Tissue plasminogen activator

CLOTBUST-Hands Free.

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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.

Source: Stroke

CLOTBUST-HF: Hands-Free Ultrasound and tPA in Acute Stroke.

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Intracranial ultrasound treatment using an operator-independent device together with tissue plasminogen activator (tPA) in stroke patients appears to be safe and produced promising recanalization rates, a new study has shown.

The study, published online in Stroke on October 24, was led by Andrew D. Barreto, MD, University of Texas Health Science Center at Houston.

He explained to Medscape Medical News that ultrasound therapy causes the meshwork of fibrin strands within the clot to disperse, thereby allowing better access of tPA to the clot. “We are particularly targeting patients who have clots that are not likely to lyse completely with tPA — those with moderate to severe strokes,” Dr. Barreto noted.

“Many smaller studies have been performed with transcranial ultrasound and it does seem to have efficacy in helping to dissolve the clot,” he said. The most cited study is the original CLOTBUST(Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic TPA) study published in 2004 in the New England Journal of Medicine, which showed a recanalization rate of 38% with the combination of ultrasound and tPA vs 13% for those given tPA alone.

However, Dr. Barreto noted that delivery of ultrasound via cranial bone windows requires training for both anatomic localization and waveform recognition, which is considered impractical for large-scale use. “As you have to hold the ultrasound device at the same time as identifying the clot, it is too difficult to train enough people to perform the procedure as an emergency bedside therapeutic,” he said.

“Mass expansion of properly trained technicians or clinicians to provide 24/7 stroke coverage to complete a pivotal clinical trial of sonothrombolysis represents a major hurdle,” the researchers write in the Stroke paper.

http://img.medscape.com/news/2012/ht_120206_clot_bust_device_300x225.png

Operator-independent transcranial stroke treatment device.Source: The investigators

“To that end, the development of an operator-independent device that can target the proximal intracranial arteries without specialized neurovascular ultrasound training would make a large-scale, phase 3 clinical trial feasible,” they add.

Hands-Free Device

Such a “hands-free” device has now been manufactured by Cerevast Therapeutics, and the current study represents the first-ever exposure of patients with acute stroke to a combination of tPA and this hands-free ultrasound device. “This device has been manufactured so that it can be used without special training and be applied to all stroke patients by just placing it on their heads,” Dr. Barreto said.

“It is battery powered and easy to fit. One size fits all, with an adjustable head size and ear position,” he explained. “It has been designed so that the probes are positioned in the areas of thinnest bone of the skull: 6 probes on the left and 6 on the right. The device rotates and sequentially fires each probe, thus targeting all the areas of the brain where a large blood clot would be.”

For the current study, known as CLOTBUST-Hands Free (CLOTBUST-HF), 20 stroke patients with a median National Institutes of Health Stroke Scale score of 15 received standard-dose intravenous tPA, along with 2-MHz pulsed-wave ultrasound therapy delivered by the CLOTBUST-HF device used for 2 hours.

Sites of occlusion were middle cerebral artery in 14 patients, terminal internal carotid artery in 3 patients, and vertebral artery in 3 patients. All patients tolerated the entire 2 hours of ultrasound treatment, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device.

40% Recanalization Rate

At 2 hours, 40% of patients had complete recanalization and 10% had partial recanalization. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate at 57%. At 90 days, 5 patients (25%) had an excellent outcome, defined as a modified Rankin scale score of 0 to 1.

“The recanalization rate of 40% is in line with that shown in the NEJM paper. But we did not have a control group in this study,” Dr. Barreto commented. “At day 90 we had a lower percentage of patients with an excellent outcome than in the previous study, but we only had 20 patients so it is difficult to say much about a clinical outcome.”

“This is just a pilot study looking at safety of delivering ultrasound treatment to different areas of the brain. We didn’t see any safety issues and the results definitely suggest the approach is feasible,” he added.

A phase 3 trial — CLOTBUST-ER — is now underway with the hands-free device. The trial is being conducted in 830 patients from 14 countries, with results expected in 2 to 3 years.

CLOTBUST-HF: Hands-Free Ultrasound and tPA in Acute Stroke

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Intracranial ultrasound treatment using an operator-independent device together with tissue plasminogen activator (tPA) in stroke patients appears to be safe and produced promising recanalization rates, a new study has shown.

The study, published online in Stroke on October 24, was led by Andrew D. Barreto, MD, University of Texas Health Science Center at Houston.

He explained to Medscape Medical News that ultrasound therapy causes the meshwork of fibrin strands within the clot to disperse, thereby allowing better access of tPA to the clot. “We are particularly targeting patients who have clots that are not likely to lyse completely with tPA — those with moderate to severe strokes,” Dr. Barreto noted.

“Many smaller studies have been performed with transcranial ultrasound and it does seem to have efficacy in helping to dissolve the clot,” he said. The most cited study is the original CLOTBUST(Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic TPA) study published in 2004 in the New England Journal of Medicine, which showed a recanalization rate of 38% with the combination of ultrasound and tPA vs 13% for those given tPA alone.

However, Dr. Barreto noted that delivery of ultrasound via cranial bone windows requires training for both anatomic localization and waveform recognition, which is considered impractical for large-scale use. “As you have to hold the ultrasound device at the same time as identifying the clot, it is too difficult to train enough people to perform the procedure as an emergency bedside therapeutic,” he said.

“Mass expansion of properly trained technicians or clinicians to provide 24/7 stroke coverage to complete a pivotal clinical trial of sonothrombolysis represents a major hurdle,” the researchers write in the Stroke paper.
Operator-independent transcranial stroke treatment device.Source: The investigators

“To that end, the development of an operator-independent device that can target the proximal intracranial arteries without specialized neurovascular ultrasound training would make a large-scale, phase 3 clinical trial feasible,” they add.

Hands-Free Device

Such a “hands-free” device has now been manufactured by Cerevast Therapeutics, and the current study represents the first-ever exposure of patients with acute stroke to a combination of tPA and this hands-free ultrasound device. “This device has been manufactured so that it can be used without special training and be applied to all stroke patients by just placing it on their heads,” Dr. Barreto said.

“It is battery powered and easy to fit. One size fits all, with an adjustable head size and ear position,” he explained. “It has been designed so that the probes are positioned in the areas of thinnest bone of the skull: 6 probes on the left and 6 on the right. The device rotates and sequentially fires each probe, thus targeting all the areas of the brain where a large blood clot would be.”

For the current study, known as CLOTBUST-Hands Free (CLOTBUST-HF), 20 stroke patients with a median National Institutes of Health Stroke Scale score of 15 received standard-dose intravenous tPA, along with 2-MHz pulsed-wave ultrasound therapy delivered by the CLOTBUST-HF device used for 2 hours.

Sites of occlusion were middle cerebral artery in 14 patients, terminal internal carotid artery in 3 patients, and vertebral artery in 3 patients. All patients tolerated the entire 2 hours of ultrasound treatment, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device.

40% Recanalization Rate

At 2 hours, 40% of patients had complete recanalization and 10% had partial recanalization. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate at 57%. At 90 days, 5 patients (25%) had an excellent outcome, defined as a modified Rankin scale score of 0 to 1.

“The recanalization rate of 40% is in line with that shown in the NEJM paper. But we did not have a control group in this study,” Dr. Barreto commented. “At day 90 we had a lower percentage of patients with an excellent outcome than in the previous study, but we only had 20 patients so it is difficult to say much about a clinical outcome.”

“This is just a pilot study looking at safety of delivering ultrasound treatment to different areas of the brain. We didn’t see any safety issues and the results definitely suggest the approach is feasible,” he added.

A phase 3 trial — CLOTBUST-ER — is now underway with the hands-free device. The trial is being conducted in 830 patients from 14 countries, with results expected in 2 to 3 years.

This study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Cerevast Therapeutics provided the study devices and was not involved in the study design, analysis, or manuscript preparation. A coauthor serves as a consultant to Cerevast Therapeutics Inc and holds a US patent on the technology.

Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial.

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Background

Few data are available from randomised trials about the effect of thrombolysis with alteplase on long-term functional outcome in patients who have had acute ischaemic stroke and no trial has reported effects on health-related quality of life. A secondary objective of the third International Stroke Trial (IST-3) was to assess the effect of thrombolysis on such outcomes at 18 months.

Methods

In this open-label, international, multicentre, randomised, controlled trial, 3035 patients with ischaemic stroke from 12 countries were randomly allocated within 6 h of onset via a secure central system to either intravenous alteplase (0·9 mg/kg; n=1515) plus standard care or standard care alone (control; n=1520). 2348 patients were scheduled for 18-month follow-up. For our main analysis, survivors were assessed at 18 months with the Oxford handicap scale (OHS; the primary outcome was the adjusted odds of OHS score 0—2). We also used the EuroQoL (EQ) instrument and asked questions about overall functioning and living circumstances. We analysed the OHS and the five EQ domains by ordinal logistic regression and calculated the mean difference between treatment groups in EQ utility index and visual analogue scale score. Analyses were adjusted for key baseline prognostic factors. This study is registered with controlled-trials.com, number ISRCTN25765518.

Findings

At 18 months, 408 (34·9%) of 1169 patients in the alteplase group versus 414 (35·1%) of 1179 in the control group had died (p=0·85). 391 (35·0%) of 1117 patients versus 352 (31·4%) of 1122 had an OHS score of 0—2 (adjusted odds ratio [OR] 1·28, 95% CI 1·03—1·57; p=0·024). Treatment was associated with a favourable shift in the distribution of OHS grades (adjusted common OR 1·30, 95% CI 1·10—1·55; p=0·002). Alteplase treatment was associated with significantly higher overall self-reported health (adjusted mean difference in EQ utility index 0·060; p=0·019). The differences between the groups in visual analogue scale score and the proportion living at home were not significant.

Interpretation

IST-3 provides evidence that thrombolysis with intravenous alteplase for acute ischaemic stroke does not affect survival, but does lead to statistically significant, clinically relevant improvements in functional outcome and health-related quality of life that are sustained for at least 18 months.

Source: Lancet

 

 

More Information on Thrombolysis Benefits for Ischemic Stroke.

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Two studies using large databases provide details on timing and outcomes.

Clinical trials of thrombolysis for acute ischemic stroke typically have included fewer than 1000 patients. Two new studies involved larger datasets, allowing investigators to analyze important clinical issues in greater detail.

Saver and colleagues analyzed data from the national Get With The Guidelines–Stroke (GWTG-Stroke) database on 58,353 patients (median age, 72; 50.3% women) treated with tissue plasminogen activator (TPA) within 4.5 hours of symptom onset over a 9-year period. The median time from symptom onset to TPA administration was 144 minutes. Factors associated with earlier treatment included greater stroke severity, arrival by ambulance, and arrival during regular hours. Intracranial hemorrhage occurred in 4.9% of patients; 38.6% were discharged home. Earlier treatment, measured in 15-minute increments, was associated significantly with reduced mortality (odds ratio, 0.96), reduced intracranial hemorrhage (OR, 0.96), increased chance of independent ambulation at discharge (OR, 1.04), and increased rate of discharge to home (OR, 1.03).

The IST-3 collaborative group examined the effects of thrombolysis on 18-month quality-of-life and functional outcomes. Among more than 2300 patients from 10 countries who were randomized to usual care or thrombolysis within 6 hours of stroke, the adjusted odds of being alive and independent at 18 months were 28% greater with thrombolysis. Survival at 18 months did not differ. On a scale measuring mobility, self care, activity, pain, and anxiety, patient or caregiver reports of wellbeing improved significantly more between 6 and 18 months after stroke, and were better at 18 months, in the thrombolysis group, although anxiety was not lower.

COMMENT

The data from the large GWTG-Stroke database emphasize the importance of timely intervention for acute ischemic stroke. Currently, fewer than one third of patients are treated with thrombolysis with a door-to-needle time of <60 minutes (Stroke 2011; 42:2983). The Target: Stroke initiative of the American Heart Association/American Stroke Association aims to improve this rate to 50% in the next few years. Accelerating the pace of treatment will have multiple important benefits, including lower mortality and improved functional outcomes.

The study from the IST-3 investigators shows long-term benefits for functional status with prior thrombolytic therapy. Although multiple factors can affect health status 18 months after stroke (such as cardiac issues and infectious complications), the persisting improvements in functional status with prior thrombolytic therapy are reassuring.

Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke..

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BACKGROUND: Stroke is a leading cause of death and disability world wide. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is licensed for treatment of acute ischaemic stroke in the early hours after symptom onset. It has been shown in randomised controlled trials (RCTs) and the 2009 Cochrane review of thrombolysis for acute ischaemic stroke to reduce dependency but at the increased risk of intracranial haemorrhage. Methods to reduce the risk of haemorrhage while retaining or enhancing the benefit could increase the use of thrombolytic treatment. While most available information comes from RCTs of intravenous rt-PA at 0.9 mg/kg, it is possible that other doses, drugs and other routes of administration might increase benefit and reduce the hazard.

OBJECTIVES: To assess the risks and benefits of different thrombolytic agents, doses and routes of administration for the treatment of acute ischaemic stroke. SEARCH
METHODS: We searched the Cochrane Stroke Group Trials Register (May 2012), MEDLINE (1966 to May 2012) and EMBASE (1980 to May 2012). We handsearched journals and conference proceedings, searched ongoing trials registers and contacted pharmaceutical companies and researchers.
SELECTION CRITERIA: Unconfounded randomised and quasi-randomised trials of different doses of a thrombolytic agent, or different agents, or the same agent given by different routes, in people with confirmed acute ischaemic stroke.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality, and extracted the data using a structured proforma. We cross-checked and resolved discrepancies by discussion to reach consensus. We obtained translations and additional information from study authors where required.
MAIN RESULTS: We included 20 trials involving 2527 patients. Concealment of allocation was poorly described. Different doses (of tissue plasminogen activator, urokinase, desmoteplase or tenecteplase) were compared in 13 trials (N = 1433 patients). Different agents (tissue plasminogen activator versus urokinase, tissue-cultured urokinase versus conventional urokinase, tenecteplase versus tissue plasminogen activator) were compared in five trials (N = 875 patients). Five trials (N = 485) compared different routes of administration. As some trials compared different agents and different doses, some patients contributed to two analyses. There was an approximately three-fold increase in fatal intracranial haemorrhages in patients allocated to higher than to lower doses of the same thrombolytic drug (odds ratio (OR) 2.71, 95% confidence interval (CI) 1.22 to 6.04). There was no difference in the number of patients who were dead or dependent at the end of follow-up between those allocated higher or lower doses of thrombolytic drug (OR 0.86, 95% CI 0.62 to 1.19). Higher versus lower doses of desmoteplase were associated with more deaths at the end of follow-up (OR 3.21, 95% CI 1.23 to 8.39). There was no evidence of any benefit for intra-arterial over intravenous treatment.
AUTHORS’ CONCLUSIONS: These limited data suggest that higher doses of thrombolytic agents may lead to higher rates of bleeding. However, the evidence is inadequate to conclude whether lower doses of thrombolytic agents are more effective than higher doses, or whether one agent is better than another, or which route of administration is the best, for acute ischaemic stroke. At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials.

Neurology

According to this Cochrane meta-analysis, we still do not know which is the best thrombolytic agent nor he best dose nor the route of administration. We just have know that treating ischemic strokes with thrombolysis gives patients better quality of life and functional capacity up to 18 months later, according to new findings from the IST-3 study, published in the Lancet Neurology.

Source: Cochrane database

 

When It Comes to Stroke Treatment, Just 15 Minutes Can Make a Difference.

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In patients with acute ischemic stroke, even small reductions in the time to thrombolytic therapy are associated with improved outcomes, according to a study in JAMA.

Using a national stroke registry, U.S. researchers examined outcomes among some 58,000 patients, at nearly 1400 hospitals, who received intravenous tissue plasminogen activator (tPA) within 4.5 hours after symptom onset. They found that with each 15-minute decrease in time to tPA therapy, patients were significantly less likely to die in the hospital or experience intracranial hemorrhage (odds ratio for each, 0.96). In addition, each 15-minute reduction was significantly associated with a greater likelihood to walk independently at discharge (OR, 1.04) and to be discharged home (OR, 1.03).

“These findings support intensive efforts to accelerate hospital presentation and thrombolytic treatment in patients with stroke,” the researchers conclude.

Source: JAMA

New Devices Reignite Hope for Endovascular Stroke Therapy.

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Two randomized trials suggest (but do not prove) that mechanical thrombectomy improves functional outcomes.

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.

Source: Journal Watch Neurology