Intravenous Tissue Plasminogen Activator Therapy Research Articles

Pseudo Todd’s palsy in a patient with medically intractable epilepsy

Patients with epilepsy may also have non-epileptic seizures (pseudo seizures). One study showed that 1 out of 5 people presenting to a comprehensive epilepsy center with the diagnosis of medically intractable epilepsy actually had non-epileptic events when monitored. It is particularly difficult to diagnose non-epileptic seizures in patients who also suffer from real epileptic seizures. Various non-epileptic clinical presentations have been reported in the literature. Patients may present with predominantly non-epileptic convulsions characterized by out of phase thrashing movements of the limbs, pelvic thrusting and side to side movements of the head. At other times the non-epileptic manifestations are predominantly psychiatric in character with patients exhibiting bizarre behavior, reporting vivid visual and somatosensory hallucinations or directed vocalizations. We present here a patient with medically intractable epilepsy who presented with dense hemiplegia and hemisensory loss after reported seizures at home. Patient was considered an ideal candidate for intravenous tissue plasminogen activator (tPA) therapy so an acute stroke up was initiated at the time of presentation to the ER. CT scan and MRI brain with DWI was negative for acute stroke. Neurological examination was suggestive of psychogenic weakness. Patient made a full recovery over a course of 2 days. Pseudoparalysis or pseudo Todd’s palsy should be considered in the differential of a patient with epilepsy presenting with acute hemiplegia and other focal neurological deficits especially if they are young and lack traditional vascular risk factors for stroke.

Impact of the Approval of Intravenous Recombinant Tissue Plasminogen Activator Therapy on the Processes of Acute Stroke Management in Japan

The Ministry of Health, Labor, and Welfare of Japan approved the use of recombinant tissue-type plasminogen activator (rt-PA) for the treatment of acute ischemic stroke in October 2005. The impact of the regulatory approval of rt-PA on the processes of acute stroke management was examined. A prospective, multicenter, observational study was conducted between December 2004 and December 2005 in 84 Japanese institutes, including 24 institutes with a stroke unit. We enrolled 4620 consecutive patients who were hospitalized within 72 hours after the onset of completed ischemic stroke; 1089 of them were hospitalized after rt-PA was approved. The patients' characteristics and the processes of stroke management were compared before and after rt-PA approval. Age, gender, stroke subtype, time from onset to hospital visit, and National Institutes of Health Stroke Scale score on admission were similar between the 2 periods. With approval, the percentage of patients treated with intravenous rt-PA therapy increased from 0.7% to 2.6% (P<0.001). The rate increased from 0.9% to 5.2% in institutes with a stroke unit (P<0.001) but did not increase in other institutes (P=0.587). Within 24 hours of stroke onset, conventional MRI (P=0.003), diffusion-weighted MRI (P<0.001), magnetic resonance angiography (P=0.001), carotid ultrasound (P=0.004), measurement of prothrombin time or activated partial thromboplastin time (P=0.034), and measurement of blood sugar (P=0.015) were performed more frequently after rt-PA approval. The present results indicate that the approval of intravenous rt-PA therapy resulted in dramatic changes in the processes of management for acute stroke patients.

Early Neurological Deterioration following Intravenous Recombinant Tissue Plasminogen Activator Therapy in Patients with Acute Lacunar Stroke

Background: The aim of this study was to examine the rate of early neurological deterioration (END) and favorable outcomes after acute lacunar stroke following the use of intravenous recombinant tissue plasminogen activator (IV rtPA). Methods: A total of 76 acute lacunar stroke patients (<12 h from symptom onset) were enrolled during a 1-year period (n = 76). Comparisons were made between those who received (group A; n = 29) or did not receive (group B; n = 47) IV rtPA. Results: END/favorable outcomes were observed in 24/31% of the subjects in group A and 21/23% in group B (p = 0.77/0.46). Subgroup analysis of the etiologic subtype of small-vessel occlusion showed that END/favorable outcomes were observed in about 33/33% and 15/19% of the patients in groups A and B, respectively (p = 0.21/0.34). Conclusions: The authors showed that the use of rtPA in cases of no lysible clots might not affect the END and favorable outcomes.

Percutaneous Clot Removal Devices in Acute Ischemic Stroke

We conducted a systematic review and meta-analysis of mechanical thrombectomy in the treatment of ischemic stroke and assessed factors for technical and clinical success and survival. We searched the literature using MEDLINE and EMBASE for January 1, 2000, through March 1, 2006. Studies were limited to those in human beings; there were no language or study design restrictions. Validity assessment was performed using the Newcastle-Ottawa Scale. The pooled cohort was compared with a historical cohort matched for sex, age, and National Institutes of Health Stroke Survey score. The search yielded 114 publications. Two authors determined inclusibility (interrater agreement, kappa = 0.94). Mean preprocedure National Institutes of Health Stroke Survey score was 20.4. The middle cerebral artery (36%) and the posterior circulation (38%) were the most frequently occluded areas. The clot was accessible in 85% of the patients. Hemorrhage occurred in 22% of the patients. Of 81 patients with concurrent thrombolysis, 18.5% had hemorrhage compared with 27.3% of 66 patients without thrombolysis (P = .21). Of the 126 patients with accessible clots, 36% had a good modified Rankin score (<or=2) and 29% died; in patients with inaccessible clots, 24% had a good modified Rankin score and 38% died. Factors associated with clinical success were younger age (P = .001) and lower National Institutes of Health Stroke Survey score at admission to the hospital (P = .001). Compared with a matched cohort, patients who received mechanical intervention were 14.8 times more likely to have a good modified Rankin score (95% confidence interval, 4.4-50.0; P < .001). Percutaneous mechanical embolectomy in the treatment of acute ischemic stroke is feasible and seems to provide an option for some patients seen after the interval for administration of intravenous tissue plasminogen activator therapy has elapsed.

Antiplatelet Therapy and the Risk of Intracranial Hemorrhage After Intravenous Tissue Plasminogen Activator Therapy for Acute Ischemic Stroke

Antiplatelet Therapy and the Risk of Intracranial Hemorrhage After Intravenous Tissue Plasminogen Activator Therapy for Acute Ischemic Stroke

Simultaneous Treatment with Intravenous Recombinant Tissue Plasminogen Activator and Endovascular Therapy for Acute Ischemic Stroke Within 3 Hours of Onset

Because intravenous (IV) recombinant tissue plasminogen activator (rtPA) does not always lead to a good outcome in a considerable proportion of patients, combined IV rtPA and rescue endovascular therapy (ET) have been performed in several recent studies. However, rescue therapy after completion of IV rtPA often results in late ineffective recanalization. We examined the efficacy and safety of combined IV rtPA and simultaneous ET as primary rather than rescue therapy for hyperacute middle cerebral artery (MCA) occlusion. A total of 29 patients eligible for IV rtPA, who were diagnosed as having MCA (M1 or M2) occlusion within 3 hours of onset, underwent thrombolysis. In the combined group, patients were treated by IV rtPA (0.6 mg/kg for 60 minutes) and simultaneous ET (intra-arterial rtPA, mechanical thrombus disruption with microguidewire, and balloon angioplasty) initiated as soon as possible. In the IV group, patients were treated by IV rtPA only. The improvement of the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours was 11 +/- 4.8 in the combined group versus 5 +/- 4.3 in the IV group (P < .001). In the combined group, successful recanalization was observed in 14 (88%) of 16 patients with no symptomatic intracranial hemorrhage, and 10 (63%) of 16 patients had favorable outcomes (modified Rankin Scale [mRS] 0, 1) at 3 months. Aggressive combined therapy with IV rtPA and simultaneous ET markedly improved the clinical outcome of hyperacute MCA occlusion without significant adverse effect. Additional randomized study is needed to confirm our results.

Safety of Antiplatelet Therapy Prior to Intravenous Thrombolysis in Acute Ischemic Stroke

There is some uncertainty whether prior use of antiplatelet (AP) drugs increases the risk of symptomatic intracerebral hemorrhage (SICH) and influences functional outcome in patients with ischemic stroke treated with intravenous thrombolysis. To assess whether prior use of AP drugs is related to outcome following intravenous tissue plasminogen activator therapy in patients with ischemic stroke. A single-center prospective observational cohort study of the relation between prior AP therapy, occurrence of SICH, and functional outcome of consecutive patients with ischemic stroke undergoing intravenous thrombolysis with tissue plasminogen activator in a university hospital between April 1, 2002, and November 30, 2006. The occurrence of SICH and favorable outcome reflecting independence defined as a modified Rankin Scale score of 2 or lower at 3 months. Of the 301 patients who received intravenous tissue plasminogen activator, 89 used AP drugs prior to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 12 patients (13.5%; 95% confidence interval, 7.8%-22.3%) who had received AP drugs and in 6 patients (2.8%; 95% confidence interval, 1.2%-6.2%) without prior AP therapy (P = .001). Multivariate analysis revealed that prior AP therapy was an independent predictor of SICH (odds ratio, 6.0; 95% confidence interval, 2.0-17.1). Nonetheless, prior AP therapy was independently associated with a favorable outcome (odds ratio, 2.0; 95% confidence interval, 1.0-4.3). Despite a higher incidence of SICH, the net benefit of intravenous tissue plasminogen activator therapy for acute ischemic stroke was greater in patients using AP drugs.

Abstract No. 46: Severity of Stroke in a Rabbit Model; Effects of Ultrasound Augmentation of Thrombolysis

Intravenous (IV) tissue plasminogen activator (tPA) therapy for acute ischemic stroke is greatly underutilized because of time constraints, limited effectiveness, and serious bleeding complications. Intraarterial interventions are often not available. Early reports of ultrasound augmented thrombolytic therapy in humans are most promising. We compare ultrasound (US) and microbubble (MB) augmented thrombolysis in an angiographic rabbit model of ischemic stroke.

Therapy for early reperfusion after stroke

Ischemic stroke is a leading cause of death and disability in the Western world. At present, intravenous administration of tissue plasminogen activator within 3 h of symptom onset is the only proven effective treatment to re-establish cerebral blood flow in the case of acute vessel occlusion. Unfortunately, few patients presenting with acute ischemic stroke qualify for intravenous tissue plasminogen activator therapy. The focus of current research is, therefore, to find new treatment options by which to obtain early reperfusion, and to extend the therapeutic window for intervention beyond 3 h. The purpose of this Review is to provide an integrated view of the current state of reperfusion therapy in patients with acute stroke, including pharmacologic agents and the methods of delivery. The focus will be on intravenous and intra-arterial use of plasminogen activators in acute supratentorial infarction. Other therapies, such as antiplatelet agents (i.e. glycoprotein IIb/IIIa inhibitors), and anticoagulant drugs will be discussed briefly.

Ultrasound Enhanced Thrombolysis for Stroke

In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy, a low rate of early arterial recanalization was suspected because only a few stroke patients may have had early dramatic clinical improvement. Tissue plasminogen activator activity can be enhanced with ultrasound, including 2 MHz transcranial Doppler (TCD). Transcranial Doppler identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. For the first time in clinical medicine, the international multicenter CLOTBUST trial showed that ultrasound enhances the thrombolytic activity of a drug in humans, thereby confirming multidisciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 h after TPA bolus occurred in 25% of patients treated with TPA+TCD compared with 8% who received TPA alone (P=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of 2 MHz TCD with ultrasound contrast agents or (microbubbles): TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C(3)F(8)). Intra-arterial TPA delivery can be enhanced with 1 x 7-2 x 1 MHz pulsed wave ultrasound (EKOS catheter, IMS trial). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are underway.

Fibrinolytic treatment for acute ischaemic stroke

Ischaemic stroke is a leading cause of death and disability in the US. At present, intravenous administration of tissue plasminogen activator within 3 h of symptom onset is the only proven effective treatment for patients with acute ischaemic stroke. Unfortunately, most treated patients do not make a functional recovery and very few patients presenting with acute stroke qualify for intravenous tissue plasminogen activator therapy. The focus of current research is to extend the therapeutic window for intervention beyond 3 h, and to improve the outcome of treated patients. The purpose of the present paper is to describe the current state of affairs for intravenous plasminogen activators, and to review recently published research. Agents and strategies under investigation include the intra-arterial delivery of plasminogen activators or antiplatelet agents, as well as combined intravenous/intra-arterial protocols.

Editorial Comment—Organized Stroke Care

The past decade has witnessed a dramatic change in treatment of acute stroke, leaving the era of an indifferent approach firmly behind. However, equally important to the development of particular emergency treatments is the recognition that the organization of stroke services per se plays a key role in the provision of effective therapies and in improving the overall outcome after stroke. In this issue of the journal, the consensus statement from the Brain Attack Coalition (BAC), a group with representatives from major professional and advocacy organizations involved in stroke care, with extensive recommendations for comprehensive stroke centers is published.1 The report is a companion to the recommendations for the establishment of primary stroke centers published by the same group in 2000.2 The previous report of the BAC2 detailed 11 key elements of a primary stroke center to improve patient care and outcomes. Recommendations included acute stroke teams, stroke units, written care protocols, and an integrated emergency response system. A major impetus for the recommendation was clearly to establish the infrastructure and logistics to permit broad implementation of intravenous tissue plasminogen activator therapy within the 3-hour window according to the criteria of the NINDS trial. A survey showed that in 2001, emergency services for acute stroke therapy were in place at the majority of hospitals,3 and the situation has further improved later on. However, and somewhat surprisingly from a non-US perspective, establishment of stroke units was given less emphasis in the BAC recommendations. Stroke units were not considered to be required for primary stroke centers that did not intend to provide care …

Rescue localized intra-arterial thrombolysis for hyperacute MCA ischemic stroke patients after early non-responsive intravenous tissue plasminogen activator therapy

The outcome of patients who show no early response to intravenous (i.v.) tissue plasminogen activator (tPA) therapy is poor. The objective of this study was to evaluate the feasibility of rescue localized intra-arterial thrombolysis (LIT) therapy for acute ischemic stroke patients after an early non-responsive i.v. tPA therapy. Patients with proximal MCA occlusions who were treated by LIT (n = 10) after failure of early response [no improvement or improvement of National Institute of Health Stroke Scale (NIHSS) scores of < or = 3] to i.v. tPA therapy (0.9 mg/kg-10% bolus and 90% i.v. infusion over 60 min) were selected. The recanalization rates, incidence of post-thrombolysis hemorrhage and clinical outcomes [baseline and discharge NIHSS scores, mortality, 3 months Barthel index (BI) and modified Rankin score (mRS)] were evaluated. Rescue LIT therapy was performed on ten MCA occlusion patients (male:female = 3:7, mean age 71 years). The mean time between the initiation of i.v. tPA therapy and the initiation of intra-arterial urokinase (i.a. UK) was 117+/-25.0 min [time to i.v. tPA 137+/-32 min; time to digital subtraction angiography (DSA) 221+/-42 min; time to i.a. UK 260+/-46 min]. The baseline NIHSS scores showed significant improvement at discharge (median from 18 to 6). Symptomatic hemorrhage and, consequent, mortality were noted in 2/10 (20%) patients. Three months good outcome was noted in 4/10 (40%, mRS 0-2) and 3/10 (30%, BI > or = 95). In conclusion, rescue LIT therapy can be considered as a treatment option for patients not showing early response to full dose i.v. tPA therapy. Larger scale studies for further validation of this protocol may be necessary.

Ultrasound Enhanced Thrombolysis for Stroke

Spontaneous arterial recanalization occurs at a rate of 6% per hour, and it can be doubled with intravenous tissue plasminogen activator (TPA) therapy since early dramatic clinical improvement, a substitute for early thrombus break-up, occurs in TPA-treated patients. TPA activity can be enhanced with ultrasound including 2-MHz transcranial Doppler (TCD). TCD identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA+TCD compared with 8% who received TPA alone ( P = 0.02). Complete clearance of a thrombus and dramatic recovery of brain function during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the Target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months, thus providing the rationale for a pivotal trial. The ability of TPA to break up thrombi can be further enhanced with harmless diagnostic ultrasound contrast agents. Current ongoing clinical trials include phase II studies of 2-MHz TCD with ultrasound contrast agents, or microbubbles: TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C 3 F 8 ImaRx). Intraarterial ultrasound-enhanced TPA delivery is tested in the Interventional Management of Stroke (IMS) clinical trial using 1.7- to 2.1-MHz pulsed-wave ultrasound catheter (EKOS). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are currently underway.

Markedly Reduced Apparent Blood Volume on Bolus Contrast Magnetic Resonance Imaging as a Predictor of Hemorrhage After Thrombolytic Therapy for Acute Ischemic Stroke

Accurate assessment of the risk of hemorrhage could help to improve patient selection for thrombolytic therapy and reduce hemorrhagic complications, especially for patients with longer or uncertain time after symptom onset. This study sought to define characteristics of hemodynamic magnetic resonance imaging (MRI), which best predict hemorrhage. Bolus contrast and diffusion MRI were performed before intravenous tissue plasminogen activator (tPA) therapy in 20 patients presenting with acute stroke symptoms within the first 6 hours after symptom onset. Hemorrhage was assessed on follow-up MRI (n=15) and computed tomography (n=5) scans. Of the 20 patients studied, 5 had detectable hemorrhage on follow-up scans. Blood volume maps demonstrated virtually no signal within much of the hemorrhagic region, indicating contrast did not arrive by the end of the imaging series (80 seconds). Within the hemodynamically abnormal region, a threshold of at least 126 voxels with blood volume <5% of contralateral normal gray matter separated hemorrhagic patients from nonhemorrhagic with a sensitivity of 100% and a specificity of 73% (P<0.01). All subjects with hemorrhage were at least partially reperfused after thrombolysis, whereas most false-positives did not reperfuse (P<0.05). The number of low blood volume voxels within individual patients correlated with the number of voxels with apparent diffusion coefficient values <550x10(-6) mm2/s (P<0.019), another previously proposed predictor of hemorrhage. Extremely low or completely absent contrast arrival may indicate tissue-at-risk for hemorrhage before tPA treatment and thus may aid in risk-benefit assessments. Occurrence of hemorrhage within at-risk areas may depend on tissue reperfusion.

Safety and Feasibility of a Lower Dose Intravenous TPA Therapy for Ischemic Stroke beyond the First Three Hours

Background: The most common reason that patients do not receive intravenous tissue plasminogen activator (TPA) is the inability to meet the strict 3-hour treatment window. The risk/benefit ratio is more unfavorable beyond this time, but some patients might still benefit. We designed a pilot study with the hypothesis that lower dose TPA might be safe in selected patients treated beyond 3 h. Subjects and Methods: To determine the range of symptomatic hemorrhage and good outcome, we prospectively gave IV TPA 0.6 mg/kg up to 60 mg (15% bolus, 85% infusion over 30 min) to patients with ischemic stroke beyond the first 3 h after last known to be normal. Other eligibility criteria were: NIH Stroke Scale ≧4, normal head CT scan, and clinical suspicion or transcranial Doppler (TCD) evidence of a proximal arterial occlusion. Results: 28 patients were treated, median age 65 (range 24–88) years, median baseline NIHSS score 18 (range 7–34) points. TPA bolus was given 372 ± 158 min after stroke onset (range 189–720). Symptomatic hemorrhage occurred in 3/28 (11%) patients, including 1 fatal bleed. Overall mortality was 6/28 (21%). Partial or complete recanalization was found in 8/20 (40%) TCD monitored patients within 2 h after TPA bolus. Early major improvement occurred in 4/28 (14%) patients. Conclusions: Lower dose IV TPA in patients presenting beyond 3 h carries a risk of intracerebral hemorrhage. However, recanalization with dramatic recovery can still occur.

Are There Time-Dependent Differences in Diffusion and Perfusion Within the First 6 Hours After Stroke Onset?

Stroke heterogeneity in computed tomography-based studies has been attributed as main cause for missing efficacy of intravenous tissue plasminogen activator (tPA) therapy within 3 to 6 hours. We investigated early time-dependent differences in acute stroke pathophysiology by multiparametric magnetic resonance imaging (MRI). Stroke MRI of 112 acute ischemic stroke patients within <6 hours were dichotomized into a <3-hour group (n=52) and a 3- to 6-hour group (n=60). Infarct volume was determined on days 5 to 8. Lesion volumes were determined for apparent diffusion coefficient (ADC_man) and the subregion with ADC values <550x10(-9) mm/s2 (ADC <550), and for the time-to-peak (TTP) delay of 2 to 4 seconds, 4 to 6 seconds, 6 to 8 seconds, and >8 seconds. A subsample analysis was performed for occlusions of the middle carotid artery (MCA) trunk (n=36) and MCA branches (n=30), and for all patients treated by intravenous tPA (n=70). ADC and TTP lesion volumes were not different within <3 hours compared with volumes at 3 to 6 hours. In patients receiving intravenous tPA (n=70), there were no significant differences in ADC_man, TTP >2 seconds, and infarct volume (days 5 to 8) between the 2 groups. There was a greater proportion of ADC <550/ADC_man, which was most pronounced in patients with MCA trunk occlusions after 3 to 6 hours and a larger mismatch in the <3-hour group compared with that of the 3- to 6-hour group. In MCA branch occlusions, there was a less severe TTP delay after 3 to 6 hours. However, all differences missed the significance level (P=0.05) after correction for multiple testing. We observed no significant time-dependent differences within 6 hours after stroke onset in degree and volume of diffusion and perfusion impairment. An exclusion from intravenous tPA solely based on a rigid 3-hour time window seems unjustified in MRI-confirmed ischemic stroke.

CLOTBUST: Design of a Randomized Trial of Ultrasound‐Enhanced Thrombolysis for Acute Ischemic Stroke

Intravenous tissue plasminogen activator (TPA) therapy can be monitored with 2 MHz transcranial Doppler (TCD). This article describes the design of CLOTBUST (combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic TPA), the first prospective international multicenter randomized clinical trial of noninvasive externally applied ultrasound to enhance systemic thrombolysis in human stroke. Patients with acute ischemic stroke eligible for intravenous TPA therapy within 3 hours of symptom onset who have detectable middle cerebral artery occlusion on a prebolus TCD are included in this trial. All patients receive standard 0.9 mg/kg TPA therapy. Patients are randomized (1:1) to either 2 hours of continuous monitoring with TCD or placebo monitoring. FDA-approved portable diagnostic TCD equipment and standard headframes (Marc series, Spencer Technologies, Seattle, WA) are used. Output of TCD units is set at 100% power achievable at depths of insonation that display the worst TIBI flow grade signals. METHODS AND END-POINTS: Acute MCA occlusion on prebolus TCD is defined as thrombolysis in brain ischemia (TIBI) flow grades 0-3. Treating physicians are blinded to randomization assignment, and certified scorers measure stroke severity using the National Institute of Health Stroke Scale (NIHSS). Safety of continuous TCD monitoring is determined by rates of symptomatic (NIHSS score increase by 4+ points) intracerebral hemorrhage within 72 hours after initial symptom onset. Potential enhancement of TPA therapy will be determined using combined primary end-point of early complete recanalization on TCD (TIBI flow grades 4-5), dramatic recovery (NIHSS < or = 3 points), or decline in the NIHSS > or = 10 points repeatedly measured every 30 minutes within 2 hours after TPA bolus. Other end-points include recovery at 24 hours and 3 months, modified Rankin scores (mRS) are obtained at 90 days, and favorable outcome is determined as NIHSS or mRS scores 0-1. The aim of phase II CLOTBUST trial is to determine the rates of early complete recanalization and dramatic/early clinical recovery in TPA + TCD and TPA groups. The sample size is set at 126 patients since a medium effect size (.50) is anticipated for TPA + TCD group vs TPA alone to achieve combined primary end-point.

Residual Flow Signals Predict Complete Recanalization in Stroke Patients Treated With TPA

Residual blood flow around thrombus prior to treatment predicts success of coronary thrombolysis. The authors aimed to correlate the presence of residual flow signals in the middle cerebral artery (MCA) with completeness of recanalization after intravenous tissue plasminogen activator (TPA). The authors studied consecutive patients treated with intravenous TPA therapy who had a proximal MCA occlusion on pretreatment transcranial Doppler (TCD). Patients were continuously monitored for 2 hours after TPA bolus. Absent residual flow signals correspond to the thrombolysis in brain ischemia (TIBI) 0 grade, and the presence of residual flow signals was determined as TIBI 1-3 flow grades. Complete recanalization was defined as flow improvement to TIBI grades 4-5. Seventy-five patients with a proximal MCA occlusion had median pre-bolus NIHSS 16 (85% with > or = 10 points). TPA bolus was given at 141 +/- 56 minutes (median 120 minutes). Complete recanalization was observed in 25 (33%), partial in 23 (31%), and no early recanalization was seen in 27 (36%) patients within 2 hours after TPA bolus. Only 19% with absent residual flow signals (TIBI grade 0, n = 26) on pretreatment TCD had complete early recanalization. If pretreatment TCD showed the presence of any residual flow (TIBI 1-3, n = 49), 41% had complete recanalization within 2 hours of TPA bolus (P = .03). Patients with detectable residual flow signals before IV TPA bolus are twice as likely to have early complete recanalization. Those with no detectable residual flow signals have less than 20% chance for complete early recanalization with intravenous TPA and may be candidates for intra-arterial therapies.

Ultrasound-enhanced thrombolysis for stroke: clinical significance

In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy for ischemic stroke, a low rate of early arterial recanalization was suspected due to the small numbers of patients who had early dramatic clinical improvement. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD can identify residual signals around the thrombus with the thrombolysis in brain ischemia (TIBI) flow grading system and therefore expose more thrombus surface to circulating TPA. A phase I clinical study, monitoring TPA infusion with diagnostic ultrasound resulted in an unexpectedly high rate of complete recanalization (36% of proximal middle cerebral artery (MCA) occlusions) and associated early dramatic clinical recovery (24%) among treated patients. The external application of diagnostic ultrasound in our studies raised the possibility that a synergistic TPA and ultrasound action accelerated flow improvement and achieved faster and more complete thrombus dissolution as predicted from experimental models. The CLOTBUST (combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic TPA) trial is testing this hypothesis in a phase II clinical randomized multi-center setting. Dramatic clinical recovery from stroke and complete recanalization shortly after TPA bolus are feasible goals for thrombolysis assisted with TCD monitoring.