May 12, 2015

New data from several studies suggest that thrombolysis may be effective in stroke patients who present later than 4.5 hours after symptom onset and who have a particular abnormality identified by sophisticated imaging techniques.

The studies, all presented at the recent inaugural European Stroke Organisation (ESO) Conference 2015, include the DIAS-3 and -4 trials with the thrombolytic agent, desmoteplase, and a small feasibility study using new penumbral imaging techniques to select patients for tenecteplase therapy.

The DIAS-3 and DIAS-4 results did not show a benefit of desmoteplase given 3 to 9 hours in the overall population enrolled, but positive effects occurred in certain subgroups. The DIAS-3 trial was also published online in The Lancet Neurology on April 30.

"We cannot prove thrombolysis is effective after 4.5 hours but there are some interesting observations from our data," Rüdiger von Kummer, MD, Dresden University, Germany, who presented the DIAS data, concluded. "The per protocol analysis was positive in the pooled analysis."

He added: "Thrombolysis should not be forgotten in the later population. I still have hope that we can find a way to make it effective for some patients."

Dr von Kummer says imaging is the key to selecting suitable patients. "We can define the pathology well with imaging. Time does not tell us anything about the pathology. It is a poor surrogate."

Co-investigator of the small feasibility study, Mahesh Kate, MD, University of Alberta, Edmonton, Canada, explained that the key was to identify patients with "target mismatch." These are patients who have a small area of unsalvageable brain tissue but a large area of tissue at risk that could be salvageable.

They did this in their study using new perfusion computed tomography (CT) technology and showed encouraging results in a small group of patients treated an average of 11 hours after symptom onset with tenecteplase.

These patients had less infarct growth and better penumbral salvage and a higher chance of a good functional outcome at 90 days compared with two other groups of patients not given thrombolysis.

"This is just a feasibility study," Dr Kate commented to Medscape Medical News. "We can't make any recommendations based on this one small study. But it looks encouraging."

DIAS-3 and -4

The DIAS-3 trial randomly assigned 492 stroke patients with proven major artery occlusion but no major ischemic damage to treatment with desmoteplase, 90 μg/kg, or placebo. Main results showed no effect on functional outcomes at 90 days. However, the subgroup of patients with strokes with a small ischemic core — defined as less than 25 mL on diffusion-weighted imaging — did show a nominally significant benefit.

DIAS-4, which had a design similar to that of DIAS-3, was stopped after 270 patients had been enrolled because of the negative results of DIAS-3.

"If we pool the data there is a trend for patients with small ischemic lesions to have better outcomes with desmoteplase," Dr von Kummer told attendees here. "The odds ratios are better if MRI was used to identify these patients rather than CT. We need larger numbers to understand what is going on."

Other observations from the DIAS studies were that recanalization was not improved with desmoteplase in DIAS-3 but was improved in the DIAS-4 study and in the pooled analysis. There was also a numeric increase in good outcomes in the DIAS-4 study and the pooled analysis.

In a post hoc analysis combining data from DIAS-3, DIAS-4, and DIAS-Japan, recanalization was associated with a higher likelihood of a good outcome in both desmoteplase and placebo recipients.

Dr von Kummer also pointed out that the trials tried to exclude patients with occlusions of the internal carotid artery or the basilar artery, as well as those who had too much ischemic injury. However, 10% of included patients did not comply with the inclusion criteria when the scans were evaluated by the imaging committee.

"If we exclude these patients, we get a positive result with desmoteplase on good outcomes in the pooled data analysis (odds ratio, 1.6; P = .04)," he said.

He concluded that reperfusion may still be beneficial in patients in this late time window if recanalization can be achieved.

"DIAS-3 and -4 together suggest desmoteplase is safe when given to stroke patients arriving late, but the crucial question is whether the dose is too low," he told Medscape Medical News.

Noting that the sponsor, Lundbeck, has now discontinued development of desmoteplase, Dr von Kummer suggested that if the thrombolytic were to be taken forward by another party he would recommend they study a higher dose, maybe 100 to 125 μg/kg.

In an editorial accompanying the DIAS-3 Lancet Neurology paper, Michael D. Hill, MD, and Bijoy K. Menon, MD, University of Calgary, point out that endovascular therapy will be appropriate only for 10% to 15% of stroke patients and that smaller and distal occlusions will always be better treated with medical therapy. Therefore, the search for better thrombolytics and imaging methods to identify patients who may benefit must continue.

They add that imaging is the only biomarker for stroke. "We must learn how to use it in a reliable way across multiple vendors, multiple processing algorithms, and multiple centers."

Dr von Kummer added that thrombolysis could also be suitable as an additional treatment after thrombectomy to deal with the small pieces of clot that may break off during removal and become lodged in smaller arteries.

Penumbral Imaging Feasibility Study

Presenting the small feasibility study with tenecteplase, Dr Kate noted that up to 30% of patients with acute stroke have uncertain time of symptom onset and so are not at present eligible for thrombolysis or endovascular therapy. "If we use CT perfusion imaging, we can select patients who may still benefit from these reperfusion therapies even if they present after the current 4.5-hour limit."

His study involved 53 patients with ischemic stroke (National Institutes of Health Stroke Scale score of 4 to 18) who were 4.5 to 24 hours from symptom onset.

They underwent CT perfusion imaging to identify patients with target mismatch. A cerebral blood volume Alberta Stroke Program Early CT (ASPECT) score of 7 or greater defined patients with a small area of unsalvageable brain tissue, and a mean transit time ASPECT mismatch score greater than 2 demonstrated a large area of at-risk tissue that could be salvageable.

Dr Kate explained that these patients are the ones whom reperfusion therapy is most likely to benefit. "CT perfusion imaging gives us much more information. The brain is scanned continuously over multiple time points before and after contrast injection so that we get a clearer image to identify salvageable and nonsalvageable tissue."

Of the 30 patients fulfilling the mismatch criteria, 12 received thrombolysis with tenecteplase and the other 18 did not receive any reperfusion therapy. In addition, 23 patients were found not to have target mismatch and were also not treated.

The 12 treated patients received tenecteplase at a mean of 11 hours from symptom onset. The latest was 18 hours from onset.

Nine of the 12 mismatch patients treated with tenecteplase had more than 80% reperfusion at 24 hours, and this group had less infarct growth and better penumbral salvage than the other two groups. They also had a higher chance of a good functional outcome (modified Rankin Scale score [mRS], 0 to 2) at 90 days.

Table 1. Efficacy Results

Endpoint Mismatch Tenecteplase (n = 12) Mismatch Untreated (n = 18) No Mismatch Untreated (n = 23)
Infarct growth (mL) 3.2 16 79
Penumbral salvage (mL) 35 17 91
mRS score 0 - 2 at 90 d (%) 66 22 4.3


Dr Kate said the safety results looked encouraging, with only one patient in the tenecteplase group having a symptomatic intracerebral hemorrhage.

Table 2. Safety Results

Endpoint Mismatch Tenecteplase (n = 12) Mismatch Untreated (n = 18) No Mismatch Untreated (n = 23)
Any hemorrhagic transformation (n) 5 2 8
Symptomatic hemorrhagic transformation (n) 1 0 1
Mortality (n) 0 0 10


He concluded that thrombolysis with tenecteplase is feasible and may be beneficial later than 4.5 hours if a mismatch pattern is present on perfusion CT.

He said the perfusion imaging used in this study is not routinely used at present but is easy to perform. "Most doctors with some training in imaging can do it. Most centers can do CT angiography. This software is proprietary but most centers can do it. If you can do CT angiography you can do perfusion CT, but there is a need for training and uniformity."

A new study is now planned using tenecteplase plus endovascular therapy in patients 6 to 12 hours after symptom onset.

Dr Kate said they used tenecteplase because it has higher fibrin selectivity than alteplase and a longer duration of action and thus can be given as a bolus.

The DIAS-3 and -4 studies were sponsored by Lundbeck. Dr von Kummer reports personal fees from Lundbeck during the conduct of the study and personal fees from Boehringer Ingelheim, Covidien, Brainsgate, Synarc, and Penumbra Inc outside the submitted work. The feasibility study was funded by grants from Canada Research Chair program and the Heart and Stroke Foundation of Alberta, Northwest Territories and Nunavut (Professorship in Stroke Medicine). Tenecteplase was provided by Roche Canada. Dr Menon has a patent pending about systems for triage of acute stroke patients. Dr Hill owns stock in Calgary Scientific Inc (a company that focuses on medical imaging software).

European Stroke Organisation (ESO) Conference 2015. Abstracts 80 and 231. Presented April 17 and 18, 2015.

Lancet Neurol. Published online April 30, 2015. DIAS-3 Abstract Editorial


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