Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke
Background and Purpose—The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health–sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion.
Results—Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5–29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%–64%) complete and 2 of 20 (10%; 95% confidence interval, 1%–32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%–82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%–49) patients had a modified Rankin scale of 0 to 1.
Conclusions—Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial.
Objective: To investigate the association of renal impairment on functional outcome and complications in strokepatients treated with IV thrombolysis (IVT).
Methods: In this observational study, we compared the estimated glomerular filtration rate (GFR) with poor 3-month outcome (modified Rankin Scale scores 3–6), death, and symptomatic intracranial hemorrhage (sICH) based on the criteria of the European Cooperative Acute Stroke Study II trial. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients without IVT treatment served as a comparison group.
Results: Among 4,780 IVT-treated patients, 1,217 (25.5%) had a low GFR (<60 mL/min/1.73 m2). A GFR decrease by 10 mL/min/1.73 m2 increased the risk of poor outcome (OR [95% CI]): (ORunadjusted 1.20 [1.17–1.24]; ORadjusted 1.05 [1.01–1.09]), death (ORunadjusted 1.33 [1.28–1.38]; ORadjusted 1.18 [1.11–1.249]), and sICH (ORunadjusted 1.15 [1.01–1.22]; ORadjusted 1.11 [1.04–1.20]). Low GFR was independently associated with poor 3-month outcome (ORadjusted 1.32 [1.10–1.58]), death (ORadjusted 1.73 [1.39–2.14]), and sICH (ORadjusted 1.64 [1.21–2.23]) compared with normal GFR (60–120 mL/min/1.73 m2). Low GFR (ORadjusted 1.64 [1.21–2.23]) and stroke severity (ORadjusted 1.05 [1.03–1.07]) independently determined sICH. Compared with patients who did not receive IVT, treatment with IVT in patients with low GFR was associated with poor outcome (ORadjusted 1.79 [1.41–2.25]), and with favorable outcome in those with normal GFR (ORadjusted 0.77 [0.63–0.94]).
Conclusion: Renal function significantly modified outcome and complication rates in IVT-treated stroke patients. Lower GFR might be a better risk indicator for sICH than age. A decrease of GFR by 10 mL/min/1.73 m2 seems to have a similar impact on the risk of death or sICH as a 1-point-higher NIH Stroke Scale score measuring stroke severity.
Atrophy in specific brain areas correlates with poor neuropsychological outcome after subarachnoid hemorrhage (SAH). Few studies have compared global atrophy in SAH with outcome. The authors examined the relationship between global brain atrophy, clinical factors, and outcome after SAH.
This study was a post hoc exploratory analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial, a randomized, double-blind, placebo-controlled trial of 413 patients with aneurysmal SAH. Patients with infarctions or areas of encephalomalacia on CT, and those with large clip/coil artifacts, were excluded. The 97 remaining patients underwent CT at baseline and 6 weeks, which was analyzed using voxel-based volumetric measurements. The percentage difference in volume between time points was compared against clinical variables. The relationship with clinical outcome was modeled using univariate and multivariate analysis.
Worse mRS score, NIHSS score, executive functioning, and EQ-5D scores were associated with greater brain atrophy and older age, male sex, and SIRS burden. These data suggest outcome is associated with factors that cause global brain injury independent of focal brain injury.
The Interventional Management of Stroke III trial was recently stopped because low-dose intravenous tissue plasminogen activator (IV TPA) combined with thrombectomy or intra-arterial TPA did not improve outcomes compared with standard-dose IV TPA alone. This disappointing preliminary report is now followed by more encouraging publications from two other trials.
SWIFT and TREVO 2 are industry-sponsored randomized trials comparing new stent retrievers with the Merci Retriever, which was FDA-approved in 2004 as the first mechanical thrombectomy device. Both trials enrolled patients who could not receive or had failed to respond to IV TPA and could undergo thrombectomy within 8 hours of stroke onset. Participants had NIH Stroke Scale (NIHSS) scores of 8 (median score, 18–19). Patients underwent up to three attempts with the randomly assigned device before receiving rescue therapy as needed with any approved endovascular technique.
In SWIFT, the Solitaire device significantly outperformed the Merci Retriever in achieving recanalization (69% vs. 30%) and in providing good neurological outcomes (modified Rankin Scale score [mRS] 2; 58% vs. 33%) and lower mortality (17% vs. 38%) at 90 days. Similarly, the Trevo Retriever achieved significantly higher rates of recanalization (86% vs. 60%) and 90-day good outcomes (mRS 2; 40% vs. 22%) than the Merci Retriever.
Comment: Although it is unlikely, the differences in clinical outcomes could reflect harm from the Merci Retriever rather than benefit from the Solitaire and Trevo devices. To definitively establish the effectiveness of thrombectomy, we need trials comparing such new devices with IV TPA alone, perhaps using advanced imaging to identify appropriate candidates. In the meantime, clinicians should strongly consider transferring patients who cannot receive or do not quickly respond to IV TPA to endovascular-capable stroke centers for consideration of available treatment options and enrollment in randomized trials.
Hospital rankings changed markedly after accounting for stroke severity, highlighting the limitations of administrative data for comparing the quality of stroke care.
Fair comparisons of hospitals‘ performance require reliable methods to account for differences in patients‘ baseline characteristics and predicted risk for adverse events, because otherwise hospitals would be penalized for treating sicker patients. The Centers for Medicare and Medicaid Services (CMS) has proposed a risk-adjustment model for comparing hospitals’ mortality rates after stroke. However, this model relies on administrative data and does not account for stroke severity, prompting concern that it would imperfectly capture baseline differences. To address this concern, investigators have compared the performance of the proposed CMS model with and without an added measure of baseline stroke severity.
By linking CMS claims data to the Get With The Guidelines–Stroke registry, the researchers could add patients’ baseline NIH Stroke Scale (NIHSS) scores to the administrative data in the CMS model. The addition of NIHSS scores substantially improved the model’s prediction of 30-day mortality: Its C statistic increased significantly, from 0.772 to 0.864. Strikingly, when hospitals were divided into the top and bottom 20% and middle 60%, 26.3% of hospitals changed category after the addition of NIHSS scores. Of hospitals with “worse than expected” mortality using the standard CMS model, 57.7% were reclassified as having “as expected” mortality after the addition of NIHSS scores.
Comment: Efforts to improve hospital accountability and institute bundled payments to hospitals and providers will rely on risk-adjustment models to account for case mix. The details of such models can be arcane, yet the stakes are enormous, because flawed models will unfairly penalize those caring for sicker patients and enable gaming of publicly-reported outcomes and reimbursement rates. This timely study is a reminder that clinicians must actively engage with policymakers to develop reliable risk-adjustment models. Measures of stroke severity clearly must be accounted for, although doing so efficiently and reliably will take some creative thinking.