Argatroban Increased the Basal Vein Drainage and Improved Outcomes in Acute Paraventricular Ischemic Stroke Patients

Background

Ischemic stroke is a leading cause of disability and death [1]. Past studies focused on the arterial side of cerebral circulation, either thrombolysis or blood clot retrieval, have shown significant clinical improvement in stroke patients [2]. However, some recanalized patients failed to improve due to non-reflow, futile reperfusion, or other causes [3–5].

However, the cerebral venous system’s participation in acute arterial ischemic stroke has been rarely investigated, and the possibility that venous congestion aggravates brain injury remains to be explored [6]. The basal vein Rosenthal (BVR) drains large areas of the brain’s ventricular walls. Indeed, Stolz et al. reported that some patients with decreased flow velocity in the BVR suffered ipsilateral herniation after ischemic lesion [7].

Argatroban, a selective direct thrombin inhibitor, has been adopted to treat acute ischemic stroke [8]. Preclinical [9,10] and clinical [11,12] studies have indicated that argatroban is effective in treating acute ischemic stroke without increasing hemorrhage in the brain. In rat models, argatroban increased blood flow to the lesion area, reduced secondary microthrombi formation, and decreased neurologic deficit [13,14]. Because of its efficacy in lessening secondary microthrombi formation, we theorized that argatroban would increase venous drainage in ischemic periventricular stroke and alleviate its aftereffects.

Material and Methods

STUDY POPULATION:

This multicenter, open-label, randomized and evaluator-blinded study has been registered with Chictr.org.cn (No. ChiCTR-IPR-16008663). The approval for the trial protocol and supportive documents was obtained from the institutional review boards of all the participating centers.

From the 526 patients with acute ischemic stroke, 60 patients with matched clinical characteristics, stroke etiology, lesion location and volume were selected and enrolled into this study in Tianjin Medical University General Hospital, Tianjin Huanhu Hospital, and Baotou Central Hospital, Bao tou, China.

At enrollment, written informed consents were obtained from all patients. The inclusion and exclusion criteria were presented as follows. Inclusion criteria were as follows: 1) age >40 years; 2) large artery atherosclerosis (LAA) defined by magnetic resonance angiography (MRA) and diffusion weighted imaging (DWI) according to the Trial of Org 10172 in acute stroke treatment classification (TOAST), i.e., the ischemic stroke caused by intracranial LAA as a parent artery (plaque or thrombus) that blocks a penetrating artery); 3) magnetic resonance imaging (MRI) scan showed an ischemic lesion in the paraventricular area, which was defined as acute paraventricular ischemic stroke; 4) acute focal neurological deficit caused by acute ischemic stroke; 5) National Institutes of Health Stroke Scale (NIHSS) ≥5; and 6) patient treated 4.5 to 48 hours after symptom onset at admission. Since stroke patients within 4.5 hours after symptom onset were normally treated with alteplase, all patients recruited for this study had passed the 4.5-hour time-window for thrombolytic treatment when recruited.

Exclusion criteria were as follows: 1) hemorrhagic stroke; 2) other central nervous diseases; 3) diabetes; 4) tumor or hematological systemic diseases; 5) infection prior to stroke; and 6) antineoplastic or immune modulating therapies. Patients with diabetes were excluded, because their prothrombotic milieu with hyperreactive platelets and hypercoagulation abnormalities may contribute to a reduction in mean flow velocity (MFV) of BVR.

STUDY DESIGN:

Sixty patients with acute paraventricular ischemic stroke were randomly divided into 2 groups: a control group (standard treatment based on guidelines of American Heart Association) and an argatroban group (standard treatment combined with argatroban, TIRP Pharmaceutical Co., Ltd., Tianjin, China). Patients in the 2 groups had similar clinical characteristics when recruited (Table 1). The control group received standard treatment (antihypertensives, antiplatelet agents, and statins) following the guidelines of American Heart Association. Meanwhile, the patients in the argatroban group were additionally given intravenous infusion of 10 mg argatroban twice a day for 7 days consecutively, starting 1 hour after the baseline MRI and no later than 48 hours after symptom onset. The patients enrolled were allocated by computer in a 1: 1 ratio to either the control or the argatroban group in a random way. A centralized web-based randomization system was used for allocation concealment, with the identifier of the participant entered before the allocation. The treatment assignment was known only to the clinicians, but not to the evaluators (Figure 1).

CLINICAL ASSESSMENTS:

Each patient was clinically assessed upon enrollment (baseline) and at day 7 and day 90 after start of treatment, which was blinded to the evaluators (Figure 1). NIHSS was used to assess the neurologic deficit. The modified Rankin scale (mRS) was used to assess the 90-day outcomes. The modified Barthel index (mBI) was used to evaluate the limited ability to perform daily activities. A score of 0 to 1 represented a good outcome and a score of 2 to 5 depicted a poor outcome.

NEUROIMAGING:

At admission, MRIs (MRA, T2FLAIR, and DWI) were conducted using 3 Tesla GE and Siemens, following a comprehensive MRI protocol for acute stroke. Characteristically, ischemic stroke lesion locates in the ventricular walls of one brain hemisphere. In our study, 2 radiologists (blinded to the study design) conducted measurements independently with MIPAV software. By manual outlining and automatic calculation, the lesion area and slice thickness on each of the DWI and FLAIR slices were determined, and then lesion volume was calculated [15]. Another radiologist validated the lesion volume using the semiautomated technique (Cheshire; Perceptive Informatics, Waltham, MA, USA).

TRANSCRANIAL DOPPLER ULTRASONOGRAPHY (TCD):

We performed transcranial Doppler ultrasonography (TCD) measurements using the TC-2000 (Nicolet EME, Kleinostheim, Germany) with a handheld transducer in a range-gated, pulsed-wave mode with a frequency of 2 MHz [16]. TCD insonated the BVR in the ambient cistern, then the posterior cerebral artery cranially and medially. The Doppler gate depth was about 62 mm [17], and the probe was steered clear of the blood flowing direction in the vessel. Bilateral BVR were examined with a TCD device at admission, day 7 and day 90 after stroke onset. MFV in the BVR was calculated and displayed automatically by the TCD device in the ipsilateral and contralateral hemispheres.

STATISTICAL ANALYSES:

Data analyses were performed by SPSS for Windows version 17.0 software (SPSS, Inc., Chicago, IL, USA). Continuous variables (e.g., MFV) were calculated and presented as means±standard error (SE). Discontinuous or abnormally distributed variables were presented as a median (range) and compared by a Mann-Whitney U test. All continuous variables were compared with the t-test used for independent samples. A chi-square test was adopted to compare the categorical variables. A P<0.05 was considered statistically significant.

Results

BASELINE CHARACTERISTICS:

Sixty acute ischemic paraventricular stroke patients at 4.5 hours to 48 hours after symptom onset were enrolled in the present study (Figure 1). They were randomly placed in a treatment group or a control group. During the 90-day study, there were no losses to follow-up, dropouts, or fatalities. At the pretreatment baseline, no differences in age, stroke etiology, NIHSS score, or lesion volume were identified (Table 1). Similarly, at that time, no differences of MFV were found in ipsilateral or contralateral BVR between the 2 groups (9.76±1.95 versus 9.50±2.12, P=0.616, 11.26±1.79 versus 11.03±2.29, P=0.663) (Figure 2A). Standard treatment, with or without argatroban, ensued within 48 hours of diagnosis. Compared to these patients’ contralateral hemispheres, BVRs in their ipsilateral hemispheres manifested significant reductions in MFV in both control and argatroban-treated patients (9.50±2.12 versus 11.03±2.29, P=0.010, 9.76±1.95 versus 11.26±1.79, P=0.003) (Figure 2A).

ARGATROBAN INCREASED THE BVR DRAINAGE:

At day 7 after treatment, the argatroban group had a significantly higher MFV in BVR of the ipsilateral hemispheres than the control group (11.80±2.18 versus 10.46±2.14, P=0.020). However, at day 90, the MFV in BVR of the ipsilateral hemispheres no longer reached the level of statistical significance in comparisons between the two groups (11.60±1.79 versus 11.00±2.15, P=0.245) (Figure 2B). In contrast, despite the administration of argatroban, the MFV in the BVR of the contralateral hemisphere did not change at day 7 or day 90 after stroke onset (12.03±2.10 versus 12.13±2.45, P=0.866; 12.23±2.02 versus 11.96±2.09, P=0.618) (Figure 2C). However, the representative TCD in Figure 2D shows that argatroban improved venous drainage from day 1 to day 7 (Figure 2D).

ARGATROBAN REDUCED INFARCTION ENLARGEMENT:

Prior to the treatment, no significant difference was found in lesion volumes between the 2 groups (Table 1). At day 7 after treatment, the argatroban recipients had a significantly smaller lesion volume (day 7 volume versus baseline volume) than the controls (1.51±0.71 versus 4.67±1.29, P=0.002) (Figure 3A, 3B).Though, in the T2FLAIR image, the argatroban group had a smaller lesion volume at day 7 (P=0.87).

ARGATROBAN IMPROVED CLINICAL OUTCOMES:

As shown by the baseline and subsequent clinical evaluations (Figure 4), the argatroban group had only moderate neurological deficits, and most diminished in 7 days after treatment. Compared with the control group, patients who received argatroban exhibited lower NIHSS scores [0.75 (range, −3 to 4) versus 1.5 (range, 0 to 6); P=0.015] from baseline to day 7. The difference in NIHSS scores reached the level of statistical significance at 90 days after symptom onset [3.0 (range, 1 to 7) versus 5.0 (range, 2 to 10); P<0.01] (Figure 4A, 4B). Additionally, the argatroban group had significantly higher mBI scores (which reflected the ability to perform routine activities), than the control group at day 7 and day 90 (76.5±10.9 versus 70.5±11.6, P=0.045; 83.3±7.7 versus 75.3±10.1, P=0.001). And the mRS scores for clinical recovery of 0–1 at post-stroke day 90 were 69% in the argatroban group, compared to 51% in the control group (P=0.014; Figure 4C, 4D).

SAFETY:

None of the argatroban recipients had recurrent strokes while 3% of patients in the control group had recurrent strokes. One patient in the control group had lung infection after stroke with temperatures >38°C and was administered antibiotics. One patient in the argatroban group had an upper respiratory tract infection. None of the patients in the argatroban group were given antibiotics. One patient had mild hemorrhage of digestive tract (Table 2).

Discussion

LIMITATIONS:

There were 2 limitations to our present study: First, the sample size of the present study was too small to draw a solid conclusion. Studies of larger scales are needed in the future to confirm the results of the present study. Second, there still exists a possibility that infarction reduction and neurological improvement might be directly related to improved BVR outflow in acute ischemic stroke after argatroban treatment. Although our observations in this study precluded us from drawing such a conclusion, this study is a first observation to show that argatroban increased flow velocity of the basal vein after acute ischemic paraventricular stroke for up to 7 days. This effect of argatroban on expanding venous blood flow was accompanied by a reduced infarction volume and improved clinical outcomes at day 7 and day 90 from the onset of stroke. Future confirmation directly linking argatroban to the reduction of venous microthrombi formation is well-warranted.

Conclusions

Vein drainage change may contribute to the acute phase of brain edema and the outcomes of ischemic stroke patients.