Fisher exact test for categorical outcomes. Logistic regression analysis was used to analyze shift in graded outcomes. A P value <0.05 was considered statistically significant. All analyses were performed using SPSS 20.0.
A total of 195 patients who presented with MIS within 4.5 hours were identified. Fifty-five patients with contraindications to thrombolysis or contrast studies did not have CTP performed and were excluded. Two patients were lost to follow-up. Of the remaining 138 patients, 73 (52.9%) had a demonstrable penumbra on CTP and 28 (20.3%) had an intracranial vascular occlusion on CTA. All patients with a vascular occlusion also had a demonstrable penumbra on CTP. Inter-rater agreement for CTP and CTA evaluation was κ=0.946 and κ=0.973, respectively.
Of the 73 patients with demonstrable penumbra, 34 patients were thrombolyzed, whereas 39 patients received standard stroke unit care. The overall median age was 73.2 (interquartile range, 67.3–82.8); median premorbid mRS was 0. Overall median NIHSS was 2; there was a trend for a higher median presenting NIHSS in the thrombolyzed group (P=0.057). Both groups had similar risk factors, baseline demographics, stroke location and cause, rates of vascular occlusion (38.2% versus 38.5%; P=1.000), and mean penumbral volume (41.3 versus 25.1 mL; P=0.150; Table I in the online-only Data Supplement)
Neither group developed a symptomatic intracranial hemorrhage. Three patients in the IV-tPA group (P=0.109) developed an asymptomatic remote parenchymal hemorrhage7 with none in the standard stroke unit care group. There were no mortality recorded.
Significantly more thrombolyzed patients had an excellent functional outcome (mRS≤1) at discharge (88.2% versus 53.9%; P=0.002; absolute benefit increase=34.3%) and at 90 days (91.2% versus 71.8%; P=0.042; absolute benefit increase=19.4%). The number needed to treat for 1 additional patient to have an excellent functional outcome at discharge and at 90 days was 2.9 and 4.8, respectively. There was a shift in the distribution of mRS on ordinal analysis in favor of thrombolysis at discharge (odds ratio, 5.23; 95% confidence interval, 1.83–12.20) and 90 days (odds ratio, 4.35; 95% confidence interval, 1.77–11.36; Figure). Overall, 24 (32.8%) of the 73 patients were disabled (mRS≥2) at discharge with 15 (20.5%) remaining disabled at 90 days.
There were no differences between the groups for inpatient length-of-stay (P=0.837), inpatient stroke progression (P=0.417), or proportion of patients unable to be discharged directly home (P=0.725).
We found that IV-tPA is associated with improved outcomes in selected patients with stroke who had a demonstrable penumbra on CTP, despite mild symptoms. We have shown in MIS that IV-tPA is safe and is associated with excellent outcomes. Randomized controlled trial data are lacking in this area, and previous observational studies and meta-analyses have yielded conflicting results.9,10 Two recent large registry-based observational studies reported the effectiveness of IV-tPA in MIS patients, but they were underpowered to evaluate patients with NIHSS<5.9,11 This is the first study to demonstrate the efficacy of IV-tPA in a MIS cohort with symptoms as mild as NIHSS≤3.
In agreement with previous reports,1–3 our data showed that a substantial proportion of MIS patients had vascular occlusion, and nearly one third had a persistent disability at discharge. Our data suggest that CTP may be a valuable radiological selection criterion in addition to CTA to increase study power in future MIS studies. In our cohort of thrombolysis-eligible MIS patients, only 20% of patients had identifiable occlusion on CTA, whereas 53.5% had a penumbra on CTP. Solely selecting MIS patients with a CTA occlusion for thrombolysis may exclude a substantial proportion of patients who may benefit from treatment.
Our study has several limitations. Apart from the small sample size, the decision to thrombolyze in each case was not randomized but instead based on physician preference given the state of clinical equipoise. Confounding factors such as differences in the proportion of patients considered to have disabling symptoms favoring the IV-tPA cohort are possible, but no difference in the NIHSS domains was evident between the groups while there was a trend for a higher presenting NIHSS (P=0.057) and penumbra volume (P=0.150), both poor prognostic factors, in the IV-tPA cohort instead. Second, although the mRS is a well-established disability measure, subtle deficits not addressed by the mRS cannot evaluated in this analysis. Finally, the effect of IV-tPA on MIS patients with no penumbra was not investigated given only 3 of such patients were treated during the study period.
In conclusion, our study demonstrated the safety and efficacy of IV-tPA in selected MIS with demonstrable penumbra. Our data support the hypothesis that CTP may be useful in selecting patients for thrombolysis in clinical practice and in future clinical trials in MIS. Prospective, randomized clinical trials in MIS treatment incorporating CTP will help to advance the standard of care for MIS patients.
Presented in part as a poster presentation at the European Stroke Organisation Conference, Barcelona, Spain, May 10–12, 2016.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.013021/-/DC1.
- Received February 3, 2016.
- Revision received March 22, 2016.
- Accepted April 13, 2016.
- © 2016 American Heart Association, Inc.
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