DIAS-2 trial fails to replicate findings of previous trials showing benefit desmoteplase for stroke

December 17, 2008

Despite the promising results of the DIAS and DEDAS trials of fibrinolytic therapy with the novel drug desmoteplase, the much-awaited follow-up phase III DIAS-2 trial did not show any improvement in clinical response at 90 days between the patients who were given either of two doses of desmoteplase up to 9 hours after the onset of symptoms of stroke compared with those who were given placebo. These are the findings of an Article by Werner Hacke of the University of Heidelberg, Germany, and international colleagues, published early online and in the February issue of The Lancet Neurology.

The clot-busting drug alteplase* is the only recommended treatment for acute ischaemic stroke, but alteplase is only approved for use within 3 hours of the onset of symptoms. In previous trials (DIAS1 and DEDAS2), a new drug, desmoteplase, which is derived from vampire bat saliva, was shown to have a highly specific action, and to be safe and effective over a longer treatment window (3¬�� hours) than alteplase. Efficacy in these trials was measured as the amount of reperfusion (restoration of blood flow) and clinical outcome at 3 months for patients who were judged most likely to benefit from treatment.†

In the DIAS II study, desmoteplase was randomly assigned in two bodyweight-adjusted doses (90 μg/kg or 125 μg/kg) to 123 patients (57 and 66, respectively), and 63 patients were given a placebo. The aim of the study was to confirm the previous results and further assess the safety and efficacy of desmoteplase. Patients who had acute ischaemic stroke were included if they were randomised within 3�� hours of the onset of symptoms and had tissue at risk as defined by multimodal CT or MR imaging. The efficacy of the treatments was assessed at 90 days with a composite score of clinical response, comprising three clinical indices of the amount of disability and function‡.

The clinical response rates were low and there was no significant difference in outcome among the patients who received either dose of desmoteplase or placebo (47% for low-dose desmoteplase, 36% for high-dose desmoteplase, or 46% for placebo). The mortality rates were higher in the patients who were given desmoteplase than in those given placebo (11% for low-dose desmoteplase, 21% for high-dose desmoteplase, and 6% for placebo), although the number of patients who had symptomatic intracranial haemorrhages was similar to that reported in the previous studies. (4% in the low-dose group, 5% in the high-dose group, and no patients in the placebo group had this adverse effect).

The authors attribute the failure to replicate the results of the preceding studies mostly to the mild strokes recorded in the DIAS-2 group. "NIHSS score at presentation is a major contributor and predictor of clinical outcome. The milder the initial stroke is, the better the spontaneous outcome. A difference of 2 to 3 points [in the NIHSS score] compared with the previous studies might explain most of the positive placebo response." Furthermore, "small core lesions and small mismatch values that were associated with no vessel occlusion...could possibly reduce the potential to detect any effect of desmoteplase."

This conclusion is reiterated in an accompanying Comment by Michael Hill of the Calgary Stroke Program. He also highlights the difficulties in selecting the patients with the best and worse prognoses over those with tissue at risk, assessed with multimodal imaging techniques--which can overestimate the volume of tissue at risk--and not looking at blood vessel occlusion--which is the target of the thrombolytic therapy. He is optimistic that despite the results of DIAS-2, which "forged too far ahead of the imaging science", desmoteplase "might yet prove to be the thrombolytic of choice" if the lessons learned are applied to the DIAS-3 study. DIAS-3 should, however, "test a single hypothesis--does the drug work--and vascular status should be measured, non-invasively, before treatment as an inclusion criterion and used as an outcome".
Professor Werner Hacke, University of Heidelberg, Heidelberg, Germany T) +49 6221 568210 E) werner.hacke@med.uni-heidelberg.de

Dr Michael Hill University of Calgary, Calgary, Canada T) +1 403 944 8065 E) michael.hill@albertahealthservices.ca

Full Article and Comment: http://press.thelancet.com/TLNdesmoteplasefinal.pdf

1 Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute ischaemic Stroke trial (DIAS). A phase II MRI-based 9-hour window acute stroke throbolysis trial with intravenous desmoteplase. Stroke 2005; 36: 66-73.
2 Furlan AJ, Eyding D, Albers GW, et al. Dose escalation of desmoteplase for acute ischaemic stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006; 37: 1227-31.

Notes to editors

*Alteplase is in the family of tissue plasminogen activators [tPA], which can break down blood clots through converting an inactive protein in the blood (plasminogen) into its active form (plasmin), which can degrade fibrin clots in a process known as fibrinolysis.

†The patients in these trials were selected by use of magnetic resonance (MR) imaging techniques (MR perfusion imaging-diffusion-weighted imaging or perfusion CT) that are thought to be able to distinguish the areas to which the supply of blood has been completely cut off (which are dead and unsalvageable) from the areas where the blood supply has been greatly reduced but the tissue could potentially be saved by timely restoration of the full blood supply (reperfusion). Patients who were deemed to have a high proportion of salvageable tissue relative to dead tissue (mismatch) were included.

‡ The composite measures were an improvement [reduction] in National Institutes of Health stroke scale (NIHSS) score‡ of 8 points or a score of 1 point or more, a modified Rankin scale score§ of 0-2 points, and a Barthel index** of 75-100)].

The NIHSS is a 15-item impairment scale, intended to evaluate neurological outcome and recovery of patients with stroke in clinical trials. The scale assesses level of consciousness, extraocular movements, visual fields, facial muscle function, extremity strength, sensory function, coordination (ataxia), language (aphasia), speech (dysarthria), and hemi-inattention (neglect). High scores indicate normal function.

The modified Rankin scale score measures the degree of disability or dependence in activities of daily living in people who have had a stroke (0=no impairment; 6=death).

The Barthel index is a 10-item measure of a person's daily functioning, particularly the activities of daily living and mobility such as feeding, moving from wheelchair to bed and return, grooming, transferring to and from a toilet, bathing, walking on level surface, going up and down stairs, dressing, continence of bowels and bladder. High scores indicate greater independence.


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