The study included participants from two multicenter RCTs with cilostazol or pitavastatin as treatment agents from 2012 to 2016.19,20 These two RCTs enrolled 256 patients with aSAH, of whom 74 received cilostazol, 54 received pitavastatin, and 128 were used as controls. This study analyzed the effects of cilostazol and pitavastatin on occurring DCI and patient outcomes following aSAH using cerebral peripheral circulation time (iCCT). Participants’ inclusion and exclusion criteria are detailed in the previous publication.18 All participants or their legal representatives obtained written, informed consent before treatment. The present study was conducted in compliance with the Declaration of Helsinki.
A baseline DSA was performed on admission within 24 hours of the ictus. A follow-up DSA was performed 9 ± 2 days after the SAH ictus and/or within four hours of the onset of DCI to assess aVS and iCCT. DCI was defined as clinical deterioration of more than two points on the Glasgow Coma Scale (GCS), development of new focal neurological signs, or both when the cause was considered vasospasm-related ischemia after excluding other possible causes. All cerebral angiographies were performed using flat-panel DSA (AXIOM-ArtiszeeVR, Siemens Health Care). Using standard angiographic techniques via the transfemoral route in all patients, images were acquired using a 4 Fr catheter with the tip positioned at the C3-4 level. The 2D DSA series were acquired at 16 frames per second. For image acquisition, 6 ml of contrast agent (Iohexol 300, GE Healthcare, Japan) was injected in all series by mechanical injection at a flow rate of 8 ml/s for 2 seconds. The diameters of the proximal cerebral arteries, i.e., bilateral C1 segments of the internal carotid artery, M1 segments of the middle cerebral artery, and A1 segments of the anterior cerebral artery, were measured.21 The time-density curve of DSA was analyzed to measure the time to peak (TTP). The iCCT was defined as the time difference between TTP at the cortical segment of the rolandic artery and TTP at the rolandic vein (Figure. 1). 18
The percentage reduction in arterial diameter was calculated by comparing the baseline DSA with the follow-up DSA. The severity of cerebral vasospasm was categorized as none or mild: 0–25% reduction; moderate: 25–50% reduction; and severe: >50% reduction in arterial diameter on follow-up images compared with baseline DSA. DSA images were stored on a separate DVD in Digital Imaging and Communications in Medicine (DICOM) format. Representative, sequential DICOM images from the DSA were loaded onto a personal computer. Using post-processing image analysis, we analyzed the time density curve to measure time to peak (TTP) and intracerebral circulation time (iCCT).
The regions of interest (ROIs) consisting of four pixels were placed at the vertical intracavernous portion of the internal carotid artery (ROIC5), the cortical segment of the rolandic artery (ROIM4) and the rolandic vein (ROIVR). The time-density curve regarding image intensity divided by DSA acquisition time was analyzed at the selected ROIs to measure TTP (Fig. 1). TTP at ROIM4 (TTPM4) and TTP at ROIVR (TTPVR) were defined as the time from TTP at the carotid siphon (TTPC5) to the maximum level of contrast density at each ROI. An illustration of these ROIs and measurement methods in the context of the iCCT can be found in the previous publication.18
We then defined the iCCT as the difference in time between TTPM4 and TTPVR. We defined the baseline iCCT as measured in the ultra-early phase after the ictus and the follow-up iCCT as measured in the subacute phase 7–11 days after the ictus. In addition, the difference in iCCT was obtained by subtracting the baseline iCCT value from the follow-up iCCT value for each patient. Neurological examination and CT scan were performed on admission within 24 hours after SAH onset and 6–12 hours after aneurysm treatment. Follow-up examinations were performed 7 ± 2 days, 14 ± 2 days, 1 and 3 months after the ictus and whenever neurological deterioration occurred.
The clinical outcome was assessed using the Glasgow Outcome Scale. Neurological examination and CT scan were performed within 24 hours of admission and 6 − 12 hours after aneurysm treatment. Follow-up examinations were performed 7 ± 2 days, 14 ± 2 days, and one month after the ictus and whenever neurological deterioration occurred. DCI was defined as the clinical deterioration of more than two points on the Glasgow Coma Scale, the development of new focal neurological signs, or both after excluding other possible causes of deterioration save for ischemia due to vasospasm. 22 Poor patient outcomes were described either as severe disability, vegetative state, or death (D). In contrast, favorable outcomes were defined as good recovery or moderate disability (MD). Two independent, blinded site investigators adjudicated outcomes.
Differences between groups were described using Student’s t-test, Mann–Whitney U test, Pearson chi-squared test, or Fisher exact probability test. There were three study arms, two treatment arms (cilostazol and pitavastatin), and one control arm. Intragroup iCCT comparisons were made using aVS, DCI, and outcome status. The iCCT among the three arms was compared using the Kruskal-Wallis’s test.
Multivariate logistic regression analyses were performed to identify independent factors influencing patient outcome by adjusting for possible confounders, including severe aVS, DCI, cilostazol and pitavastatin use, Hunt & Hess grading, age, IVH, and clipping treatment based on the factor analysis of previous results.19,23 A two-tailed probability value < 0.05 was considered significant. All analyses were performed using the JMP Pro ver. 13 (SAS Institute Inc.).