April Sisson

The Argatroban and Tissue-Type Plasminogen Activator Stroke Study Final Results of a Pilot Safety Study

Background and Purpose— Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. Methods— During standard-dose intravenous tPA, a 100-&mgr;g/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. Results— Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38–60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2–7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7–15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). Conclusions— The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00268762.

CLOTBUST-Hands Free 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. Methods— All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. 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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356.

Safety and Tolerability of Early Noninvasive Ventilatory Correction Using Bilevel Positive Airway Pressure in Acute Ischemic Stroke

Background and Purpose— Hypercapnia can induce intracranial blood-flow steal from ischemic brain tissues, and early initiation of noninvasive ventilator correction (NIVC) may improve cerebral hemodynamics in acute ischemic stroke. We sought to determine safety and tolerability of NIVC initiated on hospital admission without polysomnography study. Subjects and Methods— Consecutive acute ischemic stroke patients were evaluated for the presence of a proximal arterial occlusion, daytime sleepiness, or history of obstructive sleep apnea, and acceptable pulse oximetry readings while awake (96%–100% on 2 to 4 L supplemental oxygen delivered by nasal cannula). NIVC was started on hospital admission as standard of care when considered necessary by treating physicians. NIVC was initiated using bilevel positive airway pressure at 10 cmH2O inspiratory positive airway pressure and 5 cmH2O expiratory positive airway pressure in combination with 40% fraction of inspired oxygen. All potential adverse events were prospectively documented. Results— Among 356 acute ischemic stroke patients (median NIHSS score, 5; interquartile range, 2–13), 64 cases (18%) received NIVC (median NIHSS score, 12; interquartile range, 6–17). Baseline stroke severity was higher and proximal arterial occlusions were more frequent in NIVC patients compared to the rest (P<0.001). NIVC was not tolerated by 4 patients (7%). Adverse events in NIVC included vomiting (n=1), aspiration pneumonia (n=1), respiratory failure/intubation (n=1), hypotension requiring pressors (n=1), and facial skin breakdown (n=3). The in-hospital mortality rate was 13% in NIVC patients and 8% in the rest (P=0.195). Neurological improvement during hospitalization tended to be greater in the NIVC group (median NIHSS score decrease, 2 points; interquartile range, 0–4) compared to the rest (median NIHSS score decrease, 1; interquartile range, 0–2; P=0.078). Conclusions— In acute ischemic stroke patients with proximal arterial occlusion and excessive sleepiness or obstructive sleep apnea, NIVC can be initiated early with good tolerability and a relatively small risk of serious complications.

CLOTBUST-Hands Free Initial Safety Testing of a Novel Operator-Independent Ultrasound Device in Stroke-Free Volunteers

Background and Purpose— We aimed to evaluate safety and tolerability of a novel operator-independent ultrasound device among stroke-free volunteers. Methods— A headframe containing 18 ultrasound transducers (each operating at 2 MHz, pulsed-wave) was used to expose both temporal windows and the suboccipital window. The transmission characteristics were set to emulate the acoustic characteristics of the exposure levels in the Combined Lysis of Thrombus in Brain Ischemia using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial and to never exceed Food and Drug Administration mandated diagnostic ultrasound exposure limits. Volunteers underwent 2 hours of insonation with transducer activation one at a time. Safety was captured using serial neurological examinations and pre- and postinsonation MRI for detection of the blood brain barrier permeability. Results— A total of 15 volunteers (40% men; 49±16 years; 27% black; all pre-exposure National Institutes of Health Stroke Scale scores 0) were enrolled. Five volunteers received pulsed-wave ultrasound via the best pair temporal transducers, 5 via sequential activation of the suboccipital transducers, and 5 via sequential activation of all bilateral temporal and suboccipital transducers. All subjects were safely insonated with no adverse effects as indicated by the neurological examinations during, immediately after the exposure, and at 24 hours, and no abnormality of the blood brain barrier was found on any of the MRIs. Conclusions— Our novel device was well tolerated by stroke-free volunteers and did not cause any neurological dysfunction nor did it affect blood brain barrier integrity. The safety and efficacy of the device are now being tested in stroke patients receiving intravenous tissue-type plasminogen activator in phase II–III clinical trials.

Systemic Inflammatory Response Syndrome in Tissue-Type Plasminogen Activator–Treated Patients is Associated With Worse Short-term Functional Outcome

Background and Purpose— Systemic inflammatory response syndrome (SIRS) is a generalized inflammatory state. The primary goal of the study was to determine whether differences exist in outcomes in SIRS and non-SIRS intravenous tissue-type plasminogen activator–treated patients. Methods— Consecutive patients were retrospectively reviewed for the evidence of SIRS during their admission. SIRS was defined as the presence of ≥2 of the following: body temperature <36°C or >38°C, heart rate >90, respiratory rate >20, and white blood cells <4000/mm or >12 000 mm, or >10% bands. Patients diagnosed with infection (via positive culture) were excluded. Results— Of the 241 patients, 44 had evidence of SIRS (18%). Adjusting for pre–tissue-type plasminogen activator National Institutes of Health Stroke Scale, age, and race, SIRS remained a predictor of poor functional outcome at discharge (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.16–5.73; P=0.0197). Conclusions— In our sample of tissue-type plasminogen activator–treated (tPA) patients, ~1 in 5 patients developed SIRS. Furthermore, we found the presence of SIRS to be associated with poor short-term functional outcomes and prolonged length of stay.

Predictors of Systemic Inflammatory Response Syndrome in Ischemic Stroke Undergoing Systemic Thrombolysis with Intravenous Tissue Plasminogen Activator

BACKGROUND Systemic inflammatory response syndrome (SIRS) is an inflammatory process associated with poor outcomes in acute ischemic stroke (AIS) patients. However, no study to date has investigated predictors of SIRS in AIS patients treated with intravenous (IV) tissue plasminogen activator (tPA). METHODS Consecutive patients were retrospectively reviewed for evidence of SIRS during their acute hospitalization. SIRS was defined as the presence of 2 or more of the following: (1) body temperature less than 36°C or greater than 38°C, (2) heart rate greater than 90, (3) respiratory rate greater than 20, or (4) white blood cell count less than 4000/mm or greater than 12,000/mm or more than 10% bands for more than 24 hours. Those diagnosed with an infection were excluded. A scoring system was created to predict SIRS based on patient characteristics available at the time of admission. Logistic regression was used to evaluate potential predictors of SIRS using a sensitivity cutoff of ≥65% or area under the curve of .6 or more. RESULTS Of 212 patients, 44 had evidence of SIRS (21%). Patients with SIRS were more likely to be black (61% versus 54%; P = .011), have lower median total cholesterol at baseline (143 versus 167 mg/dL; P = .0207), and have history of previous stroke (51% versus 35%; P = .0810). Ranging from 0 to 6, the SIRS prediction score consists of African American (2 points), history of hypertension (1 point), history of previous stroke (1 point), and admission total cholesterol less than 200 (2 points). Patients with an SIRS score of 4 or more were 3 times as likely to develop SIRS when compared with patients with a score of ≤3 (odds ratio = 2.815, 95% confidence interval 1.43-5.56, P = .0029). CONCLUSIONS In our sample of IV tPA-treated AIS patients, clinical and laboratory characteristics available on presentation were able to identify patients likely to develop SIRS during their acute hospitalization. Validation is required in other populations. If validated, this score could assist providers in predicting who will develop SIRS after treatment with IV tPA.

Safety of Intravenous Tissue Plasminogen Activator Administration with Computed Tomography Evidence of Prior Infarction

BACKGROUND Prior stroke within 3 months excludes patients from thrombolysis; however, patients may have computed tomography (CT) evidence of prior infarct, often of unknown time of origin. We aimed to determine if the presence of a previous infarct on pretreatment CT is a predictor of hemorrhagic complications and functional outcomes after the administration of intravenous (IV) tissue plasminogen activator (tPA). METHODS We retrospectively analyzed consecutive patients treated with IV tPA at our institution from 2009-2011. Pretreatment CTs were reviewed for evidence of any prior infarct. Further review determined if any hemorrhagic transformation (HT) or symptomatic intracerebral hemorrhage (sICH) were present on repeat CT or magnetic resonance imaging. Outcomes included sICH, any HT, poor functional outcome (modified Rankin Scale score of 4-6), and discharge disposition. RESULTS Of 212 IV tPA-treated patients, 84 (40%) had evidence of prior infarct on pretreatment CT. Patients with prior infarcts on CT were older (median age, 72 versus 65 years; P=.001) and had higher pretreatment National Institutes of Health Stroke Scale scores (median, 10 versus 7; P=.023). Patients with prior infarcts on CT did not experience more sICH (4% versus 2%; P=.221) or any HT (18% versus 14%; P=.471). These patients did have a higher frequency of poor functional outcome at discharge (82% versus 50%; P<.001) and were less often discharged to home or inpatient rehabilitation center (61% versus 73%; P=.065). CONCLUSIONS Visualization of prior infarcts on pretreatment CT did not predict an increased risk of sICH in our study and should not be viewed as a reason to withhold systemic tPA treatment after clinically evident strokes within 3 months were excluded.

Hemorrhagic Transformation (HT) and Symptomatic Intracerebral Hemorrhage (sICH) Risk Prediction Models for Postthrombolytic Hemorrhage in the Stroke Belt

Background Symptomatic intracerebral hemorrhage (sICH) remains the most feared complication of intravenous tissue plasminogen activator (IV tPA) treatment. We aimed to investigate how previously validated scoring methodologies would perform in treated patients in two US Stroke Belt states. Methods and Results We retrospectively reviewed consecutive patients from two centers in two Stroke Belt states who received IV tPA (2008–2011). We assessed the ability of three models to predict sICH. sICH was defined as a type 2 parenchymal hemorrhage with deterioration in National Institutes of Health Stroke Scale (NIHSS) score of ≥4 points or death. Among 457 IV tPA-treated patients, 19 (4.2%) had sICH (mean age 68, 26.3% Black, 63.2% female). The Cucchiara model was most predictive of sICH in the entire cohort (AUC: 0.6528) and most predictive of sICH among Blacks (OR = 6.03, 95% CI 1.07–34.1, P = 0.0422) when patients were dichotomized by score. Conclusions In our small sample from the racially heterogeneous US Stroke Belt, the Cucchiara model outperformed the other models at predicting sICH. While predictive models should not be used to justify nontreatment with thrombolytics, those interested in understanding contributors to sICH may choose to use the Cucchiara model until a Stroke Belt model is developed for this region.

The Argatroban and tPA Stroke Study: final results of a pilot safety study

Background and Purpose— Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion. Methods— During standard-dose intravenous tPA, a 100-&mgr;g/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography. Results— Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38–60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2–7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7–15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%). Conclusions— The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00268762.

Noninvasive Ventilatory Correction as an Adjunct to an Experimental Systemic Reperfusion Therapy in Acute Ischemic Stroke

Background. Obstructive sleep apnea (OSA) is a common condition in patients with acute ischemic stroke and associated with early clinical deterioration and poor functional outcome. However, noninvasive ventilatory correction is hardly considered as a complementary treatment option during the treatment phase of acute ischemic stroke. Summary of Case. A 55-year-old woman with an acute middle cerebral artery (MCA) occlusion received intravenous tissue plasminogen activator (tPA) and enrolled into a thrombolytic research study. During tPA infusion, she became drowsy, developed apnea episodes, desaturated and neurologically deteriorated without recanalization, re-occlusion or intracerebral hemorrhage. Urgent noninvasive ventilatory correction with biphasic positive airway pressure (BiPAP) reversed neurological fluctuation. Her MCA completely recanalized 24 hours later. Conclusions. Noninvasive ventilatory correction should be considered more aggressively as a complementary treatment option in selected acute stroke patients. Early initiation of BiPAP can stabilize cerebral hemodynamics and may unmask the true potential of other therapies.