Kuei-Hong Kuo1*, Yi-Ju Pan3,4, Yen-Jun Lai1, Chih-Chun Wu2, Feng-Chi Chang2, 3

Kuei-Hong Kuo: goman178@gmail.com1. Division of Medical Image, Far Eastern Memorial Hospital, Banciao, Taiwan2. Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan3. National Yang Ming University, School of Medicine, Taipei, Taiwan 4. Department of Psychiatry, Far Eastern Memorial Hospital, Banciao, Taiwan

Effectiveness and Complication of Intravenous Thrombolysis in an Asian Sample of Patients with

Acute Large Arterial Infarction: Focus on Presence of Hyperdense Artery Sign?

Control #: 1016 / Poster #: EP-64

Disclosures

The authors have no financial conflicts of interest.

Background

• The hyperdense artery sign (HAS) of non-enhanced brain CT has been recognized, since Gacs et al ‘s first report in 1983, as an indicator of occluding blood clot in acute cerebral infarction and usually associated with poor prognosis1-3.

• Liebeskind et al. has further correlated HAS with RBC content of the clot by the histopathological study from thombectomy clot 4 -

• Clots with HAS tend to have more RBCs, therefore histopathologically red clots,

• whereas clots without HAS tend to have higher fibrin content, namely white clots.

• Hypothetically, red clots might be formed in slow flow conditions, (e.g. atrial fibrillation), while white clots were more frequently considered in conditions involving endothelial injury by high shearing flow of atherosclerosis disease5.

Background

It is reasonable to assume that :(1) The HAS might be correlated with the mechanism of clot formation, which is the underlying etiology of infarction (e.g. cardiogenic or atherosclerotic).

(2) Assume white clot might have favorable outcomes after intravenous rtPA thrombolytic therapy (IV-rtPA), given that fibrin of clot is the primary target of recombinant tissue plasminogen activator (rtPA).

However, previous studies examining relationships among presence of HAS, underlying etiology, and outcomes after IV-rtPA yielded divergent findings. In addition, most prior researches on HAS and IV-rtPA (or acute arterial infarctions) were from Western countries. Whether those previous results could be generalized into Asian populations remains questionable because differences in etiology of stroke and prognosis of IV-rtPA were (frequently) reported across ethnicities6.

Purpose

Therefore, to examine the relationships among presence of HAS, etiology of stroke, and prognosis to IV-rtPA, we recruited a sample of consecutive patients who suffered from acute large arterial infarction and received IV-rtTA treatment in a general hospital in Taiwan from March 2012 to December 2014. Correlations between HAS and TOAST etiology as well as prognosis/complication of IV-rtPA were then explored in this Asian sample.

The specific objectives are: (1) To correlate presence of HAS with clinical stroke

etiology using TOAST classification, and (2) To examine relationship between presence of HAS

and outcomes (both effectiveness/hemorrhage as complication) after IV-rtPA thrombolysis.

Data collection

• This is a retrospective analysis of patients selected from a registry of acute ischemic stroke patients admitted in Far Eastern Memorial Hospital, Taiwan, between March 2012 and December 2014.

• We included all intravenous rt-PA-treated patients within 3-hour window following NINDS criteria. Baseline stroke severity was assessed with National Institutes of Health Stroke Scale (NIHSS) and the patients’ score (<5 and >26) were excluded. The cases finally proven lacunar infarction was further excluded because we want to enroll only large arterial stroke.

• Demographics (age, gender…), neurological deficits (NIHSS) and vascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking…) were recorded. Finally, stroke etiology was classified using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria 7.

Materials & Methods

Brain imaging evaluation: (Fig 1).

• The HAS was judged by two neuroradiologists with criteria of (1) abrupt higher CT density comparing to adjacent artery (2) Focal engorged artery with a ratio of 1.2 when compared to the non-affected contralateral vessel.

• The “pseudo-clot” condition, such as calcified atherosclerotic plaque, or high concentrationof hemoglobin level are excluded1, 8, 9, 10.

• All patients had initial brain CT “source” images, CTA and post-treatment 24hr CT and CTA and/or CT perfusion and/or MR images. The locations of thrombus may reflect the “clot burden”, and were recorded as :

• involving “main stem” versus (larger clot, heavy burden)• defined by involving larger arteries (VA, BA, and M1 of MCA) +/- branches

• only lodging at “branches” (smaller clot, light burden)• defined by only involving smaller arteries (M2-4 of MCA, A1-3 of ACA, P1-3

of PCA and all cerebellar arteries).

Materials & Methods

Figure 1

A) CT source image showed a hyperdense artery sign (~HAS(+)) at the left proximal M1 of MCA (~Main trunk)

B) The 24hr Post treatment CTA revealed that the clot propagated to the distal M1.

C) There was no intracranial hemorrhage complication at the 24-hour follow up CT.

D) DWI of MR revealed large left MCA territory acute infarction, which compatible with the findings of left occluded M1.

Treatment and outcome evaluation:• The IV-tPA treatment data (rt-PA dosages, treatment timing) were

recorded. • The dosage was modified in some patients according to an Asian report

in Japan13.

Post treatment 24hr outcome data: • Early improvment was defined as improved NIHSS > 3 points of best

improvement within 24 hours after treatment.

• Complication of ICH was evaluated at the 24-hour follow up images (CT or MR).

Materials & Methods

Patient sampleFrom March 2012 to December 2014, there were 2277 patients visited emergency department of FEMH due to acute stroke, 561 patients had ischemic infarction with onset in 3 hour window, 85 patients received IV tPA treatment. Among them, 5 were excluded because lac of data and 5 were excluded because favored lacunar infarction. Finally, 75 patients were included in this study.

Clinical characteristics There were 38 (50.7%) patients presenting with HAS, whereas, 37 (49.3%) cases without HAS. There were no differences in basic demographics, clinical characteristics, and vascular risk factors, except that patients without HAS tended to have higher smoking and hyperlipidemia rate. It’s worth noted it is close to statistic significant that patients with HAS are older and the initial NIHSS is higher. (p=0.054 and 0.059 separately)

Treatment profile There is no differences in IV rtPA profile including time interval from onset to treatment (HAS(+) vs. HAS(-) : 118.9 vs. 105.6 minutes) and rtPA dosage (HAS(+) vs. HAS(-): both 0.8mg/kg).

Site of clot location 84.2% HAS (+) clot involving main trunk, whereas 75.7% HAS (-) clot only involving distal cerebral branches.

Results (Table 1).

Table1. Baseline data of acute large arterial infarcted patients with and without HAS clot.

  Patients withHAS(+) thrombusn= 38 (50.7%)

Patients withHAS (-) thrombusn=37 (49.3%)

P value 

Total n=75 (100%)

Patient demographics        Age, years (median [IQR]) 66 (59-72) 62 (52-69) 0.054* 64 (56-72)Male gender (n [%]) 20 (52.6) 25 (67.6) 0.187+ 45 (60.0)Stroke risk factors          Hypertension (n [%]) 29 (76.3) 31 (83.8) 0.453+ 60 (80.0)  Diabetes (n [%]) 13 (34.2) 13 (35.1) 0.933+ 26 (34.7)  Hyperlipidemia (n [%]) 11 (28.9) 22 (59.5) 0.008+ 33 (44.0)  Smoking, current or previous (n [%]) 9 (23.7) 17 (45.9) 0.043+ 26 (34.7)  Previous stroke (n [%]) 13 (34.2) 13 (35.1) 0.933+ 26 (34.7)  Atrial fibrillation (n [%]) 23 (60.5) 18 (48.6) 0.302+ 41 (54.7)Clinical data          Hemoglobin (mean +/- SD) 14.1 +/- 1.5 14 +/- 2.5 0.837* 14.1+/-2.1  Initial NIHSS score (median [IQR]) 15 (11-19) 13 (9-17) 0.059* 15 (11-18)

IQR interquartile range; SD standard deviation, * P value calculated by student T test ; + P value calculated by chi square test$ P vale calculated by mean whiteney Q test

Table1. Baseline data of acute large arterial infarcted patients with and without HAS clot. (con.)

IQR interquartile range; SD standard deviation, * P value calculated by student T test ; + P value calculated by chi square test$ P vale calculated by mean whiteney Q test

  Patients withHAS(+) thrombusn= 38 (50.7%)

Patients withHAS (-) thrombusn=37 (49.3%)

P value 

Total n=75 (100%)

Brain CT profile        

 Onset-to-CT time period, min (mean +/- SD)

71.3+/-39.5 60.9+/-32.0 0.217* 66.2+/-36.1

Clot location           Lodge at main trunk +/- branches (n [%])

32 (84.2) 9 (24.3) <0.001+

41 (54.7)

   Lodge only at branches (n [%]) 6 (15.8) 28 (75.7)   34 (45.3)

IV rtPA Treatment profile        Onset-to-tPA time period, min (mean +/- SD)

118.9 +/-41.9 105.6 +/- 31.1 0.122* 112.4+/-37.3

rt-PA dosage, mg/kg (mean +/- SD) 0.8 +/- 0.12 0.8 +/- 0.10 0.392* 0.8+/-0.11

Table2. Comparison in stroke etiology and treatment outcome between large arterial infarcted patients with and without HAS

IQR interquartile range; SD standard deviation, * P value calculated by student T test ; + P value calculated by chi square test$ P vale calculated by mean whiteney Q test

  Patients withHAS(+) thrombusn= 38 (50.7%)

Patients withHAS (-) thrombusn=37 (49.3%)

P value 

Total n=75 (100%)

Stroke etiology: TOAST classification ++

    0.031$  

  Vascular atherosclerosis (n [%]) 13 (34.2) 16 (43.2)   29 (38.7)  Cardiogenic (n [%]) 18 (47.4) 10 (27.0)   28 (37.3)  Undetermined (n [%]) 4 (10.5) 11 (29.7)   15 (20.0)  Special (n [%]) 3 (7.9) 0 (0)   3 (4.0)IV rTPA treatment Outcome        Early Improvement in 24hrs 23 (60.5) 25 (67.6) 0.525+ 48 (64.0)Bleeding at 24hrs   9 (23.7) 3 (8.1) 0.066+ 12 (16)

Table 3. Results of multivariate analysis to identify predictors of early improvement after IV rtPA treatment

  MultivariateVariables OR 95% CI P value

Atrial fibrillation 5.442 1.244-23.805 0.024

Initial NIHSS 0.837 0.731-0.959 0.010

(CI = Confidence interval, OR = odds radio)

Multivariate analysis adjusted for age, sex, hypertension, diabetes, hyperlipidemia, smoking, previous stroke, atrial fibrillation, Onset to tPA time period, site of occlusion, initial NIHSS, and tPA dosage.

Table 4. Results of multivariate analysis to identify predictors of intracranial hemorrhage present on the 24-hour follow up CT/MR after

IV rtPA treatment.

  MultivariateVariables OR 95% CI P valueAge 1.249 1.022-1.527 0.030

Hypertension 0.005 0.000-0.564 0.028

Smoking 30.869 1.064-895.465 0.046

Previous stroke 93.956 2.167-4073.19 0.018

(CI = Confidence interval, OR = odds radio)

Multivariate analysis adjusted for age, sex, hypertension, diabetes, hyperlipidemia, smoking, previous stroke, atrial fibrillation, Onset to tPA time period, site of occlusion, initial NIHSS, and tPA dosage.

• In our sample, the prevalence of HAS is 50.7%. • This result is similar to that from previous studies from Western countries

using thin-slice CT images. and highlights the importance of thin section protocol 11, 12.

• Patients with HAS were similar with those without HAS in demographic/clinical data as well as profiles regarding IV-rtPA treatments, except that patients without HAS had higher prevalence of hyperlipidemia and smoking.

• Patients with HAS tend to have clot lodging at main trunk of cerebral artery, presumably having heavier ‘clot burden’. In accordance, people with HAS seemed to have more severe symptoms as represented by having higher initial NIHSS in this sample despite that difference between the two groups did not reach statistical significance.

• In our sample, the stroke etiology of the cardiogenesis/atherosclerosis ratio by TOAST classification is nearly 1, which is lower than most of the Western studies 6, 14.

Discussion

• Previous studies also emphasized the importance of RBC content and clot size in determining presence of HAS, and suggested that HAS (+) is correlated to higher cardiogentic etiology, which may be through above two effects.

• Another factor may be related to HAS is visual perception error in judging of HAS. This error could be a particular concern when the high density clot is surrounded by high density atherosclerotic plaques, commonly seen in Asian patients.

• The clot could propagate and change in its content and form with time.

• Although we agreed that presence of HAS may be associated with selected etiology of acute arterial infarction (for instance, 47.4% of patients with HAS had cardiogenic emboli, in this study, Table 2), it would be difficult for presence of HAS to be justified as part of TOAST criterion to support cardioembolism.

Discussion

Discussion

???

Is presence of HAS correlated with clinical stroke etiology using TOAST classification?? YES ! It is correlated to some extent. But in reality, HAS is affacted by many other factors.

• There are many debating literatures discussed could the clot with HAS sign influence the efficacy of IV-tPA treatment? Several papers supported that patient with HAS sign are more beneficial from IV tPA treatment11, 15, 17-19, and more papers support the other way2, 5, 20-25.

• Theoretically, it has been proved that the amount of RBC inside clot determine presenting HAS sign or not4. And in vitro experiment model, RBC rich clot could disrupt fibrin structure, and should reduce the efficacy of tPA regimen5, 20.

• However, our study, in consistence with another literatures, support neither of above, and show no statistic difference between two groups in univariate and multivariate analysis4, 26, 27.

• In fact, in human level, there are more influenced factors determine the improvement after IV tPA treatment: (1)clot factors: shape, burden, freshness, source of origin, microstructure organization and evolution 28, (2)Patient factor: brain circulation status and collateral, (3)Disease factor: site of occlusion, and (4)therapeutic factor: time to tPA.

• In the other way, in consistence with previous literature, our study showed that the initial lower NIHSS has better chance to improve from IV tPA treatment.

Discussion

Discussion

• No! There is no correlation between HAS and IV rtPA treatment. In human level, there are many factors, which determine the efficacy of rtPA.

???

Is there correlation between HAS and treatment efficacy of IV tPA??

Discussion

• Although not statistic significant, we found a trend (p=0.06) that patients with HAS seemed to suffered from more intracerebral hemorrhage in 24-hour follow up image.

• But consistent with other studies, HAS was not associated with ICH in further multivariate analysis after controlling for demographics and clinical variables.

Conclusion

Our study provided data concerning the relationships among presence of HAS in brain CT, stroke etiology, and effectiveness/complication of IV-rtPA in acute large arterial infarction in an Asian population. The prevalence of HAS in our sample is 50.7% with thin slice CT evaluation. Patients with HAS tend to have bigger clot lodging at main trunk of cerebral artery (84.2%) and to have infarctions probably resulting from cardiogenic emboli (47.4%). However, no significant associations between HAS and IV-rtPA outcome (early improvement and bleeding) were found in this study.

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